Mayo Clinic Gastroenterology and Hepatology

About the book…

Written by an experienced and dedicated team of Mayo Clinic gastroenterologists and hepatologists, this newly expanded and updated Third Edition of the best-selling Mayo ClinicGastroenterology and Hepatology Board Review is the go-to comprehensive resource for acomplete scope of essential knowledge in all areas of gastroenterology and hepatology and inthe related areas of pathology, endoscopy, nutrition, and radiology.

The new edition is an easy-to-use, case-based text expertly designed for those preparing to takethe gastroenterology board examination and for gastroenterologists in need of recertification.Medical students and residents in the areas of internal medicine and gastroenterology, gastroen-terology fellows, and physicians seeking a practical and comprehensive review of gastroenterologyand hepatology will also benefit from this stand-alone guide.

New features in the Third Edition include:

• Several new multiple-choice questions and answers addressing the growing areas of concernin gastroenterology and hepatology

• 12 substantially updated and revised chapters by new authors who provide fresh, cutting-edge perspectives

• A new chapter on drug-induced liver injury• Increased emphasis on case-based learning, which is critical to superior diagnostic and thera-

peutic approaches to patient care• The addition of more than 100 high-quality color photographs• Content that is organized by subspecialty areas, including esophageal, gastroduodenal, and

colonic disorders, small-bowel disease and nutrition, pancreaticobiliary and liver diseases,and other miscellaneous disorders

• An abundance of additional new material appropriate for the board review and practice

About the editors...

STEPHEN C. HAUSER, MD, is Consultant, Division of Gastroenterology and Hepatology,Mayo Clinic, Rochester, Minnesota; Assistant Professor of Medicine, College of Medicine,Mayo Clinic

DARRELL S. PARDI, MD, is Consultant, Division of Gastroenterology and Hepatology,Mayo Clinic, Rochester, Minnesota; Associate Professor ofMedicine, College of Medicine, Mayo Clinic

JOHN J. POTERUCHA, MD, is Consultant, Division ofGastroenterology and Hepatology, Mayo Clinic, Rochester,Minnesota; Associate Professor of Medicine, College ofMedicine, Mayo Clinic

Mayo ClinicGastroenterology and Hepatology

Board Review

Third Edition

EditorStephen C. Hauser, MD

Co-EditorsDarrell S. Pardi, MD

John J. Poterucha, MD

MAYO CLINIC SCIENTIFIC PRESS

Mayo C

linic Gastroenterology and H

epatology Board R

eviewThird

Edition

Hauser

HauserSpread 8/5/08 12:25 PM

Third Edition


Board Review




MAYO CLINIC SCIENTIFIC PRESS ANDINFORMA HEALTHCARE USA, INC

Third Edition


Board Review

The triple-shield Mayo logo and the words MAYO, MAYO CLINIC, and MAYO CLINIC SCIENTIFICPRESS are marks of Mayo Foundation for Medical Education and Research.

©2008 Mayo Foundation for Medical Education and Research.

All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in aretrieval system, or transmitted, in any form or by any means—electronic, mechanical, photocopying,recording, or otherwise—without the prior written consent of the copyright holder, except for briefquotations embodied in critical articles and reviews. Inquiries should be addressed to ScientificPublications, Plummer 10, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.

For order inquiries, contact Informa Healthcare, Kentucky Distribution Center, 7625 Empire Drive,Florence, KY 41042 USA.

E-mail: [email protected]; Web site: www.informahealthcare.com.

www.taylorandfrancis.com

Library of Congress Cataloging-in-Publication DataMayo Clinic gastroenterology and hepatology board review/edited by Stephen C. Hauser, Darrell S.Pardi, John J. Poterucha. — 3rd ed. p. ; cm.

Includes bibliographical references and index.ISBN-13: 978-1-4200-9223-3 (pbk. : alk. paper)ISBN-10; 1-4200-9223-5 (pbk. : alk. paper) 1. Gastroenterology—Examinations, questions, etc. 2.

Gastrointestinal system—Examinations, questions, etc. 3. Liver—Diseases—Examinations, questions,etc. I. Hauser, Stephen C. II. Pardi, Darrell S. III. Poterucha, John J. IV. Mayo Clinic. V. Title:Gastroenterology and hepatology board review.

[DNLM: 1. Gastrointestinal Diseases—Examination Questions. WI 18.2 M473 2008]RC801.M33 2008616.3’30076—dc22

2008024970

Care has been taken to confirm the accuracy of the information presented and to describe generallyaccepted practices. However, the authors, editors, and publisher are not responsible for errors or omis-sions or for any consequences from application of the information in this book and make no warranty,express or implied, with respect to the contents of the publication. This book should not be relied onapart from the advice of a qualified health care provider.

The authors, editors, and publisher have exerted efforts to ensure that drug selection and dosageset forth in this text are in accordance with current recommendations and practice at the time of pub-lication. However, in view of ongoing research, changes in government regulations, and the constantflow of information relating to drug therapy and drug reactions, readers are urged to check the packageinsert for each drug for any change in indications and dosage and for added warnings and precautions.This is particularly important when the recommended agent is a new or infrequently employed drug.

Some drugs and medical devices presented in this publication have Food and Drug Administration(FDA) clearance for limited use in restricted research settings. It is the responsibility of the health careproviders to ascertain the FDA status of each drug or device planned for use in their clinical practice.

Printed in Canada

ix

Jeffrey A. Alexander, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Assistant Professor of Medicine, College ofMedicine, Mayo Clinic

Paul Angulo, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Associate Professor of Medicine, College ofMedicine, Mayo Clinic

Amindra S. Arora, MBBChirConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Assistant Professor of Medicine, College ofMedicine, Mayo Clinic

Todd H. Baron, Sr., MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Professor of Medicine, College of Medicine,Mayo Clinic

Adil E. Bharucha, MBBS, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Professor of Medicine, College of Medicine,Mayo Clinic

Lisa A. Boardman, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Assistant Professor of Medicine, College ofMedicine, Mayo Clinic

Michael Camilleri, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Professor of Medicine and of Physiology, Collegeof Medicine, Mayo Clinic

Suresh T. Chari, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Professor of Medicine, College of Medicine,Mayo Clinic

Albert J. Czaja, MDEmeritus Staff Consultant, Division ofGastroenterology and Hepatology, Mayo Clinic,Rochester, Minnesota; Emeritus Staff Professorof Medicine, College of Medicine, Mayo Clinic

Dawn L. Francis, MD, MHSConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Assistant Professor of Medicine, College ofMedicine, Mayo Clinic

Stephen C. Hauser, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Assistant Professor of Medicine, College ofMedicine, Mayo Clinic

J. Eileen Hay, MB,ChBConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Professor of Medicine, College of Medicine,Mayo Clinic

Patrick S. Kamath, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Professor of Medicine, College of Medicine,Mayo Clinic

Paul J. Limburg, MD, MPHConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Associate Professor of Medicine, College ofMedicine, Mayo Clinic

Keith D. Lindor, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Professor of Medicine, College of Medicine,Mayo Clinic

G. Richard Locke III, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Professor of Medicine, College of Medicine,Mayo Clinic

LIST OF CONTRIBUTORS

v

DEDICATION

To the many persons who have taught, encouraged, and inspired us.

PREFACE

astroenterology and hepatology encompass a large assortment of organs with diversestructure and function that potentially are afflicted by a multiplicity of disease

processes. We have designed the revised edition of the Mayo Clinic Gastroenterologyand Hepatology Board Review book and course to assist physicians-in-training who arepreparing for the gastroenterology board examination and the growing number of gas-troenterologists who are awaiting recertification. The book is not intended to replace themore encyclopedic textbooks of gastroenterology, hepatology, pathology, endoscopy,nutrition, and radiology now available. Nor is it intended to serve as an “update” tophysicians who are looking for the newest advances in the science and art of gastroen-terology and hepatology. Instead, this book is intended to provide a core of essentialknowledge in gastroenterology, hepatology, and integral related areas of pathology,endoscopy, nutrition, and radiology. Clinical knowledge related to diagnostic and ther-apeutic approaches to patient management is emphasized. Case-based presentations andmultiple short board-examination–type, single best-answer questions with annotatedanswers are featured. As such, this text also is intended to be used by medical students andresidents for their clerkships during rotations in internal medicine and gastroenterologyand by gastroenterology fellows in training. Physicians in practice should find this book tobe a practical review to consolidate their knowledge in gastroenterology and hepatology.

The book is organized by subspecialty topics, including esophageal disorders, gastroduo-denal disorders, small-bowel disease and nutrition, colonic disorders, pancreaticobiliarydisease, liver disease, and miscellaneous disorders. Numerous color and black-and-whitefigures are used to illustrate the text. Each subspecialty section concludes with a chaptercontaining multiple board examination-type, single best-answer multiple-choice ques-tions with annotated answers. Materials in the questions and answers are not included inthe index. The faculty responsible for the book at the time of its production are all MayoClinic gastroenterologists and hepatologists who spend most of their time caring forpatients, but who also have a commitment to teaching medical students, house-officers,fellows, nurses, and physicians. Most of the faculty have particular interests in subspecialtyareas of clinical gastroenterology and hepatology, providing broad expertise.

We thank the staffs of the Section of Scientific Publications, Media Support Services,and the Mayo School of Continuing Medical Education at Mayo Clinic for their help in pro-ducing this book. The support of the publisher, Mayo Clinic Scientific Press and InformaHealthcare USA, also is greatly appreciated. We also want to give special thanks to oursecretaries and to Dr. Greg Gores for his ongoing enthusiasm and support for our faculty andteaching mission.

Stephen C. Hauser, MD

vii

G

x

Conor G. Loftus, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Assistant Professor of Medicine, College ofMedicine, Mayo Clinic

Edward V. Loftus, Jr., MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Professor of Medicine, College of Medicine,Mayo Clinic

Joseph A. Murray, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Professor of Medicine, College of Medicine,Mayo Clinic

Amy S. Oxentenko, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Assistant Professor of Medicine, College ofMedicine, Mayo Clinic

Darrell S. Pardi, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Associate Professor of Medicine, College ofMedicine, Mayo Clinic

Randall K. Pearson, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Associate Professor of Medicine, College ofMedicine, Mayo Clinic

Bret T. Petersen, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Professor of Medicine, College of Medicine,Mayo Clinic

John J. Poterucha, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Associate Professor of Medicine, College ofMedicine, Mayo Clinic

Lewis R. Roberts, MB,ChB, PhDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Associate Professor of Medicine, College ofMedicine, Mayo Clinic

Yvonne Romero, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Assistant Professor of Medicine, College ofMedicine, Mayo Clinic

William J. Sandborn, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Professor of Medicine, College of Medicine,Mayo Clinic

Vijay H. Shah, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Professor of Medicine, College of Medicine,Mayo Clinic

Nicholas J. Talley, MD, PhDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Jacksonville, Florida;Professor of Epidemiology and Medicine, Collegeof Medicine, Mayo Clinic

William J. Tremaine, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Professor of Medicine, College of Medicine,Mayo Clinic

Santhi Swaroop Vege, MDConsultant, Division of Gastroenterology andHepatology, Mayo Clinic, Rochester, Minnesota;Professor of Medicine, College of Medicine,Mayo Clinic

xi

TABLE OF CONTENTS

Section I: Esophagus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1

1. Gastroesophageal Reflux Disease Joseph A. Murray, MD . . . . . . . . . . . . . . . . . . . . .3

2. Barrett’s Esophagus and Esophageal Cancer Yvonne Romero, MD . . . . . . . . . . . . . . 21

3. Normal and Abnormal Esophageal Motility Amindra S. Arora, MBBChir, and

Nicholas J. Talley, MD, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Questions and Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Section II: Stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .53

4. Peptic Ulcer Disease Dawn L. Francis, MD, MHS . . . . . . . . . . . . . . . . . . . . . . . . . 55

5. Gastritis Dawn L. Francis, MD, MHS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

6. Gastric Neoplasms and Gastroenteropancreatic Neuroendocrine Tumors Dawn L. Francis, MD, MHS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

7. Gastrointestinal Motility Disorders Michael Camilleri, MD, and

G. Richard Locke III, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97


Section III: Small Bowel and Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

8. Clinical Features of Malabsorptive Disorders, Small-Bowel Diseases, and Bacterial Overgrowth Syndromes Amy S. Oxentenko, MD . . . . . . . . . . . . . . . . . . . . . . . . . 117

9. Nutritional Disorders Vitamins and Minerals Stephen C. Hauser, MD . . . . . . . . . . . 135


Section IV: Miscellaneous Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

10. Gastrointestinal Manifestations of Human ImmunodeficiencyVirus Infection Stephen C. Hauser, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

11. Nonvariceal Gastrointestinal Tract Bleeding Jeffrey A. Alexander, MD . . . . . . . . . . . 159

12. Vascular Disorders of the Gastrointestinal Tract Stephen C. Hauser, MD . . . . . . . . . 167

13. Gastrointestinal Manifestations of Systemic Disease Stephen C. Hauser, MD . . . . . . .175


xii

Section V: Colon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .191

14. Inflammatory Bowel Disease: Clinical Aspects William J. Tremaine, MD . . . . . . . . . . 193

15. Inflammatory Bowel Disease: Therapy William J. Sandborn, MD . . . . . . . . . . . . . . 199

16. Inflammatory Bowel Disease: Extraintestinal Manifestations and CancerEdward V. Loftus, Jr., MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215

17. Gastrointestinal Infections, Clostridium difficile-Associated Disease, and Diverticular Disease Conor G. Loftus, MD, and Darrell S. Pardi, MD . . . . . . . . . . . . . . . . . . . . 223

18. Colorectal Neoplasms Lisa A. Boardman, MD, and Paul J. Limburg, MD, MPH . . . . . .241

19. Irritable Bowel Syndrome G. Richard Locke III, MD . . . . . . . . . . . . . . . . . . . . . . 251

20. Constipation and Disorders of Pelvic Floor Function Adil E. Bharucha, MBBS, MD . . . 257


Section VI: Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .281

21. Approach to the Patient With Abnormal Liver Tests and Fulminant Liver FailureJohn J. Poterucha, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283

22. Chronic Viral Hepatitis John J. Poterucha, MD . . . . . . . . . . . . . . . . . . . . . . . . . 293

23. Clinical Approach to Liver Mass Lesions Lewis R. Roberts, MB,ChB, PhD . . . . . . . . 307

24. Alcoholic Liver Disease Vijay H. Shah, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325

25. Vascular Diseases of the Liver Patrick S. Kamath, MD . . . . . . . . . . . . . . . . . . . . . 337

26. Portal Hypertension-Related Bleeding Patrick S. Kamath, MD . . . . . . . . . . . . . . . . 345

27. Ascites, Hepatorenal Syndrome, and Encephalopathy J. Eileen Hay, MB,ChB . . . . . . 351

28. Metabolic Liver Disease John J. Poterucha, MD . . . . . . . . . . . . . . . . . . . . . . . . . 363

29. Cholestatic Liver Disease: Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis, and AIDS-Associated Cholangiopathy Keith D. Lindor, MD . . . . . . . . . . . . . . . . . . 377

30. Drug-Induced Liver Injury John J. Poterucha, MD . . . . . . . . . . . . . . . . . . . . . . . 383

31. Autoimmune Hepatitis Albert J. Czaja, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391

32. Nonalcoholic Fatty Liver Disease Paul Angulo, MD . . . . . . . . . . . . . . . . . . . . . . . 407

33. Liver Disease and Pregnancy J. Eileen Hay, MB,ChB . . . . . . . . . . . . . . . . . . . . . . 419

34. Liver Transplantation J. Eileen Hay, MB,ChB . . . . . . . . . . . . . . . . . . . . . . . . . . 431


Section VII: Pancreas and Biliary Tree . . . . . . . . . . . . . . . . . . . . . . . . . . . . .457

35. Acute Pancreatitis Santhi Swaroop Vege, MD, and Todd H. Baron, Sr., MD . . . . . . . . . 459

36. Chronic Pancreatitis Suresh T. Chari, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469

37. Pancreatic Neoplasms Randall K. Pearson, MD . . . . . . . . . . . . . . . . . . . . . . . . . 475

38. Gallstones Bret T. Petersen, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .485


Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .503

SECTION I

Esophagus

Gastroesophageal reflux is the reflux of gastriccontents other than air into or through the esoph-agus. Gastroesophageal reflux disease (GERD) refersto reflux that produces frequent symptoms orresults in damage to the esophageal mucosa orcontiguous organs of the upper aerodigestivesystem and occasionally the lower respiratory tract.

ETIOLOGYGastroesophageal reflux results from several fac-tors that lead to symptoms or injury of themucosa of the esophagus or the airway by refluxof corrosive material from the stomach (Table 1).These factors include a weak or defectivesphincter, transient lower esophageal sphincterrelaxations (TLESRs), hiatal hernia, poor acidclearance from the esophagus, diminished sali-vary flow, reduced mucosal resistance to injury,increased acid production, delayed gastric emp-tying of solids, and obstructive sleep apnea (Fig.1). The relative contribution of these varies frompatient to patient.

3

CHAPTER 1

Gastroesophageal Reflux Disease

Joseph A. Murray, MD

Abbreviations: CREST, calcinosis cutis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia;GERD, gastroesophageal reflux disease; H2, histamine2; TLESR, transient lower esophageal sphincter relaxation.

Table 1. Etiologic Factors ofGastroesophageal Reflux Disease

Motility disorders Transient lower esophageal relaxations*

Weak lower esophageal sphincter*

Weak esophageal peristalsisScleroderma and CRESTDelayed gastric emptying

Damaging factorsIncreased gastric acid productionBile and pancreatic juice

Resistance factorsReduced saliva and HCO3 productionDiminished mucosal blood flowGrowth factors, protective mucus

Others Hiatal hernia*

Obstructive sleep apnea

CREST, calcinosis cutis, Raynaud’s phenomenon,esophageal dysfunction, sclerodactyly, andtelangiectasia.

*Major/common factors.

FACTORS CONTRIBUTING TOGASTROESOPHAGEAL REFLUXDISEASE

Barrier Function of the Lower EsophagealSphincterThe lower esophageal sphincter and its attachedstructures form a barrier to reflux of material acrossthe esophagogastric junction and is the central pro-tection against pathologic reflux of gastric con-tents into the esophagus. This barrier has severalcomponents, including the smooth muscle loweresophageal sphincter, the gastric sling fibers, andthe striated muscle crural diaphragm. The loweresophageal sphincter maintains tone at rest andrelaxes with swallowing and gastric distention asa venting reflex. This latter relaxation has beentermed transient lower esophageal sphincter relax-ation (TLESR). In persons with mild reflux disease,acid liquid contents instead of air alone are vented,resulting in many episodes of acid reflux. Inpatients with severe reflux, the resting pressure

of the lower esophageal sphincter usually is dimin-ished and easily overcome.

The presence of hiatal hernia has an importantrole in defective barrier function, both by removingthe augmentation that the crural diaphragm pro-vides the lower esophageal sphincter and loweringthe threshold for TLESRs to occur.

Acid ClearanceThe clearance of acid from the esophagus is a com-bination of mechanical volume clearance (gravityand peristalsis) and chemical neutralization of thelumen contents (saliva and mucosal buffering).This may be delayed in patients with refluxbecause of either impaired esophageal peristalsisor reduced buffering effects of swallowed saliva.The defective peristalsis can be a primary idio-pathic motor disorder or, occasionally, it can resultfrom a connective tissue disorder such as CREST(calcinosis cutis, Raynaud’s phenomenon,esophageal dysfunction, sclerodactyly, and telang-iectasia) syndrome or scleroderma. Many drugsand Sjögren’s syndrome can decrease salivary flow.Normally, salivary flow is decreased at night; thus,if reflux occurs during the night when the personis supine, acid will not be cleared by either gravityor saliva. This is why episodes of reflux at nightare long-lasting and have a greater chance ofcausing severe injury to the mucosa.

Intrinsic Mucosal FactorsThe mucosa of the esophagus has intrinsic factorsthat protect the esophageal lining against aciddamage. These include the stratified squamousmucosa, intercellular tight junctions, growth fac-tors, buffering blood flow, and production ofmucin, bicarbonate, and epidermal growth factors.When these factors are overcome, GERD causesreflux esophagitis (Fig. 2 and 3).

Gastric FactorsDelayed gastric emptying or increased gastric pro-duction of acid is less frequently part of GERD.Reflux esophagitis is rarely a manifestation ofZollinger-Ellison syndrome. The availability ofcorrosive gastric contents in the cardia of thestomach is necessary for reflux to occur duringTLESR or when a defective lower esophagealsphincter is overcome during recumbency or

4 Esophagus

Fig. 1. Causes of increased exposure of theesophagus to gastric refluxate. (From AstraZenecaPharmaceuticals LP [Internet]. Wilmington (DE).Available from: http://www.astrazeneca.com. Usedwith permission.)

abdominal straining. The cardia is often submergedunder liquid gastric contents in the recumbent,especially in the right lateral decubitus, position. Ithas been suggested recently that what differenti-ates patients with GERD from normal subjects isnot the number of actual reflux events but the reflux

of acidic gastric contents instead of the release of airalone. The timing of reflux is also important.Because gastric acid is buffered by food during thefirst hour after eating, normal physiologic refluxthat may occur during maximal gastric distentionis not as harmful as the reflux that occurs later after

Gastroesophageal Reflux Disease 5

Fig. 2. Mechanism of action of refluxate in gastroesophageal reflux disease. The sequence of events hypothesizedto lead to symptoms and tissue damage in gastroesophageal reflux disease is as follows: A and B, Acid-pepticattack weakens cell junctions and, C, widens the cell gaps, thus allowing acid penetration. Exposure to gastricacid and pepsin can cause microscopic damage to the esophageal mucosa, which may not be visible endoscopicallybut still result in heartburn. (From AstraZeneca Pharmaceuticals LP [Internet]. Wilmington (DE). Availablefrom: http://www.astrazeneca.com. Used with permission.)

Fig. 3. Mechanism of action of refluxate in gastroesophageal reflux disease. A, Penetration of acid and pepsininto the mucosa allows contact of acid with epithelial nerve endings (which may result in heartburn). B,Additional influx of acid and pepsin into the mucosa triggers a cascade of events ultimately leading to cellrupture and mucosal inflammation. (From AstraZeneca Pharmaceuticals LP [Internet]. Wilmington (DE).Available from: http://www.astrazeneca.com. Used with permission.)

the stomach pH has again decreased. Any obstruc-tion of the outflow from the stomach increases thepropensity to reflux, although this is often associatedwith nausea and vomiting. Pure bile reflux mayoccur in patients who have had gastric surgery.More common is pathologic reflux associated witha restrictive bariatric procedure such as verticalbanded gastroplasty. If too much acid-producingmucosa is present above the restriction, pathologicreflux may occur.

Helicobacter pylori and GastroesophagealReflux DiseaseWhether chronic Helicobacter pylori infection pro-tects against GERD is a matter of controversy.Duodenal ulcers and distal gastric cancer (bothcaused by H. pylori infection) are becoming rare inthe developed world, and adenocarcinoma of theproximal stomach and esophagus is becomingmore common as the carriage rates of H. pyloridecrease. Patients with GERD symptoms may beless likely to carry H. pylori than the populationwithout GERD symptoms. Reports that symptomsof GERD developed after the eradication of H.pylori have led to a reexamination of those treat-ment trials of duodenal ulcers, which included H.pylori eradication, for the new development ofGERD symptoms. The evidence is conflictingwhether the symptoms of GERD are more commonin those in whom H. pylori eradication has beensuccessful or in those with persistent infection. Insome persons, H. pylori infection may cause chronicatrophic gastritis that affects the corpus of thestomach, resulting in diminished acid secretion.It is this relative hypochlorhydria that protectsagainst GERD. Indeed, it has been suggested thatacid suppression heals reflux esophagitis fasterin patients with H. pylori infection (Fig. 4). Otherexplanations for the apparent occurrence of GERDafter the eradication of H. pylori may includeunrecognized GERD injury or symptoms presentbefore eradication, rebound acid secretion aftercessation of potent acid suppression, or other unre-lated factors.

Connective Tissue DiseaseScleroderma, CREST syndrome, or mixed connec-tive tissue diseases are rare causes of reflux, butthese should be considered in young women who

have Raynaud’s phenomenon or subtle cutaneousfeatures of scleroderma in the hands or face.Occasionally, GERD may be the first manifesta-tion of these disorders. Esophageal manometryusually demonstrates a low-pressure loweresophageal sphincter and decreased amplitude ofcontractions in the esophagus (Fig. 5).

Mechanism of Extraesophageal SymptomsThe mechanism for extraesophageal manifesta-tions of GERD, such as wheeze or cough, may notalways be direct aspiration or damage of mucosain the respiratory tract but a vagally mediated reflextriggered by acidification of the distal esophagealmucosa. Subglottic stenosis and granuloma of thevocal cords are very serious consequences of refluxcaused by direct contact injury of the delicatemucosa of the airway, resulting in stridor, cough,or dysphonia (Fig. 6).

EPIDEMIOLOGY OFGASTROESOPHAGEAL REFLUXDISEASEGERD can be defined as chronic symptoms ofheartburn, acid regurgitation or dysfunction, orinjury to the esophagus or other organs becauseof abnormal reflux of gastric contents. Symptoms

6 Esophagus

% P

atie

nts

heal

edat

4 w

eeks

p = 0.0005

60

40

20

0

87

80

100

76

H. pylori + H. pylori –

Fig. 4. The efficacy of proton pump inhibitortherapy may be greater in patients withgastroesophageal reflux disease who are positive forHelicobactor pylori (H. pylori +) than in those negativefor H. pylori (H. pylori −).

suggestive of GERD are common: 40% of the adultpopulation in the United States report heartburnmonthly and 18% report it weekly (Fig. 7). GERDbecomes more common with increasing age (Fig.8). Previously, GERD and its complications were

rare in China, Japan, and other Asian countries,but this is changing rapidly with the adoption of aWestern diet. A protective role of H. pylori–inducedhypochlorhydria has been suggested as a protectiveinfluence in countries with high carriage rates ofinfection. However, actual organ damage isobserved less frequently, and fewer than 50% ofpatients who present for medical attention forreflux symptoms have esophagitis. Of patientswho have endoscopy for GERD, 10% have benignstrictures and only 3% to 4% have Barrett’s esoph-agus; an extremely small number have adenocar-cinoma. Complications of GERD may be morecommon in males and whites and with advancingage. Whether reflux is becoming more common isnot clear, but it certainly is diagnosed more fre-quently than in the past. Also, because of direct-to-consumer advertising and public educationcampaigns, the public is more aware of GERD.

For patients with GERD, the quality of life maybe impaired even more than for those with con-gestive heart failure or angina pectoris (Fig. 9).Treatment of GERD has important health economic


Fig. 5. Esophageal manometric tracing illustrating complete absence of peristalsis or absence of loweresophageal sphincter (LES) pressure consistent with involvement of the esophagus by scleroderma.

Fig. 6. Laryngeal stenosis. (Courtesy of Dr. DanaThompson, Otorhinolaryngology/PediatricOtolaryngology, Mayo Clinic.)

effects because, currently, proton pump inhibitorsare among the most commonly prescribed andmost expensive drugs.

PRESENTATIONThe classic symptoms of GERD, that is, heartburnand acid regurgitation, are common in the generalpopulation and usually are readily recognized.GERD may be manifested in a wide array ofesophageal and extraesophageal symptoms. GERDmay contribute to many clinical syndromes, eitheras a common factor or a rare culprit (Table 2).

SYMPTOMS

Esophageal SymptomsThe cardinal symptoms of GERD are heartburn(defined as retrosternal burning ascending towardthe neck) and acid regurgitation (the unpleasantreturn of sour or bitter gastric contents to thepharynx). This is to be differentiated from thenonacid (bland) regurgitation of retained esophagealcontents in an obstructed esophagus, as occurs inachalasia or the almost volitional regurgitation ofrecently swallowed food which is remasticated andagain swallowed that typifies rumination. Patientsymptoms of “GERD,” “reflux,” and “heartburn”should be differentiated from the burning epigas-tric sensation of dyspepsia.

Patients may report relief of symptoms withantacids or milk. The symptoms of heartburn andespecially acid regurgitation are specific for GERD.Their presence with sufficient frequency andseverity alone usually justifies medical therapy.Objective confirmation is required before surgeryor endoscopic treatment is recommended.

Although regurgitation of acid is a specificsymptom highly suggestive of GERD, heartburnmay have many different meanings for patients,and, indeed, patients may use different and impre-cise terms to describe their symptoms, such as “indi-gestion,” “stomach upset,” and “sour stomach.”Less common symptoms suggestive of but notdiagnostic of GERD include water brash (hyper-salivation associated with an episode of esophagealacid exposure), dysphagia (difficulty swallowing),odynophagia (painful swallowing), and chest dis-comfort not identified as heartburn. Reflux is morecommon after eating. Although reflux symptomscan occur at any time, they tend to aggregate in theperiod 1 to 3 hours after eating, when acid productionovercomes the buffering effects of food (Fig. 10). Ithas been reported that a layer of acid may remainunbuffered on the surface of the gastric meal con-tents. Reflux may occur also at night or when a personwith a weak lower esophageal sphincter is supineor, especially, in the right lateral decubitus position.

Esophageal Chest PainGERD is the most common esophageal cause ofnoncardiac chest pain. The pain may be referredto any point on the anterior or posterior chest, with

8 Esophagus

Fig. 8. Incidence of gastrointestinal reflux diseaseincreases with age. Note that the incidenceincreases markedly after age 40 years. (FromBrunnen PL, Karmody AM, Needham CD. Severepeptic oesophagitis. Gut. 1969;10:831-7. Used withpermission.)

810

1417

22

10

4

10 11

18

0

5

10

15

20

25

Italyn = 999

Japann = 500

Nordicn = 1010

Canadan = 1036

USAn = 1020

Heartburn

Regurgitation

3-M

onth

pre

vale

nce

(%)

Fig. 7. Prevalence of gastroesophageal reflux diseaseworldwide. Note that the prevalence variesmarkedly from country to country, largely because ofdifferences in physicians’ awareness andunderstanding of the condition.

0

5

10

15

20

<9 10-19 20-29 30-39 40-49 50-59 60-69 >70

Age (years)

Ann

ual i

ncid

ence

(cas

es p

er 1

00,0

00)

radiation to the neck, arm, or back. It may be indis-tinguishable from cardiac pain. Because of thepotential fatal significance of cardiac pain, it is

imperative that cardiac investigation precedeesophageal investigation. Frequently, patients whohave both cardiac and esophageal diseases cannotdistinguish between reflux-associated pain andreal angina. GERD may decrease the threshold forcoronary ischemia, further confusing the clinicalpicture. This emphasizes the importance of firstinvestigating the heart and, when appropriate,other vital structures.

Extraesophageal SymptomsGERD may contribute to symptoms originating inother areas of the upper aerodigestive system.These symptoms, which can occur without theclassic symptoms of heartburn and acid regurgi-tation, include cough, wheeze, hoarseness, sorethroat, repetitive throat clearing, postnasal drip,neck or throat pain, globus, apnea, or otalgia. Theyare not specific for GERD. Indeed, GERD is onlyone of many causes of most of these symptoms.Like GERD, cough and wheezing are very commonand likely to coexist by chance alone. Whether thesesymptoms are due to GERD needs to be confirmedby investigation or by the response to an empirictrial of potent acid-blocking therapy. Ideally, the


Psychological General Well-being Index (PGWBI) score

Psychiatric patients

Erosive esophagitis, untreated

Duodenal ulcer, untreated

Angina pectoris

Heart failure (mild)

Normal female

Normal male

Hypertension, untreated105

103

101

94

87

85

84

67

60 70 80 90 100 110

Fig. 9. Gastroesophageal reflux disease has a greater effect on quality of life than other common diseases.Quality of life, assessed by the PGWBI, was compared between patients with untreated gastroesophageal refluxdisease and those with other disorders. For example, the mean PGWBI score of patients with untreated erosiveesophagitis is similar to that of patients with untreated duodenal ulcer and lower (ie, worse) than that of patientswith angina pectoris or mild heart failure. Normal scores are 101 for women and 103 for men, but they varyslightly from country to country. (Modified from Dimenäs E. Methodological aspects of evaluation of Quality ofLife in upper gastrointestinal diseases. Scand J Gastroenterol Suppl. 1993;199:18-21. Used with permission.)

Table 2. Symptoms of GastroesophagealReflux Disease

Esophageal symptomsHeartburnAcid regurgitationOdynophagiaDysphagiaAngina-like chest painWater brash (hypersalivation)

Airway symptomsCoughWheezingHoarsenessThroat clearingGlobusTracheal stenosisAspiration pneumoniaPulmonary fibrosisApnea in infants

demonstration of a pathologic degree of GERDand a response of the atypical symptoms to an ade-quate antireflux regimen are needed to concludethat GERD is the cause. GERD may produce extra-esophageal symptoms in one of two ways. Thefirst is by direct irritation or inflammation of the del-icate mucosa of the larynx, trachea, or bronchi. Thesecond is by reflex-mediated changes in function.Both mechanisms may operate in some patients.

ESTABLISHING A DIAGNOSIS

Therapeutic TrialSeveral studies have investigated the usefulnessof empirical trials of acid-suppressive therapy withproton pump inhibitors (Table 3).

Typical Symptoms of GastroesophagealReflux DiseasePatients who present with typical symptomswithout alarm symptoms should be given acid-supressive therapy. Complete resolution of thesymptoms with treatment and relapse when treat-ment is discontinued confirm the diagnosis andsuggest the need for a long-term managementstrategy. However, even in these patients, the speci-ficity of a response to potent acid suppression isnot specific for GERD because other acid pepticdisorders respond to acid-suppressive therapy. Ifsymptomatic improvement is limited, either anincrease in dose or additional diagnostic testing isneeded. If there is little or no symptomaticimprovement with acid-suppressive therapy, fur-ther investigation is indicated.

10 Esophagus

Time of day

0

15

30

45

6 am

9 am

12 n

oon

3 pm

6 pm

9 pm

12 m

idnight

3 am

6 am

Num

ber

of e

pis

odes

of

reflu

x sy

mp

tom

s/ho

ur(m

ean

x 10

2 )

Breakfast Lunch Dinner

n = 105

Fig. 10. Distribution of symptoms of gastroesophageal reflux disease over 24 hours in 105 patients who took theirmajor meals at the same time of day. Note that food intake was associated with a marked increase in the numberof symptom episodes and relatively few episodes occurred during the night. (From Johnsson L, Adlouni W,Johnsson F, Joelssson B. Timing of reflux symptoms and esophageal acid exposure. Gullet. 1992;2:58-62. Usedwith permission.)

Table 3. Empiric Trials of Acid-Suppressive Therapy With Proton Pump Inhibitors for Diagnosis

Sensitivity,* Specificity,Symptom Treatment % %

Heartburn and Omeprazole twice daily for 7 days 80 56regurgitation

Noncardiac chest Omeprazole twice daily for 14 days 75 85pain

Extraesophageal Proton pump inhibitor twice daily for 3 months

*For the confirmation of gastroesophageal reflux disease.

Atypical Symptoms of GastroesophagealReflux DiseaseGERD may cause or contribute to many differentclinical syndromes. The more common or dan-gerous causes of these syndromes should be eval-uated first. For example, patients with chroniccough or hoarseness should be evaluated forasthma or laryngeal neoplasm, respectively. IfGERD is a possible cause, a therapeutic trial of acidsuppression may be attempted. For esophagealsymptoms such as chest pain, a 2-week trial oftherapy usually is sufficient. For extraesophagealsymptoms, a more prolonged therapeutic trial (2-3 months) may be necessary.

The acid-suppression test uses a potent reg-imen of acid suppression, for example, protonpump inhibitors (omeprazole, 40 mg in themorning and 20 mg in the evening). If the symp-toms resolve, the patient should receive long-termtreatment, with an attempt at dose reduction orcessation. For atypical symptoms, it is important toconsider that they may have had alternative causesthat resolved spontaneously. However, if there arereversible factors that are altered and if GERD isthe major cause, the symptoms are likely to recurwhen therapy is discontinued. If the symptoms donot resolve completely, further evaluation withupper endoscopy or 24-hour ambulatoryesophageal pH monitoring with symptom-refluxcorrelation (or both) is indicated. Ideally, the testshould be conducted when the patient is not takinga proton pump inhibitor.

If GERD is confirmed, long-term acid-sup-pressive therapy is indicated. If symptoms persist,ambulatory esophageal pH monitoring may berepeated to document that the esophagus is nolonger exposed to acid.

DIAGNOSTIC TESTS FORGASTROESOPHAGEAL REFLUXDISEASEDiagnostic tests are unnecessary for most personswith GERD. Investigations should be conductedin patients who have alarm symptoms, equivocalresults on a treatment trial, or atypical symptomsof sufficient importance to warrant confirmation ofGERD and in those undergoing surgical or endo-scopic therapy for GERD. For most patients, the

endoscopic demonstration of esophagitis is suffi-cient proof of GERD and further investigation isunnecessary. However, more than 50% of patientswith symptoms typical of GERD have normalendoscopic findings, and additional tests arerequired to identify increased esophageal exposureto acid. This is done either directly with ambulatorypH monitoring or indirectly by showing the refluxof a detectable material such as barium or a radio-labeled compound during a provocative maneuveror by reproducing symptoms through the instil-lation of acid (Table 4).

Endoscopic ExaminationEndoscopic examination allows direct visualizationof the esophageal mucosa. In reflux esophagitis,the characteristic finding is linear erosions in thedistal esophagus. These usually start at the esoph-agogastric junction and extend for various dis-tances. The degree of severity varies. By theirappearance alone, these erosions usually arereadily differentiated from rarer infectious, allergic


Table 4. Uses of Diagnostic Tests forGastroesophageal Reflux Disease

EndoscopyDifferentiate from other causes of reflux

esophagitisBiopsy Barrett’s esophagus, adenocarcinomaDilate stricturesEndoscopic therapy (?)

Contrast radiographyHiatal herniaIdentify stricturesReproduce reflux of barium (?)

Ambulatory 24-hour pH studiesQuantify acid reflux in the absence of

esophagitisDetermine temporal correlation between

gastroesophageal reflux and atypicalsymptoms

Bernstein testProvoke symptoms with acid

Gastroesophageal scintigraphyQuantify gastroesophageal reflux Identify aspiration

(eosinophilic), or corrosive causes of inflammation.If the diagnosis is in question, biopsy specimensshould be obtained, not primarily to confirm refluxbut to identify alternative pathologic conditions.

Several grading schemes, generally based onthe extent of involvement, have been used. TheLos Angeles classification system is the one usedmost commonly worldwide (Fig. 11). Erythemaand increased vascularity are nonspecific features,and a break in the mucosa is required to make thediagnosis of reflux esophagitis. Careful scrutinyof the esophagogastric junction with adequate airinsufflation is needed to examine the mucosa inits entirety. Endoscopy identifies the esophagealcomplications of GERD, including esophagealulceration and stricture, Barrett’s esophagus, andesophageal adenocarcinoma. Alarm symptomsthat suggest these complications include longduration (>10 years) of typical symptoms, dys-phagia, hematemesis or melena, and weight loss.The presence of these symptoms is a strong indi-cation for diagnostic testing, especially endoscopy.Male sex, middle age, and nocturnal heartburnmay be associated with a higher risk of esophagitisand its complications.

Barium Upper Gastrointestinal Tract SeriesAlthough the barium contrast study is a readilyavailable test, it is of limited usefulness in theevaluation of patients with GERD. Its major use-fulness in GERD is in identifying strictures andlarge hiatal hernias. It is insensitive for detectingerosions or superficial mucosal changes. Theability to reflux barium while at rest or in responseto a provocative maneuver or postural change isnot a sensitive test for GERD because mostpatients have a normal-pressure lower esophagealsphincter. In patients with extraesophageal symp-toms, reflux of barium to or above the level of theaortic arch suggests the possibility of proximalreflux. The contrast study has limited value indetecting mucosal changes other than the mostpronounced inflammation, which requires adouble contrast study. The sensitivity for GERDis only 20%. When provocative maneuvers areadded, the sensitivity increases but at great costto specificity. A barium contrast study may beuseful in delineating postoperative anatomicalrelationships and the intactness of an antirefluxrepair. Its use is discouraged in the evaluation ofuncomplicated GERD.

12 Esophagus

Fig. 11. Erosive esophagitis. Summary of Los Angeles (LA) classification. Grade A, one or more mucosal breaksnot more than 5 mm in maximal length. Grade B, one or more mucosal breaks more than 5 mm in maximallength, but not continuous between the tops of two mucosal folds. Grade C, mucosal breaks that are continuousbetween the tops of two or more folds but involve less than 75% of the esophageal circumference. Grade D,mucosal breaks that involve at least 75% of the esophageal circumference. (From AstraZeneca PharmaceuticalsLP [Internet]. Wilmington (DE). Available from: http://www.astrazeneca.com. Used with permission.)

Prolonged Ambulatory Esophageal pHMonitoring StudiesAmbulatory pH monitoring of the esophageallumen, a well-established test, was introduced inthe early 1970s. It provides objective evidence ofthe degree of GERD and its timing. For mostpatients with symptoms of GERD and for whomthe diagnosis is not in doubt, this test is not needed.The indications for ambulatory esophageal pHmonitoring are listed in Table 5. The test is per-formed with a probe that has a pH sensor at its tip.The tip is placed 5 cm above the proximal borderof the lower esophageal sphincter. Accurate loca-tion of this sphincter is critical because normalvalues for acid exposure apply only if the distancebetween the pH probe and the sphincter is 5 cm.The position of the lower esophageal sphincterusually is determined manometrically with a stan-dard stationary esophageal manometry study orwith a combined single water-perfused pressuretransducer with a pH probe that can locate accu-rately the proximal border of the sphincter andrequires only a single intubation. Other methodssuch as endoscopic measurement and pH step-upon withdrawal are not sufficiently accurate for theplacement of the nasoesophageal probe. The pHis recorded by a small portable recorder. A newermethod uses a tubeless pH capsule that is pinnedto the distal esophagus 6 cm above the endoscop-ically determined squamocolumnar junction. Ittransmits the pH measurements to a recorder wornon the chest. Its advantages are that it can record forprolonged periods and patients may eat more nor-mally, without the discomfort of the nasal tube.The patient should maintain his or her usual diet,

activity, and habits during the study to allow theassessment of findings relative to the patient’snormal lifestyle. The recorders have a patient-acti-vated event button (or buttons) to indicate meals,changes in posture, and symptom events. The dura-tion of the recording must be long enough to reflectall periods of the day, especially postprandialperiods. Ideally, 20 hours or more of analyzablerecordings are made.

The recordings are analyzed initially by visualinspection of the graphs and then by computer-assisted quantitative analysis of the number andduration of reflux episodes and the relation to anysymptoms the patient may have recorded (Fig. 12).Reflux of acid is defined as a sudden decrease inintraesophageal pH <4.0 that lasts longer than 5seconds. The six most commonly reported mea-surements are 1) the percentage of total time thatpH is <4.0, 2) the percentage of upright time thatpH is <4.0, 3) the percentage of recumbent timethat pH is <4.0, 4) the total number of reflux events,5) the number of reflux episodes that last longerthan 5 minutes, and 6) the longest episode of reflux(in minutes). The first three measurements of acidexposure are used most frequently in everydaypractice, and combined, they have a reported sen-sitivity of 85% and a specificity greater than 95% fordiagnosing GERD associated with esophagitis.Another important strength of ambulatoryesophageal pH monitoring is its ability to deter-mine whether a temporal relation exists betweenthe patient’s recorded symptoms and acid reflux.This determination is made initially by examiningthe tracing on which the symptom events havebeen marked and then performing a semiquanti-tative analysis.

Several measures have been used to calculatethe correlation between symptoms and reflux,including the symptom index (ie, the percentageof symptom events that occur at the time of anacid reflux event). A symptom index greater than50% usually is regarded as significant. Thesymptom sensitivity index is the percentage of refluxevents associated with symptoms. A symptomsensitivity index greater than 5% usually isregarded to indicate an association betweensymptoms and acid reflux. More recently, thesymptom association probability has been used as amore robust test for association. The ability to


Table 5. Indications for AmbulatoryEsophageal pH Monitoring

Atypical symptoms: respiratory, ear, nose, andthroatFrequent atypical chest painRefractory symptoms in well-establishedGERD*

Preoperative confirmation of GERD

GERD, gastroesophageal reflux disease.*Done on acid blockade.

determine whether a temporal association existsdepends on the number of symptom events andthe amount of reflux that occurs. The patient mustrecord his or her symptoms diligently and accu-rately during the study. If the symptoms occur oncea week, there is little use in performing pH testing.

The 24-hour ambulatory esophageal pH mon-itoring test has limitations. Absolute values forsensitivity and specificity have been estimatedbecause no standards exist for comparison withprolonged ambulatory pH monitoring. Also, pHmonitoring may give false-negative results in 17%of patients with proven erosive esophagitis. Thismay reflect day-to-day variability in reflux orpatients may have limited their diet or activitiesthat would lead to reflux. Even simultaneousrecording of pH from adjacent sensors may givedifferent results in 20% of subjects. Some patientshave a physiologic degree of acid reflux but havea strong correlation between the short-lived refluxevents and symptoms. This may be due to a hyper-sensitive esophagus. Patients who frequently have

symptoms of heartburn but no correspondingreflux may have what is termed functional heartburn.

Generally, pH monitoring is performed whenthe patient is not taking any acid-suppressive med-ication. However, occasionally and for specificindications, pH monitoring may be performedwhen a patient is taking these medications. Theseindications include frequent typical reflux symp-toms that are refractory to what should be adequateacid-suppressive therapy with usual doses ofproton pump inhibitors. Another indication ispersistent extraesophageal symptoms despitehigh-dose proton pump inhibitor therapy inpatients with confirmed reflux disease. Usually, aprerequisite for performing the test while thepatient is receiving treatment is that the diagnosisof GERD is fairly certain and the intent is to verifythat the suppression of acid reflux is complete.

Establishing a temporal correlation betweensymptoms and acid reflux events may be a sec-ondary aim of the study. However, heartburn andregurgitation may occur in the absence of acid

14 Esophagus

Fig. 12. Typical traces of 24-hour pH monitoring. The test was performed in a patient with chest pain. Uppertrace, Electrode placed 20 cm above the lower esophageal sphincter. Lower trace, Electrode placed in the distalesophagus, 5 cm above the lower esophageal sphincter. Traces were recorded simultaneously. Esophageal pHmust be <4 to be categorized as acid reflux. Marker flags, symptom episodes. Both episodes of chest pain (★)occurred during reflux episodes (symptom index = 100%). Abnormal upright and recumbent esophageal acidexposure occurs in the distal esophagus, suggesting both daytime and nightime reflux.

reflux. This may be due to nonacid reflux, gastricdyspepsia, rumination, or an unrelated process.A newer technique that measures both pH andintraluminal impedance may be able to detectnonacid reflux, but its role is not fully acceptedand its clinical usefulness has not been demonstrated.Often, gastric pH is measured simultaneously toassess the degree of gastric acid suppression.Approximately one-third of patients receiving reg-ular doses of proton pump inhibitors have markedproduction of acid in the stomach at night, but thisbreakthrough acid production does not always pro-duce symptoms or actual esophageal acid reflux.

Gastroesophageal ScintigraphyGastroesophageal scintigraphy is used rarely todemonstrate gastroesophageal reflux or aspira-tion. The technique involves feeding the patient atechnetium 99m sulfur colloid-labeled meal andobtaining postprandial images with a gammacamera. Delayed images obtained the followingmorning may show scintigraphic activity withinthe lung fields, demonstrating aspiration (usually,gross aspiration is needed). The test may be moreuseful in patients who have concomitant symptomsof delayed gastric emptying.

Bernstein TestThe Bernstein test is a provocative test in whichacid (0.1N HCl) and water are infused alternatelythrough a nasoesophageal tube into the mides-ophagus, with the patient unaware of the order ofinfusion. Of patients with GERD, 70% complainof heartburn within a few minutes after the startof the infusion of acid. Ideally, the symptom isrelieved promptly when water is instilled. Becauseof low sensitivity and poor tolerance of the infu-sion, this test is not performed frequently. Greatcare must be taken to ensure that the tube is not inthe airway, because instillation of acid into thelungs may have severe consequences.

TREATMENTPatient- or physician-initiated empirical treatmentfor presumed GERD has become commonplace.Indeed, guidelines for primary care have supportedthis approach for patients who do not have alarmsymptoms. Treatment options for GERD are sum-

marized in Table 6. Potent acid suppression withproton pump inhibitors is effective and heals refluxesophagitis after only a few weeks of therapy. Thishas resulted in a shift in the disease as it appears toendoscopists. It is rare to find severe disease inpatients who have been treated with proton pumpinhibitors. This practice poses a problem whensymptoms do not resolve as expected. Perhapsthere is partial improvement in symptoms.Although the diagnosis of GERD was suggestedat the time of presentation and initiation of protonpump inhibitor therapy, the disease cannot be con-firmed by the usual method without stopping themedications for a substantial time, and this maynot be acceptable to patients in whom proton pumpinhibitors have healed the esophagitis. A carefulreexamination of the pretreatment symptoms mayshow that what the patient thought was GERD mayhave been something else, for example, dyspepsia.

Acid-suppressive therapy is the cornerstoneof the treatment of GERD. It provides excellenthealing and relief of symptoms in patients withesophagitis or classic heartburn. The relief appearsto be related directly to the degree of acid sup-pression achieved.

Long-term maintenance therapy is needed formost patients. Lifestyle modifications alone mayproduce remission in 25% of patients with symp-toms, but only a few patients are compliant with therestrictions. The same principles that apply toshort-term therapy apply also to long-term therapy.Less acid equals less recurrence.

Histamine2 Receptor BlockersHistamine2 (H2) receptor blockers act by blockingthe histamine-induced stimulation of gastric pari-etal cells. H2 blockers provide moderate benefitwhen given in moderate doses (cimetidine 400 mgtwice daily, famotidine 20 mg twice daily, nizati-dine 150 mg twice daily, ranitidine 150 mg twicedaily) and heal esophagitis in 50% of patients.Higher doses suppress acid more rapidly. Lowerdoses are less effective, and nighttime-only dosingmisses all the daytime reflux that predominates.A particular role for H2 blockers may be to augmentproton pump inhibitors when given at night to blocknocturnal acid breakthrough; however, nocturnal H2blockade does not produce sustained nocturnal acidsuppression because of tachyphylaxis.


Proton Pump InhibitorsProton pump inhibitors are absorbed rapidly andtaken up and concentrated preferentially in pari-etal cells. They irreversibly complex with the H+-K+-ATPase pump, which is the final step in acidproduction. To produce acid, parietal cells mustform new pumps, a process that takes many hours.Proton pump inhibitors are more potent than H2blockers as suppressors of acid reflux. The healingof esophagitis and the relief of symptoms are morerapid with proton pump inhibitors than with H2blockers. With proton pump inhibitor therapy,esophagitis heals within 4 weeks in more than 80%of patients and in virtually 100% by 8 weeks.However, the rate of complete relief from symp-toms is less than the rate of healing.

Whether a proton pump inhibitor should begiven as initial therapy and then replaced with H2blocker therapy or whether H2 blocker therapyshould precede proton pump inhibitor therapy isdebated. Economic analysis, which takes intoaccount the patient’s quality of life, suggests thatthe latter approach is preferred. It is well estab-lished that therapy sometimes can be “steppeddown” successfully after treatment with a protonpump inhibitor or switched to on-demand therapy,

although this is rarely suitable for patients withsubstantial complications of GERD. This approachis not recommended unless cost considerationsare paramount.

Although routine doses of proton pumpinhibitors (esomeprazole 40 mg/day, lansopra-zole 30 mg/day, omeprazole 20 mg/day, panto-prazole 40 mg/day, rabeprazole 20 mg/day) areadequate for most patients with GERD, some mayrequire higher or more frequent dosing to sup-press GERD completely. Data have demonstratedthat proton pump inhibitors are not entirely effec-tive in blocking nocturnal production of acid inthe stomach. Complete acid blockade can beachieved by dose escalation or by adding a noc-turnal H2 blocker. However, the latter strategydoes not have a sustained effect; nor is it clear thatcomplete suppression of gastric acid is desirable.

Incomplete blockade may be the result of dif-ferences in metabolism or bioavailability. Omeprazoleis absorbed more readily on an empty stomach andis most effective if the stomach parietal cells arestimulated. This is achieved by having patients eatwithin an hour after taking the medication.

With maintenance proton pump inhibitortherapy, the rate of relapse of esophagitis is 20%

16 Esophagus

Table 6. Summary of Treatment Options for Gastroesophageal Reflux Disease

HealingTreatment Options rate, %

Lifestyle modifications Elevate the head of the bed 20-30Avoid eating within 3 hours before going to bedModerate size and fat content of mealsLoss of excess weightReduce intake of caffeine, chocolateStop smoking

Acid neutralization Antacids 20-30Chewing gumAlginate preparations

Acid suppression H2 blockers 50Proton pump inhibitors ≥80

Prokinetics Metoclopramide (not useful) 30-40Others in development

Mechanical prevention Laparoscopic surgery ≥80of reflux Endoscopic therapies ≥50

or less, which is lower than for H2 blockers (Fig.13). A slight escalation in dose may be needed withlong-term therapy. Also, maintenance protonpump inhibitor therapy is more effective than H2blockers in reducing the need for redilatation inpatients with reflux-associated benign strictures.

Proton pump inhibitor therapy causes a clin-ically insignificant increase in the serum level ofgastrin. Although this has caused concern abouta theoretical risk of carcinoid, the risk has not beenrealized after more than 10 years of long-term useof these agents. The increase in serum levels of gas-trin and parietal cell mass may lead to reboundacid secretion after the therapy is stopped. Thesame effect also occurs, but for a shorter time, afterH2 blocker therapy is stopped. Epidemiologicstudies have also raised the possibility of an asso-ciation between proton pump inhibitor therapyand hip fractures.

ProkineticsThe idea that a motility disorder is the genesis ofGERD made a prokinetic approach intellectuallyenticing. Drugs such as metoclopramide and, for-merly, cisapride, which increase the tone of the loweresophageal sphincter and esophageal clearance and

accelerate gastric emptying, have been used to treatreflux. However, the healing rate and safety ofthese drugs have been questioned. Cisapride hasbeen withdrawn from use in the United States, andthe long-term use of metoclopramide is associatedwith so many side effects that it is rarely prescribedfor GERD unless that is incidental to its use for gas-troparesis. Several prokinetic agents are beingstudied for the treatment of GERD, but the lowerefficacy of prokinetics compared with that ofproton pump inhibitors limits their potential use-fulness. Drugs that target the TLESRs also havebeen used, including baclofen, which probably canreduce reflux but is not approved or widely usedfor that indication.

Refractory RefluxRefractory reflux disease can be defined as symp-toms of GERD that are refractory to treatment withregular dosages of proton pump inhibitors. Themany common causes of refractory reflux symptomsare listed in Table 7.

Functional Chest PainMany patients who complain the most bitterly ofsevere reflux often have very little reflux on 24-hour


*P <.05 vs. H2RA†P <.05 vs. prokinetic‡P <.05 vs. H2RA + prokinetic

49 5466

8089

0

20

40

60

80

100

Pat

ient

s in

rem

issi

onat

12

mon

ths,

%

*

H2RA Prokinetic H2RA +prokinetic

PPI PPI +prokinetic

*†*†‡

Fig. 13. Proton pump inhibitors (PPI) are the most effecive drugs for maintenance therapy of gastroesophagealreflux disease. Although the remission rate was slightly higher with PPI + prokinetic than with PPI alone, thedifference was not significant. H2RA, histamine2 receptor antagonist. (Data from Vigneri S, Termini R, LeandroG, Badalamenti S, Pantalena M, Savarino V, et al. A comparison of five maintenance therapies for refluxesophagitis. N Engl J Med. 1995;333:1106-10.)

pH monitoring and have no endoscopic features ofreflux. This condition has been termed nonerosivereflux disease. As with other functional gastrointestinaltract problems, females are overrepresented.Features of anxiety, panic, hyperventilation, andsomatization may be clues to the diagnosis.Antacid therapies may help reduce the frequencyof the symptoms, but they rarely relieve them com-pletely. Therapies aimed at decreasing visceralhypersensitivity may be helpful, for example, alow dose of an antidepressant.

Surgical and Endoscopic AntirefluxProceduresWhat is the role of laparoscopic and endoscopicmethods of therapy? Medical therapy has beenreduced to acid neutralization or suppression ofacid production. Surgeons and endoscopists havefocused on the role of the mechanical or functionalfailure of the antireflux barrier, and this has becomethe prime target of various approaches for preventingthe reflux of gastric contents into the esophagus.

For many years, antireflux surgery was per-formed through a transabdominal or transthoracicapproach, with considerable morbidity. Surgicaltreatment was reserved for intractable reflux thatthe available weak medical therapy failed to cure.With the advent of proton pump inhibitors, evensevere degrees of reflux came to be well controlled,although the therapy is expensive. With the adventof minimally invasive surgery, surgical treatmenthas had a renaissance. The laparoscopic antirefluxprocedure has become a staple of the communitysurgeon. Its outcomes are similar to those of theopen approach. With well-chosen patients andexperienced surgeons, an 80% to 90% success rateis expected. The success rate decreases remarkablyif the patients have symptoms refractory to protonpump inhibitor therapy or poorly documentedreflux disease and if the procedure is performedby less experienced surgeons. A substantialnumber of these patients resume taking acid-blocking medications, often for unclear reasons.Preoperatively, it is important to verify that thepatient’s symptoms in fact are due to reflux. Thisis accomplished by documenting reflux esophagitisand a response to proton pump inhibitor therapyor by confirming the pathologic degree of refluxwith a 24-hour pH assessment while the patient is

not receiving therapy. If the patient belches fre-quently, he or she should be informed that belchingmay not be possible after the operation and gas bloatmay result. Preoperative esophageal manometryhas been widely recommended. It identifies a severemotility disturbance such as achalasia or connectivetissue disease, and some surgeons want confirmationof a weak lower esophageal sphincter (if present).

Postoperatively, 20% of patients have somedysphagia, but this persists in only 5%. Gas bloat,

18 Esophagus

Table 7. Causes of Refractory RefluxSymptoms in Patients ReceivingProton Pump Inhibitor Therapy

Incorrect initial diagnosisNonreflux esophagitis—pill injury, skin

diseases, eosinophilic esophagitis, infectionHeart diseaseChest wall painGastric pain

Additional diagnosesDyspepsia—delayed gastric emptying,

gastritis, peptic ulcer disease, nonulcerdyspepsia

Above diagnosesInadequate acid suppression

NoncomplianceRapid metabolizers of proton pump

inhibitorsDose timingToo low a doseZollinger-Ellison syndrome

Adenocarcinoma in Barrett’s esophagusPostoperative reflux—partial gastrectomy,

vertical-banded gastroplastyEsophageal dysmotility

SpasmAchalasiaNutcracker esophagus

Functional chest painHypersensitive esophagusSomatic features of depression

Free regurgitationAbsence of lower esophageal sphincter toneLarge hiatal herniaAchalasiaRumination

diarrhea, and dyspepsia may occur or becomemore evident postoperatively and may be trou-bling to patients. As many as one-third of thepatients may still require proton pump inhibitortherapy postoperatively for persistent reflux ordyspepsia. Patients who have respiratory symp-toms, free regurgitation, or simple but severeheartburn without gastric symptoms seem to havethe best response to antireflux surgery. Female sex,lack of objective evidence of pathologic reflux, andfailure to respond to proton pump inhibitortherapy all predict a poor response to surgery.Patient selection and operator experience seem tobe the main determinants of a favorable surgicaloutcome. Reflux surgery is superior to long-termtreatment with H2 blockers to maintain the healingof GERD; however, follow-up for more than 10years has shown an unexplained increase in mor-tality, predominantly due to cardiovascular disease,in the surgical group.

Who Not to Send to SurgeryIt would be prudent to reconsider carefully thewisdom of sending to surgery a patient who hassymptoms that are refractory to proton pumpinhibitors. A hypersensitive esophagus or gastricdysmotility may be worse after fundoplication.Also, symptoms of irritable bowel syndrome mayworsen postoperatively.

Endoscopic Methods of TherapySeveral endoscopic methods have been tried or arein development for the treatment of GERD.Endoscopic methods to alter the shape or to tightenthe esophagogastric junction are in various stagesof development. These consist of inserting suturesor other devices into the gastric wall to generate amechanical barrier or “speed bump” to reflux.Although some of these methods have been in clin-ical use, evidence for long-term efficacy is lacking.

RECOMMENDED READINGDent J. Patterns of lower esophageal sphincter func-

tion associated with gastroesophageal reflux.Am J Med. 1997;103:29S-32S.

Dent J, Brun J, Fendrick AM, Fennerty MB, JanssensJ, Kahrilas PJ, et al. An evidence-basedappraisal of reflux disease management: the

Genval Workshop Report. Gut 1999;44 Suppl2:S1-S16.

DeVault KR, Castell DO, the Practice ParametersCommittee of the American College ofGastroenterology. Updated guidelines for thediagnosis and treatment of gastroesophagealreflux disease. Am J Gastroenterol.1999;94:1434-42.

Fletcher J, Wirz A, Young J, Vallance R, McCollKE. Unbuffered highly acidic gastric juiceexists at the gastroesophageal junction after ameal. Gastroenterology. 2001;121:775-83.

Furuta T, Ohashi K, Kosuge K, Zhao XJ, TakashimaM, Kimura M, et al. CYP2C19 genotype statusand effect of omeprazole on intragastric pHin humans. Clin Pharmacol Ther. 1999;65:552-61.

Gillen D, Wirz AA, Ardill JE, McColl KE. Reboundhypersecretion after omeprazole and its rela-tion to on-treatment acid suppression andHelicobacter pylori status. Gastroenterology.1999;116:239-47.

Hogan WJ, Shaker R. Supraesophageal complica-tions of gastroesophageal reflux. Dis Mon.2000; 46:193-232.

Holtmann G, Cain C, Malfertheiner P. GastricHelicobacter pylori infection accelerates healingof reflux esophagitis during treatment withthe proton pump inhibitor pantoprazole.Gastroenterology. 1999;117:11-6.

Kahrilas PJ, Shi G, Manka M, Joehl RJ. Increasedfrequency of transient lower esophagealsphincter relaxation induced by gastric dis-tention in reflux patients with hiatal hernia.Gastroenterology. 2000;118:688-95.

Katzka DA, Paoletti V, Leite L, Castell DO.Prolonged ambulatory pH monitoring inpatients with persistent gastroesophagealreflux disease symptoms: testing while ontherapy identifies the need for more aggres-sive anti-reflux therapy. Am J Gastroenterol.1996;91:2110-13.

Klauser AG, Schindlbeck NE, Muller-Lissner SA.Symptoms in gastro-oesophageal reflux dis-ease. Lancet. 1990;335:205-8.

Klinkenberg-Knol EC, Nelis F, Dent J, Snel P,Mitchell B, Prichard P, et al. Long-termomeprazole treatment in resistant gastro-esophageal reflux disease: efficacy, safety, and


influence on gastric mucosa. Gastroenterology.2000;118:661-9.

Locke GR III, Talley NJ, Fett SL, Zinsmeister AR,Melton LJ III. Prevalence and clinical spec-trum of gastroesophageal reflux: a popula-tion-based study in Olmsted County,Minnesota. Gastroenterology. 1997;112:1448-56.

Orlando RC. Why is the high grade inhibition ofgastric acid secretion afforded by proton pumpinhibitors often required for healing of refluxesophagitis? An epithelial perspective. Am JGastroenterol. 1996;91:1692-6.

Stanghellini V. Three-month prevalence rates ofgastrointestinal symptoms and the influenceof demographic factors: results from the

Domestic/International GastroenterologySurveillance Study (DIGEST). Scand JGastroenterol Suppl. 1999;231:20-8.

Tobey NA. How does the esophageal epitheliummaintain its integrity? Digestion. 1995;56 Suppl1:45-50.

Tobey NA. Systemic factors in esophageal mucosalprotection. Digestion. 1995;56 Suppl 1:38-44.

Vakil N, Kahrilas P, Magner D. Does baseline Hpstatus impact erosive esophagitis (EE) healingrates? [Abstract]. Am J Gastroenterol.2000;95:2438-9.

Vigneri S, Termini R, Leandro G, Badalamenti S,Pantalena M, Savarino V, et al. A comparisonof five maintenance therapies for refluxesophagitis. N Engl J Med. 1995;333:1106-10.

20 Esophagus

DEFINITIONSBarrett’s esophagus is the strongest risk factor known foresophageal adenocarcinoma (Fig. 1). Endoscopic andpathologic criteria need to be met to make the diagnosisof Barrett’s esophagus. Endoscopy must demonstratesalmon-colored mucosa in the tubular esophagus (Fig.2), and biopsy specimens must show intestinal meta-plasia with goblet cells (so-called specialized intestinalmetaplasia) (Fig. 3).

Arbitrarily, the term long-segment Barrett’s esophagusrefers to a salmon-colored segment of specializedintestinal metaplasia at least 3 cm long (Fig. 4). Essentiallyall the reports before 1985 refer to long-segment Barrett’s

esophagus. The term short-segment Barrett’s esoph-agus refers to macroscopic segments or tongues ofsalmon-colored epithelium less than 3 cm in lengthseen at endoscopy (Fig. 4). Biopsy specimens fromthese segments show intestinal metaplasia withgoblet cells. Intestinal metaplasia of the cardia refersto the histologic finding of intestinal metaplasiawith goblet cells at a normally located and normal-appearing squamocolumnar junction (the so-calledzig-zag line, or Z line) (Fig. 4). Currently, intestinalmetaplasia of the cardia is not classified as Barrett’sesophagus. Because the neoplastic risk of intestinalmetaplasia of the cardia is thought to be low, the

21

CHAPTER 2

Barrett’s Esophagus and Esophageal Cancer

Yvonne Romero, MD

Fig. 1. Squamous epithelium, Barrett’s esophagus,and the consequence: esophageal adenocarcinoma.A, Endoscopic view of three types of mucosa: icypink squamous epithelium, salmon-coloredmucosa, which is diagnostic of Barrett’s esophagusif biopsy specimen shows intestinal metaplasiawith goblet cells, and the mushroom-like growth ofesophageal adenocarcinoma. B, Close-up view ofexophytic esophageal adenocarcinoma in a field ofBarrett’s esophagus.

Abbreviations: CT, computed tomography; GERD, gastroesophageal reflux disease; PET, positron emission tomography.

A B

American Gastroenterology Association ChicagoWorkshop has advised that “the normal-appearingand normally located squamocolumnar junctionshould not be biopsied.”

PathophysiologyBarrett’s esophagus is an acquired disorder inwhich columnar epithelium replaces the stratifiedsquamous epithelium that normally lines the distalesophagus. This disorder is thought to occur inresponse to years of reflux of gastric contents intothe distal esophagus. Hiatal hernias, weaker loweresophageal sphincter tone, and abnormal distalesophageal acid exposure, as measured with 24-hour pH testing, are more frequent in patients withBarrett’s esophagus than in normal healthy con-trols and patients with erosive esophagitis.Currently, it is presumed that hiatal herniationand weak lower esophageal sphincter tone pre-dispose to more severe reflux and chronic refluxinitiates the metaplastic change from a squamousto a columnar epithelial lining. The length of thesalmon-colored mucosal segment seen endoscop-ically does not change over time in patients withlong-segment Barrett’s esophagus. In one study,

22 Esophagus

the segmental length remained constant in 21 patientswho had repeat examinations at least 5 years apart (mean,7.3 years). It is not clear if this is true also of short-seg-ment Barrett’s esophagus. With the common use ofproton pump inhibitors and, thus, significant acid sup-pression, islands of squamous epithelium are oftenidentified overlying Barrett’s mucosa. These islandshave not been shown to be clinically significant.

EPIDEMIOLOGY OF BARRETT’SESOPHAGUSBarrett’s esophagus is associated with reflux symp-toms, advancing age, male sex, and white race. To amuch lesser extent, alcohol use and exposure to nico-tine also are associated with Barrett’s esophagus. Therole of genetics and obesity is being investigated.

Fig. 2. Barrett’s esophagus. (Courtesy of Drs.Kenneth K. Wang and Louis M. Wong Kee Song,Gastroenterology and Hepatology, Mayo Clinic.)

Fig. 3. Intestinal metaplasia with goblet cells. (Courtesy ofDr. Thomas C. Smyrk, Anatomic Pathology, Mayo Clinic.)

Prevalence of Barrett’s EsophagusThe prevalence of Barrett’s esophagus among whitesof European background in developed countries doesnot appear to have changed remarkably over the pasttwo decades. This statement is based on two landmarkstudies published in 1990 and 2005. The first studyreported on Olmsted County, Minnesota, which hasan enumerated population of predominantlyScandinavian, German, and others of Europeandescent. The second study was from Sweden, whosepopulace is well enumerated. With enumerated pop-ulations, epidemiologic estimates can be calculatedaccurately because all the members are accounted forand the denominator is known.

In the 1980s, autopsy was performed on 37% ofthe residents who died in Olmsted County, Minnesota.The esophagi of autopsy specimens were examinedprospectively over an 18-month period during 1986and 1987. To confirm intestinal metaplasia with gobletcells, biopsy specimens were collected from esophagithat appeared to have at least 3 cm of salmon-coloredmucosa. Thus, the prevalence of short-segmentBarrett’s esophagus and intestinal metaplasia of thecardia, concepts that were either nascent or nonexis-tent in 1986, was not determined. Of 733 consecutive

unselected autopsies, 7 had long-segment Barrett’sesophagus, giving a sex- and age-adjusted preva-lence of long-segment Barrett’s esophagus of 376cases per 100,000 population, or 0.34%.

The prevalence of the combination of long-seg-ment and short-segment Barrett’s esophagus andintestinal metaplasia of the cardia was reported in2005 in a Swedish population-based studyinvolving two municipalities with a total populationof 21,610. A validated symptom questionnaire wasmailed to a random sample of 3,000 persons, and theresponse rate was 74%. A random subsample of1,000 subjects who completed the questionnairewas invited to undergo upper endoscopy. Of these1,000 people who had endoscopy, 5 were found tohave intestinal metaplasia with goblet cells at least2 cm in length, for an overall estimate of 0.5% with“longish” Barrett’s esophagus. Because the authorsdid not report the prevalence of long-segment (≥3cm) Barrett’s esophagus, a direct comparison cannotbe made with the 1987 autopsy data from OlmstedCounty, Minnesota. Nonetheless, both estimatesare similar. The overall prevalence of Barrett’sesophagus of any length, which included intestinalmetaplasia of the cardia, was 1.6%.

Barrett’s Esophagus and Esophageal Cancer 23

Fig. 4. Patients with long-segment or short-segment Barrett’s esophagus have salmon-colored mucosa extending upinto the tubular esophagus. Biopsy specimens must demonstrate intestinal metaplasia with goblet cells. If intestinalmetaplasia with goblet cells is found at a normally located zig-zag line (Z line), the patient has intestinal metaplasiaof the cardia, which confers a lower cancer risk. * End of tubular esophagus and beginning of stomach.

Currently, in Olmsted County, Barrett’s esoph-agus is diagnosed more frequently than it was inthe past partly because more persons haveendoscopy now than previously (Fig. 5). Also,endoscopists now probably are more aware of thisclinical entity and, hence, less likely to overlookor miss it.

Although the number of people in whomBarrett’s esophagus is being diagnosed hasincreased over the past 3 decades, this does notnecessarily reflect a change in prevalence. Theincrease can be explained by two phenomena:increased recognition by physicians, especially ofshort-segment Barrett’s esophagus, and increaseddetection because of increased use of diagnosticendoscopy (ie, the more endoscopic examinationsperformed, the more cases of Barrett’s esophagusdiagnosed). As seen in Figure 5, the first case ofshort-segment Barrett’s esophagus was diagnosedin Olmsted County in 1985, not because short-seg-ment Barrett’s esophagus did not occur before 1985but because it was not recognized as a diseasebefore that time. In the early 1980s, it was commonclinical practice to biopsy salmon-colored mucosaonly if it extended 3 cm or more in length.

The number of new cases of long-segment Barrett’sesophagus diagnosed per 100,000 population per yearincreased from 0.37 in 1965-1969 to 10.5 in 1995-1997, a28-fold increase. During the same period, the numberof upper endoscopic examinations performed onOlmsted County residents increased from 65 to 1,461per 100,000 population per year, a 22-fold increase.Without knowing the denominator of persons under-going endoscopy, one could erroneously conclude thatthe prevalence of Barrett’s esophagus was increasing.

On the basis of the autopsy study described above,it was estimated that in 1987 in Olmsted County,Minnesota, for every 16 people with long-segmentBarrett’s esophagus, only 1 was aware of the disease.Thus, only 1 of 16 people with a preneoplastic conditionhad the opportunity to participate in a surveillanceprogram. In 1998, this ratio was 1 in 7 in OlmstedCounty, likely because of open access endoscopy. Forevery seven people in Olmsted County with long-segment Barrett’s esophagus, the disease has beendiagnosed clinically in one and surveillance likelyrecommended. A recent systematic review hasreported that fewer than 5% of patients who haveboth Barrett’s esophagus and esophageal adenocar-cinoma documented in a surgical resection specimen

24 Esophagus

Fig. 5. Incidence of diagnosed long- and short-segment Barrett’s esophagus and number of upper endoscopicexaminations performed annually in residents of Olmsted County, Minnesota, from 1965 to 1995. (From Conio M,Cameron AJ, Romero Y, Branch CD, Schleck CD, Burgart LJ, et al. Secular trends in the epidemiology and outcomeof Barrett’s oesophagus in Olmsted County, Minnesota. Gut. 2001;48:304-9. Used with permission.)

had the diagnosis of Barrett’s esophagus before seekingmedical care for symptoms of cancer (dysphagia,weight loss of unclear origin, or anemia). It is unlikelythat surveillance will be shown to be beneficial indecreasing the mortality rate of esophageal adenocar-cinoma until Barrett’s esophagus has been diagnosedin the majority of persons with this condition well inadvance of progression to cancer. To date, case serieshave shown that patients with Barrett’s esophagus inwhom esophageal adenocarcinoma is diagnosedduring routine surveillance are usually found to haveearlier stage disease and longer survival than patientsin whom Barrett’s esophagus and cancer are diagnosedsimultaneously. Because of the possibility of lead timebias in case series, it cannot be concluded confidentlythat surveillance increases survival. The hope is thatonce Barrett’s esophagus has been diagnosed in all per-sons with the condition, trials can be conducted toassess the benefit, or lack of benefit, of surveillance.

Risk Factors for Barrett’s Esophagus

AgeBarrett’s esophagus is an acquired disorder. Thus, theprevalence of long-segment Barrett’s esophagus

increases with age (Fig. 6). The mean age at thetime of clinical diagnosis is 63 years. Long-segmentBarrett’s esophagus is rare in children. A recentcohort study found that 8 of 166 children whoreceived long-term proton pump inhibitor therapyhad Barrett’s esophagus, most commonly childrenolder than 11 years who had altered mental statusor another gastroesophageal reflux disease-pre-disposing disorder, such as Down’s syndrome orcerebral palsy. Barrett’s esophagus was exceedinglyrare in children who had simple reflux disease.

Male SexIn a Mayo Clinic study of patients who hadendoscopy between 1976 and 1989, long-segmentBarrett’s esophagus was twice as common in malesas in females. In a large multicenter Italian study(patients enrolled from 1987 to 1989), Barrett’sesophagus was 2.6 times more common in malesthan in females. A higher male-to-female ratio hasbeen reported also in studies of military popula-tions in which females were in the extreme minority.In the 2005 Swedish population-based study, themale-to-female ratio of biopsy-proven Barrett’sesophagus that was at least 2 cm in length was 1.5:1.


Pat

ient

s en

dos

cop

ed w

ho h

adB

arre

tt’s

eso

pha

gus,

%

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0.0

Age, years

0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89

M

M + F

F

Fig. 6. Prevalence of Barrett’s esophagus increased with age up to seventh decade. Half the maximum prevalencewas reached by about age 40 years. Mean age at diagnosis was 63 years. F, females; M, males. (Courtesy of Dr. AlanJ. Cameron, Emeritus, Mayo Clinic.)

Geography and EthnicityLong-segment Barrett’s esophagus is describedfrequently in Western countries but appears to beless common in other countries, for example, Japan.In a recent single-center US retrospective cross-sectional cohort study of 2,100 people (37.7% white,11.8% black, 22.2% Hispanic) who had endoscopyfrom 2005 to 2006, whites (6.1%) were more likelyto have Barrett’s esophagus of any length thanblacks (1.6%, P=.004) or Hispanics (1.7%, P=.0002).

Reflux SymptomsThe symptoms of gastroesophageal reflux disease(GERD) include heartburn, which is described assubsternal burning pain, and acid regurgitation,which is a bitter or sour taste that travels to themouth. About 15% to 20% of adults in the UnitedStates report experiencing heartburn at least oncea week, and 7% report daily symptoms. Of adultswith symptoms of GERD, long-segment Barrett’sesophagus is diagnosed at endoscopy in 3.5% to7% (an age- and sex-adjusted estimate). In con-trast, long-segment Barrett’s esophagus is found atendoscopy in only 1% of adults who deny havingsymptoms of GERD.

Risk factor estimates for short-segmentBarrett’s esophagus are based mainly on cohort orcase-control studies, which increase the possibilityof overestimation of risk because of the limitationsof study design. In a study in which all subjectsreported heartburn at least twice a week, short-segment Barrett’s esophagus was diagnosed in 7 of378 (1.8%) consecutive patients who had endoscopyfor various indications. In a case-control study,patients with short-segment Barrett’s esophaguswere more likely to have reflux symptoms thancontrols without this condition who hadendoscopy for another indication.

Intestinal Metaplasia of the CardiaBefore 1994, biopsy specimens were not commonlycollected from the normal-appearing zig-zag line(the junction of the cardia and the pale stratifiedsquamous lining of the distal esophagus). It waspresumed that biopsy specimens from this junc-tion would show gastric cardia-type mucosa or, ifthe specimen was from an adjacent area, fundicmucosa. In 1994, Spechler et al reported on 143consecutive patients who did not have endoscopic

evidence of Barrett’s esophagus but from whom biopsyspecimens were obtained from the squamocolumnarjunction according to protocol. Histologic evidence ofintestinal metaplasia was found in 18% of these patients.Intestinal metaplasia with goblet cells at a normal-appearing Z-line has been demonstrated repeatedlyby numerous investigators. For all patients who haveendoscopy for any indication, the prevalence estimatesrange from 6% to 36%. The prevalence increases withage, suggesting that it is an acquired condition.However, unlike long-segment or short-segmentBarrett’s esophagus, intestinal metaplasia of the cardiais found equally in males and females and in whitesand blacks, regardless of whether symptoms of GERDare present. Intestinal metaplasia of the stomach isassociated with Helicobacter pylori. The role of H. pyloriinfection in the development of intestinal metaplasia ofthe cardia is being investigated.

CANCER RISK

Barrett’s EsophagusReports of long-term follow-up of patients with long-segment Barrett’s esophagus suggest that one cancerdevelops per 180 to 208 patient-years; that is, annually,esophageal adenocarcinoma develops in 0.5% ofpatients with Barrett’s esophagus. Although a patientwith Barrett’s esophagus has a 30- to 125-fold higherrisk of the disease progressing to adenocarcinoma thansomeone without this premalignant lining, the absoluterisk of cancer is approximately 0.005 cancer per patientannually, which is exceedingly low. Thus, a 50-year-oldman with Barrett’s esophagus and otherwise normallife expectancy has a 3% to 10% lifetime risk (cumulativeincidence) of developing esophageal adenocarcinoma.

The rate of neoplastic transformation is less forpatients with shorter segments of specialized intestinalmetaplasia. The findings from three series suggest thatone cancer develops in short segments every 293 patient-years (ie, of 293 patients with 1 year of follow-up, 1 willhave progression to esophageal adenocarcinoma). Astudy has demonstrated that the most important riskfactor for predicting neoplastic progression is the degreeof dysplasia and not the length of the Barrett’s esoph-agus segment. Although length was not an independentrisk factor for neoplastic progression, there was a trendtoward significance, suggesting that perhaps this studywas underpowered to address this specific outcome.

26 Esophagus

Because short-segment Barrett’s esophagus is morecommon than long-segment Barrett’s esophagus, theformer is highly relevant from a societal perspective.

Intestinal Metaplasia of the CardiaEsophageal adenocarcinoma is uncommon; approxi-mately 7,000 cases were reported in the United Statesin 2007, at which time the country’s population reached300 million. For the general population, the prevalenceof esophageal adenocarcinoma is 4 per 100,000 personsper year. This rate includes people with undiagnosedBarrett’s esophagus who develop adenocarcinoma.Population follow-up studies of patients with intestinalmetaplasia of the cardia are not available, but the prac-tical conclusion seems clear. If one in five adults hasintestinal metaplasia of the cardia, the risk that a singleperson with this finding will develop adenocarcinomamust be extremely small.

SURVEILLANCEBecause transformation to neoplasia depends more onthe degree of dysplasia than on mucosal length, thecurrent practice in the United States is to offer the samesurveillance regimen to patients with short-segmentor long-segment Barrett’s esophagus. The guidelines ofthe American College of Gastroenterology recommendthat the initial diagnostic endoscopic examination mea-sure the proximal extent of salmon-colored mucosa andthe distal end of the tubular esophagus–proximal extentof the gastric folds. Biopsy specimens are to be collectedfirst from any suspicious lesions, for example, nodules,raised edges of an ulcer, or stricture. Thereafter, biopsyspecimens are to be collected from every quadrant at 2-cm intervals along the length of the segment.

Currently, dysplasia is the best indicator of cancerrisk. Surveillance endoscopy should be recommendedto patients deemed eligible for intervention when anearly lesion is identified. If no dysplasia is found at ini-tial endoscopy, surveillance endoscopy is recom-mended in 1 year to exclude incident cancers or dys-plasia. If no dysplasia is found at this examination, thesurveillance interval can be extended to 3 to 5 years. Ifdysplasia of any degree is identified, with the exceptionof cancer, the Guidelines for the Diagnosis, Surveillance,and Therapy of Barrett’s Esophagus, published in 2008by the American College of Gastroenterology, recom-mend that additional acid-suppressive medicationsbe administered before endoscopy is repeated.

Inflammation commonly causes “reactive atypia,”a cellular response to inflammation that easily canbe overinterpreted as dysplasia. On repeatendoscopy, focused biopsy specimens should becollected from the level at which dysplasia wasdetected initially in addition to the usual four-quadrant biopsy specimens obtained at 2-cm inter-vals for follow-up of low-grade dysplasia or at 1-cmintervals for high-grade dysplasia. The AmericanCollege of Gastroenterology has recommendedconsideration of endoscopic resection of the mucosaof any focal lesion to obtain more tissue for moreaccurate staging of disease. All slides should bereviewed by at least two gastrointestinal patholo-gists who are experts at staging Barrett’s esophagus.

Low-Grade DysplasiaIf low-grade dysplasia is the most severe grade ofdysplasia detected, a change in acid-suppressiveregimen is recommended along with repeatendoscopy in 1 year. If low-grade dysplasia stillpersists, annual surveillance is recommended. Ifthere is no evidence of dysplasia on two annualexaminations, the surveillance endoscopy intervalcan be extended to 3 to 5 years.

High-Grade DysplasiaIf at least two gastrointestinal pathologists agreeon the presence of focal high-grade dysplasia (dys-plasia involving five or fewer crypts), four majoroptions are available: 1) observation; 2) endoscopicmucosal resection, followed by photodynamictherapy; 3) photodynamic therapy alone; and 4)esophagectomy. The option of observation impliesthat the patient’s acid-suppressive regimen willbe altered and endoscopy will be performed every3 months, at which time four-quadrant biopsyspecimens will be collected at 1-cm intervals alongthe entire extent of the Barrett’s segment. The obser-vation option also implies that after frank cancer isfound at biopsy, a more aggressive approach willbe pursued. The American College of Gastro-enterology has less confidence in the safety ofsimple observation for patients with multifocalhigh-grade dysplasia.

For decades, the standard of care for patientswho have Barrett’s esophagus with high-gradedysplasia or early stage I esophageal adenocarci-noma was esophagectomy. Endoscopic mucosal


resection is a technique in which epinephrine isinjected submucosally beneath a nodule to raise itaway from the circular muscle layers of the esoph-agus, thus diminishing the risk of perforation. Thisoption is available for patients with high-gradedysplasia or early cancer in a nodule that is lessthan 2 cm in diameter and T1a (intramucosal) indepth. Endoscopic mucosal resection is commonlyfollowed by photodynamic therapy administeredto the remaining Barrett’s mucosa. In patientswithout a nodular lesion, photodynamic therapyalone is administered. With photodynamictherapy, a systemically administered photosensi-tizer becomes concentrated in Barrett’s mucosaand facilitates cell death when exposed to aparticular wavelength of light administered atendoscopy. In 2007, a prospective cohort studyshowed that the 5-year survival for patients whohad Barrett’s esophagus with high-grade dysplasiaor early stage I cancer was similar whether theyhad photodynamic therapy, with or without endo-scopic mucosal resection, or esophagectomy.Consequently, photodynamic therapy, with orwithout endoscopic mucosal resection, is now con-sidered a standard approach for selected patientswho have Barrett’s esophagus with high-gradedysplasia or early stage T1a (intramucosal) cancer.Because of patient hesitancy, a randomized controlledtrial designed to compare directly endoscopic versussurgical therapy will likely never be performed.

Esophagectomy should be offered to physicallyfit patients. It is still the standard-of-care treatmentoption because it is the only treatment in whichlocoregional lymph nodes are removed. Patientsinterested in pursuing esophagectomy should bereferred to a high-volume center. Perioperativemortality rates for this complex procedure varygreatly, from less than 3% to 20%, depending on theexperience of the center.

Other treatment options under investigationinclude cryotherapy and radiofrequency ablation.However, because of the short-term follow-up ofpatients who have received these treatments, theiruse currently is considered experimental.

ESOPHAGEAL CANCERSquamous cell carcinoma and adenocarcinomaare the most common types of esophageal cancer.

Worldwide, esophageal cancer is the fifth mostcommon type of gastrointestinal malignancy, mostcommonly, squamous cell carcinoma. In the UnitedStates, esophageal cancer is uncommon; approximately14,000 cases are diagnosed annually, and since 2002,slightly more than half of these have been the adeno-carcinoma type. The incidence of esophageal adeno-carcinoma has been increasing exponentially over thepast three decades for reasons that are unclear. Broadlyspeaking, the incidence of esophageal adenocarcinomain the 1970s was 0.4 new cases/100,000 people per year.Currently, the incidence is 4 cases/100,000 people peryear.

The incidence of squamous cell carcinoma in theUnited States is 2.6/100,000 people per year. In certainregions of China and Iran, squamous cell carcinoma isexceedingly common, occurring in 132 /100,000 peopleper year. This is thought to be related to environmentalexposures.

Overall, neoplasms of the esophagus carry a poorprognosis. The 5-year overall survival rate ranges from2% to 26%, depending on the stage at diagnosis.

Risk Factors for Squamous Cell CancerSeveral environmental risk factors are associated withsquamous cell carcinoma, including the following:tobacco, alcohol, nitrosamines (eg, those generated bygrilling meat), drinking scalding hot liquids and causticsubstances (eg, lye), and chronic stasis (eg, that seen inpatients with achalasia). Nutritional deficiencies, suchas deficiency in vitamin C, and previous exposure toradiation, as in the treatment of Hodgkin’s lymphomaor breast cancer, are also risk factors for squamous cellcarcinoma. There is considerable geographic variation,with especially high incidence rates in some parts ofChina, Iran, and Afghanistan. The variation is thoughtmore likely to be due to environmental, not genetic,factors because adjacent communities can have lowincidence rates of cancer. However, several factors raisethe possibility of a genetic component to squamouscell carcinoma, including the higher risk for blacks, orAfrican Americans, than for whites and the strong asso-ciation of squamous cell carcinoma with tylosis and afair association with esophageal lichen planus.

Risk Factors for AdenocarcinomaThe risk factors for esophageal adenocarcinomamirror the risk factors for Barrett’s esophagus, andBarrett’s esophagus is the strongest risk factor for

28 Esophagus


adenocarcinoma. Established risk factors for esophagealadenocarcinoma are advancing age, male sex, chronicreflux of gastric contents into the tubular esophagus,white ethnicity, and obesity. Heartburn and acid regur-gitation, especially if present for more than 12 years, arealso risk factors. The challenge is that 40% of patientswith esophageal adenocarcinoma deny ever experi-encing symptoms of GERD. Therefore, heartburn andacid regurgitation are helpful when present, but thelack of these symptoms does not mean the patient isnot at risk for esophageal cancer.

Signs and Symptoms of Esophageal CancerThe symptoms of esophageal cancer include new onsetof solid food dysphagia that in a short time progressesto include dysphagia to soft solids and then liquids.Odynophagia, or painful swallowing, occurs either byulceration directly from the tumor or secondarily frompill esophagitis. In some patients, the pain radiates tothe midchest or back, especially during meals.Unintentional weight loss is commonly reported withlater-stage disease. Other than the skin changes oftylosis or lichen planus in patients with squamous cellcarcinoma, there are no signs of esophageal cancer. Inmost patients, the physical examination findings arenormal. With late-stage disease or disease of the prox-imal esophagus, supraclavicular lymphadenopathycan be palpated.

Diagnosis and StagingEsophageal cancers are staged to direct managementand to inform prognosis. Two main components mustbe considered in therapeutic decision making: thepatient’s condition and the stage of disease. What isthe patient’s performance status? Is the patient an ade-quate surgical candidate? Does the patient havecomorbid conditions that need to be addressed beforean operation is considered? Is low-molecular-weight

heparin appropriate? Does the patient have severalcomorbid conditions that will sway your recom-mendation away from surgery? Basically, stage isdivided into early curable disease, advanced incur-able disease, or something inbetween (Table 1).

Staging is usually performed in the followingorder: computed tomography (CT) of the chestand abdomen is performed first to screen for dis-tant metastases. If CT findings are negative,positron emission tomography (PET) is recom-mended because it can detect unsuspectedmetastatic disease in 10% to 15% of cases, thusavoiding futile surgery. PET is superior to CT fordetecting distant metastases but is more expen-sive and, hence, performed only if the CT findingsare negative. If distant metastases are not found,the next step is endoscopic ultrasonography forlocoregional staging (Fig. 7). If possible, it is mostefficient to arrange for endoscopic mucosal resec-tion at the time of endoscopic ultrasonography incase the tumor is found to be T1 in depth withoutsuspicious lymphadenopathy. If tumor invasionis more advanced or lymph node involvement isdocumented with fine-needle aspiration, endo-scopic mucosal resection can be cancelled.Mediastinoscopy and laparoscopy are rarely nec-essary to exclude carcinomatosis.

ConsultationsUpon diagnosis of esophageal cancer, consultationsshould be considered with a gastroenterologist,medical oncologist, radiation oncologist, andthoracic surgeon. A team approach helps thepatient learn the most about the disease, prog-nosis, and plethora of treatment options avail-able for the stage of disease in the hope ofachieving the best long-term outcome andoptimal quality of life.

30 Esophagus

Table 1. Disease Extent, Treatment Options Based on Stage, and 5-Year Survival Rates by Stage

Disease TNM Treatment 5-Year survivalextent Stage classification options rate, %

Confined to 0 TisN0M0 a) Photodynamic therapy 90esophageal wall (high-grade b) ± Endoscopic mucosal

dysplasia) resectionc) Esophagectomy

I T1intramucosalN0M0 a) Photodynamic therapyb) ± Endoscopic mucosalresection

c) Esophagectomy

50-70

I T1submucosalN0M0 Esophagectomy

IIA T2-T3N0M0 Esophagectomy

Local lymph IIB T1-T2N1M0 a) Definitive combinationnode III T3N1M0 chemotherapy withinvolvement T4N0M0 or radiotherapy

T4N1M0 b) Neoadjuvant combinationchemoradiation therapy 10-33with restaging; if distantmetastases are notdemonstrated thereafter,esophagectomy

Celiac or IVA TanyNanyM1a If in otherwise good health, <5supra- consider definitiveclavicular combination chemotherapylymph node with radiotherapyinvolvement

Distant IVB TanyNanyM1b Palliation <2metastases

RECOMMENDED READINGAbrams JA, Fields S, Lightdale CJ, Neugut AI. Racial

and ethnic disparities in the prevalence of Barrett’sesophagus among patients who undergo upperendoscopy. Clin Gastroenterol Hepatol. 2008Jan;6:30-4. Epub 2007 Dec 11.

Conio M, Cameron AJ, Romero Y, Branch CD, SchleckCD, Burgart LJ, et al. Secular trends in the epi-demiology and outcome of Barrett’s oesophagusin Olmsted County, Minnesota. Gut. 2001;48:304-9.

Dulai GS, Guha S, Kahn KL, Gornbein J, WeinsteinWM. Preoperative prevalence of Barrett’s esoph-agus in esophageal adenocarcinoma: a systematicreview. Gastroenterology. 2002;122:26-33.

Hassall E, Kerr W, El-Serag HB. Characteristics of chil-dren receiving proton pump inhibitors continu-ously for up to 11 years duration. J Pediatr.2007;150:262-7, 267.e1.

Lagergren J, Bergstrom R, Lindgren A, Nyren O.Symptomatic gastroesophageal reflux as a riskfactor for esophageal adenocarcinoma. N EnglJ Med. 1999;340:825-31.

Prasad GA, Wang KK, Buttar NS, Wong Kee SongLM, Krishnadath KK, Nichols FC 3rd, et al.Long-term survival following endoscopic andsurgical treatment of high-grade dysplasia inBarrett's esophagus. Gastroenterology2007;132:1226-33. Epub 2007 Feb 7.

Sharma P, McQuaid K, Dent J, Fennerty MB,Sampliner R, Spechler S, et al; AGA ChicagoWorkshop. A critical review of the diagnosisand management of Barrett’s esophagus: theAGA Chicago Workshop. Gastroenterology.2004;127:310-30.

Spechler SJ. Clinical practice: Barrett’s esophagus.N Engl J Med. 2002;346:836-42.


T and N T1

T2

T3 T4 T1

Fig. 7. T and N staging of high-grade dysplasia and esophageal cancer. HGD, high-grade dysplasia. (Courtesy of Dr.Thomas Rice, Thoracic and Cardiovascular Surgery, Cleveland Clinic.)

Vakil N, van Zanten SV, Kahrilas P, Dent J, JonesR; Global Consensus Group. The Montreal def-inition and classification of gastroesophagealreflux disease: a global evidence-based con-sensus. Am J Gastroenterol. 2006;101:1900-20.

Wang KK, Sampliner RE, Practice ParametersCommittee of the American College ofGastroenterology. Updated guidelines 2008 for thediangosis, surveillance and therapy of Barrett’sesophagus. Am J Gastroenterol. 2008;103:788-97.

32 Esophagus

33

CHAPTER 3

Normal and AbnormalEsophageal Motility

Amindra S. Arora, MBBChirNicholas J. Talley, MD, PhD

Swallowing is a complex neuromuscular processthat depends on motor and sensory innervation.The oropharyngeal phase of swallowing is undervoluntary control. However, once the bolus hasbeen moved into the pharynx, the process becomesinvoluntary, with the initiation of an integratedpattern of esophageal motor activity. Difficultyswallowing (dysphagia) can occur when the neu-romuscular process is interrupted.

ANATOMYShaped like a funnel, the elastic pharynx joins themouth to the esophagus and trachea. The upperesophagus consists of striated muscle. The upperesophageal sphincter (UES) consists of the cricopha-ryngeus muscle. The esophagus is a relativelysimple neuromuscular tube that contains an innercircular layer of muscle and an outer longitudinallayer of muscle. Approximately at the level of theaortic arch, which is 22 to 24 cm from the incisors,the striated muscle begins to be replaced bysmooth muscle in the transition zone. The lower50% of the esophagus consists entirely of smoothmuscle. A ring of thickened smooth muscle at theesophagogastric junction marks the lower

esophageal sphincter (LES). Between swallows, theUES and LES protect from esophagopharyngealand gastroesophageal reflux, respectively, becausethey keep the esophageal lumen closed.

Swallowing PhysiologyAfter the lips are closed and the teeth areclenched, the tongue is elevated, anteriorly toposteriorly, against the palate, forcing the bolusto the pharynx. This initial process is under con-scious control. However, entry of the bolus intothe pharynx triggers the swallowing reflex, whichis involuntary. The soft palate is elevated againstthe posterior pharyngeal wall, thus sealing theoropharynx and nasopharynx, and the larynx iselevated and the laryngeal inlet is closed, thuspreventing aspiration. The long axis of thepharynx shortens, removing the recesses formedby the piriform sinuses, valleculae, and laryngealvestibule. Passage of the bolus stimulates the peri-staltic contraction of the pharyngeal muscles. Asperistaltic contraction approaches the cricopha-ryngeus muscle, the muscle relaxes and the larynxis elevated, actively pulling open the UES. As thecontraction passes, the UES closes tightly. As theUES opens, the LES relaxes and remains relaxed

Abbreviations: GERD, gastroesophageal reflux disease; LES, lower esophageal sphincter; UES, upper esophageal sphincter.

until the bolus has entered the stomach, at whichtime the LES closes.

Relaxation of the LES occurs through therelease of nitric oxide from myenteric neurons thatinnervate the LES. Myenteric neurons are alsoimportant in maintaining the resting basal tone ofthe upper esophagus. Peristaltic contractions areunder local control of the myenteric plexus. Therelease of acetylcholine (excitatory effect) and nitricoxide (inhibitory effect) from neurons that supplythe circular smooth muscle are involved in thisprocess, which is activated by swallowing.

The smooth muscle of the esophagus is inner-vated by axons of cranial nerve X (vagus nerve)that originate in the dorsal motor nucleus of thevagus and synapse on myenteric plexus neuronsin the esophagus. The striated muscle of thepharynx, the UES, and striated muscle in the prox-imal esophagus are innervated by cranial nerves IX(glossopharyngeal nerve) and X.

OROPHARYNGEAL DISORDERSDisease that affects striated muscle causes oropha-ryngeal motor dysfunction and oropharyngealdysphagia. These disorders can occur at the levelof the muscle, the peripheral nerves, or the centralnervous system.

To diagnose oropharyngeal dysphagia, considerthe following important hints from the history:

• True dysphagia is present• Food bolus transfer from the pharynx or

hypopharynx is impaired (difficulty starting toswallow, food caught in the throat, unusualhead or neck maneuvers during swallowing)

• Nasopharyngeal regurgitation is common (regur-gitation of swallowed liquids through the nose)

• Aspiration is common (coughing or choking whenswallowing, difficulty breathing when eating)

Neurologic disease can cause oropharyngealincoordination, whereas muscle disease can resultin weak pharyngeal contractions. The causes oforopharyngeal dysphagia are listed in Table 1.

InvestigationsOropharyngeal dysphagia is assessed best withvideofluoroscopy. For this test, patients swallow

boluses of different texture. Ideally, the test shouldbe conducted with the assistance of a speechpathologist working with a radiologist. The fol-lowing can be identified with videofluoroscopy:

• An uncoordinated tongue, which will impairtransmission of the bolus

• Soft palate dysfunction, which can lead tonasopharyngeal regurgitation

• Poor laryngeal closure, which can lead to aspiration

• Poor pharyngeal peristalsis, which results inresidue in the valleculae or piriform sinuses

Identifying the presence of a cricopharyngealbar is important. This is an indentation of thecricopharyngeal muscle that is seen as bariumpasses by slowly and the muscle relaxes poorlyduring swallowing. A cricopharyngeal bar can bethe primary cause of oropharyngeal dysphagia inthe absence of other neuromuscular disease, butthe latter must be excluded. It is important to lookfor a pharyngeal or esophageal diverticulum(Zenker’s diverticulum). This diverticulum is theresult of abnormal opening of the UES and can bedue to localized muscle disease. Most patients whopresent with Zenker’s diverticulum are older than50 years.

The presence of Zenker’s diverticulumincreases the risk of perforation by esopha-gogastroduodenoscopy or nasogastric tube

34 Esophagus

Table 1. Causes of Oropharyngeal Dysphagia

Brain—cerebrovascular accident, head injury,Parkinson’s disease, brainstem disease,multiple sclerosis, motor neuron disease,phenothiazines

Muscle or nerve—dermatomyositis,poliomyelitis, muscular dystrophies,myasthenia gravis

Cricopharyngeal dysfunctionInadequate opening from fibrosis resultingin Zenker’s diverticulum

Reduced muscle compliance leading to a cricopharyngeal bar

placement, so it is important that intubation beperformed under direct vision if the history issuggestive of oropharyngeal dysphagia. This isanother reason videofluoroscopy should be theinitial test of choice.

Computed tomography of the neck can behelpful for excluding rare structural causes oforopharyngeal dysphagia, such as malignancy orcervical osteophytes. An ears-nose-throat evalua-tion may detect malignancy missed by other testsif the diagnosis is unclear. Esophageal manometryhas a limited role and is generally unhelpful.

TreatmentThe underlying neuromuscular disease, if present,should be treated. Speech therapy can be useful;learning new swallowing maneuvers can aid theprocess despite underlying abnormalities. If mal-nutrition is an issue and the patient has noimprovement with speech therapy, placement of apercutaneous endoscopic gastrostomy tube shouldbe considered. If Zenker’s diverticulum is present,surgical diverticulectomy with UES myotomy isthe treatment of choice. Endoscopic myotomy isan alternative to surgery; also, botulinum toxincan be injected into the UES.

ESOPHAGEAL DISORDERSDisorders of esophageal motility can be identi-fied with manometry. An example of a normalmanometric recording of primary peristalsis isshown in Figure 1. After a water swallow, peri-staltic progression occurs at a rate of 2 to 8 cmper second, followed by complete relaxation ofthe LES. The LES is tonically closed at rest, witha normal mean pressure of 20 mm Hg (range, 10-45 mm Hg). However, a water swallow can altersubsequent swallows for up to 20 to 30 seconds,so it is important to note the time intervalsbetween the water swallows provided on atracing. The normal distal wave amplitude is 30to 180 mm Hg.

Clinical AssessmentClassically, patients with esophageal motility dis-orders present with dysphagia for both liquids andsolids. Symptoms typically are intermittent. Chestpain is common.

Classification of Esophageal MotilityDisordersA classification of esophageal motility disordersis summarized in Table 2.

Normal and Abnormal Esophageal Motility 35

Fig. 1. Normal esophageal motor function.Manometric recording of normal esophagealperistalsis and relaxation of the lower esophagealsphincter (LES). The most distal sensor (bottomtrace) is in the LES, which is defined as a region ofincreased pressure near the gastroesophagealjunction that decreases with swallowing. Aperistaltic sequence is recorded in the sensors abovethe LES. WS, occurrence of a wet swallow.

Table 2. Esophageal Motility Disorders

Inadequate LES relaxation: achalasia(aperistalsis), atypical disorders

Uncoordinated contractions: diffuse esophagealspasm

Hypercontractile: nutcracker esophagus,isolated hypertensive LES

Hypocontractile: ineffective motility(nonspecific motility disorder)

LES, lower esophageal sphincter.

From Spechler SJ, Castell DO. Classification of

oesophageal motility abnormalities. Gut. 2001;49:145-

51. Used with permission.

Achalasia

DefinitionUnlike most esophageal motility disorders, acha-lasia is a well-accepted neuropathic disease.Achalasia literally means “failure to relax.” Its pri-mary features are failure of peristalsis and failureof relaxation or incomplete relaxation of the LES.

PathophysiologyThe hallmark pathologic feature of achalasia is adecreased number of nonadrenergic, noncholinergicinhibitory ganglion cells. The cause of achalasia isunknown. Infection, especially varicella-zoster virus,has been implicated. A similar disease pathologi-cally is Chagas’ disease, which is due to infectionby Trypanosoma cruzi. In Chagas’ disease, a parasiticantigen that is similar to a protein on myentericneurons produces an immunologic attack againstthe myenteric plexus.

Achalasia has a possible genetic component.Myenteric neuronal antibodies have been identifiedin up to 60% of patients with achalasia. However,whether this is an epiphenomenon or is causallyrelated to the disease is unclear.

Clinical PresentationAny age group can be affected by achalasia, but ittypically occurs in the third to fifth decades. Menand women are affected equally. Often, there is along history before the correct diagnosis is made.Virtually all patients have dysphagia for solids,and two-thirds of them have dysphagia for liquids.The dysphagia typically fluctuates, which is a hint.Regurgitation occurs in 60% to 90% of patients.Heartburn is common, not only from acid refluxbut also from fermentation of food in the aperi-staltic esophagus. Approximately one-third ofpatients report chest pain, although the mechanismis unclear. Weight loss may occur. Patients may havecough and pulmonary symptoms from aspiration.

DiagnosisBarium swallow with fluoroscopy is an excellentscreening test for achalasia. If the classic bird’sbeak appearance with a dilated esophagus is seenand typical symptoms are present, the diagnosis ofachalasia is virtually certain (Fig. 2). However,pseudoachalasia needs to be actively excluded.

Manometrically, aperistalsis occurs with incompleteor failed relaxation of the LES after a swallow (Fig.3). Increased LES pressure is common but not diag-nostic. Low-amplitude simultaneous contractions

36 Esophagus

Fig. 2. Barium swallow study in a patient withachalasia. Note the dilated esophagus and tapering(“bird’s beak”) (arrow) at the gastroesophageal junction.

X4

50

50

50

50

50

0

0

0

0

0

0

50

LES

WS

15 sec6:30.0

Pre

ssur

e, m

m H

g

Fig. 3. Manometric recording from a patient withclassic achalasia. The most distal sensor (bottomtrace) is in the lower esophageal sphincter (LES).Note that the LES does not relax with wet swallows(WS). Wet swallows do not produce peristalticpressure waves in the esophagus; instead, there arelow-amplitude, simultaneous pressure waves with anearly identical configuration.

may be seen. Intraesophageal pressure usually isincreased because the esophagus is behaving as acommon cavity. Consider the esophagus as thoughit were a sausage-shaped balloon filled with eitherliquid or air and containing a manometry catheter.If you squeeze the balloon anywhere (withoutblocking the lumen), an increase in pressure will berecorded nearly everywhere simultaneously in theballoon. In vigorous achalasia, simultaneous repet-itive high-amplitude contractions occur in theesophagus. However, this manometric change doesnot have any clear clinical correlate.

Differential DiagnosisIt is essential to exclude malignancy-causingpseudoachalasia. This can occur from infiltrationof the neural plexus directly by tumor, from alarge constricting mass in the esophagus, or,rarely, from antineuronal nuclear autoantibodies,for example, as in a paraneoplastic syndrome,often in association with small cell lung cancer.Manometry cannot distinguish between pseudo-achalasia and achalasia. Although presentationat older age, short duration of symptoms, andrapid weight loss all suggest pseudoachalasia,the history alone is insufficient for making thediagnosis. Endoscopy is essential in examiningfor evidence of malignancy. Other conditionsthat can cause pseudoachalasia include amyloi-dosis, sarcoidosis, postvagotomy, chronicintestinal pseudo-obstruction, neurofibromatosis,and even pancreatic pseudocyst.

ManagementThe four major options for management are drugs,botulinum toxin, pneumatic dilatation, and sur-gical myotomy.

DrugsAll drugs for achalasia have very limited effi-cacy. Nifedipine (10-30 mg), a calcium channelantagonist, was shown in a small crossover trialof 10 patients to reduce dysphagia and LES pres-sure in achalasia, although the overall resultswere not impressive. Sublingual isosorbide dini-trate (a nitric oxide donor) can relax the LES.Sildenafil (which increases cyclic guanosinemonophosphate) also may have some benefit forLES relaxation.

Botulinum ToxinInjection of botulinum toxin into the LES is effective.The toxin binds to the presynaptic cholinergicreceptors and inhibits the release of acetylcholinefrom the presynaptic terminals of the neuromus-cular junctions. The injection decreases LES pres-sure by more than 30% and induces a clinicalresponse in 60% to 75% of patients. However,symptoms usually recur within 3 to 12 months,leading to the need for repeated injections.Furthermore, antibodies develop against the bot-ulinum toxin, usually resulting in its loss of efficacy.Although botulinum toxin can cause fibrosis, pain,or rash after injection, it generally is well tolerated.This treatment is not a contraindication to surgeryeven though it potentially can cause tissue reac-tions that obscure fascial planes. Botulinum toxinis a useful option for “buying time” in achalasia, ifthis is needed. It is the optimal approach for frailelderly patients who are not candidates for surgeryor pneumatic dilatation.

Pneumatic DilatationPneumatic dilatation has more than a 60% and upto a 90% good response rate in achalasia. Theforceful dilatation disrupts the LES, and this isbelieved to be the mechanism producing the ben-efit. If patients do not have a response to a seconddilatation, they are less likely to have a responseto additional dilatations, but some physiciansattempt pneumatic dilatation one more time afterother options have been discussed with the patient.The response tends to be better in patients who areolder and have a long history of achalasia. Thepoorest response occurs if patients are youngerthan 40 years and the postdilatation LES pressureis more than 20 mm Hg.

Treatment should begin with the smallest (3-cm diameter) achalasia balloon (eg, MicrovasiveRigiflex). The dilatation should be performedunder fluoroscopic guidance. The balloon shouldbe inflated gradually until the indentation at theesophagogastric junction is obliterated (7-10 psi)for 60 seconds. If dysphagia has not improved in 4to 8 weeks, then a 3.5-cm balloon should be used.The largest balloon is 4 cm.

A major disadvantage of pneumatic dilatationis the risk of complications. The reported rate ofesophageal perforation is approximately 3%, with


one-half of the patients requiring surgical repair.The overall procedure mortality rate is less than0.5%. Because of this risk, it is important to givewater-soluble contrast after dilatation and observepatients for 6 hours before discharge. Small con-tained perforations can be treated conservativelyby not allowing any oral intake and administeringantibiotics and by close observation with a sur-gical colleague. Gastroesophageal reflux disease(GERD) can develop after pneumatic dilatation(3%-15% of patients). After a patient has pneu-matic dilatation, annual quantitative bariumesophageal studies can be useful to quantifyesophageal emptying.

Standard bougienage has been compared withpneumatic dilatation in a study of 18 patients withChagas’ disease. The results suggested that dilata-tion of the esophagus by bougienage has no long-term value, although patients may report briefimprovement of symptoms.

Surgical Myotomy, Open or LaparoscopicCurrently, laparoscopic surgical myotomy is theprocedure of choice. The previous use of botu-linum toxin or pneumatic dilatation is not a con-traindication to surgery. Data suggest that patientshave the best symptom response rate (90%) anddurability with surgery. Postoperatively, up toone-half of patients may require acid suppressionfor GERD.

If dysphagia recurs after being treated suc-cessfully with pneumatic dilatation or surgery, theliterature provides little guidance about the optimalnext step in management. However, pneumaticdilatation or repeat myotomy can be performedafter myotomy fails, with a success rate better than50%. In very severe disease unresponsive to all theabove-mentioned approaches, esophagectomy isthe only option.

Long-term OutcomePatients with achalasia have a slight increase inthe risk of squamous cell carcinoma. However,routine surveillance is not standard practice. Ifnew or worsening dysphagia develops in apatient who has a history of achalasia, upperendoscopy should be repeated. Aspirationpneumonia is a well-recognized complicationof achalasia.

Esophageal Spastic Disorders

Diffuse Esophageal SpasmThis is a relatively rare disease, and the manometricfindings correlate poorly with symptoms.Approximately 3% to 10% of patients with non-cardiac chest pain or unexplained dysphagia mayhave esophageal spasm. In about 3% to 5% ofpatients, esophageal spasm progresses to achalasia.Diffuse esophageal spasm may improve sponta-neously in some patients during follow-up.Whether esophageal spasm results from an imbal-ance of inhibitory and excitatory motor innervationof the esophagus is unclear.

The esophagogram may be abnormal (Fig. 4),but manometry is usually required to make thediagnosis. The manometric definition of esophagealspasm is that more than 30% of wet swallows havesimultaneous pressure waves (Fig. 5). A prolongedpressure wave (>6 seconds) of the wet swallow,normal peristalsis, and normal relaxation of theLES support the diagnosis. Vigorous achalasia is acombination of diffuse esophageal spasm andfailure of the LES to relax.

Nutcracker EsophagusThis manometric condition is characterized by high-pressure (>180 mm Hg) peristaltic contractions.

38 Esophagus

Fig. 4. Barium swallow study in a patient with diffuseesophageal spasm. Note the irregular border of theesophagus (“corkscrew esophagus”), suggestinguncoordinated contractile activity.

Importantly, the peristaltic contractions propagatenormally in the esophagus; also, the LES relaxes nor-mally. It is unclear whether this is a “real” disease.

TreatmentIn a crossover study of 22 patients with nutcrackeresophagus, diltiazem (60-90 mg 4 times daily)versus placebo was tested. Diltiazem significantlylowered mean distal esophageal peristaltic pres-sure compared with placebo and also had a ten-dency to reduce chest pain scores, but the resultswere not impressive. Use of other therapies foresophageal spastic disorders is largely anecdotal.Nitrates and sildenafil may provide some benefit.Tricyclic antidepressants may reduce noncardiacchest pain, but this is irrespective of the underlyingmanometric findings (which may reflect that themanometric findings are irrelevant). In uncontrolledstudies, botulinum toxin has been helpful.

Spastic esophageal disorders can be triggeredby underlying GERD. Thus, aggressive treatmentof documented gastroesophageal reflux is reason-able. Pneumatic dilatation of the esophagus has notbeen shown to improve diffuse esophageal spasm.Long myotomy for refractory diffuse esophagealspasm is effective in 50% to 70% of patients.

Hypomotility of the EsophagusThis is characterized by a decreased or absentresting LES and reduced or absent peristaltic wavepressures. Sometimes it is difficult to distinguishbetween esophageal hypomotility and achalasia.

Scleroderma and other connective tissue diseasescan present with esophageal hypomotility (Fig. 6).Muscular dystrophies and familial visceralmyopathies also may present in this way.

Nonspecific Esophageal Motor AbnormalityIn the esophageal manometry laboratory, about one-half of the patients with dysphagia have nonspecificmotor abnormalities, which may or may not occur inrelation to reflux disease. These abnormalities arenot associated with dysphagia and are not specific.Diseases such as diabetes mellitus, amyloidosis, orhypothyroidism can be associated with a nonspe-cific esophageal motor abnormality.

Eosinophilic EsophagitisPatients presenting with unexplained solid-fooddysphagia or intermittent food impaction may haveeosinophilic esophagitis. This is most common inyoung, typically male patients who do not havesymptoms of GERD. Endoscopic examination mayshow a corrugated (“ringed”) esophagus, particu-larly in the proximal middle esophageal region.Increased intraepithelial eosinophils (>20/high-power field) are seen in biopsy specimens. There areno distinct underlying esophageal motility find-ings, although abnormalities may be seen onmanometry. Many adult patients have a response


X1

100

100

100

100

100

0

0

0

0

0

0

100

Pre

ssur

e, m

m H

g

WS

WS

30 sec14:29.4

LES

Fig. 5. Manometric recording from a patient withdiffuse esophageal spasm. The most distal sensor(bottom trace) is in the lower esophageal sphincter(LES). WS, occurrence of a wet swallow.

Fig. 6. Manometric recording from a patient withscleroderma. The most distal sensor (bottom trace) isin the lower esophageal sphincter (LES). Typicalmanometric findings of scleroderma include low-amplitude or absent peristaltic pressure waves in thesmooth muscle part of the esophagus and a low-pressure LES. Generally, the striated muscle part ofthe esophagus (top trace) functions normally. WS,occurrence of a wet swallow.

to corticosteroids applied topically for 6 weeks.Montelukast also has been used successfully.

Post-Fundoplication Motor DisordersSeveral abnormalities are detected with esophagealmanometry after fundoplication. The resting LESpressure may be higher than normal or the LES maynot relax normally in response to swallowing. Also,the intrabolus pressure may increase just before theperistaltic pressure wave (“proximal escape”) (Fig.7). Dilatation of the esophagus for persistent dys-phagia after fundoplication can be helpful.

SUMMARYGenerally, asymptomatic esophageal manometricfindings should be ignored. Achalasia is the bestestablished esophageal motility disorder. Mostother esophageal motility disorders have ques-tionable associations with clinical presentations.GERD is a common cause of dysphagia, and thiscan be secondary to motor dysfunction. Disordersof the UES produce oropharyngeal dysphagia,which clinically is quite distinct from the symptomsof distal esophageal motor disorders. An algorithmfor assessing dysphagia is given in Figure 8.

40 Esophagus

100

050

050

050

050

050

0

Pre

ssur

e, m

m H

g

WS

15 sec

Distance from

nares

LES

18 cm

23 cm

28 cm

33 cm

38 cm

43 cm

Fig. 7. Manometric recording from a patient withNissen fundoplication. All the sensors are within theesophagus. Note that in the distal esophagus thepressure waves are biphasic. The first pressure wave(arrow) is the pressure in the bolus, preceding theperistaltic contraction; this is the intrabolus pressure.The second is the pressure wave accompanying theperistaltic contraction. Normally, the intraboluspressure is seen during esophageal manometry, but it isof lower amplitude. The intrabolus pressure in thisexample is increased because of the distal esophagealobstruction produced by a tight fundoplication. LES,lower esophageal sphincter; WS, occurrence of a wetswallow.

History/examination

“Probably pharyngeal” “Probably esophageal”

Clear clinical setting No apparent cause or Suspect dysmotility Suspect structural(eg, acute onset with stroke) suspected malignancy or ring cause (eg, stricture)

VIDEOSWALLOW VIDEOSWALLOW Normal ENDOSCOPY

Abnormal Normal Esophageal Probable Normal Abnormalring dysmotility

Confirm motordysfunction &

define mechanismsNormal

Normal Structural lesion(ie, motor (cancer, web,disorder) stricture, pouch)

Abnormal

Therapy Normal Cancer Surgery

ENDOSCOPICDILATATION/BIOPSY

ESOPHAGEALMANOMETRY

ENT EXAMINATION(laryngoscopy)

ESOPHAGOGRAM

ENDOSCOPYENDOSCOPY

DYSPHAGIA

Fig. 8. Management of dysphagia. ENT, ears-nose-throat. (Modified from Cook IJ. Difficulty swallowing andpain on swallowing. In: Talley NJ, Martin CJ, editors. Clinical gastroenterology: a practical problem-basedapproach. 2nd ed. Sydney (Australia): Elsevier; 2006. p. 20-35. Used with permission.)

RECOMMENDED READINGAnnese V, Bassotti G, Coccia G, Dinelli M,

D’Onofrio V, Gatto G, et al. A multicentre ran-domised study of intrasphincteric botulinumtoxin in patients with oesophageal achalasia:GISMAD Achalasia Study Group. Gut.2000;46:597-600.

Arora AS, Yamazaki K. Eosinophilic esophagitis:asthma of the esophagus? Clin GastroenterolHepatol. 2004;2:523-30.

Cook IJ. Treatment of oropharyngeal dysphagia. CurrTreat Options Gastroenterol. 2003;6:273-81.

Furuta GT, Liacouras CA, Collins MH, Gupta SK,Justinich C, Putnam PE, et al; First InternationalGastrointestinal Eosinophil Research Symposium(FIGERS) Subcommittees. Eosinophilicesophagitis in children and adults: a systematicreview and consensus recommendations for diag-nosis and treatment. Gastroenterology.2007;133:1342-63. Epub 2007 Aug 8.

Mikaeli J, Fazel A, Montazeri G, Yaghoobi M,Malekzadeh R. Randomized controlled trial com-paring botulinum toxin injection to pneumaticdilatation for the treatment of achalasia.Aliment Pharmacol Ther. 2001;15:1389-96.

Pandolfino JE, Kahrilas PJ; AmericanGastroenterological Association. AGA technicalreview on the clinical use of esophageal manom-etry. Gastroenterology. 2005;128:209-24.

Spechler SJ, Castell DO. Classification ofoesophageal motility abnormalities. Gut.2001;49:145-51.

Sperandio M, Tutuian R, Gideon RM, Katz PO,Castell DO. Diffuse esophageal spasm: not dif-fuse but distal esophageal spasm (DES). DigDis Sci. 2003;48:1380-4.

Straumann A, Spichtin HP, Grize L, Bucher KA,Beglinger C, Simon HU. Natural history of pri-mary eosinophilic esophagitis: a follow-up of 30adult patients for up to 11.5 years.Gastroenterology. 2003;125:1660-9.

Vela MF, Richter JE, Khandwala F, Blackstone EH,Wachsberger D, Baker ME, et al. The long-termefficacy of pneumatic dilatation and Hellermyotomy for the treatment of achalasia. ClinGastroenterol Hepatol. 2006;4:580-7.

Vela MF, Richter JE, Wachsberger D, Connor J,Rice TW. Complexities of managing achalasiaat a tertiary referral center: use of pneumaticdilatation, Heller myotomy, and botulinumtoxin injection. Am J Gastroenterol.2004;99:1029-36.

Williams RB, Grehan MJ, Hersch M, Andre J,Cook IJ. Biomechanics, diagnosis, and treat-ment outcome in inflammatory myopathypresenting as oropharyngeal dysphagia. Gut.2003;52:471-8.


43

Esophagus

Questions and Answers

QUESTIONS

Abbreviations used:CT, computed tomographyEGD, esophagogastroduodenoscopyGERD, gastroesophageal reflux diseaseLES, lower esophageal sphincterPET, positron emission tomographyPPI, proton pump inhibitor

Multiple Choice (choose the best answer)1. During an endoscopic examination to evaluate

diarrhea in a 63-year-old man, mild LosAngeles Classification System Grade A refluxesophagitis, small hiatal hernia, and a 2-cmsegment of Barrett’s esophagus with low-grade dysplasia were diagnosed. He is referredto you for management. He has researchedBarrett’s esophagus on the Internet and is veryunhappy with the diagnosis of a premalignantdisorder. He requests an intervention to pre-vent the progression to cancer. He states thathe has not experienced heartburn, acid regur-gitation, dysphagia, and unintentional weightloss. You recommend:

a. PPI therapy for 6 months before repeatendoscopy

b. Surveillance endoscopy in 6 monthsc. Photodynamic therapyd. Fundoplicatione. Esophagectomy

2. A 75-year-old male swimmer with a 10-cmsegment of Barrett’s esophagus is found atsurveillance endoscopy to have a 3-cm area ofnodularity at the proximal aspect of theBarrett’s segment. Six biopsy specimens fromthe nodular region show high-grade dysplasia,as confirmed by two gastrointestinal pathol-ogists. Biopsy specimens from the remainingBarrett’s segment show high-grade dysplasiaat the most distal aspect. Otherwise, biopsyspecimens show diffuse low-grade dysplasia.He has been taking a PPI for 7 years and issymptomatically well. Chest and abdominalCT scans are without lymphadenopathy.There are no suspicious lesions in the lungsor liver. The results of cardiac stress testingare normal. Both of the patient’s parents livedwell into their 90s, and he has always plannedto do the same. For treatment, you recommend:

a. Alteration of the PPI regimen, followed byrepeat EGD in 3 months, with four-quadrantbiopsy specimens collected every 1 cm

b. Endoscopic mucosal resectionc. Endoscopic mucosal resection, followed by

photodynamic therapyd. Photodynamic therapye. Esophagectomy

3. Because of a family history of Barrett’s esoph-agus, a 67-year-old white man with rare GERDsymptoms of 20 years’ duration presents for

endoscopy. He states that he does not havedysphagia or unintentional weight loss. Atupper endoscopy, he is found to have a 5-cmsegment of Barrett’s esophagus, with a 2-cmpolypoid nodule present at the proximalaspect of the segment. Biopsy results showadenocarcinoma. He has stable coronary arterydisease and hypertension. CT of the chest andabdomen and PET findings are negative fordistant metastases. Endoscopic ultrasonographyshows the lesion to be T2N0. You recommend:

a. Endoscopic mucosal resection with photo-dynamic therapy

b. Esophagectomyc. Neoadjuvant combination chemoradiation

therapy, followed by esophagectomyd. Esophagectomy, followed by adjuvant

chemotherapye. Definitive combination chemoradiation

therapy

4. A 50-year-old African American woman hasrheumatoid arthritis, class IV ischemic car-diomyopathy, and rheumatoid restrictive pul-monary disease requiring nocturnal oxygensupplementation. She informs her rheuma-tologist that her weekly heartburn and rarenocturnal regurgitation of 20 years’ durationhave worsened over the past 2 months. Shehas new nonspecific substernal chest pain withmild odynophagia. She states that she doesnot have dysphagia, impaction, or uninten-tional weight loss. She is a nonsmoker. She hastaken famotidine at bedtime for 10 years. Nochanges have been found in her cardiac status.Her rheumatologist refers her to you. She hasnever had EGD. You recommend:

a. Upper gastrointestinal barium swallowb. Esophageal capsule study

c. EGDd. Empiric treatment with a PPIe. Surgical consultation

5. One month ago, during upper endoscopyperformed to investigate iron deficiencyanemia, Barrett’s esophagus of unknownlength was diagnosed in a 35-year-oldwoman who did not have heartburn, acidregurgitation, dysphagia, or upper respira-tory tract symptoms. She has been referredto you for management. The slides havebeen reviewed by your pathologist, whoconfirms the presence of intestinal meta-plasia with goblet cells, without dysplasia.You recommend:

a. A prescribed PPIb. An over-the-counter PPIc. Fundoplicationd. Repeat endoscopy nowe. Repeat endoscopy in 1 year

6. A 62-year-old woman with intermittent chestpains and dysphagia comes to your officewith a report from an outside institution,following an esophageal motility test. Thetest report is as follows: “The loweresophageal sphincter pressure was elevatedat 52 mm Hg (normal 10-45) and, after wetswallows, there was a failure of completerelaxation to the gastric baseline.” Five ofthe 10 wet swallows were peristaltic and fivewet swallows were simultaneous. What isthe most likely diagnosis?

a. Sclerodermab. Achalasiac. Diffuse esophageal spasmd. Nutcracker esophaguse. Nonspecific motility disorder

44 Esophagus

7. A 42-year-old man with a 7-year history of regur-gitation and heartburn has come to you becauseof worsening symptoms. He describes difficultygetting food down (both liquids and solids). Also,when he bends down, he occasionally regurgi-tates all food. He has had to elevate the head ofhis bed. A barium swallow study was performed.

The most likely diagnosis is:

a. Sclerodermab. Achalasiac. Diffuse esophageal spasmd. Nutcracker esophagus

8. A 52-year-old man has at least a 6-month historyof progressive dysphagia. He has difficulty swal-lowing both liquids and solids. On physicalexamination, some fasciculation of the tongueis noted. The most appropriate test to order toevaluate this man’s dysphagia would be:

a. EGDb. Video swallowc. Esophageal manometryd. Ambulatory 24-hour pH testing

9. A 62-year-old man has come to discuss man-agement options for his achalasia. He has hadsymptoms of regurgitation for several years,but has not lost much weight during this time.He has not had pneumonia. A barium swallowstudy was performed.

The most appropriate therapy for this manwould be:

a. Injection of botulinum toxinb. Pneumatic dilatation c. Medical therapy with nitrates and calcium

channel blockers before mealsd. Diverticulectomye. Heller myotomy with diverticulectomy

Questions and Answers 45

Question 7Question 9

10. A 32-year-old woman has had heartburn for the last 2 years. She regularly hasregurgitation when she bends down. Also, she has dysphagia for liquids andsolids. She has had minimal weight loss. The findings of upper endoscopywere unremarkable. An esophageal motility study was performed.

46 Esophagus

Question 10

Lower esophagealsphincter

Body of theesophagus

The most appropriate therapy for this woman’s condition would be:

a. Injection of botulinum toxinb. Endoscopic dilatationc. Medical therapy with double-dose antisecretory therapy and elevation of

the head of the bed d. Heller myotomye. Laparoscopic Nissen fundoplication

11. A 23-year-old woman has experienced substernal and epigastric burning sen-sation as well as postprandial bloating for the past 2 to 3 years. She has not hada response to trials of antacids or H2 blockers, and she is referred to you for con-sultation. She has no alarm features such as bleeding or dysphagia. Findingson upper endoscopy are negative. An ambulatory pH study shows 14episodes of acid reflux, which occurred during 1.2% of the total study time.Of the 14 reflux episodes, 5 were correlated with symptoms of epigastricburning sensation. Treatment with PPIs at the standard dose once daily andthen twice daily has not led to any appreciable improvement in her symp-toms. What is the appropriate next step?

a. Continue PPI twice daily and repeat endoscopy in 1 year to survey forBarrett’s esophagus

b. Refer patient for antireflux surgeryc. Double the dose of PPId. Begin a trial with amitriptyline e. Perform esophageal manometry


Question 12 Manometric recording

12. A 48-year-old man presents with a 4-year history of dysphagia. His symp-toms began insidiously but have now progressed to the point that he hastrouble swallowing at every meal and has difficulty with liquids as well assolids. He has a sense that food sits in his chest. If he interrupts his meal andwaits, the food often passes down into his stomach, particularly after hedrinks a large amount of water. However, he has been noticing somenasopharyngeal regurgitation when attempting this maneuver and alsonotices regurgitation of sour fluid when he bends over. His weight had beenstable, but with progressive symptoms over the past 12 months or so, he hasnow lost approximately 10 lb. Findings on upper endoscopy were unre-markable, including a retroflexed view of the gastroesophageal junction.A manometric recording from the patient is shown below.

What is the diagnosis?

a. Achalasiab. Nutcracker esophagus c. Esophageal spasmd. Severe GERDe. Scleroderma

13. A 14-year-old boy presents with a 2-day historyof chest pain, odynophagia, and dysphagia.He says he does not have any fever, and hehas not previously had any swallowing dif-ficulties. EGD shows ulceration and inflam-mation in the midesophagus without mass.The gastroesophageal junction is normal, andthere is no hiatal hernia. What is the mostlikely diagnosis?

a. Candida esophagitisb. Pill esophagitisc. Reflux esophagitisd. Eosinophilic esophagitis

14. A 48-year-old woman presents with a 2-yearhistory of progressive dysphagia. During arecent episode, food got caught in her chest foran hour. She decided to go to the emergencydepartment, but en route, the dysphagia spon-taneously resolved and she returned home. Shealso has a history of progressively severe heart-burn over the past 4 to 5 years. Initially, she hada response to once-daily PPI, but therapybecame refractory to the treatment. Morerecently, she has been taking antacids in additionto the PPI, but this affords only partial relief. Shehas lost approximately 10 lb over the past 6months because of progressive dysphagia. Shestates that she does not have any fever, chills,or sweats but has noticed that her fingers oftenbecome white or even purple and painfulwhen she is in the cold. EGD shows severedistal esophagitis with a stricture, but no evi-dence of a mass or Barrett’s esophagus. Whatis the diagnosis?

a. Severe GERDb. Pill esophagitisc. Sclerodermad. Eosinophilic esophagitis

15. The patient presented in question 14 hadesophageal manometry that showed normalperistalsis and contractions in the upper esoph-agus but a significantly decreased amplitudeof contractions with suggestion of aperistalsisin the distal esophagus and low LES pressure.What would be the appropriate next step?

a. Injection of botulinium toxin (Botox) intothe LES

b. Titrate up the dose of PPI to controlsymptoms

c. Fundoplication d. Swallowed fluticasone spray

ANSWERS1. Answer aDysplasia is a histologic proxy for genetic instability.It is difficult to distinguish dysplasia from reactiveatypia that is present in response to inflammation.The 2008 American College of Gastroenterologyguidelines recommend, even in the absence of ero-sive esophagitis, that patients with newly diag-nosed low-grade dysplasia alter the PPI regimenand undergo repeat endoscopy in 6 months. If apatient is not already taking a PPI, he or she shouldbegin taking one, even if asymptomatic. If thepatient is already using a PPI, confirm that he or sheis taking it correctly (meaning on an emptystomach, 20-60 minutes before chewing a solid).If the medicine is taken correctly once daily, thepatient has a choice of either increasing the doseto twice daily or changing to a different PPI.Repeat endoscopy in 8 to 12 weeks serves twopurposes: to ensure healing of the esophagitisand to clarify the degree of dysplasia in the under-lying Barrett’s segment.

The 6-month repeat endoscopy optionreflects the 1998 American College of Gastro-enterology guidelines for the management oflow-grade dysplasia.

Photodynamic therapy should be offered topatients who have high-grade dysplasia or carci-noma in situ. Because photodynamic therapy hasa significant morbidity profile, with 33% of patientsexperiencing recalcitrant esophageal strictures orskin reactions affecting the quality of life, it is notrecommended for patients with a low risk ofcancer. Also, in most series, 15% of patients haveresidual intestinal metaplasia after photodynamictherapy. The effect of laser treatment on theseresidual clones is not clear.

Although fundoplication may be an excellentoption in the near future for this patient, he is betterserved by ensuring that there is no significant dys-plasia underlying the esophagitis. If repeat

48 Esophagus

endoscopy shows that the esophagitis has healedand there is no significant dysplasia in the Barrett’ssegment, fundoplication with hiatal hernia repairwould be a reasonable option. If the patientinstead has high-grade dysplasia or neoplasm,esophagectomy, not fundoplication, would bethe optimal operation.

Neither fundoplication nor acid-suppressionmedications have been shown definitively todiminish the risk of esophageal adenocarcinoma inpatients with GERD or Barrett’s esophagus.

In response to the patient’s query, esophagec-tomy is the only option that would diminish hisrisk of esophageal cancer. However, esophagec-tomy would not be a wise choice because of itsinherent high risk of mortality (ranging from 1% athigh volume centers up to 20% at centers that per-form few operations) and morbidity. Over time,there also is a possibility of recurrent Barrett’sesophagus proximal to the esophagogastric anas-tomosis. The risks of esophagectomy are too greatto offer this option to a patient with reactiveatypia or low-grade dysplasia in the shortBarrett’s segment.

2. Answer eEsophagectomy is the standard of care forpatients confirmed to have high-grade dysplasia.The 3-cm area of nodularity is of concern for con-comitant neoplasm.

Alteration of the PPI regimen, followed byrepeat EGD in 3 months with intensive biopsy sam-pling is an option permitted by the AmericanCollege of Gastroenterology. The underlyingassumption of this option is that definitive treat-ment will be recommended when the cancer isdemonstrated. The challenge is that locoregionalmicrometastases or, worse, distant metastases maybe present by that time. For patients with significantcomorbid conditions that also threaten longevity,this watchful waiting approach is very reasonable.Because the patient is in otherwise excellent health,observation is a less attractive option.

Performing endoscopic mucosal resection forstaging purposes is an excellent option, but it isnot an excellent choice for treatment in this sce-nario. Endoscopic mucosal resection is technicallyeasier to perform on lesions 1 cm or smaller indiameter, although a piecemeal approach can be

undertaken for larger lesions. Mucosectomy of theregion of nodularity might treat the nodule, but itwill not address the high-grade dysplasia presentat the distal aspect of the Barrett’s segment.

The challenge in opting for endoscopicmucosal resection of the nodule, followed by pho-todynamic therapy of the remaining Barrett’s seg-ment, is the risk of micrometastases in regionallymph nodes. For patients with superficial tumors,this risk is approximately 7%.

Photodynamic therapy alone does not treatthe nodule.

3. Answer bThe standard of care for early potentially curableesophageal adenocarcinoma is esophagectomy.Regional lymph nodes are resected en bloc withthis maneuver, which is the major advantage overmucosal resection with superficial ablation therapy.If the patient is able to tolerate surgery,esophagectomy should be offered. Endoscopicmucosal resection with photodynamic therapy isbest for patients with a nodule of high-grade dys-plasia or cancer of T1 extent.

In a recent survey of gastroenterologists,medical oncologists, radiation oncologists, andthoracic surgeons, the patient group for whom allsubspecialists were in agreement about treatmentwere those with early-stage disease. Consistently,esophagectomy was recommended by all subspe-cialists. Definitive chemoradiation therapy andendoscopic mucosal resection, followed by pho-todynamic therapy, usually are offered to patientswho are not surgical candidates or to those whodecline esophagectomy. Neoadjuvant chemora-diation therapy usually is recommended to patientswithout distant metastases in whom spread toregional lymph nodes has been demonstrated.Adjuvant chemoradiation therapy usually is rec-ommended for patients who had surgery and forwhom the preoperative impression was early-stagedisease but postoperative examination of thespecimen shows micrometastases to regionallymph nodes.

4. Answer dThe differential diagnosis for this African Americanwoman includes nonerosive reflux disease, pillesophagitis, and reflux esophagitis. Because of her


comorbid conditions, some of which may betreated with immunosuppressive medications,infection with Candida or a virus (cytomegalovirusor herpes), is also part of the differential diagnosis.In view of her race and sex, neoplasm and Barrett’sesophagus are highly unlikely. Barrett’s esoph-agus is an uncommon disorder (3.5%-7% of symp-tomatic adults who undergo endoscopy). Theprevalence of Barrett’s esophagus is 3- to 4-foldless in females than in males and least commonamong African American females.

An upper gastrointestinal barium study usu-ally is helpful in evaluating dysphagia, in searchingfor fine rings or webs, or in helping to distinguishachalasia from scleroderma in patients withesophageal aperistalsis. Because the patient doesnot have dysphagia, an upper gastrointestinalbarium study would likely have low yield.

Although a capsule study to screen forBarrett’s esophagus and reflux esophagitis is rea-sonable, its ability to screen for viral disorders orpill esophagitis has not been documented.

Diagnosing Barrett’s esophagus is presumedto be beneficial for patients in whom dysplasia oran early curable esophageal neoplasm is found (T1or T2N0M0), because steps can be taken to eradi-cate the disease. With this patient’s general poorhealth status (New York Heart Association classIV heart failure), she is not an optimal surgical can-didate. Were endoscopy performed and Barrett’sesophagus diagnosed, long-term surveillancewould not be recommended. Even for persons withexcellent general health, surveillance of Barrett’sesophagus has not been proven to save lives.Despite this fact, largely due to biologic plausi-bility, surveillance is recommended for personshealthy enough to tolerate an intervention (suchas esophagectomy or photodynamic therapy) ifhigh-grade dysplasia or carcinoma in situ isfound. The recent availability of new therapeuticoptions, including endoscopic mucosal resectionwith photodynamic therapy and balloon-basedcircumferential endoscopic radiofrequency abla-tion, is making the decision for whom to end sur-veillance more difficult.

It is premature to recommend fundoplicationfor this patient because the diagnosis is not yet clearand the patient is not a good surgical candidate.

Empiric treatment with a PPI, changing themedications to liquid form, and encourageing herto drink a glass of water with the pills and thenremaining upright for 1 hour are reasonable initialrecommendations.

5. Answer eIt is not clear if this patient has Barrett’s esophagusor intestinal metaplasia of the cardia, which isthought to be a normal variant. Intestinal meta-plasia of the cardia is common. It occurs equallyin males and females, despite the presence orabsence of GERD symptoms. Regardless of theindication for endoscopy, biopsy specimens fromthe end of the tubular esophagus show intestinalmetaplasia with goblet cells (so-called Barrett’scells) in the distal esophagus of 15% to 20% of USadults. Patients with Barrett’s esophagus, in whomthe endoscopist observes abnormal salmon-col-ored mucosa in the tubular esophagus and thepathologist confirms specialized intestinal mucosa,have a 30- to 125-fold increased risk of adenocar-cinoma. Although no prospective study has shownprolongation of life expectancy with surveillance,professional gastrointestinal societies have rec-ommended surveillance for patients with Barrett’sesophagus. Because persons with intestinal meta-plasia with goblet cells at the cardia have the samerisk of esophageal adenocarcinoma as the generalpopulation, about 3 to 4 per 100,000 persons peryear, surveillance has not been recommended byany gastrointestinal society. One multi-internationalexpert consensus panel has written guidelines thatoppose the collection of biopsy specimens fromthe normally located, normal-appearing zig-zagline (squamocolumnar junction) because of thefear and anxiety it generates in patients and thenegative societal outcomes, including an increasein insurance premiums, associated with the diag-nosis of Barrett’s esophagus.

On the basis of the endoscopic description, itis unclear whether this patient has Barrett’s esoph-agus or intestinal metaplasia of the cardia.Therefore, it probably is wise to assume that thepatient may have Barrett’s esophagus and, hence,reasonable to schedule confirming/surveillanceendoscopy 1 year after the initial endoscopic exam-ination. Because the first endoscopic examination

50 Esophagus

did not show dysplasia or overlying erosiveesophagitis, the examination does not need to berepeated any sooner than 1 year.

Treatment with a PPI, generic or otherwise, isnot recommended because the patient is asymp-tomatic and no dysplasia was detected. Similarly,fundoplication is not recommended because thepatient is asymptomatic.

6. Answer cThe definition of achalasia requires aperistalsisthroughout the smooth muscle part of the esoph-agus, often with increased LES pressure. A patientwith scleroderma would present with very low-amplitude esophageal waves and occasionallywith aperistalsis, although the LES tone would bevery low. Nutcracker esophagus is a phenomenonthat has been described as high-amplitude wavesthat are peristaltic. According to the definitionof diffuse spasm, more than 30% of the wet swal-lows are simultaneous but occasional peristalsisis present.

7. Answer bThe radiograph clearly shows findings typical ofachalasia, that is, a dilated esophagus that tapers,producing a “bird’s beak” appearance. With dif-fuse spasm, the radiograph would show a morecorkscrew appearance. With scleroderma, theradiograph may be normal, with a widely patentLES. Nutcracker esophagus is a manometricfinding, with the mean distal esophageal amplitudemore than 180 mm Hg. Peristalsis is maintained and,in most cases, the esophagogram is normal.

8. Answer bThe tongue fasciculations suggest motor neuron dis-ease and bulbar palsy, in which oropharyngeal dys-phagia frequently occurs. Oropharyngeal dysphagiais evaluated with real-time videofluoroscopy. EGDis not helpful in evaluating this form of dysphagia;it would be more appropriate in differentiatingcauses of esophageal dysphagia. Furthermore, stan-dard esophageal manometry has very limited appli-cation in evaluating the oropharynx. Ambulatory24-hour pH studies would be useful to evaluate foracid reflux and regurgitation, but this patient doesnot have any of these symptoms.

9. Answer eThe barium swallow study shows evidence of adistal esophageal diverticulum and a dilatedesophagus. This is seen in achalasia, with a diver-ticulum forming in response to a hypertensive LES.The treatment of choice would include divertic-ulectomy and myotomy. Diverticulectomy alonewould not solve the problem of the increased LESpressure causing the diverticulum. No medicaltherapy is effective for distal esophageal diver-ticula or achalasia. Injection of botulinum toxinwould not be effective in treating a well-estab-lished symptomatic diverticulum, and pneumaticdilation would not have an effect on the diver-ticulum. It would treat only the LES, and, thispatient may have a higher risk of perforation.

10. Answer dThe tracing shows an aperistaltic esophagus withan LES that has normal tone but does not relax.Often, the LES is hypertensive, but in up to one-third of cases, it may appear to be in the normalrange. This is typical of achalasia, and for a youngperson, the treatment would be laparoscopic Hellermyotomy. Endoscopic dilation with the pneumaticballoon technique is a possibility; however, giventhe patient’s age, surgery would be preferablebecause it is more durable. In addition, up to 30%of patients with achalasia complain of heartburnsymptoms that are thought to be caused by fer-mentation. However, antireflux surgery wouldmake the problem worse by further obstructingthe esophagus (increased LES pressure). AlthoughPPI therapy may be prescribed, it does not treatthe underlying condition. Injection of botulinumtoxin in a young person with achalasia is not rec-ommended because its durability is limited.

11. Answer dThis patient has symptoms of dyspepsia and sub-sternal burning sensation. She has not had a responseto PPI therapy, and the ambulatory pH value is notconsistent with significant GERD. Therefore, sur-veillance is not needed for Barrett’s esophagus, andthere is no reason to expect fundoplication toimprove these functional symptoms. In fact, func-tional symptoms often worsen after fundoplication.Similarly, there is no reason to expect improvement


after doubling the dose of PPIs. Because she has nodysphagia, manometry is not indicated. As for otherfunctional problems, functional heartburn mayrespond to tricyclic antidepressants, and a trial ofamitriptyline would be indicated.

12. Answer aThis man’s history is consistent with an esophagealdysmotility. Manometry shows aperistalsis in thebody of the esophagus, increased resting LES pres-sures, and incomplete relaxation of the LES. Thishistory and these manometric findings are classicfor achalasia. The manometric features are not con-sistent with any of the other options.

13. Answer bMidesophageal ulcers without associated mass orstricture is suggestive of pill esophagitis. The acuteonset of these symptoms with odynophagia wouldbe unusual for GERD; furthermore, his gastro-esophageal junction is normal. Midesophagealulceration is not a typical finding for Candidaesophagitis, and in this otherwise healthy youngman that diagnosis would be unusual. Eosinophilicesophagitis is an increasingly appreciated causeof esophageal symptoms, particularly in youngmen. However, findings of midesophageal ulcersand acute onset of symptoms would be unusualfor this diagnosis. This young man had recently

started taking tetracycline for severe acne. Hissymptoms resolved with PPI therapy and discon-tinuation of tetracycline therapy.

14. Answer cThis patient has had progressively severe heart-burn and progressive dysphagia. The response toPPI therapy has been lost, and she is now losingweight. Her age and severe esophagitis make thediagnosis of eosinophilic esophagitis unlikely.The constellation of progressively severe heart-burn and dysphagia with Raynaud’s phenom-enon and telangiectasias makes scleroderma themost likely diagnosis.

15. Answer bManometry confirms the clinical suspicion of scle-roderma. Injection of botulinium toxin into theLES may afford temporary relief for achalasia butwould not be expected to have a benefit and per-haps would even cause worsening of this patient’scondition; she already has low LES pressure. Withthe progressive dysphagia and poor motor func-tion in the distal esophagus, fundoplication maywell worsen swallowing function. This optionmight be considered if titration of the PPI dosefails. The history and findings are not consistentwith eosinophilic esophagitis, and there is noreason to try swallowed fluticasone spray.

52 Esophagus

SECTION II

Stomach

A peptic ulcer is a break in the gastric or duodenalmucosa that penetrates down to the muscularismucosae (Fig. 1). The presence of such an ulcerconstitutes the diagnosis of peptic ulcer disease(PUD). PUD is common and is a major source ofmorbidity and health care expenditure in theUnited States, affecting 200,000 to 400,000 peopleannually and accounting for as much as 10% ofmedical costs for digestive diseases.

EPIDEMIOLOGYThe incidence of patients with diagnosed PUDranges from 0.1% to 0.3% per year. Peptic ulcersbecome more common with increasing age, andtraditionally, they have been more common inmen than in women. Persons infected withHelicobacter pylori have nearly a tenfold increasein incidence at 1% per year. The incidence increaseswith age for both duodenal and gastric ulcers. Thelifetime prevalence of clinically evident PUD inthe United States is approximately 10% for the gen-eral population and 20% for patients infected withH. pylori.

Several trends are notable in the prevalence ofPUD in the United States: the prevalence has beendecreasing during the past several decades; the dis-ease now affects males and females at increasinglysimilar rates (previously, males were affected moreoften), and the frequency of gastrointestinal tracthemorrhage due to PUD is decreasing in youngerpersons but increasing in the elderly.

PATHOPHYSIOLOGYThe acid environment of the stomach and the fre-quency with which noxious agents are ingested

55

CHAPTER 4

Peptic Ulcer Disease

Dawn L. Francis, MD, MHS

Fig. 1. Diagram of a peptic ulcer. (From MedicineNet[Internet]. Peptic ulcer disease. San Clemente, CA:MedicineNet Inc.; c1996-2008. [cited 2008 May 19];[about 6 screens]. Available from:http://www.medicinenet.com/peptic_ulcer/article.htm. Used with permission.)

Abbreviations: CLO, Campylobacter-like organism; COX, cyclooxygenase; EGD, esophagogastroduodenoscopy; NSAID,nonsteroidal antiinflammatory drug; PUD, peptic ulcer disease.

create a fertile ground for the development ofulcers. Indeed, in view of these continuing insults,PUD is surprisingly uncommon, a fact that under-scores the importance of the protective mechanismsof the gastric mucosa.

Peptic ulcers are the result of an imbalancebetween mucosal insults and mucosal defensemechanisms. Several protective mechanisms cankeep peptic ulcers from developing in the healthystate. These include the surface mucus and bicar-bonate layer, the epithelial barrier, tight intercel-lular junctions, mucosal blood flow-mediatedremoval of back-diffused acid, and cell restitutionand epithelial renewal (Fig. 2). When these mech-anisms are interrupted or are nonfunctioning, themucosa is vulnerable to various insults. This islikely why certain disease states, such as shock orcardiovascular disease, liver disease, or renal failure,are predisposing conditions for the developmentof PUD.

Most ulcers, however, occur when the normalmechanisms are disrupted by superimposedmucosal insults that overwhelm the protectivemechanisms of the upper gastrointestinal tract. Themost common insults are the result of H. pylori infec-tion and use of nonsteroidal antiiflammatory drugs(NSAIDs). Uncommon causes include gastric acidhypersecretion (as in Zollinger-Ellison syndrome),

antral G-cell hyperplasia, and mastocytosis. Viralinfections with herpes simplex virus andcytomegalovirus, inflammatory disorders such asCrohn’s disease or sarcoidosis, and radiation injurycan all cause ulceration in the gastrointestinal tract,including the stomach and duodenum.

Helicobacter pyloriH. pylori infection is the major cause of PUD world-wide. The infection rate for patients with PUDranges from region to region: in high prevalenceregions, such as Southern Europe and Japan, therate is more than 90%, whereas in low prevalenceregions, such as Northern Europe and the UnitedStates, it is 50% to 75%.

Throughout the world, the infection isacquired typically in childhood. The specific modeof transmission has not been defined fully, butthere is evidence that the organism is transmittedfrom person to person. It likely is transmitted byoral-oral or fecal-oral routes.

In the developing world, the majority of chil-dren are infected with H. pylori before the age of 10years and more than 80% of adults are infected bythe age of 50 years. In the United States, serologic evi-dence of H. pylori infection is uncommon before age10 years and is found in about 60% of the populationby the age of 60 years.

There is broad evidence to support a patho-genic role of H. pylori in PUD. Most notably,patients with PUD have a much higher rate ofinfection with H. pylori than the general popula-tion; antibiotic therapy heals ulcers at the samerate as H2-receptor antagonists; the recurrence rateof peptic ulcers is lower after H. pylori infectionhas been eradicated than after conventional ulcertreatment, and ulcer recurrence usually is associ-ated with failure to eradicate the infection.

The OrganismH. pylori is a gram-negative helical-shaped bac-terium that has four to six flagella. These bacteriacolonize only gastric epithelium. When they arefound elsewhere in the gastrointestinal tract (eg, thegastroesophageal junction or duodenum), they areassociated with metaplastic gastric epithelium.

To survive the hostile environment of thestomach, H. pylori produce urease that generatesammonia, which, in turn, neutralizes acid. These

56 Stomach

First-line defenseMucus/bicarbonate barrier

Second-line defenseEpithelial cell mechanisms

Barrier function of apical plasma membraneExtrusion of acid

Third-line defenseBlood flow-mediated removal of

black-diffused H+

Fig. 2. Mucosal defense mechanisms.

organisms also produce a protease that allows themto move through the mucous layer. However, thisprotease thins the mucous layer and is respon-sible for damaging this first barrier of mucosaldefense.

H. pylori infection causes a chronic active gas-tritis that involves predominantly the gastricantrum. The presence of these bacteria in theantrum leads to a loss of D cells that release somato-statin, and this allows the uninhibited release ofgastrin by antral G cells. This leads to increasedgastric acid secretion that promotes and sustainsulcer formation. H. pylori infection also incites thedevelopment of duodenitis and gastric metaplasiaof the duodenum, which may contribute to thedevelopment of duodenal ulceration.

The critical role of H. pylori in the developmentof PUD is clear. What is not clear is why so fewpatients with H. pylori infection develop clinicalulcerations. Host immune responses, genetic pre-disposition, bacterial virulence factors, and otherenvironmental factors have been implicated, butnone has been established clearly as the singlefactor responsible for the development of PUD.

Nonsteroidal Antiinflammatory DrugsPUD that is not due to H. pylori infection usually isdue to the use of NSAIDs. Many patients do notreport using these drugs, so for any patient withPUD, clinicians must maintain a high degree ofsuspicion. In the United States, up to 17 millionpeople take NSAIDs daily. Of these, 200,000 willhave serious side effects (including gastrointestinaltract bleeding) and approximately 6,000 will die.Up to 3% of all NSAID users will develop seriousgastrointestinal complications (symptomatic PUD,bleeding, or perforation), and 20% will developasymptomatic PUD or gastropathy within the firstyear of use.

NSAIDs disrupt the gastrointestinal tractmucosal defense mechanisms by topical and sys-temic effects. Topical damage can occur within thestomach by direct injury to the gastric epithelium.Systemically, the inhibition of prostaglandins dis-rupts mucosal blood flow, alters mucus secretion,and inhibits bicarbonate secretion, all of whichmay lead to increased hydrogen ion back diffusionand mucosal injury. Also, the inhibition ofprostaglandins may lead to a break in the tight

intercellular junctions and to trapping of neutrophilswithin the capillaries. These neutrophils releasecytokines and increase the inflammatory reaction.

The American College of Gastroenterologyhas reviewed the data regarding the risk factorsfor NSAID toxicity and has listed the five mostimportant characteristics that place patients at riskfor NSAID-related gastrointestinal complications:previous history of a gastrointestinal event (ulceror hemorrhage), age older than 60 years, highdosage of NSAIDs, concurrent use of glucocorti-coids, and concurrent use of anticoagulants.Assessment of these risk factors is appropriate toidentify patients who should be considered forprophylaxis if it is thought that NSAID therapyis required.

Specific Agents

Low-dose AspirinAspirin has been in use for more than a century asan analgesic and in use for the past several decadesfor the prevention and treatment of cardiovasculardisease and stroke. With widespread usage, itsassociation with gastrointestinal complications,including PUD and hemorrhage, has become clear.The effects of aspirin on the gastrointestinal tractlikely are due to the mechanisms mentioned above,but they also may be due to the antiplatelet aggre-gation mechanism of aspirin. Therefore, not onlyis there a higher likelihood of mucosal injury, butthe result of the insult (ie, PUD) is more likely to beassociated with hemorrhage. The effects of aspirinon the gastrointestinal tract are dose dependent inthe dosage range of 75 to 300 mg daily, which maycause a twofold to threefold increase in the risk ofgastrointestinal tract bleeding due mostly to uppergastrointestinal tract ulceration but also to injuryto the lower gastrointestinal tract.

Cyclooxygenase-2 InhibitorsCyclooxygenase (COX)-2 inhibitors have been pro-moted as selective NSAIDs with less risk of gas-trointestinal complications than nonselectiveNSAIDs. Controlled trials with COX-2 inhibitorshave shown a decreased risk of clinically apparentpeptic ulcers and their complications, althoughthe incidence of PUD among those taking thesedrugs appears to be as high as 5%. In addition, low-

Peptic Ulcer Disease 57

dose aspirin has a synergistic effect with COX-2inhibitors; thus, patients who take both drugs areat greater risk for gastrointestinal complicationsthan if they take either drug alone.

There is no evidence that COX-2 inhibitorshave advantages over other NSAIDs for patientswith unhealed ulcers. Also, COX-2 inhibitorsappear to inhibit the healing of peptic ulcers. Overthe past several years, many drugs from this classhave been removed from the US market because ofan apparent increase in risk of stroke and cardio-vascular disease.

Helicobacter pylori and NonsteroidalAntiinflammatory Drugs The relationship between H. pylori and NSAIDs iscomplex. H. pylori infection appears to be a signif-icant risk factor for PUD in NSAID-naïve patientswho begin NSAID therapy. Several randomizedcontrolled trials have shown that patients in whomH. pylori infection is eradicated before they aretreated with NSAIDs have a much lower rate ofPUD. In addition, a meta-analysis of observationalstudies found evidence of synergism between H.pylori infection and NSAIDs in both PUD and ulcerwith hemorrhage.

The available data support testing for andtreating H. pylori infection before the initiation oflong-term NSAID therapy. If patients with PUDhave H. pylori infection and must continuereceiving NSAID therapy, the infection shouldbe treated and consideration should be given toproviding the patient with a prophylactic acid-suppressive regimen (ie, a proton pump inhibitor)to reduce the risk of additional ulcers and asso-ciated complications.

Gastric AcidThe presence of gastric acid is the reason the uppergastrointestinal tract is especially prone to thedevelopment of ulceration. The long-held dictum“no acid, no ulcer” still applies. Once there is amucosal break, whether due to failure of theinherent protective mechanisms or overwhelmingmucosal injury, the break is maintained and prop-agated by the presence of gastric acid.

Gastric acid is produced by parietal cells.Parietal cells have receptors for three stimulants:histamine, acetylcholine, and gastrin (Fig. 3).

Histamine is manufactured by enterochromaffin-like cells and mast cells. Acetylcholine is releasedby the vagus nerve. Gastrin is produced andreleased by the antral G cells. G cells are inhibitedby gastric acid, creating an important negativefeedback mechanism to protect against the hyper-secretion of gastric acid.

The two major inhibitors of acid production byparietal cells are prostaglandins and somatostatin.Prostaglandins are released by both epithelial andnonepithelial cells in the stomach, and somato-statin is released by D cells in the stomach.

Most patients with gastric ulcers do not havean increased amount of gastric acid. In fact, mosthave normal or low-normal amounts of gastricacid (perhaps because H. pylori infection candecrease the production of gastric acid). This is alsotrue for most patients who have duodenal ulcers,but there is a small subset of patients with duo-denal ulcers who are gastric acid hypersecretors(see below).

Hypersecretion of Gastric AcidThe risk of developing PUD is augmented byhypersecretion of gastric acid. Acid hypersecretorystates are often complicated by multiple ulcerationsin unusual locations. Because the mechanism ofinjury is damage from gastric acid, the stomachtypically is not involved. More commonly, ulcer-ations occur in the duodenum and esophagus.

The increased production of gastric acid dis-rupts normal digestion and absorption. Many

58 Stomach

Fig. 3. Physiology of the parietal cell. ECL,enterochromaffin-like.

digestive enzymes require an alkaline environmentto be active, and ulcer disease itself can limitdirectly the absorption of nutrients because ofdisruption of the intestinal villi. As a result, diseasestates associated with gastric acid hypersecretioncan be associated with diarrhea, malabsorption,and weight loss. These disease states includeZollinger-Ellison syndrome, systemic mastocy-tosis, antral G-cell hyperplasia, and retainedantrum syndrome.

Zollinger-Ellison SyndromeZollinger-Ellison syndrome is characterized byPUD, gastric acid hypersecretion, and a gastrin-producing tumor (gastrinoma). Gastrinomas arerare and occur in fewer than 1% of patients whohave PUD. If surgical resection of the gastrinomais not possible, then the main objective of treat-ment is suppression of gastric acid production.This typically requires administration of a protonpump inhibitor twice daily.

Systemic MastocytosisSystemic mastocytosis is characterized by multi-organ mast cell infiltration, including infiltration ofthe skin, gastrointestinal tract, lymph nodes, bonemarrow, and liver. Hypersecretion of acid, producedby increased histamine levels, is found in approx-imately 30% of patients. Because the hypersecretionof acid in this condition is due to histamine stimu-lation of parietal cells, H2-receptor antagonists areeffective therapy.

Antral G-cell HyperplasiaAntral G-cell hyperplasia is a rare conditiondescribed in a cluster of patients with an extensivefamily history of PUD and an increased number ofantral G cells. These patients have hypergastrinemiaand, as a result, gastric acid hypersecretion. A secretinstimulation test can distinguish between antral G-cell hyperplasia and Zollinger-Ellison syndrome.Rather than the marked increase in gastrin inresponse to secretin stimulation seen in Zollinger-Ellison syndrome, the response in antral G-cellhyperplasia is a decrease, no change, or a slightincrease in the serum level of gastrin (<200 pg/mL).Once antral G-cell hyperplasia is diagnosed, aggres-sive acid suppression is often effective for healingand preventing ulcers.

Retained Antrum SyndromeRetained antrum syndrome is a rare form of hyper-gastrinemia in patients who have had a Billroth IIoperation (Fig. 4). If a small cuff of antrum remainsin the afferent limb and is excluded from exposureto gastric acid, the gastrin-producing G cells willrelease gastrin without control by the negativefeedback loop, leading to hypersecretion of acidin the remaining stump.

Viral Causes of Upper GastrointestinalTract UlcerationViruses can cause ulceration of the upper gastroin-testinal tract in any patient, but this is more commonin patients with immunodeficiency. The mostcommon causes for immunodeficiency associatedwith viral infection of the gastrointestinal tract areimmunosuppression related to solid-organ or bonemarrow transplantation, human immunodeficiencyvirus infection associated with acquired immunod-eficiency syndrome, and treatment of autoimmuneor inflammatory diseases (including treatment ofinflammatory bowel diseases with biologic agents).The viruses commonly associated with ulcerationof the upper gastrointestinal tract are herpes sim-plex virus and cytomegalovirus. Viral infectionshould be strongly suspected in patients who areimmunosuppressed and develop PUD. In such cases,


Retained antraltissue with gastrin-

secreting cells

Fig. 4. Retained antrum after Billroth II operation.(Modified from Costamagna G. ERCP after Billroth IIreconstruction [Internet]. UpToDate c2008 [cited 2008May 9]. Available from: http://www.uptodate.com/.Used with permission.)

biopsy specimens should be obtained from the ulcermargin (where herpes simplex virus commonlyresides) and the ulcer base (where cytomegalovirusis found). If an upper gastrointestinal tract ulcera-tion has a viral cause, it is important that it be diag-nosed because the management is completely dif-ferent from that of PUD due to other causes.

RadiationThe second portion of the duodenum is espe-cially sensitive to radiation injury after abdom-inal radiation. These ulcers usually can be treatedwith aggressive acid suppression. In rare cases,surgical resection of large nonhealing ulcers hasbeen necessary.

SarcoidosisWhen sarcoidosis involves the gastrointestinal tract,it usually affects the stomach. Ulceration can occurthat resembles PUD. Other endoscopic findingsmay be nodular gastritis, thickened mucosal folds,polypoid lesions, or deformities in the gastric bodyor antrum. Acid suppression may be helpful inpatients with PUD due to sarcoidosis. Systemictreatment with corticosteroids or NSAIDs may behazardous in patients with a sarcoid-induced ulcer.Surgery is often required in patients with pyloricstenosis or gastrointestinal tract bleeding.

Additional Risk Factors

Smoking Smoking has an important facilitative role forPUD. Studies performed before the discovery ofH. pylori showed that smokers were more likelyto develop ulcers, and the ulcers were more diffi-cult to treat and more likely to recur. There areseveral potential mechanisms by which smokingcan foster PUD. The most likely are compromisedblood flow to the mucosa and nicotine stimulationof basal acid output.

AlcoholAlcohol can damage the gastric mucosal barrierdirectly and cause acute gastric mucosal lesionscharacterized by mucosal hemorrhages. Alcoholalso stimulates acid secretion. However, despitethe acute effects of alcohol on the gastric mucosa,there is no clear evidence that alcohol causes or

exacerbates chronic PUD. When alcohol use is asso-ciated with chronic liver disease, the liver diseaseitself can increase the risk of PUD, likely becauseof altered mucosal blood flow.

Other Drugs

CorticosteroidsCurrent evidence supports a role of corticosteroidsin increasing the risk of PUD, but only when coad-ministered with NSAIDs.

Platelet-active AgentsAntiplatelet agents have been associated with ahigh risk of gastrointestinal tract bleeding, espe-cially when administered to patients with previousgastrointestinal tract bleeding. These agents arecontraindicated for high-risk patients when admin-istered alone or in combination with NSAIDs.

SirolimusSirolimus has been associated with aggressive ulcerdisease in patients undergoing transplantation.Use of this agent in patients with a history of PUDshould be approached with caution. Also, PUDthat develops while a patient is receiving sirolimustherapy should be treated aggressively.

BisphosphonatesThe association of bisphosphonates with PUD isa matter of controversy and has been studied pri-marily with the agent alendronate. Acute ulcerationhas been observed, but the frequency with whichulceration develops into a clinically significantproblem is undefined. It is known that the risk ofPUD is increased markedly with the concomitantuse of NSAIDs and bisphosphonates.

DietFor centuries, dietary indiscretion has been impli-cated as a cause of ulcers. Although it is well under-stood that particular foods, beverages, and spicescan cause dyspepsia, there is no evidence that foodscause or promote PUD or interfere with ulcerhealing. In the past, dietary modifications had beenadvised for PUD to enhance healing. Theseincluded frequent feedings, bland diets, or dairy-based diets. These interventions do not appear toaffect the outcome of PUD.

60 Stomach

Psychologic FactorsAfter decades of study, the importance of psy-chologic factors in PUD is still debated. Psychologicstressors, depression, and anxiety have been shownto impair endoscopically documented healing andto promote recurrence of endoscopically diagnosedulcers. Furthermore, the effects of stress seem tobe reversible in that PUD which develops aftertraumatic life events tends to heal after the stresshas resolved. The mechanisms that underlie stressand PUD have not been clarified. Any observationof a relationship between psychologic stressorsand PUD does not establish causality. For example,a study has found that anxiety and neuroticismwere high in a group of patients at the time of diag-nosis of duodenal ulcer, but these psychologicsymptoms had normalized in patients free of PUDat the end of 10 years of follow-up. This findingquestions whether psychologic features are theresult, rather than the cause, of PUD.

CLINICAL FEATURESThe clinical features of PUD range from silent ulcer-ation to dyspepsia and epigastric pain. The classicclinical feature of PUD is pain that occurs 2 to 3hours after a meal, improves with food or antacids,and awakens the patient several hours after thepatient falls asleep. Complicated PUD implies thatthe patient has suffered systemically from PUD,for example, with gastrointestinal tract hemorrhageor perforation.

The diagnosis of PUD usually is based on theresults of an upper gastrointestinal tract radiographicstudy or esophagogastroduodenoscopy (EGD). Thefindings of these two tests correlate in about 80% to90% of cases. EGD is the preferred method for eval-uating PUD because it allows for biopsy of theantrum for H. pylori and for biopsy of gastric ulcersto differentiate benign from malignant ulcers.

Diagnosis of Helicobacter pylori InfectionThe evaluation and treatment of H. pylori infectionare important aspects of the management of PUD.However, testing for H. pylori can be difficult. Partof the difficulty is that false-negative studies forH. pylori infection are common. Some of the mostcommon tests for H. pylori infection depend on thenumber of organisms (breath and stool antigen

tests, urease testing, histology, and culture), andthe number of organisms is influenced by treat-ment with bismuth, proton pump inhibitors, andantibiotics. If these drugs are being taken by thepatient, then H. pylori testing should be repeatedafter the patient has stopped taking them for a suf-ficient time (typically 4-6 weeks). Because of thehigh prevalence of H. pylori infection amongpatients with known ulcers and the commonality offalse-negative H. pylori infection diagnostic tests, neg-ative tests should be confirmed by a second, inde-pendent test for patients with PUD.

Several different tests can be chosen to eval-uate for the presence of H. pylori (Table 1). These canbe grouped into two categories: invasive and non-invasive tests. The noninvasive tests are H. pyloriserology, H. pylori stool antigen assay, and theurease breath test. Invasive tests includehistopathology, the Campylobacter-like organism(CLO) test, and culture.

Noninvasive Tests

SerologyThe choice of test depends on the question beingasked. For patients who have PUD and have notbeen treated previously for H. pylori infection, sero-logic testing for evidence of current or previousinfection may be appropriate. This test is inex-pensive and noninvasive, and it is as sensitive andspecific as biopsy for the initial diagnosis of H.pylori infection. However, serologic testing doeshave limitations: it only provides evidence of thepatient being infected at some point with H. pyloribut does not provide information about currentinfection. Also, as many as 10% of patients whohave been infected with H. pylori may have a negativetest result because of immunoglobulin deficiency.This problem is more common in the elderly.

Stool AntigenThe H. pylori stool antigen assay appears to behighly accurate. It is noninvasive, simple, and cost-effective. Its advantage over serologic testing isthat it evaluates active infection; thus, it can beused both as an initial test and as a test to evaluatefor eradication. As with any test that is reliant onbacterial load, the stool antigen assay can be falselynegative in patients who recently received treatment


with antibiotics, bismuth, or proton pumpinhibitors. For this reason, the test should beadministered 4 to 6 weeks after the completion oftreatment for H. pylori infection.

Urease Breath TestIf urease, produced by H. pylori, is present in thestomach, labeled carbon dioxide is split off andabsorbed and easily measured in expired breath.This test is accurate, but it also depends on bacte-rial load, making it prone to false-negative resultsin patients who recently received antibiotic orproton pump inhibitors. This traditionally hadbeen the test used to confirm the eradication ofinfection, but it should be performed 4 to 6 weeksafter therapy has been completed.

Invasive Tests

HistologyBiopsy with histologic examination is consideredthe “gold standard” for the diagnosis of active H.pylori infection. It has been recommended that twobiopsy specimens be taken from the gastric antrum,two from the gastric fundus, and one from theincisura to yield the greatest sensitivity. If thenumber of bacteria is small, a silver stain may benecessary (Warthin-Starry staining with hema-toxylin-eosin is excellent for detecting infection).In addition to the diagnosis of H. pylori infection,histologic examination of the gastric tissue may

also identify changes in the gastric mucosa causedby the H. pylori infection, such as intestinal meta-plasia or dysplasia. The disadvantage of histologyis that it requires endoscopy and is more expensivethan the noninvasive tests described.

Campylobacter-like Organism TestMucosal biopsy specimens can be tested for ureasewith the urease test, the CLO test. Like the ureasebreath test, this test relies on bacterial load and canbe affected (ie, increased rate of false-negative tests)by recent gastrointestinal tract hemorrhage. Theadvantage of the CLO test is that it can be used toevaluate active infection in patients undergoingendoscopy, and it is less expensive than histology.The disadvantages are that it requires endoscopyto obtain the tissue and, in contrast to histologicassessment, it does not allow for the detection ofother changes in the gastric mucosa caused by H.pylori infection.

TREATMENTThe treatment of PUD has changed remarkablysince H. pylori infection has been identified andassociated with PUD. The recurrence rate of PUDhas decreased from up to 95% at 1 year to lessthan 10% after H. pylori eradication. For thisreason, it is important initially to consider H. pyloriinfection as a potential cause of ulcer disease in allpatients. If the test results are negative, alternative

62 Stomach

Table 1. Diagnostic Tests for Helicobacter pylori

Sensitivity, Specificity,Test % % Cost, $

Nonendoscopic testsIn-office antibody test 88-94 74-88 10-30ELISA on serum 86-94 78-95 40-100Stool antigen test 94 92 180Urease breath test 90-96 88-98 250-300 (13C)

20-65 (14C)Endoscopic tests

Biopsy urease test 88-95 95-100 6-20Histology 93-96 98-99 60-250Culture 80-98 100 150

ELISA, enzyme-linked immunosorbent assay.

explanations, such as NSAIDs or hypersecretion ofgastric acid, should be considered and evaluated.

Treatment of Helicobacter pylori InfectionTreatment regimens for H. pylori infection haveevolved over the past decade from monotherapyto combinations of antisecretory and antibiotictherapy. A 10- to 14-day course of therapy withbismuth and antibiotics or with a proton pumpinhibitor and antibiotics is as effective for inducingulcer healing as a 4-week course of proton pumpinhibitor therapy. Combination therapy enhancesthe cure of H. pylori infection, shortens the treatmentperiod, and has a 90% cure rate at 1 week. The dif-ferent treatment regimens for H. pylori infectionare given in Table 2.

H. pylori are innately resistant to several antibi-otics (eg, vancomycin, sulfonamides, and trimetho-prim). In addition, primary resistance can occur toantibiotics used in several eradication regimens.Both metronidazole- and clarithromycin-resistant

strains of H. pylori have been reported. The additionof a proton pump inhibitor or bismuth to ametronidazole-based therapy lessens the effectof metronidazole resistance. Metronidazole resis-tance appears to be a relative phenomenon that canbe diminished with a higher dose of metronidazole(500 mg).

Clarithromycin resistance, however, is aproblem that cannot be overcome by increasingthe macrolide dose. No clarithromycin-based treat-ment has been shown to treat reliably cla-rithromycin-resistant organisms. Therefore, if aclarithromycin-based regimen fails to eradicate H.pylori infection, a metronidazole-based regimenshould be instituted. Resistance has not been foundto amoxicillin, tetracycline, or bismuth.

Currently, routine culture for H. pylori is notrecommended, but patients with refractory dis-ease may be well-served by culture and sensitivitytesting because the incidence of resistance is veryhigh in this subgroup.


Table 2. American College of Gastroenterology First-Line Regimens for Helicobacter pyloriEradication

Patients Regimen Eradication rate, %

Patients who are not allergic to penicillin Standard dose PPI twice 70-85and have not previously received a macrolide daily (or esomeprazole once

daily) plus clarithromycin 500mg twice daily, and amoxicillin1,000 mg twice daily for 10-14 days

Patients who are allergic to penicillin and Standard dose PPI twice daily, 70-85who have not previously received a macrolide clarithromycin 500 mg twice or are unable to tolerate bismuth quadruple daily, metronidazole 500 mg twicetherapy daily for 10-14 days

Patients who are allergic to penicillin and who Bismuth subsalicylate 525 mg 75-90have previously received a macrolide orally 4 times daily, metro-

nidazole 250 mg orally 4times daily, tetracycline 500 mgorally 4 times daily, ranitidine150 mg orally twice daily (orstandard dose PPI once to twicedaily) for 10-14 days

PPI, proton pump inhibitor.Modified from Chey WD, Wong BCY. American College of Gastroenterology Guideline on the management of Helicobacter

pylori infection. Am J Gastroenterol. 2007;102:1808-25. Epub 2007 Jun 29. Used with permission.

Antisecretory Treatment

Proton Pump InhibitorsProton pump inhibitors are effective for inducingulcer healing. Once-daily doses of omeprazole,from 20 to 40 mg, result in duodenal ulcer healingin 63% to 93% of patients at 2 weeks and in 80% to100% at 4 weeks. In most studies, omeprazole hasproduced more rapid healing than standard dosesof H2-receptor antagonists. Omeprazole at dosesof 20 to 40 mg daily also produces greater gastriculcer healing than H2 receptor antagonists, but therate of early healing of gastric ulcers is not accel-erated by omeprazole to the same extent as forduodenal ulcers.

Proton pump inhibitors are a group of pro-drugs that are acid labile and inactivated whenexposed to gastric juice. Most are enteric coated todissolve at pH >6. After being absorbed, they areconcentrated in the secretory canaliculus of parietalcells and irreversibly inactivate the hydrogen-potassium adenosine triphosphatase system,which disrupts the final common pathway for acidsecretion. Proton pump inhibitors are the mostpowerful drugs available to suppress gastric acidsecretion. Several important features of clinicalrelevance need to be stressed:

1. Because there is a significant lag time to peakeffectiveness, proton pump inhibitors shouldnot be administered on an “as needed” basis.

2. Because proton pump inhibitors effectivelyinhibit only stimulated parietal cells, theireffectiveness may be diminished by the coad-ministration of H2-receptor antagonists.

3. Because proton pump inhibitors inhibit onlystimulated parietal cells and parietal cells arestimulated by eating, proton pump inhibitorsare most effective when taken shortly before ameal (ie, 30 minutes to 1 hour).

H2-Receptor AntagonistsIn the mid-1970s, H2-receptor antagonists wereshown to heal ulcers in 70% to 85% of patients after4 to 6 weeks of therapy. Currently, four H2-receptorantagonists (cimetidine, famotidine, nizatidine,and ranitidine) are available. Although theirpotency, bioavailability, and side effect profilesdiffer, they are overall one of the safest classes ofdrugs available. Single-nocturnal dosing is at least

as effective as twice-daily dosing regimens (sametotal daily dose) in suppressing 24-hour gastricacid secretion and in healing duodenal ulcers. AllH2-receptor antagonists have healing rates for PUDof 90% to 95% at 8 weeks of therapy.

AntacidsAntacids that contain aluminum and magnesiumhydroxide effectively heal ulcers by binding bileand inhibiting pepsin. Antacids also promote angio-genesis in injured mucosa. However, at least seven30-mL doses daily are needed to heal ulcers. Thishigh dose can produce such adverse effects as diar-rhea (magnesium-containing agents), constipation(aluminum-containing agents), and sodium over-load. Also, calcium-containing antacids can causeacid stimulation and acid rebound.

SucralfateSucralfate is a sulfated polysaccharide that is com-pounded with aluminum hydroxide. It preventsacute ulceration and heals chronic ulcers withoutaffecting the secretion of gastric acid or pepsin. Likealuminum-containing antacids, sucralfate promotesangiogenesis and the formation of granulation tissue.Because binding of this drug to the ulcer is enhancedat pH <3.5, it should be administered 30 to 60 min-utes before meals. From 3% to 5% of this drug isabsorbed; thus, there is potential for aluminum tox-icity in patients with renal failure. Sucralfate therapyseems to be superior to placebo in healing PUD, butit is not indicated for H. pylori infection- or NSAID-induced ulcers, and its effectiveness has not beentested in non-H. pylori, non-NSAID ulcers. Therefore,its usefulness in PUD is limited.

MisoprostolMisoprostol is a prostaglandin E1 analogue thatexerts a mucosal protective effect by stimulatingthe secretion of mucus and bicarbonate and byenhancing mucosal blood flow. Misoprostol, atdoses of 400 to 800 mg daily, enhances duodenalulcer healing compared with placebo. Misoprostoldoes not seem to have any advantage over antise-cretory agents for ulcer healing. Consequently, it isnot indicated for this purpose. The primary role ofmisoprostol is in the prevention of NSAID-inducedgastroduodenal injury. Up to 30% of patients havea dose-dependent diarrhea from stimulation of the

64 Stomach

cyclic adenosine monophosphate system. In addi-tion, prostaglandins are uterotropic and may inducebleeding, cramps, and spontaneous abortion inpregnant women. These side effects and limitedclinical utility have curtailed the widespread use ofmisoprostol for both the treatment of PUD and theprevention of NSAID-induced ulceration.

Lifestyle ModificationsHistorically, bed rest, milk, and a bland diet wereprescribed for PUD. Dietary change is no longeradvised. The only general measures recommendedare to discontinue cigarette smoking and to avoidNSAIDs. Although certain foods, such as spicyfoods and sauces, may increase the dyspeptic com-plaints of patients, they do not cause ulcer diseaseor interfere with healing.

FOLLOW-UP AND MAINTENANCETHERAPY

Duodenal Ulcers Patients with uncomplicated duodenal ulcerswithout evidence of H. pylori infection who havereceived treatment do not require furtherendoscopy or radiography to ensure healing unlessthey have recurrent or persistent symptoms.

Gastric Ulcers There are no prospective outcome studies to helpguide the follow-up of patients who have gastriculcers. Repeat endoscopy with biopsy has beenadvocated to confirm gastric ulcer healing to ensurethat the ulcer is benign. However, a recent sum-mary of available data showed that more than 98%of gastric cancers associated with ulceration aredetected when the initial evaluation includes ade-quate endoscopic inspection and biopsy. If the initialbiopsy findings are negative, the yield of follow-upstudies is low. This relies on the adequacy of theinitial biopsy specimens. An adequate examina-tion and biopsy require the procurement of at leastfour biopsy specimens from the ulcer margin andone from the base, if the ulcer is not too deep and itseems safe to do so. The biopsy specimens mustcontain an adequate amount of tissue.

Because there is no consensus on how tofollow-up patients with gastric ulcers, there is a

wide range of practice. Generally, patients withulcers considered at high risk for gastric cancer whorequire extra vigilance in evaluation and follow-upinclude those raised in an endemic area with a highprevalence of gastric cancer (eg, East Asia or CentralAmerica), those with an ulcer in the absence ofNSAID use or H. pylori infection, those with a giantulcer (> 2 cm), and those without a previous ulcer.

Antisecretory Therapy After Eradicationof Helicobacter pylori InfectionNo firm guidelines are available about the continu-ation of antisecretory medication and managementafter eradication of H. pylori infection in patients withPUD. Some evidence supports the idea that eradi-cation of the infection alone is sufficient to preventrecurrence of PUD. However, two consensus panelshave addressed this issue and have recommendedmaintenance acid-suppression therapy withfollow-up after sucessful eradication of H. pyloriinfection in patients with complicated PUD.

Complicated Peptic Ulcer DiseasePatients with complicated PUD at higher risk fornonhealing or recurrent ulcers (eg, ulcers >2 cm,ulcer with fibrotic bed, or significant hemorrhage)also warrant treatment with antisecretory agents,at least until the eradication of H. pylori infectionhas been confirmed and ulcer healing has beenestablished. No studies have had the power todefine the best long-term management for thesepatients. Prolonged antisecretory therapy is likelyjustified in these patients.

Uncomplicated Peptic Ulcer DiseaseFor patients with uncomplicated PUD, antisecre-tory therapy can be discontinued safely after 4 to6 weeks. Some continued healing may occur withlonger treatment periods, but the advantages ofprolonged treatment and increased costs forpatients who are asymptomatic and uncomplicatedare debatable.

PREVENTION OF PEPTIC ULCERDISEASE AND COMPLICATIONS

NSAID-naïve patients who are being consideredfor long-term NSAID or aspirin therapy should be


evaluated for their risk of PUD. As stated above,there is support for the practice of testing thesepatients for H. pylori infection and, as a preventivemeasure against PUD, providing eradicationtherapy if H. pylori infection is found. In addition,patients who have risk factors such a previous his-tory of ulcer, advanced age, medications thatincrease the risk of PUD when taken with NSAIDs(eg, warfarin or glucocorticoids), or other comorbidconditions associated with an increased risk ofPUD should be considered for PUD prophylaxiswith misoprostol (although the side effects maybe limiting) or a proton pump inhibitor.

If possible, NSAIDs should be avoided ifpatients are taking other drugs that can increasethe risk of complicated PUD, for example, plateletaggregation inhibitors, anticoagulants, otherNSAIDs such as low-dose aspirin, or corticosteroids.

SUMMARYPUD is a common disorder worldwide. It usually iscaused by H. pylori infection or the use of NSAIDs.There are other rare causes of PUD, and most ofthem are due to hypersecretion of gastric acid.

The cornerstones of treatment for PUD includetesting for and, if appropriate, eradicating H. pyloriinfection, discontinuing treatment with NSAIDsif possible, and providing aggressive acid sup-pression with proton pump inhibitors.

There are some appropriate prevention strate-gies for PUD. For patients who are at increasedrisk for the development of PUD because of therequirement of long-term NSAID therapy or whohave comorbid conditions or medications thatincrease the risk of PUD, testing for and eradi-cating H. pylori infection and considering the pro-phylactic use of proton pump inhibitors are likelyuseful and cost-effective measures.

RECOMMENDED READINGAnnibale B, De Magistris L, Corleto V, D’Ambra G,

Marignani M, Iannoni C, et al. Zollinger-Ellisonsyndrome and antral G-cell hyperfunction inpatients with resistant duodenal ulcer disease.Aliment Pharmacol Ther. 1994;8:87-93.

Burget DW, Chiverton SG, Hunt RH. Is there anoptimal degree of acid suppression for healingof duodenal ulcers? A model of the relationshipbetween ulcer healing and acid suppression.Gastroenterology. 1990;99:345-51.

Chan FK, Ching JY, Hung LC, Wong VW, LeungVK, Kung NN, et al. Clopidogrel versus aspirinand esomeprazole to prevent recurrent ulcerbleeding. N Engl J Med. 2005;352:238-44.

Chan FK, To KF, Wu JC, Yung MY, Leung WK,Kwok T, et al. Eradication of Helicobacter pyloriand risk of peptic ulcers in patients startinglong-term treatment with non-steroidal anti-inflammatory drugs: a randomised trial. Lancet.2002;359:9-13.

Gisbert JP, Khorrami S, Carballo F, Calvet X, GeneE, Dominguez-Muñoz E. Meta-analysis:Helicobacter pylori eradication therapy vs. anti-secretory non-eradication therapy for the pre-vention of recurrent bleeding from peptic ulcer.Aliment Pharmacol Ther. 2004;19:617-29.

Huang JQ, Sridhar S, Hunt RH. Role of Helicobacterpylori infection and non-steroidal anti-inflam-matory drugs in peptic-ulcer disease: a meta-analysis. Lancet. 2002;359:14-22.

Lai KC, Lam SK, Chu KM, Wong BC, Hui WM, HuWH, et al. Lansoprazole for the prevention ofrecurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med.2002;346:2033-8.

Marshall BJ, Goodwin CS, Warren JR, Murray R,Blincow ED, Blackbourn SJ, et al. Prospectivedouble-blind trial of duodenal ulcer relapseafter eradication of Campylobacter pylori. Lancet.1988; 2:1437-42.

NIH Consensus Conference. Helicobacter pylori inpeptic ulcer disease. NIH ConsensusDevelopment Panel on Helicobacter pylori inPeptic Ulcer Disease. JAMA. 1994;272:65-9.

Podolsky I, Storms PR, Richardson CT, PetersonWL, Fordtran JS. Gastric adenocarcinoma mas-querading endoscopically as benign gastriculcer: a five-year experience. Dig Dis Sci.1988;33:1057-63.

Sonnenberg A, Everhart JE. Health impact of pepticulcer in the United States. Am J Gastroenterol.1997;92:614-20.

66 Stomach

The term gastritis has been used loosely to describevague endoscopic findings of the gastric mucosa(eg, erythema, nodularity, and erosions) and alsoto describe gastric inflammation from mucosalinjury. This ambiguity has led to confusion aboutthe term “gastritis” in both the clinical setting andthe medical literature. Strictly, gastritis refers tothe histologic finding of gastric mucosal injurywith inflammation. Gastropathy is the moreappropriate term for epithelial damage withoutassociated inflammation.

Since the discovery of Helicobacter pylori andthe gastritis associated with it, many attempts havebeen made to resolve the confusion about the termgastritis, and these attempts have resulted in multipleclassification systems. Most classification systemsdistinguish acute, short-term gastritis from chronic,long-term disease. The terms acute and chronic areused also to describe the type of inflammatory cellinfiltrate. Acute inflammation typically is charac-terized by neutrophilic infiltration, and chronicinflammation usually is associated with a prepon-derance of mononuclear cell infiltration.

In 1994, a group of pathologists met in Houston,Texas, to establish a consistent terminology for

chronic gastritis. The result is the Sydney System, aclassification based on topography, morphology,and etiology (Table 1). Although this is the mostreferenced system, its complexity has limited itswidespread use. Thus, there is no universallyadopted classification scheme for gastritis.

Both gastritis and gastropathy are discussed inthis chapter. The discussion about gastritis focuseson distinguishing between acute and chronic gas-tritis and the different causes of gastritis in eachof these categories. The discussion about gas-tropathy focuses on the two most common types:vascular and hypertrophic.

GASTRITIS

HistopathologyThe histologic evaluation of gastritis relies on thelocation, size, and number of biopsy specimens.Because different causes of gastritis can vary topo-graphically in the stomach, it is important to obtainadequate samples of gastric tissue from throughoutthe stomach. Biopsy specimens should be fromboth mucosal abnormalities and any surrounding

67

CHAPTER 5

Gastritis


Abbreviations: CMV, cytomegalovirus; GAVE, gastric antral vascular ectasia; NSAID, nonsteroidal antiinflammatory drug.

normal-appearing mucosa. Biopsy specimens fromthe incisura are often useful because it is the tran-sition zone between the antrum and body and,thus, the location where intestinal metaplasia andatrophy are found most frequently when associ-ated with gastritis. It has been recommended thatat least five biopsy specimens be obtained fromthe stomach: two from the gastric antrum, one

from the incisura, and two from the body or fundus(Fig. 1).

In some cases, biopsy specimens from the duo-denum may be useful in defining the underlyingcause of some types of chronic gastritis. For instance,duodenal biopsy specimens may show celiac dis-ease in patients with lymphocytic gastritis or Crohn’sdisease in patients with granulomatous gastritis.

68 Stomach

Table 1. Sydney System for Classification of Chronic Gastritis

Type of gastritis Etiologic factors Gastritis synonyms

Nonatrophic Helicobacter pylori SuperficialDiffuse antral gastritisChronic antral gastritisInterstitial follicularType B

Atrophic-autoimmune Autoimmunity Type AH. pylori Diffuse corporeal

Pernicious anemiaAtrophic-multifocal H. pylori Type B

EnvironmentalMetaplasticAtrophic pangastritisProgressive intestinalizingpangastritis

Chemical/radiation Bile ReactiveNonsteroidal anti- Refluxinflammatory drugs Radiation

Alcohol or other agents?Radiation

Lymphocytic Idiopathic VarioliformAutoimmune Celiac-associatedGlutenH. pylori

Granulomatous Crohn’s disease Isolated granulomatousSarcoidosisWegener’s granulomatosisInfectious

Eosinophilic Food sensitivities AllergicAllergiesIdiopathic

Infectious gastritides Bacteria PhlegmonousViruses CytomegalovirusFungi AnisakiasisParasites

Acute GastritisThe hallmark of acute gastritis is the developmentof hemorrhagic or erosive lesions soon after expo-sure of the gastric mucosa to various toxic sub-stances or immediately following a significantreduction in mucosal blood flow. The mostcommon substances associated with acute gastritisare nonsteroidal antiinflammatory drugs(NSAIDs), alcohol, and bile acids. Various clinicalscenarios can result in decreased mucosal bloodflow. The most common are trauma, burns,hypothermia, and sepsis. Many cancer therapies,including both radiation and systemic chemo-therapy, can injure gastric mucosa directly andcause decreased mucosal blood flow.

Similar to peptic ulcer disease, acute gastritismay be due to an imbalance between injurious andprotective factors. The acute mucosal injury thatis the hallmark of acute gastritis disrupts thenormal protective barrier (mucus, bicarbonate,and the epithelium itself). This permits acid andother damaging luminal substances such as bileacids and proteases to penetrate into the laminapropria, where they cause further damage to thevasculature and incite nerves to release histaminesand inflammatory mediators.

NSAIDs produce a topical injury that causesback diffusion of hydrogen ions. Furthermore,NSAIDs have a systemic effect through prost-aglandin blockade that decreases bicarbonate

release, mucus formation, and mucosal blood flow.Alcohol causes acute gastritis by disrupting

the mucosal microvasculature. Capillary conges-tion and increased vascular permeability increasethe inflammatory cell response and free radicalformation, which, in turn, cause mucosal injury.

Acute gastritis due to bile reflux is usually theresult of the reflux of bile into the stomach becauseof a surgical intervention (eg, a Billroth procedure),delayed small-bowel transit, or an incompetentpyloric sphincter. Bile salts and lysolecithin breakdown the gastric mucosal barrier, which leads toback diffusion of hydrogen ions and mucosal injury.

Hypovolemia or hypotension leads to under-perfusion of the gastric mucosa, resulting in theaccumulation of vasoactive amines and leukotrienes.This impairs the mucosal barrier and allows theback diffusion of hydrogen ions, leading to furthermucosal damage.

Histologically, acute gastritis appears as ero-sions with features of rapid healing of the mucosalinjury. In many cases, a thin regenerative epitheliumis the only evidence that erosions had been present.

The most important intervention for acute gas-tritis is the withdrawal of the offending agent ortreatment of the underlying condition (eg, hypoten-sion). The mainstay of treatment is the use ofaggressive acid suppression, such as a protonpump inhibitor, to limit injury from gastric acid inthe setting of a compromised gastric mucosa.

Chronic Gastritis

Atrophic GastritisThe term atrophic gastritis, or gastric atrophy, hasbeen used for more than a century. It refers to chronicgastritis that is associated with the loss of glands,mucosal thinning, and metaplastic changes of theepithelial cells. Atrophic gastritis has been subcate-gorized in terms of the role of the immune system(autoimmune, or type A) and functional or endocrinechanges in the antrum and body (type B). However,these designations are used inconsistently in themedical literature. Here, atrophic gastritis is sub-divided into autoimmune and multifocal types.

Autoimmune Atrophic GastritisAutoimmune atrophic gastritis is a form of chronicgastritis associated with severe diffuse atrophy of

Gastritis 69

Fig. 1. Gastric biopsy protocol to diagnose gastritis.Biopsy specimens (red circles) should be obtainedfrom the greater and lesser curvature of the antrum,incisura (dotted line), fundus, and body.

the acidophilic glands, chronic inflammation, andepithelial metaplasia. It is the result of an immuneresponse directed against parietal cells and intrinsicfactor. The chronic inflammation, gland atrophy,and epithelial metaplasia are paralleled closely byan increase in serum antibodies to parietal cellsand intrinsic factor.

The association observed between autoimmuneatrophic gastritis and the major histocompatibilityhaplotypes HLA-B8 and HLA-DR3 has led to theidea that autoimmune atrophic gastritis is a heri-table condition. Other conditions in which anti-bodies to gastric parietal cells have been detectedinclude autoimmune endocrinopathies (eg,Hashimoto’s thyroiditis, thyrotoxicosis, myxedema,Addison’s disease, and diabetes mellitus) and col-lagen vascular disease (eg, Sjögren’s syndrome).

A causal link has been suggested between H.pylori infection and autoimmune gastritis. The evi-dence supporting this link is the finding that asmany as 80% of patients with H. pylori infectionhave autoantibodies directed against the surfacemembrane of the foveolar epithelium or thecanalicular membranes of parietal cells. The devel-opment of these autoantibodies is likely due toantigenic mimicry.

Histopathologically, autoimmune atrophicgastritis is characterized by diffuse or focal lym-phocytic infiltration, including epithelial lym-phocytosis, and associated destruction of oxynticglands. If metaplasia is present, it is predominantlyin the body or fundus. The antrum typically is notaffected by metaplasia, but changes consistent withchemical gastropathy are often present.

As a result of the damage to parietal cells,patients with autoimmune atrophic gastritis havevarious potential clinical manifestations, includingachlorhydria, hypergastrinemia, and anemia(which can be due to iron deficiency or malab-sorption of vitamin B12 or both). In addition to themetaplastic changes associated with autoimmuneatrophic gastritis, there is also increased risk of hyper-plastic and adenomatous polyps, carcinoid tumors,gastric lymphoma, and gastric adenocarcinoma.

The achlorhydria associated with autoimmuneatrophic gastritis can induce hyperplasia of thegastrin-producing G cells, resulting in hypergas-trinemia. Gastrin has a trophic effect on endocrinecells in the stomach, which may give rise to hyper-

plastic nodules. Importantly, carcinoid tumors arethought to arise from the transformation of ente-rochromaffin-like cells within the oxyntic mucosaas a result of chronic stimulation by gastrin.

Multifocal Atrophic GastritisAutoimmune atrophic gastritis is distinct frommultifocal atrophic gastritis in that the latter is duedirectly to the effects of H. pylori (ie, not the resultof antigenic mimicry). Histologically, multifocalatrophic gastritis is different from autoimmuneatrophic gastritis in that there is evidence of bac-terial colonization, mature parietal cells, and amonomorphic lymphocytic cell infiltrate.Inflammation is present in both the antrum andbody, instead of predominantly in the body andfundus as in autoimmune atrophic gastritis.

When obtaining specimens from a stomachwith suspected H. pylori infection and associatedgastritis, it is important to obtain two specimensfrom the antrum and two from the body.Specimens from the body are essential because thepatient may have received proton pump inhibitortherapy, which causes the organism to relocatefrom the antrum to the body. A fifth biopsy spec-imen should be obtained from the incisura becausethis is the site most likely to show H. pylori-asso-ciated atrophic gastritis, metaplasia, and dysplasia(Fig. 1).

Chronic Reactive GastritisContinuous exposure to substances that injure thegastric mucosa can lead to chronic chemical gas-tropathy. No endoscopic findings are diagnosticof this condition, and mucosal changes are oftenconfined to the antrum. Histologically, chronicreactive gastritis is typified by variable foveolarhyperplasia, a lack of inflammation (in contrast toH. pylori-induced gastritis), edema, an increase insmooth muscle fibers in the lamina propria, andvascular congestion. These changes have been asso-ciated with the same substances that induce acutegastritis, namely, bile salts, NSAIDs, and alcohol.

As mentioned above, bile reflux gastritis usuallyis caused by the reflux of bile into the stomach asa result of a surgical intervention or compromisedmotility of the upper gastrointestinal tract. Themechanism of injury is the same as for acute gas-tritis due to bile reflux. Several medical treatments

70 Stomach

have been evaluated for bile reflux gastropathy, andnone has been particularly successful. Ineffectivetreatments include cholestyramine in combinationwith alginates, prostaglandin analogues, and sucral-fate. Ursodeoxycholic acid has been helpful indecreasing pain and nausea, but does not producehistologic improvement. The definitive treatmentfor symptomatic bile acid reflux—when a knownpredisposing factor exists (eg, previous surgery)—is surgical and usually involves a Roux-en-Y revi-sion. This intervention is associated with sympto-matic improvement in 50% to 90% of patients.

As with other toxic substances, NSAIDs cancause both acute gastritis and chronic gastritis. It isknown that a portion of patients will have a reduc-tion in the acute changes (erosions or hemorrhagicgastritis) associated with NSAIDs because ofmucosal adaptation to the injury. However, manypatients who take NSAIDs will continue to haveulcerative or inflammatory lesions, including gas-tric or duodenal ulceration in 15% of them.

It is clear that ingested alcohol (ethanol) canbe toxic to the gastric mucosa. Alcohol has beenassociated with acute gastric hemorrhage and ero-sive gastropathy in animal models and humans.However, it is not entirely clear that alcohol causeschronic gastritis. The effects of alcohol on thestomach over the long term are difficult to studybecause many patients who use alcohol may haveother risk factors for the development of chronicgastritis, including H. pylori infection, NSAID use,and smoking. Most of the studies that evaluatedthe association between alcohol ingestion andchronic gastritis were performed before the discoveryof H. pylori and, thus, have limited applicability.

Infectious Gastritis

Bacterial InfectionsH. pylori infection is the major cause of chronic gas-tritis worldwide. Rarely is acute gastritis associ-ated with H. pylori encountered clinically becausethe acute illness is mild, transient, and usuallyasymptomatic. H. pylori infection can cause bothatrophic and nonatrophic gastritis.

H. pylori is a gram-negative helical-shaped bac-terium that has four to six flagella. These bacteriacolonize only the gastric epithelium. When they arefound elsewhere in the gastrointestinal tract (eg, the

gastroesophageal junction or the duodenum), theyare associated with metaplastic gastric epithelium.

H. pylori can be detected in both the antrumand the body of the stomach in the majority ofpatients (80%). In 10% of patients, the organism isfound only in the gastric body. The reason for thisis not entirely clear, but one theory is that H. pylorimigrate to the body of the stomach in patients whoare taking proton pump inhibitors because of thesuppression of H. pylori growth in the antrum.

The histologic characteristics of chronic H. pylorigastritis are well defined. Typically, there is a con-centration of inflammatory cells (lymphocytes,plasma cells, scattered macrophages, and often anincreased number of eosinophils) in the upper partof the mucosa just below the surface epithelium.This creates the appearance of a superficial gas-tritis, especially in the oxyntic mucosa. Frequently,lymphoid follicles are present and are consideredpathognomonic for H. pylori infection. The lym-phoid follicles that result from H. pylori gastritisare the precursors to primary gastric lymphoma.

Several other species of bacteria can causechronic gastritis. These usually reside in the stomachafter antrectomy or in association with achlorhy-dria. Streptococcus, Staphylococcus, Lactobacillus,Bacteroides, Klebsiella, and Escherichia coli have allbeen cultured from gastric fluid, but they rarely haveclinical significance. In certain circumstances, suchas with severe immunosuppression or ischemia,these bacteria may produce marked morbidity. Forexample, phlegmonous gastritis is a life-threateningcondition associated with full-thickness purulentnecrosis that invades the gastric wall.

Viral InfectionsCytomegalovirus (CMV) is the most common virusassociated with gastritis. CMV can infect any cellwithin the gastrointestinal tract, including thestomach. In the stomach, CMV infection usuallycauses ulceration, but the endoscopic findings canbe vague. Biopsy specimens show mucosal inflam-mation, vascular endothelial involvement, andeven tissue necrosis. The characteristic cytome-galic cells (large cells with eosinophilic intranu-clear inclusions) are present.

CMV infection is considered an opportunisticinfection and is usually, but not always, diagnosedin the presence of immunodeficiency. Patients with

Gastritis 71

acquired immunodeficiency syndrome are proneto this infection when the CD4 count is less than100. Patients receiving immunosuppressivetherapy for a solid-organ or bone marrow trans-plant are also at risk.

The three antiviral agents that can be con-sidered for the treatment of CMV gastritis arefoscarnet, ganciclovir, and valganciclovir.Valganciclovir is used most commonly becauseof its high oral bioavailability, as opposed to fos-carnet and ganciclovir that are administeredintravenously. Valganciclovir is a valine ester ofganciclovir and is absorbed rapidly andhydrolyzed to ganciclovir. A daily dose of 900mg of valganciclovir is equivalent to 5 mg/kg ofganciclovir administered intravenously.

Patients with CMV infection of the gastroin-testinal tract should receive 6 weeks of inductionantiviral therapy. It is unclear whether they thenshould receive maintenance antiviral therapy, asfor other CMV infections such as CMV retinitis.

MycobacteriumMycobacteria may involve the stomach and causegastritis in patients with disseminated tuberculosisor systemic Mycobacterium avium-intracellulareinfection. Patients with tuberculosis have the pathog-nomonic necrotizing granulomas seen on histology.Gastric infection with M. avium-intracellulare is char-acterized by an accumulation of foamy histiocytesthat stain positive for acid-fast bacilli. Treatment istargeted at treating the systemic infection.

Syphilitic GastritisTreponema pallidum can cause chronic gastritis inthe second and third stages of the infection.Endoscopically, this infection may look like ero-sive antral gastritis. In some cases, thick gastricfolds may form from infiltration by mononuclearplasma cells and may have an appearance that sug-gests linitis plastica or lymphoma. Syphilitic gas-tritis also may cause a granulomatous gastritis.Because spirochetes generally are difficult to identify,testing for evidence of systemic infection is oftenrequired to make the diagnosis.

Fungal InfectionAlthough Candida species are known to colonizegastric ulcers, Candida has not been shown to cause

primary gastritis. Rarely, opportunistic fungi havecaused severe necrotizing gastritis, includingmucormycosis in patients with diabetes mellitus.Torulopsis glabrata and Cryptococcus neoformanshave been reported to cause gastritis in patientswith immunosuppression.

Special Forms of Gastritis

Lymphocytic GastritisLymphocytic gastritis is often asymptomatic andis diagnosed when biopsy specimens are takenfrom normal, or only slightly abnormal, appearinggastric mucosa (Fig. 2). The essential diagnosticfeature is infiltration of the surface epithelium withlymphocytes. The lymphocytes are usually T lym-phocytes, mostly CD8 cells, with cleaved nucleiand a small amount of cytoplasm. The lymphocyticinfiltration is present in both the body and antrum.

Lymphocytic gastritis is frequently encoun-tered in patients with H. pylori infection and inadult and pediatric patients with celiac disease. Ina large series of patients with biopsy-confirmedlymphocytic gastritis, 38% had celiac disease, 29%had H. pylori infection, and the rest had variousother intestinal conditions. The rate of celiac diseaseamong patients with lymphocytic gastritis is sohigh that finding lymphocytic gastritis in a patientwho is not known to have celiac disease shouldprompt clinical consideration of occult celiac disease.

Granulomatous GastritisVarious infectious and noninfectious diseases cancause granulomatous gastritis. Endoscopically,granulomatous gastritis may appear as mucosalnodularity, thickened folds, or even ulcers. Whengranulomatous gastritis has an infectious cause(eg, tuberculosis, histoplasmosis, or syphilis), theunderlying infection usually has been identifiedalready in other tissues. Granulomatous gastritisalso may result from noninfectious conditions suchas Crohn’s disease, sarcoidosis, Wegener’s granulo-matosis or, rarely, gastric neoplasm. Treatment isaimed at the underlying systemic infection or illness.

Eosinophilic GastritisEosinophilic gastritis is due to eosinophilic infil-tration that may involve the full thickness of thestomach. In this disorder, the gastric antrum is

72 Stomach

involved more often than the body or fundus. Aswith granulomatous gastritis, the gastric mucosacan show nodularity or thickened mucosal folds.

Several diseases can be associated with a smallnumber of eosinophils in the stomach. However,eosinophilic gastritis should be diagnosed onlywhen a large number of eosinophils form a sheetlikemonomorphic distribution.

Eosinophilic gastritis has been associated withconnective tissue disorders such as scleroderma. Ithas been seen also with infiltration of the wall of thestomach by parasitic larvae, as in anisakiasis.However, most cases of eosinophilic gastritis areidiopathic. Peripheral blood eosinophilia is foundin up to 75% of patients. The disease typicallyresponds to systemic corticosteroid therapy.

GASTROPATHY

Vascular GastropathiesVascular gastropathies are abnormalities in thegastric tissue that involve the mucosal vessels, withlittle or no inflammation. The two most importantvascular gastropathies are gastric antral vascularectasia (GAVE), or watermelon stomach, and portalhypertensive gastropathy.

Gastric Antral Vascular EctasiaGAVE is characterized by longitudinal columns ofvascular ectasias that cross the antrum and converge

on the pylorus. The columns have the appearanceof the outside of a watermelon, which has led tothis disorder commonly being referred to as water-melon stomach (Fig. 3). Histopathologic examinationof GAVE shows minimal inflammation in thelamina propria, but there is prominent fibromus-cular hyperplasia and dilated mucosal capillaries.

GAVE is more common in females, and isassociated with collagen vascular diseases andliver disease. Patients with GAVE can developiron deficiency anemia and may become transfu-sion dependent. For these patients, GAVE can betreated endoscopically with argon plasma coagula-tion, with treatment repeated until the abnormalityis obliterated (Fig. 3). Patients with underlying liverdisease usually benefit from liver transplantion, buta transjugular intrahepatic portosystemic shunt doesnot seem to be helpful. Patients without liver dis-ease who have refractory bleeding from GAVEdespite endoscopic therapy may require antrectomy.

Portal Hypertensive GastropathyPortal hypertensive gastropathy appears as amosaic pattern of the mucosa that usually is morepronounced in the fundus and body of the stomach(Fig. 4). As the name suggests, this gastropathy isassociated exclusively with portal hypertension.Compared with GAVE, the vascular abnormali-ties involve deeper submucosal vessels that aredilated, irregular, and tortuous.

Portal hypertensive gastropathy is gradedendoscopically as mild or severe. Severe portalhypertensive gastropathy has active oozing orhemorrhage. Patients with severe portal hyper-tensive gastropathy may develop iron deficiencyanemia and require blood transfusion. Becausedeep submucosal vessels are involved in this dis-order, there is no effective endoscopic treatment.Treatment is aimed at decreasing portal hyper-tension and, thus, may involve the administrationof nonselective β-blockers, portal decompression(such as transjugular intrahepatic portosystemicshunt), or liver transplantation.

Hypertrophic GastropathyWhen large gastric folds are observed on endoscopy,the general term hypertrophic gastropathy has beenapplied. Several infiltrative, proliferative, and inflam-matory conditions are associated with large

Gastritis 73

Fig. 2. Lymphocytic gastritis. Intraepitheliallymphocytes can be seen without any destruction ofsurrounding epithelial cells. (From Owen DA.Gastritis and carditis. Mod Pathol. 2003;16:325-41.Used with permission.)

mucosal folds in the stomach. The most commonis chronic gastritis, which is the cause of 40% ofcases of hypertrophic gastropathy. Other causesinclude benign and malignant tumors (approxi-mately 30% of cases), hypertrophy associated withZollinger-Ellison syndrome, and Ménétrier’s dis-ease, which accounts for fewer than 10% of cases inwhich large gastric folds are observed.

Ménétrier’s DiseasePatients with Ménétrier’s disease may have variousnonspecific clinical features such as abdominalpain, weight loss, nausea, diarrhea, or protein-losing enteropathy. The diagnosis requires a full-thickness gastric biopsy specimen or biopsy viaendoscopic snare of an enlarged fold. Histologicexamination shows extreme foveolar hyperplasiawith glandular atrophy.

There is no proven treatment for Ménétrier’sdisease. According to one case report, the adminis-tration of subcutaneous octreotide showed improve-ment in enteral protein loss. Patients who have severehypoalbuminemia, pyloric obstruction, intractablepain, or in whom malignancy is a concern and cannotbe excluded may warrant gastric resection.

SUMMARYWhen applied precisely, the term gastritisdescribes inflammation in the gastric mucosadue to mucosal injury. Broadly, gastritis can bedivided into acute and chronic gastritis and then

subdivided on the basis of the cause of themucosal injury. Gastritis may have variousappearances on endoscopy, including erosions,erythema, nodularity, or thickened gastric folds.Diagnosis is based on histologic findings and theclinical history. Treatment usually is targeted atwithdrawing the offending agent or treating anunderlying infection or systemic disease.

The term gastropathy denotes epithelial damagewithout associated inflammation. The two mostcommon types of gastropathy are vascular andhypertrophic. Like gastritis, the diagnosis is madeon the basis of histopathologic findings. For vas-cular gastropathies, treatments include endoscopictherapy for GAVE complicated by anemia and treat-ment of the underlying portal hypertension inpatients with portal hypertension gastropathy.Oftentimes, hypertrophic gastropathy can be treatedby addressing the underlying disease. However,Ménétrier’s disease has no known treatment and,when severe, may require surgical intervention.

RECOMMENDED READINGDavenport HW. Salicylate damage to the gastric

mucosal barrier. N Engl J Med. 1967;276:1307-12. Dixon MF, Genta RM, Yardley JH, Correa P.

Classification and grading of gastritis: theupdated Sydney System. International

74 Stomach

Fig. 3. Gastric antral vascular ectasia (GAVE) withargon plasma coagulator. A, Before treatment. B,After treatment. (Courtesy of Dr. Louis M. Wong KeeSong, Gastroenterology and Hepatology, MayoClinic. Used with permission.)

Fig. 4. Portal hypertensive gastropathy. (Courtesy ofDr. Louis M. Wong Kee Song, Gastroenterology andHepatology, Mayo Clinic. Used with permission.)

A B

Workshop on the Histopathology of Gastritis,Houston 1994. Am J Surg Pathol. 1996;20:1161-81.

Domschke S, Domschke W. Gastroduodenaldamage due to drugs, alcohol and smoking.Clin Gastroenterol. 1984;13:405-36.

Laine L, Weinstein WM. Histology of alcoholichemorrhagic “gastritis”: a prospective evalu-ation. Gastroenterology. 1988;94:1254-62.

Marshall BJ, Armstrong JA, McGechie DB, GlancyRJ. Attempt to fulfill Koch’s postulates forpyloric Campylobacter. Med J Aust.1985;142:436-9.

Olivero JJ, Graham DY. Gastric adaptation tononsteroidal anti-inflammatory drugs in

man. Scand J Gastroenterol Suppl. 1992;193:53-8.

Roth SH, Bennett RE. Nonsteroidal anti-inflam-matory drug gastropathy: recognition andresponse. Arch Intern Med. 1987;147:2093-100.

Scharschmidt BF. The natural history of hyper-trophic gastropathy (Menetrier’s disease):report of a case with 16 year follow-up andreview of 120 cases from the literature. Am JMed. 1977;63:644-52.

Sung JJ, Lin SR, Ching JY, Zhou LY, To KF, WangRT, et al. Atrophy and intestinal metaplasiaone year after cure of H. pylori infection: aprospective, randomized study. Gastro-enterology. 2000;119:7-14.

Gastritis 75

77

CHAPTER 6

Gastric Neoplasms and Gastroenteropancreatic

Neuroendocrine Tumors


Gastric neoplasms are an important contributorto cancer-related mortality. Of the various neo-plasms that can affect the stomach, adenocarci-noma is the most common and accounts for up to95% of all gastric neoplasms. Less common aregastric lymphomas, gastrointestinal stromaltumors, neuroendocrine tumors, and metastaticdisease involving the stomach (Table 1). Thischapter considers the epidemiology, pathogenesis,clinical presentation, diagnostic evaluation, treat-ment, and prognosis of these neoplastic diseases.

GASTRIC ADENOCARCINOMA

EpidemiologyThe first statistical description of cancer incidenceand mortality, from the late 1700s, showed thatgastric cancer was the most common and mostdeadly of malignancies. Currently, gastric adeno-carcinoma is the second most common cancerworldwide, with approximately 870,000 new cases

and 650,000 deaths per year. Gastric cancer mor-tality rates have remained relatively unchangedover the past 30 years, and gastric cancer continuesto be one of the leading causes of cancer-related

Table 1. Frequency of Different Types ofGastric Neoplasms

Percentage of gastric

Tumor type neoplasms

Adenocarcinoma 90-95Lymphomas (diffuse large 5B cell and extranodal marginalzone B cell)

Gastroenteropancreatic neuro- <5endocrine tumors (includingcarcinoids), gastrointestinalstromal tumors, and metastaticdisease to the stomach

Abbreviations: BAO, basal acid output; CT, computed tomography; DLBCL, diffuse large B-cell lymphoma; ENMZL,extranodal marginal zone B-cell lymphoma; EUS, endoscopic ultrasonography; GIST, gastrointestinal stromal tumor;GNET, gastroenteropancreatic neuroendocrine tumor; MALT, mucosa-associated lymphoid tissue; MEN, multipleendocrine neoplasia; VIP, vasoactive intestinal polypeptide.

death. Gastric cancer is rare before the age of 40years, but its incidence climbs steadily thereafterand peaks in the seventh decade of life.

The incidence of gastric cancer varies by geo-graphic location. Sixty percent of gastric cancersoccur in the developing world. The highest inci-dence rates are in Eastern Asia, the mountainousregions of South America, and Eastern Europe. Thelowest incidence rates are primarily in the indus-trialized nations: North America, Northern Europe,and Southeastern Asia. Regardless of region, gastriccancer is more common in men than in women.

Although gastric cancer is relatively infrequentin North America, it contributes substantially tothe burden of cancer deaths, being the third mostcommon gastrointestinal malignancy after co-lorectal and pancreatic cancer and the third mostlethal neoplasm overall.

The worldwide incidence of gastric cancer hasdecreased over the past few decades. Gastric cancerused to be the leading cause of cancer mortality inthe world until it was surpassed by lung cancer inthe 1980s. Part of the decrease in gastric cancer inthe United States may be due to the recognitionand alteration of certain risk factors, such as theidentification and treatment of H. pylori infectionand changes in diet trends. The increasingly wide-spread use of refrigerators was likely the initialturning point for the decrease in the incidence ofgastric cancer. Refrigeration decreased bacterialand fungal contamination of food, increased theavailability of fresh fruits and vegetables (whichprovide protective antioxidants), and lessened theneed for salt-based preservation—all of which mayhave reduced some of the most significant risk fac-tors for gastric cancer. Although the incidence ofgastric cancer overall is decreasing, the absolutenumber of new cases per year is increasing becauseof an increased and aging world population.Consequently, gastric cancer will continue to bean important cause of cancer and cancer-relatedmortality for the foreseeable future.

PathogenesisMuch effort has been made to understand the eti-ology of gastric adenocarcinoma. It is widely heldthat there is no single cause but rather multiplecausative factors, including diet, exogenous sub-stances, infectious agents, and genetic factors. The

most widely accepted model for the developmentof gastric cancer is the progression from chronicgastritis to the development of intestinal meta-plasia, dysplasia, and, ultimately, adenocarcinoma.

Risk Factors

Diet Epidemiologic studies have documented an asso-ciation between diet and gastric cancer. Althoughdietary factors have been shown to influence thedevelopment of gastric cancer, specific substanceshave not been isolated. The most consistent asso-ciation is the ingestion of nitroso compounds.Nitroso compounds are formed from nitrates,which are found naturally in foods such as veg-etables and potatoes but are also used as preserv-atives for meats, cheeses, and pickled foods. Thesepreservatives were used commonly before the eraof refrigerators. Regions that use nitrate-based fer-tilizers also have a higher incidence of gastric cancer.

Diets high in salt have also been linked with anincreased incidence of gastric cancer. In animalmodels, high salt intake has been associated withatrophic gastritis. Diets low in uncooked fruits(particularly citrus fruits) and vegetables and highin processed meat, fried food, and alcohol are asso-ciated with an increased risk of gastric cancer. Theprotective effect provided by fruits and vegeta-bles is thought to be due to their vitamin C con-tent, which may decrease the formation of nitrosocompounds inside the stomach.

Tobacco UseSmoking increases the risk of gastric cancer. Thisrisk decreases after 10 years of smoking cessation.Socioeconomic status also affects the risk of gastriccancer. Distal cancer is twofold higher amongpatients of low socioeconomic status, and prox-imal gastric cancer is more likely among those ofhigher socioeconomic status.

Gastric Surgery Patients who have had gastric surgery are at higherrisk for the development of gastric cancer. Thisrisk is greatest 15 to 20 years after the operation.Billroth II surgery carries a higher risk than theBillroth I surgery, likely because Billroth II surgeryincreases the reflux of bile and pancreatic juices

78 Stomach

into the stomach, which is thought to be instru-mental in the development of gastric cancer. Becausethis risk is low, patients who have had a partial gas-tric resection do not warrant endoscopic screening.

Infection The two infections that have been associated withan increased risk of the development of gastriccancer are Epstein-Barr virus infection andHelicobacter pylori infection. Epstein-Barr virusinfection has been associated with various malig-nancies, the most common being nasopharyngealcarcinoma. It has been estimated that 5% to 10%of gastric cancers are associated with Epstein-Barrvirus infection.

H. pylori infection of the human stomach is themost important risk factor for the development ofgastric cancer. Whereas persistent viral infectionleads to several cancers, H. pylori was the first bac-teria linked to a human cancer. H. pylori has beenclassified as a definite carcinogen by the WorldHealth Organization. The infection likely triggersinflammation that results in atrophy and mayprogress to intestinal metaplasia, dysplasia, andcancer. Although few patients with H. pylori infectiondevelop gastric cancer, 90% of those with gastriccancer have evidence of H. pylori infection.

The precise mechanism by which H. pyloriinfection leads to gastric cancer is not understoodclearly. It is well established that H. pylori infec-tion leads to chronic gastritis. The inflammationassociated with chronic gastritis reduces the mucuslayer overlying mucosal cells and exposes thesecells to mutagenic compounds (eg, nitroso com-pounds and free radicals). Chronic infection withH. pylori can result in the destruction of the gastricmucosa, which leads to atrophic gastritis. H. pyloriinfection has been associated most strongly withcancers in the distal portion of the stomach anddoes not seem to be associated with cancersinvolving the gastroesophageal junction and cardiaregions. All first-degree relatives of persons withgastric cancer should be tested for H. pylori infec-tion and should be treated if infected.

Genetics Genetic predisposition to the development ofgastric cancer has been identified. First-degree rel-atives of patients with gastric cancer have at least

a twofold greater incidence of this cancer than thegeneral population. Gastric cancer occasionallydevelops in families with germline mutations inthe p53 gene (Li-Fraumeni syndrome) and BRCA2.In 1% of gastric cancers, germline mutations in thegene encoding the cell adhesion protein E-cadherinleads to an autosomal dominant predisposition togastric carcinoma, referred to as hereditary diffusegastric cancer, that has a penetrance of approxi-mately 70%. It has been suggested that identifica-tion of the E-cadherin mutation should promptprophylactic gastrectomy in affected kindreds.

Also, certain cancer syndromes have beenassociated with gastric cancer, including familialadenomatous polyposis, hereditary nonpolyposiscolorectal cancer, and Peutz-Jeghers syndrome.

Blood group A appears to confer an increasedrisk of gastric cancer. Possibly, however, theincreased risk is not associated with the bloodgroup antigens themselves but rather with theeffects of the genes associated with them.

Gastric Disorders Pernicious anemia is an autoimmune-type atrophicgastritis. Patients with this condition are at anincreased risk for the development of gastriccancer. Gastric polyps also may increase the riskof gastric cancer. These polyps are usually asymp-tomatic and found incidentally. Most gastric polypsare hyperplastic, without malignant potential.Adenomatous polyps are less common but maygive rise to or coexist with gastric adenocarci-noma. Adenomatous polyps usually occur inareas of chronic atrophic gastritis. Because of theirmalignant potential, they should be removedunder most circumstances.

Hypertrophic gastropathy (Ménétrier disease)is a rare, idiopathic condition characterized byrugal fold hypertrophy, hypochlorhydria, and pro-tein-losing enteropathy. Gastric cancer reportedlyoccurs in up to 10% of patients with this disease.

Clinical FeaturesThe clinical features of gastric cancer are vague.Patients often complain of epigastric pain, earlysatiety, abdominal bloating, or meal-induced dys-pepsia. Weight loss, nausea, and anorexia arecommon with advanced lesions. Patients withcancer involving the distal antrum or pylorus may

Gastric Neoplasms and Gastroenteropancreatic Neuroendocrine Tumors 79

have vomiting due to gastric outlet obstruction.Occult or overt bleeding may occur in early- orlate-stage cancers. Dysphagia is a prominentsymptom in lesions of the gastric cardia or gas-troesophageal junction.

Gastric cancer spreads by direct extensionthrough the stomach wall to perigastric tissue, andit invades adjacent structures, including the pan-creas, colon, spleen, kidney, or liver. Lymphaticmetastases occur early, and local and regional nodesare the first to be involved. The disease then spreadsto more distant intra-abdominal lymph nodes aswell as to the supraclavicular region (Virchow’snode), periumbilical area (Sister Mary Joseph’snodule), or left axilla (Irish node) or it may result inperitoneal carcinomatosis with malignant ascites.The liver is the most common site of hematogenousspread, followed by the lungs, bones, and brain.

Patients with gastric cancer occasionally pre-sent with paraneoplastic syndromes such as acan-thosis nigricans, the sign of Lesar-Trelat (suddenonset of diffuse seborrheic keratoses on the trunk),venous thromboses, or dermatomyositis.

Tumor Features

LocationEndoscopically, gastric adenocarcinoma mayappear as an exophytic, polypoid mass or as anirregular, infiltrating lesion with surface nodu-larity or ulceration. The location of the primarytumor in the stomach has etiologic and prognosticsignificance. Proximal lesions are biologically moreaggressive and have a worse prognosis, stage forstage, than distal cancers—a finding that suggeststhe pathogenesis differs from that of cancers arisingin other parts of the stomach. Distal cancers may berelated closely to chronic H. pylori infection, whereascardia and gastroesophageal junction cancers mayhave a different cause, such as chronic gastro-esophageal reflux. A contributing factor to thepersistently high mortality rate of gastric cancermay be the change during the past 20 years in thedistribution of cancers from the body and antrumto the proximal stomach. Cancers involving theproximal stomach and gastroesophageal junctionhave increased steadily at a rate exceeding that ofany other cancer, except melanoma and lungcancer. The reasons for this are unclear. Distal

cancers (in the gastric body or antrum) are morecommon in areas with a high incidence of gastriccancer, whereas cardia cancers are more prevalentin populations with a low incidence of gastric cancer.

InfiltrationThe linitis plastica lesion occurs in up to 10% ofgastric adenocarcinomas. The presence of thislesion at the time of diagnosis is usually associ-ated with locally advanced or metastatic diseaseand portends a worse prognosis.

HistologyThe most widely used histologic classification ofgastric adenocarcinoma divides these tumors intotwo types: intestinal and diffuse. The intestinaltype of adenocarcinoma has epithelial cells thatform discrete glands, microscopically resemblingcolonic adenocarcinoma. Typically, the intestinaltype is better circumscribed than the diffuse type,and it may be polypoid or ulcerated or both. Theintestinal type is the more frequent variety incountries with a high incidence of gastric adeno-carcinoma. It often arises within an area ofintestinal metaplasia. This pathologic variant gen-erally has a better prognosis than the diffuse type.

The diffuse type of gastric adenocarcinoma ischaracterized by sheets of epithelial cells. Glandularstructure is rarely present. The diffuse type extendswidely, with no distinct margins. Mucus-producingsignet ring cells are often present (Fig. 1). The diffusetype occurs more commonly in younger persons,is less likely to be associated with intestinal meta-plasia, and tends to be infiltrating, poorly differ-entiated, and generally has a poor prognosis.

StagingAt presentation, 65% of gastric cancers in theUnited States are at an advanced stage. The mostimportant aspect of staging is determining whetherthe cancer is resectable. Staging is both clinicaland pathologic. Clinical stage is determined pre-operatively, whereas pathologic staging is based onfindings made during surgical exploration andexamination of the pathology specimen. The TNMstaging system of the American Joint Committeeon Cancer is used most frequently (Table 2).Preoperative staging of patients with gastriccancer includes physical examination; computed

80 Stomach

tomography (CT) of the chest (for proximallesions), abdomen, and pelvis; and endoscopicultrasonography (EUS).

TreatmentSurgery is the mainstay of treatment for gastriccancer. Complete surgical removal of a gastrictumor, with resection of the adjacent lymph nodes,is the only chance for cure. However, two-thirdsof patients present with advanced disease that isincurable by surgery alone. This problem is com-plicated further by a recurrence rate of 40% to 65%in patients who had resection with curative intent.

Controversy persists about what is consideredoptimal surgical resection, with many differentopinions on the extent of resection necessary forcancer found in different parts of the stomach andthe extent of lymph node dissection. In practice,the extent of dissection is determined primarily bytumor location, preoperative staging, and the con-dition of the patient. Proximal gastric tumorsrequire a more extensive resection than those inthe distal stomach. Palliative rather than curativesurgery may still be considered in certain cir-cumstances, for example, for tumor obstruction,perforation, and bleeding.

Gastric adenocarcinoma is relatively resistantto radiotherapy, which generally is administeredonly to palliate symptoms and not to improve sur-vival. Chemotherapeutic regimens have shownonly modest results, with a decrease in measurable

tumor mass in about 15% of patients and only aminimal effect in prolonging survival.

PrognosisEven with more advanced surgical techniques andchemotherapeutic agents, the prognosis for gastricadenocarcinoma remains grim for all but thosewho are candidates for surgical resection.Prognosis after resection varies according to thepathologic extent of disease and the populationstudied. In general, 5-year survival rates can be


Fig. 1. Diffuse type of gastric adenocarcinoma withmucus-producing signet ring cells. (Courtesy of Dr.Thomas C. Smyrk, Anatomic Pathology, Mayo Clinic.)

Table 2. The TNM Staging System forGastric Adenocarcinoma

Tumor (T) stageTX Primary tumor cannot be

assessedT0 No evidence of primary

tumorT1s Carcinoma in situT1 Tumor invades lamina

propria or submucosaT2 Tumor invades muscularis

propria or subserosaT3 Tumor penetrates serosa

without invading adjacentstructures

T4 Tumor invades adjacentstructures

Nodal (N) stageNX Regional nodes cannot be

assessedN0 No regional node

metastasisN1 Metastasis in 1-6 regional

lymph nodesN2 Metastasis in 7-15 regional

lymph nodesN3 Metastasis in more than 15

regional lymph nodesMetastasis (M) stage

MX Presence of distant meta-stasis cannot be assessed

M0 No distant metastasisM1 Distant metastasis

approximated as follows: stage IA, 80%-95%; IB,60%-85%; II, 30%-50%; IIIA, 20%-40%; IIIB, 10%;and IV, 7%.

GASTRIC LYMPHOMA

EpidemiologyPrimary gastric lymphoma accounts for up to 10%of lymphomas and up to 5% of gastric neoplasms.The stomach is the most common extranodal siteof lymphoma and accounts for approximately 20%of all extranodal lymphomas. It is also the mostcommon site of gastrointestinal lymphoma. Gastriclymphoma reaches peak incidence between theages of 50 and 60 years and, as with gastric ade-nocarcinoma, there is a slight male predominance.Although these are rare tumors, the incidence ofprimary gastric lymphoma appears to beincreasing, especially among elderly patients.

In the stomach, the most frequent lymphomasare low-grade extranodal marginal zone B-celllymphomas (ENMZLs) (formerly known asmucosa-associated lymphoid tissue [MALT] lym-phomas) and diffuse large B-cell lymphomas(DLBCLs).

Risk FactorsThere are several risk factors for the developmentof gastric lymphoma. They include H. pylori-asso-ciated chronic gastritis, autoimmune diseases,immunodeficiency syndromes, and long-termimmunosuppressive therapy.

Clinical FeaturesThe clinical features of gastric lymphoma are non-specific and may include abdominal discomfort,dyspepsia, gastric outlet complaints due toobstruction or impairment of gastric motility,anorexia, weight loss, and anemia due to bloodloss from ulceration.

Diagnostic EvaluationEndoscopically, gastric lymphoma has a broadrange of appearances—from large, firm rugalfolds to eroded nodules to exophytic ulceratedmasses. When enlarged folds are present, theyare due to the subepithelial infiltrative growthpattern of lymphomas.

When the disease is suspected, standard endo-scopic biopsy specimens may be inadequate or thehistologic findings equivocal, especially when theinvolvement is primarily submucosal. Deeperbiopsy or snare biopsy specimens from a polypoidmass or large rugal fold may be needed to makethe diagnosis.

CT of the abdomen and chest is useful in iden-tifying involvement of regional lymph nodes, exten-sion of the tumor into surrounding structures, anddistant metastases. If there is no evidence ofmetastatic disease, EUS is accurate for determiningthe extent of gastric wall infiltration and can pro-vide useful information for treatment planning. Inaddition, the pattern seen on EUS may correlatewith the type of lymphoma present. In one smallseries, superficial spreading or diffuse infiltratingtype lesions on EUS were due to ENMZLs and mass-forming lesions were associated with DLBCLs.

Tumor Features

Extranodal Marginal Zone B-CellLymphomaENMZLs of the MALT type, formerly known asMALT lymphoma, constitute a group of low-gradeneoplasms that have similar clinical, pathologic,immunologic, and molecular features and arise inthe context of preexisting prolonged lymphoidproliferation in mucosal sites. Previously, thisdisease was often called “pseudolymphoma,” butin recent years, it has been classified as a specificsubtype of non-Hodgkin’s lymphoma. MALT lym-phomas occur most often in the gastrointestinaltract but have been described in various extranodalsites, including the ocular adnexa, salivary glands,thyroid, lungs, thymus, and breast.

Gastric ENMZLs are associated with H. pyloriinfection in as many as 90% of cases. This associationhas been examined by several investigators, andthe mechanism underlying this association isbecoming increasingly better understood. Inhealth, the stomach does not have much lymphoidtissue. H. pylori-induced gastritis leads to an aggre-gation of CD4+ lymphocytes and B cells in thegastric lamina propria. Antigen presentationoccurs, followed by T-cell activation, B-cell prolif-eration, and lymphoid follicle formation. As thesefollicles become prominent, they develop B-cell

82 Stomach

monoclonal populations that appear to be sustainedby stimuli that come from H. pylori-sensitized Tcells. As the monoclonal B-cell populations prolif-erate, they begin to spill into the gastric epithelium.In some instances, they evolve into malignant lym-phoma cells with uncontrolled growth.

The best evidence supporting the role for H.pylori in ENMZL in the stomach is remission of thetumor after eradication of H. pylori infection withantibiotic therapy. Several clinical studies havedocumented complete remission in approximately50% of patients with ENMZL and in 80% if thetumor is in an early clinical stage.

Diffuse Large B-Cell LymphomaDLBCL describes a heterogenous group of non-Hodgkin’s lymphoma. DLBCL may occur de novo,but it may also occur as a high-grade transforma-tion from a low-grade B-cell lymphoma such as anENMZL. Transformation from indolent ENMZL toDLBCL has been described repeatedly in the courseof the disease, and some investigators believe thatall DLBCLs of the stomach are due to transformationof an ENMZL.

StagingThe staging systems for primary gastric lymphomaare complicated (a variant of the standard stagingby lymph node involvement [Fig. 2]). Generally,stage I disease is limited to the stomach and stageII disease implies localized involvement of thelymph nodes on the same side of the diaphragm. Instage III disease, both sides of the diaphragm areinvolved. Stage IV disease is disseminated disease.

TreatmentFirst-line therapy with antibiotics alone is stillconsidered experimental for gastric ENMZL inpatients infected with H. pylori and should beapproached with caution. Most patients whohave a response to antibiotics have small flatmucosal lesions and localized disease withoutlymph node spread or distant metastases. Notall patients are good candidates for monotherapydirected at eradicating H. pylori infection. Onlypatients with localized, mucosal, or submucosalflat lesions and without metastatic disease, lym-phadenopathy, or frank DLBCL are candidatesfor antimicrobial therapy alone. For patients who

do not meet these criteria, therapy for H. pylorieradication should be administered in conjunctionwith conventional therapy.

Once treatment for H. pylori infection has beenadministered, eradication of the organism mustbe proven. Histologic regression requires severalmonths after the infection has been cured withantibiotics, and patients require endoscopicfollow-up at frequent intervals. If the response toantibiotics is incomplete or the disease recurs, stan-dard therapies for lymphoma, such as systemicchemotherapy, radiation, or surgery, should beadministered. Patients who do not initially havea response to or who have disease relapse afteranti-H. pylori therapy still have a high cure rate.For these patients, the 5-year survival rate is ashigh as 90% after single-agent chemotherapy orradiation. Generally, the standard of care forlocalized gastric ENMZL that does not respondto antibiotic therapy or is H. pylori-negative isradiotherapy, which has more than a 90% sur-vival rate at 5 years. Treatment failures or patientswith recurrent or extensive (stage III or IV) dis-ease are treated with multiagent chemotherapy,such as CHOP (cyclophosphamide, doxorubicin,vincristine, and prednisone).

Conventional therapy for DLBCL depends pri-marily on tumor stage. Exploratory laparotomy andpartial gastrectomy may be indicated when stage Idisease is suspected. For stage II, III, or IV disease,the primary therapy is sytemic chemotherapy.Radiotherapy generally is used to reduce the sizeof large lesions and to control localized disease.


Fig. 2. Staging diagram for lymphoma. Orangeboxes, lymph nodes involved. (Fromhttp://www.lymphomation.org/stage.htm. c2004[cited 2007]. Used with permission.)

Rituximab (a chimeric monoclonal antibodytargeting the CD20 epitope present on virtuallyall B cells) has demonstrated activity in varioustypes of lymphoma and has been given to patientswith ENMZL or DLBCL. Promising results havebeen reported for a randomized study that com-pared rituximab plus CHOP (R-CHOP) withCHOP alone in patients with nodal DLBCL. Thisstudy demonstrated improved response rates andsurvival for the patients randomly assigned to theR-CHOP regimen.

PrognosisThe 5-year survival rate for all patients with gastriclymphoma is 50%. Patients with stage I or II tumorsless than 5 cm in diameter have a 10-year survivalrate greater than 80%.

GASTROINTESTINAL STROMALTUMORSStromal tumors affecting the gastrointestinal tractare divided into two groups: tumors identical tothose that arise in soft tissues throughout the restof the body (lipomas, hemangiomas, schwan-nomas, leiomyomas, and leiomyosarcomas) andtumors referred to as gastrointestinal stromal tumors(GISTs). GISTs can occur anywhere in the gas-trointestinal tract but usually affect the stomachand proximal small intestine.

EpidemiologyGISTs are the most common nonepithelial benigntumor involving the gastrointestinal tract, but theystill are rare tumors. The true incidence and preva-lence of GIST tumors are unknown because mostof them are found incidentally.

On the basis of trials of patients with GISTs,the annual incidence of GIST in the United Statesis approximately 6,000 cases annually (10-20 casesper million population). In an autopsy series ofpatients with gastric cancer, the frequency of inci-dental subcentimeter GISTs was much higher,which suggests that only a few microscopic tumorsgrow into a clinically relevant size.

PathogenesisOriginally, it was thought that GISTs arose solelyfrom smooth muscle. In the early 1990s, knowledge

about GISTs increased dramatically, and it wasdiscovered that some of the tumors classified asGISTs were truly myogenic, whereas others wereneural. Of importance, the almost universal expres-sion of the CD117 antigen by GISTs was identified.This allowed GISTs to be differentiated fromleiomyomas and other similar tumors of the gas-trointestinal tract.

The CD117 molecule is part of the c-kitreceptor, a membrane tyrosine kinase that is aproduct of the c-kit or KIT proto-oncogene. In 80%of cases, c-kit activation is the result of an activatingKIT mutation. It is now thought that the majorityof mesenchymal tumors arising within the gas-trointestinal tract are GISTs.

Previously, GISTs were thought to be benigntumors. Their behavior can be quite variable; how-ever, long-term follow-up studies of patients withGISTs have shown that all GISTs have potentialfor malignant behavior.

Clinical FeaturesGISTs are often asymptomatic and are found inci-dentally at endoscopy or at surgery. Patients withlarge GISTs may present with vague symptoms, aswith all cancers of the upper gastrointestinal tract,or with gastrointestinal tract bleeding. Cases havebeen reported of patients with GISTs who presentwith hypoglycemia due to paraneoplastic produc-tion of insulinlike growth factor II by the tumor.

Tumor FeaturesGISTs can arise anywhere in the gastrointestinaltract, but they are most common in the stomachand proximal small bowel. It is uncommon (25% ofcases) for them to occur elsewhere in the gas-trointestinal tract.

Criteria for distinguishing benign from malig-nant GISTs, or at least for identifying the tumorsmost likely to metastasize, have been evaluatedbut have not been clearly defined. It is known thatthe larger the tumor, the more likely it will behavein a malignant fashion. It also is understood thatthe site of origin may predict malignant behavior,with tumors arising from the stomach havingless malignant potential than those arising fromother locations.

When GISTs metastasize, it is usually to theliver. In contrast to leiomyosarcomas, GISTs rarely

84 Stomach

spread to regional lymph nodes and virtually nevermetastasize to distant locations such as the lungs,bones, or brain.

StagingStaging of GISTs primarily involves endoscopyand imaging studies. As mentioned above, mostGISTs occur in the upper gastrointestinal tract andmost are discovered incidentally. Endoscopicbiopsy specimens obtained with standard tech-niques typically are not sufficient for definite diag-nosis. Although EUS-guided biopsy may not yieldenough tissue, specific sonographic features maydistinguish GIST from other submucosal lesions(Fig. 3). CT is the imaging method of choice to char-acterize large GISTs and to identify metastaticdisease. On CT, GISTs appear as a solid mass thatenhances brightly with intravenous contrast.

If noninvasive methods are unsuccessful forcorrectly defining a GIST when it is suspected,preoperative biopsy may not be necessary if thetumor appears to be resectable and the patient isotherwise a surgical candidate. However, ifmetastatic disease is present, surgical biopsy may benecessary to confirm the diagnosis if chemotherapyis a consideration.

TreatmentBefore the year 2000, resection was the only therapythat could be offered to patients with GISTs. The dis-covery of mutations in the KIT gene and the increasein KIT protein function and their association withthe oncogenesis of most GISTs was first reported in1998. Two years later, imatinib mesylate, a potentinhibitor of KIT signaling, was first used. The next 5years established the safety and efficacy of this drugand demonstrated its clinical impact.

Complete resection is possible for most local-ized GISTs, but only 50% of patients will remainfree of disease over 5 years. For patients with recur-rent disease, locally advanced disease, or metastaticdisease, the response rate with imatinib is approx-imately 80%. Imatinib is not a cytotoxic agent, butrather oncostatic. GISTs usually stop growing withthis therapy, but they rarely recede or disappear.

PrognosisPrognosis is influenced by tumor site (small intes-tine worse than stomach), tumor size (the larger, the

worse the prognosis), the ability to resect the tumorcompletely, and the response to imatinib inadvanced disease. Because this is a rare tumor andtreatment has evolved rapidly over the past decade,it is difficult to determine an accurate prognosisthat would apply to all patients with GIST. In recentreports, 5-year survival rates have ranged from30% to 100%, depending on the above factors.


A

B

Fig. 3. A, Endoscopic and, B, endoscopicultrasonographic images of a pedunculated gastricgastrointestinal stromal tumor. Endoscopicultrasonography can demonstrate five wall layers,but only four layers are seen in B. Layer 1 ishyperechoic (white) and is the superficial mucosainterface. Layer 2 is hypoechoic (black) and is deepmucosa. Layer 3 is hyperechoic and represents thesubmucosa. Layer 4 is the muscularis propria. It ishypoechoic (black) and is the layer of origin of mostGISTs. (Courtesy of Dr. Michael J. Levy,Gastroenterology and Hepatology, Mayo Clinic.)

Layer 1 Layer 2

Layer 3

Layer 4

GASTROENTEROPANCREATICNEUROENDOCRINE TUMORSGastroenteropancreatic neuroendocrine tumors(GNETs) arise from neuroendocrine cells. Neuro-endocrine cells occur throughout the body, andneoplasms arise from these cells in many locations.GNETs have variable biologic behavior and arecategorized as poorly differentiated neuroen-docrine tumors (such as small cell carcinoma ofthe lung) and well-differentiated neuroendocrinetumors. The poorly differentiated tumors are high-grade malignancies that usually do not occur inthe gastrointestinal tract. The well-differentiatedtumors typically are indolent, and most occur inthe gastrointestinal tract. In the gastrointestinaltract, GNETs include carcinoid tumors and pan-creatic islet cell tumors (gastrinoma, insulinoma,glucagonoma, VIPoma, and somatostatinoma).

EpidemiologyGNETs are uncommon. Of these tumors, carcinoidtumors are the most common, with an annual inci-dence of 15 per 1,000,000 population. In the UnitedStates, all other GNETs combined have a preva-lence of 10 per 1,000,000 population.

PathogenesisGNETs may occur sporadically or as part of anautosomal dominant inherited multiple endocrineneoplasia (MEN) syndrome. All gastrointestinalendocrine tumors can be associated with MENtype 1 (MEN 1). MEN 1 is characterized by pituitary,parathyroid, and pancreatic hyperplasia or tumors.

Clinical FeaturesBecause GNETs are of neuroendocrine origin, theymay secrete various peptides and hormones. Mostof these tumors produce several hormones, butvery few are associated with a clinical syndrome.They also produce substances other than peptides,for example, chromogranins, which can be localizedwith immunochemical studies.

CARCINOID TUMORS ANDCARCINOID SYNDROMECarcinoid tumors, the most common GNETs, areslow growing and can occur anywhere in the ali-mentary tract. The clinical presentation varies from

an asymptomatic incidental finding to symptomatictumors, including the classic carcinoid syndrome.

Clinical and Tumor FeaturesMost carcinoid tumors are found incidentally; thus,at the time of diagnosis, most patients are asymp-tomatic. If symptoms are present, they often arenonspecific and associated with the location andextent of the tumor. Symptoms due to the directeffects of a tumor in the gastrointestinal tract maybe abdominal pain, intestinal obstruction, nausea,weight loss, or intestinal bleeding.

Carcinoid tumors are rare, and those that causecarcinoid syndrome are even rarer. Only 5% ofpatients with carcinoid tumors have carcinoid syn-drome. When the syndrome is present, it is asso-ciated most commonly with tumors in the smallbowel that have metastasized to the liver.

Carcinoid syndrome is due to peptidesreleased by the tumor into the systemic circulation.As many as 40 secretory products have been iden-tified; the common ones are histamine, kallikrein,prostaglandins, serotonin, and tachykinins. Theliver often inactivates these peptides, which is thereason patients have symptoms of carcinoid syn-drome primarily in association with liver metas-tases: the bioactive products are secreted directlyinto the hepatic veins.

The most common symptoms of carcinoid syn-drome are diarrhea and facial flushing. The mostcommon physical finding is hepatomegaly.Intermittent facial flushing occurs in up to 85% ofthe patients. The flush usually starts acutely andcan last from 30 seconds to 30 minutes. The typicalflush is red or violaceous and appears on the face,neck, and upper chest. Flushes can be associatedwith hypotension and tachycardia. Several incitingfactors are known for the flushing associated withcarcinoid syndrome: eating, alcohol ingestion, theValsalva maneuver, increased emotional states,trauma or pressure on the liver (including on phys-ical examination), and anesthesia. Anesthesia canprovoke long episodes of flushing that can resultin life-threatening hypotension known as carcinoidcrisis. Carcinoid crisis can be prevented by theadministration of octreotide before anesthesia.

Diarrhea occurs in 80% of patients with car-cinoid syndrome and can be quite severe. It is asecretory diarrhea, and patients may pass as many

86 Stomach

as 30 stools per day. Although the diarrhea usuallyis unrelated to the flushing episodes, the associateddehydration can contribute to the hypotensionfrom flushing.

Wheezing is a common component of carci-noid syndrome and is due to bronchospasm andright-sided valvular heart disease. Unlike diar-rhea, wheezing and dyspnea are worse duringflushing episodes. Of importance, wheezing asso-ciated with carcinoid syndrome should not betreated like bronchial asthma: treatment with β-agonists can incite prolonged vasodilation andsevere hypotension. Hypertension usually is notpresent in carcinoid syndrome but, as statedabove, the syndrome can cause paroxysmal andclinically important hypotension.

Aside from carcinoid syndrome, the clinicalpresentation, tumor features, treatment recom-mendations, and prognosis of carcinoid tumorsvary by the location of the primary tumor. Below,each of these characteristics is discussedaccording to the organ from which the tumorarises (Table 3).

StomachGastric carcinoid tumors tend to occur in the bodyof the stomach. They may be single or multiple,and, to endoscopists, they may appear to be anordinary ulcer, polyp, or tumor mass. They areoften round and gray or yellow.

Gastric carcinoid tumors occur more fre-quently in patients who have a disease that causes

hypergastrinemia, such as pernicious anemia andatrophic gastritis with achlorhydria. They alsoappear to be more common in patients withZollinger-Ellison syndrome. Any condition inwhich serum levels of gastrin are increased for along period should alert clinicians that gastric car-cinoid tumors may be present.

Gastric carcinoids have been divided into threeseparate types, each of which has a differentbehavior and prognosis.

Type 1Up to 80% of all gastric carcinoids are type 1. Theyare associated with pernicious anemia or chronicatrophic gastritis. The tumors are derived fromenterochromaffin-like cells and are thought todevelop from long-standing stimulation byincreased serum levels of gastrin. Type 1 carci-noids usually are diagnosed in patients in their 60sand 70s. As with chronic atrophic gastritis and per-nicious anemia, type 1 carcinoids are morecommon in women than in men. These tumors areusually small and multiple. Metastatic disease israre and occurs in fewer than 10% of tumors 2 cmor smaller but in as many as 20% of larger tumors.These tumors generally are indolent and often areconsidered a benign condition.

Type 2Carcinoid tumors of the stomach due to hyper-gastrinemia from gastrinomas are classified as type2 gastric carcinoids. They are rare (<5% of gastric


Table 3. Characteristics of Carcinoid Tumors Based on Location

Secretory Carcinoid ClinicalLocation products syndrome characteristics

ForegutStomach, duodenum, pancreas Serotonin, Rare Indolent except type

histamine 3 gastric carcinoidMidgut

Jejunum, ileum, appendix, Serotonin, prosta- Classic, but present Often multiple, ascending colon glandins, poly- in <10% of cases usually in ileum

peptidesHindgut

Transverse, descending, and None Rare Indolent except insigmoid colon and rectum colon

carcinoids) and, like type 1 gastric carcinoids, theyare typically small, multiple, slow growing, andindolent and have little malignant potential.

For types 1 and 2 gastric carcinoids smallerthan 1 cm, endoscopic resection, if possible, is thetreatment of choice. Because these patients oftenhave sustained hypergastrinemia, endoscopicsurveillance every 6 to 12 months has been recom-mended, but progression to malignant disease anddeath is unusual.

For patients with multiple tumors or advanceddisease that is not appropriate for resection, antrec-tomy or medical therapy aimed at reducing serumlevels of gastrin has been advocated. Antrectomydecreases hypergastrinemia by removing muchof the gastrin-producing cell mass in the stomach.In a small controlled study, this was shown to leadto the regression of these tumors.

Type 3Type 3 gastric carcinoids are sporadic and do notappear to be associated with hypergastrinemia.Of all gastric carcinoids, 20% are type 3. They arethe most aggressive of the gastric carcinoids, and65% of patients have local or liver metastases atthe time the tumor is discovered. Type 3 is the onlytype of gastric carcinoid that is associated withcarcinoid syndrome, because these tumors oftenproduce 5-hydroxytryptophan. Because sporadicgastric carcinoids (type 3) are more aggressive,they usually are treated by partial or total gas-trectomy with local lymph node resection.

Overall, patients who have carcinoid tumorsarising in the stomach have a 5-year survival rateof 50% to 95%.

Small Intestinal Carcinoid TumorsSmall intestinal carcinoid tumors are the carci-noid tumors most important clinically becausepatients are more likely to present with intestinalsymptoms and carcinoid syndrome, which occursin up to 10% of these patients. Abdominal painor bowel obstruction can be caused by the directmechanical effect of the tumor and an associatedfibroblastic reaction, intussusception, or mesen-teric ischemia due to tumor-associated fibrosisor angiopathy.

Most small intestinal carcinoids occur in theileum within 2 ft of the ileocecal valve. Carcinoids

that occur in the small intestine may be multicentricand have a higher likelihood than carcinoidsarising from other portions of the gastrointestinaltract to metastasize to regional lymph nodes andthe liver. Because small intestinal carcinoids,regardless of size, have the potential to metasta-size, they should be removed surgically, with locallymph node resection. These are the patients mostat risk for synchronous lesions (present in 30% ofcases), so at the time of surgery, the surgeon shouldthoroughly inspect the remaining small bowel.Resection may be required for palliation, even inpatients with metastatic disease. The prognosisfor patients with small intestinal carcinoids varieswith the stage of disease. The 5-year survival rateranges from 35% to 80%.

AppendixUp to half of intestinal carcinoids are appendicealtumors, and carcinoid tumors are the mostcommon neoplasms of the appendix. They arealmost always asymptomatic and typically arediscovered incidentally at appendectomy.Incidental carcinoids are found in 0.5% of appen-dectomy specimens. Appendiceal carcinoids areoften smaller than 1 cm. They usually are solitaryand benign. Although local invasion of appen-diceal carcinoids is common, metastatic diseaseis rare.

If symptoms are present, they usually are asso-ciated with large tumors, tumors located at thebase of the appendix, and those that have associ-ated metastatic disease. Approximately 10% ofpatients with appendiceal carcinoids have tumorsat the base of the appendix, where the tumor cancause obstruction that may result in appendicitis.Patients with appendiceal carcinoids may presentwith carcinoid syndrome, but this is almost alwaysin the setting of liver metastases.

The prognosis of appendiceal carcinoids isdetermined by the size of the tumor. Tumorssmaller than 2 cm (most tumors) are unlikely tohave metastasized when diagnosed. Tumorslarger than 2 cm are uncommon, but when theyare present, up to 30% have metastasized at thetime of diagnosis. Appendiceal tumors smallerthan 2 cm can be treated with simple appendec-tomy. Larger tumors usually can be treated withright hemicolectomy.

88 Stomach

The overall 5-year survival rate of patientswith appendiceal carcinoids is 70% to 100%, butfor patients with metastatic disease at the time ofpresentation, it ranges from 10% to 30%.

Colon Carcinoid of the colon is rare. When it occurs, it isoften located on the right side of the colon. Unlikepatients with carcinoid tumors in other locations,patients with carcinoid of the colon may presentwith symptoms, and when they do, they often havelocally advanced disease. Local resection of thetumor has been reported to be effective in the earlystages of disease, but many patients require radicalcolectomy because of advanced disease at the timeof diagnosis. Patients with colonic carcinoid tumorsrarely have carcinoid syndrome. The overall 5-yearsurvival rate for patients with colonic carcinoidtumors is 30% to 75%.

RectumRectal carcinoids nearly always are asymptomaticand found incidentally during proctosigmoi-doscopy. They are not associated with carcinoidsyndrome. Tumors smaller than 1 cm can betreated with local excision. Radical excision is moreappropriate for tumors larger than 2 cm or forsmaller tumors that have invaded the muscularispropria. The overall 5-year survival rate forpatients with rectal carcinoid tumors ranges from75% to 100%.

Diagnosis of Carcinoid Tumors andSyndromeMost carcinoid tumors are found incidentally onendoscopy or imaging studies performed for otherindications. If symptoms are present and are dueto local effects of the tumor, they usually are foundon CT. If symptoms of carcinoid syndrome arestrongly suspected, the best initial evaluation iswith urinary 5-hydroxyindoleacetic acid. Carcinoidtumors lack aromatic L-amino acid decarboxylase;thus, urinary levels of 5-hydroxyindoleacetic acidare increased. Octreotide scintigraphy (Octreascan)identifies the site of primary tumors and metastaticdisease in more than 80% of patients with carci-noid syndrome. Magnetic resonance imaging andselective angiography are sensitive for detectingmetastases to the liver.

GASTROENTEROPANCREATICNEUROENDOCRINE TUMORS OFPANCREATIC ORIGIN

GastrinomaGastrinomas produce the classic triad of symptomscalled Zollinger-Ellison syndrome. This syndromeconsists of peptic ulcer disease, gastric acid hyper-secretion, and a gastrin-producing tumor.Gastrinomas are rare and occur in fewer than 1%of patients who have peptic ulcer disease.Gastrinomas are frequently associated with MEN1 syndrome.

Etiology and PathogenesisThe majority of gastrinomas were thought to benonislet cell tumors of the pancreas. With advancesin technology, we now know that extrapancreaticgastrinomas are common. One-half of gastrinomasoccur in the duodenal wall; the pancreas is thesecond most common site. However, more than90% of gastrinomas occur in an anatomical areacalled the gastrinoma triangle (Fig. 4).

Gastrinomas are slow growing, and it can bedifficult to differentiate benign tumors frommalignant ones. Approximately two-thirds of gas-trinomas are malignant. The best indicator ofmalignancy is the presence of metastases, whichmost often affect the regional lymph nodes or theliver. It is important to determine whether livermetastases are present. If they are, the patient isnot a candidate for surgical treatment.

Clinical FeaturesPeptic ulcer disease is the most common sign ofgastrinoma and occurs in more than 90% ofpatients. Traditionally, the ulcer disease associ-ated with gastrinomas has been characterized bymultiple duodenal ulcers (including postbulbarulcers) and esophagitis that is refractory to medicaltreatment (Fig. 5). However, the most commontype of ulcer associated with gastrinoma is anordinary ulcer in the duodenal bulb.

As many as 70% of patients with a gastrinomahave symptoms or endoscopic findings of severegastroesophageal reflux, which likely is caused byhypersecretion of gastric acid. Also, 50% of thepatients have diarrhea due to the effect of acidhypersecretion on the small bowel. Increased acid


exposure to the small bowel causes morphologicand inflammatory changes that can result in mal-absorption. In addition, the low pH may inactivatepancreatic lipase and cause bile salts to precipitate,resulting in malabsorption of fat and steatorrhea.

If a patient has a duodenal ulcer that is notcaused by either H. pylori infection or nonsteroidalantiinflammatory drugs or if a patient has duo-denal ulcer disease and diarrhea, the concurrentpresence of gastrinoma should be considered.

Diagnostic TestsFor patients with the clinical manifestations of gas-trinoma, the first screening test is determining the

serum level of gastrin. This should be done afterproton pump inhibitor therapy has been withheldfor at least 7 days. A serum gastrin level of morethan 1,000 pg/mL suggests the presence of gas-trinoma. A level less than 1,000 pg/mL but morethan 110 pg/mL may be consistent with severalconditions that cause hypergastrinemia. The mostcommon cause of hypergastrinemia generally isachlorhydria. The most common cause ofachlorhydria, in turn, is atrophic gastritis. Othercauses of hypergastrinemia associated withachlorhydria include gastric ulcer, gastric carci-noma, vagotomy, or current proton pumpinhibitor therapy. Also, some disorders causehypergastrinemia with normal or increased acidsecretion. These are gastric outlet obstruction,retained gastric antrum in patients with previousgastric surgery, or a rare hereditary conditioncalled antral G-cell hyperplasia.

If the gastrin level is increased, then it mustbe determined whether there is concomitant gas-tric acid hypersecretion. This is done by measuringbasal acid output (BAO). Before BAO is measured,acid-suppressing medications must be discon-tinued: 24 hours for H2-receptor antagonists and 7days for proton pump inhibitors. In the 24 hoursbefore the test, the patient receives antacids. Anasogastric tube is placed into the antrum, and thestomach is emptied. Four samples of gastric fluidare collected; a quadruplicate of each sample is

90 Stomach

Fig. 5. Endoscopic images of, A, multiple duodenal ulcers and, B, severe esophagitis in a patient with metastaticgastrinoma who receives proton pump inhibitor therapy.

A B

Fig. 4. The gastrinoma triangle. Note that 90% ofgastrinomas occur inside the gastrinoma triangle.

titrated to pH 7 with 0.2 N sodium hydroxide,while the BAO is determined with a radiometertitrator. In a stomach that has not been operatedupon, a BAO greater than 15 mEq/hour is diag-nostic of Zollinger-Ellison syndrome. If the patientunderwent gastric resection for acid reduction, aBAO greater than 10 mEq/hour is diagnostic ofZollinger-Ellison syndrome.

A secretin stimulation test is warranted foronly a few clinical situations (Fig. 6). If a patienthas pronounced hypergastrinemia and acid hyper-secretion (not achlorhydria) but the serum gastrinlevel is less than 1,000 pg/mL, an intravenoussecretin test is indicated. In patients with Zollinger-Ellison syndrome, the serum level of gastrinincreases at least 200 pg/mL over the basal gastrinlevel. Patients with other causes of hypergas-trinemic hyperchlorhydria have only a slight orno increase in the serum level of gastrin.

Once there is biochemical evidence of gastri-noma, the tumor should be localized. Most gas-trinomas have somatostatin receptors. Thus, the

radiolabeled somatostatin analogue octreotideused with scintigraphy can localize 85% of gas-trinomas. Because most gastrinomas occur in thegastrinoma triangle, EUS is very sensitive inlocalizing the primary tumor but is less helpful inevaluating metastatic disease. CT of the abdomendetects approximately one-half of the tumors andmay be useful for directing biopsy of liver metas-tases, if present.

TreatmentSurgical resection is the treatment of choice forpatients with resectable (ie, not metastatic or locallyadvanced) disease. Patients with liver metastasesor MEN 1 syndrome (with multifocal disease) maynot be candidates for surgical treatment becausethey may have multiple tumors.

If resection is not possible, the objective intreating Zollinger-Ellison syndrome is to controlgastric acid hypersecretion. Medical treatment todecrease gastric acid hypersecretion usually con-sists of proton pump inhibitors and octreotide.


Fig. 6. Diagnostic evaluation of gastrinoma and Zollinger-Ellison syndrome (ZES). EUS, endoscopicultrasonography; MRI, magnetic resonance imaging; PPI, proton pump inhibitor.

Suspected ZES

Serum gastrin off PPIfor at least 1 week

>110 and <1,000 pg/mL

Secretin stimulation test

Negative:No furtherwork-up

Positive

EUS, somatostatinreceptor scintigraphy

(MRI)

>1,000 pg/mL

Gastric pH probe (offPPI for a week)

<4.0 >4.0

InsulinomaInsulinomas are insulin-secreting islet cell tumorsthat originate in the pancreas and cause symptomsof hypoglycemia. They are usually solitary but,rarely, may be multiple.

Clinical FeaturesMost patients present with clinical manifestationsof hypoglycemia: altered or loss of consciousness,confusion, dizziness, and visual disturbances.Symptoms may also result from catecholaminerelease caused by hypoglycemia. These symptomsare anxiety, weakness, fatigue, headache, palpita-tions, tremor, and sweating. Typically, symptomsoccur with fasting, when a meal is delayed ormissed, or during exercise. Patients may learn toavoid symptoms by eating frequently; as a result,40% of patients have a history of weight gain fromincreased eating.

DiagnosisThe presence of an insulinoma is determined bythe combination of a low fasting blood glucoselevel and an inappropriately increased plasmainsulin level. This combination is identified in 65%of patients with insulinoma. For a definitive diag-nosis, a 72-hour fast is required, with serum glucoseand insulin levels determined at regular intervalsand when the patient becomes symptomatic. Withthis fasting test, symptoms develop in 75% of thepatients with an insulinoma within 24 hours, in95% by 48 hours, and in virtually 100% within72 hours.

When there is biochemical evidence of an insuli-noma, localization of the tumor can be difficultbecause most tumors are small. Because it is lesscommon for insulinomas than for gastrinomas tohave somatostatin receptors, radiolabeled octreotidewith scintigraphy can localize only 50% of thetumors. Also, CT of the abdomen detects only 50%of insulinomas because of their small size. Thesetumors are almost exclusively in the pancreas, soEUS can detect nearly 90% of them. EUS is theimaging modality of choice. Metastatic insulinomais evaluated best with magnetic resonance imaging.

TreatmentAs for any GNET, definitive treatment is surgicalremoval of the tumor, and this is indicated for any

patient in whom metastatic disease has not beenidentified. According to most reports, 70% to 95%of all patients are cured with surgical treatment.

Patients with metastatic disease and thosewith insulinomas that have not been removed bypartial pancreatectomy can be managed withhyperglycemic agents such as diazoxide andoctreotide. Also, patients with metastatic insuli-noma may receive chemotherapy. The most effec-tive combination chemotherapy is streptozocinand doxorubicin.

VIPomaVIPoma syndrome is caused by a neuroendocrinetumor that is usually in the pancreas and producesvasoactive intestinal polypeptide (VIP). This syn-drome is characterized by severe watery diarrhea,hypokalemia, and achlorhydria and is known as theWDHA syndrome (watery diarrhea, hypokalemia,and achlorhydria), or Verner-Morrison syndrome.

PathogenesisApproximately 90% of VIPomas are in the pan-creas. Although other tumors, including intestinalcarcinoids, pheochromocytomas, and bron-chogenic carcinomas, may produce VIP, they rarelycause VIPoma syndrome. A VIPoma usually is asolitary non-beta pancreatic islet cell tumor, andmore than 75% of them occur in the body or tail ofthe pancreas. Although these tumors are slowgrowing, they frequently reach a large size beforediagnosis. Seventy-five percent of VIPomas aremalignant, and 50% have metastasized at the timeof diagnosis. VIPomas cannot be differentiated fromother pancreatic endocrine tumors with con-ventional histologic or electron microscopicexamination. However, the demonstration ofimmunoreactive VIP in the tumor and plasmaestablishes the diagnosis. VIP induces intestinalwater and chloride secretion and inhibits gastricacid secretion.

Clinical FeaturesAs stated above, VIPomas cause secretory diarrhea,which results in hypokalemia and dehydration.Stool volume may exceed 3 L/day. The waterydiarrhea resembles that of cholera, hence the termpancreatic cholera. Erythematous flushing of thehead and trunk may occur in some patients. Also,

92 Stomach

some patients develop hyperglycemia because ofVIP- and hypokalemia-induced glycogenolysis inthe liver.

DiagnosisVIPoma syndrome should be suspected if patientspresent with high-volume watery diarrhea thatpersists despite fasting and is associated withhypokalemia and dehydration. The diagnosis isconfirmed by the finding of an increased plasmaconcentration of VIP. Because these tumors arelarge, frequently malignant, and metastatic, theabdomen should be scanned with CT to localizeand determine the extent of tumor involvement.MRI is also effective for localizing the tumor anddemonstrating metastatic disease. Other imagingstudies may not be necessary. Preliminary dataindicate that somatostatin receptor scanning andEUS also are effective for imaging these tumors.

TreatmentThe first priority of treatment is to correct the dehy-dration and electrolyte abnormalities. Patients mayrequire 5 L or more of fluid per day, with aggressivepotassium replacement. Long-acting octreotidecontrols the diarrhea in most patients with VIPoma,and this agent is considered the initial treatmentof choice. For patients who do not have a responseto somatostatin analogues, concomitant adminis-tration of glucocorticoids may be tried because thecombination has had some success.

After imaging studies have localized anddetermined the extent of tumor involvement,surgery should be considered for all patientswithout evidence of metastatic disease. Surgicalresection of a pancreatic VIPoma relieves all symp-toms and is curative in approximately 30% ofpatients. Surgery also may be indicated to relievelocal effects produced by the large size of the tumor.

For patients with metastatic disease, the besttreatment option is chemotherapy. Streptozocinplus doxorubicin or fluorouracil are the most effec-tive chemotherapy regimens and achieve partialremission in up to 90% of patients.

GlucagonomaGlucagonomas produce a rare syndrome of der-matitis, glucose intolerance, weight loss, andanemia associated with a pancreatic islet cell tumor.

PathogenesisGlucagonomas usually are solitary, large tumorswith an average size of 5 to 6 cm at the time of diag-nosis. Sixty-five percent of the tumors are locatedin the head of the pancreas, and the other 35% occurequally in the body and tail. Most tumors aremetastatic at the time of diagnosis.

Clinical FeaturesGlucagonomas occur in persons 45 to 70 years old.The characteristic presentation is that of a distinctdermatitis called necrolytic migratory erythema,which usually develops a mean of 7 years beforethe onset of other symptoms. This rash starts as anerythematous area, typically in an intertriginousarea such as the groin, buttocks, thighs, or per-ineum, or it may start in periorificial areas. Theerythematous lesions spread laterally and thenbecome raised, with superficial central blistering orbullous formation. When the bullae rupture,crusting occurs and the lesions begin to heal in thecenter. Healing is associated with hyperpigmen-tation. The entire sequence usually takes 1 to 2weeks and consists of a mixed pattern of erythema,bullous formation, epidermal separation, crusting,and hyperpigmentation, which wax and wane.Glossitis, angular stomatitis, dystrophic nails, andhair thinning are other clinical findings. Themajority of patients with glucagonoma also havehypoaminoacidemia, which may be responsiblefor the rash. The rash improves with treatmentwith amino acids and nutrition.

Glucagon stimulates glycogenolysis, gluco-neogenesis, lipolysis, ketogenesis, and insulinsecretion and inhibits pancreatic and gastric secre-tion and intestinal motility. Most patients havesome glucose intolerance, and some may havefrank diabetes mellitus. Most patients withglucagonoma also have noticeable weight loss,even if the tumor is found incidentally and is small.It is believed that glucagon exerts a catabolic effect.Some patients also may have anorexia.

DiagnosisIf the clinical features of glucagonoma are present,the diagnosis can be confirmed by the finding ofan increased plasma glucagon level of more than1,000 pg/mL. Because glucagonomas occur in thepancreas and tend to be large and metastatic at the


time of clinical presentation, CT of the abdomenusually localizes the tumor.

TreatmentThe initial objective of treatment is to control thesymptoms and hyperglycemia and to restore nutri-tional status. The surgical risk of these patientsusually is increased because of the catabolic effectsof glucagon, glucose intolerance, and hypoamin-oacidemia. Patients should receive nutritionalsupport, and the hyperglycemia should be cor-rected. The rash may improve with correction ofthe hypoaminoacidemia. If anemia is pronounced,transfusion may be needed. Octreotide is usefulfor controlling symptoms, and it improves the der-matitis, weight loss, diarrhea, and abdominal painbut not diabetes mellitus. Surgery is offered to allpatients who are acceptable surgical risks and whodo not have evidence of metastatic spread of thetumor, but it is curative in only 20% of them.

In patients with metastatic disease, it is impor-tant to remember that the tumors are slowgrowing and survival is good even for those whodo not receive chemotherapy. There is no clearevidence that chemotherapy has any importanteffect on these tumors. The most commonly usedchemotherapeutic agents are streptozocin anddoxorubicin or fluorouracil.

SomatostatinomaSomatostatinomas are the least common of theGNETs. They produce a distinct syndrome of dia-betes mellitus, gallbladder disease, and steatorrhea.

PathogenesisSomatostatinomas are neuroendocrine tumors thatoccur in the pancreas and intestine. Tumors thatarise in the pancreas tend to have higher levels ofsomatostatin and are more likely to produce symp-toms. Somatostatinomas are usually solitary andlarge, and the majority have metastasized at thetime of diagnosis. Somatostatin inhibits insulinrelease, gallbladder motility, and the secretion ofpancreatic enzymes and bicarbonate.

Somatostatinomas are not associated withMEN 1. However, they have been found in patientswith pheochromocytoma, café au lait spots, andneurofibromatosis, suggesting a possible associ-ation with MEN 2B.

Clinical FeaturesDiabetes mellitus occurs in one-half of the patientswith somatostatinoma. Gallbladder disease occursin 65% of the patients and usually is manifestedas cholelithiasis, acalculous cholecystitis, orobstructive jaundice from local tumor invasion.Steatorrhea occurs in one-third of the patients.

DiagnosisMost somatostatinomas are found incidentallywhen laparotomy is performed for gallbladderdisease. The diagnosis is established by the findingof somatostatin-containing D cells in the resectedtumor and an increased plasma concentration ofsomatostatin-like immunoreactive material.Tumors are localized with CT or ultrasonographyof the abdomen.

TreatmentDiabetes mellitus usually is mild and responds tooral hypoglycemic agents or low doses of insulin.No specific medical treatment exists. Octreotidemay be helpful in treatment. However, somato-statinomas are rare, and more reports are neededto determine the efficacy of octreotide.

Surgical excision is the treatment of choice,but most patients present with metastatic disease.Cytotoxic chemotherapy is offered to patients whohave evidence of metastatic disease, but there isno clear evidence that this treatment is effective.

MANAGEMENT PRINCIPLES OF GNETS In general, the treatment of GNETs is based on thefollowing: localization of the tumor and identifi-cation of metastatic disease if present, resection ofthe primary tumor if appropriate, and control of thesymptoms of carcinoid syndrome (Fig. 7).

The liver is the predominant site of metastaticdisease. Hepatic resection is indicated for the treat-ment of metastatic liver disease in the absence ofdiffuse bilobar involvement, compromised liverfunction, or extensive extrahepatic metastases.Although surgery is not curative in the majorityof cases, symptoms of hormone hypersecretion areeffectively palliated and prolonged survival is oftenpossible because these tumors are slow growing.

Other therapies can be directed at specific com-ponents of the syndrome. Patients with flushing

94 Stomach

should avoid ingesting substances that can induceflushing, such as alcohol. Also, physical therapythat could involve pressure or trauma to the rightupper quadrant should be avoided. Certain drugs,such as codeine and cholestyramine, can help con-trol flushing and diarrhea. Severe symptoms oftenrequire a somatostatin analogue such as octreotide.

Flushing and diarrhea can be ameliorated in upto 80% of patients treated with octreotide. A depotform of octreotide (Sandostatin LAR) has beendeveloped that allows for monthly, rather thanthrice daily, administration. Typically, patientsstart a brief trial of the short-acting form ofoctreotide (to assess for symptomatic response andtolerance) and then start receiving a dose of 20 mgintramuscularly monthly, with a gradual increase

in the dose as needed for control of symptoms.Patients also can be given short-acting, subcuta-neous octreotide for breakthrough symptoms.

In addition to improving symptoms, octreotidemay retard tumor growth. Because octreotide isnot cytotoxic, the disease rarely regresses.

Patients who have progressive metastaticcarcinoid tumors have few therapeutic options,and the best systemic therapy has not been defined.Several cytotoxic drugs (streptozocin and doxoru-bicin or fluorouracil) have been tried in various com-binations and generally have had minimal effecton these tumors. The lack of effectiveness of anyone agent or combination of agents has led todebate about whether chemotherapy is appropriatefor these patients.


Diagnosis of metastatic GNET

Somatostatin analogues (if positive Octreoscan and/or symptoms of

hormonal hypersecretion)

Consider resectionof primary lesion

(if causing symptoms)

Presence of extrahepaticdisease

Carcinoidtumor

Pancreatic isletcell tumor

Streptozocin/doxorubicinor temozolomide-based

treatment

• Interferon alpha• Investigational agents (VEGF pathway inhibitor, radiolabeled somatostatin analogues)

Hepatic-predominantdisease

Surgicalresection

(if feasible)

Hepatic arteryembolization

(if not a surgicalcandidate)

Livertransplantation

Consider:

Fig. 7. Treatment algorithm for metastatic gastroenteropancreatic neuroendocrine tumors (GNETs). VEGF,vascular endothelial growth factor.

METASTATIC DISEASE TO THESTOMACHWhen a patient presents with upper gastroin-testinal tract symptoms and a history of a primaryextragastric neoplasm, metastatic involvement ofthe stomach should be considered as a possibleexplanation of the symptoms.

Malignant melanoma is one of the most fre-quently encountered metastatic lesions to thestomach. At endoscopy, it usually appears as aslightly elevated black nodule. Cancer of the breast,lung, ovary, testis, liver, or colon or sarcoma can allinvolve the stomach.

RECOMMENDED READINGCraanen ME, Dekker W, Blok P, Ferwerda J, Tytgat

GN. Time trends in gastric carcinoma:changing patterns of type and location. Am JGastroenterol. 1992;87:572-9.

Hundahl SA, Phillips JL, Menck HR. The NationalCancer Data Base Report on poor survival ofU.S. gastric carcinoma patients treated withgastrectomy: Fifth Edition American JointCommittee on Cancer staging, proximal dis-ease, and the “different disease” hypothesis.Cancer. 2000;88:921-32.

Hussell T, Isaacson PG, Crabtree JE, Spencer J. Theresponse of cells from low-grade B-cell gas-tric lymphomas of mucosa-associated lym-phoid tissue to Helicobacter pylori. Lancet.1993;342:571-4.

Jemal A, Siegel R, Ward E, Murray T, Xu J, SmigalC, et al. Cancer statistics, 2006. CA Cancer JClin. 2006;56:106-30.

Klöppel G, Perren A, Heitz PU. The gastroen-teropancreatic neuroendocrine cell system andits tumors: the WHO classification. Ann N YAcad Sci. 2004;1014:13-27.

Lau M, Le A, El-Serag HB. Noncardia gastric ade-nocarcinoma remains an important and deadlycancer in the United States: secular trends inincidence and survival. Am J Gastroenterol.2006;101:2485-92. Epub 2006 Oct 4.

Macdonald JS, Smalley SR, Benedetti J, HundahlSA, Estes NC, Stemmermann GN, et al.Chemoradiotherapy after surgery comparedwith surgery alone for adenocarcinoma of thestomach or gastroesophageal junction. N EnglJ Med. 2001;345:725-30.

Modlin IM, Kidd M, Latich I, Zikusoka MN,Shapiro MD. Current status of gastrointestinalcarcinoids. Gastroenterology. 2005;128:1717-51.

Radaszkiewicz T, Dragosics B, Bauer P.Gastrointestinal malignant lymphomas of themucosa-associated lymphoid tissue: factorsrelevant to prognosis. Gastroenterology.1992;102:1628-38.

Tamura G, Yin J, Wang S, Fleisher AS, Zou T,Abraham JM, et al. E-Cadherin gene pro-moter hypermethylation in primary humangastric carcinomas. J Natl Cancer Inst. 2000;92:569-73.

Yatsuya H, Toyoshima H, Tamakoshi A, KikuchiS, Tamakoshi K, Kondo T, et al; JapanCollaborative Cohort Study Group. Individualand joint impact of family history andHelicobacter pylori infection on the risk ofstomach cancer: a nested case-control study. BrJ Cancer. 2004;91:929-34.

96 Stomach

Motility disorders result from impaired control ofthe neuromuscular apparatus of the gut. Associatedsymptoms include recurrent or chronic nausea,vomiting, bloating and abdominal discomfort,constipation, or diarrhea, which occur in theabsence of intestinal obstruction. Occasionally,gastroparesis and intestinal pseudo-obstructionare associated with generalized disease processesthat affect other regions of the gastrointestinal tractand extraintestinal organs, including the urinarybladder. In many patients, the role of motility ingenerating symptoms is unclear. Such patients arethought to have a functional gastrointestinal dis-order, specifically functional dyspepsia.

CONTROL OF GASTROINTESTINALMOTOR FUNCTIONMotor function of the gastrointestinal tract dependson the contraction of smooth muscle cells and theirintegration and modulation by enteric and extrinsicnerves. Derangement of the mechanisms that reg-ulate gastrointestinal motor function may lead toaltered gut motility. Neurogenic modulators ofgastrointestinal motility include the central ner-vous system, the autonomic nerves, and the enteric

nervous system. Extrinsic neural control of gas-trointestinal motor function consists of the cranialand sacral parasympathetic outflow (excitatory tononsphincteric muscle) and the thoracolumbarsympathetic supply (excitatory to sphincters,inhibitory to nonsphincteric muscle). The cranialoutflow is predominantly through the vagus nerve,which innervates the gastrointestinal tract fromthe stomach to the right colon and consists of pre-ganglionic cholinergic fibers that synapse with theenteric nervous system. The supply of sympatheticfibers to the stomach and small bowel arises fromlevels T5 to T10 of the intermediolateral columnof the spinal cord. The prevertebral ganglia havean important role in the integration of afferentimpulses between the gut and the central nervoussystem and reflex control of abdominal viscera.

The enteric nervous system is an independentnervous system consisting of approximately 100million neurons organized into ganglionatedplexuses. The larger myenteric (or Auerbach)plexus is situated between the longitudinal andcircular muscle layers of the muscularis externaand contains neurons responsible for gastroin-testinal motility. The submucosal (or Meissner)plexus controls absorption, secretion, and mucosal

97

CHAPTER 7

Gastrointestinal Motility Disorders

Michael Camilleri, MDG. Richard Locke III, MD

Abbreviations: ANNA-1, anti-neuronal nuclear autoantibodies type 1; 5-HT, serotonin; TPN, total parenteral nutrition.

blood flow. The enteric nervous system is alsoimportant in visceral afferent function.

The enteric nervous system develops in uteroby migration of neural crest cells to the developingalimentary canal. This migration and the sequenceof innervation of different levels of the gut are reg-ulated by specific signaling molecules, which includetranscription factors (eg, Mash1), neurotrophic fac-tors (eg, glial-derived neurotrophic factor), and theneuregulin signaling system. These facilitate thegrowth, differentiation, and persistence of themigrating nerve cells after they arrive in the gut. Thereceptors for neuregulin proteins are tyrosinekinases, which are important in cell signaling.

Myogenic factors regulate the electrical activitygenerated by gastrointestinal smooth muscle cells.The interstitial cells of Cajal, located at the interfaceof the circular and longitudinal muscle layers ofthe small intestine, form a nonneural pacemakersystem and function as intermediaries betweenthe neurogenic (enteric nervous system) and myo-genic control systems. The interstitial cells of Cajalare in proximity to the gastrointestinal smoothmuscle cells. Electrical control activity spreadsthrough the contiguous segments of the gutthrough neurochemical activation by excitatory(eg, acetylcholine and substance P) and inhibitory(eg, nitric oxide, somatostatin, and vasoactiveintestinal peptide) transmitters.

GASTRIC AND SMALL-BOWELMOTILITYThe motor functions of the stomach and smallintestine are characterized by distinct manometricpatterns of activity in the fasting and postprandialperiods (Fig. 1). The fasting (or interdigestive)period is characterized by a cyclic motor phe-nomenon called the interdigestive migrating motorcomplex. In healthy persons, one cycle of the inter-digestive migrating motor complex is completedevery 60 to 90 minutes. The interdigestivemigrating motor complex has three phases: aperiod of quiescence (phase I), a period of inter-mittent pressure activity (phase II), and an activityfront (phase III) during which the stomach andsmall intestine contract at highest frequency (3 perminute in the stomach and 12 per minute in theupper small intestine). Phase III migrates for a

variable distance through the small intestine; thereis a gradient in the frequency of contractions from~12 per minute in the duodenum to ~8 per minutein the ileum. Another characteristic interdigestivemotor pattern in the distal small intestine is thegiant migrating complex, or power contraction; itserves to empty residue from the ileum into thecolon in bolus transfers.

In the postprandial period, the interdiges-tive migrating motor complex is replaced by anirregular pressure response pattern of variableamplitude and frequency, which enables mixingand absorption. This pattern is observed in theregions in contact with food. The maximal fre-quency of contractions is lower than that notedduring phase III of the interdigestive migratingmotor complex. The duration of the postprandialmotor activity is proportional to the number ofcalories consumed during the meal: ~1 hour forevery 200 kcal ingested. Segments of the smallintestine that are not in contact with food continueto display interdigestive motor patterns.

The proximal stomach accommodates foodthrough a decrease in its tone, facilitating the inges-tion of food without an increase in pressure. Thisreflex is mediated by the vagus nerve and involvesan intrinsic nitrergic neuron.

Liquids empty from the stomach in an expo-nential manner (Fig. 2). The half-emptying time fornonnutrient liquids in healthy persons is usuallyless than 20 minutes. Solids are retained selectivelyin the stomach until particles have been trituratedto less than 2 mm in diameter. Therefore, gastricemptying of solids is characterized by an initiallag period followed by a linear post-lag emptyingphase. The small intestine transports solids andliquids at approximately the same rate. Becauseof the lag phase for the transport of solids from thestomach, liquids typically arrive in the colon beforesolids do. Chyme moves from the ileum to thecolon intermittently in boluses (Fig. 2).

PATHOGENESIS OF MOTILITYDISORDERSGastrointestinal motility disturbances (Table 1)result from disorders of the extrinsic or entericnervous system, interstitial cells of Cajal (orintestinal pacemakers), or smooth muscle.

98 Stomach

Combined disorders occur in systemic sclerosis,amyloidosis, and mitochondrial cytopathy andcan appear initially with neuropathic patterns;later, with disease progression, they can displaymyopathic characteristics. Motility disorders canbe congenital (affecting the development of themotility apparatus) or acquired.

Embryologic Processes: Ontogeny of theGut Neuromuscular ApparatusGenetic defects in migration, differentiation, andsurvival of enteric neurons have been identified inseveral causes of gut dysmotility, including abnor-malities of cRET (the gene that encodes for thetyrosine kinase receptor), the endothelin B system(which tends to retard development of neural ele-ments, thereby facilitating colonization of the entiregut from the neural crest), Sox10 (a transcriptionfactor that enhances the maturation of neural pre-cursors), and ckit (a marker for the interstitial cellsof Cajal). Disturbances in these mechanisms resultin syndromic dysmotilities such as Hirschsprungdisease, Waardenburg-Shah syndrome (pig-mentary defects, piebaldism, neural deafness,and megacolon), and idiopathic hypertrophicpyloric stenosis.

Extrinsic Neuropathic DisordersExtrinsic neuropathic processes include vagotomy,diabetes mellitus, trauma, Parkinson’s disease,amyloidosis, and a paraneoplastic syndrome usu-ally associated with small cell carcinoma of thelung. Another common “neuropathic” problem

Gastrointestinal Motility Disorders 99

Fasting Postprandial

Antroduodenum 1

Desc. duodenum

Distal duodenum

Proximal jejunum

Antroduodenum 2

Antroduodenum 3

Antroduodenum 4

Antroduodenum 5

MMC

Catheter channel

Fig. 1. Fasting and postprandial gastroduodenal manometric recordings in a healthy volunteer. A 535-kcal mealwas ingested during the study. Note the cyclic interdigestive migrating motor complex (MMC) (left) and thesustained, high-amplitude but irregular pressure activity after the meal (right). Desc., descending. (From CoulieB, Camilleri M. Intestinal pseudo-obstruction. Annu Rev Med. 1999;50:37-55. Used with permission.)

100

50

00 1 2 43 6

Rem

aini

ng in

sto

mac

h, %

Gastricemptyingof liquids

Gastric emptyingof solids

Hours

Colonic filling

Fig. 2. Schematic representation of typical gastricemptying and colonic filling curves. Note theexponential emptying of liquids, in contrast to theinitial retention of solids (lag phase), which isfollowed by a generally linear post-lag emptyingrate. The colonic filling curve is characterized byintermittent bolus transfers.

met in clinical practice results from the effect ofmedications such as α2-adrenergic agonists andanticholinergic agents on neural control.

Damage to the autonomic nerves by trauma,infection, neuropathy, or neurodegeneration maylead to motor, secretory, and sensory disturbances,most frequently resulting in constipation ratherthan upper gastrointestinal tract motility disor-ders. However, the latter may occur in patients

with a high spinal cord injury or occur secondarilyto constipation and fecal impaction. Parkinson’sdisease and multiple sclerosis are two neurologicdiseases involving the extrinsic nervous systemthat are associated frequently with constipation.In Parkinson’s disease, a decrease in the number ofdopamine-containing neurons and the presenceof Lewy bodies in myenteric plexus neurons havebeen described. Also, failure of the striated muscles

100 Stomach

Table 1. Classification of Gastroparesis and Pseudo-obstruction

Type Neuropathic Myopathic

Infiltrative Progressive systemic sclerosis Progressive systemic sclerosis

Amyloidosis Amyloidosis

Systemic lupus erythematosus

Ehlers-Danlos syndrome

Dermatomyositis

Familial Familial visceral neuropathies Familial visceral myopathies

Metabolic myopathies

Idiopathic Idiopathic intestinal pseudo- Sporadic hollow visceral myopathy

obstruction

Neurologic Porphyria Myotonia

Heavy-metal poisoning Other dystrophies

Brainstem tumor

Parkinson’s disease

Multiple sclerosis

Spinal cord transection

Infectious Chagas’ disease

Cytomegalovirus

Norwalk virus

Epstein-Barr virus

Drug-induced Tricyclic antidepressants

Narcotic agents

Anticholinergic agents

Antihypertensive agents

Dopaminergic agents

Vincristine

Laxatives

Paraneoplastic Small cell lung cancer

Carcinoid syndrome

Postoperative Postvagotomy with or without

pyloroplasty/gastric resection

Endocrine Diabetes mellitus

Hypothyroidism/hyperthyroidism

Hypoparathyroidism

of the pelvic floor to relax may be an extrapyra-midal manifestation of Parkinson’s disease.Multiple sclerosis is associated with slow colonictransit and absence of the postprandial motor con-tractile response in the colon. Gastroparesis andpseudo-obstruction are less frequent than consti-pation in these two diseases.

A broad spectrum of gastrointestinal motilitydisorders may be related to diabetes mellitus:gastroparesis, pylorospasm, intestinal pseudo-obstruction, diarrhea, constipation, and inconti-nence. All these manifestations may be caused byautonomic dysfunction (Table 2), although evi-dence points to the importance of acute changesin glycemia and, more importantly, to changes inthe structure and function of the enteric nervoussystem. From a population perspective, constipa-tion is the most important gastrointestinalsymptom in patients with diabetes because it isthe most prevalent symptom. Moreover, in a largegroup that had screening tests for autonomic neu-ropathy, the prevalence of constipation was 22%among the diabetic patients with neuropathy butonly 9.2% among those without neuropathy, whichwas not significantly different from that of thehealthy control group. In a questionnaire-based

study of diabetic patients in the community, consti-pation was more prevalent in insulin-dependentdiabetes mellitus than in noninsulin-dependentdiabetes mellitus and was associated with symp-toms of dysautonomia and use of constipatingdrugs, for example, calcium channel blockers. Inhospital practice, gastroparesis frequently isencountered as a complication of diabetes. Apartfrom added attention needed for metabolic con-trol, its management follows that of other causes ofgastroparesis and pseudo-obstruction.

Enteric or Intrinsic Neuropathic DisordersDisorders of the enteric nervous system are usuallythe result of a degenerative, immune, or inflamma-tory process. Only rarely can the cause be ascertainedin these disturbances. Virally induced gastroparesis(eg, rotavirus, Norwalk virus, cytomegalovirus,or Epstein-Barr virus) and pseudo-obstruction aswell as degenerative disorders associated withinfiltration of the myenteric plexus by inflammatorycells suggest that infection may be an importantpredisposing factor. In idiopathic chronic intestinalpseudo-obstruction, there is no disturbance ofextrinsic neural control and no identified cause forabnormality of the enteric nervous system.


Table 2. Gastrointestinal (GI) Manifestations of Diabetes Mellitus

GI manifestationof diabetes Associated disease Clinical presentation

� Gallbladder motility Gallstones

Antral hypomotility Exocrine pancreatic insufficiency Gastric stasis

Pylorospasm Bezoars

� α2-Adrenergic Celiac sprue Diarrhea, steatorrhea

tone in enterocytes

SB dysmotility SB bacterial overgrowth Gastric or SB stasis or rapid SB

transit

Colonic dysmotility Bile acid malabsorption Constipation or diarrhea

Anorectal dysfunction Diarrhea or incontinence

Sensory neuropathy

IAS-sympathetic

neuropathy

EAS-pudendal neuropathy

EAS, external anal sphincter; IAS, internal anal sphincter; SB, small-bowel.Modified from Camilleri M. Gastrointestinal problems in diabetes. Endocrinol Metab Clin N Am. 1996;25:361-78. Used

with permission.

A full-thickness biopsy specimen from theintestine may be required to evaluate the myentericplexus and interstitial cells of Cajal. The decisionto perform a biopsy needs to be weighed againstthe risk of complications, including the subse-quent formation of adhesions and, possibly,mechanical obstruction superimposed on episodesof pseudo-obstruction.

Smooth Muscle DisordersDisturbances of smooth muscle may result in majordisorders of gastric emptying and small-boweland colonic transit. These disturbances includesystemic sclerosis and amyloidosis. Dermato-myositis, dystrophia myotonica, and metabolicmuscle disorders such as mitochondrial cytopathyare seen infrequently. In rare instances, there is apositive family history (eg, hollow visceralmyopathy may occur either sporadically or in fam-ilies). Motility disturbances may be the result ofmetabolic disorders such as hypothyroidism orhyperparathyroidism, but these patients moreoften present with constipation.

Scleroderma may result in focal or generaldilatation, diverticula (often wide-mouthed, espe-cially in the colon), and delayed transit at the levelsaffected. The amplitude of contractions isdecreased (average < 30 mm Hg in the distal esoph-agus, < 40 mm Hg in the antrum, and < 10 mm Hgin the small bowel) compared with that of controls.Bacterial overgrowth is common and may result insteatorrhea or pneumatosis intestinalis.

A mitochondrial disorder that affects the gutis called mitochondrial neurogastrointestinalencephalomyopathy. It is referred to also as oculogas-trointestinal muscular dystrophy or familial visceralmyopathy type II and is an example of a spectrum ofdiseases that affect oxidative phosphorylation. Itis an autosomal recessive condition with gas-trointestinal and liver manifestations that maypresent at any age, typically with hepatomegaly orliver failure in the neonate, seizures or diarrhea ininfancy, and liver failure or chronic intestinalpseudo-obstruction in children and adults.

Mitochondrial neurogastrointestinal encepha-lomyopathy is characterized also by external oph-thalmoplegia, ptosis, peripheral neuropathy, andleukoencephalopathy. The small intestine is dilatedor has multiple diverticula, and the amplitude of

contractions is low, typical of a myopathic disorder.Some patients have a combination of intestinaldysmotility or transfer dysphagia due to abnormalcoordination and propagation of the swallowthrough the pharynx and the skeletal muscle portionof the esophagus. This becomes even more devas-tating when the smooth muscle portion of the esoph-agus is affected by the associated mitochondrialneurogastrointestinal encephalomyopathy.

MANAGEMENT OF GASTROPARESISAND PSEUDO-OBSTRUCTION

Clinical FeaturesThe clinical features of gastroparesis and chronicintestinal pseudo-obstruction are similar andinclude nausea, vomiting, early satiety, abdominaldiscomfort, distention, bloating, and anorexia.Patients in whom stasis and vomiting are importantproblems may have considerable weight loss anddepletion of mineral and vitamin stores. Theseverity of the motility problem often manifestsitself most clearly in the degree of nutritional andelectrolyte depletion. Disturbances of bowel move-ments, such as diarrhea and constipation, indicatethat the motility disorder is more extensive than gas-troparesis. Significant vomiting may be complicatedby aspiration pneumonia or Mallory-Weiss tearsthat may result in gastrointestinal tract hemorrhage.When patients have a more generalized motility dis-order, they also may have symptoms referable toabnormal swallowing or delayed colonic transit.

A family history and medication history areessential for identifying underlying etiologicfactors. A careful review of systems helps revealan underlying collagen vascular disease (eg, sclero-derma) or disturbances of extrinsic neural controlthat also may be affecting the abdominal viscera.Such symptoms include orthostatic dizziness,difficulties with erection or ejaculation, recurrenturinary tract infections, difficulty with visualaccommodation in bright lights, absence ofsweating, and dry mouth, eyes, or vagina.

A succussion splash detected on physical exam-ination usually is indicative of a region of stasiswithin the gastrointestinal tract, typically thestomach. The hands and mouth may show signs ofRaynaud’s phenomenon or scleroderma. Testing

102 Stomach

pupillary responses to light and accommodation,testing external ocular movement, and measuringblood pressure in the supine and standing positionsand noting the general features of peripheral neu-ropathy can identify patients who have a neurologicdisturbance or oculogastrointestinal dystrophy asso-ciated typically with mitochondrial cytopathy.

Conditions to be differentiated are mechan-ical obstruction (eg, from peptic stricture or Crohn’sdisease in the small intestine), functional gas-trointestinal disorders, and eating disorders suchas anorexia nervosa and rumination syndrome.The degree of impairment of gastric emptying ineating disorders is relatively minor compared withthat of diabetic or postvagotomy gastric stasis.

A typical history of a person with ruminationsyndrome is early (0-30 minutes) postprandial,effortless regurgitation of undigested food thathappens with virtually every meal. This conditionoccurs in mentally challenged children (eg, Down’ssyndrome) but increasingly is recognized in ado-lescents and adults of normal intelligence. It istreatable with behavioral modification.

InvestigationA motility disorder of the stomach or small bowelshould be suspected whenever large volumes areaspirated from the stomach, particularly after anovernight fast or when undigested solid food orlarge volumes of liquids are observed duringesophagogastroduodenoscopy. The following fourquestions should be considered in the manage-ment of each patient:

1. Are the symptoms acute or chronic?2. Is the disease due to neuropathy or myopathy?3. What is the status of hydration and nutrition?4. What regions of the digestive tract are affected?

The recommended sequence of investigations isas follows:

1. Suspect and exclude mechanical obstruction.In patients with pseudo-obstruction, plainradiographs of the abdomen taken at the timeof symptoms typically show dilated loops ofsmall bowel with associated air-fluid levels.Mechanical obstruction should be excludedwith upper gastrointestinal endoscopy andbarium studies, including a small-bowel follow-through series. Barium studies fortuitously may

suggest the presence of a motor disorder, par-ticularly if there is gross dilatation, dilution ofbarium, or retained solid food within thestomach. However, these studies rarely iden-tify the cause. An exception is small-bowelsystemic sclerosis, which is characterized bymegaduodenum and packed valvulae con-niventes in the small intestine.

2. Assess gastric and small-bowel motility. Aftermechanical obstruction and alternative diag-noses such as Crohn’s disease have beenexcluded, a transit profile of the stomach orsmall bowel (or both) should be performed.Efficiency in the emptying of solids is the mostsensitive measurement of upper gastroin-testinal tract transit. Scans typically are per-formed at 0, 1, 2, 4, and 6 hours after ingestionof a radiolabeled meal. If the cause of themotility disturbance is obvious, such as gastro-paresis in a patient with long-standing diabetesmellitus, further diagnostic testing usually isnot needed. If the cause is unclear, gastro-duodenal manometry, with the use of a mul-tilumen tube with sensors in the distal stomachand proximal small intestine, can distinguishbetween neuropathic and myopathic processes(Fig. 3). Neuropathies are characterized bycontractions of normal amplitude, butabnormal patterns of contractility. In contrast,the predominant disturbance in myopathicdisorders is the low amplitude of contractionsin the segments affected (Fig. 3).

3. Identify the pathogenesis. Causes of gastro-paresis and intestinal pseudo-obstruction areoutlined in Table 1. In the absence of a cause fora neuropathic pattern of motor activity in thesmall intestine, it is necessary to pursue furtherinvestigations, including testing for autonomicdysfunction, type 1 anti-neuronal nuclearautoantibodies (ANNA-1) associated withparaneoplastic syndromes, and magnetic res-onance imaging of the brain to exclude abrainstem lesion (Fig. 4). Autonomic testingincludes evaluation for orthostatic hypoten-sion, assessment of supine and standing serumnorepinephrine levels, measurement of theheart rate interval change during deepbreathing, and plasma pancreatic polypeptideresponse to modified sham feeding. This


testing can identify sympathetic adrenergicor vagal neuropathy. Rarely, brain imaging isindicated for patients with vomiting. The iden-tification of a myopathic disorder on initialtesting should lead to a search for amyloidosis(immunoglobulin electrophoresis, fat aspirate,or rectal biopsy), systemic sclerosis (Scl-70),and a family history of gastrointestinal motilitydisorders. Laboratory studies to considerinclude assessment of thyroid function andlevels of antinuclear antibody, lactate, creatinephosphokinase, aldolase, and porphyrins andserologic study for Chagas’ disease. In certaincases, a laparoscopically obtained full-thicknessbiopsy specimen from the small intestine maybe required. Special staining techniques maybe needed to identify metabolic muscle dis-orders, including mitochondrial myopathy.Genetic testing is available to assess for certainmitochondrial myopathies.

4. Identify complications of the motility disorder:bacterial overgrowth, dehydration, and mal-nutrition. In patients who present with diar-rhea, it is important to assess nutritional status(essential element and vitamin levels) and toexclude bacterial overgrowth by culturingsmall-bowel aspirates. Bacterial overgrowth is

relatively uncommon in neuropathic disordersbut is more common in myopathic conditions,such as scleroderma, that are associated moreoften with bowel dilatation or low-amplitudecontractions. Bacterial overgrowth may be dif-ficult to detect with culture of small-bowelaspirates; however, breath hydrogen after aglucose or lactose load is a nonspecific test thatshould be interpreted with caution and in con-junction with small-bowel transit time becausethe early breath hydrogen peak may be dueto bacterial metabolism of the substrate in thecolon resulting from fast small-bowel transit.Often, an empirical trial of antibiotic therapyis used as a surrogate for formal testing.

TREATMENT OF GASTROPARESISAND INTESTINAL PSEUDO-OBSTRUCTIONTreatment should be designed for each patient,depending on the findings of the investigation.The principal methods of management includecorrection of hydration and nutritional deficiencies,use of prokinetic and antiemetic medications,suppression of bacterial overgrowth, decom-pression, and surgical treatment.

104 Stomach

Antroduodenum 1

Desc. duodenum

Distal duodenum

Proximal jejunum

Antroduodenum 2

Antroduodenum 3

Antroduodenum 4

Antroduodenum 5

Catheter channel

MyopathyControlNeuropathy

Fig. 3. Postprandial manometric profiles in small-bowel dysmotility due to neuropathy (diabetes mellitus, left)and myopathy (systemic sclerosis, right). Note the simultaneous, prolonged contractions of low amplitude inmyopathy. Although the contraction amplitudes are normal in neuropathy, contractile activity is uncoordinatedand contractile frequency is decreased. Desc., descending. (From Coulie B, Camilleri M. Intestinal pseudo-obstruction. Annu Rev Med. 1999;50:37-55. Used with permission.)

Correction of Hydration and NutritionalDeficienciesRehydration, electrolyte repletion, and nutritionalsupplementation are particularly important duringacute exacerbations of gastroparesis and chronicintestinal pseudo-obstruction. Restoration ofnutrition can be achieved orally, enterally, or par-enterally, depending on the severity of the clinicalsyndrome. Initial nutritional measures includelow-fiber supplements with the addition of iron,folate, calcium, and vitamins D, K, and B12. Patientswith more severe symptoms may require enteral orparenteral supplementation of nutrition. If it isanticipated that enteral supplementation may berequired for more than 3 months, it is usually bestto provide feedings through a jejunostomy tube.Gastrostomy tubes should be avoided in gastro-paresis except for venting purposes. Many patientswho require long-term parenteral nutrition con-tinue to tolerate some oral feeding.

MedicationsIncreasingly, medications are being used to treatneuromuscular motility disorders. However, thereis little evidence that they are effective in myopathicdisturbances, except for the rare case of dystrophia

myotonica affecting the stomach and for small-bowel systemic sclerosis.

Erythromycin, a macrolide antibiotic that stim-ulates motilin receptors at higher doses (eg, 250-500 mg) and cholinergic mechanisms at lowerdoses (40-80 mg), results in the dumping of solidsfrom the stomach. It has been shown to accelerategastric emptying in gastroparesis; it also increasesthe amplitude of antral contractions and improvesantroduodenal coordination. Erythromycin is mosteffective when it is given intravenously duringacute exacerbations of gastroparesis or intestinalpseudo-obstruction. The usual dose of intravenouserythromycin lactobionate is 3 mg/kg every 8hours. The effect of oral erythromycin appears tobe restricted by tolerance and gastrointestinal sideeffects, which often prevent treatment for longerthan 1 month; sometimes a low dose of liquid for-mula erythromycin (eg, 40-80 mg 3 times dailybefore meals) can be tolerated. The elixir formulationmay improve absorption in the setting of dys-motility. Although initial studies demonstrated that2 weeks of treatment was effective for patients withdiabetic gastroparesis, there is little evidence thatcontinued therapy produces long-term improve-ment in gastric emptying or associated symptoms.


Abnormal gastric or small-bowel transit

Knownunderlyingdisorder

No knownunderlying disorder

UPPER GIMANOMETRY

Obstruction Neuropathy Myopathy

TREAT Autonomic reflexesANNA-1Seek cause

Family history, Scl-70, ANA, fat biopsyCPK, lactate, muscle biopsy

Fig. 4. Flow diagram outlining steps involved in diagnosing gastroparesis and intestinal pseudo-obstruction.ANA, antinuclear antibodies; ANNA-1, anti-neuronal nuclear antibodies type 1; CPK, creatine phosphokinase;GI, gastrointestinal. (Modified from Camilleri M, Prather CM. Gastric motor physiology and motor disorders.In: Feldman M, Sleisenger MH, Scharschmidt BF, editors. Sleisenger & Fordtran’s gastrointestinal and liverdisease: pathophysiology/diagnosis/management. Vol 1. 6th ed. Philadelphia: WB Saunders Company; 1998. p.572-86. Used with permission.)

Metoclopramide is a dopamine antagonist thathas both prokinetic and antiemetic properties.Antiemetic effects are due partly to its anti-5-HT3antagonist actions. Long-term use of metoclo-pramide is limited by the side effects of tremor andParkinson-like symptoms, a consequence of anti-dopaminergic activity in the central nervous system.It is available in tablet or elixir form and typically istaken 30 minutes before meals and at bedtime. Usualdoses range from 5 to 20 mg 4 times daily.

Serotonergic (5-HT) agents may prove to bebeneficial in the treatment of gastroparesis andintestinal pseudo-obstruction. The combined 5-HT4 agonist and 5-HT3 antagonist, cisapride, wasessentially the only medication for which therewas evidence for efficacy in the medium- andlong-term; the medication is no longer availablefor prescription because of the risks of cardiacdysrhythmias (torsades de pointes).

Octreotide, a cyclized analogue of somato-statin, has been shown to induce activity fronts inthe small intestine that mimic phase III activity ofthe interdigestive migrating motor complex.Activity fronts in the small bowel are characterizedby a simultaneous or very rapidly propagatedactivity front that is not well coordinated. The clinicaleffects of octreotide include an initial accelerationof gastric emptying, a decrease in postprandialgastric motility, and inhibition of small-boweltransit. Therefore, the therapeutic efficacy ofoctreotide in intestinal dysmotility associated withgastroparesis and pseudo-obstruction requiresfurther assessment in clinical trials. Currently,octreotide appears to be more useful in the treatmentof dumping syndromes associated with acceler-ated transit. However, it may be used at nighttimeto induce activity of the migrating motor complexand to avoid bacterial overgrowth. If requiredduring the daytime, octreotide is often given incombination with oral erythromycin to “normalize”the gastric emptying rate.

Antiemetics, including diphenhydramine,trifluoperazine, and metoclopramide, are impor-tant in the management of nausea and vomitingin patients with gastroparesis and intestinalpseudo-obstruction. The more expensive sero-tonin 5-HT3 antagonists (eg, ondansetron) havenot proved to have greater benefit than the lessexpensive alternatives.

Antibiotic therapy is indicated for patientswho have documented symptomatic bacterialovergrowth. Although formal clinical trials havenot been conducted, it is common practice to usedifferent antibiotics for 7 to 10 days each month inan attempt to avoid development of resistance.Common antibiotics include doxycycline (100 mgtwice daily), metronidazole (500 mg 3 times daily),ciprofloxacin (500 mg twice daily), and double-strength trimethoprim-sulfamethoxazole (twotablets twice daily). Antibiotic therapy forpatients with diarrhea and fat malabsorption dueto bacterial overgrowth produces considerablesymptomatic relief.

DecompressionDecompression is rarely necessary in patients withchronic pseudo-obstruction. However, ventingenterostomy (jejunostomy) is effective in relievingabdominal distention and bloating. It has beenshown to decrease significantly the frequency ofnasogastric intubations and hospitalizations foracute exacerbations of severe intestinal pseudo-obstruction in patients requiring central parenteralnutrition. Access to the small intestine by enteros-tomy also provides a way to deliver nutrientsenterally and should be considered for patientswith intermittent symptoms. The currently avail-able enteral tubes allow for aspiration and feedingby a single apparatus.

Surgical TreatmentSurgical treatment has a limited role in patientswith gastroparesis and intestinal pseudo-obstruc-tion. For patients who have had multiple abdom-inal operations, it becomes difficult to discernwhether exacerbations of symptoms reflect anunderlying disease or adhesions and mechanicalobstruction. Surgical treatment should be con-sidered whenever the motility disorder is localizedto a resectable portion of the gut. Three instancesin which to consider this approach include 1)duodenojejunostomy or duodenoplasty forpatients with megaduodenum or duodenal atresiain children, 2) completion gastrectomy for patientswith postgastric surgical stasis syndrome, and3) colectomy with ileorectostomy for intractableconstipation associated with chronic colonicpseudo-obstruction.

106 Stomach

Novel Therapies Preliminary data suggest that gastric pacing mayimprove gastric emptying and symptoms inpatients with severe gastroparesis. In humans, gas-tric pacing has not been able to entrain gastric slowwaves to normalize gastric dysrhythmias or toaccelerate gastric emptying. Gastric electrical stim-ulation is an approved treatment, but data on effi-cacy are inconclusive and additional controlledclinical trials are needed to assess the long-termbenefits, complications, and optimal selection ofpatients for this treatment.

Currently, small-bowel transplantation is limitedto patients with intestinal failure who havereversible total parenteral nutrition (TPN)-inducedliver disease or life-threatening or recurrentcatheter-related sepsis. Combined small-boweland liver transplantation is being performed inpatients with irreversible TPN-induced liver dis-ease. Complications following small-boweltransplantation include infection, rejection, andlymphoproliferative disorders due to long-termimmunosuppression and Epstein-Barr virus infec-tion. Studies have suggested that small-boweltransplantation may improve quality of life andbe more cost-effective than long-term TPN. In thefuture, improvements in immunosuppressive reg-imens, earlier detection of rejection, and treatmentof cytomegalovirus infection based on polymerasechain reaction detection may enable small-boweltransplantation to become the definitive treatmentfor short bowel syndrome or severe pseudo-obstruction uncontrolled by TPN. In the mean-time, parenteral nutrition is the treatment ofchoice for most patients.

FUNCTIONAL DYSPEPSIASymptoms of dyspepsia such as epigastric pain ordiscomfort, nausea, vomiting, early satiety, post-prandial fullness, and upper abdominal bloatingare seen commonly in clinical practice. Other chap-ters of this book review the role of gastroesophagealreflux, peptic ulcer disease, gastritis, and cancerin causing these symptoms. Yet, many patientsstill have symptoms after testing and eradicationof Helicobacter pylori and a trial of acid inhibition,usually with a proton pump inhibitor. Thesepatients then undergo upper endoscopy, which

usually produces negative findings, that is, noulcer, esophagitis, or cancer is found. When thesymptoms last longer than 3 months, the diagnosisof functional dyspepsia can be made. Multiplepotential pathogenetic mechanisms have been pos-tulated for functional dyspepsia (Table 3).Similarly, many different therapies have been tried.This multitude of diagnostic and therapeuticoptions underscores the fact that the cause of func-tional dyspepsia is not known. Currently, there isno clear consensus about how best to managepatients who have functional dyspepsia.

DefinitionDyspepsia is not a condition: it is a symptomcomplex. Dyspepsia can be defined as persistent orrecurrent abdominal pain or abdominal discom-fort centered in the upper abdomen. The term dis-comfort includes symptoms of nausea, vomiting,early satiety, postprandial fullness, and upperabdominal bloating. Symptoms typically are asso-ciated with eating but not with bowel movements.The symptoms of heartburn and acid regurgita-tion are often included as symptoms of dyspepsia;yet, if they are the main symptoms, the patientshould be considered to have reflux rather thandyspepsia. Patients with symptoms or signs typicalfor biliary tract or pancreatic disease should notbe considered to have functional dyspepsia. Thus,right upper quadrant pain or epigastric pain thatradiates to the back should not be included in thedefinition of dyspepsia.

Functional dyspepsia can be defined as dyspepsiasymptoms of more than 3 months’ duration, without


Table 3. Proposed Causes of FunctionalDyspepsia

Acid/Helicobacterpylori Motility

H. pylori infection GastroparesisGastritis, duodenitis Abnormal relaxationMissed peptic ulcer Visceral

disease hypersensitivityAcid sensitivity Brain-gut disorderOccult gastroesophageal Psychologic disorder

reflux disease

an anatomical or biochemical abnormality.Typically, this means negative findings on bloodtests and a negative evaluation of the upper gas-trointestinal tract with either endoscopy or bariumradiography. However, defining endoscopy as“negative” can be difficult. Does this includebiopsy study of the esophagus for esophagitis orbiopsy study of the stomach for gastritis or H. pyloriinfection? Are erythema, erosions, or histologicinflammation meaningful findings? These issuesare somewhat controversial.

Surveys have evaluated how many people inthe community experience symptoms of dyspepsia.The rates vary in large part because of the defini-tions used. Some surveys include the symptom ofheartburn in the definition of dyspepsia and reporta prevalence rate of 40%. Other surveys exclude sub-jects with symptoms of heartburn or irritable bowelsyndrome and report prevalence rates of less than5%. Nonetheless, it is reasonable to state that 15%(about one in seven) of the adult population has dys-pepsia. Not all these people with dyspepsia havefunctional dyspepsia. In one study, a random sampleof the population with dyspepsia underwentendoscopy and only 53% had normal endoscopicfindings. The remarkable findings were esophagitis,peptic ulcer disease, duodenitis, and duodenogas-tric reflux. Of note, only 66% of the asymptomaticcontrols in this study had normal endoscopic find-ings! Peptic ulcer disease and duodenitis were morecommon in the subjects with dyspepsia than in thecontrols. Other findings such as gastritis were foundin a similar number of cases and controls.

PathophysiologyThe most frequently mentioned etiologic possi-bilities for functional dyspepsia are listed in Table3. In some ways, thinking about the possible causeshas been divided into two camps: acid-H. pyloriversus motility. This led investigators to try toidentify specific symptom subtypes. The idea wasthat even though the symptoms of dyspepsia couldresult from multiple causes, refining thesymptom criteria would allow more specificcauses to be identified. The most recent diag-nostic criteria for functional dyspepsia (RomeIII) introduced the terms epigastric pain syndromeand postprandial distress syndrome in an effort tosubclassify the condition.

Whether H. pylori infection causes symptomsin the absence of an ulcer is still debated. The preva-lence of H. pylori infection and gastritis is onlyslightly more common in patients with dyspepsia.Still, physicians, investigators, and patients havebeen interested in the idea that the histologicinflammation produces symptoms. In multicenter,placebo-controlled clinical trials, the effect of theeradication of H. pylori on functional dyspepsiahas been small.

Patients commonly take antacids for relief ofdyspepsia; yet, gastric acid secretion is normal inpatients with functional dyspepsia. One hypothesisis that patients with functional dyspepsia may bemore sensitive to acid. Placebo-controlled trials haveshown that acid suppression is modestly more effec-tive than placebo in functional dyspepsia. Thequestion has been whether this is due to occult gas-troesophageal reflux that manifests as dyspepsia.

Although clinicians often focus on epigastricpain as the cardinal symptom of functional dys-pepsia, most investigators include other symptomssuch as nausea, fullness, and early satiety. Thesesymptoms suggest that motor abnormalities mayhave a role in causing this condition. Betweenone-third and one-half of patients with functionaldyspepsia who are evaluated in gastrointestinalclinics of referral centers have delayed gastric emp-tying. Multiple studies, primarily in Europe, haveevaluated the role of prokinetics in functional dys-pepsia. Generally, prokinetics are 30% more effec-tive than placebo, although the rates varied con-siderably among studies. Most of these studieswere with cisapride or domperidone, neither ofwhich is currently available in the United States.Metoclopramide may be helpful in part becauseof its antiemetic effects. Still, long-term treatmentwith metoclopramide needs to be avoided becauseof the risk of tardive dyskinesia. Whether a proki-netic efficacious in treating functional dyspepsiawill be available in the United States is not clear.

More recently, attention has shifted from gas-tric emptying to gastric accommodation. Like theheart, the stomach has both systolic and diastolicfunctions. Recent studies have shown that gas-tric accommodation (ie, the relaxation of thestomach in response to a meal) is abnormal inpatients with functional dyspepsia. Medicationssuch as nitroglycerin, calcium channel blockers, and

108 Stomach

anticholinergics are being evaluated to determinewhether they improve the accommodation response.Currently, their effectiveness is not known.

The functional disorders are a continuum ofillnesses characterized by gastrointestinal symp-toms with negative diagnostic evaluations. Thereis significant overlap among these disorders.Specifically, at least one-third of patients with func-tional dyspepsia also have symptoms of irritablebowel syndrome. Patients with irritable bowel syn-drome have been shown to have a lower thresholdfor rectal distention. A similar phenomenon hasbeen noted in functional dyspepsia for distentionof the stomach. More recently, imaging of the centralnervous system has highlighted the activation ofdifferent parts of the brain in subjects with functionalgastrointestinal disorders. Thus, the concept ofvisceral hypersensitivity remains a strong con-sideration in all the functional gastrointestinaldisorders, including functional dyspepsia.Currently, however, no specific medication is avail-able for visceral hypersensitivity, although newagents are being investigated. Clinically, low-doseantidepressants are being prescribed, althoughthere are not any formal clinical trial data.

Recommendations for Evaluation and TherapyBecause of all the controversy from conflictingstudies and inadequate data, how is the clinician toproceed? Current practice guidelines recommendeither a trial of acid inhibition or testing for H. pyloriinfection before any diagnostic investigation fordyspepsia. Patients who remain symptomatic needto undergo either upper gastrointestinal tractradiography or endoscopy to exclude peptic ulcerdisease, esophagitis, and malignancy. After thediagnosis of functional dyspepsia has been made,the first step is to provide reassurance. Somepatients with functional dyspepsia want only tobe assured that they do not have cancer. They findtheir symptoms tolerable and require no furtherintervention. The more difficult decision is whetherto perform additional diagnostic testing. The alter-native is to proceed directly with empirical trials.Often, the diagnostic tests can be interfaced withtherapeutic trials of H. pylori eradication, protonpump inhibitors, prokinetics, mucosal protectantssuch as sucralfate, anticholinergics or, finally,low-dose antidepressants. Some patients prefer to

consider herbals, hypnosis, or cognitive behav-ioral psychologic therapy.

Between one-third and one-half of patients withdyspepsia have symptoms that resolve sponta-neously. Yet, some are plagued by symptoms longterm. It is hoped that newer medications directedat visceral hypersensitivity or gastric accommoda-tion will be useful and strengthen the clinician’sarmamentarium against this common disorder.

SUMMARYDisorders of gastric and small-bowel motility mayresult in either stasis or accelerated transit.Understanding the mechanisms that controlmotility and the pathophysiologic mechanisms isthe key to optimal management. Simple, quanti-tative measures of transit and an algorithmicapproach to identifying the underlying cause maylead to correction of abnormal function. Correctingdehydration and nutritional abnormalities andproviding symptomatic relief are important stepsin the management of these patients. Patient edu-cation is essential to avoid aggravation of symptomscaused by dietary indiscretions.

Functional dyspepsia remains a challenge.Currently, emphasis is on the art of medicine andreassurance, limited investigation, treatment trials,and, most importantly, good physician-patientinteractions. The hope for the future is that newtests will identify the actual pathophysiologicmechanism, whether in the brain or the gut, thatproduces the symptoms. This knowledge, in turn,will allow the selection of treatment that will effec-tively alleviate the patient’s symptoms.

RECOMMENDED READINGBytzer P, Talley NJ, Leemon M, Young LJ, Jones

MP, Horowitz M. Prevalence of gastroin-testinal symptoms associated with diabetesmellitus: a population-based survey of 15,000adults. Arch Intern Med. 2001;161:1989-96.

Camilleri M. Clinical practice: diabetic gastro-paresis. N Engl J Med. 2007;356:820-9.

Camilleri M. Enteric nervous system disorders:genetic and molecular insights for the neuro-gastroenterologist. Neurogastroenterol Motil.2001;13:277-95.


Camilleri M. Functional dyspepsia: mechanismsof symptom generation and appropriate man-agement of patients. Gastroenterol Clin NorthAm. 2007; 36:649-64.

Coulie B, Camilleri M. Intestinal pseudo-obstruc-tion. Annu Rev Med. 1999;50:37-55.

Delaney BC, Moayyedi P, Forman D. Initial man-agement strategies for dyspepsia. CochraneDatabase Syst Rev. 2003;(2):CD001961.Update in: Cochrane Database Syst Rev.2005;(4):CD001961.

Di Lorenzo C. Pseudo-obstruction: currentapproaches. Gastroenterology. 1999;116:980-7.

Fischler B, Tack J, De Gucht V, Shkedy ZI, PersoonsP, Broekaert D, et al. Heterogeneity ofsymptom pattern, psychosocial factors, andpathophysiological mechanisms in severefunctional dyspepsia. Gastroenterology.2003;124:903-10.

Johnsen R, Bernersen B, Straume B, Førde OH,Bostad L, Burhol PG. Prevalences of endo-scopic and histological findings in subjectswith and without dyspepsia. BMJ. 1991;302:749-52.

Karamanolis G, Caenepeel P, Arts J, Tack J.Association of the predominant symptom withclinical characteristics and pathophysiolog-ical mechanisms in functional dyspepsia.Gastroenterology. 2006;130:296-303.

Locke GR 3rd. Prevalence, incidence and naturalhistory of dyspepsia and functional dyspepsia.Baillieres Clin Gastroenterol. 1998;12:435-42.

Maleki D, Locke GR 3rd, Camilleri M, ZinsmeisterAR, Yawn BP, Leibson C, et al. Gastrointestinal

tract symptoms among persons with diabetesmellitus in the community. Arch Intern Med.2000;160:2808-16.

Moayyedi P, Soo S, Deeks J, Delaney B, Harris A,Innes M, et al. Eradication of Helicobacter pylorifor non-ulcer dyspepsia. Cochrane DatabaseSyst Rev. 2005;(1):CD002096. Update in:Cochrane Database Syst Rev. 2006;(2):CD002096.

Pachnis V, Durbec P, Taraviras S, Grigoriou M,Natarajan D. Role of the RET signal transduc-tion pathway in development of the mam-malian enteric nervous system. Am J Physiol.1998;275:G183-6.

Rayner CK, Samsom M, Jones KL, Horowitz M.Relationships of upper gastrointestinal motorand sensory function with glycemic control.Diabetes Care. 2001;24:371-81.

Rhee PL, Kim YH, Son HJ, Kim JJ, Koh KC, PaikSW, et al. Lack of association of Helicobacterpylori infection with gastric hypersensitivityor delayed gastric emptying in functional dys-pepsia. Am J Gastroenterol. 1999; 94:3165-9.

Tack J, Talley NJ, Camilleri M, Holtmann G, HuP, Malagelada JR, et al. Functional gastro-duodenal disorders. Gastroenterology.2006;130:1466-79.

Talley NJ, Vakil N, Practice Parameters Committeeof the American College of Gastroenterology.Guidelines for the management of dyspepsia.Am J Gastroenterol. 2005;100:2324-37.

Wood JD, Alpers DH, Andrews PL. Fundamentalsof neurogastroenterology. Gut. 1999; 45 Suppl2:II-6-II-16.

110 Stomach

111

Stomach


QUESTIONS

Abbreviations:CMV, cytomegalovirusEGD, esophagogastroduodenoscopyERCP, endoscopic retrograde cholangiopancre-

atographyNSAID, nonsteroidal antiinflammatory drug

Multiple Choice (choose the best answer)1. Which of the following inhibits the produc-

tion of gastric acid by the parietal cell?

a. Histamineb. Acetylcholinec. Prostaglandinsd. Gastrine. Lipase

2. Which of the following is not a known mech-anism of injury induced by H. pylori?

a. Injury to D cells that produce somatostatin,allowing uninhibited gastric acid production

b. Disruption of the function of a mismatchrepair gene that, in turn, leads to the devel-opment of gastric cancer

c. Production of a protease that thins themucous layer, leaving the mucosa moreprone to injury

d. Inciting the development of autoantibodiesthat cross-react with gastric epithelial cells

e. Causing lymphoid tissue aggregation thatmay develop into MALT (mucosa-associ-ated lymphoid tissue) lymphoma

3. What percentage of patients will develop agastric ulcer (symptomatic or asymptomatic)within the first 3 months of taking nonsteroidalantiinflammatory drugs?

a. 1%b. 15%c. 50%d. 70%e. 90%

4. Which of the following clinical scenarios mayresult in a decrease in the serum concentrationof gastrin?

a. Taking an H2-receptor antagonist for 6months

b. H. pylori infectionc. Chronic atrophic gastritisd. Administration of secretin to a healthy subjecte. Administration of secretin to a patient with

Zollinger-Ellison syndrome

5. The overall 5-year survival rate for gastriccancer (all patients) in the United States is:

a. 1%b. 10%c. 30%d. 50%e. 80%

6. A 65-year-old woman with no history of pepticulcer disease develops new-onset epigastric pain.EGD shows a 1.5-cm ulcer in the gastric fundus.Which of the following statements is true?

a. The lesion is in an atypical location, andmultiple biopsies should be performed

b. If biopsy findings are negative for malig-nancy, endoscopic ultrasonography shouldbe performed

c. If H. pylori infection is found and treated,the patient does not require endoscopicfollow-up

d. If H. pylori is not seen in biopsy specimens,the patient should be treated empiricallyfor H. pylori infection because of the highrisk of ulcer recurrence

e. If this ulcer is malignant, it is most likelyMALT (mucosa-associated lymphoidtissue) lymphoma

7. The 5-year survival rate for patients with stageI or II gastric lymphoma is:

a. 1%b. 10%c. 30%d. 50%e. 80%

8. Which of the following statements is true aboutgastric carcinoids?

a. Gender has no influence on type or prog-nosis of gastric carcinoids

b. Multifocal gastric carcinoid tumors havea worse prognosis than a solitary gastriccarcinoid

c. Prognosis of carcinoid is determined byclinical course more than by stage

d. Carcinoid regression has no relation toserum gastrin levels when the carcinoid isrelated to Zollinger-Ellison syndrome

e. Gastric carcinoids related to chronic activegastritis typically are aggressive tumors

9. A 62-year-old man is admitted to the hospitalwith a 1-day history of hematemesis. Recently,he has had fevers and intermittent epigastricpain. He has a history of hypertension, aorticsclerosis, and polymyalgia rheumatica. He doesnot smoke or drink, and there is no personal orfamily history of ulcers. His medications includehydrochlorothiazide, a baby aspirin, low-doseprednisone, and omeprazole. His weight isstable. At endoscopy, several 8- to 12-mm ulcersare noted in the body and fundus of hisstomach, with some coffee ground material.Which of the following is the most likely expla-nation for the stomach ulcers in this patient?

a. Lymphoma, B-cell type, secondary to H.pylori infection

b. Lymphoma, T-cell type, secondary to celiacdisease

c. Benign gastric ulcerationd. CMV ulceratione. Gastric adenocarcinoma

10. A 42-year-old woman undergoes cholecys-tectomy, an open procedure, because of denseadhesions from a previous appendectomy.Intraoperative hypotension results in sub-stantial mesenteric ischemia and small-bowelresection. A few days later, diarrhea andhematemesis develop. Bulbar and postbulbarulcers are found at endoscopy. Which of thefollowing is most likely?

a. She has an increased fasting serum levelof gastrin

b. She has a history of peptic ulcer diseasec. She has been given high doses of NSAIDsd. She has recurrent, further mesenteric ischemiae. She has CMV enteritis

112 Stomach

11. A 19-year-old female model for a shampoocompany presents with a several-week his-tory of vague epigastric discomfort, halitosis,early satiety, poor appetite, and a 10-lb weightloss. She is hospitalized and afebrile, withnew jaundice. Her serum level of lipase isfourfold normal. Ultrasonography showsmild dilatation of the common bile duct anda normal gallbladder. Abdominal radiog-raphy shows a mottled appearance within anenlarged stomach. Which of the followingwould you recommend?

a. ERCPb. Cholecystectomyc. Low fiber dietd. Conservative therapye. Surgery

12. Gastroduodenal manometry is a useful clinicaltest in which of the situations below?

a. In the evaluation of a patient with sclero-derma who has delayed gastric emptying

b. In the evaluation of a patient with suspectedrumination syndrome

c. In a patient with unexplained obstructivesymptoms (negative small-bowel follow-through) and history of previous abdominaloperations

d. In the evaluation of a patient with severeupper gastrointestinal tract symptomswhen all other tests are entirely normal

e. In the evaluation of a patient with amyloi-dosis who has delayed gastric emptying

13. A 16-year-old previously healthy high-schoolathlete is referred to you because of an 18-month history of daily vomiting, which occursduring and after meals. He has lost 18 lb. Thefindings of the usual laboratory tests, EGD,computed tomography, abdominal ultra-sonography, duodenal biopsies, magnetic res-onance imaging of the brain, and adrenal testswere all unremarkable. Which of the followingis most likely to be diagnostic?

a. Human immunodeficiency virus testingb. Additional historyc. Testing for C1 esterase deficiencyd. Porphyrin analysise. Esophageal manometry for achalasia

14. Which of the following statements about gas-tric motility is true?

a. Solids are emptied from the stomach afteran initial lag phase, followed by a linearemptying phase

b. Liquids are emptied from the stomachwithout a lag phase, in a linear manner

c. Delayed gastric emptying is the principalcause of symptoms in functional dyspepsia

d. During phase III of the migrating motorcomplex, gastric contraction waves occurat a maximum of 3 cycles per second

e. Indigestible solids are emptied from thestomach via the migrating motor complexwhen they are smaller than 3 cm in diameter

ANSWERS

1. Answer cProstaglandins

2. Answer bDisruption of the function of a mismatch repairgene, that, in turn, leads to the development ofgastric cancer

3. Answer b15%

4. Answer dAdministration of secretin to a healthy subject

5. Answer c30%

6. Answer aThe lesion is in an atypical location, and multiplebiopsies should be performed.


7. Answer e80%

8. Answer cPrognosis of carcinoid is determined more byclinical course than by stage.

9. Answer dThis patient, who is receiving immunosuppressivetherapy, presents with fever, pain, bleeding, andmultiple areas of gastric ulceration. This presen-tation is very likely to be due to CMV ulceration.B-cell lymphomas due to H. pylori infection moreoften appear as bulkier mass lesions with ulcera-tion or more diffuse, infiltrative maltomas. Thereis no history of celiac disease, and the associated T-cell lymphomas usually occur in the small bowel.The presentation of gastric adenocarcinoma isunlikely to include multiple ulcerations. Benignstomach ulcers are unlikely in this patient receivingtreatment with omeprazole.

10. Answer aHer presentation with bulbar and postbulbarulcers, diarrhea, and hematemesis suggests an acidhypersecretory state. Sudden removal of large por-tions of the small bowel eliminates intestinal-phaseinhibitors of gastric acid secretion and can dra-matically increase serum levels of gastrin and gas-tric acid production. Recurrent ischemia severaldays postoperatively is unlikely, as is CMV infec-tion in an otherwise healthy patient. It is unlikelythat she would have received high doses ofNSAIDs. Even if she had a history of a previousulcer, the acute onset, postbulbar ulceration, anddiarrhea would not be explained by a previoushistory of an ulcer.

11. Answer eThe key observation is the mottled appearancewithin an enlarged stomach seen in an abdominalradiograph. This, plus her early satiety and othersymptoms, suggests a bezoar. Vegetable bezoarsusually do not interfere with ampullary drainage(jaundice, dilated bile duct, and pancreatitis) buttrichobezoars can. A low fiber diet or conserva-

tive therapy is unlikely to be helpful. There is noneed for cholecystectomy. ERCP could help gethair and material out of the ampullary region, buta large gastric bezoar due to hair requires surgicalremoval. This patient has Rapunzel’s syndromedue to chewing hair, either consciously or uncon-sciously (while asleep).

12. Answer cManometric findings are reasonably specific formechanical obstruction even when radiographicstudies are negative. Patients who have a specificdiagnosis that is associated with delayed gastricemptying, such as scleroderma, amyloidosis, ordiabetes mellitus, do not need an additional diag-nostic test. Rumination is diagnosed on the basisof the history; manometric findings are less sen-sitive and specific. Gastroduodenal manometryis invasive, not always well tolerated, and unlikelyto be helpful in a setting in which other assess-ments of gastrointestinal function (eg, scintig-raphy) are normal.

13. Answer bDaily vomiting in combination with all the normaltest results is peculiar. Additional history showseffortless regurgitation, not vomiting, which oftenis seen in young stressed persons with eating dis-orders and weight loss (bulimia or anorexia). Distalesophagitis is not unusual. Psychiatric evaluationand behavioral therapy with diaphragmaticbreathing exercises can be helpful. The other testsare not likely to be helpful in this scenario.

14. Answer aLiquids empty in an exponential manner duringthe fed state, without a lag phase. Triturated solidsless than 2 mm in diameter are emptied in a linearmanner during the fed state, after a lag phase.Indigestible solids smaller than 2 cm are emptiedduring the fasting state by the migrating motorcomplex, with maximal gastric contraction wavesat 3 cycles per minute. Objects more than 5 cm inlength or larger than 2 cm in diameter will not passthrough the pylorus. Delayed gastric emptying isnot common in functional dyspepsia.

114 Stomach

SECTION III

Small Boweland Nutrition

MALABSORPTIVE DISORDERS ANDDIARRHEAMalabsorption (defect in the mucosal absorptionof nutrients) and maldigestion (defect in thehydrolysis of nutrients) both imply disorderedphysiologic mechanisms in the gastrointestinalsystem. Malabsorption and maldigestion of nutri-tional substrates can occur in multiple phases: 1)the luminal phase, in which there is contact withvarious digestive enzymes, 2) the mucosal phase,in which substances are assimilated and absorbedin the required constituent form, and 3) thedelivery phase, in which nutrients are taken upinto the cytoplasm and transported to the lym-phatics or portal venous system (Table 1).

Carbohydrate MalabsorptionStarch, sucrose, and lactose account for nearly 85%of ingested carbohydrates, with starches alonecomprising 50%. For starches to be absorbed,they first are digested by salivary α-amylase andpancreatic α-amylase—mainly the latter—intodisaccharides and oligosaccharides of maltose,maltotriose, and α-dextrins, which are then

hydrolyzed by brush border enzymes to form themonosaccharide glucose. Sucrose is hydrolyzedby sucrase to form glucose and fructose, whereaslactose is hydrolyzed by lactase to form glucoseand galactose. After being cleaved by the brushborder disaccharidases, these monosaccharidescan be absorbed into the cytoplasm. Fructose istransported by facilitated diffusion, but glucoseand galactose are transported by a sodium-depen-dent active transporter (SGLT-1); oral rehydrationsolutions are effective because of the inclusion ofboth sodium and glucose in concentrations thatmaximize use of this transport system (see below).

Carbohydrate malabsorption can be causedby either a decrease in mucosal surface area(absolute or functional) or a decrease in disaccha-ridases or transport proteins. Carbohydrates thatare not absorbed increase the osmolality withinthe intestinal lumen, which draws more fluid intothe lumen in order to maintain an isosmotic state.Colonic bacterial fermentation of these substancesincreases intestinal gas. The most common clinicalsyndrome of carbohydrate malabsorption is fromlactase deficiency. Congenital lactase deficiency

117

Abbreviations: EATL, enteropathy-associated T-cell lymphoma; PAS, periodic acid-Schiff; PCR, polymerase chain reaction;SIBO, small intestinal bacterial overgrowth; tTG, tissue-transglutaminase antibody.

CHAPTER 8

Clinical Features of Malabsorptive Disorders, Small-Bowel Diseases,

and Bacterial Overgrowth Syndromes

Amy S. Oxentenko, MD

is present at birth and is rare. Primary lactasedeficiency has a delayed onset, and its highestprevalence is among Native Americans and peoplefrom sub-Saharan Africa and Asia. A secondary, orlate-onset, acquired lactase deficiency may occurafter intestinal resection, mucosal disease, or apostinfectious syndrome. Less common condi-tions associated with disaccharidase deficienciesinclude sucrase-isomaltase deficiency (an inheritedcondition) and trehalase deficiency (trehalose is asugar found in various mushrooms).

The clinical features of carbohydrate malab-sorption include odorless flatus, bloating, andosmotic diarrhea. Weight loss should not occurwith isolated carbohydrate malabsorption. Adetailed dietary history can suggest the disorder.The diagnosis may be supported by the findings ofan increased stool osmotic gap and stool pH <6.

Quantification of the mucosal enzyme activity ofthe various disaccharidases is invasive and notwidely available. Hydrogen breath tests havereplaced oral tolerance tests; an increase in breathhydrogen of 20 parts per million above baselineis indicative of colonic fermentation of the non-absorbed carbohydrate by bacteria. If the test ispositive and the patient has unfavorable clinicalsymptoms such as bloating or diarrhea, this isindicative of malabsorption with clinical intol-erance. False-positive results (small intestinalbacterial overgrowth [SIBO]) and false-negativeresults (recent treatment with antibiotics or non-hydrogen producers) can occur with breath testing.

Fat MalabsorptionFat malabsorption is a complex process thatrequires adequate function of the pancreas, liver,

118 Small Bowel and Nutrition

Table 1. Mechanisms of Malabsorption

Category Defect Cause Examples

Luminal defect Defective fat hydrolysis Decreased lipase Pancreatic insufficiencyDecreased duodenal pH Zollinger-Ellison syndromeImpaired mixing Postgastrectomy

Defective protein Decreased proteases Pancreatic insufficiencyhydrolysis Absence of enterokinase Congenital deficiency

Impaired solubilization Decreased micelle Liver diseaseformation Biliary obstruction

Ileal resection/diseaseDrugs (cholestyramine)

Deconjugation of bile salts Bacterial overgrowthMucosal defect Diffuse mucosal damage Diminished surface area, Celiac disease, tropical

altered absorption/ sprue, Crohn’s disease,secretion Whipple’s disease,

amyloidosisDecreased brush border Congenital/acquired Lactase, trehalase, sucraseenzymes deficiency

Small-bowel damage Postinfectious lactaseTransporter defects Single enzyme defects Hartnup disease, cystinuria

Delivery defect Lymphatic derangement Ectasia of lymphatics LymphangiectasiaIncreased lymphatic Congestive heart failure,pressure constriction, lymphoma,

fibrosis

Data from Riley SA, Marsh MN. Maldigestion and malabsorption. In: Feldman M, Scharschmidt BF, Sleisenger MH,editors. Sleisenger & Fordtran’s gastrointestinal and liver disease: pathophysiology/diagnosis/management. Vol 2. 6th ed.Philadelphia: WB Saunders Company; 1998. p. 1501-22.

small-bowel mucosa, and lymphatic system.Triglycerides constitute the majority of dietary fat.Initial lipolytic activity begins in the stomachthrough the action of gastric lipase, although thiscontributes little to digestion in most people.Pancreatic lipase has a much larger role inhydrolyzing dietary triglycerides. Because theoptimal activity of this enzyme is at pH 8, it is inac-tivated in acid overproduction states (eg, Zollinger-Ellison syndrome). Pancreatic lipase hydrolyzesdietary triglycerides into free fatty acids and β-monoglycerol. These constituents then combinewith conjugated bile salts from the liver to formwater-soluble micelles, which allow the con-stituents to pass into the enterocyte. At the levelof the enterocyte, triglycerides are reesterified andthen synthesized into chylomicrons and distrib-uted systemically through the lymphatics.Although pancreatic function is required for fatdigestion, a person may lose nearly 90% of lipaseoutput from the pancreas before the efficiency of fatdigestion and absorption is affected. Unlike long-chain triglycerides, which require bile salts forabsorption, medium-chain triglycerides do notrequire micellar formation for absorption and canbe absorbed directly into the portal blood. Thismechanism can be used to provide triglyceridesin the diet without worsening fat malabsorptionin patients with bile salt deficiency.

The clinical features of fat malabsorptioninclude diarrhea, weight loss, and complicationsfrom fat-soluble vitamin deficiencies (vitamins A,D, E, and K). Although the amount of fat in thestool can be assessed qualitatively with Sudanstaining, this test has relatively low sensitivity andspecificity. Quantitation of fecal fat excretion isconsidered the “gold standard” for establishingthe presence of fat malabsorption. The normalvalue for fecal fat excretion is less than 7 g/day,but patients with diarrhea from any cause mayhave up to 14 g/day before it may represent truefat malabsorption. A 72-hour stool collection isoptimal, and the patient should be placed on a dietcontaining 100 g of fat per day several days beforestool collection commences.

Once fat malabsorption has been confirmed, thecause needs to be determined. In some cases, thecause may be apparent clinically. The most commonclinical conditions result from small-bowel diseases

or pancreatic insufficiency. Although D-xylosetesting has limited clinical availability, it can helpdistinguish between a small-bowel and a pan-creatic source of fat malabsorption because D-xylose is absorbed normally by the small-bowelmucosa and excreted in the urine. After ingestionof 25 g of D-xylose, a 1-hour serum or a 5-hour urinesample (or both) can be collected. A serum levelof D-xylose less than 20 mg/dL per hour or a urineconcentration less than 5 g/5 hours suggests failureof small-bowel absorption. Increased levels of D-xylose in the serum or urine suggest that the small-bowel mucosa is intact, thus indicating pancreaticinsufficiency. Many factors can influence the testresults, including gastroparesis, vomiting, andinadequate collection of urine. Small-bowel abnor-malities that lead to fat malabsorption should beevaluated with a combination of small-bowelbiopsy, aspiration, and imaging studies. To eval-uate for pancreatic causes of fat malabsorption,imaging (computed tomography, magnetic reso-nance cholangiopancreatography/endoscopic ret-rograde cholangiopancreatography, or endoscopicultrasonography) can be used to examine forchanges due to chronic pancreatitis. Calcificationsseen in the pancreas on plain films can be helpful,but they occur in only a small number of cases.Tests of pancreatic function are not widely avail-able, but they can be performed with secretin (tomeasure bicarbonate) and cholecystokinin (to mea-sure lipase or trypsin). Alternatively, an empirictrial of pancreatic enzymes can be recommended.

Protein MalabsorptionProtein digestion and absorption require adequatepancreatic function and integrity of the intestinalmucosa. Ingested proteins are cleaved initially bypepsin (an endopeptidase), which is producedfrom the precursor pepsinogen in response to agastric pH 1 to 3, with inactivation at a pH >5.When gastric chyme reaches the small intestine,enterokinase from the duodenal enterocyte acti-vates trypsin. Trypsin then converts pancreaticproteases from inactive to active forms in a cas-cade fashion, subsequently cleaving proteins intovarious amino acids and small peptides. Additionalmucosal brush border oligopeptidases furthercleave small peptides, with free amino acids andoligopeptides crossing into the cytoplasm either

Malabsorptive Disorders, Small-Bowel Diseases, Bacterial Overgrowth Syndromes 119

freely or through carrier-mediated channels, someof which are sodium mediated.

In addition to disorders that affect proteindigestion and absorption, there can be significantloss of protein from the intestinal tract; these con-ditions are referred to as protein-losing enteropathies.Although the liver can respond to protein loss byincreasing the production of various proteins suchas albumin, a protein-losing state develops whennet loss exceeds net production. Three major cat-egories of gastrointestinal-related disorders areassociated with excess protein loss: 1) diseases withincreased mucosal permeability without erosions,2) diseases with mucosal erosions, and 3) diseaseswith increased lymphatic pressure. Examples ofclinical conditions in each of these categories arelisted in Table 2.

The clinical features of a protein-losingenteropathy include diarrhea, edema, ascites, andpossible concomitant carbohydrate and fat mal-absorption, because isolated protein malabsorp-tion or loss is infrequent. Laboratory studies mayshow a low serum level of protein, albumin, andgamma globulins, except for IgE, which has a shorthalf-life and rapid synthesis. If the protein-losingstate is from lymphangiectasia (primary oracquired), patients may also have lymphocy-topenia. To diagnose a protein-losing enteropathy,an α1-antitrypsin clearance test should be per-formed. α1-Antitrypsin is unique in that it is neitherabsorbed nor secreted from the intestinal mucosa,

and unlike other proteins, it is resistant to proteol-ysis (with the exception of pepsin). Therefore, itsclearance reflects a true protein-losing state. If aprotein-losing gastropathy is suspected, the patientshould receive acid-suppressive therapy before anα1-antitrypsin clearance test is performed to avoiddegradation of α1-antitrypsin by pepsin.

DiarrheaThe mechanism for diarrhea is often from a combi-nation of decreased absorption (a villous function)and increased secretion (a crypt function). Diarrheacan be categorized in several ways: inflammatoryversus noninflammatory and secretory versusosmotic. The clinical features of inflammatory diar-rhea may include abdominal pain, fever, andtenesmus. Although dehydration can occur, it isnot typical. Stools may be mucoid, bloody, smallervolume, and more frequent, unless the small bowelalso is affected diffusely. Microscopically, the stoolscan contain blood and leukocytes. However, if theinflammation is microscopic, these clinical andstool features may be absent. Common causes ofinflammatory diarrhea include invasive infections,inflammatory bowel disease, radiation enteropathy,and ischemia. Noninflammatory causes of diar-rhea tend to produce watery diarrhea, withoutfever or gross blood, and the stool appears normalon microscopy. There are many causes, but infec-tions, particularly by toxin-producing organisms,are common.


Table 2. Causes of Protein-Losing Enteropathies

Nonerosive disease Erosive disease Increased lymphatic pressure

Ménétrier’s disease Amyloidosis Congestive heart failureHelicobacter pylori gastritis Inflammatory bowel disease Constrictive pericarditisEosinophilic gastroenteritis Graft-versus-host disease Lymphangiectasia (primary vsCeliac disease Clostridium difficile colitis acquired)Small intestinal bacterial Ischemia Lymphatic obstruction (lymphoma)overgrowth Mesenteric venous thrombosis

Whipple’s disease Retroperitoneal fibrosisVasculitides

Modified from Greenwald DA. Protein-losing gastroenteropathy. In: Feldman M, Friedman LS, Brandt LJ, editors.Sleisenger & Fordtran’s gastrointestinal and liver disease: pathophysiology/diagnosis/management. Vol 1. 8th ed.Philadelphia: Saunders Elsevier; 2006. p. 557-64. Used with permission.

Distinguishing whether diarrhea is osmoticor secretory can be useful clinically. Osmotic diar-rhea is due to the ingestion of poorly absorbedcations, anions, sugars, or sugar alcohols. Theseingested ions obligate retention of water in theintestinal lumen to maintain osmolality equal tothat of other body fluids (290 mOsm/kg); this sub-sequently causes diarrhea. Osmotic diarrhea canoccur also from maldigestion or malabsorption(pancreatic insufficiency or disaccharidase defi-ciency). The stool osmotic gap is calculated byadding the stool sodium concentration and thepotassium concentration, multiplying by two, andsubtracting this amount from 290 mOsm/kg. Agap greater than 100 strongly supports an osmoticcause for the diarrhea, whereas a gap less than 50supports a secretory cause. Stool osmolality doesnot necessarily need to be measured because thevalue should be the same as that of the serum, withlower values indicating urine or water contami-nation and higher values indicating that the spec-imen was not processed readily. Stool volumestend to be less with osmotic diarrhea than withsecretory diarrhea, and the diarrhea tends to abatewith fasting.

For secretory diarrhea to occur, the primarybowel function converts from net absorption tonet secretion. Normally, up to 9 to 10 L of intestinalfluid crosses the ligament of Treitz each day and allbut 1.5 L crosses the ileocecal valve, demonstratingthe tremendous absorptive capacity of the smallbowel. The colon then absorbs all but 100 to 200mL of the fluid, which is evacuated as stool. Insecretory diarrhea, net absorption converts to netsecretion and the small bowel loses its capacity toabsorb the large volume of fluid that it normallydoes; thus, liters of fluid pass into the colon.Although the colon can adapt and absorb nearly4 L of liquid from the stool each day, larger fluidloads cannot be absorbed, and this results in large-volume diarrhea, often liters per day. Secretorydiarrhea does not abate with fasting. Dehydrationcan occur easily, and replacement fluids need tocontain adequate concentrations of both sodiumand glucose, as in oral rehydration solutions, tomaximize small-bowel absorption of sodium andwater. Sodium and glucose absorption from thesmall bowel occurs through a Na-glucose trans-porter, SGLT-1. Characteristics, common causes,

and testing strategies for secretory and osmoticdiarrhea are listed in Table 3.

Intestinal Resections and Short BowelDiarrhea and malabsorption can result from anyprocess that shortens the length of the functioningsmall bowel, whether from surgery or from relativeshortening caused by underlying disease. Whetherdiarrhea and malabsorption occur with a short-ened small bowel depends on several factors: thelength of bowel resected, the location of the bowelresected, the integrity of the remaining bowel, andthe presence of the colon. The length and locationof the resected small bowel affect the enterohep-atic circulation of bile. Typically, bile salts are reab-sorbed from the terminal ileum. If less than 100 cmof ileum is resected, the liver can compensate forthe loss of absorptive capacity by producing anincreased amount of bile salts, which enter thecolon and cause a bile-irritant diarrhea. This diar-rhea is treated with cholestyramine, which bindsthe excess bile salts and improves diarrhea. If morethan 100 cm of small bowel is resected, includingthe terminal ileum, the liver can no longer com-pensate for the loss of absorptive capacity. Theresulting bile salt deficiency leads to steatorrhea.This can be managed by prescribing a diet that con-sists of medium-chain triglycerides, which do notrequire bile salts or micellar formation for absorp-tion because they are absorbed directly into theportal blood.

The location of the small-bowel resection isalso important. The terminal ileum has the spe-cialized function of absorbing and recirculatingbile salts and binding the cobalamin-intrinsic factorcomplex. When the jejunum is resected, the ileumis able to assume all the functions of the jejunum.However, the opposite is not true; the jejunum isnot able to compensate for the loss of the spe-cialized functions of the ileum. Outcomes of ilealresection include diarrhea (from either an excess ofor a deficiency of bile salts, depending on length),vitamin B12 deficiency, SIBO (from resection of theileocecal valve), gallstones (from disruption of thecholesterol pool), and calcium oxalate kidneystones. Normally, in the small bowel, calcium bindsto oxalate, and this passes into the colon and isexcreted in the stool. With a shortened small boweland absence of the colon, calcium preferentially


binds to the fatty acids in the stool, leaving oxalateunbound. Unbound oxalate is incorporated intothe stool and excreted through the ostomy. In thecase of a shortened small bowel and intact colon,free oxalate is absorbed from the colon, leading tothe formation of calcium oxalate kidney stones.Although the absolute length of small bowel thatis resected is important, the integrity of theremaining bowel is crucial because diffuse patho-logic processes such as Crohn’s disease or radia-tion enteritis can result in a functionally shortenedbowel, effectively shortening the bowel furtherwithout surgical resection. Whether a patient hasan intact colon is of considerable importance if thesmall bowel has been resected. The colon can adaptby increasing water and sodium absorption, by

acting as an intestinal “brake” to slow motility,and by salvaging nonabsorbed carbohydrates toprovide additional calories for patients with shortbowel syndrome.

In short bowel syndrome, multiple mecha-nisms contribute to malabsorption. In the earlypostoperative stage, hypersecretion of gastric acidinactivates pancreatic enzymes, leading to diar-rhea and steatorrhea. Until the remaining smallbowel has time to adapt, intestinal transit is rapidbecause of the loss of surface area. As mentionedabove, patients may be at risk for bacterial over-growth, and because of the disruption of theenterohepatic circulation of bile, bile acid wastingor steatorrhea (or both) develop. Early managementof short bowel syndrome includes aggressive


Table 3. A Comparison of Osmotic and Secretory Diarrhea

Diarrhea

Feature Osmotic Secretory

Stool volume, L/day <1 >1Effect of fast on diarrhea Stops ContinuesStool osmotic gap >100 <50Common causes Disaccharidase deficiency Infections/toxins

Lactase CholeraTrehalase Bile acidsSucrase-isomaltase Microscopic colitis

Iatrogenic Neuroendocrine tumorsPolyethylene glycol solution Medullary carcinoma of thyroidLactulose (calcitonin)Magnesium antacids/ VIPomasupplementation Gastrin (not pure secretory)

Sweeteners/elixirs Carcinoid syndromeSorbitol Laxatives (nonosmotic)Xylitol Diabetic diarrheaFructose Transporter defects/deficiencies

ChloridorrheaIdiopathic

Testing strategies Dietary review Stool culturesCarbohydrate malabsorption Structural/mucosal evaluation

Breath testing Neuroendocrine hormone levelsStool pH <6 Cholestyramine trialAvoidance

Stool magnesium

treatment with antidiarrheal agents, total par-enteral nutrition, and gastric acid suppression.Later management includes the introduction of alow fat enteral diet, with progressive increase incarbohydrates, medium-chain triglyceride sup-plementation as needed, lactose restriction, andtreatment of bacterial overgrowth, if it is presentor suspected.

SMALL-BOWEL DISEASES

Celiac DiseaseCeliac disease may occur in genetically susceptiblepersons as an immune response to gliadins in thediet. The prevalence is highest among persons ofEuropean descent, and the disease is being diag-nosed with greater frequency in North America asclinicians become more familiar with the many man-ifestations of the disease. In the general population,the prevalence of celiac disease is nearing 1:100.Among symptomatic patients, it is 1:56, and amongfirst-degree relatives of a patient with the disease, itis 1:22. Celiac disease occurs in patients of all ages,but 20% are older than 60 years at diagnosis.

The diagnosis of celiac disease can be madeon the basis of the following: 1) the presence ofclinical feature(s) compatible with the disease, 2)supportive serologic studies, 3) characteristic small-bowel biopsy findings, and 4) a clinical response toa gluten-free diet. The diagnosis no longer requiresrechallenging the patient with gluten to invokesymptoms, because of the risk this presents tohighly sensitive patients. Patients who come toclinical attention with celiac disease represent thetip of the “celiac iceberg.” Patients with classicceliac disease have features of malabsorption,whereas those with atypical celiac disease tend tohave extraintestinal manifestations alone. These“atypical” forms of celiac disease now representthe most common clinical presentations of thedisease. The gastrointestinal and extraintestinalmanifestations of celiac disease are outlined inTable 4. Patients with silent celiac disease do nothave symptoms despite small-bowel biopsy spec-imens showing the features characteristic of thedisease. In these cases, alternative causes of thehistologic findings need to be considered. In latentceliac disease, patients have no clinical features

and normal small-bowel biopsy findings, butpositive serologic findings. No consensus existsabout how to manage these patients; however,follow-up with small-bowel biopsies could be con-sidered. The many diseases associated with celiacdisease are listed in Table 5.

The three clinically applicable serologic testsfor evaluating patients for celiac disease are 1) anti-gliadin antibodies, 2) endomysial antibodies, and3) tissue-transglutaminase antibodies (tTG). TheIgA-based tTG test is considered the single besttest for screening for celiac disease. The anti-gliadinantibody test has less sensitivity and specificitythan other serologic markers and is seldom used forevaluation. The various IgA-based serologicstudies, including their sensitivity, specificity, andadvantages or disadvantages, are listed in Table6. A serum IgA level is not necessary for first-linescreening for celiac disease because of the rela-tively low prevalence (2%-3%) of IgA deficiencyin patients with the disease. In patients with knownIgA deficiency, an IgG-based tTG should be per-formed; the sensitivity and specificity are bothnearly 100%. However, this test alone should notbe used for first-line screening for the disease inall patients because the sensitivity of the testdecreases to approximately 70% in non-IgA–defi-cient patients. Serologic tests for celiac diseaseshould be considered for 1) patients with typicalgastrointestinal manifestations of the disease, 2)patients with atypical manifestations, 3) at-riskgroups, and 4) patients who are being followed fortheir response to a gluten-free diet. For symptomaticpatients, however, small-bowel biopsy studies areneeded regardless of the results of serologic testing.Also, any positive serologic study needs to be con-firmed with a small-bowel biopsy study.

The endoscopic findings in celiac diseaseinclude the loss of folds, a mosaic pattern, scal-loping, and nodularity. The sensitivity of theseendoscopic markers is quite poor; however, if theyare seen, small-bowel biopsy specimens should beobtained regardless of the indication for upperendoscopy because of their high yield in showinga pathologic process. Small-bowel biopsy studiesare required for the diagnosis of celiac disease, andbiopsy studies should be performed in all patientsbefore treatment is initiated. The classic histologicfindings include villous atrophy (total or partial),


crypt hyperplasia, intraepithelial lymphocytosis(>40 intraepithelial lymphocytes per 100 surfaceenterocytes), and chronic inflammatory cells in thelamina propria (Fig. 1). There is a spectrum of his-tologic findings in celiac disease, as indicated by theMarsh Classification (Fig. 2). Early Marsh lesionsare more likely to produce fewer or no symptoms

than late Marsh lesions. An increase in the numberof intraepithelial lymphocytes is the minimal his-tologic lesion needed for the diagnosis of celiacdisease; villous atrophy alone is not sufficient fordiagnosis because it is a nonspecific finding. Otherconditions that may show villous flattening insmall-bowel biopsy specimens are listed in Table 7.


Table 4. Manifestations of Celiac Disease

Clinical features Details

Gastrointestinal Diarrhea, steatorrheaFlatulence, distentionWeight loss, anorexiaAbdominal painNausea, vomitingConstipationAphthous stomatitisAngular cheilosis

ExtraintestinalLaboratory findings Anemia Iron, vitamin B12, folate (may be

normocytic, dimorphic)Vitamin deficiencies Vitamins A, D, E, KTransaminase levels Hepatic steatosisincreased

Skin Dermatitis herpetiformis Pruritic, papulovesicular, on extensorsurfaces

Hematologic Splenic atrophy Functional, predisposed to encapsulatedorganisms

Musculoskeletal Osteopenia/osteoporosis Calcium or vitamin D loss or lactoseavoidance

Osteomalacia Vitamin D deficiency, increasedalkaline phosphatase level

Enamel defects Similar to Sjögren’s syndromeArthropathy Nonerosive, polyarticular, symmetrical,

large jointMuscle cramps/tetany From low calcium, vitamin D, or

magnesium levelsNeurologic Peripheral neuropathy Symmetrical, distal, small-fiber most

commonAtaxia CerebellarEpilepsy Bilateral parieto-occipital calcifications

Reproductive Infertility Female or maleRecurrent miscarriage

Psychiatric Depression/anxiety One-third of celiac patients

Modified from Farrell RJ, Kelly CP. Diagnosis of celiac sprue. Am J Gastroenterol. 2001;96:3237-46. Used with permission.

These should be considered if the results of sero-logic studies are negative.

Approximately 95% of patients with celiac dis-ease are positive for HLA-DQ2, and the other 5%

are positive for HLA-DQ8. However, 30% to 40%of the general population is also positive forHLA-DQ2 or HLA-DQ8. Therefore, the presenceof one of these genetic markers is necessary butnot sufficient for the diagnosis of celiac disease.HLA testing is not necessary for most patientsbeing evaluated for celiac disease; however, thenegative predictive value of 100% can be usefulin evaluating 1) patients who have early Marshlesions, 2) patients who have negative serologicresults, 3) patients who already have been pre-scribed a gluten-free diet, or 4) patients who arein certain higher risk populations (eg, Down’ssyndrome) for whom reporting symptoms maybe difficult.

The only treatment for celiac disease is a life-long gluten-free diet, which includes the avoidanceof wheat, barley, and rye. Food items that containoats can be tolerated by most patients with the dis-ease, but cross-contamination or hypersensitivitymay limit oat tolerability for some of them.Consultation with a skilled dietician is imperativefor patients with celiac disease. Evaluating bonedensitometry, determining vitamin and minerallevels and providing replacement therapy, andvaccinating for encapsulated organisms becauseof functional asplenia should all be considered.


Table 5. Disorders Associated With CeliacDisease

Endocrine Type 1 diabetes mellitusAutoimmune thyroiditis

Connective tissue Sjögren’s syndromedisorders Rheumatoid arthritis

Immunologic IgA deficiencyInflammatory Inflammatory bowel

conditions diseaseMicroscopic colitis

Hepatic Primary biliary cirrhosisNeurologic EpilepsyRenal IgA mesangial nephropathyCardiopulmonary Carditis

Fibrosing alveolitisPulmonary hemosiderosis

Other Down’s syndrome

Modified from Farrell RJ, Kelly CP. Diagnosis of celiacsprue. Am J Gastroenterol. 2001;96:3237-46. Usedwith permission.

Table 6. IgA-Based Serologic Studies for Celiac Disease

Serologic test Sensitivity, % Specificity, % Features

IgA AGA 85-90 90 ELISAFalse positive with mucosal damageReplaced in clinical use by other serologic markers

IgA EMA 90.2 (human 99.6 Immunofluorescence with human umbilical cordumbilical or monkey esophaguscord) or Subjective, time consuming, expensive97.4 (monkeyesophagus)

IgA tTG 95.1 98.3 ELISA, human recombinant or RBC-derived, usedmost frequently

Nonsubjective, less expensiveLoss of specificity with autoimmunity

AGA, anti-gliadin antibody; ELISA, enzyme-linked immunosorbent assay; EMA, endomysial antibody; RBC, red bloodcell; tTG, tissue transglutaminase.

Data from Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA) Institute technicalreview on the diagnosis and management of celiac disease. Gastroenterology. 2006;131:1981-2002. Used with permission.

Dermatitis herpetiformis is an intensely pruriticpapulovesicular rash, typically on the extensorsurfaces, that represents an intestinal sensitivityto gluten in the diet. Biopsy specimens from theskin adjacent to the affected area may show granularIgA deposits in the papillary dermis; these depositsare pathognomonic for dermatitis herpetiformis(Fig. 3). The treatment for dermatitis herpetiformis,as for celiac disease, is a lifelong gluten-free diet.Dapsone may help with healing the skin, but itdoes not heal the intestinal lesion.

For patients with diagnosed celiac disease inwhom initial therapy fails or symptoms recur afterearly clinical improvement, several questionsshould be answered. First, was the initial diag-nosis of celiac disease correct? In this instance, thesmall-bowel biopsy findings and supportive sero-logic studies should be reviewed. Second, has therebeen inadvertent or surreptitious ingestion of

gluten? The ingestion of gluten is the most likelycause of ongoing or recurring symptoms in apatient with celiac disease; thus, the patient’s dietand medications should be reviewed. Patients withceliac disease are at risk for other conditions thatcan cause diarrhea, and these should be consid-ered: microscopic colitis, bacterial overgrowth,pancreatic insufficiency, lactase deficiency, andinflammatory bowel disease. Celiac-specific com-plications also need to be considered, includingulcerative jejunitis, refractory sprue, and malignancy.Imaging or small-bowel biopsy studies (or both)would be required. Patients with celiac disease areat increased risk for enteropathy-associated T-celllymphoma (EATL), which may be manifested as arecurrence of symptoms. EATL is associated withpoor survival. Compliance with a gluten-free dietcan significantly reduce the risk of EATL. Othermalignancies for which patients with celiac disease


Fig. 1. Small-bowel histopathologic findings in celiacdisease. Small-bowel biopsy specimens show thefollowing: A, Normal. B, Intraepithelial lymphocytesalone as seen in an early Marsh lesion of celiacdisease. C, Classic histologic findings of celiac disease,with marked villous atrophy, crypt hyperplasia, andintraepithelial lymphocytosis, with a chronicinflammatory cell infiltrate in the lamina propria.

C

A B

are at increased risk include other forms of non-Hodgkin’s lymphoma, small-bowel adenocarci-noma, and oropharyngeal and esophageal cancers.

Whipple’s DiseaseWhipple’s disease is a multisystem disorder causedby the gram-positive bacillus Tropheryma whippelii.This disease usually occurs in white males in thefourth and fifth decades of life. The clinical fea-tures include diarrhea, weight loss, adenopathy,arthralgias, fevers, carditis, hyperpigmentation,pleural effusions, and ocular and neurologic symp-toms. The diagnosis can be established with a com-bination of small-bowel biopsy studies and thepolymerase chain reaction (PCR). Small-bowelbiopsy specimens typically contain periodic acid-Schiff (PAS)–positive macrophages (Fig. 4). Thisneeds to be differentiated from Mycobacteriumavium-intracellulare, which in addition to beingPAS-positive is acid-fast–positive. Electronmicroscopy can be used to show sickle-shaped T.whippelii bacteria with their trilaminar cell wall. Ifthe biopsy specimens are PAS-positive and PCRis positive, the diagnosis is established. A testingalgorithm is provided in Figure 5. Treatment for


Table 7. Causes of Small-Bowel VillousAtrophy

Celiac diseaseBacterial overgrowthNonsteroidal antiinflammatory drugsGiardiasisCrohn’s diseaseViral gastroenteritisEosinophilic gastroenteritisCombined variable immunodeficiencyTropical sprueLymphomaZollinger-Ellison syndromeHypersensitivity to nongluten proteins

Fig. 2. Marsh classification of the spectrum of histologic findings in celiac disease. IEL, intraepitheliallymphocyte. (From Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA)Institute technical review on the diagnosis and management of celiac disease. Gastroenterology. 2006;131:1981-2002. Used with permission.)

Whipple’s disease includes long-term treatmentwith antibiotics that penetrate the blood-brainbarrier. If the patient has pronounced clinicalsymptoms, penicillin G and streptomycin is oftengiven for 2 weeks intravenously, with trimethoprim-sulfamethoxazole given orally and continued for atleast 1 year. Other therapies have had variable suc-cess, including doxycycline, hydroxychloroquine,and interferon-based regimens. Disease relapse isnot uncommon.

Tropical SprueTropical sprue may have features that are indis-tinguishable from those of classic celiac disease,

with diarrhea, weight loss, anorexia, and lactoseintolerance. Tropical sprue needs to be consideredif the patient has traveled to certain geographicareas at risk, such as Asia, India, the Caribbean,and Central and South America. Acute tropical spruehas rapid onset of clinical features and is inde-pendent of the length of stay in a tropical area. Incomparison, chronic tropical sprue has a more steplikepresentation and requires several years of resi-dence in a tropical area. Physical examination mayshow evidence of weight loss or cachexia, glossitis,and hyperactive bowel sounds. Laboratory featurescan indicate megaloblastic anemia with vitaminB12 and folate deficiency and a protein-losing state.


Fig. 3. Dermatitis herpetiformis. A, Pruritic papulovesicular rash on the extensor surface of the skin. (FromBennett ML, Jorizzo JL, Sherertz EF. Skin lesions associated with gastrointestinal and liver diseases. In: YamadaT, editor. Textbook of gastroenterology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2003. p. 992-1009.Used with permission.) B, Immunofluorescence of biopsy specimen showing the characteristic IgA deposits inthe papillary dermis. (Courtesy of Dr. Kristin M. Leiferman, Immunodermatology Laboratory, University of Utah.)

Fig. 4. Histopathologic features of Whipple’s disease. Note the widened villi (A) filled with foamymacrophages that are periodic acid-Schiff–positive (B).

A B

A BA


Suspicion of Whipple’s disease

Small-bowel biopsy with PASstaining and PCR assay

PAS-positive PAS- and PCR-positive PCR-positive

Whipple’s disease possible Whipple’s disease certain Whipple’s disease possible

Suspicion of localizedWhipple’s disease

Selection of samples tested with PAS staining and PCR assay based on clinical manifestations:

Clinical manifestations

PAS-positive PAS- and PCR-positive

Whipple’s disease possible Whipple’s disease certain

PCR-positive

Whipple’s disease possible

Arthritis—synovial fluid or biopsyLymphadenopathies—lymph nodesNeurologic manifestation—cerebrospinal fluid; if negative, brain biopsy may be requiredUveitis—aqueous humorEndocarditis – cardiac valveSpondylodiskitis—disk biopsy

Fig. 5. Strategy for diagnosing Whipple’s disease by using periodic acid-Schiff (PAS) staining and thepolymerase chain reaction assay (PCR). (From Fenollar F, Puéchal X, Raoult D. Whipple’s disease. N Engl J Med.2007;356:55-66. Used with permission.)

No specific test helps establish the diagnosis, andother infectious disorders need to be ruled out. Small-bowel biopsy specimens may show villous atrophysimilar to that apparent in celiac disease; therefore,for all patients with newly diagnosed celiac disease,the travel history needs to be documented, espe-cially if the serologic test results are negative.

Treatment with folate, 5 mg/day, and vitamin B12replacement produces rapid improvement in theanemia, glossitis, and weight loss of many patientswith tropical sprue. In addition, antibiotic therapywith tetracycline, 250 mg 4 times daily, may beneeded in combination with folate for 3 to 6 months,especially to treat the chronic form of the disease.

Eosinophilic GastroenteritisIn patients with atopy, eosinophilic gastroenteritishas various clinical manifestations depending onthe location of bowel involvement. With mucosaldisease, patients often have diarrhea, malabsorp-tion, and evidence of a protein-losing enteropathy.Muscular involvement in the submucosa may leadto features of bowel obstruction, whereas serosalinvolvement may lead to ascites and peritonitis.

Laboratory studies typically show an increasedserum level of IgE and peripheral eosinophilia,with a more marked increase in the serumeosinophil count in patients with serosal disease.However, a normal serum eosinophil count doesnot exclude eosinophilic gastroenteritis. Eosinophilicgastroenteritis needs to be differentiated fromhypereosinophilic syndrome which is character-ized by a serum eosinophil count greater than1,500/μL (>1.5 × 109/L) for more than 6 monthsand often has multiorgan involvement.

An elimination diet may be incorporated inthe treatment program for eosinophilic gastroen-teritis, although it has a limited role. Prednisone,20 to 40 mg orally daily, often produces a promptclinical response, regardless of the layer of bowelinvolved. Treatment with mast cell stabilizers, suchas sodium cromoglycate, and leukotriene receptorantagonists, such as montelukast, has had vari-able success.

Intestinal LymphangiectasiaIntestinal lymphangiectasia occurs as either aprimary or a secondary form. Primary lym-phangiectasia is characterized by diffuse or local-ized ectasia of the enteric lymphatic system andoften is diagnosed at a young age. The secondaryform of the disease occurs with conditions thatproduce impaired lymphatic flow; the causes arecardiac (congestive heart failure or constriction),neoplastic (lymphoma), or structural (retroperi-toneal fibrosis).

Patients present with pronounced edema, diar-rhea, nausea, and vomiting; also, chylothorax andchylous ascites may be present. Steatorrhea may beconcurrent with a protein-losing enteropathy.Laboratory findings include a decrease in theplasma level of proteins and lymphocytopenia,which may affect cellular immunity. Endoscopically,punctate white dots may be seen on the bowel

mucosa; histologic examination shows markeddilation of the lacteals (Fig. 6). Abnormalities ofthe lymphatics may also be assessed with contrastlymphangiography or nuclear scintigraphy after ahigh fat load. The protein-losing state can be ver-ified with an α1-antitrypsin clearance test.

Treatment for the primary form includes a lowfat, high protein diet, with supplementation withmedium-chain triglycerides as needed. If the dis-ease is localized, resection could be considered.For the secondary form, treatment should bedirected at the underlying disease process.

AmyloidosisAmyloidosis is a multisystem disease that fre-quently involves the gastrointestinal tract.Amyloid deposits can be found at various levels ofthe bowel wall, although it usually is detected inthe submucosa. Amyloid can be deposited also inneuromuscular or perivascular sites. Patients withamyloidosis may have diarrhea for many reasons.There may be delayed or accelerated transit relatedto autonomic neuropathy, which may lead tosmall-bowel bacterial overgrowth or bile acid mal-absorption, respectively. Also, the amyloiddeposits may act as a barrier that prevents properabsorption; patients can have a combination of fat,protein, or carbohydrate malabsorption, and theyare commonly lactose intolerant. The endoscopicfindings in amyloidosis include granularity, fri-ability, and erosions, but often they may benormal. The yield of detecting gastrointestinal


Fig. 6. Lymphangiectasia. Note dilated lacteals inseveral contiguous villi.

tract involvement by amyloidosis depends on thesite from which biopsy samples are obtained, asfollows: esophageal 70%, gastric 75% to 95%, smallbowel 85% to 100%, and colorectum 75% to 95%. Afat aspirate can be obtained for diagnostic pur-poses, but this may have a lower yield thanintestinal biopsies if there is clinical suggestion ofinvolvement of the gastrointestinal tract. Congored staining can show the apple-green birefringence,which is seen best in the walls of the vasculature ifthe biopsy specimens contain lamina propria.Treatment for involvement of the gastrointestinaltract by amyloidosis includes treating the under-lying disease, but treatment for bacterial overgrowthand lactose avoidance should be considered.

Other Conditions

SclerodermaPatients with systemic scleroderma may havediarrhea and malabsorption from gastrointestinaldisease. The diarrhea may be due to ineffectualmotility, which may lead to SIBO. Also, intestinalpseudo-obstruction may occur with systemic scle-roderma. In addition, diarrhea may occur fromdecreased mucosal blood flow due to vasospasm.Treatment of diarrhea in patients with sclerodermaincludes antibiotics for bacterial overgrowth anda lactose-free diet. Treatment with low-doseoctreotide, 50 μg at bedtime, could be consideredbecause it can help stimulate intestinal motility andimprove symptoms; however, octreotide can be pro-hibitively expensive.

Diabetes MellitusPatients with diabetes mellitus may present withdiarrhea or malabsorption (or both) for variousreasons. First, several oral hypoglycemic agentsare associated with diarrhea, such as metforminand acarbose; the relation between the initiationof treatment with these medications and the onsetof diarrhea needs to be determined. Second,delayed intestinal transit in patients with diabetesputs them at risk for bacterial overgrowth. Third,because of the increased prevalence of gluten-sen-sitive enteropathy among patients with type 1insulin-dependent diabetes mellitus, celiac diseaseneeds to be considered. Fourth, pancreatic insuf-ficiency needs to be considered because it may

explain not only the diarrhea but also the hyper-glycemia. Fifth, patients with diabetes may ingesta significant amount of sugar-free substances forbetter glycemic control; these substances often con-tain sorbitol, xylitol, or other sugar alcohols thatmay induce osmotic diarrhea. Sixth, patients whohave diabetes with end-organ involvement maydevelop an autonomic neuropathy that will affectthe gastrointestinal tract and lead to “diabetic diar-rhea,” for which clonidine therapy may be helpfulif the patient does not have orthostatism.

Hospitalized PatientsNew diarrhea or malabsorption in hospitalizedpatients has a broad differential diagnosis thatincludes the following: antibiotics, Clostridium dif-ficile infection, tube feedings (based on the loca-tion, concentration, and bolus effect of the nutri-tion), elixir medications (which contain sorbitol),magnesium (as in antacids or replacement/sup-plementation), intestinal ischemia (especially incritically ill patients), and fecal impaction with sec-ondary overflow. Also, any treatment started witha new medication during hospitalization shouldbe scrutinized as a cause of new diarrhea. Diarrheathat is long standing or present before hospital-ization requires evaluation and work-up forchronic diarrhea.

MiscellaneousMany other conditions are associated with diarrhea,malabsorption, and mucosal disease of the smallbowel but cannot be considered in detail here.Conditions to review include immunodeficiencies(IgA deficiency, combined variable immunodefi-ciency, and graft-versus-host disease), autoimmuneenteropathy, collagen vascular diseases and vas-culitides, radiation enteritis, ischemia, mastocy-tosis, abetalipoproteinemia, and endocrinopathies(thyroid and adrenal).

BACTERIAL OVERGROWTHSYNDROMESNormally, the small-bowel flora contains a relativelysmall number of bacteria (<103 organisms/mL),with a predominance of gram-positive organisms.In contrast, the colonic flora has a significantlyhigher concentration of bacteria, which are largely


gram-negative and anaerobic organisms. Whenthere is stasis, altered motility, or loss of protectivedefenses in the proximal intestinal tract, bacteriathat resemble colonic flora can overgrow in thesmall bowel and result in a syndrome of diarrheaand nutritional deficiencies known as smallintestinal bacterial overgrowth (SIBO).

The many risk factors for SIBO are listed inTable 8, with the principal causes associated withstasis of small-bowel contents or loss of protectivegastric acid. Structural or surgical changes in thebowel that produce relative stasis or reflux ofcolonic flora into the small bowel can be obtainedfrom the history and radiographic imaging of thesmall bowel. Any motility disorder that affects thesmall bowel (scleroderma, diabetes mellitus, orpseudo-obstruction) can lead to stasis and over-growth. Gastric acid is thought to be a protectivebarrier that keeps pathogenic bacteria out of thesmall intestine; when there is loss of gastric acid,SIBO may ensue. Advancing age alone may be afactor. In many patients, no discrete risk factoris identified.

Symptoms of bacterial overgrowth includeabdominal pain, bloating, flatulence, diarrhea,and weight loss. Malabsorption of fat, protein, orcarbohydrates (or a combination of these) canoccur with secondary diarrhea. Fat malabsorp-tion results from bacterial deconjugation of bilesalts and leads to steatorrhea. Carbohydrate mal-absorption can occur because of early sugar break-down and fermentation from bacteria as well asfrom decreased disaccharidase activity causedby mucosal damage and bacteria by-products.Mucosal damage is thought to have a role in pro-tein malabsorption because of the effect onoligopeptidase levels.

A classic pattern of laboratory findings inSIBO includes a low serum level of vitamin B12and an increased serum level of folate. The lowlevel of vitamin B12 is the result of the bacteriacleaving vitamin B12 prematurely from intrinsicfactor and from the competitive binding and con-suming of vitamin B12 by anaerobic bacteria. Inthis instance, results of the Schilling test shouldnormalize after the administration of antibiotics.The increased serum level of folate is the result offolate synthesis by the intestinal bacteria. In addi-tion to the above laboratory findings, there also

may be low serum levels of iron, protein, albumin,and fat-soluble vitamins, depending on the degreeof malabsorption.

The standard for making the diagnosis of SIBOis small-bowel cultures from direct aspiration, withmore than 105 organisms/mL of aerobes andanaerobes being diagnostic. Limitations of small-bowel cultures include availability, lack of excessintestinal secretions for aspiration, and recentantibiotic therapy. Also, breath testing can be usedto diagnose SIBO, with lactulose hydrogen, glu-cose hydrogen, or 14C-xylose substrates, in whichan oral load of the substrate is given and breathhydrogen concentration is measured every 15 to30 minutes for 2 to 4 hours. An increase of morethan 20 parts per million above baseline duringthe first 90 minutes is indicative of SIBO. Anincrease is seen again as these substances reach


Table 8. Risk Factors for BacterialOvergrowth

Structural Small-bowel diverticulaIntestinal strictures (Crohn’sdisease, radiation, mediation)

Enterocolonic fistulaSurgical Blind loops, afferent limbs

Ileocecal valve resectionDysmotility Chronic intestinal pseudo-

obstructionSclerodermaGastroparesisDiabetic autonomic neuropathy

Diminished Achlorhydria/gastric atrophyacid Gastric resection

Acid suppressionOthers Cirrhosis

PancreatitisImmunodeficienciesCeliac diseaseAge

Modified from Dukowicz AC, Lacy BE, Levine GM.Small intestinal bacterial overgrowth: a comprehensivereview. Gastroenterol Hepatol. 2007;3:112-22. Usedwith permission.

the colon, thus producing a “double peak” thatalso can be used as a criterion for diagnosis (Fig.7). False-positive results of breath testing can resultfrom rapid intestinal transit, in which the carbo-hydrate substance rapidly reaches the colon andproduces an early but not double-peaked pattern.False-negative results of breath testing can occurfrom recent antibiotic therapy. Also, the resultswill be falsely negative in 20% of the populationwho are nonhydrogen formers. Breath testingresults can be affected by recent laxative use,changes in diet, and smoking. Once SIBO is diag-nosed on the basis of cultures or breath testing,evaluating for predisposing conditions, forexample, with small-bowel imaging, should beconsidered. Also, an empiric trial of antibioticscould be considered for patients in whom testingfor SIBO may not lead to accurate results.

Treatment for SIBO lies in managing thesymptoms and replacing the deficiencies.Although modifying the underlying risk factor(tighter glycemic control in diabetes patients,surgery for patients with stricturing disease, andoctreotide for patients with scleroderma) thatpredisposes to SIBO is feasible in only a smallfraction of patients, it should be considered.Vitamin and mineral levels should be measuredand deficiencies corrected before irreversiblesequelae ensue (eg, as with vitamin B12 defi-ciency). The role of antibiotic therapy is not tosterilize the small-bowel bacterial flora, but ratherto decrease and modify the bacterial make-up sothat it more closely resembles the flora thatshould be present in the small intestine, withtherapy targeting gram-negative and anaerobicorganisms. Various antibiotics have been used,such as amoxicillin-clavulanate, cephalosporins,fluoroquinolones, tetracycline derivatives, andmetronidazole. Initial treatment may consist of 7to 10 days of an antibiotic, with repeated courseswhen symptoms recur. Some patients may needmonthly rotating antibiotic therapy. Also, lactoseavoidance should be considered.


0

0

Hyd

rog

en, p

pm

Time, min

6030 90 120 150 180

20

40

60

80

100

120

0

0

Hyd

rog

en, p

pm

Time, min

6030 90 120 150 180

20

40

60

80

100

120

0

0

Hyd

rog

en, p

pm

Time, min

6030 90 120 150 180

20

40

60

80

100

120

140

160

Fig. 7. Breath testing patterns for bacterialovergrowth. A, Lactulose breath test withoutbacterial overgrowth. B, Lactulose breath test withbacterial overgrowth. C, Lactulose breath testshowing double-peak pattern. (From Dukowicz AC,Lacy BE, Levine GM. Small intestinal bacterialovergrowth: a comprehensive review. GastroenterolHepatol. 2007;3:112-22. Used with permission.)

A

B

C

RECOMMENDED READINGAGA Institute. AGA Institute Medical Position

Statement on the Diagnosis and Managementof Celiac Disease. Gastroenterology. 2006;131:1977-80.

Babbin BA, Crawford K, Sitaraman SV.Malabsorption work-up: utility of smallbowel biopsy. Clin Gastroenterol Hepatol.2006;4:1193-8. Epub 2006 Sep 18.

Dukowicz AC, Lacy BE, Levine GM. Smallintestinal bacterial overgrowth: a compre-hensive review. Gastroenterol Hepatol.2007;3:112-22.

Farrell RJ, Kelly CP. Diagnosis of celiac sprue. AmJ Gastroenterol. 2001;96:3237-46.

Fenollar F, Puéchal X, Raoult D. Whipple’s disease.

N Engl J Med. 2007;356:55-66.Khan S. Eosinophilic gastroenteritis. Best Pract Res

Clin Gastroenterol. 2005;19:177-98.Misiakos EP, Macheras A, Kapetanakis T, Liakakos T.

Short bowel syndrome: current medical andsurgical trends. J Clin Gastroenterol. 2007;41:5-18.

Rostom A, Murray JA, Kagnoff MF. AmericanGastroenterological Association (AGA)Institute technical review on the diagnosis andmanagement of celiac disease. Gastro-enterology. 2006;131:1981-2002.

Thomas PD, Forbes A, Green J, Howdle P, LongR, Playford R, et al. Guidelines for the inves-tigation of chronic diarrhoea, 2nd edition. Gut.2003;52(Suppl 5):v1-v15.


135

CHAPTER 9

Nutritional Disorders Vitamins and Minerals


Vitamins and minerals are critical to normal healthbecause they are essential to a vast assortment ofmetabolic functions. This chapter focuses onselected important vitamins and minerals and theirrelationships with gastrointestinal disorders.

WATER-SOLUBLE VITAMINS

Vitamin B12Dietary intake of vitamin B12 (cobalamin) requiresthe ingestion of animal products (meat, dairy, fish,and shellfish). Although adults require only 1 to 2μg/day, most adults in developed countries ingest10 to 20 μg/day. Because cobalamin is bound toanimal proteins, it must be released. Gastric con-tractions, gastric acid, and gastric pepsins accom-plish this function. Free vitamin B12 then binds tosalivary and gastric R proteins (haptocorrins), aprocess that is facilitated by the acid pH in thestomach. The production and secretion of intrinsicfactor by gastric parietal cells are critical for thetransfer of cobalamin from haptocorrins to intrinsicfactor, which occurs in the duodenum and is facil-itated by pancreatic proteases (degradation ofhaptocorrins) and the more neutral pH of theduodenum. Finally, in the terminal ileum, thecobalamin-intrinsic factor complex is bound tospecific receptors and vitamin B12 is absorbed into

the circulation, where it binds to transcobalamin II.About half of the circulating vitamin B12 in cobal-amin-transcobalamin II is secreted into bile, ofwhich one-half is recycled and the other half isexcreted in stool. Cobalamin in bile is bound to abiliary haptocorrin, and this binding protein isthen degraded by pancreatic proteases in the duo-denum, once again liberating vitamin B12 for itsbinding to intrinsic factor.

Deficiency of vitamin B12 results in mega-loblastic anemia and hyperhomocystinemia, iden-tical to that in folic acid deficiency. In contrast to folicacid deficiency, vitamin B12 deficiency can causeneuropsychiatric abnormalities, including dementiaand subacute combined degeneration of the poste-rior columns of the spinal cord (loss of lowerextremity vibratory and sometimes proprioceptivesensation), loss of taste, anorexia, and diarrhea.Serum methylmalonic acid levels (normal in folicacid deficiency) may be increased (abnormal) beforevitamin B12 levels are subnormal. Because largeamounts of cobalamin are stored in the body, espe-cially in the liver, the lack of adequate dietary vit-amin B12 (eg, in a person who decides to be a truevegan, without supplements) may take years tocause cobalamin deficiency. Achlorhydria is a notuncommon cause of vitamin B12 deficiency in theelderly. Pernicious anemia is another not uncommoncause of vitamin B12 deficiency because of the lack

of intrinsic factor and acid. In contrast to achlorhy-dria, hyperacidity, as in Zollinger-Ellison syndrome,can disrupt the duodenal phase of absorption (lackof more neutral pH and inactivation of pancreaticproteases) of cobalamin and result in cobalamin defi-ciency. Vitamin B12 deficiency rarely occurs withpancreatic insufficiency itself or with the use of acid-suppressive medications. Bacterial overgrowth,infestation with Diphyllobothrium latum, and ilealdisease or resection also can result in deficiency of vit-amin B12. Often, gastric bypass surgery is compli-cated by subsequent cobalamin deficiency (lack ofintrinsic factor, acid, and gastric grinding function).Pitfalls of the Schilling test include the use of crys-talline (not food-bound) cobalamin, which bypassesthe first step in vitamin B12 absorption (release ofcobalamin from its food-bound state, as in elderlypersons with achlorhydria), false-normal values,and abnormal ileal absorption due to ileal macro-cytosis (ongoing uncorrected cobalamin deficiency).

Folic AcidThere are many dietary sources of folic acid, includinggreen leafy vegetables, grains, orange juice, and organmeats. Adults should ingest 200 mg/day of folic acid.Brush border membrane hydrolysis of dietaryfolylpolyglutamates is followed by active transportof folylmonoglutamates, principally in the duo-denum and upper jejunum. Megaloblastic anemia,diarrhea (macrocytic enterocytes), glossitis, neuraltube defects in newborns (maternal folic acid defi-ciency in the first 2 weeks of pregnancy), andincreased risk of colorectal cancer and cardiovas-cular disease may occur from folic acid deficiency.Persons with dietary deficiency of folic acid (bodystores may last for up to 4 months), intestinal mal-absorption states (small-bowel diseases, drugssuch as sulfasalazine, phenytoin, methotrexate,and alcohol), pregnancy, or chronic liver diseaseare at increased risk for folic acid deficiency.

Other Water-Soluble VitaminsVitamin C deficiency results in scurvy, whichmay include perifollicular hyperkeratotic papulesand petechiae; swollen, red, bleeding gums; oranemia. Severe malabsorptive disease and chronicalcoholism increase the risk of vitamin C deficiency.Vitamin C supplementation can increase the riskof adverse cardiovascular events in persons with

advanced iron storage disease (hemochromatosis).Supplementation with vitamin C also can producefalse-negative results on fecal occult blood tests.

Thiamine (vitamin B1) deficiency can resultin beriberi with cardiac (cardiomyopathy andhigh-output failure) or neurologic (peripheralneuropathy, cerebellar dysfunction, gaze pareses,or Wernicke-Korsakoff syndrome) disorders,which may be exacerbated by the administrationof glucose to thiamine-deficient patients. Chronicalcoholism, long-term renal dialysis, pregnancy,and chronic malnutrition all are risk factors forthiamine deficiency.

Riboflavin (vitamin B2) deficiency can causeangular stomatitis, cheilosis, glossitis, seborrheicdermatitis, and visual impairment. Chronic alco-holism and malabsorptive disorders are risk factors.

Niacin (vitamin B3) deficiency due to malab-sorptive syndromes, chronic alcoholism, carcinoidsyndrome, and isoniazid therapy can produce pel-lagra (diarrhea, dermatitis, and dementia), glossitis,and angular stomatitis. Excess niacin can causeflushing and hepatocellular injury.

Pyridoxine (vitamin B6) deficiency can occurin patients treated with isoniazid, cycloserine,hydralazine, oral contraceptives, dopamine, and D-penicillamine. Malabsorptive syndromes andchronic alcoholism also are risk factors. Glossitis,cheilosis, angular stomatitis, seborrheic dermatitis,sideroblastic anemia, and peripheral neuropathymay supervene. Vitamin B6 deficiency may beresponsible for both the only modest increase inaminotransferase values and the increased ratioof aspartate aminotransferase to alanine amino-transferase in alcoholic hepatitis.

Although biotin deficiency is rare, it can occurin patients receiving total parenteral nutrition butnot biotin. Altered mental status, metabolic acidosis,and seborrheic dermatitis may occur.

FAT-SOLUBLE VITAMINS

Vitamin A As with other fat-soluble vitamins, the absorptionof vitamin A requires luminal bile salts and pan-creatic esterases, assembly into chylomicrons, andlymphatic transport. Lack of vitamin A can producenight blindness, xerophthalmia, a follicular hyper-


keratotic rash, abnormalities of taste and smell,and increased risk of infections. Liver disease may beaccompanied by vitamin A deficiency, especiallyalcoholic liver disease. However, persons withalcoholic liver disease and vitamin A deficiencywho receive vitamin A supplementation are atrisk for hepatotoxicity. Similar to other fat-solublevitamins, excess vitamin A can cause toxicity (liverfailure, increased cerebrospinal fluid pressure,desquamating rash, alopecia, or hypercalcemia).

Vitamin DAdequate vitamin D levels are achieved with diet,dietary supplementation, and sunlight. Liver dis-ease and kidney disease, as well as malabsorptiveconditions, are the major risk factors for vitaminD deficiency. Excess vitamin D can result inanorexia, nausea, vomiting, constipation andabdominal pain (hypercalcemia), and polyuria andkidney stones (hypercalciuria).

Vitamin EMalabsorptive disorders and particularly chroniccholestasis in children are major risk factors forvitamin E deficiency. Manifestations of vitamin Edeficiency include neurologic symptoms (posteriorcolumn disease, peripheral neuropathy, and brain-stem and cranial nerve damage), retinal disease,and hemolysis. High doses of vitamin E may causecoagulation disorders.

Vitamin KVitamin K is acquired from exogenous dietary (greenleafy vegetables) and endogenous (intestinal bac-teria) sources. Malabsorptive syndromes, dietaryinadequacy, and antibiotic administration are riskfactors for vitamin K deficiency. Factor VII usuallyis the rate-limiting factor for normal prothrombintime (or international normalized ratio). Excessivedoses of vitamin E can interfere with vitamin K-dependent metabolism, resulting in hemorrhage.

MINERALS

IronLoss of endogenous iron from the gastrointestinaltract (usually 1.0-2.0 mg/day), urinary tract, andskin and menstrual loss in women needs to be

matched by iron absorption from the duodenumand upper jejunum. Iron contained in the form ofheme from meat is absorbed (up to 25%) morereadily than inorganic ferric iron salts (3%-10%).Gastric grinding, gastric acid, and gastric ascor-bate help make ferric iron compounds more sol-uble. Ferric reductase (duodenal cytochrome B),as well as ascorbate, reduces inorganic iron fromthe ferric to the ferrous form. An iron transporter,divalent metal transporter 1, facilitates absorptionof ferrous iron. This same transporter also can facil-itate the absorption of divalent copper, zinc, andmanganese, each of which can compete with andinhibit the absorption of divalent iron. Ferroportin1 with ferroxidase hephaestin transports iron intothe circulation, oxidizes it to the ferric form, andallows it to bind to transferrin. Normally, with ade-quate total body iron stores, up to about 10% ofdietary inorganic iron can be absorbed. With irondeficiency, this may increase to 30%.

Iron deficiency can result in microcytichypochromic anemia, angular stomatitis, koilony-chia, and atrophic lingual papillae. Lack of dietaryiron, increased gastrointestinal loss of iron(bleeding), poor absorption of iron (upper small-bowel mucosal dysfunction as in celiac disease),bypass of the upper small bowel (gastrojejunalbypass surgery), gastric resection and achlorhydria,and persistent ingestion of iron-binding com-pounds (soil or laundry starch) all can contributeto iron deficiency. Iron overload is discussed inChapter 28, Metabolic Liver Disease.

ZincZinc is required as a cofactor for many enzymes(eg, alkaline phosphatase), and its deficiencyimpairs growth, development, and reproductiveand immune functions. Chronic diarrhea, short-bowel syndrome, cystic fibrosis, pancreatic insuf-ficiency, cirrhosis, alcoholism, chronic renal failure,anorexia nervosa, pregnancy, sickle cell anemia,and use of the drug D-penicillamine are risk fac-tors for zinc deficiency. A scaly red rash involvingthe face, groin, and hands may occur with zincdeficiency itself or as a result of the autosomalrecessive disorder of zinc metabolism, acroder-matitis enteropathica. Alopecia, loss of taste sen-sation, growth retardation, poor wound healing,hypogonadism, diarrhea, and night blindness also

Nutritional Disorders Vitamins and Minerals 137

may occur from zinc deficiency. Excess zinc intake(eg, supplements such as those used to treatWilson’s disease) can cause copper deficiency.

CopperCopper deficiency can result in microcytichypochromic anemia, leukopenia, neutropenia,diarrhea, neurologic disturbances, and bonychanges. Clinical conditions in adults that predis-pose to copper deficiency include total parenteralnutrition without copper supplementation, mal-absorptive syndromes, and chronic biliary fistulas.Toxicity from excess administration of oral copperincludes acute hemorrhagic gastritis.

Miscellaneous MineralsDeficiencies of selenium (cardiomyopathy andmyositis), chromium (hyperglycemia and neu-rologic symptoms), manganese (night blindness,tachycardia, tachypnea, headache, and vom-iting), or molybdenum (neurologic symptoms)may develop in patients receiving long-termtotal parenteral nutrition or tube feeding withoutproper supplementation.

RECOMMENDED READINGAlvarez-Leite JI. Nutrient deficiencies secondary

to bariatric surgery. Curr Opin Clin NutrMetab Care 2004;7:569-75.

Annibale B, Capurso G, Delle Fave G. The stomachand iron deficiency anaemia: a forgotten link.

Dig Liver Dis. 2003;35:288-95.Basu TK, Donaldson D. Intestinal absorption in

health and disease: micronutrients. Best PractRes Clin Gastroenterol. 2003;17:957-79.

Eussen SJ, de Groot LC, Clarke R, Schneede J,Ueland PM, Hoefnagels WH, et al. Oralcyanocobalamin supplementation in olderpeople with vitamin B12 deficiency: a dose-finding trial. Arch Intern Med 2005;165:1167-72.

Fessler TA. Trace element monitoring and therapyfor adult patients receiving long-term totalparenteral nutrition. Pract Gastroenterol.2005;29:44-65.

Klein S. A primer of nutritional support for gas-troenterologists. Gastroenterology. 2002;122:1677-87.

Leslie WD, Bernstein CN, Leboff MS, AmericanGastroenterological Association ClinicalPractice Committee. AGA technical review onosteoporosis in hepatic disorders. Gastro-enterology. 2003;125:941-66.

Miret S, Simpson RJ, McKie AT. Physiology andmolecular biology of dietary iron absorption.Annu Rev Nutr. 2003;23:283-301. Epub 2003Feb 26.

Scott EM, Gaywood I, Scott BB, British Society ofGastroenterology. Guidelines for osteoporosisin coeliac disease and inflammatory bowel dis-ease. Gut. 2000;46 Suppl 1:1-8.

Sharma N, Trope B, Lipman TO. Vitamin supple-mentation: what the gastroenterologist needsto know. J Clin Gastroenterol. 2004;38:844-54.


139

Small Bowel and Nutrition


QUESTIONS

Abbreviations used:ALT, alanine aminotransferaseAST, aspartate aminotransferaseCT, computed tomographyEGD, esophagogastroduodenoscopyICU, intensive care unitMRI, magnetic resonance imagingNSAID, nonsteroidal antiinflammatory drugTPN, total parenteral nutritionTSH, thyroid-stimulating hormone

Multiple Choice (choose the best answer)1. A 68-year-old woman is evaluated for abdom-

inal bloating and intermittent diarrhea thathas been present for 6 months. The bloatingimproves after a bowel movement. She hashad a 10-lb weight loss during the 6 months.She says she has no other symptoms. There isno history of recent travel, sick contacts, ormedication changes. Her medical history isremarkable for pernicious anemia, for whichshe receives vitamin B12 injections monthly.Laboratory studies are notable for iron defi-ciency anemia, normal level of vitamin B12,and serum level of folic acid >20 µg/L. TheTSH level is normal, and tissue transglutam-inase antibody is negative. Stool microbiologic

findings were negative. EGD shows anatrophic-appearing gastric mucosa. Small-bowel biopsy specimens show increased cel-lularity in the lamina propria. Colonoscopy,with random biopsy specimens, was negative.HLA testing shows DQ4 and DQ7 positivity.What is the most likely diagnosis?

a. Celiac diseaseb. Small intestinal bacterial overgrowthc. Irritable bowel syndromed. Lactose intolerancee. Giardiasis

2. A 64-year-old man is referred by his primaryphysician because of abnormalities on recenttests. Within the last week, he had EGD andcolonoscopy because of mild iron deficiencyanemia. EGD showed multiple small antralerosions. Although the duodenum appearedgrossly normal, small-bowel biopsy specimensshowed subtotal villous atrophy. Evaluationfor H. pylori infection was negative. Thecolonoscopic findings were normal. Tissuetransglutaminase antibody was negative. Hismedical history is unremarkable except forarthritis in the neck, for which he has takenibuprofen daily for the last few months. Hestates that he does not have abdominal pain,

diarrhea, or weight loss. Which of the fol-lowing is the most likely diagnosis?

a. Celiac diseaseb. Whipple’s diseasec. Crohn’s diseased. NSAID effectse. Zollinger-Ellison syndrome

3. A 19-year-old woman with celiac disease is eval-uated for recurrent symptoms of diarrhea andweight loss. Celiac disease was diagnosed 2 yearsago when she presented with similar symptoms.Findings at that time included an increased levelof tissue transglutaminase antibody and subtotalvillous atrophy and intraepithelial lymphocy-tosis seen in small-bowel biopsy specimens. Sheinitially had a response to a gluten-free diet, butfor the past 3 months, her symptoms haverecurred. She states that her diet has not changed.She started college 6 months ago and lives in adormitory supplied by city water. The initialsmall-bowel biopsy specimens were reviewed,and the pathologist thinks that the initial diag-nosis was correct. Which of the following is themost likely cause of her symptoms?

a. Inadvertent gluten ingestionb. Microscopic colitisc. Enteropathy-associated T-cell lymphomad. Pancreatic insufficiencye. Giardiasis

4. A 32-year-old woman with a history of Crohn’sdisease presents with worsening of her base-line diarrhea. She states that she does not havemelena, hematochezia, fevers, or chills. She hasmild abdominal cramps, but no localizing pain.She has had a 15-lb weight loss during the last4 months. She has had extensive small-bowelresections in the past, with approximately 200cm of small bowel removed. She has been takingthe same dose of azathioprine since her lastoperation 4 months ago, when segments offibrostenotic bowel were removed. She hadtaken loperamide intermittently, which wassuccessful in the past, but is no longer helpful.Laboratory findings include a normal completeblood count, C-reactive protein, and TSH. Stool

cultures are negative; no fecal leukocytes arenoted. No change is seen in the radiographicappearance of the small bowel. Which of the fol-lowing is most likely to be helpful?

a. Cholestyramineb. Prednisonec. Mesalamined. Metronidazolee. Medium-chain triglycerides

5. A 47-year-old woman presents with a 2-yearhistory of diarrhea. She describes her stoolsas being pale and foul smelling. She has had a30-lb weight loss over the last 2 years. Physicalexamination shows a thin female, but the find-ings are unremarkable otherwise. Laboratoryfindings include a low serum level of vitaminB12. Because steatorrhea is suspected, a 72-hour fecal fat collection is performed andshows that she excretes 27 g/day of fat. A 5-hour urine collection after ingestion of 25 g ofD-xylose discloses excretion of 11 g of D-xylose.Which of the following is most likely?

a. Worsening of symptoms with wheat productsb. A significant alcohol history with recurrent

abdominal painc. Past history of intestinal resectiond. Known jejunal diverticulosis from sclerodermae. Family member with recent diagnosis of

giardiasis

6. A 67-year-old woman with atrial fibrillationdevelops sudden, poorly localized abdominalpain and some time later is admitted to thehospital. An abdominal-pelvic CT scan isnormal. Angiography demonstrates a largeembolus involving the superior mesentericartery. At surgery, she has an extensive small-bowel resection. By the fifth day postopera-tively, she still cannot eat and has significantnasogastric tube output, but otherwise feelswell. Which of the following is most likely tohelp with her nutritional management?

a. Start nasojejunal tube feedings nowb. Increase the dose of her intravenous H2-

blocker


c. Start nasojejunal tube feedings in 5 daysd. Check the serum level of albumine. Start TPN

7. A 35-year-old woman with severe Crohn’sdisease of the terminal ileum, cecum, andascending colon that is unresponsive to max-imal medical therapy presents with chronic,partial, low-grade, distal small-bowel obstruc-tion. She is hospitalized and surgery isplanned. TPN was started 1 week ago, beforeher planned surgery a few days from now.Laboratory tests today show a newly increasedALT level, twice the upper limit of normal. Sixdays ago she received 2 units of packed redblood cells. Which of the following statementsmost likely is true?

a. Her husband has chronic hepatitis C virusinfection

b. The increased ALT level is due to the TPNc. The patient has acute posttransfusion

hepatitis C virus infectiond. The increased ALT level is due to Crohn’s

diseasee. The patient has primary sclerosing

cholangitis

8. A 26-year-old woman with a long history ofWilson’s disease is referred with a 2-monthhistory of an erythematous, scaly rash aroundher nares and mouth. She is receiving treat-ment with D-penicillamine as well as pyri-doxine. Which of the following is most likelyto help her?

a. Begin niacin supplementationb. Begin medium-chain triglyceride

supplementationc. Begin zinc supplementationd. Begin vitamin A supplementatione. Begin riboflavin supplementation

9. A 35-year-old male alcoholic visits his brotherwho is staying at a Holiday Inn and relates tohim his new problems with vision at night.Several months later, the patient’s night visionis better but his doctor notes new hepato-splenomegaly, ascites, and hair loss. Which of

the following did his brother most likely advisehim to take?

a. Zinc, 15 mg/dayb. Vitamin A, 10,000 IU/dayc. Riboflavin, 1.5 mg/dayd. Chromium, 200 μg/daye. Copper, 2 mg/day

10. A 33-year-old woman with short bowel syn-drome after a vascular event has been doingwell on TPN for nearly 5 years. Recently, dif-fuse, persistent myalgias developed. Valuesfor the following are normal: complete bloodcount, thyroid-stimulating hormone, glucose,creatinine, bilirubin, ALT, and alkaline phos-phatase. However, the value for AST is 5 timesnormal. Which of the following is most likelyto be diminished in her blood?

a. Vitamin Eb. Chromiumc. Manganesed. Seleniume. Copper

11. A 63-year-old woman presents with anorexia,weight loss, hair loss, and diarrhea. She com-plains that her food “tastes like garbage.” Sheunderwent vagotomy and antrectomy 20 yearsago for peptic ulcer disease. She was ques-tioned recently by the police for puttinggarbage bags onto neighbors’ cars. On physicalexamination, her tongue appears erythema-tous and shiny. Which of the following is themost likely?

a. Physical examination shows loss of positionsense but not vibratory sensation in her arms

b. She has celiac diseasec. The serum homocysteine level is decreasedd. The serum methylmalonic acid level is

increasede. She has pancreatic insufficiency

12. A 52-year-old woman is admitted to the med-ical ICU with recent onset of confusion. Herfamily notes that she “drinks a lot of alcohol,eats poorly, and has been bumping into


things.” She also has chronic diarrhea and sub-stantial weight loss. On admission, she is alert,disoriented, confused, and quite weak. Theblood glucose level is slightly low, and she hasmild metabolic acidosis. Findings on CT of thehead and abdomen and chest radiographywere unremarkable. Vital signs are normalexcept for mild tachycardia and tachypnea.Which of the following is most important toadminister intravenously?

a. Hydrocortisoneb. Glucosec. Bicarbonated. Thyroid hormonee. Thiamine

13. A 62-year-old male farmer is in the hospitalwith acute-on-chronic alcoholic pancreatitis.He has just been transferred to the generalmedical ward from the ICU. Two trials of oralfeeding are unsuccessful, with recurrent vom-iting. On hospital day 8, a nasojejunal tube ispassed and enteral feeding is begun. Congestiveheart failure then develops. Which of the fol-lowing is most likely to explain his subsequentcardiac decompensation?

a. Selenium deficiencyb. Hyperkalemiac. Hypophosphatemiad. Volume overloade. Excess fat in tube feeding

14. A 38-year-old woman with a long history ofileocolonic Crohn’s disease, short bowel syn-drome after multiple bowel resections, pri-mary sclerosing cholangitis, and home TPNfor several years is evaluated because of aresting tremor, muscle rigidity, abnormal gait,and periodic confusion. Which of the followingshould be done with her TPN?

a. Add more zinc to TPNb. Discontinue TPNc. Decrease the total nitrogen content of TPNd. Remove manganese from TPNe. Remove copper from TPN

15. A 41-year-old woman presents for evaluationof diarrhea that she has had for 4 months, fol-lowing a hospitalization for complicatedappendicitis. At the time of hospitalization,she presented with right lower quadrant painand fevers, and a large appendiceal abscesswas noted. In addition to removal of theappendix and drainage of the abscess, the last150 cm of terminal ileum was removedbecause of fistulous connections to the abscesscavity. She recently underwent takedown ofthe diverting ileostomy and now has an ileo-colonic anastomosis. Which of the followingwill not be malabsorbed?

a. Bile acidsb. Oxalatec. Vitamin B12d. Calciume. Fat

16. A 46-year-old woman with known celiac dis-ease presents with diarrhea. Since celiac diseasewas diagnosed, she has followed a strictgluten-free diet and has responded well.However, after 6 months, her diarrheareturned. She states that she has no othersymptoms. Her stool frequency is 5 to 6 timesdaily. Review of her diet shows strict compli-ance, and the endomysial antibody level isnow normal, but initially it was increased.Stool studies show 6 g of fat/24 hours, whichhas improved from 28 g/24 hours at diagnosis.The best next step in the evaluation should be:

a. Repeat small-bowel biopsyb. Colonoscopy with biopsy c. Abdominal CTd. Small-bowel imaginge. Quantitative small-bowel culture

17. A 40-year-old man with a history of alco-holism, diarrhea, and flushing is admitted tothe hospital. He was found recently to have apositive PPD (purified protein derivative[tuberculin]) and has been receiving treatmentwith isoniazid. The serum transaminase levelsare mildly elevated. A scaly, erythematous,


and hyperpigmented rash is noted on sun-exposed areas of his body. His skin findings aremost consistent with which of the following?

a. Niacin deficiencyb. Pyridoxine deficiencyc. Carcinoid syndromed. Cutaneous tuberculosise. Riboflavin deficiency

18. A 62-year-old woman with chronic primarybiliary cirrhosis develops new problems withbalance. Loss of proprioception is found onphysical examination. She is positive for anti-mitochondrial antibody. The serum bilirubinlevel is inceased. Which of the following mostlikely is true?

a. There is heavy metal deposition in thebasal ganglia

b. The M1 antibody is positivec. The serum homocysteine level is diminishedd. The serum vitamin E level is diminishede. She is vitamin B12 deficient

19. A 24-year-old woman from Montana is foundto have severe iron deficiency anemia. Multiplestool specimens are guaiac and HemoQuantnegative. Which of the following is most likely?

a. She has celiac diseaseb. Cameron’s ulcerations are found at

endoscopyc. Small-bowel capsule enteroscopy shows

multiple angioectatic lesionsd. She has cecal adenocarcinomae. She is gravida 5 para 5

ANSWERS

1. Answer bGastric acid has the protective effect of limitingbacterial growth in the proximal gastrointestinaltract. Thus, patients with decreased gastric acid orachlorhydria are at risk for small intestinal bacte-rial overgrowth. This patient has perniciousanemia, which is associated with an autoimmune

atrophic gastritis that can lead to achlorhydria.Bacterial overgrowth can cause a low serum levelof vitamin B12 (in a person who is not receivingreplacement therapy) and an increased serum levelof folic acid, because folic acid is synthesized bysmall-bowel bacteria. Achlorhydria also can affectabsorption of iron and lead to iron deficiencyanemia. Small intestinal bacterial overgrowth cancause histologic changes of subtotal villous atrophyand increased cellularity in the lamina propria,occasionally making it difficult to distinguish thiscondition from celiac disease. Therefore, the clin-ical features presented are highly suggestive ofsmall intestinal bacterial overgrowth, and a rotatingregimen of antibiotics may be needed to controlher symptoms. Because this patient is negative fortissue transglutaminase antibody, has a markedlyincreased folic acid level, and is not positive forDQ2 or DQ8 (seen in >95% of those with celiac dis-ease), celiac disease is highly unlikely. Althoughher symptoms may suggest irritable bowel syn-drome, this would not account for her weight loss.Patients with bacterial overgrowth may be secon-darily lactose intolerant, but this alone would notexplain all the clinical or laboratory features.Although giardiasis can cause bloating and diar-rhea, the negative stool studies and small-bowelbiopsy findings make this diagnosis unlikely.

2. Answer dThis patient’s anemia and endoscopic and histo-logic findings are likely all a consequence of hisrecent NSAID use. Villous atrophy is not specificfor celiac disease. It can occur with NSAID use,giardiasis, bacterial overgrowth, Crohn’s disease,immunodeficiency syndromes, lymphoma, andgastrin-producing states such as Zollinger-Ellisonsyndrome. The paucity of abdominal complaints,the negative tissue transglutaminase antibody, andthe lack of other histologic clues (intraepitheliallymphocytes and crypt hyperplasia) make celiacdisease less likely. Patients with Whipple’s diseasemay have large-joint arthritis along with gas-trointestinal symptoms, but biopsy specimensusually show swollen villi and the lamina propriadistended with histiocytes. The endoscopic find-ings of antral erosions are more likely to be fromNSAID use than from inflammatory bowel disease,


especially without other gastrointestinal symp-toms. Although Zollinger-Ellison syndrome cancause peptic ulcer disease and villous flattening, itwould be quite unlikely without obvious clinicalfeatures. This patient’s recent NSAID use is muchmore likely to have caused the aforementionedclinical features.

3. Answer aIn a patient with celiac disease and persistent orrecurrent symptoms, the initial step is to reviewthe small-bowel biopsy results with an expert gas-trointestinal pathologist to ensure that the diag-nosis is well established. After that has been done,it is imperative that the gluten-free diet be reviewedwith a trained dietician because approximatelyone-half of patients with persistent or recurrentsymptoms have gluten contamination, either inten-tionally or inadvertently, in the diet. If the gluten-freediet has been followed, an evaluation for celiac-associated conditions needs to be considered.Although microscopic colitis, enteropathy-associ-ated T-cell lymphoma, and pancreatic insufficiencyall need to be considered in a patient with celiacdisease who has recurrent symptoms, gluten inges-tion would be more likely, especially with thechange in the patient’s social support and livingenvironment. Infection with Giardia could causethe above symptoms, but the patient has no specificrisk factors for the infection.

4. Answer eIf a patient has had more than 100 cm of smallbowel resected, the usual enterohepatic circula-tion of bile acids is disrupted, which leads to bileacid deficiency and fat malabsorption. In this case,the patient has had a significant length of smallbowel removed, which would put her at risk forbile acid deficiency and fat malabsorption. Herweight loss is supportive evidence of fat malab-sorption. In this setting, medium-chain triglyc-erides can be administered as a source of fatty acidsbecause they are absorbed directly through theintestinal cell membranes. If less than 100 cm isresected, there can be an excess of bile acids andthis can act as an irritant in the colon, in which casecholestyramine can be given to bind the excess bileacids. However, cholestyramine would likelyworsen this patient’s symptoms by binding the

remaining bile acids she has. Because none of thelaboratory findings provide evidence of activeCrohn’s disease, it is not clear that prednisonewould be of benefit. Similarly, mesalamine wouldhave no role in this case. Metronidazole may beprescribed for patients with irritable bowel dis-ease who have pouchitis or fistulous disease, butit has no purpose in this scenario.

5. Answer bThis patient has significant steatorrhea, as evidentby her quantitative fecal fat collection. After steat-orrhea has been identified, the evaluation needsto focus on the cause, which most often is a small-bowel or pancreatic source. Although not commonlyused, the D-xylose test can distinguish betweenthese two sources. After a 25-g oral load of D-xylose,urine or serum levels can be measured at 1 and 5hours. For D-xylose to be excreted in the urine,small-bowel and mucosal absorption need to benormal. Detection of D-xylose in the urine (>5 g)suggests that the small-bowel mucosa is intact,pointing to a pancreatic source for the steatorrhea.One of the most common causes of pancreatic steat-orrhea is chronic alcoholic pancreatitis, in whichcase a significant history of alcohol consumptionand recurrent abdominal pain would be impor-tant clues. Recurrent abdominal pain suggests thatthe patient may have developed chronic alcoholicpancreatitis. Pancreatic exocrine insufficiency alsocan cause vitamin B12 deficiency because pancre-atic enzymes are required to separate R proteinfrom cobalamin so that it may preferentially bindintrinsic factor. All the other choices would leadto abnormalities of the small bowel, which wouldresult in low urinary excretion of D-xylose.

6. Answer eThis patient had an extensive small-bowel resectionand 5 days postoperatively still requires nasogas-tric suction. It is unlikely that the gastrointestinaltract will be ready for any kind of feedings soon.She has been without nutrition for nearly a week,and TPN is indicated. Determining the serum levelof albumin is not useful for deciding when andhow to feed this patient. It is appropriate that sheis receiving intravenous acid-suppressive therapyto avoid acid-induced mucosal injury from therebound increase in gastric acid secretion that can


occur after resection of large portions of the smallbowel (loss of postgastric acid-inhibitory factors).She has no pain or bleeding, and increasing thedose of the H2-blocker is unlikely to affect nutri-tional management.

7. Answer bThe ALT level could be increased for all these rea-sons. Because it is a new increase, it is not likely tobe due to either Crohn’s disease or her husband’schronic hepatitis C virus infection. The overall riskof her being infected while in a long-term monog-amous relationship with her husband is about 5%.Posttransfusion acute hepatitis C virus infectionnow, and since 1992, in the United States isextremely rare and would not be manifested as anincreased ALT level in only 6 days. There is nothingto support the diagnosis of primary sclerosingcholangitis, which is a cholestatic disorder. TPNis the most likely reason for the increased ALTlevel, either due to overfeeding or as a nonspecificlaboratory finding that usually improves over time.

8. Answer cD-Penicillamine administration can cause pyri-doxine deficiency, which is why the patient istaking pyridoxine. Zinc deficiency also can occurfrom the chelation of zinc. Alopecia, loss of tastesensation, growth retardation, poor woundhealing, hypogonadism, diarrhea, and nightblindness also can occur with zinc deficiency. D-Penicillamine does not affect riboflavin, which,like pyridoxine, can cause a seborrheic dermatitis.Essential fatty acid deficiency can cause a similarrash, but this patient has no history to suggest sucha deficiency, and the essential fatty acids are long-chain, not medium-chain, fatty acids. Niacin defi-ciency causes a scaly, hyperpigmented rash insun-exposed areas. This patient has no history tosuggest niacin deficiency or vitamin A deficiency.

9. Answer bProblems with night vision in an alcoholic could bedue to vitamin A or zinc deficiency, but not tochromium, copper, or riboflavin deficiency.Vitamin A excess, which is more of a risk in alco-holics taking near-therapeutic or “safe” doses ofvitamin A, can result in hepatosplenomegaly, cir-rhosis, loss of head and body hair, fever, night

sweats, cytopenias, headache, bone pain, pro-teinuria, and pruritus.

10. Answer dSelenium deficiency can cause cardiomyopathy ormyositis. Vitamin E deficiency causes neurologicdysfunction (posterior columns, brainstem, cra-nial nerves, and peripheral nerves). Chromiumdeficiency results in hyperglycemia, neuropathy,and encephalopathy. Copper deficiency can causemicrocytic anemia, neutropenia, hypopigmenta-tion, infection, and bone abnormalities. Manganesedeficiency (extremely rare, not reported in TPNpatients) can cause dermatitis. In persons receivingprolonged TPN, one should be sure that seleniumis included.

11. Answer dThis patient most likely has vitamin B12 deficiency,given her surgical history, age, and presentation.An erythematous atrophic tongue, anorexia, dys-geusia, neuropsychiatric symptoms, weight loss,and diarrhea are all consistent with this diagnosis.Loss of vibratory sensation occurs before loss ofposition sense and usually involves the lowerextremities. Both the serum methylmalonic acidand serum homocystine levels are increased in per-sons with vitamin B12 deficiency. Celiac diseaseand pancreatic insufficiency would be unlikely toexplain all the findings.

12. Answer eAn alcoholic person with poor nutritional intake isat risk for many vitamin and mineral deficienciesas well as for alcoholic ketoacidosis and hypo-glycemia. This patient may well have thiaminedeficiency, and it could be fatal to administer glu-cose before administering thiamine. She is alertand not particularly hypoglycemic. Her mild meta-bolic acidosis does not require urgent bicarbonate,nor does she immediately need hydrocortisone orthyroid hormone. She may well have Wernicke’ssyndrome, with confusion, ataxia, and mild high-output heart failure.

13. Answer cThis patient has not been fed adequately for morethan a week and most likely is experiencingrefeeding syndrome. Hypophosphatemia, as well


as hypokalemia and hypomagnesemia, is oftenfound with this syndrome. The cardiac decom-pensation is unlikely to be from volume overloadalone, and there may be both chronic (malnutritionor thiamine deficiency) and acute (hypophos-phatemia) contributing factors. Excess fat in tubefeedings is unlikely to be a factor, and seleniumdeficiency is not likely because of the subacute pre-sentation and lack of history of prolonged TPNwithout selenium supplementation.

14. Answer dManganese accumulation and toxicity can occurwith chronic TPN, and the patient presents withparkinsonian-like neurologic symptoms. MRI ofthe basal ganglia may show abnormality. Patientswith chronic cholestasis are at greater risk formanganese toxicity.

15. Answer bBecause this patient has lost more than 100 cm ofthe terminal ileum, bile acids and vitamin B12 arelikely to be malabsorbed. With steatorrhea due toinadequate levels of bile acid in the duodenum,calcium is bound to fatty acids and, thus, malab-sorbed. Oxalate is overabsorbed by the colon (notbound to calcium, which is unavailable becauseof its bound state with fatty acids), leading tohyperoxaluria and kidney stones.

16. Answer bIn a patient who has known celiac disease,increased serum antibody levels, and steatorrheaand who has a response to therapy, recurrentsymptoms such as diarrhea most often are due toinadvertent (or noncompliance) ingestion of gluten.Because this patient has been compliant and teststo date are normal, she may well have microscopic

colitis. All the answers listed are possibilities, butrecurrent disease, lymphoma, and bacterial over-growth are less likely.

17. Answer aPatients with chronic alcoholism are at risk forpellagra, with dermatitis (as described here) anddiarrhea. Exposure to isoniazid binds pyridoxineand decreases the conversion of tryptophan toniacin. Pyridoxine deficiency by itself is unlikelyto account for this patient’s constellation of find-ings. Atrophic tongue, angular stomatitis, andcheilitis can be seen with niacin, pyridoxine, orriboflavin deficiency.

18. Answer dVitamin E deficiency is rare in adults and usu-ally is seen in association with chronic cholestaticliver disease. Posterior column disease, periph-eral neuropathy, hemolysis, retinal damage, andbrainstem (ataxia) and cranial nerve damage canoccur. This patient is unlikely to have vitaminB12 deficiency or a diminished homocysteinelevel, and the M2, not M1, antibody would bepositive. Heavy metal deposition in her basalganglia from chronic liver disease is unlikely toexplain the loss of proprioception.

19. Answer eNew iron deficiency anemia in a young womanis not unusual with multiple pregnancies. Celiacdisease is less likely. Blood loss from Cameron’sulcerations would be accompanied by HemoQuant-positive, if not guaiac-positive, stools. Angioectaticlesions with blood loss also would be accompa-nied by a positive test for occult blood in the stool.Cecal adenocarcinoma would be rare at her agewithout a positive family history.


SECTION IV

MiscellaneousDisorders

Nearly 40 million people worldwide have beeninfected with human immunodeficiency virus(HIV) type 1 and more than 25 million have died.Highly active antiretroviral therapies (HAARTs)with multiple drugs—now widely used in theUnited States and highly effective—have greatlydiminished the incidence of opportunistic infec-tions in patients infected with HIV. Suppressionof viral load to less than 50 copies/mL and main-tenance of adequate CD4 lymphocyte counts(>500/µL [0.5×109/L]) are crucial. Opportunisticinfections and malignancies are uncommon inHIV-infected patients with plasma HIV viral loadsless than 10,000 copies/mL and CD4 counts greaterthan 200 to 500/µL (0.2–0.5×109/L). However,because of cost, compliance, lack of availability oftreatment in certain parts of the world, drug resis-tance, drug toxicity, and drug-drug and drug-alter-native substance interactions, not all patients withHIV infection receive adequate therapy. Inimmunosuppressed HIV-infected patients, mul-tiple infections often occur simultaneously.Presentations may be typical or atypical, and there

is great overlap in clinical signs and symptomsbetween infections and malignancies. In patientswith successfully treated HIV infection, gastroin-testinal disorders are more likely to be similar tothose in non–HIV-infected and otherwise healthypersons (eg, dysphagia due to gastroesophagealreflux disease rather than an opportunistic infec-tion). Opportunistic infections that previouslywere difficult to treat in immunosuppressed HIV-infected patients (ie, Cryptosporidium andMicrosporida infections) may resolve with suc-cessful HAART.

Side effects of antiretroviral therapy involvingthe gastrointestinal tract (and liver) are commonand need to be considered in patients who havecommon complaints and disorders such asanorexia, nausea, vomiting, oral ulcers, abdom-inal pain, diarrhea, pancreatitis, or liver functiontest abnormalities.

• Successful antiretroviral drug therapy hasdiminished greatly the incidence of oppor-tunistic infections in patients infected with HIV.

149

CHAPTER 10

Gastrointestinal Manifestationsof Human Immunodeficiency

Virus Infection


Abbreviations: CMV, cytomegalovirus; HAART, highly active antiretroviral therapy; HIV, human immunodeficiencyvirus; HSV, herpes simplex virus.

• Multiple infections often occur simultaneouslyin immunosuppressed HIV-infected patients.

• Side effects of antiretroviral drug therapyinvolving the gastrointestinal tract are common.

ORAL CAVITYOral lesions are common in HIV-infected patients(up to 80%) and may be the first symptom in upto 10% of patients (Table 1).

ESOPHAGUSCase—A 27-year-old man who has HIV infectionpresents with new dysphagia to solids. He is aninjection drug user and has been noncompliantwith antiretroviral drug therapy. Thrush is foundon physical examination. The CD4 count is 110/µL(0.110×109/L), and his plasma HIV viral load ismore than 30,000 copies/mL.

The clinical presentation of this patientstrongly suggests an opportunistic infection of theesophagus with Candida, and initial treatmentshould focus on the HIV infection and empiricadministration of fluconazole.

Common symptoms of esophageal disordersinclude dysphagia, odynophagia, and chest painunrelated to swallowing. With successful anti-retroviral treatment of HIV infection, common dis-orders such as gastroesophageal reflux diseaseand pill esophagitis are more likely to occur thaninfectious esophagitis. Of the opportunistic infec-tions involving the esophagus, Candida is the mostcommon fungal infection and cytomegalovirus(CMV) is the most common viral infection; herpessimplex virus (HSV) infection is less common.Candida often causes dysphagia, whereas CMVand HSV infections and idiopathic esophagealulceration often cause odynophagia. Two-thirdsof patients with Candida esophagitis have oralthrush, hence the role of empiric therapy; how-ever, nearly 25% have a second cause of their symp-toms (multiple coexistent pathogens). CMV infec-tion and idiopathic esophageal ulceration areunusual if the CD4 count is more than 100/µL(0.1×109/L).

Empiric treatment with fluconazole is rec-ommended for patients with mild to moderate

symptoms (dysphagia or odynophagia) who havethrush. About 75% have a response in 3 to 5 daysto a 200-mg loading dose on the first day, followedby 100 mg/day for 14 to 28 days. Endoscopy isindicated for patients who do not have a promptresponse to treatment or who are severely symp-tomatic. Barium studies are not useful. Atendoscopy, brush cytology is more sensitive thanbiopsy to diagnose Candida esophagitis, althoughthe typical appearance (multiple plaquelike, oftenlinear or confluent creamy-white lesions, withbleeding points when removed) is very specific.Candida often (up to 50% of cases) is an oral com-mensal and usually (up to 90% of cases) is found instool specimens. Also, Candida esophagitis can beasymptomatic. Treatment may be topical for mildcases. Ketoconazole and itraconazole absorptionare dependent on acid in the stomach. Somepatients with Candida esophagitis may not have aresponse to fluconazole. Voriconazole, caspo-fungin, or micafungin also may be effective.Amphotericin compounds are used less often nowthan previously. Only rare cases with frequent,severe recurrences merit fluconazole (100-200mg/day) secondary prophylaxis. Primary pre-vention is not recommended.

CMV infection often produces large, but some-times small, shallow or deep, focal or serpiginous,usually painful (odynophagia or chest pain) ulcersin the middle to distal third of the esophagus.Erosions, strictures, fistulas, perforations, or masslesions are less frequent. Up to 15% of persons withCMV esophagitis have concomitant retinitis; thus,a complete ophthalmologic examination shouldbe performed. The diagnosis of CMV esophagitisrequires endoscopy, with biopsy specimens takenfrom the base of the ulcer (CMV involves the vesselsand endothelium, whereas HSV affects epithelialcells at the edge of ulcers) to examine for cytopathiceffects (intranuclear inclusions, perinuclear halo,and cytoplasmic inclusions). Serologic studies(most patients are already positive) and culturestudies (contamination with blood) are less specific.Immunohistochemistry and in situ hybridizationcan improve sensitivity. Treatment with ganci-clovir, foscarnet, or cidofovir, as well as HAART,usually helps.

HSV esophagitis often presents with mul-tiple small, superficial ulcers (“volcano” ulcers)

150 Miscellaneous Disorders

or erosive esophagitis (Fig. 1). Strictures and fis-tulas are rare. Vesicles rarely are visualized.Biopsy specimens from the edge of ulcerationsshould show cytopathic changes (ground-glassnuclei, eosinophilic Cowdry type A intranuclear

inclusions, and multinucleate cells). Treatmentwith acyclovir usually is successful. Primaryprophylaxis is not recommended. Some patientswith frequent, severe recurrences require sec-ondary prophylaxis.

Gastrointestinal Manifestations of Human Immunodeficiency Virus Infection 151

Table 1. Oral Lesions in HIV-Infected Patients

Condition Features Treatment

Candidiasis (usually albicans; With/without pain: pseudo- Topical nystatin, clotrimazolenon-albicans strains may be membranous (thrush), vs systemic fluconazole,azole-resistant) erythematous (atrophic), hyper- itraconazole

plastic (painless, white, doesnot rub off)

Culture, KOH, Gram stain, rarelybiopsy

Cryptococcus, histoplasmosis, Painful, nodular, ulcerated: rare Antifungalsgeotrichosis, Penicilliummarneffei (Asia), Leishmania

Oral hairy leukoplakia Painless, often on tongue, not If symptomatic, high-dose(Epstein-Barr virus) red, does not peel off acyclovir or ganciclovir

Biopsy, viral studiesHerpes simplex virus Biopsy, Tzanck preparation Acyclovir, famciclovir,

valacyclovirIf resistance, foscarnet orcidofovir

Herpes zoster Rare AntiviralsCytomegalovirus Rare Ganciclovir, foscarnet, or

cidofovirOral condylomata Human papillomavirusAphthous ulcers Painful; no organisms in Topical anesthetics, dexa-

biopsy specimen methasone, systemicHIV-induced (?) corticosteroids, thalidomide

Bacillary angiomatosis Bartonella henselae or quintana,papules or ulcers

BiopsySyphilis RareLymphomatoid granulomatosis RareGranuloma annulare RareMycobacterium avium- Rare

intracellulareNon-Hodgkin’s lymphomaKaposi’s sarcomaSquamous cell carcinomaNecrotizing gingivitis and

periodontitis

HIV, human immunodeficiency virus.

Idiopathic esophageal ulcers may be single ormultiple, and they often occur in the distal esoph-agus. By definition, all diagnostic studies (biopsy,brush, cultures, and special studies) are negative.Pain is the norm, and fistulas may occur. Treatmentincludes corticosteroids or thalidomide.

Other unusual causes of esophageal lesionsinclude infections with papillomavirus, Epstein-Barr virus, papovavirus, Histoplasma, Aspergillus,Mucorales, Cryptococcus, Actinomyces, Nocardia,bacillary angiomatosis, Leishmania, Cryptosporidium,Pneumocystis, Mycobacterium tuberculosis, andMycobacterium avium-intracellulare, as well aslymphomatoid granulomatosis, non-Hodgkin’slymphoma, and Kaposi’s sarcoma.

• Candida and CMV are the most commonopportunistic infections of the esophagus.

• Cytopathic changes diagnostic of CMV or HSVulceration involving the esophagus are foundmost often in biopsy specimens from the baseor edge of the ulceration, respectively.

STOMACHGastric disorders related to immunosuppressionof persons infected with HIV are uncommon.

Epigastric discomfort may be due to CMV infec-tion involving the stomach or, more likely, gas-troesophageal reflux disease, distal esophagealulceration (due to CMV infection, idiopathicesophageal ulceration, or HSV infection), pepticulcer disease, or dyspepsia. Gastric lymphoma canpresent with anorexia, nausea, vomiting, pain, orbleeding, whereas Kaposi’s sarcoma involving thestomach is more likely to be asymptomatic. Whether“AIDS gastropathy” (achlorhydria or hypochlorhy-dria with gastric atrophy and antiparietal cell anti-bodies) exists is unclear. Rare infections of thestomach include cryptosporidiosis, histoplasmosis,bacillary angiomatosis, herpes zoster, and infectionwith M. avium-intracellulare. Also, idiopathic aph-thous ulcers have been identified in the stomach.

SMALL BOWELCase—A 35-year-old woman with HIV infectionsuccessfully treated with antiretroviral drugs pre-sents with voluminous watery diarrhea after a tripto Haiti. She complains of nausea, cramps, and arecent 5-lb weight loss, but she states that she doesnot have fever or gastrointestinal tract bleeding.Fecal leukocytes and occult blood are not observedon stool examination. Standard stool cultures for


Fig. 1. Endoscopic photograph of herpes simplex esophagitis showing multiple superficial ulcers. A, Distal and,B, mid esophagus. (From Treadwell TL, Peppercorn MA, Koff RS. The gastroenterology teaching project, unit6—gastrointestinal infections and AIDS. Used with permission.)

A B

bacteria are negative. Mild eosinophilia is apparenton a peripheral blood smear.

The clinical presentation of this patient is con-sistent with Isospora belli infection of the smallbowel, which is endemic in Haiti. This shouldrespond promptly to antibiotic treatment withtrimethoprim-sulfamethoxazole. Because anti-retroviral drug therapy has been successful in thispatient, recurrent infection is not likely.

The principal presentation of small-boweldisease in HIV-infected patients is enteritis, withdiarrhea that is often high-volume, watery, andfecal-leukocyte–negative and sometimes withnausea, vomiting, bloating, periumbilical cramps,weight loss, or malabsorption. Diarrhea of colonicorigin is more likely to be small-volume, with fre-quent, urgent, loose stools, lower abdominal pain,and often fecal-leukocyte–positive, with or withoutblood. Opportunistic infections are more likely tooccur in persons with CD4 lymphocyte counts lessthan 100 to 200/µL (0.1–0.2×109/L). Medicationsused to treat HIV infection commonly are impli-cated as a cause of diarrhea. In diarrhea thoughtto be due to infection, a pathogen is identified inonly 50% to 85% of cases, and, in up to 25% of cases,more than one pathogen may be discovered.

The initial diagnostic approach to chronic diar-rhea in HIV-infected patients should include thefollowing: 1) freshly collected stools for bacterialculture (including Salmonella, Campylobacter, andShigella), ova and parasites, fecal leukocytes, andClostridium difficile toxin; 2) special studies (mon-oclonal antibodies, modified acid-fast andtrichrome stains) for Giardia, Cryptosporidium,Cyclospora, and Microsporida; and 3) blood cul-tures for enteric pathogens and M. avium-intracel-lulare (especially if the patient is febrile). If thesestudies are negative, especially in sicker and moreimmunosuppressed patients, endoscopic evalua-tion is indicated. Persons who are less ill and havea CD4 lymphocyte count greater than 200/µL(>0.2×109/L) and no pronounced weight loss usu-ally do not have an opportunistic infection and canbe given an empiric trial of antidiarrheal medica-tions. Endoscopy with small-bowel (preferablydistal duodenum or proximal jejunum) biopsy andaspiration for parasites can be performed when a

small-bowel source for the diarrhea is suspected.Colonoscopy with ileoscopy and ileal biopsy canbe helpful in the detection of selected small-bowelinfections (Cryptosporidium).

Small-bowel infections often include the fol-lowing: Cryptosporidium—This parasite is ubiqui-tous and transmitted as a zoonosis (humans, cats,dogs, calves, lambs, and other animals, especiallynewborn pets), by fecal-oral transmission, and,worldwide, through food (raw oysters and unpas-teurized juices) and water (including recreational)contamination by as few as 10 to 100 oocysts. Itusually infects small-bowel epithelial cells (apical,small [2-8 µm], extracytoplasmic but intracellularsporozoites [Fig. 2]), with various degrees of villousatrophy, but it also can involve the esophagus,stomach, colon, biliary tree, or lung. Diagnosis canbe made by examining the stool for oocysts (mod-ified acid-fast stain, or enzyme-linked immunosor-bent assay) or performing biopsy of the small bowel(biopsy of the terminal ileum may be more sensitivethan that of the proximal small bowel). Rectal biopsyfindings also may be diagnostic. Severe high-volumediarrhea with wasting (malabsorption, lactose intol-erance, or vitamin B12 deficiency) is most commonwhen CD4 counts are less than 50/µL (<0.05×109/L).Specific therapy with medications such as paro-momycin, nitazoxanide, and azithromycin can behelpful, but antiretroviral therapy has the best chanceof improving the diarrhea.

Microsporida—Two species of this former par-asite now reclassified as a fungus, Enterocytozoonbieneusi and Encephalitozoon (Septata) intestinalis,can be transmitted as a zoonosis or by fecal-oraltransmission. Ingestion of watermelon can be arisk factor. E. bieneusi involves small-bowel epithe-lium (small-bowel biopsy, intracellular, 1-2-mmmeronts and spores [Fig. 3]) or the hepatobiliarytree. E. intestinalis involves intestinal and oftenextraintestinal sites (kidney or lung). Currently,the diagnosis usually can be made with stool exam-ination (modified trichrome stain, chemofluores-cent agents, or monoclonal antibody testing) orwith small-bowel biopsy (villous atrophy may beseen) or aspiration. The clinical presentation ofimmunosuppressed HIV-infected patients is sim-ilar to that of patients infected with Cryptosporidium.No effective antibiotic therapy is available for E.bieneusi infection. HAART is more likely to be


helpful. The less common E. intestinalis infectioncan be treated with albendazole. E. intestinalis maybe identified in the lamina propria of the smallintestine and in urine sediment.

Isospora—I. belli is another protozoan that istransmitted among humans by fecal-oral routesand contaminated water. It is endemic in devel-oping countries (Haiti and Africa). Multiple largeintracellular forms (schizonts, merozoites, andgametocytes), mild villous atrophy, and infiltratingeosinophils can be identified in small-bowel biopsyspecimens, and stool examination (modified acid-fast stain) may show large oocysts and Charcot-Leyden crystals. Eosinophilia can be observed inperipheral blood smears. Infection with this parasiteis treated with sulfonamides such as trimethoprim-sulfamethoxazole or with ciprofloxacin. However,recurrences are common in immunosuppressedpatients and may require repeat courses of therapyor secondary prophylaxis.

Cyclospora—This parasite is larger thanCryptosporidium but smaller than Isospora, andthe species that infects humans, Cyclospora cayeta-nensis, is transmitted through fecal-oral routesand contaminated water, herbs (Thai basil), andfruit. Diagnosis can be made with stool exami-nation (acid-fast stains) or small-bowel biopsy(various degrees of villous atrophy are seen inbiopsy specimens). As for Isospora infection,

trimethoprim-sulfamethoxazole or ciprofloxacintherapy is effective, but relapse may be frequentand require re-treatment or secondary prophylaxis.

Giardia and Entamoeba—Giardia lamblia andEntamoeba histolytica infections are not morecommon, severe, or prolonged in HIV-infectedpatients than in non–HIV-infected patients; how-ever, infections are more common in those whopractice oral-anal sex. Entamoeba histolytica has beenfound more often in HIV-infected persons in Taiwanthan in HIV-infected persons elsewhere. Stoolexamination (for cysts and trophozoites), duodenalaspirates, and stool antigen tests are used to makethe diagnosis. Treatment is with metronidazole.

Cytomegalovirus—Infection with CMV canoccur throughout the gastrointestinal tract but ismost common in the esophagus and colon.

Mycobacterium—M. avium-intracellulare caninvolve the small bowel. Patchy areas of edema,erythema, friability, erosions, nodularity, a frostedappearance, or yellowish nodules or plaques maybe found at endoscopy. Patients with this infectionusually have low CD4 lymphocyte counts(<100/µL [<0.1×109/L]) and often have fever,weight loss, diarrhea, abdominal pain, anemia, andmalabsorption. Small-bowel biopsy specimens typ-ically show macrophages stuffed with many acid-fastorganisms. Stool and blood cultures also may bediagnostic. Differentiation from M. tuberculosis


Fig. 2. Jejunal biopsy specimen has apicalsporozoites of Cryptosporidium parvum.(Hematoxylin-eosin; original magnification, x400.)(From Goodgame RW. Understanding intestinalspore-forming protozoa: Cryptosporidia, Microsporidia,Isospora, and Cyclospora. Ann Intern Med.1996;124:429-41. Used with permission.)

Fig. 3. Small intestinal biopsy specimen has a clusterof microsporidial spores within apical cytoplasm(arrow). (Hematoxylin-eosin; original magnification,x350.) (From Case Records of the MassachusettsGeneral Hospital [Case 51-1993]. N Engl J Med.1993;329:1946-54. Used with permission.)

requires culture results. When present, M. tuber-culosis usually affects the ileocecal region. Patientswith mycobacterial infections may have extensiveand bulky mesenteric or retroperitoneal adenopathy,with areas of central necrosis seen on computedtomography (Fig. 4). Multidrug therapeutic regi-mens improve symptoms, and HAART ultimatelycan clear this systemic infection.

Other, more uncommon infections that mayinvolve the small intestine include leishmaniasis,toxoplasmosis, Pneumocystis carinii (now, P.jiroveci) infection, histoplasmosis, candidiasis, coc-cidioidomycosis, aspergillosis, cryptococcosis,mucormycosis, and strongyloidiasis. Intestinalinvolvement with Kaposi’s sarcoma, often relatedto human herpesvirus 8 (purplish red submucosallesions, frequently difficult to diagnose with endo-scopic biopsy), is usually asymptomatic, but someof the lesions can hemorrhage. Recent reports sug-gest that saliva is an infectious source. Non-Hodgkin’s lymphoma often involves the smallintestine and frequently is associated with fever,weight loss, abdominal pain, mass lesions,bleeding, and diarrhea. Most of these cases of lym-phoma are of B-cell origin.

• Small-bowel disease often can be distin-guished from large-bowel disease on the basisof clinical presentation.

• Medications used to treat HIV infection com-monly cause gastrointestinal symptoms.

• Patients who are less ill, have CD4 countsgreater than 200/μL, and do not have pro-nounced weight loss usually do not haveopportunistic infections and can be given anempiric trial of antidiarrheal medications.

COLONCase—A 32-year-old man who recently was foundto be infected with HIV comes to the emergencydepartment with new fever, abdominal pain, andbloody diarrhea. He recently bought his daughtera puppy at the local mall. The puppy has had non-bloody diarrhea.

The clinical presentation of this patient is con-sistent with colitis due to Campylobacter infectionacquired from the infected young dog and empha-sizes the importance of preventing exposure inHIV-infected persons.

Diarrhea due to colon disease is extremelycommon in HIV-infected patients. Immunosup-pressed patients are more likely to have entericinfections from Salmonella, Shigella, or Campylobacter.These infections, some of which also can involvethe small bowel, tend to be more common, morepersistent, more often resistant to antibiotics, andmore likely to recur. Blood cultures and stool exam-ination for fecal leukocytes often are positive, espe-cially for Salmonella enteritidis and S. typhimurium.Other bacterial infections include Yersinia;Aeromonas; enteroadherent, enteroinvasive, andenteropathogenic Escherichia coli; Vibrio vulnificus(raw shellfish); and Listeria. Exposure to the fol-lowing should be avoided: reptiles (Salmonella);young or sick pets (Salmonella, Campylobacter, andCryptosporidium); raw or undercooked eggs; meatand shellfish (Salmonella, noncholera vibrios, E.coli O157:H7); unpasteurized dairy products,poorly washed produce, soft cheeses, ready-to-eatcold cuts or hot dogs (Listeria and Salmonella); rawseed sprouts, refrigerated meat spreads, and delifoods that cannot be reheated; and unpasteurized


Fig. 4. Abdominal computed tomogram showingpunctate areas of central necrosis within enlargedceliac and peripancreatic lymph nodes (arrows).(From Jeffrey RB Jr. Abdominal imaging in AIDS.Curr Probl Diagn Radiol. 1988;17:109-17. Usedwith permission.)

apple cider (E. coli O157:H7). Streptococcus bovissepsis and endocarditis may be associated withgastrointestinal abnormalities such as colon cancer.Empiric treatment with ciprofloxacin may be usefulfor presumed bacterial infections before the agentis identified. Thus, HIV-infected patients shouldavoid the following: human and animal feces, con-taminated water (drinking and recreational),newborn and very young pets, calves, lambs, rep-tiles, stray pets, contaminated soil, raw meat, rawfish, raw shellfish, travel to parts of the world withprobable exposure to unsafe food or water, unpas-teurized juices, raw seed sprouts, questionablecold cuts, unclean produce, soft cheeses (eg, Brie,Camembert, feta, and blue-veined and Mexican-style cheese such as queso fresco), refrigeratedpâtes, refrigerated meat spreads, poorly cookedeggs, poorly cooked and reheated leftovers, manydeli foods, and food from street vendors.

CMV infection often affects the colon, with diar-rhea, abdominal pain, bleeding, ulceration (Fig. 5),mass lesion, perforation, fistula, and weight loss asclinical manifestations. The CD4 lymphocyte countsusually are low (<50-100/µL [<0.05–0.1×109/L]).Infection may be asymptomatic. Diagnosis requirestissue biopsy specimens showing cytopathicchanges; biopsy specimens from even normal-appearing areas can be diagnostic and should betaken. Use of immunohistochemistry increases thediagnostic yield. Also, CMV DNA testing of blood,tissue, and body fluids may be helpful. Up to 18%of cases may involve the right colon alone, and theinfection would not be diagnosed with flexible sig-moidoscopy. Antiviral therapy with agents such asganciclovir, foscarnet, or cidofovir usually is indi-cated, as well as HAART.

Clostridium difficile colitis is common, but it isnot more severe, persistent, or recurrent inimmunosuppressed than in nonimmunosup-pressed persons. Other less common infections aredue to M. avium-intracellulare, M. tuberculosis,Bartonella henselae (bacillary angiomatosis),Cryptosporidium, E. histolytica (symptomatic colitisis rare), Cryptococcus, Toxoplasma, Pneumocystis,Leishmania, Penicillium marneffei (Southeast Asia),and Candida. Histoplasmosis and schistosomiasisare also less common than C. difficile infections.

Several organisms found in stool samples areof uncertain clinical significance, including non-

histolytica Entamoeba, Balantidium coli, spirochetes,Blastocystis hominis, adenovirus, Rotavirus, Astrovirus,coronavirus, picobirnavirus, and Calicivirus.

Other processes may occur, including lym-phoma, Kaposi’s sarcoma, toxic megacolon (bacte-rial infections; CMV, C. difficile, or Cryptosporidiuminfections; and Kaposi’s sarcoma-related), typhlitis(sometimes without neutropenia), pneumatosisintestinalis (often associated with infections suchas CMV, C. difficile, Cryptosporidium, and M.avium-intracellulare), idiopathic colonic ulcer, andintussusception (due to infections, neoplasms,or lymphoid hyperplasia). Anorectal disease ismore common in HIV-infected men who have sexwith men than in other HIV-infected patients.These patients are at increased risk for herpes sim-plex (chronic cutaneous perianal ulcers, pain,tenesmus, mucopurulent discharge, inguinal lym-phadenopathy, dysuria, and saddle paresthesias),CMV infection, gonorrhea, syphilis, idiopathiculcer, condylomata (human papillomavirus), mol-luscum contagiosum, anal squamous cell carcinoma(especially with HIV and human papillomavirus


Fig. 5. Barium enema shows cytomegalovirus colitis.Note mucosal edema, ulcerations, and narrowing ofthe transverse colon. These findings are nonspecificand can occur in other infections as well as inischemic colitis. (From Treadwell TL, PeppercornMA, Koff RS. The gastroenterology teaching project,unit 6—gastrointestinal infections and AIDS. Usedwith permission.)

coinfection), Chlamydia as well as Actinomycesinfection, Kaposi’s sarcoma, lymphoma, andLeishmania infection.

• Many infections in immunocompromisedHIV-infected patients can be prevented.

• Enteric infections may be diagnosed with bloodculture and stool studies.

• Noninfectious causes of diarrhea have becomemore common in HIV-infected patientsreceiving antiretroviral medications.

PANCREASPancreatic involvement in immunosuppressedHIV-infected patients often results from medicationsand infections (pancreatitis) and less often frommalignancy. Hyperamylasemia, pancreatic inorigin or due to renal failure or macroamylasemia,may occur in asymptomatic persons. Medicationsoften implicated in pancreatitis include dideoxy-cytidine, dideoxyinosine, pentamidine, dapsone,and trimethoprim-sulfamethoxazole. Infectionsreported to involve the pancreas are protean andinclude CMV, Toxoplasma, Pneumocystis, Candida,Cryptococcus, histoplasmosis, aspergillosis, M. avium-intracellulare, and M. tuberculosis. Kaposi’s sarcomaand lymphoma also may affect the pancreas.

RECOMMENDED READINGCall SA, Heudebert G, Saag M, Wilcox CM. The

changing etiology of chronic diarrhea in HIV-infected patients with CD4 cell counts less than200 cells/mm3. Am J Gastroenterol. 2000; 95:3142-6.

Cappell MS. The pancreas in AIDS. GastroenterolClin North Am. 1997;26:337-65.

Clayton F, Clayton CH. Gastrointestinal pathologyin HIV-infected patients. Gastroenterol ClinNorth Am. 1997;26:191-240.

Datta D, Gazzard B, Stebbing J. The diagnosticyield of stool analysis in 525 HIV-1-infectedindividuals. AIDS. 2003;17:1711-3.

Department of Health and Human Services/NIHAIDS treatment and information service [cited2005 Mar 21]. Available from: http://www.aidsinfo.nih.gov.

Horvath KD, Whelan RL. Intestinal tuberculosis:return of an old disease. Am J Gastroenterol.1998;93:692-6.

Koshy M, Kauh J, Gunthel C, Joyner M, Landry J,Thomas CR. State of the art: gastrointestinalmalignancies in the human immunodeficiencyvirus (HIV) population. Int J GastrointestCancer. 2005;36:1-14.

Lewthwaite P, Gill GV, Hart CA, Beeching NJ.Gastrointestinal parasites in the immunocom-promised. Curr Opin Infect Dis. 2005;18: 427-35.

Mönkemüller KE, Call SA, Lazenby AJ, WilcoxCM. Declining prevalence of opportunisticgastrointestinal disease in the era of combina-tion antiretroviral therapy. Am J Gastroenterol.2000;95:457-62.

Noyer CM, Simon D. Oral and esophageal disorders.Gastroenterol Clin North Am. 1997; 26:241-57.

Wei SC, Hung C-C, Chen M-Y, Wang CY, ChuangCY, Wong JM. Endoscopy in acquiredimmunodeficiency syndrome patients withdiarrhea and negative stool studies.Gastrointest Endosc. 2000;51:427-32.

Wilcox CM. Current concepts of gastrointestinaldisease associated with human immunodefi-ciency virus infection. Clin Perspect Gastro-enterol. 2000;3:9-17.


UPPER GASTROINTESTINAL TRACTBLEEDING

IntroductionUpper gastrointestinal (UGI) tract bleeding (“UGIbleeding”) constitutes 75% to 80% of all cases ofacute gastrointestinal tract bleeding. The incidencehas decreased, but the mortality rate from acuteUGI bleeding, ranging from 3% to 10%, has notchanged appreciably in the past 50 years. This lackof change in mortality rate likely is related to theincreased age of patients who present with UGIbleeding and the increase in associated comorbidconditions. Peptic ulcers are the most commonsource of UGI bleeding, accounting for about 40%of cases. Other major causes are gastric erosions(15%-25% of cases), bleeding varices (5%-30%),and Mallory-Weiss tears (5%-15%). The use ofaspirin or nonsteroidal antiinflammatory drugs(NSAIDs) is prevalent in 45% to 60% of all casesof acute bleeding. Moreover, the risk of UGIbleeding is increased in patients who take as fewas one “baby aspirin” (81 mg) per day.

Initial Approach to Patients With UpperGastrointestinal Tract BleedingThe initial evaluation of a patient with UGIbleeding should focus on assessment of 1) hemo-dynamic status and 2) comorbid conditions.

Melena can result when as little as 100 mL ofblood is instilled into the UGI tract, and instilla-tion of 1,000 mL or more initially leads to hema-tochezia. Hematochezia from UGI bleeding is asign of significant bleeding and, if associated witha red nasogastric aspirate, has a mortality rate near30%. Patients still bleed whole blood; therefore,the hematocrit may not decrease immediately withacute bleeding. Extravascular fluid will enter thevascular space and restore volume for up to 72hours, thereby leading to a subsequent decreasein the hematocrit. Similarly, the hematocrit maycontinue to decrease for a few days after bleedinghas stopped, and a decrease in hematocrit withoutclinical evidence of blood loss is not diagnostic ofrecurrent bleeding. Adequate intravenous accessshould be provided. Volume and blood resusci-tation and stabilization of any other comorbid

159

CHAPTER 11

Nonvariceal Gastrointestinal Tract Bleeding

Jeffrey A. Alexander, MD

Abbreviations: H2, histamine2; NSAID, nonsteroidal antiinflammatory drug; UGI, upper gastrointestinal.

active medical conditions should be achievedbefore endoscopy. Rarely, massive bleeding cannotbe stabilized adequately before endoscopy.Intubation for airway protection should be con-sidered in patients with ongoing hematemesis orthose with suspected active bleeding anddecreased consciousness or loss of the gag reflex.There is no evidence that nasogastric lavage helpsstop bleeding, although it may be helpful incleansing the stomach before endoscopy.

Prognostic Factors

ClinicalAge older than 70 years is a risk factor for mor-tality. Comorbid conditions that increase mortalityinclude pulmonary disease (acute respiratoryfailure, pneumonia, and symptomatic chronicobstructive pulmonary disease), malignancy, liverdisorders (cirrhosis and alcoholic hepatitis), neu-rologic disorders (delirium and recent stroke),sepsis, postoperative state, and possibly cardiacdisease (congestive heart failure, ischemic heartdisease, and dysrhythmia) and renal disorders(acute renal failure, creatinine >4 mg/dL, and dial-ysis). Signs of large-volume bleeding include freshhematemesis or bright red nasogastric aspirateand shock, the two most predictive risk factors formortality. Tachycardia (heart rate >100beats/minute), orthostasis, and hypotension (sys-tolic blood pressure <100 mm Hg) are predictive ofrebleeding. Coffee ground emesis has no prog-nostic value. A transfusion requirement of 4 unitsof blood or more per resuscitative event is predic-tive of rebleeding and mortality. Laboratory find-ings of note include thrombocytopenia, leukocy-tosis, and abnormal coagulation profile, all ofwhich increase mortality. Corticosteroid useincreases mortality, and anticoagulant useincreases the risk of rebleeding.

EndoscopicOnly the finding of varices or gastric cancer hasbeen shown clearly to be a predictor of mortality.Active arterial spurting has been associated incon-sistently with increased mortality. Endoscopicfindings, however, have clear prognostic valuein accessing rebleeding rates. For reliable prog-nostication of rebleeding, endoscopy should be

performed within 24 hours after presentation.Nearly 94% of episodes of rebleeding occur by 72hours and 98% within 96 hours. The three endo-scopic observations that are independent predictorsof rebleeding regardless of the type of lesion arearterial spurting (rebleeding in 70%-90% of cases),visible vessel or pigmented protuberance (40%-50%),and adherent clot resistant to washing (10%-35%).Ulcers larger than 2 cm and posterior duodenalbulb ulcers also are predictive of rebleeding.

Specific Lesions

Peptic UlcersThe approach to a patient who has bled from pepticulcer disease is determined at the time ofendoscopy. There are many options for endoscopictherapy. Thermal-coaptive coagulation involvesthe placement of the coagulating probe directlyon the bleeding vessel. This is uniformly effectivefor vessels up to 2 mm in diameter with the heaterprobe (typical setting in cases of peptic ulcer dis-ease, 30 J) or BICAP probe (14-16 W). Injectiontherapy results in short-term tamponade andvasospasm and can be induced with the liberal useof epinephrine (1:10,000). Vasodestruction is long-term and can be induced by sclerosants or alcohol(total injection volume not to exceed 2 mL).Endoscopic clipping has not been shown to be anymore effective than thermal therapy. However, itmay have appeal for use in patients with coagula-tion disorders or in cases in which further coaptivecoagulation may not be desirable.

Endoscopic therapy is indicated for patientswith active arterial bleeding and those with a non-bleeding visible vessel (pigmented protuberance).An adherent clot is a predictor of rebleeding andcan be managed with endoscopic therapy or high-dose proton pump inhibitor therapy (or both). Allthree endoscopic treatment options have beenshown to have a relatively similar efficacy.However, epinephrine injection, followed by amore permanent form of treatment (coagulation,vasodestruction, or clipping), has been shown tobe more effective than epinephrine therapy alone.Patients with a clean ulcer base (rebleeding rates<5%) and a flat pigmented spot (rebleeding rates5%-10%) do not require endoscopic therapy andlikely could be discharged soon after endoscopy.


Deep ulcers may tend to expose larger vessels thatmay not be amenable to endoscopic coagulation.Deep ulcers in the stomach, particularly those inthe upper body on the lesser curvature (left gas-tric artery), or posterior duodenal bulb (gastro-duodenal artery) with nonbleeding visible vesselsmore than 2 to 3 mm in diameter should not betreated. Rebleeding after endoscopic therapyoccurs 20% to 30% of the time. Re-treatment forrecurrent bleeding achieves long-term hemostasisin more than 70% of cases.

If endoscopic therapy fails, angiographicembolization of the bleeding vessel is an option inpatients with a poor operative risk. No data sup-port the use of histamine2 (H2)-blockers or antacidsin controlling peptic ulcer bleeding. Several studieshave suggested that high-dose proton pumpinhibitor therapy is beneficial for patients withpeptic ulcer bleeding and high-risk stigmata, bothwith and without endoscopic therapy. Presumably,the benefit is related to clot stabilization occurringin a nonacid environment. In vitro studies suggestthat pH >6.0 is required for platelet aggregationand fibrin formation, whereas pH <5.0 is associ-ated with clot lysis. This level of pH increase isachieved best with proton pump inhibitor therapyadministered as a continuous intravenous infusion.Octreotide may be of some benefit in torrentialbleeding as a temporizing measure because of itseffects on decreasing splanchnic blood flow.

Patients with UGI bleeding and Helicobacterpylori infection should be treated, and eradicationof the H. pylori infection should be proven. Patientstaking NSAIDs should avoid them, if possible.Patients without a reversible cause of peptic ulcerdisease should receive long-term ulcer prophy-laxis with either a full-dose H2-blocker (ranitidine300 mg/day) or a proton pump inhibitor. Withouttreatment, recurrent ulcer bleeding will occur inapproximately one-third of these patients in 3 to5 years’ time. This rate can be decreased to lessthan 10% with full-dose H2-blocker prophylaxis.Ulcer rebleeding is uncommon in patients withproven eradication of H. pylori infection who avoidthe use of NSAIDs. However, ulcer prophylaxismay be reasonable for patients in whom H. pyloriinfection has been eradicated but who have a clin-ically important comorbid condition, especially ifthey take NSAIDs continuously or intermittently.

Mucosal Erosive Disease Endoscopic esophagitis, gastritis, and duodenitisare defined by the endoscopic findings of hemor-rhage, erythema, or erosions. These lesions rarelyare associated with major UGI bleeding. Largehiatal hernias can be associated with chronic bloodloss related to Cameron lesions, which are linearerosions along the crests of gastric folds at or nearthe diaphragmatic hiatus. Gastric erosive diseaseusually is related to NSAID use, alcohol intake, orstress gastritis. Bleeding generally is minor unlessulceration develops. Prophylaxis of NSAID injurywith misoprostol or omeprazole or treatment withcyclooxygenase-2–specific NSAIDs decreases therisk of ulcer development. Stress gastritis leads toclinically significant UGI bleeding in more than3% of patients in intensive care units. At higherrisk are patients receiving mechanical ventilationfor more than 48 hours, patients with coagulopathy,and patients with head injury or extensive burninjuries. Prophylactic therapy should be reservedfor these groups with H2-receptor antagonists,proton pump inhibitors, or sucralfate. Althoughnot universally agreed upon, it appears that H2-receptor antagonists may be slightly more effectivethan sucralfate. However, they may be associatedwith a greater incidence of pneumonia and, possibly,mortality. The limited amount of data on protonpump inhibitor therapy for stress ulcer prophy-laxis suggests that it is similarly beneficial.

Mallory-Weiss TearMallory-Weiss tears occur at the gastroesophagealjunction and often are present with a classic historyof recurrent retching, frequently in an alcoholicpatient, before the development of hematemesis.Most tears occur on the gastric side of the gastro-esophageal junction, but 10% to 20% of them mayinvolve the esophagus. Bleeding stops spontaneouslyin 80% to 90% of patients and rebleeding occurs in 2%to 5%. Endoscopic therapy with thermal coagula-tion or injection therapy is of benefit for activebleeding. Angiographic therapy with intra-arterialvasopressin or embolization also can be effective, ascan oversewing the lesion intraoperatively.

Portal Hypertensive GastropathyThis lesion is more frequent in the proximal thandistal stomach and gives the gastric mucosa a

Nonvariceal Gastrointestinal Tract Bleeding 161

mosaic or snakeskin appearance, with or withoutred spots. Severe portal hypertensive gastropathyhas the mosaic pattern as well as diffuse red spotsand can be associated with both chronic and acutegastrointestinal tract bleeding. Bleeding usuallyis not massive, and therapy is directed at loweringportal pressure. Rebleeding can be decreased withnonselective β-blocker therapy.

Aortoenteric FistulaFistulas can occur between any major vascularstructure and the gastrointestinal tract.Aortoesophageal fistulas are caused by thoracicaortic aneurysms, esophageal foreign bodies, orneoplasms. Up to 75% of aortoenteric fistulas com-municate with the duodenum, usually in the thirdportion. These may develop from an aorticaneurysm but are related more commonly toabdominal aortic (graft) reconstructive surgery.Infection appears to have a major pathogenic rolein the development of these fistulae, which usu-ally develop off the origin of the graft, often withpseudoaneurysm formation. The classic “heraldbleed,” in which bleeding stops spontaneouslyhours to months before massive bleeding, occursin about one-half of patients. Evaluation shouldbegin with extended upper endoscopy to examinefor evidence of distal duodenal bleeding (positivein <40% of cases) and to exclude other sources ofbleeding. For a patient with an aortic graft, severebleeding, and negative endoscopic findings,explorative surgery is indicated. Angiographyrarely is helpful and may delay appropriate treat-ment. Computed tomography or magnetic reso-nance imaging may be helpful in demonstratingair surrounding the graft in proximity to the duo-denum or an absence of a tissue plane between thegraft and the duodenum, which suggests the diag-nosis. The correct diagnosis is established preop-eratively in as few as one-third of patients.

Hematobilia and HemosuccusPancreaticusHematobilia is manifested classically as UGIbleeding accompanied by biliary colic and jaun-dice. The diagnosis is made endoscopically byseeing blood coming from the ampulla. The mostcommon cause of hematobilia is trauma, includingliver biopsy, to the liver or biliary tree. Extrahepatic

or intrahepatic artery aneurysms often are causedby trauma and may communicate with the bileducts. Bleeding can be caused also by gallstones,hepatic or bile duct tumors, and cholecystitis.Hemosuccus pancreaticus usually representsbleeding from peripancreatic blood vessels intothe pancreatic duct. This commonly is due to ruptureof true aneurysms or pseudoaneurysms oftenassociated with pancreatitis and pseudocysts.Angiography is used to locate the bleeding site.Transcatheter embolization is the treatment of choice.Surgery may be required for embolization failures.

NeoplasmsBleeding can occur from primary (adenocarcinoma,stromal tumors, lymphomas, or neuroendocrinetumors) and, occasionally, metastatic UGI tumors(melanoma or breast). Gastrointestinal stromaltumors often appear as a submucosal mass withcentral ulceration and are not an infrequent causeof severe UGI bleeding. Effective therapy generallyis surgical.

Vascular Anomalies

Anomalies With Skin LesionsVascular lesions can be seen throughout the gas-trointestinal tract in several systemic diseases andsyndromes such as Osler-Weber-Rendu disease(or hereditary hemorrhagic telangiectasias), theelastic tissue disorders of pseudoxanthoma elas-ticum and Ehlers-Danlos syndrome, CREST (cal-cinosis cutis, Raynaud phenomenon, esophagealdysfunction, sclerodactyly, and telangiectasias)syndrome, and blue rubber bleb nevus syndrome.Endoscopic coagulation therapy is the treatment ofchoice. Therapy with high-dose estrogen-proges-terone therapy is of debatable value but has beenreported to decrease bleeding in patients withhereditary hemorrhagic telangiectasias notamenable to complete endoscopic therapy.

Anomalies Without Skin LesionsVascular ectasias can occur anywhere in the UGItract but are more common in the duodenum andstomach, particularly in older patients and thosewith chronic renal failure or previous radiotherapy.These lesions are cherry red and often fernlike inappearance. Histologically, dilated, ectatic, or


tortuous submucosal blood vessels (or a combi-nation of these) are seen; the pathogenesis of thesevessels is not known. These lesions may be diffuseor localized. Vascular ectasias are treated withendoscopic thermal coagulation. Estrogen-proges-terone therapy has been shown to be effective occa-sionally and can be attempted when endoscopictherapy fails.

Gastric antral vascular ectasia, or “watermelonstomach,” is a specific type of localized ectasiaoften seen in elderly women who present with irondeficiency anemia and evidence of mild UGI tractblood loss. This lesion is associated with severalother disease processes, most notably, connectivetissue disorders, atrophic gastritis, perniciousanemia, and portal hypertension. Red streaks thattraverse the gastric antrum and converge at thepylorus, resembling the stripes on a watermelon,are seen with endoscopy. Histologically, largeblood vessels with intravascular fibrin thrombiand fibromuscular hyperplasia are seen, but thediagnosis usually is made on the basis of the classicendoscopic appearance. If iron replacement is inad-equate to maintain a normal level of hemoglobin,endoscopic thermal therapy often is helpful. Argonplasma coagulation is the preferred thermal treat-ment for gastric antral vascular ectasia because ofthe large area usually requiring treatment.Occasionally, antrectomy is necessary.

Dieulafoy’s lesion is an abnormally large sub-mucosal artery that can rupture and bleed. Thebleeding is arterial and is usually moderate tosevere. Most of these lesions are within 6 cm of theesophageal junction, but they can occur in the duo-denum and jejunum as well as in the esophagus,colon, rectum, and biliary tree. They can be difficultto diagnose when the bleeding has stopped, andendoscopy may need to be repeated several timesto identify the lesion. When the lesion is identified,endoscopic tattooing of the lesion often is helpful,especially if surgical therapy is planned.Dieulafoy’s lesion appears as a small protrudingvessel surrounded by normal mucosa or as aminute mucosal defect. These lesions are amenableto conventional endoscopic therapy, band ligation,and endoscopic clipping. Rebleeding rates afterendoscopic therapy are low. A nonbleeding visiblevessel should be treated. Angiographic emboliza-tion can be effective in high-risk surgical patients.

NON-UPPER GASTROINTESTINALTRACT BLEEDING

IntroductionGastrointestinal tract bleeding has been classifiedaccording to the level of the tract: 1) upper—prox-imal to the ampulla of Vater, 2) mid—from theampulla of Vater to the terminal ileum, and 3)lower—distal to the terminal ileum. Only 3% to5% of episodes of gastrointestinal tract bleedingoriginates from a mid bowel source.

Depending on the transit time, which in turnis determined by the volume of bleeding, patientswith non-upper gastrointestinal tract (non-UGI)bleeding may present with melena, hematochezia,or occult bleeding. It is important to note that bac-terial metabolism needs sufficient time for melenato be generated from fresh blood.

Hematochezia most commonly indicatesbleeding from a colonic source. However, thesource is more proximal in 5% to 10% of patients.It would be extremely uncommon for hema-tochezia to originate from a source in the prox-imal gastrointestinal tract without hemodynamicevidence of bleeding or clinical evidence of rapidgastrointestinal transit (eg, hyperperistalsis).

If blood is limited to the toilet paper or surfaceof formed stool, a perianal source (eg, hemorrhoidsor fissures) is likely. Tenesmus suggests a rectal origin(eg, proctitis). For all patients, the possibility of neo-plasia must at least be considered and often excluded.

Specific Lesions

Diverticular BleedingPatients with diverticular bleeding typically pre-sent with acute blood loss, as manifested bymaroon-colored stools or hematochezia. Minor oroccult bleeding is not characteristic of diverticularbleeding or diverticulosis. Diverticular bleedingand diverticulitis are distinct conditions that rarelyoccur together. Diverticular bleeding is painlessexcept for the cramping that may occur with thecathartic effect of blood within the colon.

Diverticular bleeding is thought to originatemore commonly from the right colon where ostiatend to be wider and the colon wall thinner. It isestimated that 3% to 5% of patients with divertic-ulosis will develop diverticular bleeding. Bleeding


most commonly occurs during the sixth and sev-enth decades of life and stops spontaneously inmore than 75% of patients. Generally, rebleedingoccurs in 25% of patients. After a second episode,the risk of rebleeding is approximately 50%.

For ongoing or recurrent bleeding, angiog-raphy often is performed with the intention ofidentifying an actively bleeding vessel. If thevessel is identified, transcatheter embolizationcan be attempted, although in some seriescolonic infarction has been as high as 20%.Transcatheter vasopressin can control bleedingin 90% of cases, but rebleeding rates are high.Endoscopic therapy has been reported to be safeand effective, but locating the actual bleedinglesion may be difficult.

Vascular EctasiaVascular ectasias are typically smaller than 5 mmand are found in 3% to 6% of patients undergoingcolonoscopy. Most commonly, they are in the rightcolon but may occur anywhere in the gastroin-testinal tract. These lesions are usually angiodys-plasias, which are often multiple and believed to berelated to the aging process. Less than 10% ofpatients with angiodysplasia eventually havebleeding. Not uncommonly, these lesions areuncovered by bleeding diathesis, such as antico-agulation or platelet dysfunction. The lesions maylead to acute overt as well as occult gastrointestinaltract bleeding.

For many patients, iron repletion therapy aloneis sufficient. Endoscopic therapy is effective butassociated with a significant rebleeding rate.Angiographic embolization can be used to controlacute bleeding. Estrogen and progesterone whentaken together may be of benefit for some patients,particularly those with hereditary hemorrhagictelangiectasia, but the data are conflicting.

NeoplasmPatients with neoplasm of the colon and smallbowel may present with either acute or occult non-UGI bleeding. Tumors of the small intestine maybe a relatively common cause of obscure non-UGIbleeding in patients younger than 50 years and aremalignant two-thirds of the time. Carcinoids, ade-nocarcinomas, and gastrointestinal stromal tumorsaccount for most of these lesions.

Ischemic ColitisPatients with ischemic colitis often present withpain and low-volume hematochezia. This may beseen in patients who have had abdominal vascularsurgery, in those who have vasculitis or clottingdisorders, or in those who receive estrogen therapy.However, in most cases, no etiologic factor is iden-tified. Large-vessel disease is rarely found, andangiography generally is not indicated. There isno specific therapy, and recovery is usually com-plete in several days. Occasionally, however, acolonic stricture may develop.

Meckel’s Diverticulum Meckel’s diverticulum, a remnant of the vitellineduct, usually occurs 100 cm proximal to the ileocecalvalve. Autopsy series suggest a prevalence rate of0.3% to 3%. Approximately 50% of these diverticulacontain gastric mucosa, and patients, typically achild or young adult, may present with bleeding.

Inflammatory Bowel Disease Patients with inflammatory bowel disease maypresent with gross, bloody diarrhea, which is theclassic presentation for ulcerative colitis. Majorhemorrhage is uncommon but can occur.

Benign Rectoanal Disease Patients with benign rectoanal disease often pre-sent with hematochezia. Painless hematocheziawith blood on the toilet paper or the surface offormed stool is most suggestive of hemorrhoidalbleeding. Painful outlet bleeding is typical of arectal fissure.

Stercoral ulcers are associated with constipa-tion and occur most commonly in the rectosigmoidarea or, occasionally, in the more proximal colon.They often become manifest after disimpaction.Solitary rectal ulcer syndrome often is associatedwith excessive straining. The ulcer usually occurson the anterior wall, 6 to 10 cm above the analverge. Both of these lesions may come to attentionbecause of significant bleeding.

Patients with radiation proctitis may presentmonths to years after receiving radiation to theprostate or pelvic organs. Sigmoidoscopy showscharacteristic mucosal telangiectasias. The bleedingis rarely severe, and endoscopic argon plasmacoagulation therapy is the treatment of choice.


InfectionInfections may be associated with non-UGIbleeding. Obvious clues include a travel historyor evidence of systemic toxicity such as fevers,rashes, arthralgias, eosinophilia, or diarrhea. Inpatients infected with human immunodeficiencyvirus, common causes for non-UGI bleeding arecytomegalovirus colitis and lymphoma.

NSAID Enteropathy and ColopathyIncreasingly, NSAID enteropathy and colopathyare being recognized as explanations for non-UGIbleeding. Autopsy studies have documented smallintestinal ulcers in 8% of patients who had takenNSAIDs within the preceding 6 months.Diaphragmatic strictures are strongly suggestiveof NSAID-induced inflammation. NSAIDs also areknown to reactivate inflammatory bowel disease.

ApproachThe evaluation and management of patients whopresent with non-UGI bleeding is determinedlargely by the clinical presentation and the differ-ential diagnosis that has been generated. Essentialpoints to keep in mind when answering questionsare the following:

• Patients who are being evaluated because ofpositive findings on fecal occult blood testingrequire colonic imaging. Without signs orsymptoms of UGI tract disease or iron defi-ciency, the value of esophagogastroduo-denoscopy is debatable.

• Generally, the yield of a small-bowel follow-through study in patients with obscure gas-trointestinal tract bleeding is less than 5%. Thisyield increases to 5% to 10% with enteroclysis.

• Technetium 99m-tagged red blood cell radionu-clide scans can detect bleeding rates as low as0.1 mL/minute. The patient may be scannedrepeatedly over a 12- to 24-hour period in anattempt to capture intermittent bleeding.Radionuclide scans generally are not useful inidentifying a specific site of bleeding. They aremore sensitive for bleeding and are less inva-sive than angiography and often are used todetermine the best timing for angiography.

• Mesenteric angiography is more accurate thanradionuclide scans but requires a faster

bleeding rate (>0.5 mL/minute). Angiographicyields are much greater with active gastroin-testinal bleeding (60%-70%) than when angiog-raphy is performed after bleeding has ceased(<20%). Angiographic therapy with trans-catheter infusion of vasopressin or emboliza-tion has been effective but does carry a signif-icant risk of bowel infarction.

• Capsule endoscopy clearly is the best methodfor evaluating the entire small bowel inpatients with obscure bleeding. It shows anabnormal finding about 70% of the time. Thetechnology for localization and blood detec-tion is improving, but capsule retention thatrequires surgery is still an issue.

• Push enteroscopy has been reported to iden-tify probable bleeding sites in 50% of patientswith obscure gastrointestinal tract bleeding.This can be done with an adult or pediatriccolonoscope, but the depth of insertion isgreater with a dedicated enteroscope (length200-250 cm) used with an overtube. Of note,about 25% of the diagnoses made with pushenteroscopy are within the reach of a stan-dard endoscope.

• Balloon-assisted endoscopy can be performedby the peroral or peranal route (or both), witha diagnostic yield of 50%. Most of the smallintestine can be evaluated, and endoscopictherapy can be administered.

• Intraoperative enteroscopy has been reportedto detect abnormalities in about 70% ofpatients. However, recurrent bleeding is notuncommon, and only about 40% to 50% ofthese patients are free of bleeding at 2 years.

RECOMMENDED READINGBarkin JS, Ross BS. Medical therapy for chronic

gastrointestinal bleeding of obscure origin.Am J Gastroenterol. 1998;93:1250-4.

Fortun PJ, Hawkey CJ. Nonsteroidal antiinflam-matory drugs and the small intestine. CurrOpin Gastroenterol. 2005;21:169-75.

Khuroo MS, Khuroo MS, Farahat KL, Kagevi IE.Treatment with proton pump inhibitors inacute non-variceal upper gastrointestinalbleeding: a meta-analysis. J GastroenterolHepatol. 2005;20:11-25.


Laine L. Management of ulcers with adherent clots.Gastroenterology. 2002;123:632-6.

Laine L. Upper gastrointestinal bleeding. ClinicalUpdate: American Society for GastrointestinalEndoscopy. 2007;14:1-4.

Lanas A, Hunt R. Prevention of anti-inflammatorydrug-induced gastrointestinal damage: ben-efits and risks of therapeutic strategies. AnnMed. 2006;38:415-28.

Lin S, Rockey DC. Obscure gastrointestinalbleeding. Gastroenterol Clin North Am.2005;34:679-98.

Palmer KR, British Society of GastroenterologyEndoscopic Committee. Non-variceal uppergastrointestinal haemorrhage: guidelines. Gut.2002;51 Suppl IV:iv1-iv6.

Pennazio M. Capsule endoscopy: where are weafter 6 years of clinical use? Dig Liver Dis.2006;38:867-78. Epub 2006 Oct 11.

Raju GS, Gerson L, Das A, Lewis B. AmericanGastroenterological Association (AGA)Institute technical review on obscure gas-trointestinal bleeding. Gastroenterology.2007;133:1697-717.

Rockall TA, Logan RF, Devlin HB, Northfield TC.

Risk assessment after acute upper gastroin-testinal haemorrhage. Gut. 1996;38:316-21.

Stollman N, Metz DC. Pathophysiology and pro-phylaxis of stress ulcer in intensive care unitpatients. J Crit Care. 2005;20:35-45.

Targownik LE, Nabalamba A. Trends in manage-ment and outcomes of acute nonvariceal uppergastrointestinal bleeding: 1993-2003. ClinGastroenterol Hepatol. 2006;4:1459-66. Epub2006 Nov 13.

Yavorski RT, Wong RK, Maydonovitch C, BattinLS, Furnia A, Amundson DE. Analysis of 3,294cases of upper gastrointestinal bleeding in mil-itary medical facilities. Am J Gastroenterol.1995;90:568-73.

Zimmerman J, Siguencia J, Tsvang E, Beeri R,Arnon R. Predictors of mortality in patientsadmitted to hospital for acute upper gas-trointestinal hemorrhage. Scand J Gastro-enterol. 1995;30:327-31.

Zuccaro G Jr. Management of the adult patientwith acute lower gastrointestinal bleeding.American College of Gastroenterology.Practice Parameters Committee. Am JGastroenterol. 1998;93:1202-8.


Mesenteric ischemia can occur from any of themyriad of conditions that decrease intestinal bloodflow. Cappell divided these conditions into 1)secondary mesenteric ischemia due to extrinsicvascular compression or trauma (Table 1) and 2)primary mesenteric ischemia (mesenteric ischemicvasculopathy) resulting from arterial emboli, arte-rial or venous thrombi, low-flow states, or vas-culitis. The esophagus receives its principal bloodsupply segmentally from small vessels from theaorta, right intercostal artery, bronchial arteries,inferior thyroid artery, left gastric artery, shortgastric artery, and left phrenic artery. Vasculardisease of the esophagus is extremely rare, exceptafter surgical resection and in rare cases of vas-culitis (Behçet’s syndrome). The stomach, duo-denum, and rectum have numerous arterial inputswith rich collateralization. Vascular disordersaffecting the stomach, duodenum, or rectum areextremely rare also except for the reasons men-tioned above for the esophagus.

The principal arterial supply to the gut distalto the esophagus is from the celiac, superiormesenteric, and inferior mesenteric arteries.Embolic disease most frequently affects the supe-rior mesenteric artery because of its large diameter

and narrow angle of take-off from the abdominalaorta. Collaterals may include the meanderingmesenteric artery or arc of Riolan at the base of themesentery (connects the superior mesenteric andinferior mesenteric arteries), the marginal arteryof Drummond along the mesenteric border (con-nects the superior mesenteric and inferior mesen-teric arteries), the pancreaticoduodenal arcade(connects the celiac and superior mesenteric

167

CHAPTER 12

Vascular Disorders of theGastrointestinal Tract


Abbreviation: CT, computed tomography.

Table 1. Conditions Predisposing toSecondary Mesenteric Ischemia

AdhesionsHerniationVolvulusIntussusceptionMesenteric fibrosisRetroperitoneal fibrosisCarcinoid syndromeAmyloidosisMalignancy (peritoneal, mesenteric, colonic)NeurofibromatosisTrauma

arteries), the arc of Barkow (connects the celiacand superior mesenteric arteries), and the arc ofBuhler (connects the celiac and superior mesentericarteries). They enlarge rapidly in response to local-ized mesenteric ischemia. The inferior mesentericvein joins the splenic vein, which in turn joins thesuperior mesenteric vein to form the portal vein.

PATIENT HISTORY AND EXAMINATIONPrimary mesenteric ischemia is responsible forabout 1 per 1,000 hospital admissions, with casesdistributed equally between the small and largebowel. Risks include age (older than 50 years) andconditions that predispose to stasis, thrombosis,inflammation, or embolism of the mesenteric vas-culature (Table 2). Symptoms may be acute(sudden, hours), subacute (days), chronic (inter-mittent, over weeks to months), or a combination(usually acute and chronic). Patients with acutemesenteric ischemia involving the small boweloften present with abdominal pain that is severe,persistent (lasting hours), and poorly localized.The pain typically is more severe than the findingson abdominal palpation (ie, pain is much greaterthan tenderness). Prompt evaluation is critical.

Other nonspecific complaints can include fever,nausea, vomiting, abdominal distention, anddiarrhea. Physical findings can include abdominaldistention, diminished or increased bowel sounds,and nonspecific diffuse abdominal tenderness.Localized abdominal tenderness, rebound, rigidity,altered mental status, and visible gastrointestinaltract bleeding usually are late manifestations ofmore severe ischemic damage to the small bowel.Occult gastrointestinal bleeding can be an earlyfinding. Leukocytosis with left shift, hemocon-centration, and an increase in amylase, aspartateaminotransferase, lactate, creatine kinase, lactatedehydrogenase, or phosphate levels may or maynot occur. These tests lack both sensitivity andspecificity, but when results are abnormal, theysuggest more advanced (necrotic) bowel ischemia.Attention to predisposing conditions, their extrain-testinal manifestations (congestive heart failure,hypotension, sepsis, arrhythmias, or splanchnicvasoconstrictors such as digoxin and cocaine), andtheir initial management are critical in resuscitationof the patient (volume replacement, enhancingcardiac output, diminishing splanchnic vasocon-striction, and administration of broad-spectrumantibiotics). Patients with primary mesenteric


Table 2. Conditions Predisposing to Primary Mesenteric Ischemia

Atherosclerosis or fibromuscular dysplasiaCholesterol atheromatous embolismHypercoagulable or hyperviscosity statesVasculitis (Fabry’s disease, Behçet’s syndrome, thromboangiitis obliterans, giant cell arteritis,

Takayasu’s arteritis, Buerger’s disease, Crohn’s disease, systemic lupus erythematosus, polyarteritisnodosa, rheumatoid arthritis, syphilis, Henoch-Schönlein purpura, dermatomyositis, Köhlmeier-Degos syndrome, Churg-Strauss syndrome, Wegener’s granulomatosis, cryoglobulinemia,hypersensitivity vasculitis, Cogan’s syndrome, Kawasaki’s disease, lymphocytic phlebitis,mesenteric phlebosclerosis)

Cardiac arrhythmias, valvular disease, subacute bacterial endocarditis, myxomaCardiomegaly, myocardial dyskinesia, intracardiac thrombosisCardiac catheterization, myocardial infarction, congestive heart failureAortic or mesenteric artery aneurysm or dissectionLow-flow states, systemic hypotensionVasoconstrictive agents (amphetamines, cocaine, digitalis, ergot, pseudoephedrine, sumatriptan,

vasopressin)Abdominal traumaRadiation

ischemia of the colon (ischemic colitis) usually pre-sent with acute abdominal pain (commonly leftlower quadrant), often with urgency, diarrhea, andpassage of bright red blood per rectum.

INITIAL DIAGNOSTIC EVALUATIONIn an acutely ill patient, plain abdominal radi-ographs are important to rule out secondary causesof mesenteric ischemia and other causes of acuteabdominal pain, principally obstruction and perfo-ration. “Thumbprinting” may be seen. Pneumatosisintestinalis or portal venous gas is a late findingthat suggests transmural necrosis of the intestine(gangrene). Contrast-enhanced abdominal-pelviccomputed tomography (CT) may help excludeother causes of acute intra-abdominal pain andhas been recommended to diagnose acute (oracute-on-chronic) mesenteric venous thrombosisin patients with a history of deep venous throm-bosis or thrombophlebitis or a family history of ahypercoagulable state. CT findings may be normalin acute mesenteric ischemia involving the smallbowel or may show nonspecific changes such asbowel wall thickening, submucosal hemorrhage,mesenteric stranding, and pneumatosis. CT shouldnot defer resuscitation or arteriography in very illpatients with suspected acute mesenteric ischemiaof the small bowel. Patients with subacute orchronic pain syndromes benefit from a morecomplete evaluation, including CT and duplexultrasonography (see below).

Acutely ill patients with suspected small-bowel ischemia require prompt diagnosis andtreatment, for which selective mesenteric arte-riography is the standard. If angiography is notreadily available or transmural intestinalnecrosis (gangrene) is suspected, laparotomy isindicated. Resuscitation and administration ofbroad-spectrum antibiotics constitute initialtherapy for all patients.

SUPERIOR MESENTERIC ARTERYEMBOLUSSuperior mesenteric artery emboli are common,accounting for 5% of peripheral emboli and 50%of cases of primary mesenteric ischemia of the smallbowel. The emboli are usually from the heart; an

aortic origin is less common. Arrhythmias, car-dioversion, cardiac catheterization, myocardialinfarction or dyskinesia, congestive heart failure,previous embolism, and age older than 50 yearsare major risk factors. Peritonitis requires laparot-omy, with or without resection and with or withoutembolectomy. Otherwise, embolectomy (usuallysurgical) is indicated. Patients with acute onset ofa partial or small occlusion of a distal branch of thesuperior mesenteric artery may be candidates forthrombolytic therapy, intra-arterial papaverine,or anticoagulation (Fig. 1). Generalized vasocon-striction of the superior mesenteric artery occursfrom occlusion of a single branch of the artery andoften persists after embolectomy. Hence, manyexperts recommend intra-arterial papaverinebefore and for 24 hours after embolectomy or untila second-look operation (if indicated) is performed.Prophylaxis against further embolization (antico-agulation) usually is indicated preoperatively thenrestarted 24 to 48 hours postoperatively.

Vascular Disorders of the Gastrointestinal Tract 169

Fig. 1. Anteroposterior view of the aorta showingembolic occlusion of the proximal superiormesenteric artery. Note the normal-appearingproximal jejunal arterial branches (arrowheads) andabrupt cutoff (arrow) of the superior mesentericartery. (From McKinsey JF, Gewertz BL. Acutemesenteric ischemia. Surg Clin North Am.1997;77:307-18. Used with permission.)

SUPERIOR MESENTERIC ARTERYTHROMBUSSuperior mesenteric artery thrombus accounts forabout 15% of cases of primary mesenteric small-bowel ischemia. Risk factors for superior mesen-teric artery thrombus include old age, low-flowstates (arrhythmia, hypotension, sepsis, myocardialinfarction, dyskinesia, and congestive heartfailure), atherosclerosis (acute-on-chronic ischemia,hypertension, diabetes mellitus, and vascu-lopathy), hypercoagulable states, vasculitis, andaortic or mesenteric artery aneurysm. Up to one-thirdof patients have a history of chronic mesentericischemia (see below). Therapy usually involvesintra-arterial papaverine and surgical thrombec-tomy or surgical bypass grafting, bowel resection,or some combination of these.

NONOCCLUSIVE MESENTERICISCHEMIANonocclusive mesenteric ischemia accounts for20% of cases of acute primary mesenteric ischemiaof the small bowel. Risks for low-flow state includedecreased cardiac output (myocardial infarction

or dyskinesia, arrhythmia, shock, sepsis, pancre-atitis, burns, multiple organ failure, congestiveheart failure, or hemorrhage), vasospasm (digoxin,α-adrenergic agonists, or cocaine), and preexistingatherosclerotic disease (hypertension, diabetesmellitus, hyperlipidemia, or vasculopathy).Angiography can be diagnostic (lack of thrombusor embolus, alternating spasm and dilatation[“string-of-sausages” sign], pruning, and spasmof mesenteric arcades) (Fig. 2). Treatment involvesoptimization of cardiac output, avoidance ofvasospastic medications, and prolonged (up toseveral days) selective intra-arterial infusion ofvasodilators such as papaverine, tolazoline, nitro-glycerin, or glucagon. Laparotomy with or withoutresection and warm saline lavage may be neededin selected cases. Anticoagulation generally is notprescribed. Broad-spectrum antibiotics shouldbe administered.

MESENTERIC VENOUS THROMBOSISMesenteric venous thrombosis, usually superiormesenteric vein thrombosis (up to 95% of cases),accounts for about 5% to 10% of cases of acute


Fig. 2. Patient with nonocclusive mesenteric ischemia before, A, and after, B, treatment with papaverine. A,Angiogram showing spasm of main superior mesenteric artery, origins of its branches, and the intestinalarcades. B, Angiogram after 36 hours of papaverine infusion showing that the arteriospasm has resolved. Theabdominal symptoms and signs also had resolved. (From Boley SJ, Brandt LJ, Veith FJ. Ischemic disorders of theintestines. Curr Probl Surg. 1978;15[4]:1-85. Used with permission.)

A B

mesenteric ischemia. Risk factors include a personalor family history of hypercoagulopathy and a his-tory of deep venous thrombosis. Causes includehypercoagulable states, hyperviscosity syndromes,intra-abdominal infections (pyelophlebitis) orinflammation, malignant obstruction, portal hyper-tension, and trauma (Table 3). Symptoms may beacute (hours) or subacute-chronic (days to months)and include abdominal pain (severe, out of pro-portion to physical findings, or less severe andvague), anorexia, nausea, vomiting, diarrhea,constipation, abdominal distention, and gas-trointestinal tract bleeding. Patients may presentwith bacteremia (especially Bacteroides). Becausethe differential diagnosis is broad and includesobstruction, perforation, and other causes of acute

abdominal pain and acute mesenteric ischemia,the initial evaluation usually involves plain abdom-inal radiography and contrast-enhanced CT; thelatter generally is diagnostic of mesenteric venousthrombosis with or without portal vein or splenicvein thrombosis (Fig. 3). Although angiographyis less reliable for the diagnosis of mesentericvenous thrombosis, it allows intra-arterial infusionof vasodilators. Therapy involves laparotomy withor without bowel resection when infarction is sus-pected, fluid resuscitation, broad-spectrum antibi-otics, avoidance of vasoconstrictors, a nasogastrictube if there is distention, and anticoagulation (inthe absence of bleeding). Selected patients withacute onset of mesenteric venous thrombosis maybe candidates for thrombolytic therapy, followedby anticoagulation. Underlying conditions suchas hypercoagulable states, hyperviscosity syn-dromes, intra-abdominal infections, and malignancyrequire concomitant diagnosis and treatment.

Mesenteric venous thrombosis may have thepresentation of a subacute or chronic illness, withvague abdominal pain and distention or no symp-toms. It may be an incidental CT finding in patientswith portal hypertension, chronic pancreatitis, ormalignancy. Long-term anticoagulation should beconsidered except for higher-risk patients such as theelderly or those with portal hypertension and promi-nent varices or portal hypertensive gastropathy.


Table 3. Risk Factors for Mesenteric VenousThrombosis

Hypercoagulable and hyperviscosity statesProtein S deficiencyPrimary myeloproliferative disorderG20210A factor II gene mutationC677T MTHFR gene mutationAntiphospholipid syndromeG1691 factor V gene mutationAntithrombin deficiencyProtein C deficiencyHyperfibrinogenemiaThrombocytosisSickle cell diseaseEstrogen or progesterone

Intra-abdominal infections and inflammationAppendicitisDiverticulitisAbscessCrohn’s diseasePancreatitisCholecystitisNeonatal omphalitis

Portal hypertensionCirrhosisSclerotherapy of varices

Malignant obstructionTraumaVasculitis

Fig. 3. Abdominal computed tomogram of apatient with acute mesenteric venous thrombosis.Arrow, thrombus in the superior mesenteric vein.(From Rhee RY, Gloviczki P. Mesenteric venousthrombosis. Surg Clin North Am. 1997;77:327-38.Used with permission.)

CHRONIC MESENTERIC ISCHEMIAPatients with classic chronic mesenteric ischemiapresent with episodic ischemic abdominal painthat typically is postprandial, lasts 1 to 3 hours,and becomes worse with time. Thus, patients loseweight because of fear of eating (sitophobia).Arteriography of these patients usually shows ath-erosclerotic stenosis of the origin of at least two ofthe three major visceral arteries. However, this isa common angiographic finding in otherwisehealthy age-matched controls. Rarely, the presen-tation of vasculitis or aortic aneurysm can bechronic mesenteric ischemia. A history of previousvascular disease, hypertension, diabetes mellitus,renal insufficiency, and smoking is common.Nausea, vomiting, diarrhea, constipation, andbloating may occur in addition to abdominal painand weight loss. Some patients may have malab-sorption, otherwise unexplained gastroduodenalulcerations, and small-bowel biopsy findings ofnonspecific surface cell flattening, chronic inflam-mation, and villous atrophy. More than one-half ofpatients have a bruit on abdominal examination.

Doppler ultrasonography—if able to visualizethe celiac and superior mesenteric arteries (eachabout 80% of cases)—may show increased flowvelocities, consistent with marked stenosis. CTangiography and magnetic resonance imaging alsomay be useful in the identification of proximal large-vessel arterial lesions. However, considering thediagnosis, excluding other causes of abdominal painand other symptoms (ie, pancreatic cancer, gastriccancer, gastroparesis, small-bowel bacterial over-growth syndromes, partial small-bowel obstruction,biliary disease, gastric volvulus, or paraesophagealhernias), and obtaining arteriographic results con-sistent with the clinical findings are crucial. Surgicalreconstruction and, in selected cases, angioplastywith or without stents can be therapeutic.

ISCHEMIC COLITISIschemic colitis represents nearly one-half of allcases of mesenteric ischemia. Atherosclerotic orthrombotic occlusion of the inferior mesentericartery or its branches and nonocclusive low-flowstates are not uncommon causes of ischemic colitis(with associated vasospasm). Less common causesinclude embolus, vasculitis, hypercoagulable states,

iatrogenic ligation of the inferior mesenteric artery(aortic surgery), and colonic obstruction (coloncancer, diverticulitis, or strictures). Other unusualassociations include long-distance running, intra-abdominal infections or inflammatory disease, anduse of birth control pills, danazol, alosetron, digitalis,vasopressin, gold, pseudoephedrine, psychotropicdrugs, ergot, amphetamines, cocaine, orsumatriptan.Often, there is no recognizable cause. Some gas-trointestinal infections, such as cytomegalovirus,Escherichia coliO157:H7, and Clostridium difficile infec-tions, and chronic inflammatory bowel disease canmimic ischemic colitis clinically and histologically.Ischemic colitis due to low-flow states often affectswatershed areas such as the splenic flexure,descending colon, and rectosigmoid junction andthe right colon. Often, but not always, the rectum isspared in ischemic colitis.

The clinical symptoms of ischemic colitis varybut often include acute abdominal pain (in two-thirds of patients, usually the left lower quadrant),urgency, diarrhea, distention, anorexia, nausea,vomiting, or bright red blood or maroon materialper rectum (variable amounts), or some combina-tion of these. Physical findings often include one ormore of the following: abdominal tenderness overthe affected bowel, distention, fever, and tachy-cardia. Laboratory findings range from normal inpatients with less severe ischemic colitis to thosefound in persons with severe ischemic necrosis(see above). Plain radiographs of the abdomenmay show evidence of submucosal edema andhemorrhage (“thumbprinting”) or the findingsmay be nonspecific. Colonoscopy often providesendoscopic and histologic findings consistent withischemic colitis (segmental, patchy ulceration,edema, erythema, and submucosal hemorrhagicor purple nodules) and helps exclude other causesof abdominal pain and gastrointestinal tractbleeding. CT may help exclude other disorders,especially in more symptomatic, sicker patients.Gastrointestinal infections (acute bacterial col-itis, C. difficile infection, and parasitic infections),inflammatory bowel disease, diverticulitis, pan-creatitis, and other causes of acute abdominalpain (pelvic disorders in women) need to beexcluded. Typically, angiography is not required,but it may be for patients with more severeischemic colitis and it should be for patients with


right-sided involvement (which may include thesmall bowel).

As for all types of mesenteric ischemia, treat-ment depends on the cause and includes supportivetreatment (volume replacement, correction of low-flow states, broad-spectrum antibiotics, transfusions,and avoidance of vasoconstrictive medications) and,in selected cases, surgery (signs and symptoms oftransmural necrosis, perforation, massive bleeding,recurrent sepsis, failure to improve over time, orstricture formation). In most patients, ischemic col-itis resolves promptly with supportive therapy alone.Patients younger than 60 years should be evaluatedfor thrombophilic states. Recent studies also lendsupport to the usefulness of thrombophilic screeningin older patients with idiopathic ischemic colitis.

MISCELLANEOUS SYNDROMES

Celiac Artery CompressionCeliac artery compression, also called median arcuateligament syndrome, is a rare syndrome with abdom-inal pain, which is caused most likely by extrinsiccompression of the celiac axis (neural structures andthe wall of the celiac artery) by the arcuate ligament.Rarely, the superior mesenteric artery also may beinvolved. Ischemia to the gut is unlikely to causethe pain (because only one vessel is involved andcollateral vessels are well developed). Celiac arterycompression usually occurs in young women, oftenwith upper abdominal pain, especially after eating(increased blood flow through the celiac artery),often with weight loss, and with a loud systolic bruitdetected in the epigastric area on physical exami-nation. Lateral aortography should demonstrate atypical concave defect over the superior aspect ofthe celiac artery near its take-off from the aorta, withrespiratory variability. Collaterals may be seen.Surgical release of the compression of the celiacartery or reconstruction of the artery (or both) maybe curative. Preoperatively, other possible causesof the symptoms must be excluded.

VasculitisMany vasculitic syndromes can involve the gas-trointestinal tract. Buerger’s disease can causemultiple distal occlusions of medium- and small-sized arteries of the mesenteric circulation.

Polyarteritis nodosa typically involves medium-and small-sized vessels, resulting in segmentalmicroaneurysms. Many patients have fever, anincreased erythrocyte sedimentation rate, hyper-tension, and multiple organ involvement. Nearlyhalf are infected with hepatitis B virus. Also, thegallbladder and spleen may be involved. The gas-trointestinal tract often is involved in Churg-Strauss syndrome and Henoch-Schönlein purpura(sometimes with E. coli O157:H7 or Campylobacterjejuni infection). With Henoch-Schönlein purpura,IgA is deposited in multiple organs, including thewalls of blood vessels. Patients with severerheumatoid arthritis, high titers of rheumatoidfactor, nodules, cryoglobulinemia, low serumlevels of complement, and extra-articular mani-festations also may have vascular lesions involvingthe gut, pancreas, gallbladder, spleen, andappendix, as may patients with systemic lupuserythematosus (especially those with antiphos-pholipid or cardiolipin antibodies). Vasculitis withbowel involvement is less common in patients withBehçet’s syndrome or Wegener’s granulomatosis.Mesenteric venous involvement can occur withChurg-Strauss syndrome, systemic lupus erythe-matosus, Behçet’s syndrome, lymphocytic phlebitis,and idiopathic mesenteric phlebosclerosis.

Bowel as well as large-vessel rupture can be alife-threatening complication of Ehlers-Danlossyndrome type IV, with thin fragile skin, easybruisability, hyperextensible distal interphalangealjoints, and splanchnic artery aneurysms due to adefect in type III collagen. Similar vascular cata-strophes with gastrointestinal tract bleeding canoccur in patients with pseudoxanthoma elasticumtype I, which often is accompanied by peaud’orange skin and choroiditis. Occasionally, mesen-teric vasculitis is found in patients with carcinoidsyndrome. Splanchnic artery aneurysms includesplenic artery aneurysms (due to atherosclerosis,fibrodysplasia of the media, portal hypertension,pregnancy, pancreatitis, vasculitis, infection, ortrauma), hepatic artery aneurysms (often due totrauma, including liver biopsy), mesentericaneurysms (often due to atherosclerosis), andaneurysms of the arterial supply to the pancreas(often due to pancreatitis and pseudocysts)—allof which may present with gastrointestinal tractor intraperitoneal hemorrhage.


RECOMMENDED READINGAmerican Gastroenterological Association Medical

Position Statement. Guidelines on intestinalischemia. Gastroenterology. 2000;118:951-3.

Amitrano L, Brancaccio V, Guardascione MA,Margaglione M, Iannaccone L, Dandrea G, etal. High prevalence of thrombophilic genotypesin patients with acute mesenteric vein throm-bosis. Am J Gastroenterol. 2001;96:146-9.

Bech FR. Celiac artery compression syndromes.Surg Clin North Am. 1997;77:409-24.

Brandt LJ, Boley SJ. AGA technical review onintestinal ischemia. Gastroenterology.2000;118:954-68.

Cappell MS. Intestinal (mesenteric) vasculopathy.I. Acute superior mesenteric arteriopathy andvenopathy. Gastroenterol Clin North Am.1998;27:783-825.

Cappell MS. Intestinal (mesenteric) vasculopathy.II. Ischemic colitis and chronic mesentericischemia. Gastroenterol Clin North Am.1998;27:827-60.

Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW,Creager MA, Halperin JL, et al, AmericanAssociation for Vascular Surgery; Society forVascular Surgery; Society for CardiovascularAngiography and Interventions; Society forVascular Medicine and Biology; Society ofInterventional Radiology; ACC/AHA TaskForce on Practice Guidelines Writing Committeeto Develop Guidelines for the Management ofPatients With Peripheral Arterial Disease;American Association of Cardiovascular andPulmonary Rehabilitation; National Heart,Lung, and Blood Institute; Society for VascularNursing; TransAtlantic Inter-Society Consensus;Vascular Disease Foundation. ACC/AHA 2005Practice Guidelines for the management ofpatients with peripheral arterial disease (lowerextremity, renal, mesenteric, and abdominalaortic): a collaborative report from the AmericanAssociation for Vascular Surgery/Society forVascular Surgery, Society for CardiovascularAngiography and Interventions, Society forVascular Medicine and Biology, Society of

Interventional Radiology, and the ACC/AHATask Force on Practice Guidelines (WritingCommittee to Develop Guidelines for theManagement of Patients With PeripheralArterial Disease): endorsed by the AmericanAssociation of Cardiovascular and PulmonaryRehabilitation; National Heart, Lung, andBlood Institute; Society for Vascular Nursing;TransAtlantic Inter-Society Consensus; andVascular Disease Foundation. Circulation.2006;113:e463-654.

Koutroubakis IE, Sfiridaki A, Theodoropoulou A,Kouroumalis EA. Role of acquired and hered-itary thrombotic risk factors in colon ischemiaof ambulatory patients. Gastroenterology.2001;121:561-5.

Krupski WC, Selzman CH, Whitehill TA. Unusualcauses of mesenteric ischemia. Surg Clin NorthAm. 1997;77:471-502.

Kumar S, Sarr MG, Kamath PS. Mesenteric venousthrombosis. N Engl J Med. 2001;345:1683-8.

Midian-Singh R, Polen A, Durishin C, Crock RD,Whittier FC, Fahmy N. Ischemic colitis revis-ited: a prospective study identifying hyper-coagulability as a risk factor. South Med J.2004;97:120-3.

Noyer CM, Brandt LJ. Colon ischemia: unusualaspects. Clin Perspect Gastroenterol. 2000;36:315-26.

Rosenblum JD, Boyle CM, Schwartz LB. Themesenteric circulation: anatomy and physi-ology. Surg Clin North Am. 1997;77:289-306.

Segatto E, Mortele KJ, Ji H, Wiesner W, Ros PR. Acutesmall bowel ischemia: CT imaging findings.Semin Ultrasound CT MR. 2003;24:364-76.

Silva JA, White CJ, Collins TJ, Jenkins JS, AndryME, Reilly JP, et al. Endovascular therapy forchronic mesenteric ischemia. J Am CollCardiol. 2006;47:944-50.

Sreenarasimhaiah J. Diagnosis and management ofischemic colitis. Curr Gastroenterol Rep.2005;7:421-6.

Yasuhara H. Acute mesenteric ischemia: the chal-lenge of gastroenterology. Surg Today.2005;35:185-95.


Many systemic disorders can have gastrointestinalmanifestations. This chapter is an overview of thesediseases as they affect the gastrointestinal tractand liver, with emphasis on disorders not con-sidered elsewhere in this book.

SYMPTOMS AND SIGNS

Eating Disorders and WeightObesity can have adverse effects on the gastroin-testinal tract, including an increased risk of symp-tomatic gastroesophageal reflux disease; increasedrisk of esophageal, stomach, pancreas, liver, gall-bladder, and colorectal adenocarcinoma; increasedgallstone formation in women; fatty liver and non-alcoholic steatohepatitis; and complications inobese patients with pancreatitis (gallstones andhypertriglyceridemia). Hypothyroidism, Cushing’ssyndrome, hypothalamic disorders, Stein-Leventhalsyndrome, and drugs (especially antipsychoticagents, tricyclic antidepressants, monoamine oxi-dase inhibitors, lithium, and glucocorticoids)should be considered in the differential diagnosisof obesity. Crash diets with rapid weight loss canresult in gallstones (increased cholesterol saturation

of bile and decreased gallbladder motility),nausea, vomiting, diarrhea, or severe constipa-tion. Patients with eating disorders (eg, bulimiaor anorexia nervosa) may present with a widevariety of gastrointestinal problems: nausea,vomiting, gas, abdominal pain, diarrhea, dys-phagia, gastroesophageal reflux disease, rumi-nation, Mallory-Weiss tear, gastric dilatation,gastroparesis, constipation, superior mesentericartery syndrome, cholelithiasis, pancreatitis,increased values on liver function tests, andabnormal gastrointestinal motility.

Nausea and VomitingThe differential diagnosis is protean and includesdrugs (especially narcotics, dopamine agonists,digitalis, chemotherapy, and nonsteroidal antiin-flammatory drugs), toxins (alcohol, hypervita-minosis A, and poisoning), infections, vestibulardiseases, central nervous system diseases, preg-nancy (see below), metabolic disorders (eg, Reye’ssyndrome, Jamaican vomiting illness, uremia,parathyroid disease, diabetic ketoacidosis, hyper-thyroidism, sepsis, and Addison’s disease),myocardial infarction (congestive heart failure),and radiation.

175

CHAPTER 13

Gastrointestinal Manifestationsof Systemic Disease


Abbreviation: ALA, aminolevulinic acid.

DiarrheaOn occasion, diarrhea can be caused by systemicdisorders such as hyperthyroidism, Addison’sdisease, hypoparathyroidism, collagen vasculardiseases, vasculitis, malignancies (eg, carcinoid,gastrinoma, pheochromocytoma, VIPoma, medul-lary carcinoma of the thyroid, glucagonoma, mas-tocytosis, and other neuroendocrine tumors),immunologic disorders (see below), amyloidosis(see below), autonomic nervous system disease,diabetes mellitus (see below), and, more commonly,drugs and toxins, including alcohol and radiation.

ConstipationThe differential diagnosis should include drugsand toxins, metabolic disorders (hypothyroidism,hypercalcemia, hypokalemia, hypopituitarism,diabetes mellitus, pheochromocytoma, and gluca-gonoma), neurologic disorders (central, periph-eral, or autonomic), myopathies, collagen vasculardisease, amyloidosis, porphyria, and pregnancy.

Abdominal PainExtra-abdominal causes of acute or intermittentabdominal pain include thoracic disorders (eg,myocardial infarction, pulmonary embolus,pneumonia, and pericarditis), metabolic disor-ders (diabetic ketoacidosis, diabetic radiculopathy,pheochromocytoma, Addison’s disease, uremia,hyperlipidemia, porphyria, angioedema [seebelow], and hyperparathyroidism), hematologicdisorders (sickle cell crisis, hemolysis, and acuteleukemia), neurologic diseases (herpes zoster, tabesdorsalis, abdominal epilepsy, and abdominalmigraine), drugs, toxins, narcotic withdrawal,aneurysm, and heat stroke.

Jaundice and Abnormal Results of LiverFunction TestsUnconjugated hyperbilirubinemia in the newborncan be caused by hypothyroidism. In adults, con-gestive heart failure is one of the most commoncauses of mild abnormal results of liver functiontests, including mild unconjugated hyperbiliru-binemia, mild increases in alanine aminotransferaseand aspartate aminotransferase levels, and, lessoften, a mild increase in the alkaline phosphataselevel. Many connective tissue diseases (see below)can be associated with abnormal liver function test

results. Hodgkin’s disease without involvement ofthe liver or biliary tree, like many infections andsepsis, can be associated with increased alkalinephosphatase levels and even jaundice.

SYSTEMIC DISORDERS

DermatologicMany dermatologic disorders can be associated withgastrointestinal vascular bleeding lesions. Hereditaryhemorrhagic telangiectasia is an autosomal domi-nant disorder. Telangiectasias can involve any partof the bowel and the lips, tongue, mouth, extremities,chest, nose, liver, central nervous system, retina, andlung. Endoscopically, these mucosal telangiectasiasare indistinguishable from angiodysplastic lesions.Lesions may involve all histologic layers (mucosato serosa) of the bowel wall. Blue rubber bleb nevussyndrome, sometimes autosomal dominant, consistsof intestinal and cutaneous cavernous hemangiomaswith a bluish, rubbery consistency. Other internalorgans also may be involved. Intestinal lesions canresult in intussusception. Similar hemangiomas mayoccur in the sporadic disorder Klippel-Trénaunay-Weber syndrome, involving the gut and skin andhemihypertrophy of a limb and varicose veins.Malignant atrophic papulosis (Degos’ disease)consists of painless skin papules with cigarette-paperlike white centers and a telangiectaticperiphery and gastrointestinal and central ner-vous system involvement. All these disorders cancause bleeding and require therapeutic endoscopicor surgical intervention.

Several bullous skin disorders can manifestwith involvement of the gastrointestinal tract,including epidermolysis bullosa (trauma-inducedblisters, oral cavity, esophagus, and anal area, withbullae, webs, strictures, dysphagia, bleeding, andconstipation), pemphigus vulgaris (oral involve-ment, esophagus less common, occasionally thelower gastrointestinal tract with bleeding), andbullous pemphigoid (oral, less often esophageal oranal involvement). Dilatation (trauma) of stric-tures in epidermolysis bullosa may lead to morestricturing, and soft diets and corticosteroids maybe helpful. Topical or systemic corticosteroids maybe useful in treating bullous pemphigoid andpemphigus vulgaris.


Lichen planus can affect the mouth and esoph-agus (ulcers, strictures, pain, dysphagia; also, anassociation with hepatitis C virus infection andprimary biliary cirrhosis), psoriasis can affect theskin and esophagus (webs and dysphagia), andtylosis (autosomal dominant) can affect the skin(palmoplantar keratoderma) and esophagus (squa-mous cell carcinoma; family screening and sur-veillance endoscopy are indicated).

ImmunologicA host of immunologic disorders have gastroin-testinal manifestations. X-linked (Burton’s) hypogam-maglobulinemia, a maturational hereditary defectin B cells, results in gastrointestinal infections(Campylobacter, Giardia, and rotavirus), smallintestinal bacterial overgrowth, and perirectalabscesses. Typically, plasma cells are not seen inrectal biopsy specimens. Selective IgA deficiencyoccurs in about 1 in 500 persons; it is usually spo-radic but is sometimes familial. It is associated witha lack of secretory immunoglobulin A1 and A2.Most persons are well, and gastrointestinal infec-tions (Giardia) are not common. The prevalence ofimmunoglobulin A deficiency (1:50) is increasedamong persons with celiac disease. Other gas-trointestinal associations include perniciousanemia, bacterial overgrowth with vitamin B12deficiency, Crohn’s disease, and nodular lymphoidhyperplasia. Common variable (late-onset or acquired)hypogammaglobulinemia, often sporadic, alsoinvolves abnormal maturation of B cells, gastroin-testinal tract infections (Giardia and other parasites,small intestinal bacterial overgrowth, rotavirus,and bacterial diarrhea), malabsorption, pancreaticinsufficiency, spruelike disorders, perniciousanemia, gastric cancer, nodular lymphoid hyper-plasia, cholelithiasis, autoimmune chronic hepatitis,sclerosing cholangitis, and biliary parasitosis (cryp-tosporidiosis). Also, carcinoma or lymphoma of thesmall and large bowel may occur.

Chronic mucocutaneous candidiasis is a hetero-geneous group of disorders with defective T-cellfunction, oropharyngeal or esophageal candidiasis,skin and nail lesions, and various autoimmune(pernicious anemia) and endocrine (hypoadrenal,hypothyroid, hypoparathyroid, and diabetesmellitus) deficiencies. Hereditary angioedema is anautosomal dominant (chromosome 11q11-13) dis-

order with a quantitative or qualitative deficiencyof C1 esterase inhibitor, resulting in attacks of non-pitting, painless, nonpruritic angioedema that caninvolve the skin, mouth, larynx, or gastrointestinaltract. Gastrointestinal tract involvement includesattacks of pain, sometimes with diarrhea, vomiting,intussusception, or transient ascites. Imaging mayshow edematous bowel. Similar presentations maybe due to acquired C1 esterase inhibitor deficiency(collagen vascular diseases and lymphoprolifera-tive disorders). Diagnostic testing includes C1esterase inhibitor levels (low in 85% of patients), C1esterase function (low in the 15% with normal orincreased inhibitor levels), and C4 levels (absentduring attacks and decreased between attacks). C1levels are normal. Danazol can prevent attacks, andC1 esterase inhibitor concentrate or fresh frozenplasma can be used during attacks. Angiotensin-converting enzyme inhibitors also can causeangioedema of the intestine, independently of dimin-ished complement or C1 esterase inhibitor levels.Angiotensin II receptor antagonists also have beenimplicated. An estrogen-dependent inherited formof angioedema, also independently of diminishedcomplement or C1 esterase inhibitor levels, has beenreported during pregnancy or with the administra-tion of exogenous estrogens.

CardiovascularCongestive heart failure can present with liverinvolvement (hepatomegaly, right upper quadrantpain, mild abnormal results on liver function tests,and ascites with an increased serum-to-ascitesalbumin gradient) and gastrointestinal involvement(anorexia, nausea, bloating, abdominal pain, diar-rhea, malabsorption, protein-losing enteropathy,and low-flow mesenteric ischemia). It is now thoughtthat valvular aortic stenosis might be associated withgastrointestinal angiodysplasia, perhaps on the basisof abnormal von Willebrand multimers. Cardiactransplantation may be complicated by an increasedrisk of bowel perforation, ulcers, cytomegalovirusinfection, pancreatitis, and gallstone-related disease.

Pulmonaryα1-Antitrypsin deficiency can be thought of as eithera pulmonary disease with liver manifestations ora liver disorder with pulmonary consequences.Liver disease, including cirrhosis and hepatocellular

Gastrointestinal Manifestations of Systemic Disease 177

carcinoma, is due to the inability of the liver toexport an abnormal gene product (usually the ZZprotease inhibitor type, with low serum α1-anti-trypsin levels) and does not occur in the null-nullphenotype (no gene product). Patients with chronicobstructive pulmonary disease are at increased riskfor peptic ulcer disease. Chronic obstructive pul-monary disease and asthma can facilitate gas-troesophageal reflux. Sarcoidosis is a systemicgranulomatous disorder that commonly involvesthe liver (often asymptomatic, with or withoutmild increases of alanine aminotransferase,bilirubin, or alkaline phosphatase levels; occa-sionally progressive hepatic fibrosis resulting incirrhosis; some patients have severe cholestasiswith ductopenia). Less often, sarcoidosis affectsthe gastrointestinal tract (esophageal involvementwith dysphagia, dysmotility, or stricture is rare,often due to hilar or mediastinal lymph nodeinvolvement; stomach involvement, with antralulceration, pyloric stenosis or gastric outlet obstruc-tion, occurs more often; small-bowel disease, withmalabsorption or protein-losing enteropathy israre; colonic involvement is very rare). Lung trans-plantation may be complicated by postoperativecolonic perforation and vagal injury, with esophagealand gastric dysmotility, ulcers, pancreatitis,cholelithiasis, and cytomegalovirus infection.

RenalChronic renal failure can be complicated by dys-geusia, anorexia, nausea, vomiting, esophagitis,gastritis, angiodysplasias of the gastrointestinaltract, peptic ulcer disease, duodenitis, duodenalpseudomelanosis (asymptomatic), abdominalpain, constipation, pseudo-obstruction, perforatedcolonic diverticula, small-bowel and coloniculceration, intussusception, gastrointestinalbleeding, amyloidosis, diarrhea, fecal impaction,and bacterial overgrowth. In patients undergoinghemodialysis, a refractory exudative ascites ofunclear pathogenesis can develop; this resolveswith renal transplantation. These patients also aremore at risk for ischemic colitis. Patients who havehad renal transplantation often develop infectionsand ulcerative complications of the gastrointestinaltract, diverticulitis, and perforated colonic diver-ticula. The adult form of polycystic kidney disease isassociated with hepatic cysts, congenital hepatic

fibrosis, and Caroli’s disease. (There are rarereports of hyperammonemia and hepaticencephalopathy in patients without previous liverdisease who have severe urease-producing Proteusor Escherichia coli bacterial infections.)

EndocrineEndocrine disorders commonly affect the gas-trointestinal tract and liver. Diabetes mellitus canbe complicated by disorders of the esophagus(dysmotility, gastroesophageal reflux disease,and candidiasis), stomach (dysmotility, gastro-paresis, bezoars, and pernicious anemia), smallbowel (dysmotility, bacterial overgrowth, andceliac disease association), colon (dysmotility,constipation, fecal incontinence, and diarrhea),biliary tree (cholelithiasis), pancreas (pancreaticinsufficiency), and liver (fatty liver and nonalco-holic steatohepatitis). Diabetic neuropathy andketoacidosis can present as abdominal pain, anddiabetes mellitus is a risk factor for several formsof primary mesenteric ischemia. Acromegaly is asso-ciated with an enlarged tongue, an increased riskof colonic adenomas (which may be large, mul-tiple, and right-sided), colon cancer, and, perhaps,stomach cancer. Gallstones are a risk in patientsreceiving octreotide therapy. Patients withAddison’s disease may present with anorexia,nausea, vomiting, weight loss, malabsorption,abdominal pain, and diarrhea. Also, the diseasemay be associated with atrophic gastritis and per-nicious anemia. Serum levels of aminotransferaselevels may be increased. Hypercortisolism may beassociated with gastric ulceration and increasedaminotransferase levels. Pheochromocytoma mayoccur with hypertension, abdominal pain, ischemiccolitis, and diarrhea or ileus. Hyperthyroidism maymanifest as hyperphagia, weight loss, mild diarrhea,steatorrhea, abdominal pain, vomiting, concomi-tant atrophic gastritis, dysphagia, ascites, jaundice,and nonspecific mild abnormalities in liver functiontest results. Autoimmune chronic hepatitis and pri-mary biliary cirrhosis also may be associated dis-orders. Hypothyroidism often results in anorexia,weight gain, constipation, dysphagia, heartburn,and, less often, intestinal pseudo-obstruction,achlorhydria, and ascites (high protein). Associatedgastrointestinal diseases include perniciousanemia, ulcerative colitis, primary biliary cirrhosis,


autoimmune chronic hepatitis, and celiac disease.Hyperparathyroidism, with hypercalcemia, classicallyproduces anorexia, nausea, vomiting, constipation,and abdominal pain; rarely, peptic ulcer disease andpancreatitis develop. Patients with hypoparathy-roidism can present with diarrhea, steatorrhea,abdominal pain, pseudo-obstruction, protein-losing enteropathy, and lymphangiectasia.

HematologicSickle cell anemia often results in severe abdominalpain with sickle cell crisis. The liver also may beaffected, with pain (congestion and infarction), fever,and increased values on liver function tests. As inother hemolytic states, cholelithiasis (black pigmentstones) is common. Hemolytic uremic syndrome andthrombotic thrombocytopenic purpura can be compli-cated by gastrointestinal tract bleeding, ulceration,perforation, toxic megacolon, cholecystitis, andpancreatitis, and often they are associated withgram-negative infections, such as those caused byE. coli O157:H7, Shigella, Salmonella, Yersinia, andCampylobacter. A host of hypercoagulable states, somecaused by hematologic malignancies, have beenimplicated in cases of Budd-Chiari syndrome, portalvenous thrombosis, and primary mesenteric(venous and arterial) ischemic states. Hypocoagulablestates, such as hemophilia, and platelet abnormalitiesoften result in gastrointestinal tract bleeding,obstruction, intramural hematomas, or intussus-ception. Bone marrow transplantation frequentlyis complicated by acute graft-versus-host disease,with gastrointestinal (nausea, vomiting, and diar-rhea; epithelial cell apoptosis seen in biopsy speci-mens), liver (abnormal liver function tests), and skinabnormalities. Sinusoidal obstruction syndrome(veno-occlusive disease) usually develops beforeday 20 after transplantation with hepatomegaly,jaundice, and weight gain. Chronic graft-versus-host disease may include severe cholestatic liverdisease and esophageal webs and strictures.

Four of the porphyrias can occur with acuteabdominal crises (abdominal pain, vomiting, con-stipation, and hyponatremia are common). Thesefour are acute intermittent porphyria, variegateporphyria, hereditary coproporphyria, and aminolev-ulinic acid (ALA) dehydratase deficiency. The firstthree are autosomal dominant. Acute intermittentporphyria is the most common acute porphyria. It

is associated with increased levels of ALA and por-phobilinogen; there are no skin findings. Variegateporphyria is characterized by increased levels ofurine coproporphyrin and stool protoporphyrinand coproporphyrin; patients can have skin disease,with or without an abdominal attack. In hereditarycoproporphyria, stool and urine coproporphyrinlevels are increased; skin disease can be present,usually with an abdominal attack. In the very rareALA dehydratase deficiency, only the ALA level isincreased; there are no skin findings, and the con-dition is autosomal recessive. Abdominal crisesmay be precipitated by fasting, medications,alcohol, intercurrent illnesses, and menstruation.Urine ALA and porphobilinogen levels (ALA onlywith ALA dehydratase) are always increasedduring an acute abdominal crisis. In acute inter-mittent porphyria, urinary ALA and porpho-bilinogen values usually are increased betweenattacks. Porphyria cutanea tarda affects only the skinand is associated with alcohol abuse or alcoholicliver disease, mild iron overload or hemochro-matosis, and hepatitis B or C virus infection.Erythropoietic protoporphyria, with skin manifesta-tions, can result in cirrhosis and liver failure due tohepatic deposition of protoporphyrin.

Mastocytosis is a systemic infiltrative disorderof bone marrow, skin, bone, spleen, the central ner-vous system, the gastrointestinal tract, and the liver.Periodic flushing (precipitated by alcohol, stress,heat, or medications), hypotension, urticaria pig-mentosa, Darier’s sign (urticaria after scratching),chest pain, dyspnea, abdominal pain, vomiting,diarrhea, and paresthesias may occur. Malabsorption,peptic ulcer disease (gastric acid hypersecretion),complicated gastroesophageal reflux disease,hepatomegaly, splenomegaly, increased serumalkaline phosphatase value, and, rarely, portalhypertension and hepatic fibrosis may occur.

OncologicLeukemias and lymphomas commonly involve thegastrointestinal tract and liver. Hodgkin’s diseasecan involve the liver, extrahepatic bile ducts, orlymph nodes, or it can manifest as intrahepaticcholestasis without hepatobiliary involvement.Unusual tumors affecting the gut include α chaindisease (immunoproliferative small intestine dis-ease), which diffusely infiltrates the small bowel


and adjacent lymph nodes (B cells, α heavy chainsproduced in excess); mantle cell lymphomas, whichmimic a multiple polyposis syndrome; multiplemyeloma or amyloidosis, with focal plasmacytomas(mass, ulceration, bleeding, or obstruction), gas-trointestinal mucosal infiltration with malabsorp-tion, or hyperviscosity syndrome (ischemia);Waldenström’s macroglobulinemia, with gastroin-testinal and hepatosplenic infiltration and malab-sorption; and small cell carcinoma of the lung and othermalignancies, with paraneoplastic pseudo-obstruc-tion (patients may be positive for anti-neuronalnuclear antibody, type I Purkinje cell antibody,or N-type calcium channel-binding antibody).

Bone marrow transplantation often is complicatedby graft-versus-host disease. Acute graft-versus-hostdisease with rashes, small and large intestinalmucosal involvement (diarrhea, protein-losingenteropathy, malabsorption, pain, bleeding, andapoptotic bodies seen in biopsy specimens, even inendoscopically normal-appearing areas), andcholestatic liver disease usually occurs in the first100 days after transplantation. Chronic graft-versus-host disease with cholestatic liver disease (vanishingbile ducts), esophageal disease (dysphagia, stric-tures, and webs), skin disease, and polyserositisusually occurs after 100 days. Veno-occlusive diseaseof the liver, with bland, nonthrombotic obliterationof small hepatic veins and venules due to condi-tioning (radiation or chemotherapy) therapy,usually occurs 8 to 23 days after transplantation.

NeuromuscularMany neurologic and muscular disorders affectthe gastrointestinal tract. Acute head injury withintracranial hypertension, like many other seriousillnesses, can result in stress gastritis. However,deep ulceration, sometimes with perforation, canoccur in this setting, apparently as a result of vagalstimulation of gastrin and gastric acid production.Similar ulceration can occur after body burns cov-ering a large surface area. Abdominal pain, nausea,and vomiting rarely are attributed to migraine ortemporal lobe epilepsy, the latter often includingcentral nervous system symptoms. Cyclic vom-iting may present with recurrent attacks of abdom-inal pain, nausea, and vomiting. Cerebrovasculardisease and cerebral palsy commonly result inoropharyngeal dysphagia due to dysmotility.

Multiple sclerosis frequently affects the gastroin-testinal tract with oropharyngeal dysphagia, gas-troparesis, constipation, or disorders of defecationor fecal incontinence. Patients with Parkinson’s dis-ease often have oropharyngeal dysphagia, gastro-esophageal reflux disease, esophageal dysphagia,constipation, and fecal incontinence. Amyotrophiclateral sclerosis and myasthenia gravis both can causeoropharyngeal dysphagia. More diffuse gastroin-testinal tract dysmotility syndromes occur withpoliomyelitis, Huntington’s chorea, dysautonomiasyndromes, Shy-Drager syndrome, Chagas’ disease,and spinal cord injuries. Patients with dementia maybe at risk for aspiration because of oropharyngealdysphagia, and they may have weight loss becauseof decreased intake, poor diet, and pica.

Muscular dystrophies such as oculopharyngealmuscular dystrophy (third nerve palsy, often French-Canadian ancestry) and Duchenne’s muscular dystrophycan be complicated by oropharyngeal dysphagia.Duchenne’s muscular dystrophy is associated withmore widespread gastrointestinal tract dysmotility.

RheumatologicInvolvement of the gastrointestinal tract in sclero-derma, a common effect, is due to smooth muscleatrophy, fibrosis, small vessel vasculitis, and neuraldamage. Typically, the esophagus is affected(decreased motility, weak lower esophagealsphincter, gastroesophageal reflux disease, Barrett’sesophagus, adenocarcinoma, and pill esophagitis).However, the stomach (gastroparesis), small bowel(bacterial overgrowth and pseudo-obstruction),and colon and rectum (decreased motility, mega-colon, fecal incontinence and impaction, rectal pro-lapse, and anorectal sphincter dysfunction) alsomay be affected. Pancreatic exocrine secretion maydecrease. Telangiectasias and diverticula may befound throughout the gastrointestinal tract,including gastric antral vascular ectasia, which isassociated with connective tissue disease in general.Mild increases in aminotransferase levels, autoim-mune liver disease, and primary biliary cirrhosismay be associated with scleroderma, as in otherconnective tissue diseases.

Gastrointestinal tract manifestations mayoccur in other connective tissue disorders such asrheumatoid arthritis (esophageal dysmotility; vas-culitis with ischemic cholecystitis, appendicitis,


and colitis; and amyloidosis), systemic lupus ery-thematosus (esophageal dysmotility, gastrointestinalvasculitis, serositis, and pancreatitis), polymyositis(oropharyngeal dysmotility, gut smooth muscledysfunction, and vasculitis), dermatomyositis(malignancies, including stomach, pancreas, ovary,lung, and colorectal), and Sjögren’s syndrome(esophageal webs and pancreatic insufficiency).Rheumatoid arthritis may be part of Felty’s syn-drome (splenomegaly and neutropenia) withnodular regenerative hyperplasia and portal hyper-tension (variceal hemorrhage). Nodular regenerativehyperplasia itself also occurs with scleroderma,polymyalgia rheumatica, vasculitis, and lympho-proliferative or myeloproliferative syndromes.Rheumatoid arthritis also is associated with liverdisease, including mild liver function test abnor-malities, autoimmune chronic hepatitis, primarybiliary cirrhosis, and amyloidosis (see below).Sjögren’s syndrome is associated with autoimmunechronic hepatitis and primary biliary cirrhosis.

Patients with seronegative spondyloarthropathiesmay have ileocolonic inflammation similar to that ofCrohn’s disease. Systemic vasculitides, including Behçet’ssyndrome (oral and genital ulcers, gastrointestinalinvolvement similar to that of Crohn’s disease, andBudd-Chiari syndrome), polyarteritis nodosa (gall-bladder, pancreas, appendix, and ischemia involvingthe gastrointestinal tract; 50% of patients have hepatitisB virus infection), Wegener’s granulomatosis (gas-trointestinal tract), and Churg-Strauss syndrome(gallbladder and gastrointestinal tract), can havediverse gastrointestinal and hepatic manifestations.

Pregnancy and Gynecologic ConditionsPregnancy has many effects on the gastrointestinaltract. Nausea and vomiting are extremely commonduring the first trimester of pregnancy. When theseeffects become protracted and severe (hyperemesisgravidarum), dehydration, weight loss, malnutrition,and liver function test abnormalities may occur (seeChapter 33, Liver Disease and Pregnancy). Riskfactors include young age, obesity, multiparity,multiple births, first and molar pregnancies, andprevious hyperemesis gravidarum. Hyperthyroidismmust be excluded. Treatment is supportive, andsymptoms usually resolve by week 20 of pregnancy.

Gastroesophageal reflux disease also is commonduring pregnancy because of the combined

relaxing effects of estrogens and progestins on thesmooth muscle of the body of the esophagus andthe lower esophageal sphincter. Once symptomsoccur during a pregnancy, they often persist untilterm and recur with subsequent pregnancies.Antacids (with avoidance of magnesium-containingantacids near term) and sucralfate appear safe,and, often, histamine2-receptor blockers are used.Proton pump inhibitors probably are best avoidedduring pregnancy. Endoscopy rarely is indicatedduring pregnancy; if used, it is usually for sub-stantial bleeding, intractable emesis, or persistent,severe upper abdominal pain. Lidocaine spray andmeperidine (50 mg) are preferred as medications,although many use midazolam or diazepam. Fetalmonitoring should be performed during endoscopicprocedures, certainly after week 23. Pregnancyappears to decrease the frequency, severity, andrisk of complications of peptic ulcer disease.

Constipation is another common gastroin-testinal tract manifestation in pregnancy. Alteredmotility (hormonal), altered diet, constipating med-ications (iron), compression of the sigmoid colonby an enlarged uterus, and decreased activity allcontribute. Treatment should include dietaryadvice, liquids, activity, fiber, and, if necessary,docusate- and magnesium-containing cathartics(except close to term). Castor oil (premature labor),mineral oil (maternal malabsorption of fat-solublevitamins and severe aspiration pneumonia), andanthraquinones (possible malformations) shouldbe avoided. Pregnancy is unlikely to cause diar-rhea. Fiber, pectin, kaolin, and loperamide can beused, but diphenoxylate with atropine (Lomotil)and any bismuth-containing compound (Pepto-Bismol) should not be used. Colonoscopy shouldbe avoided during pregnancy. Flexible sigmoid-oscopy is thought by many to be safe. Small-bowelobstruction during pregnancy (about 1:1,500) is duemost often to adhesions; volvulus is the second mostcommon cause, especially in the third trimester,when incarcerated hernias are less common.Appendicitis is not more common during pregnancy(about 1:1,500), but the diagnosis often is delayed,with increased maternal (up to 11%) and fetal (upto 37%) mortality, especially late in pregnancy,when the enlarged uterus pushes the appendixand cecum up into the right upper quadrant,resulting in atypical signs and symptoms.


Endometriosis, if severe, often affects the gut;most frequently, the sigmoid colon is involved. Itsometimes results in obstruction (adhesions), per-foration, bleeding, diarrhea, and, more often,abdominal pain or constipation. These gastroin-testinal tract symptoms may or may not be cyclical.Associated gynecologic symptoms, such as painwith intercourse, are common. Estrogen adminis-tration after menopause may be associated withsymptoms. Meigs’ syndrome presents with ascitesand, often, pleural effusion in association withbenign ovarian neoplasms.

MiscellaneousSystemic amyloidosis includes AL amyloidosis (pri-mary, myeloma, and plasma cell-related), AAamyloidosis (secondary, chronic infections, andinflammation), familial forms, dialysis-associatedamyloidosis, and senile amyloidosis. Systemic formscan infiltrate the gastrointestinal tract, resulting inmacroglossia (usually primary AL amyloidosis),esophageal dysphagia or dysmotility, gastro-esophageal reflux disease, gastroparesis, gastriculceration, tumors, bleeding, or obstruction, small-and large-bowel dysmotility or pseudo-obstruc-tion, diarrhea, malabsorption, bacterial overgrowth,bleeding, ischemia, ulceration, constipation, andfecal incontinence. Liver involvement also is fre-quent, with hepatomegaly, increased alkalinephosphatase level, and, rarely, severe intrahepaticcholestasis (usually primary AL amyloidosis) orliver failure. Pancreatic exocrine insufficiency alsohas been described. Rectal, stomach, and liver (rarereports of rupture) biopsy findings often are diag-nostic. Chemotherapy may be useful in treatingprimary AL amyloidosis, and colchicine may beuseful in AA amyloidosis due to familialMediterranean fever (fever, serositis, arthritis, vas-culitis, and chest or abdominal pain; family his-tory, recessive, chromosome band 16p13.3) andinflammatory bowel disease. Liver transplantationmay be helpful for certain familial forms (ATTRor type I familial amyloid neuropathy, autosomaldominant, mutant transthyretin protein) withsymptoms, but not after severe irreversible (espe-cially neurologic) damage has occurred.

Ehlers-Danlos syndrome type IV, usually auto-somal dominant, is associated often with bowelperforation, vascular aneurysms, arteriovenous

fistulas, and rupture. Paraneoplastic syndromes withdiffuse gastrointestinal tract motor dysfunctionoccur most often with small cell lung carcinoma,often with autonomic neuropathy, cerebellardegeneration, peripheral neuropathy, seizures, orsyndrome of inappropriate secretion of antidi-uretic hormone. Antineuronal nuclear antibodies,type 1, usually are detectable.

RECOMMENDED READINGAnderson KE, Bloomer JR, Bonkovsky HL,

Kushner JP, Pierach CA, Pimstone NR, et al.Recommendations for the diagnosis and treat-ment of the acute porphyrias. Ann Intern Med.2005;142:439-50.

Chial HJ, McAlpine DE, Camilleri M. Anorexianervosa: manifestations and management forthe gastroenterologist. Am J Gastroenterol.2002;97:255-69.

Falk RH, Comenzo RL, Skinner M. The systemicamyloidoses. N Engl J Med. 1997;337:898-909.

Golkar L, Bernhard JD. Mastocytosis. Lancet.1997;349:1379-85.

Hasler WL, Chey WD. Nausea and vomiting.Gastroenterology. 2003;125:1860-7.

Iqbal N, Salzman D, Lazenby AJ, Wilcox CM.Diagnosis of gastrointestinal graft-versus-hostdisease. Am J Gastroenterol. 2000;95:3034-8.

Kaplan LM. Gastrointestinal management of thebariatric surgery patient. Gastroenterol ClinNorth Am. 2005;34:105-25.

Nzeako UC, Frigas E, Tremaine WJ. Hereditaryangioedema: a broad review for clinicians.Arch Intern Med. 2001;161:2417-29.

Rose S, Young MA, Reynolds JC. Gastrointestinalmanifestations of scleroderma. GastroenterolClin North Am. 1998;27:563-94.

Solomon JA, Abrams L, Lichtenstein GR. GI man-ifestations of Ehlers-Danlos syndrome. Am JGastroenterol. 1996;91:2282-8.

Verne GN, Sninsky CA. Diabetes and the gas-trointestinal tract. Gastroenterol Clin NorthAm. 1998;27:861-74.

Wald A. Constipation, diarrhea, and symptomatichemorrhoids during pregnancy. GastroenterolClin North Am. 2003;32:309-22.

Yanovski SZ, Yanovski JA. Obesity. N Engl J Med.2002;346:591-602.


183

Miscellaneous Disorders


QUESTIONS

Abbreviations used:CT, computed tomographyEGD, esophagogastroduodenoscopyESR, erythrocyte sedimentation rateGERD, gastroesophageal reflux diseaseHIV, human immunodeficiency virusINR, international normalized ratioMCV, mean corpuscular volumeMRA, magnetic resonance angiographyPPI, proton pump inhibitorT3/T4, triiodothyronine/thyroxine

Multiple Choice (choose the best answer)1. A 52-year-old man presents with hematemesis

times 3. This occurred 24 hours after percuta-neous transluminal coronary angioplasty andstenting for unstable angina. Currently, he takesaspirin, clopidogrel (Plavix), atenolol(Tenormin), and eptifibatide (IIB/IIIA receptorinhibitor). Blood pressure is 90/60 mm Hg, andthe pulse rate is 120. The abdominal examinationis otherwise unremarkable. Hemoglobin is 8.3g/dL, platelet count 210,000/mm3 (210×109/L),INR 1.1, and partial thromboplastin time 32 sec-onds. Your next step would be:

a. Upper endoscopy after blood transfusionb. Fresh frozen plasma

c. Vitamin K intravenouslyd. Platelet transfusionse. Intravenous infusion of octreotide

2. A 60-year-old woman presents with melenatimes 4 over the past 12 hours. She takes 81mg of aspirin daily for cerebrovascular dis-ease. She has no history of gastrointestinaltract bleeding. She has no abdominal pain. Onphysical examination, supine blood pressureis 110/70 mm Hg, with a pulse rate of 105.Upon standing, blood pressure decreases to90/60 mm Hg, with a pulse rate of 130.Abdominal examination findings are unre-markable. Rectal examination shows mushyblack stool. Hemoglobin is 10.6 g/dL, MCV89 fL, blood urea nitrogen 32 mg/dL, and cre-atinine 0.8 mg/dL. After 2 L of normal saline,the blood pressure is 120/85 mm Hg, with apulse rate of 90. Upper endoscopy was per-formed. For which of the following findingswould endoscopic injection of epinephrineand thermal therapy be appropriate?

a. An adherent clot in the anterior duodenalbulb

b. A 1-cm ulcer in the gastric antrum, with aflat red spot

c. A 1-cm ulcer high in the lesser curvature ofthe stomach, with a 3-mm nonbleedingvisible vessel

d. A 1-cm ulcer in the gastric antrum, with aclean base

e. A 2-cm ulcer in the gastric antrum, with aflat black spot

3. Which patient(s) should receive prophylaxisfor stress ulcer?

a. Patient with sepsis and acute renal failureb. Patient with chronic renal failure and coro-

nary artery disease who is receivingaspirin therapy

c. Patient on day #3 of mechanical ventilationfor pneumonia

d. Patient on day #1 after cholecystectomye. Patient on day #2 after appendectomy who

is receiving low-dose heparin therapy

4. A 34-year-old man presents with bleeding of aduodenal ulcer. He has a clean ulcer base, anda biopsy study confirms Helicobacter pyloriinfection. He receives 4 weeks of treatmentwith a PPI and 10 days of treatment with clar-ithromycin, PPI, and amoxicillin, all twice daily.To prove eradication of the H. pylori infection,which of the following should be done?

a. Repeat upper endoscopy and obtain biopsyspecimens for histologic study 2 weeks afterstopping PPI therapy

b. Urease breath test 1 week after stoppingPPI therapy

c. H. pylori stool antigen at least 2 weeks afterstopping PPI therapy

d. H. pylori serologic testing 1 week after stop-ping PPI therapy

e. H. pylori serologic testing 2 weeks after stop-ping PPI therapy

5. A 54-year-old man with no previous historyof anemia presents with fatigue. Hemoglobinis 8.2 g/dL, MCV 71 fL, and serum ferritin 3μg/L. Findings on upper endoscopy andcolonoscopy into the terminal ileum arenormal. Further testing should include whichof the following?

a. Stool testing for occult bloodb. Computed tomography of the abdomen

and pelvisc. Capsule endoscopyd. Small-bowel follow-through studye. Barium enema

6. A 22-year-old woman previously in goodhealth is evaluated for new-onset unilateral,throbbing, temporal headaches that are pre-ceded by sensitivity to light and sound andnausea. The findings on physical examina-tion, including a complete neurologic exam-ination, are normal. The patient’s mother hashad similar headaches. The patient is givenadvice about medication. Several weeks later,she develops acute left lower quadrant pain,then several small-volume loose stools, firstwithout blood then with “several table-spoons” of bright red blood. Most likely,which of the following was the advice shewas given for her headaches?

a. At the first sign of an impending headache,take ibuprofen, 800 mg, by mouth

b. At the first sign of an impending headache,take sumatriptan, 100 mg, by mouth

c. Stop taking birth-control pillsd. Begin taking propranolol (Inderal), 20 mg,

twice daily by mouthe. Begin taking topiramate, 25 mg, by mouth,

and increase by 1 tablet a week up to a max-imum of 4 tablets twice daily

7. A 62-year-old previously healthy farmerdevelops acute bandlike constant pain acrossthe top of his abdomen, with nausea andvomiting. He has been hospitalized for 3weeks with necrotizing pancreatitis and isrecovering. Early in the hospitalization, hisgallbladder was removed for cholelithiasis.Now, dull, achy, persistent periumbilicalpain; loose stools; nausea; and a poor appetitedevelop, just after he has resumed a full diet.He is afebrile. Physical examination findingsare remarkable only for mild abdominal dis-tention without tenderness to palpation. Theserum levels of lipase and amylase arenormal, as is the leukocyte count. Which of


the following is most likely to be found onabdominal/pelvic CT?

a. Thrombosis of the splenic veinb. Organized pancreatic necrosis with air

bubblesc. Partial small-bowel obstructiond. Thrombosis of the splenic vein and superior

mesenteric veine. Peripancreatic 4-cm diameter oval fluid

collection

8. A 50-year-old man with a history of lone atrialfibrillation undergoes screening colonoscopy.He has no history of hypertension, kidneydisease, thyroid disease, coronary artery dis-ease, or valvular heart disease. He takes nomedications. He is prepared for the proce-dure with a phosphosoda-based preparation.The procedure shows a sessile, 3-mm polyp inthe descending colon, which is removed bycold biopsy. Three hours after the procedure,a constant periumbilical pain develops. Onexamination, he appears uncomfortable, withblood pressure of 100/70 mm Hg, a pulse rateof 120 to 130, and an irregular rhythm. Hisabdomen has increased bowel sounds and isnontender to palpation. Which of the fol-lowing is most likely?

a. Small-bowel ischemia due to an embolusb. Small-bowel ischemia due to superior

mesenteric venous thrombosisc. Hypokalemia and hyperphosphatemia

with cardiac dysfunction and low-flowischemia of the small bowel

d. Perforation of the bowele. Gaseous distention of the bowel

9. A 62-year-old woman is evaluated for weightloss, diarrhea, and difficulty eating. Overthe past year, she has lost 25 lb and feels“sick” when she eats, with nausea andvague, diffuse abdominal pain occurring 30minutes after eating. She has been eating lessand less. She reports watery, “slimy” stools.She has a history of severe coronary arterydisease, hypertension, peripheral vasculardisease, cigarette smoking, moderate alcohol

use, and mild renal insufficiency. Results ofendoscopy with small-bowel biopsy andcolonoscopy with terminal ileal views areunremarkable. MRA shows high-gradelesions of the proximal celiac artery and supe-rior mesenteric artery. The pancreas and liverare normal. The serum level of creatine is 1.7mg/dL. Which of the following would mostlikely benefit this patient?

a. A 72-hour fecal fat studyb. Oral pancreatic enzyme therapyc. An abdominal-pelvic CT scan without intra-

venous contrast but with oral contrastd. An abdominal-pelvic CT scan with oral and

IV contrast after intravenous hydration andacetylcysteine therapy

e. Mesenteric angiography after intravenoushydration and acetylcysteine therapy

10. A 26-year-old man from Japan has recurrentabdominal pain, diarrhea, oral ulcers, firmtender reddish nodules on his shins, and nowphotophobia with conjunctival erythema sur-rounding the limbus of both eyes. The day afterphlebotomy, a pustule is noted at thevenipuncture site. Which of the following ismost likely?

a. At colonoscopy, focal ulcerations are foundin the ileocecal region, and biopsy findingsare consistent with chronic active colitis,with granulomas

b. Findings on complete ophthalmologicexamination are normal

c. Scrotal examination shows an ulcerd. The oral ulcers are due to herpes simplex

infectione. He has several relatives with Crohn’s disease

11. A 69-year-old woman presents with a 3-dayhistory of abdominal pain, retching, andinability to eat. A prominent gastric air bubbleis seen on an abdominal radiograph. A naso-gastric tube could not be passed. She has a his-tory of hiatal hernia and GERD. Physical exam-ination findings are noncontributory, and lab-oratory results are remarkable for a whiteblood cell count of 15,000/mm3 (15×109/L).


The most likely diagnosis is:

a. Gastric volvulusb. Gastric outlet obstructionc. Duodenal ulcerd. Refractory GERDe. Celiac disease

12. A 55-year-old man presents with a 6-monthhistory of nausea, vomiting, diarrhea, andabdominal pain. The symptoms are worsewith ingestion of alcohol. He also reports apruritic rash. Scattered cutaneous brown-redmacules are found on physical examination.At endoscopy, multiple postbulbar duodenalulcers are found. Which test is most likely toprovide the correct diagnosis?

a. 24-Hour urine for 5-hydroxyindoleaceticacid

b. Serum gastrinc. Serum calcitonind. Octreotide scane. Serum tryptase level

13. A 52-year-old man from Nigeria has a 6-month history of fever, a 20-lb weight loss,and malaise. On physical examination, hisabdomen is diffusely tender and doughy.Hemoglobin is 10.2 g/dL, ESR 45 mm/hour,and albumin 2.1 g/dL. Abdominal CT showsascites and thickened loops of distal smallbowel. Paracentesis of the ascites disclosesa protein level of 3.0 g/100 mL, albumin 1.9g/100 mL, glucose 30 mg/dL, and a cellcount of 350 cells/mm3 (0.35×109/L), with60% lymphocytes. The most appropriate nextstep is:

a. High-dose corticosteroidsb. Intravenous antibioticsc. EGD with biopsyd. Laparoscopye. Liver biopsy

14. A 42-year-old woman with HIV infection,recently diagnosed after she presented withCandida esophagitis, now has diarrhea withblood streaks, abdominal pain, fever, and

malaise. Which of the following will mostlikely lead to the correct diagnosis?

a. Stool examination for Cryptosporidiumb. EGD for Kaposi’s sarcomac. Blood culture for Mycobacterium avium-intra-

cellulared. Colonoscopy for cytomegaloviruse. Stool examination for Candida

15. A 53-year-old woman presents for evaluationof recent-onset constipation. She also reportspostprandial fullness. Colonoscopy findingsfrom 1 year ago were negative. She states thatshe has had an involuntary weight loss of 20lb. She has smoked for years. Finger clubbingis noted on physical examination. Hemoglobinis 12.0 g/dL, ESR 85 mm/hour; and thyroid-stimulating hormone and calcium levels arenormal. What test is most likely to lead to adiagnosis?

a. Serum angiotensin-converting enzymelevel

b. Parathyroid hormone levelc. Free T3/T4 levelsd. Anti-neuronal nuclear antibodye. Repeat colonoscopy

16. A 46-year-old man is evaluated after four self-limited episodes of acute, poorly localizedabdominal pain accompanied by nausea anddiarrhea. He has no history of fever, weightloss, or previous surgery but does have a his-tory of early uncomplicated chronic lympho-cytic leukemia. Abdominal CT during hisfourth episode showed some edema of thesmall bowel without obstruction and mildascites. Results of follow-up abdominal ultra-sonography 2 days later are normal, with noascites. Which of the following tests is mostlikely to be helpful during an episode ofabdominal pain?

a. Syphilis serologyb. Serum lead levelc. Serum aminolevulinic acid leveld. Serum C4 levele. Urgent paracentesis


17. A 22-year-old gravida 1 para 0 woman at week29 of pregnancy reports increasing constipa-tion. Before her pregnancy, she would sufferfrom constipation once or twice a month andobtain relief with a laxative. Her mother diedof colon cancer at age 55 years. The patientstates that she has not had any previous diffi-culty expelling stool or manual disimpaction.The complete blood count and thyroid-stim-ulating hormone and calcium levels arenormal. She has not had a bowel movementfor 2 days and feels bloated. Physical exami-nation findings are unremarkable. Which ofthe following would be best to do next?

a. Colonoscopyb. Flexible sigmoidoscopyc. Mineral oild. Senna or cascarae. Milk of magnesia

ANSWERS

1. Answer dIIB/IIIA Receptor inhibitors block the finalpathway of platelet aggregation, leading to essen-tially complete inhibition of platelet function. Theseeffects are reversed with the transfusion of platelets.The platelet effect of eptifibatide generally resolvesin 12 hours. The most appropriate managementwould be infusion of platelets. If bleeding con-tinues after that point, proceed with endoscopy.

2. Answer aEndoscopic treatment is appropriate for activebleeding, nonbleeding visible vessels, and in man-agement of an adherent clot. The adherent clot inthe anterior bulb would be amenable to endoscopictherapy. A nonbleeding visible vessel of 3 mm onthe lesser curvature of the stomach likely is asso-ciated with the left gastric artery and is too large tobe coagulated reliably.

3. Answer cHigh-risk medical groups for prophylaxis for stressulcer are patients with respiratory failure thatrequires ventilation for more than 48 hours and coag-ulopathy (INR >1.5, platelet count <50,000/mm3

[50×109/L] before the administration of anticoag-ulation medication).

4. Answer cRepeat histologic study is quite accurate, butendoscopy is costly and would not be indicatedfor follow-up of a duodenal ulcer. Both the ureasebreath test and H. pylori stool antigen are cost-effec-tive techniques for proving the eradication of H.pylori infection. These should be performed at least2 weeks after PPI therapy has been stopped becausethis therapy can suppress H. pylori infection.Results of serologic testing generally remain pos-itive despite eradication, and this is not a good testto confirm the resolution of an H. pylori infection.

5. Answer cNew iron deficiency in a male requires further eval-uation. Small-bowel follow-through has a yield ofless than 10%. Computed tomography of theabdomen and a barium enema would be of min-imal benefit. Further evaluation would be indi-cated even if heme were negative. Capsuleendoscopy is the test with the highest yield in theevaluation of iron deficiency anemia and wouldbe the test of choice in this setting. Celiac diseaseshould be excluded as well.

6. Answer bThis clinical scenario is most consistent with migraineheadaches with subsequent ischemic colitis. As anonsteroidal antiinflammatory drug, ibuprofen cancause mucosal damage throughout the gastroin-testinal tract, but this would be an unusual presen-tation. Propranolol (Inderal) and topiramate are notassociated with ischemic colitis, but triptans such assumatriptan are. If this young woman stopped takingbirth-control pills, it would not predispose her toischemic colitis. However starting treatment withhormonal medications, particularly in women witha personal or family history of a hypercoagulablestate, could result in ischemic colitis.

7. Answer dThis patient most likely had acute gallstone pan-creatitis with pancreatic necrosis, but he has nearlyrecovered and is beginning to take a full diet. It isunlikely that the necrotic pancreatic tissue isinfected, because he does not have a fever or an


increased leukocyte count. Thrombosis of thesplenic vein alone would not cause these symp-toms, nor would a small peripancreatic fluid col-lection. The lack of vomiting or colicky pain and theoccurrence of diarrhea are unlikely to be due tosmall-bowel obstruction. With necrotizing pan-creatitis, he is at risk for splenic vein and superiormesenteric vein thrombosis, the latter resulting insmall-bowel congestion, with dull, poorly local-ized, persistent achy discomfort; nausea; poorappetite; and loose stools.

8. Answer aAlthough this patient is at low risk for emboliza-tion, the clinical presentation with acute, poorlylocalized mid-gut pain without tenderness and anirregular pulse suggests acute mesenteric ischemiaof the small bowel. The 3-hour interval sincecolonoscopy makes gaseous distention unlikely.Also, perforation from cold biopsy of a diminu-tive polyp is unlikely. He has no history to sug-gest venous thrombosis of the superior mesentericvein; also, it is unlikely that electrolyte abnormal-ities from the phosphosoda preparation wouldcause cardiac dysfunction and a low-flow state inthis otherwise healthy 50-year-old man.

9. Answer eThis patient most likely has chronic mesentericischemia with postprandial pain due to limitedarterial blood flow to the small bowel, especiallywhen increased blood flow is needed after meals.CT will not add anything to MRA. A fecal fat studymay be abnormal, but it will not help treat the sit-uation. The patient is unlikely to have pancreaticinsufficiency despite her history of alcohol use.The recurrent postprandial pain has a mid-gut dis-tribution most consistent with abdominal angina.At angiography, a decision can be made in thishigh-risk surgical patient to pursue angioplastywith or without stenting or surgery to bypass theproximal arterial large-vessel occlusive lesions.

10. Answer cThis patient most likely has Behçet’s syndromewith vasculitic involvement of the gastrointestinaltract. As in Crohn’s disease, focal ulceration of theileocecal region can occur, with pain and diarrhea,but granulomas are not typically seen in biopsy

specimens. With all these symptoms, the eye exam-ination findings should not be normal but showuveitis, which tends to be a panuveitis in Behçet’ssyndrome in contrast to the anterior uveitis ofCrohn’s disease. Oral ulcers in Behçet’s syndromeare not due to herpes simplex infection. The patientwould be unlikely to have several relatives withCrohn’s disease. Genital ulcers, including scrotalulcers in men, are seen much more often in Behçet’ssyndrome than in Crohn’s disease. Erythemanodosum is seen in both Crohn’s disease andBehçet’s syndrome, and in Behçet’s syndrome, theymay be a clue to the presence of visceral vasculitis.

11. Answer aThis patient has Borchardt’s triad, which consistsof abdominal pain, retching without vomitus, andinability to pass a nasogastric tube. The other dis-orders could cause pain and retching, but not theinability to pass a nasogastric tube. The history isquite acute for refractory GERD or celiac disease.Vomiting would occur often with gastric outletobstruction. Surgical consultation would be indi-cated for acute gastric volvulus.

12. Answer eAn increased serum level of gastrin could be sug-gestive of Zollinger-Ellison syndrome; an increasedurine concentration of 5-hydroxyindoleacetic acid,of carcinoid syndrome; and an increased serumlevel of calcitonin, of medullary thyroid cancer.All these could include diarrhea, but the rash(urticaria pigmentosa) is typical of systemic mas-tocytosis, with diarrhea, hypersecretion of gastricacid (ulcers), and an increased serum level oftryptase. An octreotide scan would not be useful.

13. Answer dThe ascitic fluid analysis suggests a peritonealprocess. Because of the 6-month history, tubercu-losis or malignancy are likely, and laparoscopyaffords the best chance for a diagnosis, comparedwith endoscopy or liver biopsy (low yield).Corticosteroid or antibiotic therapy has no role(most of the cells are lymphocytes).

14. Answer dCryptosporidiosis does not cause bloody diarrhea.Kaposi’s sarcoma of the gastrointestinal tract can


bleed, but does not cause diarrhea. Infection withMyobacterium avium-intracellulare complex usuallyoccurs much later in very advanced immunosup-pressed HIV patients. Candidacan be found in normalstool and does not cause bloody diarrhea. The casepresentation is most consistent with CMV infection.

15. Answer dThe new constipation, weight loss, clubbing,anemia, and increased ESR are suggestive of malig-nancy. A paraneoplastic syndrome with gastroin-testinal dysmotility is likely, and the anti-neuronalnuclear antibody (ANNA-1) test is a noninvasivetest that, in this patient, is likely to lead to a diag-nosis, for example, of small cell lung cancer.

16. Answer dAcute attacks of poorly localized abdominal painin a person with no history of abdominal surgery

could be due to syphilis, lead poisoning, or por-phyria (aminolevulinic acid level). However, thetransient small-bowel edema and ascites are sug-gestive of angioedema, which in this case may beacquired rather than congenital, secondary to thepatient’s lymphoproliferative disorder. During anattack, the levels of C4 and total complementshould be decreased, and deficient C1 esteraseinhibitor levels (quantitative or qualitative) couldconfirm the diagnosis.

17. Answer eThere is no reason to perform a procedure. Thepatient most likely has late pregnancy-associatedconstipation. Mineral oil should be avoided inpregnancy (aspiration, fat-soluble vitamin mal-absorption), as should anthraquinone laxatives(malformation). Milk of magnesia is safe until theonset of labor and delivery.


SECTION V

Colon

Ulcerative colitis is an idiopathic chronic inflam-matory disorder of the colonic mucosa, with thepotential for extraintestinal inflammation. Thedisease extends proximally from the anal verge inan uninterrupted pattern to involve all or part ofthe colon.

Crohn’s disease is an idiopathic chronicinflammatory disorder of the full thickness of theintestine, most commonly in the ileum and thecolon, with the potential to involve the gastroin-testinal tract at any level from the mouth to the anusand perianal region. There is also the potential forextraintestinal inflammation. Typically, there ispatchy disease in the gastrointestinal tract, withintervening areas of normal mucosa.

EPIDEMIOLOGYMen and women are generally at similar risk forinflammatory bowel disease (IBD). Onset of IBD ishighest among adolescents; the peak incidence isbetween ages 15 and 25 years. IBD is more commonamong Ashkenazi Jews than non-Jews. The inci-dence and prevalence of ulcerative colitis aresimilar in a given location, but the values vary

depending on the patient population of thereporting center. The prevalence of the disease ismuch higher than the incidence for several rea-sons: disease onset is often in young adults andchildren, the disease is chronic and lifelong, andthe mortality rate associated with the disease islow. In Europe and North America, the incidenceof ulcerative colitis and Crohn’s disease roughlydoubled during the 1960s and 1970s, and the inci-dence for both conditions has been relatively stablesince that time. With this doubling of the incidence,the prevalence also increased, and it will be severalmore decades before the prevalence levels off.

The incidence of ulcerative colitis is 7.3 per100,000 in Olmsted County, Minnesota, and 14.0per 100,000 in Winnipeg, Manitoba. The preva-lence in Olmsted County, Minnesota, is 181 per100,000. The proportion of patients with ulcera-tive proctitis varies in different series from 17% to49% of the totals.

The incidence of Crohn’s disease also variesamong different reporting centers. It is 5.8 per100,000 in Olmsted County and 15.0 per 100,000in Winnipeg, and the prevalence in OlmstedCounty is 133 per 100,000.

193

CHAPTER 14

Inflammatory Bowel Disease:Clinical Aspects

William J. Tremaine, MD

Abbreviation: IBD, inflammatory bowel disease.

Mortality rates with IBD are slightly higher thanthose for the general population. In a study fromStockholm, the standardized mortality ratio was1.37 for ulcerative colitis and 1.51 for Crohn’s disease.

GENETICSFrom 10% to 15% of patients with ulcerative colitishave a relative with IBD, mainly ulcerative colitisand, less commonly, Crohn’s disease. About 15%of patients with Crohn’s disease have a relativewith IBD, mainly Crohn’s disease and, less com-monly, ulcerative colitis. Several genetic linkageshave been identified, and specific genetic defectshave been determined in IBD. The first to be char-acterized was the CARD15/NOD2 gene, presentin the homozygous form in up to 17% of patientswith Crohn’s disease and in less than 15% of con-trols. This genetic defect is associated withfibrostenotic disease involving the distal ileum.Other associations are with the IBD5 haplotype ofchromosome 5 and the IL23R gene on chromosome1p31. The latter gene encodes a proinflammatorycytokine, interleukin-23. Other genetic linkageshave been identified, but so far the phenotypeshave not been characterized. Three genetic syn-dromes are associated with IBD: Turner’s syn-drome, Hermansky-Pudlak syndrome (oculocu-taneous albinism, a platelet aggregation defect,and a ceroidlike pigment deposition), and glycogenstorage disease type 1B.

DIETPatients have no specific dietary restrictions.Although lactose intolerance is more common withCrohn’s disease than in the general population,lactose and other milk components do not seemto influence the inflammatory disease. Elementaldiets and parenteral hyperalimentation are usefulfor correction of malnutrition and for growthfailure in children with IBD. Corticosteroids aresuperior to enteral nutrition for the treatment ofCrohn’s disease. Parenteral nutrition has not beenfound to be superior to enteral nutrition for Crohn’sdisease. The role of enteral and parenteral nutritionas primary therapy for Crohn’s disease is contro-versial, and they are used primarily as an alternativeto corticosteroids. There is no convincing evidence

that elemental or parenteral nutrition is therapeuticfor ulcerative colitis.

PREGNANCYFertility is normal in inactive ulcerative colitis andCrohn’s disease. Fertility is decreased in somewomen with active IBD, but most patients areable to conceive. Sulfasalazine causes reversibleinfertility in men as a result of abnormalities ofspermatogenesis and decreased sperm motility.There is debate about the risk of birth defects inthe offspring of a parent with IBD: although moststudies do not show an increased risk in associationwith the disease or the treatments, one study foundmore birth defects among the offspring of fatherswith Crohn’s disease who took 6-mercaptopurine.The course of pregnancy is usually normal,although there is an increased chance of a pretermdelivery and decreased birth weight. For womenwith IBD in remission before pregnancy, two-thirds remain in remission through the pregnancyand postpartum. Flares occur most commonlyduring the first trimester and postpartum.Previous colectomy with an end-ileostomy or witha continent ileal pouch does not preclude preg-nancy, and for some women, vaginal delivery isstill an option.

ENVIRONMENTAL INFLUENCESUlcerative colitis is primarily a disease of non-smokers. Only 13% of patients with ulcerativecolitis are current smokers, and the rest are non-smokers or former smokers. Pouchitis afterproctocolectomy with an ileal J pouch-to-analanastomosis for ulcerative colitis is less commonamong smokers. In contrast, patients with Crohn’sdisease are more commonly smokers than thegeneral population, and smoking increases therisk of symptomatic recurrences.

IBD is more common in colder climates thanin warmer climates, and it is more common indeveloped countries than in developing countries.

DIAGNOSISThe diagnosis of IBD is confirmed by a combina-tion of endoscopic, radiographic, and pathology

194 Colon

studies, and the specific diagnostic tests are basedon the presenting symptoms and physical exami-nation findings.

CLINICAL PRESENTATIONS

Ulcerative ColitisThe onset may be gradual or sudden, with anincrease in bowel movements and bloody diarrhea,fecal urgency, cramping abdominal pain, and fever.The course is variable, with periods of exacerba-tion, improvement, and remission that may occurwith or without specific medical therapy. Abouthalf of the patients have disease involving the leftside of the colon to some extent, including proc-titis, proctosigmoiditis, and disease extending fromthe splenic flexure distally. Constipation with rectalbleeding is a presenting symptom in about 25% ofpatients with disease limited to the rectum.Diarrhea may vary from 1 to 20 or more loose orliquid stools a day, usually worse in the morningand immediately after meals, and patients withmoderate or severe symptoms often have nocturnalstools. Abdominal pain is usually cramping, whichis worse after meals or bowel movements.Anorexia, weight loss, and nausea in the absenceof bowel obstruction are common with severe andextensive disease but uncommon with mild to mod-erate disease or disease limited to the left colon. Inchildren, urgency, incontinence, and upper gas-trointestinal tract symptoms are more frequentand growth failure is common. Extraintestinalsymptoms occur in up to 36% of patients.

Crohn’s DiseaseSymptoms depend on the anatomical location ofthe disease. With ileocecal disease, abdominal pain,diarrhea, and fever are typical. With colonic dis-ease, bloody bowel movements with diarrhea,weight loss, and low-grade fever are common.Patients with gastroduodenal Crohn’s disease oftenhave burning epigastric pain and early satiety, andthese symptoms usually overshadow the symp-toms from coexisting ileal or colonic disease. Thesymptoms of oral or esophageal Crohn’s diseaseinclude dysphagia, odynophagia, and chest pain,even without eating. The findings of perianalCrohn’s disease include perirectal abscess, painful

and edematous external hemorrhoids, and analand perianal fistulas. Enterovesical fistulas cancause pneumaturia and recurrent urinary tractinfections. Rectovaginal fistulas occur in up to 10%of women with rectal Crohn’s disease and maycause gas or stool to be passed from the vagina. Inchildren, the onset of Crohn’s disease is often insid-ious; weight loss occurs in up to 87% before thediagnosis, and 30% of children have growth failurebefore the onset of intestinal symptoms.

Physical ExaminationIn mildly active ulcerative colitis, physical exam-ination findings are often normal or there may beabdominal tenderness, particularly with palpa-tion over the sigmoid colon. Patients with moresevere disease may have pallor, dehydration,tachycardia, fever, diminished bowel sounds, anddiffuse abdominal tenderness with rebound.Tenderness with rebound is ominous and suggeststoxic dilatation or perforation. In Crohn’s disease,physical examination findings may be normal orinclude one or more of the following: fever, weightloss, muscle wasting, abdominal tenderness (par-ticularly in the lower abdomen), and a palpablemass, usually in the ileocecal region of the rightlower abdomen. Rectal examination may showlarge, edematous, violaceous external hemor-rhoidal tags; fistulas; anal canal fissures; and analstenosis. Ulcers in Crohn’s disease may occur onthe lips, gingiva, or buccal mucosa. Physical exam-ination findings due to the extraintestinal mani-festations of IBD are discussed in Chapter 16(Inflammatory Bowel Disease: ExtraintestinalManifestations and Cancer).

Laboratory FindingsIn mild disease, laboratory results may be normal.Iron deficiency anemia due to gastrointestinal tractblood loss may occur in ulcerative colitis andCrohn’s disease, and anemia of chronic disease,presumably due to cytokine effects on the bonemarrow, may occur with either disorder.Malabsorption of vitamin B12 or folate is an addi-tional cause for anemia in patients with Crohn’sdisease. Hypoalbuminemia, hypokalemia, andmetabolic acidosis can occur with severe diseasebecause of potassium and bicarbonate wastingwith diarrhea. An increased leukocyte count may

Inflammatory Bowel Disease: Clinical Aspects 195

be a consequence of active IBD or be due to acomplicating abscess.

Acute phase reactants, including the erythro-cyte sedimentation rate, C-reactive protein, andorosomucoid, usually correlate with disease activitybut may be normal in mildly active disease. The peri-nuclear antineutrophil cytoplasmic antibody is pos-itive in about two-thirds of patients with ulcerativecolitis and about one-third of patients with Crohn’sdisease. The anti-Saccharomyces cerevisiae antibodyis positive in about two-thirds of patients withCrohn’s disease and about one-third of patients withulcerative colitis. These tests may be used togetherto help distinguish ulcerative colitis from Crohn’sdisease. However, the positive predictive value of thetwo tests together is 63.6% for ulcerative colitis and80% for Crohn’s disease; thus, distinguishing thetwo diseases with these serologic tests is less thanideal (Table 1). With new-onset IBD or at relapse,infection should be ruled out with stool studies,including cultures for bacterial pathogens and exam-inations for ova and parasites and Clostridium diffi-cile toxin. For patients with systemic symptoms suchas fever, malaise, and myalgias, cytomegalovirusinfection should be excluded by mucosal biopsy.

EndoscopyFlexible proctosigmoidoscopy or colonoscopy canidentify characteristic mucosal changes of ulcera-tive colitis, including loss of the normal vascularmarkings, mucosal granularity, friability, mucous

exudate, and focal ulceration (Fig. 1). Withcolonoscopy, the extent of disease can be deter-mined and the terminal ileum can be examinedfor evidence of backwash ileitis in ulcerative colitisor ileal involvement in Crohn’s disease. Patientswith left-sided ulcerative colitis may have inflam-matory changes around the appendix, called a cecalpatch, as a manifestation of the disease; this findingshould not be confused with segmental colitis dueto Crohn’s disease. Only a limited examination ofthe rectosigmoid colon should be performed inpatients with severely active colitis, because of therisk of perforation or hemorrhage with an extensiveexamination. In Crohn’s disease, characteristiclesions at colonoscopy are deep linear ulcers (rakeulcers) with surrounding erythema and granu-larity and skip areas of normal-appearing mucosabetween areas of involvement (Fig. 2). Upper gas-trointestinal endoscopy can confirm the presenceand distribution of disease in the upper gut anddefine how severely the mucosa is affected.Wireless capsule endoscopy is useful in makingthe diagnosis of small-bowel Crohn’s disease insome patients, but its precise role in the work-upof IBD has not been defined.

In Crohn’s disease, the endoscopic findingsdo not correlate closely with clinical diseaseactivity. For patients with ulcerative colitis(extending proximal to the rectum), the risk ofmalignancy is increased above that for the generalpopulation after 8 to 10 years of disease. For thatreason, periodic colonoscopy with biopsies for sur-veillance for dysplasia is indicated after 8 to 10years of disease. The risk of malignancy for patientswith less extensive ulcerative colitis (with involve-ment of the colon distal to the splenic flexure) alsois increased, but the magnitude of the risk is notdefined. There does not appear to be an increasedrisk of rectal cancer for ulcerative proctitis withoutcolitis above the rectum. Patients with left-sidedulcerative colitis of 8 to 10 years’ duration, or longer,should undergo periodic surveillance biopsies. Theoptimal interval between surveillance examinationshas not been defined, and the examinations usuallyare performed at 1- to 2-year intervals.

Radiologic FeaturesPlain abdominal films with supine and uprightviews should be obtained in cases of severely active

196 Colon

Table 1. Positive Predictive Value ofSerologic Markers in Patients WithIndeterminate Colitis

Positive predictive

Disease Marker value, %

Ulcerative colitis pANCA+ 63.6ASCA−

Crohn’s disease pANCA− 80ASCA+

ASCA, anti-Saccharomyces cerevisiae antibody; pANCA,perinuclear antineutrophil cytoplasmic antibody.

colitis to examine for complications, including per-foration with free air and toxic dilatation with aluminal diameter of 5 cm or more. In Crohn’s dis-ease, computed tomographic enterography (Fig. 3)can identify the location and extent of disease andcomplications such as fistulas, strictures, or abscesses.Alternative studies are small intestinal enteroclysis,a single-contrast small-bowel follow-through exam-ination, and an air contrast barium enema. A bariumswallow may be useful for assessment of Crohn’sdisease that involves the esophagus, stomach, andduodenum. Abdominal computed tomography andultrasonography are useful for identifying intra-abdominal abscesses. Magnetic resonance imagingis superior to computed tomography for identifyingpelvic and perianal abscesses as well as intra-abdom-inal Crohn’s disease and abscesses.

HistologyMucosal biopsy specimens from involved areas ofthe gastrointestinal tract are useful for excludingself-limited colitis and other infections and non-infectious colitis due to ischemia, collagenous andlymphocytic colitis, drug effect, radiation injury,and solitary rectal ulcer syndrome. Noncaseatinggranulomas are a feature of Crohn’s disease and canbe helpful for distinguishing it from ulcerativecolitis, but even when multiple specimens aretaken, granulomas are identified in only 30% ofresected Crohn’s disease specimens. The presence

of focal, patchy inflammation with normal inter-vening mucosa is characteristic of Crohn’s diseasebut not invariably identifiable.

Differential DiagnosisUlcerative colitis and Crohn’s disease must be dis-tinguished from infectious causes of colitis and alsofrom the noninfectious causes of inflammation in

Inflammatory Bowel Disease: Clinical Aspects 197

Fig. 1. Diffuse changes of colitis include mucosalgranularity and erythema, with mucus exudate. Thisis typical of moderately active ulcerative colitis.

Fig. 2. Linear ulcers and surrounding mucosalerythema, edema, and granularity. This is typical ofCrohn’s disease.

Fig. 3. Coronal computed tomographic enterographyshowing distal ileal hyperenhancement and wallthickening (arrows) of active inflammatory Crohn’sdisease.

the colon and small intestine (Table 2). Microscopic co-litis is a descriptive term for a syndrome of chronicwatery diarrhea with characteristic histologic abnor-malities but without specific endoscopic or radi-ographic features. Specific forms of microscopic co-litis include lymphocytic colitis, in which there areintraepithelial lymphocytes and chronic inflamma-tory cells in the lamina propria, and collagenous co-litis, which includes the features of lymphocytic co-litis plus the presence of a subepithelial collagenband. Diverticular disease-associated chronic colitisis a segmental colitis in which there are chronicinflammatory changes of the mucosa limited to areasof the sigmoid colon where diverticula are present.

Nonsteroidal antiinflammatory drugs can causeulcerations throughout the gastrointestinal tract,including the colon and rectum, which can be con-fused with Crohn’s disease. Ischemia more com-monly causes segmental colitis that may be confusedwith Crohn’s disease, but occasionally it can causea diffuse colitis that can appear as ulcerative colitis.Injury to the rectum from radiation for prostatecancer or gynecologic malignancy may appear asulcerative proctitis or Crohn’s disease with fistulasand strictures. Injury to the small intestine and moreproximal colon from radiation may cause chronicdiarrhea, strictures, malabsorption, and other fea-tures that may mimic extensive Crohn’s disease.Solitary rectal ulcer syndrome may be confused withCrohn’s disease involving the rectum but can be dif-ferentiated on the basis of histologic features showingmarked subepithelial fibrosis without inflamma-tion. Diverticulitis may mimic Crohn’s disease withfistulas, localized abscesses, and segmental colitis. Inaddition, patients with diverticulitis may haveextraintestinal symptoms, just as patients with IBD.

RECOMMENDED READINGDuerr RH. Update on the genetics of inflamma-

tory bowel disease. J Clin Gastroenterol.2003;37:358-67.

D’Haens G, Geboes K, Peeters M, Baert F, Ectors N,Rutgeerts P. Patchy cecal inflammation asso-ciated with distal ulcerative colitis: a prospec-tive endoscopic study. Am J Gastroenterol.1997;92:1275-9.

Joossens S, Reinisch W, Vermeire S, Sendid B, PoulainD, Peeters M, et al. The value of serologic markers

in indeterminate colitis: a prospective follow-upstudy. Gastroenterology. 2002;122:1242-7.

Kornbluth A, Legnani P, Lewis BS. Video capsuleendoscopy in inflammatory bowel disease:past, present, and future. Inflamm Bowel Dis.2004;10:278-85.

Loftus EV Jr. Clinical epidemiology of inflamma-tory bowel disease: incidence, prevalence, andenvironmental influences. Gastroenterology.2004;126:1504-17.

Podolsky DK. Inflammatory bowel disease. N EnglJ Med. 2002;347:417-29.

198 Colon

Table 2. Differential Diagnosis ofInflammatory Bowel Disease

Acute self-limited colitisBacteria

Toxigenic Escherichia coliSalmonellaShigellaCampylobacterYersiniaMycobacteriumNeisseria gonorrhoeaeClostridium difficile

ParasitesAmebiasisChlamydia

VirusesCytomegalovirusHerpes simplex

Collagenous/lymphocytic colitisDiverticular disease-associated colitisMedication-induced

Nonsteroidal antiinflammatory drugsGold

Ischemic colitisRadiation enterocolitisDiverticulitisAppendicitisNeutropenic enterocolitisSolitary rectal ulcer syndromeMalignancy

CarcinomaLymphomaLeukemia

Many different medical and surgical therapies areavailable for inflammatory bowel disease. Medicaltherapies include antiinflammatory drugs such assulfasalazine, olsalazine, balsalazide, andmesalamine; antibiotics; corticosteroids, includingbudesonide; immunosuppressive medications suchas azathioprine, 6-mercaptopurine, methotrexate,cyclosporine, and tacrolimus; and biotechnologymedications such as infliximab and adalimumab.Surgical therapies include colectomy withileostomy, ileoanal pouch, or Kock pouch for ulcer-ative colitis and surgical resection, stricturoplasty,and placement of setons for Crohn’s disease.

Many of the treatments for ulcerative colitisand Crohn’s disease are designed to deliver med-ications topically to the inflamed bowel, with thegoal of achieving local efficacy with minimal sys-temic absorption, thus minimizing toxicity. A thor-ough understanding of the anatomical classificationof both ulcerative colitis and Crohn’s disease isrequired in order to choose the optimal drugdelivery system for a patient.

Ulcerative colitis can be divided into ulcerativeproctitis (rectal involvement only, with the max-imal extent of 10 cm from the anal verge), ulcerative

proctosigmoiditis (inflammation is limited to therectum and sigmoid colon), left-sided ulcerativecolitis (inflammation does not extend proximal tothe splenic flexure), and extensive colitis or pancolitis(inflammation extends proximal to the splenicflexure or involves the entire colon). Crohn’s dis-ease can be divided into Crohn’s ileitis (only thesmall bowel is involved), Crohn’s colitis (only thecolon is involved), and Crohn’s ileocolitis (both thesmall bowel and colon are involved).

ANTIINFLAMMATORY MEDICATIONS(5-AMINOSALICYLATES)Sulfasalazine, oral mesalamine (Pentasa, Asacol,and Lialda), rectal mesalamine (Rowasa andCanasa), olsalazine, and balsalazide are drugsthat deliver 5-aminosalicylate (mesalamine) to thecolon (Table 1). Sulfasalazine, the first drug devel-oped in this class, was designed to combine theantiinflammatory properties of 5-aminosalicylatewith the antibacterial properties of sulfapyridinefor the treatment of rheumatoid arthritis.Subsequently, sulfasalazine was discovered to beeffective for ulcerative colitis and to serve as a

199

CHAPTER 15

Inflammatory Bowel Disease:Therapy

William J. Sandborn, MD

Abbreviations: CIR, controlled ileal release; TNF, tumor necrosis factor.

200 Colon

Table 1. 5-Aminosalicylate (5-ASA) Preparations for Treating Ulcerative Colitis (UC)

Proprietary Sites of Daily dose, g*

Generic name name Formulation delivery Active Maintenance Indication

Mesalamine Rowasa Enema Distal to 4 1-4 Active distalsuspension splenic UC

flexure Remissionmain-tenancedistal UC

Canasa Suppository Rectum 1-1.5 0.5-1 Active proctitis

Remission main-tenancedistal UC

Asacol Eudragit-S– Terminal 1.6-4.8 0.8-4.8 Active UCcoated tablets ileum, colon Remission (release main-at pH ≥7.0) tenance UC

Pentasa Ethylcellulose- Duodenum, 2-4 1.5-4 Active UCcoated micro- jejenum, Remission granules (time- ileum, colon main-and pH-depen- tenance UCdent release)

Lialda Eudragit-S– Terminal 2.4-4.8 2.4 Active UCcoated tablets ileum, Remission(release at colon main-pH ≥7.0) and tenance UClipophilic andhydrophilicmatrices

Olsalazine Dipentum 5-ASA dimer Colon 2-3 1 Remission linked by azo main-bond tenance UC

Sulfasalazine Azulfidine 5-ASA linked to Colon 2-4 2-4 Active UCsulfapyridine Remission by azo bond main-

tenance UCBalsalazide Colazal 5-ASA linked to Colon 2-6.75 2-6.75 Active UC

inert carrier by Remission azo bond main-

tenance UC

*Dose ranges reflect those commonly used in clinical practice and are broader than those specifically studied in clinical trials.

prodrug for the active ingredient 5-aminosalicy-late. 5-Aminosalicylate is linked to sulfapyridine byan azo bond that is cleaved by bacteria in the colon.Olsalazine and balsalazide are also prodrugs for5-aminosalicylate. Olsalazine consists of a dimer oftwo 5-aminosalicylate molecules linked by an azobond. Balsalazide consists of 5-aminosalicylatelinked to an inert carrier by an azo bond. Parent 5-aminosalicylate (mesalamine) can be deliveredorally in a capsule covered with the pH-dependentpolymer Eudragit-S, which dissolves at pH 7 inthe terminal ileum and cecum (Asacol), as ethyl-cellulose-coated granules that give a timed releasethroughout the gastrointestinal tract, beginningin the duodenum, jejunum, and ileum and endingin the colon and rectum (Pentasa), or as a tabletcovered with the pH-dependent polymer Eudragit-S, which dissolves at pH 7 in the terminal ileumand cecum, exposing lipophilic and hydrophilicmatrices that reportedly prolong mesalaminerelease throughout the colon (Lialda). Mesalaminecan be administered also as an enema (Rowasa) ora suppository (Canasa).

In placebo-controlled trials, sulfasalazine atdoses of 2 to 6 g daily is effective in both inducingremission in mildly to moderately active ulcerativecolitis and maintaining remission. In comparativetrials, sulfasalazine is less effective than oral cor-ticosteroids for active ulcerative colitis. In contrast,placebo-controlled trials of sulfasalazine at 3 to 5 gdaily for mildly to moderately active Crohn’s dis-ease demonstrated only modest efficacy forinducing remission (this effect was limited topatients with Crohn’s colitis or ileocolitis). In com-parative trials, sulfasalazine was less effective thanoral corticosteroids for active Crohn’s disease.Sulfasalazine at 2.5 to 3 g daily was not more effec-tive than placebo for maintaining remission inCrohn’s disease. Drug-associated toxicity occurs inup to 30% of patients receiving treatment with sul-fasalazine. Commonly observed adverse eventsinclude headache, epigastric pain, nausea and vom-iting, and skin rash. Less common but severe adverseevents include hepatitis, fever, autoimmune hemol-ysis, aplastic anemia, leukopenia, agranulocytosis,folate deficiency, pancreatitis, drug-induced lupus,pneumonitis, and Stevens-Johnson syndrome.Reversible male infertility may occur. Sulfasalazinemay be taken during pregnancy and breastfeeding.

Similar to those for sulfasalazine, placebo-controlled trials of mesalamine enemas, 1 to 4 gdaily, and mesalamine suppositories, 0.5 to 1.5 gdaily, have demonstrated efficacy for both inducingremission in mildly to moderately active left-sidedulcerative colitis and ulcerative proctitis and main-taining remission. Oral mesalamine delivered tothe terminal ileum and cecum (Asacol and Lialda)at doses of 1.6 to 4.8 g daily or throughout the gas-trointestinal tract (Pentasa) at 2 to 4 g daily inpatients with mildly to moderately active ulcerativecolitis is effective for inducing remission, andAsacol, 0.8 to 1.6 g daily, and Pentasa, 4 g daily,are effective for maintaining remission.

The data for use of oral mesalamine in thetreatment of Crohn’s disease are less clear. Placebo-controlled trials have shown that low-dosemesalamine (1-2 g daily) is not effective forinducing remission in mildly to moderately activeCrohn’s disease. Data from placebo-controlledtrials for high-dose mesalamine (3.2-4 g daily) forinducing remission in active Crohn’s disease areconflicting (if there is benefit, it is relatively small).A comparative trial demonstrated that oralmesalamine is less effective than controlled ilealrelease (CIR) budesonide, 9 mg daily, for activeCrohn’s disease. Data from placebo-controlledtrials of oral mesalamine, 1 to 4 g daily, for main-tenance of medically induced remission or post-operative remission of Crohn’s disease are con-flicting (however, a meta-analysis has suggested asmall benefit for postoperative maintenance ofremission). Oral mesalamine, 4 g daily, is notsteroid-sparing.

Placebo-controlled trials have shown thatolsalazine at 0.75 to 3 g daily is effective forinducing remission in patients with mildly to mod-erately active ulcerative colitis. Placebo-controlledtrials have demonstrated that olsalazine at 1 g dailyis effective for maintaining remission in ulcerativecolitis. Comparative trials have shown that bal-salazide at 6.75 g (contains 2.4 g of 5-aminosalicylate)daily has an efficacy similar to that of oralmesalamine at 2.4 g daily for inducing remission inmildly to moderately active ulcerative colitis. Dose-response trials demonstrated that balsalazide at 4to 6 g daily is more effective than balsalazide at 2to 3 g daily for maintaining remission in ulcerativecolitis (this evidence of dose response demonstrates

Inflammatory Bowel Disease: Therapy 201

a maintenance benefit for balsalazide even thougha placebo-controlled trial has not been performed).

Olsalazine, balsalazide, and mesalamine gen-erally are better tolerated than sulfasalazine.Commonly occurring adverse events includeheadache and gastrointestinal symptoms attrib-utable to underlying inflammatory bowel disease.Sometimes, rash, alopecia, and a hypersensitivityreaction resulting in a syndrome of worseningdiarrhea and abdominal pain may occur. Rarely,serious adverse events, including interstitialnephritis, pericarditis, pneumonitis, hepatitis, andpancreatitis, are observed. Ileal secretory diarrheacan occur with olsalazine. Olsalazine, balsalazide,and mesalamine may be taken during pregnancyand breastfeeding.

ANTIBIOTICSControlled trials of various antibiotics, includingvancomycin, metronidazole, ciprofloxacin, andtobramycin, have not demonstrated efficacy inulcerative colitis. Thus, as a primary treatment forulcerative colitis, antibiotic therapy is not appro-priate. The data for use of antibiotics in Crohn’sdisease are less clear cut. Three small underpoweredcomparative studies suggested equivalence of eithermetronidazole or ciprofloxacin to sulfasalazine,methylprednisolone, and oral mesalamine (Pentasa).However, a placebo-controlled trial of metronida-zole at 10 mg/kg daily or 20 mg/kg daily did notdemonstrate efficacy in active Crohn’s disease.Similarly, a comparative trial of budesonide 9 mgdaily or combination therapy with budesonide 9mg + metronidazole 1.5 g + ciprofloxacin 1.0 gdaily did not demonstrate an adjunctive role forantibiotics in patients receiving budesonidetherapy for active Crohn’s disease. A single con-trolled trial of metronidazole, 1,500 mg daily for3 months after ileal resection, showed that theoccurrence of severe endoscopic lesions could bedelayed for up to 1 year in patients undergoing anoperation for Crohn’s disease. Because of theresults of these studies, the role of antibiotic therapyfor Crohn’s disease is debated. Many cliniciansundertake a trial of antibiotic therapy before pre-scribing corticosteroids for active Crohn’s disease.

Uncontrolled studies have reported thatmetronidazole, 750 to 1,500 mg daily, and

ciprofloxacin, 1,000 mg daily, may be effective forfistulizing Crohn’s disease, particularly in patientswith perianal fistulas. No controlled trials havebeen performed, but antibiotic therapy is usedwidely for this treatment indication and is con-sidered to be the first-line therapy.

Small placebo-controlled and comparative trialshave shown that metronidazole, 750 to 1,500 mgdaily, and ciprofloxacin, 1,000 mg daily, are effectivefor inducing remission in patients with active acutepouchitis after colectomy and ileoanal anastomosisfor ulcerative colitis. Uncontrolled clinical obser-vations have suggested that metronidazole andciprofloxacin may be effective for maintainingremission in patients with chronic pouchitis.

Adverse events observed with metronidazoleinclude paresthesias, peripheral neuropathy, yeastvaginitis, anorexia, nausea, a metallic taste, andpossible intolerance to alcohol. Adverse eventsobserved with ciprofloxacin include photosensi-tivity, nausea, rash, increased levels of liverenzymes, and Achilles tendon rupture (rare).Ciprofloxacin should not be taken during preg-nancy or breastfeeding, and metronidazole shouldbe avoided during the first trimester of pregnancy.

CORTICOSTEROIDS A small number of pharmacologic studies havebeen conducted with corticosteroids in inflam-matory bowel disease, and they can be used toguide dosing and route of administration. A dose-response study in patients with active ulcerativecolitis demonstrated that prednisone at doses of40 or 60 mg daily is more effective than prednisoneat 20 mg daily. More side effects occurred in the60-mg daily dose group. These results have beenextrapolated to patients with Crohn’s disease. Mostclinicians initiate oral corticosteroid therapy withprednisone at a dose of 40 mg daily and then taperthe dose over 2 to 4 months. Pharmacokineticstudies in patients with active ulcerative colitishave demonstrated decreased bioavailability ofprednisolone compared with that of controls. Thus,patients with severely active ulcerative colitis orCrohn’s disease who do not have a response tooral corticosteroid therapy are hospitalized andgiven corticosteroids intravenously to ensure ade-quate bioavailability of the corticosteroid dose.

202 Colon

Placebo-controlled trials have demonstratedthat orally administered cortisone, 100 mg daily, orprednisone, 40 to 60 mg daily, is effective forinducing remission in mildly to severely activeulcerative colitis. In contrast, placebo-controlledtrials have shown that low-dose oral corticosteroidtherapy (cortisone at 25 mg twice daily, prednisoneat 15 mg daily, or prednisone at 40 mg every otherday) is not effective for maintaining remission inulcerative colitis.

No controlled trials of intravenous corticosteroidtherapy for severely active ulcerative colitis havebeen conducted. Uncontrolled studies have sug-gested that intravenous prednisolone, 60 mg daily,or hydrocortisone, 300 to 400 mg daily, is effectivefor severely active ulcerative colitis. Most cliniciansadminister methylprednisolone, 40 to 60 mg daily,intravenously as a single bolus dose, in divideddoses (2-4 times daily), or as a continuous infusion.

Placebo-controlled trials have demonstratedthat hydrocortisone administered rectally as anenema at a dose of 100 mg daily or prednisolone ata dose of 5 mg daily is effective for inducing remis-sion in mild to moderately active left-sided ulcera-tive colitis or ulcerative proctitis. Placebo-controlledtrials also have shown that hydrocortisone enemasat a dose of 100 mg two nights per week are noteffective for maintaining remission in left-sidedulcerative colitis or ulcerative proctitis.

Placebo-controlled trials have demonstratedthat oral prednisone administered at a dose of 60mg daily and 6-methylprednisolone at 48 mg dailyare effective for inducing remission in mildly tomoderately active Crohn’s disease. In contrast,placebo-controlled trials have shown that low-dosecorticosteroids (oral prednisone, 20 mg daily, or6-methylprednisolone, 8 mg daily) are not effectivefor maintaining remission in Crohn’s disease.

Both short-term and long-term adverse eventsoccur frequently in patients receiving corticosteroidtherapy. Short-term adverse events include moonface, acne, ecchymoses, hypertension, hirsutism,petechial bleeding, striae, and psychosis. Long-termadverse events include diabetes mellitus, increasedrisk of infection, osteonecrosis, osteoporosis,myopathy, cataracts, and glaucoma. Corticosteroidsmay be taken during pregnancy and breastfeeding.

Budesonide is a newer corticosteroid, with90% first-pass metabolism in the liver. It can be

administered orally as a CIR formulation (releaseis pH dependent) or rectally as an enema. These“topical” formulations have fewer side effects thanconventional corticosteroids. A placebo-controlledtrial demonstrated that CIR budesonide at doses of9 to 15 mg daily is effective for inducing remissionin mild to moderately active ileal or right colonicCrohn’s disease. Comparative studies have shownthat oral CIR budesonide at 9 mg daily is moreeffective than mesalamine at 4 g daily and equiv-alent to oral corticosteroids for inducing remissionin active Crohn’s disease. In contrast, oral CIRbudesonide at 3 mg daily is not effective for main-taining remission in Crohn’s disease and 6 mg hasonly a modest short-term maintenance benefit.

AZATHIOPRINE AND 6-MERCAPTOPURINE Azathioprine is a prodrug that, after being admin-istered, is converted rapidly to 6-mercaptopurine.6-Mercaptopurine, then, is either inactivated to6-thiouric acid by xanthine oxidase or to 6-methylmercaptopurine by thiopurine methyl-transferase, or it is activated through severalenzyme steps to the 6-thioguanine nucleotides,which are thought to be the active metabolites. Theenzyme activity of thiopurine methyltransferaseis determined genetically: 1 in 300 patients haveno enzyme activity, 10% have intermediate enzymeactivity, and 90% have normal enzyme activity.

Placebo-controlled trials have demonstratedthat azathioprine at doses of 1.5 to 2.5 mg/kg dailyare effective for steroid-sparing in patients withsteroid-dependent ulcerative colitis. Similarly, aplacebo-controlled trial showed that azathioprineat 100 mg daily is effective for maintaining remis-sion in ulcerative colitis, and another trial showedthat azathioprine at 2.0 mg/kg daily was moreeffective than oral mesalamine at 3.2 g daily forthis indication.

Placebo-controlled trials have demonstratedalso that azathioprine at doses of 2 to 3 mg/kgdaily and 6-mercaptopurine at a dose of 1.5 mg/kgdaily are effective for inducing remission andclosing fistulas in patients with active Crohn’s dis-ease. Similarly, placebo-controlled trials haveshown that azathioprine at 2 to 3 mg/kg daily and6-mercaptopurine at 1.5 mg/kg daily are effective


for maintaining remission in Crohn’s disease andare steroid-sparing.

Adverse events that have been associated withazathioprine and 6-mercaptopurine includenausea, allergic reactions, pancreatitis, bonemarrow suppression, drug hepatitis, and infectiouscomplications. Patients with inflammatory boweldisease treated with azathioprine or 6-mercap-topurine have approximately a fourfold increasein the risk of lymphoma. In selected cases, azathio-prine and 6-mercaptopurine can be administeredduring pregnancy.

METHOTREXATEA placebo-controlled trial demonstrated thatmethotrexate administered orally at a dose of 12.5mg weekly is not effective for active ulcerativecolitis or for maintaining remission.

Placebo-controlled trials have demonstratedthat low-dose oral methotrexate, 12.5 mg weekly,is not effective for inducing or maintaining remis-sion in Crohn’s disease. In contrast, as shown byplacebo-controlled trials, higher-dose methotrexate,25 mg weekly given intramuscularly and possibly15 mg weekly given orally, is effective for inducingremission in patients with steroid-dependent andsteroid-refractory active Crohn’s disease. Aplacebo-controlled trial also showed thatmethotrexate at doses of 15 to 25 mg weekly givenintramuscularly is effective for maintenance ofremission and steroid-sparing in Crohn’s disease.

The adverse events that may occur withmethotrexate therapy include rash, nausea, mucositis,diarrhea, bone marrow suppression, hypersensi-tivity pneumonitis, increased levels of liver enzymes,and liver fibrosis or cirrhosis. Methotrexate is con-traindicated for pregnant women.

CYCLOSPORINE AND TACROLIMUSA placebo-controlled trial of intravenouscyclosporine administered as a continuous infusionat a high dose of 4 mg/kg daily (equivalent to 12-16 mg/kg daily of oral cyclosporine) demonstratedefficacy for inducing remission in patients withseverely active, steroid-refractory ulcerative colitis.A comparative trial showed that monotherapywith moderate-dose intravenous cyclosporine (2

mg/kg as a continuous daily infusion) has efficacysimilar to that of high-dose intravenous cyclosporine(4 mg/kg as a continuous daily infusion) forinducing remission in patients with severely activeulcerative colitis. There are no controlled trials oforal cyclosporine for the treatment of active ulcera-tive colitis or for maintaining remission in ulcera-tive colitis. A placebo-controlled trial demonstratedthat oral tacrolimus titrated to a target wholeblood level of 10 to 15 ng/mL was more effectivethan placebo for inducing remission in patientswith severely active, steroid-refractory ulcerativecolitis.

Placebo-controlled trials of cyclosporine admin-istered orally at a low dose of 5 mg/kg daily did notdemonstrate efficacy for inducing remission in activeCrohn’s disease or for maintaining remission inCrohn’s disease. There are no controlled trials ofhigh-dose cyclosporine administered intravenouslyfor severely active or fistulizing Crohn’s disease.

A placebo-controlled trial of oral tacrolimus,0.2 mg/kg daily, demonstrated efficacy for treat-ment of fistulizing Crohn’s disease.

The adverse effects that may occur withcyclosporine therapy include headache, tremor,paresthesias, seizures, hypertrichosis, gingivalhyperplasia, renal insufficiency, hypertension, infec-tions, hepatotoxicity, nausea and vomiting, and ana-phylaxis. The adverse effects that may occur withtacrolimus therapy include headache, tremor, pares-thesias, renal insufficiency, hypertension, infections,and diabetes mellitus. Although not absolutely con-traindicated, cyclosporine and tacrolimus therapygenerally should be avoided for pregnant women.

INFLIXIMAB AND ADALIMUMABInfliximab is a chimeric IgG1 monoclonal antibodydirected toward tumor necrosis factor (TNF)-α.Adalimumab is a fully human IgG1 monoclonalantibody directed toward TNF-α. Controlled trialshave shown that infliximab at 5 mg/kg admin-istered 3 times over 6 weeks as an intravenousinfusion is effective for inducing remission andclosing fistulas in active Crohn’s disease and forinducing remission in patients with active ulcera-tive colitis. For patients who have a response toinduction therapy with infliximab, re-treatmentwith infliximab at doses of 5 mg/kg or 10 mg/kg

204 Colon

administered intravenously every 8 weeks iseffective for maintaining remission in Crohn’s dis-ease and ulcerative colitis and is steroid-sparing.Controlled trials have demonstrated that adali-mumab administered subcutaneously at a dose of160 mg at week 0 and 80 mg at week 2 is effectivefor inducing remission in active Crohn’s disease,including in patients who previously had aresponse to infliximab therapy and then becameintolerant or lost response to it. For patients whohave had a response to adalimumab therapy, re-treatment with it at a dose of 40 mg every otherweek or every week is effective for maintainingremission in Crohn’s disease and is steroid-sparingand can result in fistula closure. Treatment of ulcer-ative colitis with adalimumab is investigational.

Adverse events that may occur with infliximaband adalimumab therapy include formation ofhuman anti-chimeric antibodies (infliximab) orhuman anti-human antibodies (adalimumab), infu-sion reactions (infliximab), injection site reactions(adalimumab), delayed hypersensitivity reactions(infliximab), autoantibody formation, drug-induced lupus, infection (particularly tuberculosisand fungal infections such as histoplasmosis), andpossibly non-Hodgkin’s lymphoma. Human anti-chimeric antibodies frequently lead to higher ratesof infusion reactions and loss of efficacy in patientsreceiving infliximab. The frequency of formationof human anti-chimeric antibodies in patientsreceiving infliximab is decreased when patientsreceive 1) three induction doses of infliximab, fol-lowed by systematic maintenance infusions every8 weeks; 2) concomitant immunosuppressivetherapy with azathioprine, 6-mercaptopurine, ormethotrexate; or 3) pretreatment with 200 mg ofhydrocortisone administered intravenously.Human anti-human antibodies occur infrequentlyin patients receiving adalimumab when they aregiven a loading dose of adalimumab at weeks 0and 2 and then systematic maintenance injectionsevery 1 to 2 weeks. Although data are limited,infliximab and adalimumab can be prescribed forpregnant women in selected circumstances.

SURGERY FOR ULCERATIVE COLITISThe original operation for ulcerative colitis consistedof total proctocolectomy with Brooke ileostomy

(Fig. 1). In the 1970s, the continent ileostomy, orKock pouch, served as an alternative to ileostomy(Fig. 1). Reoperation was frequently required withthe Kock pouch. In the 1980s, the ileoanal pouchlargely replaced the Kock pouch for patients withulcerative colitis who required operation (Fig. 1).Colectomy is indicated for patients with ulcerativecolitis who have definite low-grade or high-gradedysplasia, who have colorectal cancer, who aresteroid-dependent, or who have disease refractoryto medical therapy (including severely activesteroid-refractory ulcerative colitis and toxic mega-colon). Pouchitis is inflammation of the ileoanalpouch that leads to recurrent symptoms of diarrhea,urgency, and fecal incontinence. The cumulativefrequency of acute pouchitis after colectomy withileoanal pouch approaches 50% by 5 years. The fre-quency of chronic pouchitis is 5% to 10% by 5 years.

SURGERY FOR CROHN’S DISEASEThe probability of surgical resection in patientswith Crohn’s disease increases with time. By 15years after diagnosis, 70% of patients have had atleast one operation, and one-half of these have hadtwo or more operations. In patients with extensivestricturing or numerous previous operations (orboth), bowel-sparing techniques such as strictur-oplasty may be used (Fig. 2). In patients with peri-anal fistulas, incision and drainage of abscesses,fistulotomy, and placement of setons (drains) maybe used in an attempt to avoid proctectomy.

TREATMENT STRATEGIES FORULCERATIVE COLITIS

Induction of RemissionSulfasalazine, oral mesalamine, olsalazine, andbalsalazide are effective for inducing remission inpatients with active extensive or pancolonic ulcera-tive colitis. Patients with active ulcerative proctitis,ulcerative proctosigmoiditis, or left-sided ulcera-tive colitis may receive treatment with rectalmesalamine enemas or suppositories, cortico-steroid enemas, the oral therapies outlined abovefor extensive and pancolonic ulcerative colitis, ora combination of oral and rectal therapy. Forpatients who have disease that is moderate to


severe and for patients for whom sulfasalazine,oral or rectal mesalamine, olsalazine, or balsalazidetherapy failed, the next step is second-line therapywith prednisone. Patients with moderately activedisease can receive oral prednisone as an outpatient.Patients who require corticosteroid therapy oftenbecome steroid dependent. Patients with persis-tent symptoms may require oral corticosteroids,azathioprine or 6-mercaptopurine, infliximab, orcolectomy with ileostomy or ileoanal pouch.However, because of the slow onset of action, aza-thioprine and 6-mercaptopurine have limited useas induction agents in patients with significantlyactive ulcerative colitis. Infliximab is effective forthe treatment of active ulcerative colitis refractory

to other therapies, usually corticosteroids orimmunosuppressive medications (or both).Patients who are more severely ill should be hos-pitalized for intravenous corticosteroid therapy,and if the disease does not respond, colectomyshould be performed (intravenous cyclosporine,oral tacrolimus, and infliximab may be consideredas alternatives to colectomy). Methotrexate is noteffective for ulcerative colitis, and adalimumab isinvestigational for this condition.

Maintenance of RemissionSulfasalazine, oral mesalamine, olsalazine, andbalsalazide are effective for maintaining remissionin patients with extensive or pancolonic ulcerative

206 Colon

Fig. 1. Surgical options for ulcerative colitis.

Fig. 2. Stricturoplasty for Crohn’s disease.

Conventional ileostomy(Brooke)

Continent ileostomy(Kock pouch)

Ileoanal anastomosiswith reservoir

colitis. Patients with ulcerative proctitis, ulcerativeproctosigmoiditis, or left-sided ulcerative colitiscan receive maintenance treatment with rectalmesalamine enemas or suppositories or with theoral therapies outlined above for extensive andpancolonic disease. Low-dose prednisone is noteffective for maintaining remission, and patientswho receive corticosteroid therapy for active ulcer-ative colitis often become steroid dependent.Azathioprine and 6-mercaptopurine are effectivefor maintaining remission, particularly steroid-induced remission, and for steroid-sparing.Infliximab is effective for maintaining remissionin patients with disease refractory to other thera-pies. Administration of three induction doses over6 weeks and then systematic maintenance dosingevery 8 weeks and/or concomitant immunosup-pression decreases the frequency of human anti-chimeric antibody formation. Methotrexate is noteffective for ulcerative colitis, and adalimumab isinvestigational for this condition.

TREATMENT STRATEGIES FORCROHN’S DISEASE

Induction of RemissionSulfasalazine is modestly effective for inducingremission in patients with active Crohn’s disease,with the benefit confined largely to patients withCrohn’s colitis and ileocolitis. Mesalamine andmetronidazole are not consistently effective forinducing remission. Nevertheless, many clinicianscontinue to prescribe these agents for inducingremission in patients with mild to moderatelyactive Crohn’s disease. Budesonide is more effectivethan mesalamine and similarly effective to butsafer than prednisone. Thus, budesonide is thefirst-line treatment of choice for inducing remissionin patients with mild to moderately active Crohn’sdisease that involves the terminal ileum or rightcolon, whereas sulfasalazine is the optimal first-linetherapy for patients with Crohn’s colitis. A tradi-tional treatment algorithm for first-line therapyfor Crohn’s disease is shown in Figure 3. A newerevidence-based treatment algorithm for first-linetherapy for Crohn’s disease is shown in Figure 4.

For patients who have moderate to severedisease and for patients for whom budesonide or

sulfasalazine therapy failed, the next step issecond-line therapy with prednisone. Patientswith moderately active disease can receive oralprednisone as outpatients, but more severely illpatients should be hospitalized for intravenouscorticosteroid therapy. Often, patients who requirecorticosteroid therapy become steroid dependent.Because of the slow onset of action, azathioprine,6-mercaptopurine, and methotrexate are of lim-ited use as induction agents in patients with sig-nificantly active Crohn’s disease. Infliximab andadalimumab are effective for the treatment of activeCrohn’s disease refractory to other therapies,usually corticosteroids or immunosuppressivemedications (or both). Administration of threeinduction doses over 6 weeks and then systematicmaintenance dosing every 8 weeks and/or con-comitant immunosuppression reduces the frequencyof human anti-chimeric antibody formation inpatients receiving infliximab. Administration of twoinduction doses over 2 weeks and then systematicmaintenance dosing every 1 to 2 weeks results in


Yes

Maintenance program

Mild to moderate Crohn’s disease

Oral aminosalicylate (sulfasalazine)or metronidazole

Evaluate responseActive therapy to remission orfailure to continue improving

No

Treat for moderate-severe disease

Symptomaticremission?

Disease activity

Therapeuticintervention

Follow-up

Key phases/surgicalintervention

Persistent symptoms

Fig. 3. Suggested treatment algorithm for mildly tomoderately active Crohn’s disease using thetraditional approach to induction. (Modified fromSandborn WJ. Medical therapy for Crohn’s disease.In: Sartor RB, Sandborn WJ, editors. Kirsner’sinflammatory bowel diseases. 6th ed. Edinburgh:Saunders; 2004. p. 530-54. Used with permission.)

a low rate of human anti-human antibody formationin patients receiving adalimumab.

Maintenance Of Medically InducedRemissionSulfasalazine is not effective for maintenance ofmedically induced remission, and mesalamine isnot consistently effective. Metronidazole has notbeen evaluated for this indication. Low-dose pred-nisone is not effective for maintaining remission,and patients with active Crohn’s disease treatedwith corticosteroids often become steroid depen-dent. Budesonide, 6 mg, prolongs the time torelapse, but a maintenance effect as defined byconventional criteria has not been demonstrated.Azathioprine, 6-mercaptopurine, and methotrexateare effective for maintaining remission, particu-larly corticosteroid-induced remission. Infliximaband adalimumab are effective for maintaining

remission in patients with disease refractory toother therapies. Administration of three inductiondoses over 6 weeks and then systematic mainte-nance dosing every 8 weeks and/or concomitantimmunosuppression decreases the frequency ofhuman anti-chimeric antibody formation inpatients receiving infliximab. Administration oftwo induction doses over 2 weeks and then sys-tematic maintenance dosing every 1 to 2 weeksresults in a low rate of human anti-human anti-body formation in patients receiving adalimumab.A treatment algorithm for maintenance therapyin patients with Crohn’s disease that is budesonideor prednisone dependent or refractory is shownin Figure 5.

Postoperative Maintenance of RemissionSulfasalazine is not effective for postoperativemaintenance of remission. Mesalamine is not

208 Colon

Mild to moderate CDModerate CD

with systemic symptoms

Disease involvingthe left colon

Disease involving ileumand/or proximal colon

Sulfasalazine 3–6 g/dayfor 16 weeks

Budesonide 9 mg/day for8–16 weeks

Failed treatment orsulfa allergy

Failed treatment

Prednisone 40–60 mg/day Prednisone 40–60 mg/day

Intolerable side effects Failed treatment

Infliximab* 5 mg/kgat weeks 0, 2, and 6;then 5 mg/kg every

8 weeks

Fig. 4. Suggested treatment algorithm for mildly to moderately active Crohn’s disease (CD), using an evidence-based approach. *Disease may need to be reclassified as moderate to severe. (From Sandborn WJ, Feagan BG,Lichtenstein GR. Medical management of mild to moderate Crohn’s disease: evidence-based treatment algorithmsfor induction and maintenance of remission. Aliment Pharmacol Ther. 2007;26:987-1003. Used with permission.)

consistently effective and is of minimal benefit.Metronidazole, 20 mg/kg for 3 months, reducesthe recurrence of severe endoscopic lesions at 3months but does not alter clinical recurrence at 1year, and adverse effects are common. Low-doseprednisone is not effective for postoperative main-tenance therapy, nor is budesonide, 6 mg.Azathioprine and 6-mercaptopurine may be effec-tive, but clinical data are sparse. In the absenceof definitive data, these agents are currently thetreatment of choice for patients who are deemedto be at “high risk” for recurrence. Methotrexateand infliximab have not been evaluated for post-operative maintenance of remission. A treatmentalgorithm for postoperative maintenance therapyfor patients with Crohn’s disease is shown inFigure 6.

Closure of Fistulas and Maintenance ofFistula ClosureAntibiotics may be effective for fistula closure, butno placebo-controlled trial has been performed.Similarly, azathioprine and 6-mercaptopurine may

be effective for this treatment indication, but nocontrolled trials in which fistula closure is the pri-mary end point have been conducted. Uncontrolledstudies have suggested that cyclosporine may beeffective. Controlled trials have not been per-formed. A placebo-controlled trial of tacrolimusdid demonstrate effectiveness for fistula closurein patients with refractory fistulizing Crohn’s dis-ease. Infliximab and adalimumab are effective forboth inducing and maintaining fistula closure.Currently, infliximab is the best evidence-basedtherapy for fistulas. Administration of a loadingdose, followed by systematic maintenance therapyor concomitant immunosuppression (or both), isrequired. An algorithm for the treatment of perianalCrohn’s disease is shown in Figure 7.

CONCLUSIONSThe conclusions regarding therapy for differenttreatment indications in patients with ulcerativecolitis and Crohn’s disease are summarized inTables 2 and 3.


Consider trial of infliximab - Infuse x3 - Weeks 0, 2, 6Adalimumab - Inject x2 - Weeks 0 and 2

Assess urgency of symptoms, impact on quality of life, risk and feasibility of surgery

Impactminor

Initiate or optimize immunomodulatory therapy (6-MP, AZA, MTX)

Assess response

Good response

Continue as maintenancetherapy

Impactmajor

Poor response

Assess response at week 4 (adalimumab) or week 10 (infliximab)

Consider increased infliximab or adalimumab dose, other therapies, or surgery

Maintenance infusions or injections

Goodresponse

Poor response

Relapse

Fig. 5. Suggested treatment algorithm for managing patients with refractory Crohn’s disease. AZA,azathioprine; 6-MP, 6-mercaptopurine; MTX, methotrexate. (Modified from Sands BE. Therapy of inflammatorybowel disease. Gastroenterology. 2000;118:S68-S82. Used with permission.)

210 Colon

Patient undergoing resection for Crohn’s disease

Higher risk of recurrence

Receivingazathioprine

Continueazathioprine

Not yet receivingazathioprine

Startazathioprine

(± metronidazole)

Lower risk of recurrence

Endoscopy 6-12months

Moderate/severe lesions No/mild lesions

Symptoms No symptoms No therapy

Budesonide+ azathioprine

Azathioprine

Fig. 6. Suggested treatment algorithm, using a new evidence-based approach, for approach to patients operated onfor Crohn’s disease. (From Sandborn WJ. Medical therapy for Crohn’s disease. In: Sartor RB, Sandborn WJ, editors.Kirsner’s inflammatory bowel diseases. 6th ed. Edinburgh: Saunders; 2004. p. 530-54. Used with permission.)

Physical exam for pain, fluctuation, strictureEndoscopic exam for rectal inflammation

Perianal fistula

EUA + EUS or MRI ifpain, fluctuation, stricture present

No pain, fluctuation, stricture

Simple fistulaNo rectal inflammation

Simple or complex fistulawith rectal inflammation

Complex fistulaNo rectal inflammation

Antibiotics,azathioprine,or infliximab

EUA +EUS or MRI

Antibiotics,azathioprine,and infliximab

Antibiotics,azathioprine,or infliximab

EUA +EUS or MRI

EUA +EUS or MRI

Fistulotomy Consider tacrolimusin selected

patients

Seton Consider tacrolimusin selected

patients

Advancementflap

Fig. 7. Treatment algorithm for managing patients with Crohn’s perianal fistulas. EUA, examination underanesthesia; EUS, anorectal endoscopic ultrasonography; MRI, pelvic magnetic resonance imaging. Complexfistula is high and/or has multiple external openings, perianal abscess, rectovaginal fistula, anorectal stricture, ormacroscopic evidence of rectal inflammation. Simple fistula is low, has a single external opening, and does nothave associated perianal abscess, rectovaginal fistula, anorectal stricture, or macroscopically evident rectalinflammation. (From Sandborn WJ, Fazio VW, Feagan BG, Hanauer SB, American GastroenterologicalAssociation Clinical Practice Committee. AGA technical review on perianal Crohn’s disease. Gastroenterology.2003;125:1508-30. Used with permission.)


Table 2. Ulcerative Colitis: Treatment According to Indication

Mildly to moderately active Remission maintenance

Drug Distal Extensive Refractory Severely active Distal Extensive

Sulfasalazine Yes Yes Yes* No† Yes YesRectal Yes No Yes* No† Yes Nomesalamine

Oral Yes Yes Yes* No† Yes Yesmesalamine

Olsalazine Yes Yes Yes* No† Yes YesBalsalazide Yes Yes Yes* No† Yes YesRectal Yes No Yes* Yes‡ No Nocortico-steroids

Oral cortico- Yes Yes Yes* No No Nosteroids

Intravenous No No Yes§ Yes No Nocortico-steroids

Azathioprine No No Yes No Yes Yes/6-mercapto-purine

Cyclosporine No No No Yes No NoTacrolimus No No No Yes No NoInfliximab No No Yes Yes Yes YesColectomy No No Yes Yes No No

*Typically continued as a carryover of treatment for mild to moderately active disease when additional agents are added.†Typically discontinued because of the possibility of intolerance to sulfasalazine, mesalamine, or balsalazide.‡Adjunctive therapy to intravenous corticosteroids.§Some patients in whom therapy with oral corticosteroids has failed will have a response to hospitalization with

intravenous administration of corticosteroids.

RECOMMENDED READINGBaumgart DC, Sandborn WJ. Inflammatory bowel

disease: clinical aspects and established andevolving therapies. Lancet. 2007;369:1641-57.

Cammá C, Giunta M, Rosselli M, Cottone M.Mesalamine in the maintenance treatment ofCrohn’s disease: a meta-analysis adjusted forconfounding variables. Gastroenterology.1997;113:1465-73.

Clark M, Colombel JF, Feagan BC, Fedorak RN,Hanauer SB, Kamm MA, et al. American gas-troenterological association consensus devel-opment conference on the use of biologics inthe treatment of inflammatory bowel disease,June 21-23, 2006. Gastroenterology. 2007;133:312-39.

Egan LJ, Sandborn WJ. Methotrexate for inflam-matory bowel disease: pharmacology and pre-

liminary results. Mayo Clin Proc. 1996;71:69-80.

Hanauer SB, Sandborn W, Practice ParametersCommittee of the American College ofGastroenterology. Management of Crohn’sdisease in adults. Am J Gastroenterol.2001;96:635-43.

Kornbluth A, Sachar DB, Practice ParametersCommittee of the American College ofGastroenterology. Ulcerative colitis practiceguidelines in adults (update): AmericanCollege of Gastroenterology, PracticeParameters Committee. Am J Gastroenterol.2004;99:1371-85.

Pearson DC, May GR, Fick GH, Sutherland LR.Azathioprine and 6-mercaptopurine in Crohndisease: a meta-analysis. Ann Intern Med.1995;123:132-42.

212 Colon

Table 3. Crohn’s Disease: Treatment According to Indication

Mildly to Severely RemissionDrug moderately active Refractory Fistulizing active maintenance

Sulfasalazine Yes ?Yes* No No† ?Yes‡

Oral mesalamine ?Yes‡ ?Yes* No No† ?Yes‡

Antibiotics ?Yes‡ ?Yes* ?Yes‡ No ?Yes‡

Budesonide Yes ?Yes* No No NoOral corticosteroids Yes Yes* No No NoIntravenous corticosteroids No Yes§ No Yes NoAzathioprine/6-

mercaptopurine No Yes Yes No YesMethotrexate No Yes No No YesCyclosporine No No ?Yes// ?Yes// NoTacrolimus No No Yes No NoInfliximab No Yes Yes ?Yes ?YesAdalimumab No Yes Yes Yes YesSurgical resection No Yes Yes Yes No

*Controlled trials do not show an adjunctive benefit for sulfasalazine, mesalamine, or antibiotics when combined withcorticosteroids or budesonide. Typically continued as a carryover of treatment for mildly to moderately active diseasewhen additional agents are added.

†Typically discontinued because of the possibility of intolerance to sulfasalazine or mesalamine.‡Controlled trials do not uniformly show benefit, but treatment commonly is used in clinical practice.§Some patients in whom therapy with oral corticosteroids has failed will have a response to hospitalization with intravenous

administration of corticosteroids.//No controlled trials conducted; uncontrolled studies suggest benefit.


Sandborn WJ. Clinical review: a critical reviewof cyclosporine therapy in inflammatorybowel disease. Inflamm Bowel Dis. 1995;1:48-63.

Sandborn WJ, Fazio VW, Feagan BG, Hanauer SB,American Gastroenterological AssociationClinical Practice Committee. AGA technicalreview on perianal Crohn’s disease. Gastro-enterology. 2003;125:1508-30.

Sandborn WJ, Feagan BG, Lichtenstein GR.Medical management of mild to moderateCrohn’s disease: evidence-based treatmentalgorithms for induction and maintenance of

remission. Aliment Pharmacol Ther. 2007;26:987-1003.

Sandborn WJ, Hanauer SB. Antitumor necrosisfactor therapy for inflammatory bowel dis-ease: a review of agents, pharmacology, clin-ical results, and safety. Inflamm Bowel Dis.1999;5:119-33.

Sandborn WJ, Pardi DS. Clinical management ofpouchitis. Gastroenterology. 2004;127:1809-14.

Sutherland LR, May GR, Shaffer EA. Sulfasalazinerevisited: a meta-analysis of 5-aminosalicylicacid in the treatment of ulcerative colitis. AnnIntern Med. 1993;118:540-9.

Although ulcerative colitis and Crohn’s diseaseare idiopathic inflammatory bowel diseases (IBDs)that by definition affect the gastrointestinal tract,they are associated with a wide variety of systemiccomplications. Classically, such extraintestinalmanifestations are defined as immune-mediatedphenomena that affect the joints, eye, skin, or hepa-tobiliary tract, but they can be defined morebroadly to include complications in other organsystems and complications that arise as a directpathophysiologic consequence of extensive bowelinflammation or resection. This chapter reviewsthe most common extraintestinal manifestations,their relationship to activity of the underlyingbowel disease, and their treatment.

One of the complications of IBD most fearedby patients and physicians alike is the develop-ment of colorectal cancer. IBD is associated lesscommonly with other malignancies, such ascholangiocarcinoma. The risk of colorectal cancermay be mitigated partially with colonoscopicsurveillance. This chapter reviews risk factorsfor cancer and provides an algorithm for sur-veillance colonoscopy.

ARTHRITISThe overall prevalence of IBD-related rheumato-logic manifestations is thought to be approximately30%. Several types of arthritis have been identified,each with its own clinical presentation, naturalhistory, and treatment (Table 1).

Arthritis affecting the axial skeleton can beclassified into the more common, frequentlyasymptomatic, sacroiliitis and the less common,more progressive, ankylosing spondylitis. Subtleinflammatory changes of the sacroiliac joints maybe detected with magnetic resonance imaging in upto 45% of patients with IBD, but most patients areasymptomatic. Typical changes seen on plain radi-ographs of the sacroiliac joints include narrowingof the joints and surrounding sclerosis. Symptomaticsacroiliitis manifests as low back pain and stiff-ness, typically worse in the morning and with rest.A subset progresses to ankylosing spondylitis,which involves the vertebral facet joints and asso-ciated ligaments, resulting in progressive stiffnessand lordosis of the spine. The prevalence of anky-losing spondylitis in IBD ranges between 1% and6% across studies, with a higher prevalence in

215

CHAPTER 16

Inflammatory Bowel Disease:Extraintestinal Manifestations

and Cancer

Edward V. Loftus, Jr., MD

Abbreviations: IBD, inflammatory bowel disease; TNF, tumor necrosis factor.

Crohn’s disease than in ulcerative colitis. The rela-tionship between spondyloarthropathy, intestinalinflammation, and classic IBD is complex. Manypatients with ankylosing spondylitis who have nogastrointestinal symptoms have evidence of subtleileal inflammation, and symptomatic Crohn’s dis-ease eventually develops in 5% to 10% of thesepatients. Radiographic changes of ankylosingspondylitis include squaring of the vertebral bodiesin the early stages, followed by the classic “bamboospine” appearance of syndesmophytes betweenthe vertebral bodies. The HLA-B27 antigen is asso-ciated with ankylosing spondylitis in 50% to 75%of patients who have concomitant IBD and anky-losing spondylitis. HLA-B27 positivity in patientswith sacroiliitis implies a higher risk of progressionto ankylosing spondylitis.

The clinical course of the axial arthritides asso-ciated with IBD appears to be unrelated to theactivity of the underlying bowel disease. Thecourse of ankylosing spondylitis is typically pro-gressive even if the associated IBD is quiescent.The treatment of ankylosing spondylitis has beenrevolutionized with the availability of tumornecrosis factor (TNF) antagonists. First-line therapyconsists of physical therapy directed at maintainingspinal mobility, analgesics such as acetaminophen(with or without mild opioid agents such aspropoxyphene or hydrocodone), and antiinflam-matory agents if needed. Conventional non-steroidal antiinflammatory drugs can be a problembecause they may trigger an exacerbation of IBD.

There is little evidence that methotrexate is effectivein treating ankylosing spondylitis. In more resis-tant cases, etanercept, infliximab, or adalimumabis indicated.

The peripheral arthritis that occurs with IBDconsists of two subtypes that are associated withdifferent HLA antigens. Type 1, the more commontype, is an asymmetric oligoarticular arthritis thataffects primarily large joints such as the knees,ankles, wrists, and elbows. The clinical presentationconsists of joint pain and swelling, with limitedrange of motion. Plain radiographs typically donot show destructive changes, although they rarelymay be apparent. Type 1 arthritis is usually self-limited, and its activity mirrors the activity of theunderlying IBD. Rarely, this form of peripheralarthritis becomes more chronic. Type 2 arthritis isa more chronic symmetric polyarthritis, similar torheumatoid arthritis; however, rheumatoid factoris typically absent. The activity of this arthritis isindependent of the associated IBD. Initial treat-ment of peripheral arthritis consists of physicaltherapy and analgesics. Nonsteroidal antiinflam-matory drugs may exacerbate the underlying IBD.Sulfasalazine should be considered the aminosa-licylate of choice because it has mild efficacy forsymptoms of peripheral arthritis. Corticosteroids,administered by either oral ingestion or intra-articular injection, may be required. Considerableevidence supports the use of methotrexate fortreating peripheral manifestations of spondy-loarthropathy in patients with IBD. For refractorycases of peripheral arthritis, an anti-TNF agentmay be required.

OCULAR MANIFESTATIONSInflammatory ocular complications occur in 1%to 13% of patients with IBD (Table 2). The mostcommon forms are anterior uveitis (also knownas iritis) and scleritis. An inflammatory retinopathyor keratitis (corneal inflammation) may occur lessfrequently. Anterior uveitis occurs in up to 6% ofpatients with IBD and manifests with ocular pain,redness, photophobia, or blurred vision. The pre-sentation may be either acute or chronic. The acuteform is associated with HLA-B27 in 50% of patients;the chronic form is not associated with any partic-ular HLA antigen. If the diagnosis is suspected, it

216 Colon

Table 1. Bone and Joint Manifestations ofInflammatory Bowel Disease

SpondyloarthropathyAxial skeleton

SacroiliitisAnkylosing spondylitis

PeripheralType 1 (oligoarticular)Type 2 (polyarticular) (rare)

Metabolic bone diseasesOsteoporosis or osteopeniaOsteomalacia (rare)Osteonecrosis (rare)

should be confirmed with a slit-lamp examinationby an ophthalmologist. (Indeed, any ocular symp-toms in a patient with IBD should prompt referralto an ophthalmologist.) The activity of the HLA-B27–associated form does not necessarily correlatewith the activity of the IBD, whereas the activityof the chronic form unrelated to HLA antigens typ-ically mirrors the activity of the bowel disease. Arecent retrospective study suggested that sul-fasalazine treatment caused fewer exacerbationsof uveitis in the year after therapy was initiatedthan during the previous year (from 3.4 to 0.9 flaresper year). If left untreated, uveitis can result in irre-versible complications such as adhesions, cataracts,and glaucoma. Initial treatment consists of topicalcorticosteroids and cycloplegic agents. For morerefractory disease, oral corticosteroids may berequired. Recent studies have shown the steroid-sparing qualities of methotrexate in this setting, andthe results of open-label studies of TNF inhibitors forthe treatment of uveitis have been promising.

Episcleritis and scleritis produce symptomsof eye irritation (eg, burning and itching) and con-junctival erythema. The activity of these conditionstypically correlates with the activity of the IBD. Initialtreatment consists of topical corticosteroids, but oralcorticosteroids may be required for refractory scle-ritis. Again, because an untrained physician cannotdifferentiate vision-threatening conditions such asscleritis from nonthreatening conditions such asepiscleritis, ocular symptoms in a patient with IBDshould prompt referral to an ophthalmologist.

Some ocular complications may be treatment-related (Table 2). The most common example iscataract formation after prolonged treatment with

corticosteroids. The cumulative incidence ofcataract formation may be as high as 85% after 4years of corticosteroid use. Less commonly, pro-longed corticosteroid therapy may precipitate thedevelopment of glaucoma. Patients with IBD whohave required prolonged courses of corticosteroids(ie, several years) should have periodic eye exam-inations even if they are asymptomatic.

DERMATOLOGIC MANIFESTATIONSThe two most common dermatologic extraintestinalmanifestations are pyoderma gangrenosum anderythema nodosum. However, numerous otherdisorders of the skin have been described in asso-ciation with IBD (Table 3). Pyoderma gangrenosumis an idiopathic ulcerative skin disease that occursin up to 12% of patients with IBD. It is manifestedinitially as a pustular lesion, which evolves to anulcer with undermining borders. The lesion oftenexhibits “pathergy,” or a tendency to worsen withtrauma. The most common location is the lowerextremity, but the lesion can occur anywhere,including peristomal areas in patients withostomies. Although skin biopsy findings may behelpful in excluding other conditions, pyodermagangrenosum has no pathognomonic histologicfeatures, and the diagnosis is a clinical one.Bacterial and fungal superinfection should be

Inflammatory Bowel Disease: Extraintestinal Manifestations and Cancer 217

Table 2. Ocular Manifestations ofInflammatory Bowel Disease

InflammatoryAnterior uveitis (iritis)ScleritisEpiscleritisRetinitis (rare)

Treatment-related (corticosteroids)CataractsGlaucoma

Table 3. Dermatologic Manifestations ofInflammatory Bowel Disease

CommonPyoderma gangrenosumErythema nodosumCutaneous (“metastatic”) Crohn’s diseaseAphthous stomatitis

Less commonBowel-associated dermatosis-arthritis

syndrome (bowel bypass syndrome)Sweet’s syndrome (acute neutrophilic

dermatosis)Epidermolysis bullosa acquisitaMucosal cobblestoning of buccal mucosa

and palatePyostomatitis vegetans

excluded. The course of pyoderma gangrenosumis independent of the associated IBD. First-linetreatment consists of oral corticosteroids. Thereshould be a low threshold for institution ofimmunosuppressive therapies so that the dose ofcorticosteroids can be tapered rapidly. The mostcommonly used immunosuppressive agents arecyclosporine and tacrolimus, although azathio-prine and mycophenolate mofetil have been usedoccasionally for more chronic lesions. Case reportsand case series have reported the efficacy of inflix-imab in both adult and pediatric patients withrefractory pyoderma gangrenosum.

Erythema nodosum occurs more commonlyin Crohn’s disease (up to 15% of cases) but mayoccur rarely in ulcerative colitis (up to 5% of cases).For reasons that are unclear, this complication ismost likely to develop in young women. The pre-sentation is painful, tender, erythematous subcu-taneous nodules, most typically in the pretibialareas. The activity of erythema nodosum tends tocorrelate with that of the underlying IBD, and thelesions typically resolve with aggressive treatmentof the bowel disease. Supportive care for erythemanodosum includes leg elevation, support stockings,bed rest, and nonsteroidal antiinflammatory drugs.Cutaneous Crohn’s disease refers to granulomatouslesions of the skin, most commonly in the perianalregion. When such changes occur distant to theperineum, they are sometimes called metastaticCrohn’s disease. These lesions occur as erythematousplaques or nodules. Disease activity may not corre-late with that of the underlying IBD, and treatmentmay be difficult. Corticosteroids and immunosup-pressive therapy frequently are required.

Oral manifestations of inflammatory boweldisease include oral aphthous ulcers (which occurin up to 10% of patients with Crohn’s disease) and,less commonly, mucosal cobblestoning of the buccalmucosa and palate and pyostomatitis vegetans.The latter is characterized by pustules, erosions,and plaques on the buccal and gingival mucosa.

HEPATOBILIARY MANIFESTATIONSThe most important hepatobiliary condition asso-ciated with IBD is primary sclerosing cholangitis(Table 4). This idiopathic chronic cholestatic liverdisease is characterized by inflammation and

fibrosis of the biliary tree. Approximately 75% to80% of all patients with primary sclerosing cholan-gitis have associated IBD, and most of these haveulcerative colitis. Conversely, 2% to 7% of patientswith ulcerative colitis and an even smaller percentageof patients with Crohn’s disease have associated pri-mary sclerosing cholangitis. Patients present withpruritus and jaundice in advanced stages of thecondition; however, with increased diagnosticawareness, the most frequent presentation is in anasymptomatic patient with IBD who has abnormalresults on liver biochemistry tests. The presenceof numerous strictures and dilatations of the extra-hepatic or intrahepatic biliary tree found on endo-scopic retrograde cholangiopancreatography mostcommonly confirms the diagnosis. Liver biopsymay be necessary for diagnosis in small duct pri-mary sclerosing cholangitis (formerly known as“pericholangitis”). The IBD associated with pri-mary sclerosing cholangitis is commonly mild inactivity and almost always pancolonic in extent.Rectal sparing and “backwash ileitis” appear tobe more common in primary sclerosing cholan-gitis-related IBD than in typical ulcerative colitis,suggesting that primary sclerosing cholangitis-associated IBD may be a unique phenotype. Thecourse of primary sclerosing cholangitis is com-pletely independent of the underlying IBD, andeven total proctocolectomy is thought to have noeffect on its natural history. The disease course istypically progressive, and there are no proven

218 Colon

Table 4. Hepatobiliary Manifestations ofInflammatory Bowel Disease

BiliaryPrimary sclerosing cholangitis (large duct) Small duct primary sclerosing cholangitis

(formerly known as “pericholangitis”)Cholelithiasis or choledocholithiasisCholangiocarcinoma (rare)Primary biliary cirrhosis (rare)

HepaticFatty liver or steatohepatitisAutoimmune hepatitisDrug-induced liver injury (thiopurines,

methotrexate, 5-aminosalicylates)

medical therapies, although high-dose ursodeoxy-cholic acid appears promising. Orthotopic liver trans-plantation may be required. Complications includeacute cholangitis, formation of dominant biliarystrictures, choledocholithiasis, and cholangiocarci-noma (see Chapter 29, Cholestatic Liver Disease).

Autoimmune hepatitis is associated rarelywith IBD, but when it is, it usually is associatedwith ulcerative colitis. Some patients may have fea-tures of both autoimmune hepatitis and primarysclerosing cholangitis (the so-called overlap syn-drome) (see Chapter 31, Autoimmune Hepatitis).

Cholelithiasis is a common consequence ofCrohn’s disease. Either inflammation or surgicalresection of the distal ileum impairs enterohepaticrecycling of bile salts and upsets the balance of bilesalts, cholesterol, and phospholipids, leading to anincreased tendency to form cholesterol crystals andstones. Pigment stones also have been implicatedin patients with steatorrhea, most likely because ofimpaired enterohepatic circulation of bilirubin.

OSTEOPENIA AND OSTEOPOROSISAccumulating evidence strongly suggests thatosteopenia and osteoporosis are highly prevalentin IBD (up to 50%-70% of patients, depending onthe patients studied and definitions used) (Table 1).Several factors may have a role, including cortico-steroid use, malabsorption of calcium and vitaminD, malnutrition, low body mass index, cigarettesmoking, and increased concentrations of cytokines,which contribute to bone resorption. However, con-ventional risk factors for osteoporosis such asfemale sex, menopause, and increasing age areequally important in patients with IBD. Althoughcorticosteroid use is thought by some investigatorsto be the most important risk factor for osteoporosisin IBD, vertebral compression fractures have beendiagnosed occasionally in patients with IBD whohave never received corticosteroids. Bone loss asso-ciated with corticosteroid use is rapid, and the bulkof the loss occurs within the first several monthsof therapy. Unexpectedly, population-based studiesof patients with IBD have shown only a modestlyincreased risk of actual bone fracture compared withthat of the general population. The diagnosis of osteo-porosis is made with bone mineral densitometry(dual photon absorptiometry). A T score of –2.5

(more than 2.5 standard deviations below mean bonemass for a young adult) signifies osteoporosis, anda T score between –1 and –2.5 signifies osteopenia.There is as yet no consensus about which patientswith IBD should have densitometry screening.Patients with IBD who have the usual risk factors,including the postmenopausal state and low bodymass index, should have the screening test. Also,patients whose cumulative systemic corticosteroidexposure is more than 6 months should be consid-ered for testing. Treatment consists of calcium andvitamin D supplementation (1,200 mg calcium and800 IU vitamin D), sex hormone replacement ifdeficient, and an oral bisphosphonate (alendronate,risedronate, or ibandronate). For patients who areintolerant of oral bisphosphonates, therapeuticoptions include intravenous bisphosphonates(pamidronate, zoledronic acid, or ibandronate)intranasal calcitonin, or parenteral teriparatide.

MISCELLANEOUS COMPLICATIONSRenal complications are most common in Crohn’sdisease (Table 5). Nephrolithiasis may occur in upto 10% of patients with Crohn’s disease, mostly aresult of calcium oxalate stone formation. Intestinalinflammation or resection cause excessive absorp-tion of oxalate. With fat malabsorption, theintestinal luminal calcium, which normally bindsto oxalate, binds instead to fatty acids, leavingoxalate free to be absorbed from the colonic lumen.Patients with ulcerative colitis, especially thosewho have had colectomy, have a slightly increasedtendency to form uric acid stones. Other renal com-plications include glomerulonephritis, rightureteral obstruction due to ileal inflammation, andenterovesical fistula formation. Interstitial nephritiscan result from an idiosyncratic reaction to 5-aminosalicylate products, and it is recommendedthat renal function be assessed at baseline and mon-itored periodically thereafter.

Hematologic complications such as anemia,thrombocytosis, and leukocytosis are common.Anemia may be multifactorial (eg, iron or vitaminB12 deficiency and anemia of chronic disease),and, rarely, it is a sign of an associated hemato-logic disorder such as autoimmune hemolyticanemia, myelodysplastic syndrome, or promye-locytic leukemia.


Various cardiopulmonary complications havebeen described, including pericarditis, myocarditis,conduction abnormalities, eosinophilic pneumonia,and interstitial pneumonitis. Pericarditis and pneu-monitis may arise both as a true extraintestinal man-

ifestation and as an allergic complication of treat-ment with sulfasalazine or other 5-aminosalicylates.

In IBD, pancreatitis most commonly occurs as acomplication of medical therapy. Azathioprine and6-mercaptopurine are most likely to result in pan-creatitis (3%-5% of patients). Also, but rarely, acutepancreatitis has developed after treatment with sul-fasalazine or other 5-aminosalicylates. In patientswith duodenal Crohn’s disease, pancreatitis mayresult from a stricture or fistula formation. However,up to 50% of patients with IBD have no obvious causeof pancreatitis, and a subset of these may have a trueextraintestinal manifestation. In some patients withCrohn’s disease, granulomatous inflammation ofthe pancreas seems to develop. Furthermore,antipancreatic antibodies have been described in upto 30% of patients with Crohn’s disease.

Thromboembolism is more common inpatients with IBD than in the general population,probably because of various factors. Activation ofthe inflammatory cascade in IBD appears to resultin secondary activation of important mediators ofthrombosis, such as platelets, fibrinogen, and fi-brinopeptide A. A single genetic mutation doesnot appear to be responsible, but cases of factor VLeiden mutation, protein C deficiency, and pro-tein S deficiency have been described. Initially, therisk of thromboembolism was tied to the activityof IBD, but there are numerous reports of throm-boembolic activity in the absence of active IBD.

COLORECTAL CANCERPatients with ulcerative colitis, and likely Crohn’scolitis, are at increased risk for colorectal cancer,and this remains an important cause of mortalityin patients with IBD. In most population-basedstudies of ulcerative colitis, the relative risk of col-orectal cancer is 2 to 8 times higher than that of thegeneral population. Overall, the absolute risk, orcumulative incidence, of colorectal cancer is 8% to18% after 20 to 30 years of ulcerative colitis.However, when the risk is stratified by the extentof disease, it is clear that more extensive diseaseconfers a higher risk of colorectal cancer (Table 6).The cumulative incidence of colorectal canceramong patients with extensive ulcerative colitis(ie, extent of disease proximal to the splenic flexure)ranges from 6% to 50% after 30 years of disease.

220 Colon

Table 5. Miscellaneous ExtraintestinalManifestations and Complicationsof Inflammatory Bowel Disease

RenalNephrolithiasis (oxalate, urate)Glomerulonephritis (rare)Right ureteral obstructionUrinary system fistulas (eg, enterovesical,

colovesical, rectourethral)Tubulointersitial nephritis (5-

aminosalicylates)Hematologic

AnemiaIron deficiencyVitamin B12 deficiencyFolic acid deficiencyAnemia of chronic diseaseAutoimmune hemolytic anemia

NeoplasticMyelodysplastic syndrome (rare)Promyelocytic leukemia (rare)

CardiopulmonaryPericarditis (extraintestinal manifestation or

drug-induced)MyocarditisConduction abnormalitiesPneumonitisEosinophilic pneumoniaBronchiolitis obliterans with organizing

pneumoniaPancreatic

Acute pancreatitisDrug-induced (purine analogues, 5-aminosalicylates)

Duodenal Crohn’s diseaseGranulomatous involvement of pancreas (rare)

Chronic pancreatitisAutoimmune pancreatitis

ThrombophiliaMultifactorial

Another major risk factor appears to be duration ofulcerative colitis. The cumulative risk of colorectalcancer does not seem to be higher than that for thegeneral population until 8 to 10 years after diagnosis,and the increase in risk is 0.5% to 1% each yearthereafter. Whether age at onset of colitis is a riskfactor independent of disease duration is unclear.

Another important risk factor for colorectalcancer in IBD appears to be the presence of primarysclerosing cholangitis. Whether primary sclerosingcholangitis is a truly independent risk factor for co-lorectal cancer or whether it functions as a marker forlong-standing but asymptomatic pancolitis is notclear. Also, a family history of colorectal cancer in apatient with IBD appears to be a risk factor for cancerindependent of the aforementioned factors.

In many studies, prolonged treatment with 5-aminosalicylates or sulfasalazine appears todecrease the risk of colorectal cancer substantially.Conversely, in the period when non-sulfonamide5-aminosalicylate agents were not available com-mercially, the presence of sulfonamide allergyappeared to be a risk factor for colorectal cancer.However, the data are conflicting on this point, inthat some studies have not found a risk reductionfor patients receiving treatment with 5-aminosali-cylates. Several studies also have suggested that theuse of ursodeoxycholic acid is associated with alower risk of colorectal neoplasia among patientswith primary sclerosing cholangitis who have IBD.

Dysplasia frequently precedes or is associ-ated with IBD-related colorectal cancer. The dys-plastic change may be flat or polypoid onendoscopy. Surveillance colonoscopy with biopsyat regular intervals is offered to many patients

with long-standing and extensive ulcerative colitisin an attempt to manage the increased risk of co-lorectal cancer. Although surveillance colonoscopyhas never been proved to decrease colorectal cancer-related mortality of patients with IBD, several retro-spective studies have suggested this to be the case.Surveillance is thought to detect early, curable cancersand to identify patients at increased risk for the devel-opment of cancer. The use of staining dyes in com-bination with high-magnification lenses (also knownas chromoendoscopy) may increase substantially theability of the endoscopist to detect dysplastic lesions.This technique is actively being studied.

We recommend institution of regular surveil-lance colonoscopy with biopsy after 8 to 10 yearsof left-sided or extensive colitis in both ulcerativecolitis and Crohn’s disease. This procedure shouldbe performed at least every other year, and someexperts advocate yearly procedures. Patients withonly proctitis do not have an increased risk of co-lorectal cancer and do not require surveillancecolonoscopy. Patients with primary sclerosingcholangitis should begin surveillance colonoscopyimmediately. Random biopsy specimens shouldbe obtained in a consistent fashion (“the morebiopsies, the better”). Some experts advocate four-quadrant biopsies every 10 to 15 cm, which resultsin approximately 40 biopsy specimens. At MayoClinic, we obtain a minimum of 32 biopsy speci-mens (4 each from the cecum, ascending, proximaltransverse, distal transverse, proximal descending,distal descending, and sigmoid colon and rectum).These are placed in four bottles (eight per bottle).In addition to the 32 random samples, specimensare obtained from suspicious lesions or nodulesand placed in separate bottles.

Most investigators agree that patients withflat, high-grade dysplasia are at particularly highrisk for either synchronous cancer or metachronouscancer in the near future. Immediate colectomy isrecommended. However, debate continues aboutwhether patients with flat, low-grade dysplasiashould be offered immediate colectomy or moreintensive surveillance colonoscopy. At MayoClinic, we recommend immediate colectomybecause most retrospective studies have suggestedthat the 5-year risk for progression to high-gradedysplasia, polypoid dysplasia, or cancer after adiagnosis of low-grade dysplasia may be as high as


Table 6. Risk Factors for Colorectal Cancer inInflammatory Bowel Disease

Extent of colitisDuration of diseaseFamily history of colorectal cancerPrimary sclerosing cholangitisMedical noncompliance or lack of follow-upNo or minimal use of sulfasalazine or 5-

aminosalicylatesSulfonamide allergy

50%. The management of polypoid dysplasia (for-merly known as dysplasia-associated lesion ormass) also is evolving. Previous dogma suggestedthat all such lesions were an indication for imme-diate colectomy. However, recent studies havesuggested that if these lesions are not associatedwith flat dysplasia in the surrounding mucosa,they can be removed safely with colonoscopicpolypectomy and then followed up closely.

OTHER CANCERSPatients with ulcerative colitis are at increased riskfor cholangiocarcinoma, likely because of theincreased risk of primary sclerosing cholangitis inthe population with ulcerative colitis. (Primarysclerosing cholangitis is a risk factor for cholan-giocarcinoma.) Patients who have Crohn’s diseasewith small-bowel involvement seem to be atincreased risk for small-bowel adenocarcinomacompared with the general population. However,the absolute risk is low, and surveillance for thislesion is not recommended. Whether IBD is a riskfactor for lymphoma is a matter of controversy.Population-based studies generally have notshown an increased relative risk, although this hasbeen suggested by several referral center-basedstudies. The question has become more complicatedwith widespread use of immunosuppressiveagents such as azathioprine, 6-mercaptopurine,methotrexate, and infliximab. It is well recognizedthat immunosuppressed states, such as posttrans-plantation state and acquired immunodeficiencysyndrome, are associated with an increased risk oflymphoproliferative disorders. Although mostindividual studies of patients with IBD who havereceived immunosuppressive agents have notshown an increased risk of lymphoma, a meta-analysis of lymphoma risk among patients with IBDbeing treated with 6-mercaptopurine or azathio-prine suggested a threefold increase in lymphomarisk. It is important to emphasize that the absoluterisk of lymphoma is small, and, in most situations,the benefits of the drug outweigh this potential risk.

RECOMMENDED READINGBernstein CN, Blanchard JF, Rawsthorne P, Yu N.

The prevalence of extraintestinal diseases in

inflammatory bowel disease: a population-basedstudy. Am J Gastroenterol. 2001;96:1116-22.

Broomé U, Bergquist A. Primary sclerosing cholan-gitis, inflammatory bowel disease, and coloncancer. Sem Liver Dis. 2006;26:31-41.

Hoffmann RM, Kruis W. Rare extraintestinal man-ifestations of inflammatory bowel disease.Inflamm Bowel Dis. 2004;10:140-7.

Jones JL, Loftus EV Jr. Lymphoma risk in inflam-matory bowel disease: is it the disease or itstreatment? Inflamm Bowel Dis. 2007;13:1299-1307.

Koutroubakis IE. Therapy insight: vascular com-plications in patients with inflammatory boweldisease. Nat Clin Pract Gastroenterol Hepatol.2005;2:266-72.

Lichtenstein GR, Sands BE, Pazianas M. Preventionand treatment of osteoporosis in inflamma-tory bowel disease. Inflamm Bowel Dis.2006;12:797-813.

Loftus EV Jr. Management of extraintestinal man-ifestations and other complications of inflam-matory bowel disease. Curr Gastroenterol Rep.2004;6:506-13.

Loftus EV Jr, Harewood GC, Loftus CG, TremaineWJ, Harmsen WS, Zinsmeister AR, et al. PSC-IBD: a unique form of inflammatory boweldisease associated with primary sclerosingcholangitis. Gut. 2005;54:91-6.

Maggs JR, Chapman RW. Sclerosing cholangitis.Curr Opin Gastroenterol. 2007;23:310-6.

Meier C, Plevy S. Therapy insight: how the guttalks to the joints: inflammatory bowel diseaseand the spondyloarthropathies. Nat Clin PractRheumatol. 2007;3:667-74.

Rothfuss KS, Stange EF, Herrlinger KR.Extraintestinal manifestations and complica-tions in inflammtory bowel disease. World JGastroenterol. 2006;12:4819-31.

Smale S, Natt RS, Orchard TR, Russell AS, BjarnasonI. Inflammatory bowel disease and spondy-loarthropathy. Arthritis Rheum. 2001;44:2728-36.

Solem CA, Loftus EV, Tremaine WJ, Sandborn WJ.Venous thromboembolism in inflammatorybowel disease. Am J Gastroenterol. 2004;99:97-101.

Taylor SR, McCluskey P, Lightman S. The ocularmanifestations of inflammatory bowel dis-ease. Curr Opin Ophthalmol. 2006;17:538-44.

222 Colon

Infections are a common cause of gastrointestinaldisease. This chapter focuses on the more commoninfectious causes of diarrhea, food poisoning, anddiverticulitis. It does not review Helicobacter pyloriinfection, bacterial overgrowth, or infections inpatients seropositive for human immunodefi-ciency virus (HIV), because they are consideredin other chapters.

Worldwide, an estimated 1 billion cases ofinfectious diarrhea occur annually, and the deathrates are second only to those of cardiovasculardisease. It is estimated that every 10 seconds world-wide infectious diarrhea causes the death of onechild younger than 5 years. Thus, in some areas,diarrheal diseases are responsible for more yearsof life lost than all other causes combined.Infectious diarrhea is more common in childrenand in developing countries than in adults in devel-oped countries. In developed countries, the infec-tions are usually mild and self-limited and, thus,antibiotic therapy is unnecessary. In specific cases,antibiotics are not effective (Table 1). The clinicalfeatures of infectious diarrhea vary, depending on

whether the organism is invasive and whether theinfection occurs in the small bowel or colon (Table 2).

VIRUSESIn the United States, most cases of gastroenteritisare viral and usually are brief and self-limited(Table 3). Viral gastroenteritis usually is charac-terized by diarrhea of brief duration, often withnausea and vomiting, but the absence of high fever,severe abdominal pain, and bloody diarrhea.Therapy is symptomatic with antiemetics, antipy-retics, and attention to adequate hydration.

RotavirusRotavirus is the most common cause of diarrhea inyoung children worldwide. Adult infection oftenoccurs after contact with a sick child or as part ofan institutional epidemic. In tropical climates,rotavirus infection occurs year-round; in temperateclimates, it is more common in the winter. Spreadis by the fecal-oral route, facilitated by prolongedsurvival in the environment and resistance to many

223

CHAPTER 17

Gastrointestinal Infections,Clostridium difficile-Associated

Disease, and Diverticular Disease

Conor G. Loftus, MDDarrell S. Pardi, MD

Abbreviations: AIDS, acquired immunodeficiency syndrome; EAEC, enteroaggregative E. coli; EHEC, enterohemorrhagicE. coli; EIEC, enteroinvasive E. coli; ELISA, enzyme-linked immunosorbent assay; EPEC, enteropathogenic E. coli;ETEC, enterotoxigenic E. coli; HIV, human immunodeficiency virus; HUS, hemolytic uremic syndrome; TMP-SMX,trimethoprim-sulfamethoxazole; TTP, thrombotic thrombocytopenic purpura.

disinfectants. Symptoms occur within 72 hoursafter exposure, last up to 5 days, and include mildfever, diarrhea, and vomiting. Most adults aremildly symptomatic or asymptomatic, but thedisease can be severe in persons who are immuno-compromised, malnourished, or chronically ill.Death can occur from dehydration and acidosis,usually in the very young or elderly. Symptomsmay be prolonged because of transient disaccha-ridase deficiency caused by severe small-bowelinfection. Treatment focuses on dehydration. Oralrehydration is optimal because oral nutrition stim-ulates mucosal repair, leading to shorter durationand less severe diarrhea. Protective immunity maynot develop after natural infections, although rein-fection tends to be less severe. An effective vaccinewas developed but was withdrawn because of anassociation with intussusception.

CalicivirusesCaliciviruses, also known as small round-structuredviruses, are the most important cause of viral gas-troenteritis in adults, and they cause many outbreaksin young children and adults. The most commoncaliciviruses are the Norwalk-like viruses. Outbreaksare associated with contaminated food (eg, shellfish),water, or person-to-person spread. Caliciviruses arecommon in the environment and are resistant to dis-infectants and chlorination. The incubation periodis less than 48 hours, followed by illness lasting upto 3 days. Infection occurs in the proximal smallbowel. Diarrhea, nausea, vomiting, abdominal pain,fever, headache, and malaise are common but typ-ically mild. Postinfectious immunity is not perma-nent or fully protective against reinfection.

AstrovirusAstrovirus is an important cause of diarrhea ininfants and children, particularly in developingcountries. Nausea and vomiting are common,although usually less severe than with rotavirus.The incubation period is 2 to 4 days. Illness is mildand lasts up to 5 days.

Enteric AdenovirusMost adenoviruses cause respiratory infection,although some strains cause diarrhea. Respiratorysymptoms may precede gastrointestinal mani-festations. A long incubation period (up to 10days) and diarrhea of long duration (1-2 weeks)are characteristic.

BACTERIABacteria are relatively uncommon causes of acutediarrhea, and the indiscriminate culturing of stoolfrom patients with acute diarrhea produces fewpositive findings, with an unacceptably high costper positive culture. However, stool cultures areappropriate for patients who have bloody diarrhea,high fever or pain, fecal leukocytes, immuno-compromise, or diarrhea persisting longer than afew days. In most laboratories, routine stool cul-tures detect Salmonella, Shigella, and Campylobacter.Escherichia coli O157:H7, Yersinia, Vibrio, and othersoften require a special request.

Many bacterial causes of diarrhea do not requireantibiotic therapy in healthy adults. However, in

224 Colon

Table 1. Effectiveness of Antibiotic Therapyfor Infectious Diarrhea

Antibiotics are effective and indicatedSalmonella enterocolitis in an

immunocompromised hostSalmonella typhoid feverShigellaClostridium difficileYersinia sepsis or systemic infectionModerate-to-severe traveler’s diarrheaCampylobacter dysentery or sepsisVibrio choleraeGiardiaAmebiasis

Antibiotics are possibly effectiveEnteroinvasive Escherichia coliEnteropathogenic Escherichia coliCampylobacter enteritisVibrio parahaemolyticus

Antibiotics probably are not effectiveEnterohemorrhagic Escherichia coli (including

O157:H7)Salmonella enterocolitisYersinia enteritis without sepsisMild-to-moderate traveler’s diarrhea

Modified from Banerjee S, LaMont JT. Treatment ofgastrointestinal infections. Gastroenterology. 2000;118Suppl 1:S48-S67. Used with permission.

those presenting with bloody stools or high feveror those with a chronic illness, including immuno-compromise, empiric antibiotic therapy is often pro-vided while the results of stool culture are pending.Quinolones are usually given for empiric coveragein adults. The more common causes of bacterialdiarrhea are summarized in Table 4.

CampylobacterCampylobacter is the most commonly identifiedbacterial cause of diarrhea in the United States andis twice as common as Salmonella and sevenfoldmore common than Shigella. Most infections aredue to C. jejuni and typically are acquired fromcontaminated poultry (up to 90% of chickens maybe colonized) or unpasteurized milk in the summeror early autumn. Infection is most common in veryyoung children, teens, and young adults.

Fevers, myalgias, malaise, abdominal pain,and headache follow an incubation period of 1 to4 days. Diarrhea begins later and ranges from pro-fuse watery to bloody, lasting up to 1 week.Prolonged carriage can occur for several months,and recurrent infection can occur in up to 25% ofpatients. A chronic carrier state is rare. Hemolyticuremic syndrome (HUS), reactive arthritis (HLA-B27), and Guillain-Barré syndrome can occur.

In most healthy patients, symptoms are mildto moderate, and by the time the slow-growingCampylobacter is identified, the patient’s condition

Gastrointestinal Infections, C. difficile-Associated Disease, Diverticular Disease 225

Table 3. Summary of Viral Diarrhea

Incubation, Duration, Virus days days

Rotavirus 1-3 4-5Norwalk virus 1-2 2-3Adenovirus 8-10 7-14Astrovirus 2-4 3-5

Modified from Czachor JS, Herchline TE. Infectiousdiarrhea in immunocompetent hosts. Part 1. Bacteria,viruses and parasites. Hosp Physician. 1996;8:10-7.Used with permission.

Table 2. Clinical Features of Infectious Diarrhea

Location

Feature Small bowel Large bowel

Pathogens Salmonella CampylobacterVibrio cholerae SalmonellaEscherichia coli (ETEC, EPEC) ShigellaYersinia YersiniaRotavirus Escherichia coli (EIEC, EHEC)Norwalk virus Clostridium difficileAdenovirus Entamoeba histolyticaGiardia CytomegalovirusCryptosporidium

Location of pain Mid abdomen or diffuse Lower abdomen, rectumVolume of stool Large SmallType of stool Watery Mucoid, bloodFecal leukocytes Rare CommonOther Dehydration, malabsorption Tenesmus if proctitis

EIEC, enteroinvasive serogroups; EHEC, enterohemorrhagic groups; EPEC, enteropathogenic strains; ETEC,enterotoxigenic strains.

Modified from Hamer DH, Gorbach SL. Infectious diarrhea and bacterial food poisoning. In: Feldman M, Sleisenger MH,Scharschmidt BF, editors. Sleisenger & Fordtran’s gastrointestinal and liver disease: pathophysiology/diagnosis/management. Vol 2. 6th ed. Philadelphia: WB Saunders Company; 1998. p. 1594-632. Used with permission.

has begun to improve. For these patients, antibiotictherapy is unnecessary. Antibiotics are recom-mended for prolonged (>1 week) or worseningsymptoms, dysentery, high fever, bacteremia,pregnant women, and persons at risk for compli-cations (extremes of age, immunocompromise, orcirrhosis). Quinolones and erythromycin are effec-tive therapy. Erythromycin is less expensive, withless resistance, but treatment must be started early(within the first 3 days of symptoms). Treatmentwith quinolones can be started later in the illness,but high rates of resistance have been reported.

SalmonellaInfection with Salmonella causes a spectrum of dis-eases ranging from gastroenteritis to typhoid fever(Table 5). Infection can be complicated by bac-teremia resulting in disseminated infection. S. typhiand S. paratyphi cause typhoid fever. The otherserotypes (~2,000 described) cause nontyphoidalsalmonellosis. S. enteritidis and S. typhimurium arethe two most commonly isolated serotypes in theUnited States.

Outbreaks typically occur in the summer orautumn and are associated with contaminatedfood (undercooked or raw poultry or eggs, meat,

or dairy products), reflecting the high colonizationrates of Salmonella in poultry and livestock. Pets,including turtles, reptiles, cats, and dogs, can carryand transmit the organism. Person-to-personspread is also important in outbreaks and in devel-oping countries. Because typhoidal Salmonella existsonly in humans, a new case of typhoid fever indi-cates exposure to a carrier. Attack rates are highestamong infants, the elderly, and persons withdecreased stomach acid. Conditions that predisposeto Salmonella, in addition to eating raw or under-cooked eggs and poultry, are listed in Table 6.

Gastroenteritis occurs in 75% of infections andtypically begins within 48 hours after exposure,with nausea and vomiting, followed by diarrheaand cramps. Diarrhea may range from mild tosevere and from watery to bloody. Fever andabdominal pain are common. Localized tender-ness can simulate an acute abdomen and is oftenlocalized to the right lower quadrant, reflectingthe ileal location of most infections. Gastroenteritisusually lasts for 7 or fewer days, although inunusual cases primarily with colitis, symptomscan last for weeks. Bacteremia occurs in 5% to 10%of infections, often resulting in distant infections(eg, central nervous system infections, endocarditis,

226 Colon

Table 4. Summary of Bacterial Diarrhea

Incubation, Duration, Dysentery Bacteria days days (blood/mucus)* Source

Salmonella Chicken, eggs, meat,dairy

Gastroenteritis 1-2 3-7 0Colitis 1-2 14-21 + to ++Typhoid fever 7-14 28 +

Shigella 1-2 5-7 +++ P-P, egg salad, dairyCampylobacter 1-4 5-7 ++ Poultry, milkEscherichia coli O157:H7 3-5 3-8 +++ Hamburger, salamiVibrio parahaemolyticus <1-2 2-5 0 to ++ ShellfishVibrio cholerae 1-3 4-7 0 Water, shellfishYersinia 4-7 7-21 0 to + Pork, milk

*Scale: 0 = no to +++ = common.P-P, person-to-person.Modified from Czachor JS, Herchline TE. Infectious diarrhea in immunocompetent hosts. Part 1. Bacteria, viruses and

parasites. Hosp Physician. 1996;8:10-7. Used with permission.

or osteomyelitis). Recurrent or persistent bac-teremia can occur in patients with acquiredimmunodeficiency syndrome (AIDS).

Typhoid fever (enteric fever) is a systemicinfection characterized by a longer incubationperiod of 1 to 2 weeks, followed by systemic symp-toms that include fever, malaise, arthralgia,myalgia, headache, and delirium. Gastrointestinalsymptoms are often delayed and include abdom-inal pain and constipation more than diarrhea.Delayed bowel perforation and bleeding can occur.Physical findings include bradycardia related tofever, hepatosplenomegaly, lymphadenopathy,and a macular rash (rose spots). Typhoid fever isassociated with recurrent or sustained bacteremia,which results in metastatic infections. Symptomstypically last 4 weeks, although antibiotic therapycan hasten recovery. Recurrent infection, occur-ring 7 to 10 days after apparent recovery, is not

uncommon. The incidence of typhoid fever isdecreasing in the United States.

Prolonged asymptomatic fecal shedding ofSalmonella is common (average, ~5 weeks),although most patients clear the organism within3 months. Chronic carriage (>1 year) occurs infewer than 1% of patients with gastroenteritis andin up to 3% with typhoid fever. Risk factors includeextremes of age and cholelithiasis (associated withchronic gallbladder infection).

Therapy for uncomplicated gastroenteritisincludes hydration and avoidance of antimotilityagents. Antibiotics may prolong the carrier stateand select resistant organisms; they do not improveoutcomes and are not indicated for healthy sub-jects with uncomplicated gastroenteritis.Antibiotics (eg, quinolones, amoxicillin, andtrimethoprim-sulfamethoxazole [TMP-SMX]) areindicated for colitis, for patients with or at risk for


Table 5. Clinical Syndromes of SalmonellaInfection

Syndrome Incidence, %

Gastroenteritis 75Varies from mild to severe (dysentery)

Bacteremia 5-10With or without gastro-enteritis

Consider AIDSTyphoid (enteric) fever 5-10

With or without gastro-enteritis

Systemic infection 5Osteomyelitis, arthritis, meningitis, cholecystitis, abscess

Carrier state >1 year <1

AIDS, acquired immunodeficiency syndrome.Modified from Hamer DH, Gorbach SL. Infectious

diarrhea and bacterial food poisoning. In: Feldman M,Sleisenger MH, Scharschmidt BF, editors. Sleisenger &Fordtran’s gastrointestinal and liver disease:pathophysiology/diagnosis/management. Vol 2. 6th ed.Philadelphia: WB Saunders Company; 1998. p. 1594-632. Used with permission.

Table 6. Conditions Predisposing toSalmonella Infection

Hemolytic anemiaSickle cell disease

MalignancyLymphomaLeukemiaDisseminated carcinoma

ImmunosuppressionAIDSCorticosteroidsChemotherapy/radiation

AchlorhydriaGastric surgeryProton pump inhibitorsIdiopathic

Ulcerative colitisSchistosomiasis

AIDS, acquired immunodeficiency syndrome.Modified from Hamer DH, Gorbach SL. Infectious

diarrhea and bacterial food poisoning. In: Feldman M,Sleisenger MH, Scharschmidt BF, editors. Sleisenger &Fordtran’s gastrointestinal and liver disease:pathophysiology/diagnosis/management. Vol 2. 6th ed.Philadelphia: WB Saunders Company; 1998. p. 1594-632. Used with permission.

bacteremia (extremes of age, immunocompromise[HIV, medications, or malignancy], valvular heartdisease, hemoglobinopathy, or orthopedic implants),for severe disease, or for chronic carriers. Multidrugresistance is becoming a problem; therapy shouldbe guided by sensitivity testing. Prolonged therapyis necessary for metastatic infections.

For typhoid fever, therapy is recommended.Typically, quinolones or third-generation cephalo-sporins are given as empiric therapy while sensitivitydata are pending. Resistance to chloramphenicol,TMP-SMX, and ampicillin makes these drugs inap-propriate for empiric therapy. Corticosteroids alsomay be beneficial for patients with severe disease.In chronic carriers, therapy with a quinolone (eg,norfloxacin, 400 mg twice daily for 4 weeks) maylead to clearance. If not, cholecystectomy may beneeded to remove the nidus of chronic infection.

ShigellaShigella has 40 serotypes in four species (S. dysen-teriae, S. flexneri, S. boydii, and S. sonnei). Spread istypically person-to-person, facilitated by a lowinfective dose because of resistance to stomachacid. Outbreaks are related to contaminated foodand water. S. sonnei produces the mildest diseaseand is the most common type in the United States.Symptoms characteristically begin within 48 hoursafter ingestion and include fever, malaise, abdom-inal pain, and watery diarrhea. Rectal pain orburning can be prominent. Respiratory complaintsare common, and children may have neurologicmanifestations, including seizures. The diarrheamay decrease and become bloody with mucusand pus (ie, dysentery). This classic progressionoccurs in a small proportion of cases and is leastcommon for S. sonnei infections.

The initial watery diarrhea is thought to bedue to the Shiga toxin, whereas dysentery is due tomucosal invasion, which occurs primarily in thecolon. Bacteremia is uncommon. Predictors ofseverity include extremes of age, malnutrition,immunocompromise, and infection with S. dysen-teriae. S. dysenteriae is most likely to cause compli-cations such as HUS (see below), dysentery, andtoxic megacolon. Shigellosis typically lasts for 1 to3 days in children and 5 to 7 days in adults.Although chronic carriage is unusual, prolongedinfections can occur and be difficult to differentiate

from ulcerative colitis. A delayed asymmetriclarge-joint arthritis can occur, usually in those withHLA-B27.

Treatment focuses on hydration and perhapsavoidance of antimotility agents. Healthy patientswhose condition improves spontaneously may notrequire therapy. However, antibiotics have beenshown to decrease the duration of disease and mor-tality. Therefore, for most patients, particularlythose with chronic illnesses (including malnutritionand HIV), the elderly, day care or health careworkers, or food handlers, antibiotic therapy(quinolones, TMP-SMX, or ampicillin) is indicatedfor 1 to 5 days, depending on the severity of theinfection. Resistance to multiple antibiotics hasbeen reported, and if therapy is begun before sensi-tivity data are available, quinolones are recom-mended (for adults). For all patients, handwashingand other hygienic practices are necessary to decreaseperson-to-person spread and to limit outbreaks.

Escherichia coli

Enterohemorrhagic E. coli (eg, E. coliO157:H7)Enterohemorrhagic E. coli (EHEC) produces Shigatoxin and causes colitis after an incubation periodof 3 to 5 days. E. coli O157:H7 accounts for morethan 90% of EHEC cases in the United States; 100other serotypes have been identified. Althoughseveral outbreaks have attracted considerablemedia attention, most cases of EHEC are sporadic.It has been estimated that 50% of cattle and 90%of hamburger lots are contaminated with EHEC.Thus, EHEC is associated with the ingestion ofundercooked hamburger but also of salami,sprouts, and unpasteurized milk or juice. Althoughthe infectious dose is low, EHEC is effectively killedat temperatures higher than 156°F. A pink centerin a hamburger is associated with lower tempera-tures and an increased risk of infection. Irradiationof hamburger also effectively kills EHEC, butwhether the public embraces irradiated foodsremains to be seen.

EHEC typically produces watery diarrhea thatprogresses to bloody diarrhea after a few hours toa few days. One study suggested that EHEC isthe most common cause of bloody diarrhea inthe United States. Systemic symptoms (fatigue,

228 Colon

myalgias, and headache), severe abdominal pain,nausea, and vomiting are common, but fever isnot. Illness typically lasts 5 to 10 days. In the elderly,EHEC may be misdiagnosed as ischemic colitis.

EHEC can lead to HUS/thrombotic thrombo-cytopenic purpura (TTP) in 5% of patients,resulting in hemolytic anemia and renal failure,with or without central nervous system symptoms.The pathophysiologic mechanism of EHECappears to be vascular endothelial damage thatleads to platelet aggregation and initiation of thecoagulation cascade. This, in turn, leads to ischemiaof the colon and results in hemorrhagic colitis. Infact, some cases of “ischemic colitis” probably rep-resent misdiagnosed cases of EHEC. Similarthrombi and ischemia in the kidney may be thecause of renal insufficiency in HUS. HUS/TTP canhave high morbidity and mortality rates, particu-larly among the very young and very old.

In some laboratories, specific testing for E. coliO157:H7 (sorbitol-MacConkey agar or a newerstool toxin assay that may be more sensitive) mustbe requested; thus, the condition can be under-diagnosed. In several large series reported fromNorth America, E. coli O157:H7 was the second tofourth most commonly identified bacterium inacute diarrheal illnesses. Antibiotics do not appearto be beneficial and may increase toxin productionor release (or both). This, in turn, may increase therisk of HUS/TTP and, perhaps, death. Also, anti-motility agents, including narcotics, may increase therisk of HUS. Thus, antibiotics and antimotility agentsshould be avoided if EHEC infection is suspectedclinically (eg, absence of fever in a patient withbloody diarrhea of suspected infectious origin).

Patients with EHEC should be placed in con-tact isolation, and any personal contacts who havegastrointestinal symptoms should be tested forEHEC. It has been recommended that children, foodhandlers, and health care workers delay their returnto school or work until they are asymptomatic andhave had several stool cultures negative for EHEC.

Enterotoxigenic E. coliEnterotoxigenic E. coli (ETEC) is a common causeof diarrhea in travelers and in children in devel-oping countries. The organism attaches to the smallbowel and causes diarrhea through enterotoxins.The disease ranges from mild to severe watery

diarrhea often associated with mild upper gas-trointestinal tract symptoms that last for 2 to 5 days.Rehydration is the mainstay of therapy. Antibiotics(quinolones, TMP-SMX, and tetracycline) often aregiven empirically for moderate-to-severe traveler’sdiarrhea. As for most gastrointestinal infections,multiple-drug antibiotic resistance has been reportedwith ETEC, although resistance to quinolones doesnot appear to be a major problem yet.

Enteropathogenic E. coliEnteropathogenic E. coli (EPEC) is primarily aproblem in infants. It caused several epidemicswith high mortality in neonatal nurseries in theearly 1900s. Currently, it occurs most often in devel-oping countries. EPEC attaches to the small-bowelmucosa and causes watery mucoid diarrhea byproducing structural changes in the microvilli.Antibiotics are effective therapy, although resis-tance to TMP-SMX is emerging.

Enteroinvasive E. coliEnteroinvasive E. coli (EIEC) is a rare cause of diar-rhea associated with fever and abdominal pain. Thediarrhea is usually watery, but it can be accompa-nied by fever and leukocytes (ie, dysentery). EIECis similar to Shigella in its ability to invade the colonicmucosa and produce a Shiga-like toxin. Resistanceto TMP-SMX is common, but not to quinolones.

Enteroaggregative E. coliEnteroaggregative E. coli (EAEC) is primarily aproblem in infants in developing countries and inHIV-infected adults, although it also can causetraveler’s diarrhea. EAEC causes persistent diar-rhea that can be watery or bloody. Specific testsfor EAEC are not available clinically. Quinolonesare effective therapy, suggesting that empiric treat-ment with these agents may be reasonable forpatients with HIV who have diarrhea and negativefindings on evaluation.

The different types of E. coli are summarized inTable 7.

VibrioVibrio species are halophilic and associated withthe consumption of raw or undercooked saltwaterfish or shellfish (oysters, crabs, and mussels) orcontamination of food with seawater.


V. parahaemolyticus is a common cause of diar-rhea in the coastal United States and Japan, partic-ularly during warm months. Several toxins can beproduced, resulting in various clinical presentations.The incubation period is less than 1 to 2 days, andthe primary symptom is watery diarrhea.Abdominal pain, vomiting, and headaches are alsocommon. Uncommonly, V. parahaemolyticus maycause frank dysentery and mucosal ulceration. Illnesstypically lasts 2 to 5 days, and antibiotics usually arenot necessary. The role of antibiotics is uncertain,even for patients with severe or prolonged symp-toms. If antibiotics are administered, a reasonablechoice is quinolones, doxycycline, or tetracycline.

V. cholerae infection is not common in theUnited States, although sporadic cases occur alongthe Gulf Coast and in travelers returning fromendemic areas (Latin America, Africa, and Asia).The infectious dose is large, although hypochlorhy-dria decreases it. Cholera toxin can cause profounddehydration from profuse diarrhea (up to 1L/hour or more) and vomiting. However, mildercases (and asymptomatic carriage) are possible.In severe cases, stools are described as “ricewater” because of the watery consistency withflecks of mucus. Hypotension, renal failure, and

hypokalemic acidosis occur in severe cases and,without aggressive rehydration, often lead to death.Oral rehydration solution can be life-saving, butsevere cases usually require intravenous fluids,with attention to potassium and bicarbonatereplacement. Infection can be treated with variousantibiotics, including tetracycline, doxycycline,TMP-SMX, or erythromycin, and even a single doseof quinolones can be effective.

V. vulnificus also can cause diarrhea. Theorganism can be acquired through wound conta-mination by infected seawater or by direct con-sumption, particularly in the summer months. Inimmunocompromised patients or those withchronic liver disease, systemic infection with sepsisis a risk, with a high mortality rate. These patientsshould be instructed not to eat or to handle rawseafood, particularly oysters.

YersiniaYersinia enterocolitica is less common in the UnitedStates than in northern Europe. Yersinia typicallyis acquired in cold months from contaminatedfood, milk, or water and has an incubation periodof 4 to 7 days. Many animals can harbor theorganism and be a source of infection, which occurs

230 Colon

Table 7. Types of Escherichia coli Causing Infectious Diarrhea

Type Patients affected Pathophysiology Clinical feature

Enteropathogenic Infants in developing Attachment alters Watery diarrhea(EPEC) countries, some travelers brush border

Enterotoxigenic Children in developing Enterotoxin-mediated Watery diarrhea(ETEC) countries, travelers secretion

Enteroinvasive Rare, food and water Direct invasion Usually watery diarrhea, (EIEC) outbreak 10% have dysentery

Enterohemorrhagic Food (hamburger), Shiga-like cytotoxins Watery then bloody (EHEC, eg, sporadic or outbreak diarrhea, HUS/TTPO157:H7)

Enteroaggregative Infants in developing Adherence, toxins Prolonged watery diarrhea(EAEC) countries, HIV positive

HIV, human immunodeficiency virus; HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura.Modified from Hamer DH, Gorbach SL. Infectious diarrhea and bacterial food poisoning. In: Feldman M, Sleisenger MH,

Scharschmidt BF, editors. Sleisenger & Fordtran’s gastrointestinal and liver disease: pathophysiology/diagnosis/management. Vol 2. 6th ed. Philadelphia: WB Saunders Company; 1998. p. 1594-632. Used with permission.

primarily in the terminal ileum. Symptoms rangefrom mild (fever, diarrhea, nausea, and cramps)to severe (reflecting invasion). Uncommonly,Yersinia causes bacteremia with sepsis or distantinfection. Arthralgias and rash are more commonin adults than in children. Postinfectious arthritisalso can occur (HLA-B27).

In healthy patients, symptoms typically last1 to 3 weeks. Antibiotic therapy has not beenshown to be of benefit in uncomplicated disease.Patients at risk for sepsis (cirrhosis, iron overload,or immunocompromise) and those with severe orprolonged symptoms, bacteremia, or distantinfections may benefit from antibiotic therapy(tetracycline, quinolones, or TMP-SMX with orwithout aminoglycosides). Yersinia ileocolitis cansimulate Crohn’s disease (including extraintestinalmanifestations: aphthous ulcers, arthralgias, anderythema nodosum), and right-lower-quadranttenderness with mesenteric lymphadenitis cansimulate appendicitis.

PARASITESStool evaluation for ova and parasites is particularlyhelpful in immunocompromised patients andthose with an appropriate exposure or travel his-tory. Most parasites are shed intermittently, anda single stool evaluation is relatively insensitive.To increase sensitivity, three or more separatestools should be analyzed.

Giardia lambliaGiardia lamblia, the most common parasitic infectionin the United States, is acquired by the ingestionof water or food contaminated with cysts or byperson-to-person spread (eg, day care centers andnursing homes). Cysts can survive for months inthe environment and are resistant to chlorination.In the United States, the peak incidence occurs inthe summer and early autumn. Excystation occursin the small bowel, where the trophozoites attachto and damage the mucosa. High-risk groups aretravelers to endemic areas, children in day care,patients with immunoglobulin deficiencies, andhomosexual men. Symptoms, including waterydiarrhea, cramps, nausea, bloating, and flatulence,occur 1 to 2 weeks after ingestion. Patients maypresent with acute disease, although diarrhea may

be intermittent, leading to a delay in seeking med-ical attention. Chronic symptoms also may occurand can be associated with malabsorption. Somepersons become asymptomatic carriers withchronic cyst passage.

Examination of multiple stools for trophozoitesor cysts is reasonably sensitive in cases of acutewatery diarrhea. With chronic symptoms or lesswatery stools, this examination is insensitive andduodenal aspirate and biopsy (organisms or lackof plasma cells) or fecal analysis for Giardia antigenmay be better. Metronidazole (250 mg 3 times dailyfor 5-7 days) is usually effective therapy. Treatmentof asymptomatic carriers provides no benefit forthe individual but may help prevent outbreaks,for example, in day care or health care workers.

CryptosporidiumAlthough Cryptosporidium increasingly has beenrecognized as a pathogen during the AIDS epi-demic, it also can cause diarrhea in immunocom-petent hosts. Infection commonly is acquired fromcontaminated water or person-to-person spread. Itcan resist chlorination, resulting in outbreaks evenin industrialized areas. Several US outbreaks havebeen attributed to contaminated water sources.Cryptosporidium invades the small-bowel mucosaand causes inflammation, villous blunting, andmalabsorption. In most healthy patients, diseaseis mild and self-limited, with watery diarrhea,nausea, cramps, and flatulence developing 7 to 10days after ingestion. Stools may be intermittent andmucoid but should not contain much blood or pus.Diarrhea can last 6 weeks or longer. Headaches,fevers, or myalgias are common. The diagnosis canbe made by stool analysis (immunoassays are moresensitive than microscopy) or small-bowel biopsy.In healthy patients, treatment usually is not neces-sary. Cryptosporidiosis in patients with AIDS isdiscussed in Chapter 10, Gastrointestinal Manifest-ations of Human Immunodeficiency Virus Infection.

Entamoeba histolyticaAmebiasis is the most common parasitic diarrheain the world, although it is less common in theUnited States. Most cases in the United States occurin travelers or immigrants from endemic areas(Latin America, Africa, and India) and in homosexualmen. Infection is acquired through the ingestion of


contaminated food or water. Amebic cysts undergoexcystation in the small bowel and infect the colon.Symptoms begin 7 to 21 days after ingestion andinclude bloody diarrhea, abdominal pain, fever,and tenesmus, consistent with invasive colitis.Amebic colitis can vary from mild to fulminant,with severe bleeding or perforation. Because therisk of perforation is increased by corticosteroiduse, it is important to differentiate amebic colitisfrom ulcerative colitis. Amebic ulcers are caused bymucosal invasion by trophozoites. The ulcers varyfrom mild to severe, with the classic descriptionbeing that of undermined edges leading to a flask-shaped ulcer. Amebae can penetrate the bowelwall, enter the portal circulation, and cause liver orsplenic abscesses. Patients with liver abscessestend to be male, and they may not have a discerniblehistory of colitis. Distant infection (peritonitis,empyema, or central nervous system infection) alsocan occur. A localized infection surrounded by gran-ulation tissue or a dense fibrous coat (ameboma)can resemble colon cancer.

Diagnosis is made by stool examination. Threeor more samples may be needed to make the diag-nosis with microscopy, although stool antigentesting and the polymerase chain reaction forEntamoeba histolytica DNA are more sensitive.Metronidazole (750 mg 3 times daily for 7-10 days)is the drug of choice for treating colitis or liverabscesses. Patients with severe colitis or abscessesmay require intravenous therapy. Cysts are rel-atively resistant to metronidazole and require asecond agent such as diloxanide furoate, paro-momycin, or iodoquinol. Drainage of liverabscesses is not recommended unless rupture isimminent or medical therapy is ineffective.

Numerous nonpathologic amebae can inhabitthe human colon, including Entamoeba coli,Entamoeba hartmanni, and Endolimax nana.Distinguishing between these organisms andEntamoeba histolytica can be difficult with routinemicroscopy, even for experienced examiners,although serologic testing and stool polymerasechain reaction assay should help.

Blastocystis hominisBlastocystis hominis is found occasionally on routinestool examinations for ova and parasites. Its patho-genicity is uncertain, particularly in immunocom-

petent hosts. However, if no other cause for apatient’s symptoms is found, a trial of metronida-zole can be considered.

TRAVELER’S DIARRHEAInfectious diarrhea affects 10% to 50% of travelersto high-risk areas of Southeast Asia, the MiddleEast, India, Africa, and Latin America. The inci-dence of diarrhea varies depending on the specificarea visited (eg, urban or rural), the traveler’s age,time of year, and local conditions such as floodingor a cholera outbreak. Bacteria cause 80% to 90% ofcases of traveler’s diarrhea, and the other 10% to20% are due to parasites, viruses, or toxins. ETECis a common cause. The unusual case of prolongedtraveler’s diarrhea is more likely to be caused by aparasite such as Giardia lamblia or Cyclospora cayeta-nensis. The risk of infection can be decreased byavoiding uncooked foods, local water (includingice), and unpasteurized drinks.

Symptoms typically begin several days afterthe person arrives in the area and last for 3 to 5 days.Watery diarrhea, bloating, fatigue, and cramps arecommon. Bloody diarrhea and high fever areuncommon; their presence suggests an invasiveorganism and should prompt an evaluation for aspecific organism. For most travelers, antibiotic pro-phylaxis is not recommended. However, patientswith immunocompromise, severe chronic illness,hypochlorhydria, or proton pump inhibitor therapymay benefit from prophylaxis (eg, ciprofloxacin,500 mg daily). Bismuth subsalicylate (2 tablets 4times daily) is alternative prophylaxis.

Mild cases of traveler’s diarrhea can be treatedwith rehydration and antidiarrheals or bismuth(if no fever, severe pain, or bloody diarrhea) for 1to 3 days. For moderate-to-severe diarrhea, aquinolone is recommended, often together withan antidiarrheal. Ampicillin and TMP-SMX arenot recommended because of the high rates of resis-tance in some areas.

FOOD POISONINGFrom 1988 to 1992 in the United States, 2,423 food-borne outbreaks affected more than 77,000 people.Because of underreporting, the true burden of dis-ease may be 10 to 100 times higher. Most cases of

232 Colon

bacterial diarrhea, as indicated in Table 4, areacquired from food and can be considered forms of“food poisoning.” Also, some bacteria cause acutegastrointestinal symptoms from preformed toxinsthat are ingested with contaminated foods. Commonsymptoms of food poisoning and typical offendingagents are listed in Table 8.

Staphylococcus aureus toxin causes 1 to 2 daysof severe vomiting, cramps, and diarrhea that begin2 to 6 hours after ingestion (eg, cream-filled pas-tries, meat, or potato or egg salad). Severe infectioncan cause dehydration.

Clostridium perfringens toxin produces 1 to 2days of abdominal pain and watery diarrhea thatusually begin 8 to 24 hours after ingestion offoods typically prepared in advance and left tosit unrefrigerated (eg, beef, poultry, or gravy).An uncommon strain of C. perfringens producesthe potentially fatal enteritis necroticans, orpigbel, a condition that occurs primarily in poortropical regions.

Bacillus cereus toxin causes nausea and vom-iting that usually occur within 2 to 6 hours afteringestion (eg, pork, creams or sauces, or friedrice) and last 6 to 10 hours. Diarrhea may occurlater, probably from a toxin formed in vivo. Inhealthy hosts, antibiotic therapy is not necessaryfor these acute forms of food poisoning due topreformed enterotoxins.

Listeria monocytogenes can be found in manyfoods (eg, hot dogs, lunch meat, and cheeses),and its growth is not substantially inhibited byrefrigeration. It can cause gastroenteritis, often

with fever, that is typically mild and self-limited,lasting 1 to 2 days. However, in chronically ill orimmunosuppressed patients and in the veryyoung, the elderly, and pregnant women, Listeriaalso can cause severe disease, with bacteremia anddisseminated infection associated with a high mor-tality rate. Therapy, usually with ampicillin andgentamicin, is indicated.

CLOSTRIDIUM DIFFICILE-ASSOCIATED DISEASE

BackgroundThe first case of pseudomembranous colitis wasreported in 1893 as “diphtheritic colitis,” and theClostridium difficile organism was described in 1935.It was not until the 1970s that C. difficile was impli-cated as a causative factor in pseudomembranouscolitis. Although C. difficile-associated disease wasdescribed before antibiotics were introduced, mostcurrent cases are associated with antibiotic use. Otherconditions that can predispose to C. difficile-associateddisease include bowel ischemia, surgery, malnutri-tion, chemotherapy, and critical illness. The spec-trum of disease associated with C. difficile includes anasymptomatic carrier state, diarrhea without colitis,and various degrees of colitis with or withoutpseudomembranes.

EpidemiologyDuring the past 25 years, there has been an increasein the occurrence rate and a more modest clinical


Table 8. Food Poisoning Syndromes

IncubationSymptoms period, hours Possible agents

Acute nausea, vomiting 6 Preformed toxins of Staphylococcus aureus, Bacilluscereus

Watery diarrhea 6-72 Clostridium perfringens, B. cereus, ETEC, Vibriocholerae, Giardia

Inflammatory ileocolitis 16-72 Salmonella, Shigella, Campylobacter, EIEC, EHEC(“dysentery”) (O157:H7), V. parahaemolyticus, Yersinia

EHEC, enterohemorrhagic Escherichia coli; EIEC, enteroinvasive E. coli; ETEC, enterotoxigenic E. coli.Data from Guerrant RL, Bobak DA: Bacterial and protozoal gastroenteritis. N Engl J Med. 1991;325:327-40.

spectrum of C. difficile-associated disease, trendsthought to be due to increased use of antibiotics,more aggressive testing, and early intervention.Recent data reflect the health care burden of C. dif-ficile infection: an additional hospital cost of morethan $3,000 per patient and an extra length of stayof 3.6 days, leading to an estimated cost in theUnited States in excess of $1 billion per year.

C. difficile is detected in very few (1%-3%)healthy adults. It is more common in hospitalizedadults and in patients receiving antibiotic therapy.Up to 50% of infants and children carry the bac-terium, but pseudomembranous colitis is rare inthis age group. The incidence of antibiotic-associateddiarrhea varies from 5% to 39%, depending on theantibiotic used, and most cases are due to the antibi-otic and not to infection with C. difficile, particularlyin outpatients. Pseudomembranous colitis occursin only 10% of cases of antibiotic-associated diar-rhea. In contrast to antibiotic-associated diarrhea,most cases of pseudomembranous colitis are due toC. difficile.

Populations at high risk for C. difficile-asso-ciated disease include the elderly; patients withuremia, burns, abdominal surgery, or cancer; andpatients in an intensive care unit. It is not knownwhether these groups are more exposed to noso-comial infections or are more susceptible to C.difficile-associated disease because of their spe-cific illnesses.

• Most cases of C. difficile-associated diseaseoccur after antibiotic use, although other riskfactors exist.

• C. difficile-associated disease ranges from asymp-tomatic carriage to diarrhea without colitis tocolitis with or without pseudomembranes.

• C. difficile can be found in healthy infants butis uncommon in healthy adults.

• Most antibiotic-associated diarrhea is due tothe antibiotic and not to C. difficile.

• Most pseudomembranous colitis is due to C.difficile infection.

Case PresentationA 75-year-old man presented with a 2-day historyof crampy lower abdominal pain, nonbloody diar-rhea, tenesmus, and fever. He recently completeda course of antibiotic therapy for pneumonia. On

physical examination, he appeared ill, with a tem-perature of 101°F, normal blood pressure, and apulse rate of 98 beats/minute. The abdomen wasmildly distended and tender without guarding orrebound. Laboratory studies showed leukocytosisof 13.4 cells × 109/L, with 15% band forms. Stoolanalysis showed many leukocytes, and C. difficiletoxin was detected. Abdominal radiographyshowed mild ileus but no dilatation of the colon.Treatment with metronidazole, 500 mg 3 times dailyby mouth, promptly improved the symptoms.

Clinical PresentationThe time between starting antibiotic therapy andthe appearance of clinical symptoms varies from 1day to 6 weeks, most commonly 3 to 9 days.However, symptoms may occur after a single doseof antibiotics (including topical antibiotics) or theymay not begin until several weeks after antibiotictherapy has been discontinued.

Presentation may range from only loose stoolsto toxic megacolon (nausea, vomiting, high-gradefever, and ileus) and colonic perforation. Typically,the disease manifests with watery or mucoid diar-rhea, abdominal pain, and low-grade fever. Stoolsmay contain small amounts of blood. Extraintestinalmanifestations, such as arthritis, are rare. Diarrheamay cause dehydration and electrolyte depletion.Overall mortality rate is low (2%-3%), although itis higher among the elderly or debilitated patients(10%-20%) and with fulminant colitis or toxicmegacolon (30%-80%). In some patients (5%-19%),disease is localized to the proximal colon and maymanifest with an acute abdomen and localizedrebound tenderness, but no diarrhea, and normalfindings on sigmoidoscopy.

Despite successful treatment, 10% to 25% ofpatients have disease relapse, regardless of thetherapeutic agent used. Disease relapse usuallyresponds well to re-treatment with metronidazoleor vancomycin, but the risk of additional recurrencesis high.

• C. difficile-associated disease usually occurswithin 1 to 2 weeks after antibiotic therapy isstarted.

• In about 10% of patients, the disease is localizedabove the splenic flexure and the presentationcan be atypical.

234 Colon

• From 10% to 25% of patients have recurrentdisease.

Differential DiagnosisStaphylococcal enterocolitis and typhlitis can occurin patients receiving chemotherapy and can havea presentation similar to that of C. difficile-associateddisease. Exacerbation of Crohn’s disease andulcerative colitis can simulate C. difficile-associ-ated disease, and, importantly, C. difficile infec-tion can cause a symptom flare in patients withinflammatory bowel disease. Other disorders inthe differential diagnosis include chemical colitis(chemotherapy or gold), ischemic colitis, and otherinfections (Campylobacter, Salmonella, Shigella, E.coli, Entamoeba, Listeria, cytomegalovirus).

PathophysiologyThe development of C. difficile-associated diseaserequires an alteration in the normal gut flora ormucosal immunity, the acquisition and germina-tion of spores, overgrowth of C. difficile, and theproduction of toxin. Toxin A binds to mucosalreceptors and causes cytotoxicity by disruptingcytoplasmic microfilaments and inducing apop-tosis. Toxin B can then enter the damaged mucosaand cause further cytotoxicity, resulting in hem-orrhage, inflammation, and cellular necrosis. Thetoxins also interfere with protein synthesis, stim-ulate granulocyte chemotaxis, increase capillarypermeability, and promote peristalsis. In severecases, inflammation and necrosis may involvedeeper layers of the colon and result in toxicdilatation or perforation.

Diagnostic TestingDiagnosis is based on a combination of clinicalfindings, laboratory test results, and sometimesendoscopy. Leukocytosis and hypoalbuminemiaare not uncommon. Fecal leukocytes can be seen,but their absence does not exclude colitis. Stoolculture for C. difficile is relatively demanding andhas low predictive value.

Cytotoxicity assays are considered positivewhen cultured cells show cytopathic changes onexposure to stool filtrates. The result is then con-firmed by neutralizing these effects with specificantitoxins. This is considered the standard diag-nostic method because of its high sensitivity and

specificity. However, cytotoxicity assays areexpensive and time consuming.

Enzyme-linked immunosorbent assay (ELISA)for the detection of toxin A or B is less expensiveand faster than tissue culture and, thus, is preferredat many centers. Sensitivity is lower (75%-85%)than for cytotoxic assays, but performing the teston two or three separate stools should increasesensitivity to 90% to 95%. In addition, properstorage and handling may prevent toxin degra-dation and improve sensitivity. A newer ELISA todetect the presence of either toxin (TOX A/B test)has excellent specificity and improved sensitivitycompared with testing for either toxin alone,because some strains of C. difficile may produceonly one toxin or the other.

Although endoscopic findings may be normalin patients with mild C. difficile-associated disease,most patients have abnormal mucosa. Flexible sig-moidoscopy is diagnostic in most cases, butcolonoscopy may be required in about 10% of caseswhen disease is localized above the splenic flexure.Endoscopy may be the fastest means of suggestingthe diagnosis, but in patients with severe disease,it is hazardous and should be avoided. Colitismay range from minimal erythema or edema toulceration, often with nodular exudates that maycoalesce to form yellow “pseudomembranes” con-sisting of mucus and fibrin filled with dead leuko-cytes and mucosal cells (Fig. 1).

• C. difficile-associated disease is toxin mediated.• Stool cytotoxicity assay is the standard diagnos-

tic test, but it is expensive and time consuming.• ELISA for toxin A or B is used in most labora-

tories because it is faster and less expensivethan tissue culture. Its relatively poor sensi-tivity can be improved by testing two or threestool samples.

• For many patients, endoscopy is not necessaryfor diagnosis.

Treatment of Primary InfectionFor mild disease, supportive therapy alone(without antibiotic treatment) may be sufficient,including rehydration and discontinuation of treat-ment with the offending antibiotic. Antidiarrhealagents and narcotics should be avoided becausethey may prolong exposure to toxins and result in


more severe colitis. Specific antibiotic therapyshould be prescribed if supportive therapy fails,if treatment with the offending antibiotic cannotbe discontinued, or if symptoms are severe. Forsevere disease, hospitalization for antibiotictherapy and intravenous hydration may be nec-essary. When C. difficile-associated disease is sus-pected in elderly and severely ill patients, empiricantibiotic therapy should be started before testresults are known.

Metronidazole is inexpensive and effectiveand has response and relapse rates comparable tothose of vancomycin. The usual oral dose is 250 to750 mg 3 or 4 times daily for 7 to 10 days. Becauseof concerns about cost and resistance with van-comycin, metronidazole is the preferred first-linetherapy. However, metronidazole has more sideeffects and is not recommended for children or preg-nant women. If the patient’s condition does notimprove promptly (2-3 days), the situation shouldbe reassessed and, if the diagnosis is secure, van-comycin should be substituted for metronidazole.

Vancomycin is a reliable but more expensivetreatment, with response rates of 90% to 100%, andis the preferred treatment for severely ill patients.Because oral vancomycin is poorly absorbed, a highstool concentration can be achieved without sys-temic side effects. The usual dose is 125 mg every 6hours for 7 to 14 days. A higher dose (250-500 mg 4times daily) can be given to severely ill patients.

Parenteral therapy is less effective than oraltherapy, but when necessary (eg, paralytic ileus),

intravenous metronidazole (500-750 mg 3 or 4times daily) is recommended, perhaps supple-mented by vancomycin (500 mg 4 times daily)through a nasogastric tube or by enema.

Anion exchange resins work by binding toxin.Cholestyramine (4 g 4 times daily) can helpdecrease symptoms in mild disease, but when ithas been given alone, results have been disap-pointing, with variable but generally low curerates. Obstipation is the most common side effect.Because cholestyramine binds vancomycin, theyshould not be given simultaneously.

Treatment of Recurrent InfectionRecurrent disease usually responds well to re-treatment with metronidazole or vancomycin atstandard doses. For multiple or refractory recur-rences, several therapeutic options are available.One is a prolonged course of vancomycintherapy, followed by gradual tapering, forexample, 125 mg 4 times daily for 4 to 6 weeks,125 mg twice daily for 1 week, 125 mg daily for1 week, and 125 mg every other day for 1 week,followed by 125 mg every 72 hours for 2 weeks.A similar prolonged, tapering course of metro-nidazole can be considered, although side effectsmay increase with longer treatment. Anotheroption is to give antibiotic and anion exchangeresin for 5- to 7-day periods, alternating withperiods when antibiotic treatment is withheld.Also, treatment with a combination of van-comycin and rifampin has been successful. Otherregimens aim to suppress C. difficile with the useof oral Lactobacillus GG or nonpathogenic yeast(Saccharomyces boulardii) or with enemas con-taining feces from healthy subjects. However,none of these agents has been proved superiorto standard therapy.

Surgical TreatmentSurgical treatment usually is not necessary for C.difficile-associated disease. Diverting ileostomyor colectomy is performed for severe refractorydisease or for complications such as perforationor megacolon. Because the risk of complicationsincreases markedly after several days of inef-fective therapy, some advocate surgery forsevere disease that does not respond after 2 to 7days of treatment.

236 Colon

Fig. 1. Typical histologic appearance ofpseudomembranous colitis.

PreventionC. difficile spores can survive for up to 5 months inthe environment, and a primary mode of infectionis the hands of hospital personnel or contaminatedobjects. Therefore, prevention has a crucial role indisease management and can be facilitated by theprudent use of antibiotics, routine hand washing,disinfection of potentially contaminated objects,and isolation of infected patients, including theuse of gloves for patient contact.

Treatment of asymptomatic carriers is not rec-ommended because it may prolong the carrierstate, which usually resolves spontaneously.Restricting the use of broad-spectrum antibioticshas decreased the rate of C. difficile-associated dis-ease at some institutions.

• Metronidazole and vancomycin are equally effec-tive, particularly for mild-to-moderate disease.

• If oral therapy is not possible, intravenousmetronidazole may be useful. Intravenousvancomycin is not useful.

• Cholestyramine works by binding toxins, butit can bind vancomycin.

• Multiple recurrences of disease may requireprolonged tapering or pulses of antibiotics,with or without additional therapy.

SummaryC. difficile is a spore-forming toxigenic bacteriumthat causes diarrhea and colitis, typically afterantibiotic therapy. The clinical presentation rangesfrom self-limited diarrhea to fulminant colitis andtoxic megacolon. Although in most cases the dis-ease is mild and responds quickly to treatment, C.difficile colitis may be severe, especially if diagnosisand treatment are delayed. Recurrence can be aserious problem. Prevention is achieved best bylimiting the use of broad-spectrum antibiotics andby following good hygienic techniques and uni-versal precautions to limit the transmission of thebacteria. A high index of suspicion results in earlydiagnosis and treatment and potentially decreasesthe incidence of complications.

DIVERTICULAR DISEASEIn Western societies, colonic diverticulosis affects5% to 10% of the population older than 45 years

and 80% of those older than 85 years. Uninflamedand nonbleeding diverticula are asymptomatic.Approximately 20% of patients with diverticula havean episode of symptomatic diverticulitis. Diverticularhemorrhage is the second most common cause ofcolonic bleeding after vascular lesions.

PathophysiologyDiverticulosis affects predominantly the sigmoidcolon but may involve the entire colon. Highluminal pressure is believed to cause mucosal pro-trusion through weak areas where the vasa rectaepenetrate the bowel wall, resulting in diverticula.There is an association between diverticulosis anda Western diet high in refined carbohydrates andlow in dietary fiber; whether this represents causeand effect is unproved. If the neck of a diverticulumis obstructed, it may distend and lead to bacterialovergrowth and invasion, often with perforation,which is generally walled off by the adjacent meso-colon or appendices epiploicae.

ClassificationStage I diverticulitis is characterized by small con-fined pericolonic abscesses, and stage II diseaseincludes larger confined pericolonic collections. StageIII involves generalized suppurative peritonitis (per-forated diverticulitis); because the diverticular neck isgenerally obstructed by a fecolith, peritoneal conta-mination by feces may not occur. Stage IV indicatesfecal peritonitis.

• Colonic diverticula are common but do notcause symptoms unless they are infected orbleeding.

• Diverticula form predominantly in the sigmoidcolon by mucosal protrusion through weakspots in the bowel wall.

• Virtually all patients with diverticulitis havea microperforation.

• Stage I, small confined abscess; stage II, largeconfined abscess; stage III, suppurative peri-tonitis; stage IV, fecal peritonitis.

Clinical FeaturesSymptoms of diverticulitis include lower abdom-inal pain, fever, and altered bowel habits (typi-cally diarrhea). The stool may contain trace blood,but profuse bleeding is very uncommon. Dysuria,


urinary frequency, and urgency reflect bladderirritation, whereas pneumaturia, fecaluria, or recur-rent urinary tract infection suggests a colovesicalfistula. Physical findings include fever, left lowerquadrant tenderness, or a mass.

ComplicationsRupture of a peridiverticular abscess or uninflameddiverticulum causes peritonitis, occurs more com-monly in the elderly and immunosuppressed per-sons, and is associated with a high mortality rate.Repeated episodes of acute diverticulitis may leadto colonic obstruction. Jaundice or hepatic abscessessuggest pylephlebitis. A massively dilated (>10 cm)cecum, signs of cecal necrosis (ie, air in the bowelwall), or marked tenderness mandates immediatesurgical consultation. Colovesical and, less frequently,colovaginal and colocutaneous fistulas may occur.

Diagnostic StudiesA contrast enema shows diverticula but not diver-ticular inflammation. Moreover, contrast studiesmay cause perforation. If the clinical features arehighly suggestive of diverticulitis, imaging studiesare unnecessary. If the diagnosis is uncertain or if anabscess is suspected, computed tomography is pre-ferred, although the results may be false negativein up to 20% of cases. Ultrasonography also mayshow diverticular inflammation, but it is more oper-ator-dependent than computed tomography andabdominal tenderness may preclude application ofsufficient external pressure. Flexible sigmoidoscopyis necessary only if carcinoma or colitis is a concern.

• A contrast enema shows diverticula but notinflammation.

• Indications for computed tomography: uncer-tain diagnosis or concern about an abscess.

• Sigmoidoscopy is necessary only to excludecarcinoma or colitis.

TreatmentTreatment is influenced by severity, ability to tol-erate oral intake, previous history of diverticulitisor bleeding, and complications.

• Mild first attack, tolerate oral intake: Outpatienttherapy with a liquid diet and oral broad-spectrum antibiotics (eg, ciprofloxacin and

metronidazole). After the acute attack hasresolved, a high fiber diet and colonoscopy (toexclude cancer) are advisable. Approximately5% to 10% of patients will have a second attackwithin 2 years.

• Severe pain, inability to tolerate oral intake, per-sistent symptoms despite adequate outpatienttherapy: Hospitalization, nothing by mouth,and broad-spectrum intravenous antibiotics.Computed tomography to exclude abscess orperforation. Consider computed tomography-guided percutaneous drainage of an abscess tocontrol systemic sepsis, permitting a single-stagesurgical procedure, if necessary, at a later stage.

• Surgery: Emergency operation is indicated forperitonitis, uncontrolled sepsis, perforation,and clinical deterioration. Indications for electivesurgery include fistula formation, stricture, andrecurrent diverticulitis.

If surgical treatment can be deferred until acuteinflammation heals, then a single-stage primaryresection and reanastomosis, perhaps laparoscop-ically, can be accomplished with minimal morbidityand mortality. For emergency indications, the firststage of a two-stage procedure involves resectionof the diseased segment and creation of an endcolostomy with oversewing of the distal colonic orrectal stump (Hartmann’s procedure). Colonic con-tinuity may be reestablished in a second operation.

RECOMMENDED READINGBanerjee S, LaMont JT. Treatment of gastroin-

testinal infections. Gastroenterology. 2000;118Suppl 1:S48-S67.

Casburn-Jones AC, Farthing MJ. Management ofinfectious diarrhoea. Gut. 2004;53:296-305.

DuPont HL. Guidelines on acute infectious diarrheain adults: the Practice Parameters Committeeof the American College of Gastroenterology.Am J Gastroenterol. 1997;92:1962-75.

Hamer DH, Gorbach SL. Infectious diarrhea andbacterial food poisoning. In: Feldman M,Friedman LS, Sleisenger MH, editors.Sleisenger & Fordtran’s gastrointestinal andliver disease: pathophysiology/diagnosis/man-agement. Vol 2. 7th ed. Philadelphia: Saunders;2002. p. 1864-913.

238 Colon

McFarland LV. Epidemiology, risk factors andtreatments for antibiotic-associated diarrhea.Dig Dis. 1998;16:292-307.

Oldfield EC III. Emerging foodborne pathogens:keeping your patients and your families safe.Rev Gastroenterol Disord. 2001;1:177-86.

Pothoulakis C. Pathogenesis of Clostridium diffi-cile-associated diarrhoea. Eur J Gastroenterol

Hepatol. 1996;8:1041-7.Surawicz CM, editor. Infectious diarrhea.

Gastroenterol Clin N Am. 2001;30:599-861.Tytgat GNJ, editor. Best Pract Res Clin Gastroenterol.

2002;16(4):527-662. Yassin SF, Young-Fadok TM, Zein NN, Pardi DS.

Clostridium difficile-associated diarrhea andcolitis. Mayo Clin Proc. 2001;76:725-30.


Colorectal cancer is primarily a disease of urban,industrialized societies. In the United States, thelifetime risk for the development of this cancer isapproximately 6%. Recent data have suggestedthat the incidence rates for colorectal cancer maybe decreasing gradually in some subgroups of thepopulation. However, the mechanisms underlyingthese favorable trends have not been defined com-pletely. Several national organizations haveendorsed screening and surveillance guidelines,which undoubtedly have contributed to moreeffective prevention of colorectal cancer.

CLINICAL FEATURES

DefinitionMost cases (>95%) of colorectal cancer are adeno-carcinomas. Less common cancer subtypes includelymphoma, carcinoid, and leiomyosarcoma.Metastatic lesions to the colorectum can includelymphoma, leiomyosarcoma, malignant melanoma,and adenocarcinomas of the breast, ovary, prostate,lung, and stomach. Because of the relative rarityof these other malignancies, the term colorectal

cancer is used throughout the rest of this chapter torefer to primary adenocarcinoma. The term co-lorectal neoplasia is used to refer to either malignantadenocarcinomas or premalignant adenomas, asdescribed in more detail below.

PresentationClinical manifestations of colorectal cancer oftenare related to tumor size and location. Commonsigns and symptoms of proximal neoplasms(cecum to splenic flexure) include ill-definedabdominal pain, weight loss, and occult bleeding.The presentation of distal neoplasms (descendingcolon to rectum) may be altered bowel habits,decreased stool caliber, or hematochezia (or a com-bination of these). Colonoscopy is the test of choicefor the diagnostic evaluation of any signs or symp-toms suggestive of colorectal cancer because tissuespecimens can be obtained at the time of visualinspection. Up to 7% of patients with colorectalcancer may have additional, synchronous malig-nancies in the colon or rectum at the time of theindex cancer diagnosis. At the time of the initialdiagnosis of colorectal cancer, 39% of patients havelocalized disease, 36% have regional metastases,

241

CHAPTER 18

Colorectal Neoplasms

Lisa A. Boardman, MDPaul J. Limburg, MD, MPH

Abbreviations: AFAP, attenuated familial adenomatous polyposis; COX, cyclooxygenase; CT, computed tomography; FAP,familial adenomatous polyposis; MAP, MutYH-associated polyposis; SEER, Surveillance Epidemiology and End Results.

and 19% have distant metastases. Distant metas-tases typically occur in the liver, peritoneal cavity,and lung. Less common sites of metastases are theadrenal glands, ovaries, and bone. Central nervoussystem metastases are rare.

Adenoma-Carcinoma SequenceMost colorectal cancers are thought to developthrough an ordered series of events: normal colonicmucosa→mucosa at risk→adenoma→adeno-carcinoma. Indirect evidence to support this ade-noma-carcinoma sequence includes the following:1) prevalence rates cosegregate within popula-tions, 2) subsite distribution patterns within thecolorectum are similar, 3) benign adenomatoustissue is often juxtaposed with invasive cancer inearly-stage malignancies, and 4) incidence ratesof colorectal cancer are decreased by endoscopicpolypectomy. Also, specific molecular alterationshave been associated with the adenoma-carcinoma

sequence (Fig. 1). The APC tumor suppressor geneis considered the “gatekeeper” and is mutated inapproximately 85% of all colorectal cancers. K-rasis the most frequently activated oncogene in co-lorectal neoplasms and is mutated in approximately50% of large (≥1 cm) adenomas and adenocarci-nomas. The p53 gene appears to be mutated laterin carcinogenesis, because chromosomal loss isrelatively more common in malignant (70%-80%)than in benign neoplasms. DNA mismatch repairgenes, including MSH2, MLH1, PMS1, PMS2, andMSH6, maintain nucleic acid sequence integrityduring replication and have been termed caretakergenes. Mutations in these genes are found in 10% to15% of sporadic colorectal cancers and are asso-ciated with microsatellite instability.

Polyp SubtypesAdenomatous polyps are considered to havemalignant potential, whereas hyperplastic,

242 Colon

Fig. 1. Adenoma-to-carcinoma sequence and the associated molecular alterations involved in colon cancerdevelopment. APC, adenomatous polyposis coli; CIN, chromosomal instability; COX-2, cyclooxygenase-2; DCC,deleted in colorectal cancer; MSI, microsatellite instability. (From Niederhuber JE, Cole CE, Grochow L, Jacoby RF,Lee FT Jr, Mooney M, et al. Colon Cancer. In: Abbeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKennaWG, editors. Clinical oncology. 3rd ed. Philadelphia (PA): Elsevier; 2004. p. 1877-1941. Used with permission.)

inflammatory, and hamartomatous (juvenile)polyps generally do not. Serrated polyps alsoappear to confer at least some increased risk forfuture colorectal cancer, although the natural his-tory of these neoplasms has not been character-ized fully. Adenomas can be classified further astubular (70%-85%), villous (<5%), or tubulovillous(10%-25%) on the basis of their glandular histo-logic features and as low-grade or high-grade onthe basis of their degree of dysplasia. “Advanced”adenomas are associated with an increased risk ofcolorectal cancer and usually are defined by 1)large size (≥1 cm), 2) any villous histologic features,or 3) high-grade dysplasia. Multiple (three or more)synchronous adenomas also are associated withan increased risk of colorectal cancer.

Staging and PrognosisThe American Joint Commission on Cancer systemis commonly used to stage colon and rectal cancers(Table 1). For colon cancers, the preoperative stagetypically is determined by physical examination,computed tomography (CT), and chest radiog-raphy. For rectal cancer, endoscopic ultrasonog-raphy can provide additional information aboutthe depth of tumor invasion and regional lymphnode status. Final colorectal cancer stage incorpo-rates pathology review of the resected tumor tissue.Pathologic stage is the best predictor of survival.The overall 5-year survival rate for colorectal canceris approximately 64%. Stage-specific 5-year disease-free survival rates for colon cancer are as follows:stage I, 93%; IIa, 85%; IIb, 72%; IIIa, 83%; IIIb, 64%;IIIc, 44%; and IV, 8%. Five-year survival rates forrectal cancer are generally similar.

EPIDEMIOLOGY

General DistributionWorldwide, colorectal cancer ranks fourth in cancerincidence for men and third for women. However,the incidence rates vary by global region (25-folddifference or more). Areas with the highestreported incidence rates for colorectal cancerinclude North America, Australia/New Zealand,Western Europe, and Japan. Conversely, most partsof Africa and Asia report low incidence rates. Inthe United States, age-adjusted incidence and

mortality rates of colorectal cancer for women are44.6/100,000 and 16.4/100,000, respectively, andfor men, the rates are higher at 60.8/100,000 and23.5/100,000. From 1998 to 2004, the annual per-centage change in colorectal cancer incidence rateswas −2.5%; from 2002 to 2004, the annual per-centage change in colorectal cancer mortality rateswas −4.7%.

Race and EthnicityOf the five major racial-ethnic population sub-groups monitored by the Surveillance Epidemiologyand End Results (SEER) program, African Americanshave the highest incidence and mortality rates forcolorectal cancer, and the 5-year survival rate isalso less than that of Caucasian Americans.Although this likely is explained, at least in part, bydifferences in the stage of disease at the time ofdiagnosis, the survival gap persists when within-stage comparisons are made.

Colorectal Neoplasms 243

Table 1. Colorectal Cancer Staging

Stage TNM classification

I T1 or T2 N0 M0IIa T3 N0 M0IIb T4 N0 M0IIIa T1 or T2 N1 M0IIIb T3 or T4 N1 M0IIIc Any T N2 M0IV Any T any N M1Overall Any T any N any M

T category (primary tumor): T1, tumor invades throughthe muscularis mucosa and into the submucosa; T2,tumor invades through the submucosa and into themuscularis propria; T3, tumor invades through themuscularis propria and into the subserosa; T4, tumorinvades through the entire colorectal wall and intonearby tissues or organs.

N category (regional lymph nodes): N0, no regional lymphnode metastasis; N1, metastasis to 1-3 regional lymphnodes; N2, metastasis to ≥4 regional lymph nodes.

M category (distant metastasis): M0, distant metastasis isabsent; M1, distant metastasis is present.

Modified from AJCC cancer staging manual. 6th ed.Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM,Haller DG, et al, editors. New York: Springer-Verlag;2002. p. 116. Used with permission.

Anatomical SubsiteAnatomical subsites of the colorectum differ in theirembryologic origin, physiologic function, and vas-cular supply. Differences in the morphology, his-tology, and genetics of colorectal cancer have beenobserved across regions within the large bowel.Subsite-specific incidence rates also differ, and theproportion of cases of colorectal cancer located inthe proximal colon appears to be increasing rel-ative to that in the distal colon and rectum.

HOST AND ENVIRONMENTALFACTORS

AgeAs with most malignancies, the incidence rates ofcolorectal cancer increase with advancing age.Fewer than 5% of cases occur among personsyounger than 45 years. SEER data suggest thatage-specific incidence rates for colorectal cancerbegin to increase more rapidly during the fifthdecade. The prevalence of adenomatous polypsalso increases with age, with estimates of 30% at50 years, 40% to 50% at 60 years, and 50% to 65%at 70 years. Also, several important clinical fea-tures of adenomas may be age-related. In theNational Polyp Study, the risk of having a polypwith high-grade dysplasia was 80% higheramong subjects 60 years or older than amongyounger subjects.

Personal History of Colorectal NeoplasiaPersons with a personal history of colorectal ade-nomas or adenocarcinomas are at increased risk(up to sixfold) for additional, or metachronous,neoplasms. Adenoma characteristics associatedwith future tumor development include large size(>1 cm), villous histology, and three or more life-time colonic adenomas. Neither hyperplasticpolyps nor small, solitary tubular adenomas arestrong risk factors for metachronous neoplasms.After resection of colorectal cancer, the annual inci-dence rate for a second primary colon or rectalcancer has been estimated at 0.35%.

Family History of Colorectal NeoplasiaFamilial clustering is observed in approximately15% of all cases of colorectal cancer, including

patients with heritable cancer syndromes (seebelow). In the absence of an identifiable syndrome,a strong family history of colorectal neoplasia (typ-ically defined as having one first-degree relativewith colorectal neoplasia diagnosed before age 60years, or two or more first-degree relatives withcolorectal neoplasia diagnosed at any age) appearsto confer approximately a 1.5- to 2-fold increase inthe risk of colorectal cancer.

Inflammatory Bowel DiseaseChronic ulcerative colitis is associated with a sub-stantially increased risk of colorectal cancer overtime. Cumulative incidence rates range from 2%after 10 years to 18% after 30 years of disease. Theextent of colitis has been positively associated withcolorectal cancer risk (pancolitis > distal colitis >proctitis), but the effects of disease activity havenot been defined completely. Primary sclerosingcholangitis and a family history of colorectal cancerrepresent additional risk factors. However, theeffects of disease activity on the risk of colorectalcancer are not conclusively known. Fewer data areavailable about the association between Crohn’sdisease and colorectal cancer, but the risk appearsto be comparable to that of chronic ulcerative colitisamong patients with inflammatory bowel diseaseof similar duration. Current data do not support anincreased risk of colorectal cancer for patients withlymphocytic or collagenous colitis. Studies havesuggested that inflammatory bowel disease-relatedtumors may develop through a different molecularpathway than sporadic neoplasia, with aneuploidyoccurring early in the carcinogenic process.

Dietary ComponentsExcess body weight has been associated with a 1.5-to 2-fold increase in the risk of colorectal cancer,although not all observational studies have demon-strated consistent results. Red meat, particularlywhen consumed with a heavily browned surface,has been proposed as a risk factor for both benignand malignant colorectal neoplasia.

Vegetables and fruits contain a wide array ofpotentially anticarcinogenic substances that mayfunction through one or several independent orcodependent mechanisms. Generally, vegetable con-sumption has been one of the most consistent pre-dictors of reduced risk of colorectal cancer, but fruit

244 Colon

consumption appears to be associated less stronglywith reductions in large-bowel tumorigenesis.

Fiber enhances stool bulk, decreases the con-centration of procarcinogenic secondary bile acids,and increases the concentration of anticarcinogenicshort-chain fatty acids. Although multiple case-control studies initially suggested a protective effectby increased dietary fiber, subsequent interventiontrials have not observed appreciable reductions inthe risk of colorectal cancer.

Calcium binds to intraluminal toxins and alsoinfluences mucosal proliferation within the co-lorectum. In one clinical trial, calcium supplemen-tation was associated with a statistically significant19% decrease in the recurrence of adenoma in post-polypectomy patients after 4 years. However, inanother large, randomized, controlled trial ofpostmenopausal women, calcium and vitaminD supplementation for 7 years had no appreciableeffect on incident colorectal cancer.

Antioxidants (including retinoids, carotenoids,ascorbic acid, α-tocopherol, and selenium) havebeen hypothesized to prevent carcinogen forma-tion by neutralizing free radical compounds. Sofar, observational and experimental data have beenunimpressive, with the exception that seleniumdecreased the risk of colorectal cancer by 58% whenmeasured as a secondary end point in a skin cancerprevention study.

Folate and methionine supply methyl groupsnecessary for critical cellular functions such asnucleotide synthesis and gene regulation.Particularly in the context of excess alcohol con-sumption, dietary deficiencies of these com-pounds may be a risk factor for colorectal cancer.Nonetheless, in a recent multicenter clinical trialof participants with a previous history of benigncolorectal neoplasia, 1 mg/day of folic acid wasfound to be associated with increased risks forrecurrent advanced adenomas as well as nonco-lorectal cancers.

LifestyleAlcohol induces cellular proliferation, blocksmethyl group donation, and inhibits DNA repair.Many observational studies have suggested atwofold to threefold increase in the risk of col-orectal cancer with excess alcohol consumption,although a meta-analysis of 27 case-control and

cohort studies found only a 10% increase in riskamong daily alcohol users.

Tobacco smoke contains numerous putativecarcinogens, including polycyclic aromatic hydro-carbons, nitrosamines, and aromatic amines. On thebasis of data from several large cohort studies,smoking appears to be a risk factor for colorectalcancer after a prolonged latency of 20 or more years.

Physical activity has been associated consis-tently with a 40% to 50% decrease in the risk ofcolorectal cancer, particularly in the distal colon,through the stimulation of intestinal transit,decreased prostaglandin E2 levels, or other as-yet-undefined mechanisms.

OtherA recent meta-analysis of data from 15 observationalstudies found that patients with type 2 diabetesmellitus had a 30% increase in the risk of colorectalcancer compared with those without diabetes.Insulin resistance has been proposed as the under-lying mechanism of tumorigenesis.

Persons with acromegaly may be predisposedmetabolically or anatomically to higher risks of co-lorectal cancer. Because of the relative rarity of thiscondition, most observational studies have lackedadequate statistical power, but the preponderanceof evidence supports a positive risk association.

Cholecystectomy results in an altered fecal bileacid composition. Two meta-analyses havereported moderately increased risks of 11% to 34%for colorectal cancer (mainly in the proximal colon)after gallbladder surgery.

HERITABLE SYNDROMES Cases of hereditary colorectal cancer account forapproximately 15% of all large-bowel malignan-cies. Several well-defined syndromes have beenrecognized, as discussed below. It is important toremember that patients with gene mutations arealso at increased risk for target organ cancers out-side the colorectum.

Familial Adenomatous PolyposisGermline mutations in the APC gene form the basicmolecular foundation for familial adenomatouspolyposis (FAP) (autosomal dominant). As manyas one in five cases may represent new-onset


spontaneous mutations. The estimated prevalenceis 1/5,000 to 7,500 persons. Additional genetic andenvironmental factors, as yet unidentified, seemlikely to influence the clinical manifestations ofFAP because phenotypic features vary widelydespite similar inherited APC mutations. The hall-mark lesion of FAP is diffuse colorectal polyposis,with typically hundreds to thousands of adenomasdeveloping sometime during adolescence. Otherfindings include duodenal adenomas, gastric(fundic) gland hyperplasia, mandibular osteomas,and supernumerary teeth. In the absence of pro-phylactic colectomy, colorectal carcinoma isinevitably diagnosed in patients with FAP at amean age of approximately 40 years. Even aftercolectomy, increased cancer risks remain, partic-ularly in the periampullary region of the duo-denum and in the retained rectal remnant (if par-tial colectomy was performed).

Gardner’s syndrome is a variant of FAP inwhich patients with APC mutations have the samephenotypic features as classic FAP but in additioncan have osteomas of the skull and long bones,congenital hypertrophy of the retinal pigmentedepithelium, desmoid tumors, epidermoid cysts,fibromas, and lipomas.

Attenuated Familial AdenomatousPolyposisAttenuated FAP (AFAP) is associated with rela-tively fewer adenomas (<100) and later onset ofcolorectal cancer (approximate age, 55 years) thanin classic FAP. About 40% of these cases can befound to be associated with germline APC muta-tions. Because both the adenomas and the cancersappear to arise in the proximal colon, at-risk familymembers should have screening with fullcolonoscopy rather than flexible sigmoidoscopy, asrecommended for screening in classic FAP kindreds.

Lynch SyndromeLynch syndrome (formerly called hereditarynonpolyposis colorectal cancer) is an autosomaldominant syndrome characterized by early-onsetcolorectal cancer, usually located in the proximalcolon, and increased risk of extracolonic malig-nancies (uterus, ovaries, stomach, urinary tract,small bowel, and bile duct). The clinical criteriafor considering a person to be at risk for Lynch

syndrome are called the Amsterdam criteria (Table2). The syndrome has been associated recently withmutations in at least five DNA mismatch repairgenes. Adenomas are believed to precede carci-nomas in most instances, and colorectal cancerdevelops in 75% to 80% of patients with Lynchsyndrome, at a median age of 46 years. Jarvinenet al. reported that regularly performed colonoscopywith polypectomy can decrease the risk of large-bowel adenocarcinoma for persons with Lynchsyndrome by approximately 60%.

Turcot’s SyndromeTurcot’s syndrome refers to a familial predispositionfor both colonic polyposis and central nervoussystem tumors. It likely represents a constellationof molecular features that can be variants of eitherFAP or Lynch syndrome. Patients with early-onsetcolonic polyposis associated with APC mutationstend to have medulloblastomas (FAP variant),whereas those with DNA mismatch repair genemutations are prone to the development ofglioblastoma multiforme (Lynch syndromevariant). Of interest, glioblastoma multiforme thatarises in the setting of Turcot’s syndrome tends tooccur at an earlier age and has a better prognosisthan the sporadic form of the tumor.

Muir-Torre SyndromePatients with Muir-Torre syndrome have sebaceousneoplasms, urogenital malignancies, and gas-trointestinal tract adenocarcinomas in associationwith defective DNA mismatch repair. The ratio ofaffected men to women is 2:1.

246 Colon

Table 2. Clinical Criteria for DiagnosingLynch Syndrome

≥3 Relatives with Lynch syndrome-relatedcancers*

≥1 Persons with colorectal cancer is a first-degree relative of 2 other cases

≥2 Successive generations affected≥1 Persons with colorectal cancer diagnosed

before age 50 years

*Including cancer of the colorectum, endometrium, smallbowel, ureter, or renal pelvis.

MutYH-Associated PolyposisMYH is a DNA base excision repair enzyme.MutYH-associated polyposis (MAP) is an autosomalrecessive syndrome with a wide-ranging phe-notype. The colorectal adenoma burden in MAPcan be similar to that of AFAP, but patients withMAP who have more than 100 adenomas havebeen described. Also, duodenal and periampullaryadenomas can be found in patients with MAP,although the true incidence of upper gastrointestinaltract neoplasia is not known. Biallelic carriers, orpersons with mutations in both MYH alleles, havean 80% cumulative risk of colorectal cancer by age70 years, but monoallelic carriers do not appear tohave an increased risk for colorectal cancer.

Hamartomatous Polyposis Syndromes

Peutz-Jeghers SyndromePeutz-Jeghers syndrome is an autosomal dominantcondition characterized by multiple hamartoma-tous polyps scattered throughout the gastroin-testinal tract. Up to 60% of cases of the syndromeare related to germline mutations in the LKB1(STK11) gene. Melanin deposits usually can be seenaround the lips, buccal mucosa, face, genitalia,hands, and feet, although occasionally the skin andintestinal lesions are inherited separately. Foci ofadenomatous epithelium can develop withinPeutz-Jeghers polyps and may be associateddirectly with an increased risk of colorectal cancer.Extracolonic malignancies include other gas-trointestinal cancers (duodenum, jejunum, ileum,pancreas, biliary tree, and gallbladder), ovariansex cord tumors, Sertoli cell testicular tumors, andbreast cancer.

Tuberous SclerosisTuberous sclerosis (autosomal dominant) is asso-ciated with hamartomas, mental retardation,epilepsy, and adenoma sebaceum. Adenomatouspolyps may occur, particularly in the distal colon.

Juvenile Polyposis SyndromeJuvenile polyposis syndrome is an autosomaldominant condition in which juvenile mucousretention polyps (misnamed hamartomata) canarise in the colon, stomach, or elsewhere in thegastrointestinal tract. Both PTEN and SMAD4

mutations have been implicated as genetic causesof the syndrome. Symptoms of bleeding or obstruc-tion may arise during childhood and may warrantsurgery on the affected intestinal segments fortreatment of anemia or obstruction or for cancerprevention. The risk of colorectal cancer isincreased when synchronous adenomas or mixedjuvenile-adenomatous polyps are present. If pro-phylactic or therapeutic colonic resection is per-formed, ileorectostomy or total proctocolectomyshould be considered because of an increased riskof recurrent juvenile polyps within the retainedcolorectal segment. Of note, fewer than five juvenilepolyps (including solitary polyps) in a person withno family history of juvenile polyposis syndromedoes not indicate a heritable syndrome and, on thebasis of current knowledge, does not warrant furtherdiagnostic testing or aggressive cancer surveillance.

Cowden DiseaseCowden disease is an autosomal dominant con-dition in which persons with PTEN mutations mayhave trichilemmomas, other skin lesions, and ali-mentary tract polyps that are histologically similarto the polyps of juvenile polyposis syndrome.Patients with Cowden disease are at increased riskfor breast cancer (often bilateral) and papillary thy-roid cancer. The risk of colorectal cancer is not well-defined in this syndrome, but colonoscopy shouldbe included in the original diagnostic evaluation.

Cronkhite-Canada SyndromeCronkhite-Canada syndrome refers to a noninher-ited condition manifested by signs and symptomsof malnutrition or malabsorption. Gastrointestinalhamartomas may be present and can exhibit foci ofadenomatous epithelium. Characteristic clinicalfeatures include alopecia and hyperkeratosis ofthe fingernails and toenails. In the United Statesand Europe, Cronkhite-Canada syndrome typi-cally develops in men, whereas in Asian countries,women appear to be affected more often.

PREVENTION

Screening and SurveillanceFor average-risk patients (defined as asymptomaticadults, 50 years or older, without other known risk


factors for colorectal cancer), several screeningoptions have been endorsed by major primary careand subspecialty organizations, as follows:

• Fecal occult blood test or fecal immuno-chemical test every year

• Flexible sigmoidoscopy every 5 years• Fecal occult blood test or fecal immunochem-

ical test every year plus flexible sigmoidoscopyevery 5 years

• Double-contrast barium enema every 5 years• Colonoscopy every 10 years

Also, emerging technologies, such as CT colonog-raphy and DNA-based stool tests, show consid-erable promise. Diagnostic colonoscopy shouldbe performed in follow-up of any screening testwith positive findings.

For high-risk patients, the following recom-mendations have been adopted:

• FAP—flexible sigmoidoscopy at the onset ofpuberty for indeterminate cases

• Lynch syndrome—colonoscopy every 1 or 2years, beginning at age 20 years; it should beperformed annually after age 40 years

• Peutz-Jeghers syndrome—initial screeningcolonoscopy during the second decade of life,with subsequent surveillance intervals deter-mined by examination findings

• Strong family history of colorectal neoplasia(excluding FAP, Lynch syndrome, or otheridentifiable syndromes)—colonoscopy every5 years beginning at age 40 years (or 10 yearsbefore the youngest case diagnosis in thefamily, whichever is earlier). For patientswith one first-degree relative diagnosed atage 60 years or older, or two second-degreerelatives with colorectal cancer diagnosed atany age, any of the endorsed screeningoptions may be selected, beginning at age 40years (rather than age 50 years for average-risk patients)

• Inflammatory bowel disease—annual colon-oscopy with surveillance biopsies, beginning8 to 10 years after the onset of pancolitis.Patients with proctosigmoiditis and no otheridentifiable risk factors for colorectal cancercan be managed with annual colonoscopy with

surveillance biopsies 12 to 15 years after theonset of distal colitis

History of Colorectal NeoplasiaAfter a complete clearing colonoscopy has beenperformed, repeat examinations can be delayedfor patients who have one or two tubular ade-nomas that are smaller than 1 cm and have low-grade dysplasia at baseline. Surveillancecolonoscopy is indicated at 3 years for patientswith advanced adenomas or 3 to 10 adenomas atbaseline. Family history should be considered ona case-by-case basis when determining post-polypectomy surveillance intervals. Patients withmore than 10 adenomas at a single examinationshould have colonoscopy again in less than 3 years.

Patients with large (>2 cm), sessile adenomasthat are removed piecemeal should haveendoscopy repeated in 2 to 6 months. Residualadenomatous tissue after two or three therapeuticcolonoscopies should prompt a surgical consulta-tion. Malignant polyps, defined as neoplasms withdysplastic cells invading through the muscularismucosa, can be treated endoscopically if 1) thelesion has been excised completely and fully exam-ined by a pathologist; 2) the depth of invasion,grade of differentiation, and completeness of exci-sion can be determined accurately; 3) poor differ-entiation, vascular invasion, and lymphaticinvolvement are not present; and 4) the margin ofexcision is free of cancer cells. Follow-upcolonoscopy should be performed at 3 months formalignant polyps that meet these favorable prog-nostic criteria.

Patients with potentially curable colon or rectalcancer should have a clearing colonoscopy preop-eratively or within 3 to 6 months postoperatively ifobstructive lesions prevented preoperativecolonoscopy. After clearing colonoscopy, subse-quent surveillance examinations can be performedat 1 year, 3 years, and 5 years if no additional co-lorectal neoplasia is found.

ChemopreventionChemoprevention refers to the use of chemicalcompounds to prevent, inhibit, or reverse car-cinogenesis before the invasion of dysplasticepithelial cells across the basement membrane. Inits broadest sense, chemoprevention includes both

248 Colon

nutritional and pharmaceutical interventions. Withregard to pharmaceutical agents, nonsteroidal anti-inflammatory drugs are structurally diverse, yetappear to share abilities to decrease proliferation,slow cell cycle progression, and stimulate apop-tosis. Extensive epidemiologic data uphold a neg-ative risk (40%-60%) association between regularuse of nonsteroidal antiinflammatory drugs andcolorectal tumors. The chemopreventive effects ofthese drugs are thought to be derived throughcyclooxygenase (COX)-2 inhibition, and agentsthat selectively block this enzyme isoform (cele-coxib and rofecoxib) have been shown in severallarge clinical trials to decrease the recurrence ratesof adenoma. However, selective COX-2 inhibitorshave been associated also with increased car-diovascular toxicity, which has limited theirchemopreventive applications to high-risk clin-ical settings (such as adjunct therapy for FAP).

TREATMENT

Colon CancerIn the absence of known distant metastases or pro-hibitive comorbid conditions, surgical excision isthe initial treatment modality for most patientswho have colon cancer. Typical operations forcolon cancer include segmental resection. The pro-cedures can be performed through an open incisionor laparoscopically, if technically feasible. Moreextensive operations such as subtotal colectomyor proctocolectomy can be performed for patientswho have colorectal neoplasia in multiple colonicsegments or familial cancer syndromes, respec-tively. Operative intervention also may be con-sidered for selected patients who have isolatedliver or lung metastases. Postoperative, or adju-vant, chemotherapy is recommended for patientswith stage III colon cancer. It should be consideredalso for patients with stage II colon cancer whohave poor prognostic factors, as based on pathologyreview. The preferred regimen includes 5-fluo-rouracil, leucovorin, and oxaliplatin (FOLFOX) for6 months.

Adenocarcinomas in the middle and upperrectum usually are removed by anterior resection,with colorectal anastomosis. Cancers in the lowerrectum (0-5 cm above the anal verge) often require

abdominoperineal resection, with a permanentcolostomy, although anterior resection with lowcoloanal anastomosis may be considered for somepatients. Preoperative, or neoadjuvant, treatmentwith 5-fluorouracil-based chemotherapy in com-bination with radiotherapy generally is indicatedfor patients with tumors that are staged as T3 andhigher or N1 and higher with CT and endoscopicultrasonography. Adjuvant chemotherapy with5-fluorouracil and leucovorin (with or withoutoxaliplatin) is recommended for patients with stageII or stage III rectal cancer. Molecularly targetedtherapies (eg, bevacizumab and cetuximab) arebeing investigated as adjuvant therapy and havedemonstrated clear benefits for patients withmetastatic colorectal cancer.

RECOMMENDED READINGBernold DM, Sinicrope FA. Advances in

chemotherapy for colorectal cancer. ClinGastroenterol Hepatol. 2006 Jul;4:808-21. Epub2006 Jun 22.

Bronner MP. Gastrointestinal inherited polyposissyndromes. Mod Pathol. 2003;16:359-65.

Cress RD, Morris C, Ellison GL, Goodman MT.Secular changes in colorectal cancer incidenceby subsite, stage at diagnosis, and race/eth-nicity, 1992-2001. Cancer. 2006;107 5 Suppl:1142-52.

Giardiello FM, Brensinger JD, Petersen GM. AGAtechnical review on hereditary colorectalcancer and genetic testing. Gastroenterology.2001;121:198-213.

Giardiello FM, Trimbath JD. Peutz-Jeghers syn-drome and management recommendations.Clin Gastroenterol Hepatol. 2006;4:408-15.

Hawk ET, Umar A, Viner JL. Colorectal cancerchemoprevention: an overview of the science.Gastroenterology. 2004;126:1423-47.

Itzkowitz SH, Present DH; Crohn’s and ColitisFoundation of America Colon Cancer in IBDStudy Group. Consensus conference: colorectalcancer screening and surveillance in inflam-matory bowel disease. Inflamm Bowel Dis.2005;11:314-21.

Jemal A, Siegel R, Ward E, Murray T, Xu J, ThunMJ. Cancer statistics, 2007. CA Cancer J Clin.2007;57:43-66.


Kang H, O’Connell JB, Leonardi MJ, Maggard MA,McGory ML, Ko CY. Rare tumors of the colonand rectum: a national review. Int J ColorectalDis. 2007 Feb;22:183-9. Epub 2006 Jul 15.

Kornbluth A, Sachar DB; Practice ParametersCommittee of the American College ofGastroenterology. Ulcerative colitis practiceguidelines in adults (update). Am JGastroenterol. 2004;99:1371-85.

Lindor NM, Green MH; Mayo Familial CancerProgram. The concise handbook of familycancer syndromes. J Natl Cancer Inst.1998;90:1039-71.

Lindor NM, Rabe K, Petersen GM, Haile R, CaseyG, Baron J, et al. Lower cancer incidence inAmsterdam-I criteria families without mis-match repair deficiency: familial colorectalcancer type X. JAMA. 2005;297:1979-85.

O’Connell JB, Maggard MA, Ko CY. Colon cancersurvival rates with the new American JointCommittee on Cancer sixth edition staging. JNatl Cancer Inst. 2004;96:1420-5.

Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer

statistics, 2002. CA Cancer J Clin. 2005;55:74-108.Rex DK, Kahi CJ, Levin B, Smith RA, Bond JH,

Brooks D, et al; American Cancer Society; USMulti-Society Task Force on Colorectal Cancer.Guidelines for colonoscopy surveillance aftercancer resection: a consensus update by theAmerican Cancer Society and the US Multi-Society Task Force on Colorectal Cancer.Gastroenterology. 2006;130:1865-71.

Winawer S, Fletcher R, Rex D, Bond J, Burt R,Ferrucci J, et al; Gastrointestinal ConsortiumPanel. Colorectal cancer screening and surveil-lance: clinical guidelines and rationale-updatebased on new evidence. Gastroenterology.2003;124:544-60.

Winawer SJ, Zauber AG, Fletcher RH, Stillman JS,O’Brien MJ, Levin B, et al; US Multi-SocietyTask Force on Colorectal Cancer; AmericanCancer Society. Guidelines for colonoscopysurveillance after polypectomy: a consensusupdate by the US Multi-Society Task Force onColorectal Cancer and the American CancerSociety. Gastroenterology. 2006;130:1872-85.

250 Colon

Irritable bowel syndrome (IBS) is a common con-dition that contributes substantially to health carecosts. Historically, because the cause is not knownand no curative therapy is available, IBS has beenmanaged symptomatically. Recent discoveriesin the physiology of the enteric nervous system,the gut-brain axis, and the intestinal flora haveled to the development of therapies targeted atpotential pathophysiologic mechanisms of IBS.In addition, the role of psychologic issues hasbeen well recognized, and therapy directed atbehavioral intervention has been used moreextensively than in the past. The overall goal isto improve the patient’s symptoms and overallquality of life and, ideally, to prevent the suf-fering that patients experience.

DEFINITIONThe symptom criteria for IBS are listed in Table 1.The Rome criteria were developed in conjunctionwith the World Congress of Gastroenterology heldin Rome, Italy, in 1988 and were revised (Rome II)in 1999 and again in 2006 (Rome III). The Romecriteria are similar to the criteria established byManning et al in 1978. However, a goal of the Rome

criteria was to incorporate constipation-typesymptoms into the definition of IBS.

As with any set of criteria, there is a trade-offbetween sensitivity and specificity depending onthe threshold used. In clinical practice, this can be

251

CHAPTER 19

Irritable Bowel Syndrome

G. Richard Locke III, MD

Table 1. Diagnostic Criteria for IrritableBowel Syndrome*

Recurrent abdominal pain or discomfort† atleast 3 days per month in the last 3 monthsassociated with 2 or more of the following:

• Improvement with defecation• Onset associated with a change in

frequency of stool• Onset associated with a change in form

(appearance) of stool

*Criteria fulfilled for the last 3 months, with symptomonset at least 6 months before diagnosis.

†Discomfort means an uncomfortable sensation notdescribed as pain.

From Longstreth GF, Thompson WG, Chey WD,Houghton LA, Mearin F, Spiller RC. Functional boweldisorders. Gastroenterology. 2006;130:1480-91. Usedwith permission.

Abbreviation: IBS, irritable bowel syndrome.

helpful. The more criteria a specific patient meets,the more likely the patient is to have IBS. Nonetheless,the diagnosis can be made only if there are not anystructural or metabolic abnormalities that explainthe symptoms.

EPIDEMIOLOGYIBS is thought to be a common condition. Manypopulation-based surveys have assessed the indi-vidual symptoms of this syndrome. The preva-lence rates for symptom reporting have variedbetween 8 and 22 per 100 adults. It is simplest tothink of the prevalence of IBS as 10% (1 in 10).

Although many studies have assessed theprevalence of IBS, data on incidence are more dif-ficult to obtain. Because not everyone with the syn-drome seeks medical care, data on incidence needto come from a population-based study. The exactnumbers have varied among surveys, but over a 1-year period about 10% of the general populationreport the onset of symptoms of IBS. However, itis not known whether these people had the syn-drome in the past. Thus, this is an onset rate ratherthan a true incidence rate. Approximately one-thirdof persons with IBS report that symptoms resolveover time. A recent estimate of the incidence of clin-ically diagnosed IBS is 196 per 100,000 person-years.This clinical incidence figure is lower than the 10%onset figure, which likely reflects both the fluctu-ating pattern of symptoms and the limited seekingof health care by persons with the syndrome. Still,this is much higher than the incidence of colon cancer(50 per 100,000 person-years) and inflammatorybowel disease (10 per 100,000 person-years).

RISK FACTORSMultiple risk factors have been proposed for IBS.In clinic-based studies, there is a strong associationwith sex. However, the female-to-male ratio in thecommunity is approximately 2:1. Thus, sex mayhave a role not only in the onset of the syndromebut also in health care-seeking behavior. The preva-lence of IBS decreases slightly with age. However,the new onset of symptoms may occur in theelderly. Prevalence estimates now are availablefrom around the world. No consistent racial orethnic differences have been identified.

Multiple studies have assessed the role of per-sonality characteristics, psychiatric illness, andphysical and sexual abuse in the development ofIBS. These problems are common among patientswith IBS who are evaluated in academic medicalcenters. However, persons in the community whohave IBS are much less distressed.

Many patients with IBS report that a familymember also has the condition. Familial aggrega-tion of IBS exists, and twin studies have suggesteda genetic component. However, other studies haveshown that seeking health care for gastrointestinalproblems is increased among children of parentswith gastrointestinal symptoms. Additional studyis needed to separate nature from nurture in thedevelopment of IBS.

Symptoms of IBS can occur after acute inflam-matory conditions such as Salmonella infection.The propensity for development of postinfectiousIBS is associated with sex, duration of illness, andthe psychologic state of the person at the time ofinfection. Inflammatory markers have been iden-tified in the colons of people with postinfectiousIBS. The concept of postinfectious IBS is beingactively investigated.

Food allergies or sensitivities also may havea role in the development of IBS. Patients withsymptoms of this syndrome report more sensi-tivity to food than people without symptoms.However, the data on exclusion diets have notshown convincingly that food is a cause of thesymptoms. Recently, a trial of dietary modifica-tion based on IgG antibodies to food antigens didshow an effect.

PATHOGENESISThe cause of IBS is not understood completely.However, IBS has been associated consistentlywith visceral hypersensitivity. Balloon distentionstudies have shown that patients with this syn-drome feel discomfort at a lower volume than dosubjects without the syndrome. Patients with IBSand subjects without IBS do equally well on testsof somatic pain such as cold water immersion, sug-gesting that IBS is a disorder specific to the gut.Balloon distention studies also have suggestedthat patients with IBS have hypersensitivitythroughout the gastrointestinal tract. The frequent

252 Colon

overlap between IBS and fibromyalgia and uri-nary symptoms suggests that the problem may bean even more diffuse visceral hypersensitivity.

More recently, imaging studies of the centralnervous system during balloon distention haveshown that a different part of the brain is activatedduring balloon distention in patients with IBS thanin healthy controls. Considerable advances havebeen made in understanding this brain-gut axis.The concept of a “big brain” in the cranial vaultand a “little brain” in the abdomen has gainedwidespread acceptance. With this understanding,research has been undertaken to evaluate com-pounds that have central nervous system activityto determine whether they have a role in the man-agement of IBS. Serotonin has been investigatedmost intensively. The pathophysiologic state ofcarcinoid diarrhea shows that serotonin has a rolein gastrointestinal physiology. Other studies haveshown that serotonin has a role in visceral hyper-sensitivity, which increasingly is viewed as the pri-mary pathophysiologic mechanism of IBS. The rolesof opioid receptors, cholecystokinin receptors,dopamine receptors, cannabinoid receptors, and α-adrenergic agonists are being actively investigated.

Increasing attention is now focused on the roleof the bacteria in the gastrointestinal tract and thedevelopment of symptoms of IBS. Bacterial over-growth may be the cause of IBS in such patients.Whether this is true or the bacterial overgrowth is theresult of an underlying dysmotility is being studied.

DIAGNOSISIBS is diagnosed on the basis of symptom criteria(Table 1), in the absence of structural or metabolicabnormalities that can explain the symptoms.Many disorders can cause abdominal pain.However, the combination of abdominal pain andabnormal defecation has a more limited differen-tial diagnosis. Colon cancer, inflammatory boweldisease, thyroid disorders, celiac disease, and giar-diasis are all relatively common conditions thatcan have similar symptoms. Carcinoid syndrome,microscopic colitis, bacterial overgrowth, andeosinophilic gastroenteritis also can have similarsymptoms, but they are less common. The problemis that IBS is so common that it is difficult to jus-tify performing extensive diagnostic tests on a large

proportion of the population. All tests will have avery low yield.

Young patients with classic symptoms of IBSdo not necessarily need any tests when they presentto their primary care provider. Simple blood tests,stool tests for ova and parasites and occult blood,and an anatomical evaluation of the colon may beconsidered (Fig. 1). Patients older than 50 years needa full colonic evaluation to exclude colorectal cancer.

Recent studies have heightened the awarenessabout celiac disease. Although much needs to belearned about how common the diagnosis of thisdisease is among patients who present with symp-toms of IBS, clinicians should consider some formof testing for the disease in these patients.

As noted, bacterial overgrowth has beenreported in patients with IBS. The proportions havevaried greatly (10%-70%), which may reflect thevalidity of the tests used. Whether people with bac-terial overgrowth should still be considered to haveIBS or given a separate diagnosis is an open question.

PROGNOSISThe natural history of IBS is becoming betterunderstood. In approximately 30% of patients,the symptoms resolve over the course of a year.This contributes to the placebo response rate, whichhas made evaluation of investigative agents diffi-cult. Although the symptoms may resolve, symp-toms of another functional gastrointestinal disorderdevelop in some patients. Thus, the degree to whichthe gastrointestinal symptoms resolve completelyis not clear. A pattern of symptoms coming, going,and changing over time is quite common.

MANAGEMENTAlthough IBS often is managed with a high fiberdiet and antispasmodic agents, an approach thatconsiders the patient’s predominant symptom isrecommended (Fig. 1). Does the patient complainprimarily of constipation, diarrhea, or abdominalpain? Constipation can be treated with laxativesand a high fiber diet, and diarrhea may betreated with loperamide, especially when takenbefore meals. A high fiber diet may be helpfulfor patients who alternate between constipationand diarrhea, but the benefit of a high fiber diet

Irritable Bowel Syndrome 253

in diarrhea-predominant IBS is unproven.Antispasmodic agents are appropriate for patientswho have primarily abdominal pain. These agentshave been prescribed because of the belief thatthe pathophysiologic mechanism of IBS is spasmsand irregular contractility. The clinical trial data onthe effectiveness of antispasmodic agents aremixed. However, with the absence of alternativemedications, antispasmodic agents have been usedwidely. In each case, a dietary history is importantto ensure that the patient is not consuming productsthat may inadvertently cause diarrhea, constipa-tion, or abdominal gas. Further evaluation shouldbe withheld until the initial treatment program isundertaken (3-6 weeks).

The hope is that the patient will be reassuredabout the diagnosis and will have a response tothe initial therapy. However, some patients continueto have pronounced symptoms and seek care.What are the options for these patients? For con-stipation, therapy typically is laxatives. Furthertesting and treatment are based on the predominant

symptom. Patients with refractory constipationneed to be evaluated for problems of colonic transitand pelvic floor dysfunction (see Chapter 20,Constipation and Disorders of Pelvic FloorFunction). Patients with pelvic floor dysfunctionmay benefit from biofeedback.

Patients with documented delay in colonictransit may be considered for colonic resection.However, if the patient has symptoms of IBS,surgery for colonic inertia needs to be consideredcarefully because the abdominal pain may persistpostoperatively.

For patients with diarrhea, stool chemistry testsfor surreptitious laxative abuse, duodenal aspiratefor bacterial overgrowth, colonic biopsies for micro-scopic colitis, determination of urinary 5-hydroxy-indoleacetic acid for carcinoid syndrome, and asmall-bowel colonic transit study may all be con-sidered. The yield of these tests is low, but they areuseful for evaluating patients who have chronic diar-rhea with increased stool volume. Treatment withhigh-dose loperamide (up to 16 mg daily),

254 Colon

Symptom assessmentRome criteria for

Limited screening for organic disease

Hematology, chemistry, ESR, sTSHStool for ova and parasites

Symptomatic subgroup

Pain, gas, bloatDiarrhea Constipation

Therapeutic trial:

If intractable, consider:

AntispasmodicLoperamideDiphenoxylate

Increase roughageOsmotic laxative

Small-bowel x-rayGastrointestinal manometry

Jejunal aspirate for ovaand parasites and culture

Transit test: small boweland colon

Colonic transit testAnorectal manometry

Pelvic floor functionRectal sensation

(Further investigation or treatment if any of the tests are positive)

positive diagnosis

and emptying

Review diet history: Yes YesYesAdditional tests: Plain abdominal x-rayH2 breath test?No

Colonic evaluation (eg, colonscopy if>50 years old)

Fig. 1. Management of irritable bowel syndrome. ESR, erythrocyte sedimentation rate; sTSH, sensitive thyroid-stimulating hormone. (Modified from Drossman DA, Whitehead WE, Camilleri M. Irritable bowel syndrome: atechnical review for practice guideline development. Gastroenterology. 1997;112:2120-37. Used with permission.)

cholestyramine, clonidine, verapamil, alosetron, oreven octreotide may be considered.

Many physicians consider pain-predominantIBS the most challenging to manage. A plain radi-ograph of the abdomen obtained during a time ofsevere pain may help to exclude obstruction. Inacademic medical centers, pseudo-obstruction orother motility disorders may be evaluated, but painis not common in these conditions. Often, the nextstep is a course of treatment with a low dose of atricyclic antidepressant. The goal is not to alleviatedepression but rather to reduce visceral sensation.

Some patients with IBS report bloating as themajor symptom. Studies have reported some ben-efit with probiotics.

The association between psychologic distressand IBS is well established. When formal psychi-atric disorders are present, appropriate therapydirected toward treating the underlying disorderis mandatory. Even when there is no diagnosis ofa psychiatric disorder, the approach of using psy-chologic intervention is helpful in the managementof IBS. When traditional symptomatic measureshave not been adequate, treatment with low dosesof tricyclic antidepressants or selective serotoninreuptake inhibitors has provided improvementfor many patients. The pathophysiologic mech-anism of tricyclic antidepressants is not clear.The dosages used are much lower than thoseused to treat depression. In a randomized clin-ical trial, tricyclic antidepressants were helpfulfor people who did not experience side effects(per protocol analysis). In the intention-to-treatanalysis, cognitive behavioral therapy was shownto be effective. Patients with IBS refractory toother treatment may benefit from formal painmanagement approaches.

HEALTH CARE UTILIZATIONAnnually, IBS accounts for 3.5 million physicianvisits, 2.2 million prescriptions, and 35,000 hospi-talizations. Primary care physicians provide mostcare for patients with IBS, although a survey ofgastroenterologists indicated that 28% of theirpatient population had IBS. The exact expendi-tures accountable to IBS are difficult to determine.In one study, subjects with IBS in the communitywere found to incur an extra $300 annually in

health care expenditures. Extrapolated to the USpopulation, this is equal to $8 billion. Also, IBS isassociated with absenteeism. This and other indi-rect costs to patients and their families make thetotal cost of IBS considerable.

SUMMARYDuring the past few years, important changeshave occurred in the management of IBS. The tra-ditional approach of reassurance and a high fiberdiet is no longer adequate for everyone.Symptomatic care likely will remain the appro-priate treatment for patients with mild symptoms.However, for patients with pronounced gas-trointestinal symptoms, more aggressiveapproaches will be necessary. In time, the role ofnewer medications will be established. Similarly,the adjunctive use of behavioral intervention willgain wider use.

RECOMMENDED READINGBrandt LJ, Bjorkman D, Fennerty MB, Locke GR,

Olden K, Peterson W, et al. Systematic reviewon the management of irritable bowel syn-drome in North America. Am J Gastroenterol.2002;97 Suppl 11:S7-S26.

Camilleri M, Thompson WG, Fleshman JW,Pemberton JH. Clinical management ofintractable constipation. Ann Intern Med.1994;121:520-8.

Cash BD, Chey WD. Irritable bowel syndrome: anevidence-based approach to diagnosis.Aliment Pharmacol Ther. 2004;19:1235-45.

Clouse RE. Antidepressants for functional gastroin-testinal syndromes. Dig Dis Sci. 1994;39:2352-63.

Drossman DA, Camilleri M, Mayer EA, WhiteheadWE. AGA technical review on irritable bowelsyndrome. Gastroenterol. 2002;123:2108-31.

Drossman DA, Corazziari E, Delvaux M, SpillerRC, Talley NJ, Thompson WG, et al, editors.Rome III: The functional gastrointestinal dis-orders: diagnosis, pathophysiology, andtreatment: a multinational consensus. 3rd ed.McLean (VA): Degnon Associates, 2006.

Drossman DA, Toner BB, Whitehead WE, DiamantNE, Dalton CB, Duncan S, et al. Cognitive-behavioral therapy versus education and

Irritable Bowel Syndrome 255

desipramine versus placebo for moderate tosevere functional bowel disorders. Gastro-enterology. 2003;125:19-31.

Inadomi JM, Fennerty MB, Bjorkman D. Systematicreview: the economic impact of irritable bowelsyndrome. Aliment Pharmacol Ther. 2003;18:671-82.

Kim DY, Camilleri M. Serotonin: a mediator of thebrain-gut connection. Am J Gastroenterol.2000;95:2698-709.

Longstreth GF, Thompson WG, Chey WD,Houghton LA, Mearin F, Spiller RC.Functional bowel disorders. Gastroenterology.2006;130:1480-91.

Manning AP, Thompson WG, Heaton KW, Morris

AF. Towards positive diagnosis of the irritablebowel. Br Med J. 1978;2:653-4.

Pimentel M, Park S, Mirocha J, Kane SV, Kong Y.The effect of a nonabsorbed oral antibiotic(rifaximin) on the symptoms of the irritablebowel syndrome: a randomized trial. AnnIntern Med. 2006;145:557-63.

Whitehead WE. Behavioral medicine approachesto gastrointestinal disorders. J Consult ClinPsychol. 1992;60:605-12.

Whorwell PJ, Altringer L, Morel J, Bond Y,Charbonneau D, O’Mahony L, et al. Efficacy ofan encapsulated probiotic Bifidobacterium infantis35624 in women with irritable bowel syndrome.Am J Gastroenterol. 2006;101:1581-90.

256 Colon

CONSTIPATION

Colonic Motor Physiology andPathophysiology: Salient Aspects

FunctionColonic functions include the absorption of waterand electrolytes, storage of intraluminal contentsuntil elimination is socially convenient, andnutrient salvage from bacterial metabolism ofcarbohydrates that are not absorbed in the smallintestine. The colon absorbs all but 100 mL of fluidand 1 mEq of sodium and chloride from approx-imately 1,500 mL of chyme received over 24hours. Absorptive capacity can increase to 5 to 6L of fluid and 800 to 1,000 mEq of sodium andchloride daily. In healthy subjects, the averagemouth-to-cecum transit time is approximately 6hours, and average regional transit times throughthe right, left, and sigmoid colon are about 12hours each, with an average total colonic transittime of 36 hours. (The physiology of defecation isdiscussed in the section on “Disorders of PelvicFloor Function.”)

Regional Differences in Colonic MotorFunctionThe right colon is a reservoir that mixes and storescontents and absorbs fluid and electrolytes. Theleft colon is primarily a conduit, whereas therectum and anal canal are responsible for conti-nence and defecation. The ileocolic sphincter reg-ulates the intermittent transfer of ileal contentsinto the colon, a process that normalizes inresponse to augmented storage capacity in theresidual transverse and descending colon within6 months after right hemicolectomy.

Motor PatternsColonic motor activity is extremely irregular,ranging from quiescence (particularly at night) toisolated contractions, bursts of contractions, orpropagated contractions. In contrast to the smallintestine, rhythmic migrating motor complexesdo not occur. Contractions are tonic or sustained,lasting several minutes to hours, and shorter orphasic. Propagated phasic contractions propelcolonic contents over longer distances than non-propagated phasic contractions. High-amplitude

257

CHAPTER 20

Constipation and Disorders of Pelvic Floor Function

Adil E. Bharucha, MBBS, MD

Abbreviations: 5-HT, 5-hydroxytryptamine; MR, magnetic resonance; MRI, magnetic resonance imaging; PNTML,pudendal nerve terminal motor latency.

propagated contractions are more than 75 mm Hgin amplitude, occur about 6 times daily (frequentlyafter awakening and after meals), are responsiblefor mass movement of colonic contents, and fre-quently precede defecation. Stimulant laxativessuch as bisacodyl (Dulcolax) and glycerol inducehigh-amplitude propagated contractions.

Colonic Contractile Response to a MealNeurohormonal mechanisms are responsible forincreased colonic motor activity beginning withina few minutes after ingestion of a meal of 500 kcalor more. The term “gastrocolic reflex” is a misnomerbecause this response, induced by gastric distentionand chemical stimulation by nutrients, is observedeven after gastrectomy. This response may explainpostprandial urgency and abdominal discomfort inpatients with irritable bowel syndrome.

Colonic RelaxationColonic relaxation resulting from sympathetic stim-ulation or opiates may cause acute colonic pseudo-obstruction, or Ogilvie’s syndrome. Stimulation ofα2-adrenergic receptors decreases the release ofacetylcholine from excitatory cholinergic terminalsin the myenteric plexus, thereby inhibiting gas-trointestinal motility. Conversely, reduced tonicinhibition of the sympathetic system impairs the netabsorption of water and electrolytes and acceleratestransit in patients who have diabetic neuropathy,thus explaining their diarrhea. Clonidine restoresthe sympathetic brake, reducing diarrhea.

Colocolonic Inhibitory ReflexesPeristalsis is a local reflex mediated by intrinsicnerve pathways and characterized by contractionproximal to and relaxation distal to the distendedsegment. In addition, rectal or colonic distentioncan inhibit motor activity in the stomach, smallintestine, or colon. These inhibitory reflexes aremediated by extrinsic reflex pathways withsynapses in the prevertebral ganglia, independentof the central nervous system. They may accountfor delayed left colonic or small intestinal (or both)transit in patients with obstructive defecation.

Serotonin and the GutAbout 95% of the body’s serotonin (5-hydroxytrypt-amine [5-HT]), a monoamine neurotransmitter, is in

the gut: 90% in enterochromaffin cells and 10% inenteric neurons. The effects of serotonin are medi-ated by receptors located on gut neurons, smoothmuscle, and enterochromaffin cells. There are sevenfamilies of 5-HT receptors. The 5-HT3 and 5-HT4receptors and, to a lesser degree, 5-HT1p, 5-HT1a,and 5-HT2 receptors are important targets of phar-macologic modulation in the gut. Cisapride,prucalopride, and tegaserod maleate (Zelnorm)are 5-HT4 receptor agonists. Alosetron andcilansetron are more potent 5-HT3 receptor antag-onists than ondansetron.

The effects of 5-HT are as follows: Motor—Stimulation of serotoninergic 5-HT4

receptors facilitates both components of the peri-staltic reflex, that is, proximal excitation coordinatedwith distal inhibition. Thus, stimulation of 5-HT4receptors located on cholinergic enteric neuronsinduces the release of acetylcholine and enhancescontractility, whereas 5-HT4 receptor-mediatedstimulation of inhibitory neurons releasesinhibitory neurotransmitters, for example, nitricoxide or vasoactive intestinal polypeptide, whichrelax smooth muscle.

Sensory—5-HT3 and 5-HT4 receptors arelocated on intrinsic primary afferent neurons,which initiate peristaltic and secretory reflexes.5-HT3 receptors also are located on extrinsic sen-sory afferents and vagal afferents, partly explainingwhy 5-HT3 antagonists reduce nausea.

Other—Central 5-HT participates in the reg-ulation of appetite, sexual function, and mood.

Assessment of Colonic TransitColonic transit can be measured with commer-cially available radiopaque markers (Sitz capsule).These techniques entail counting the number oforally ingested markers that remain in the colonas seen on plain radiographs of the abdomen. Oneapproach is to administer a capsule containing 20markers on day 1. Delayed colonic transit is man-ifested by eight or more markers seen on plainfilms on day 3 or by five or more markers seen onday 5. With scintigraphy, the isotope (generally99m Tc or 111In) is delivered into the colon by oro-cecal intubation or within a delayed-release capsule.The delayed-release capsule contains radiolabeledactivated charcoal covered with a pH-sensitivepolymer (methacrylate) designed to dissolve in

258 Colon

the alkaline pH of the distal ileum. This releasesthe radioisotope within the ascending colon.Gamma camera scans taken 4, 24, and, if neces-sary, 48 hours after ingestion of the isotope showthe colonic distribution of isotope. Regions ofinterest are drawn around the ascending, trans-verse, descending, and sigmoid colon and therectum; counts in these areas are weighted by fac-tors 1 through 4, respectively, and stool counts areweighted by a factor of 5. Thus, colonic transit maybe summarized as an overall geometric center (Fig.1). The 4-hour scan identifies rapid colonic transit,and the 24-hour and 48-hour scans show slowcolonic transit. Assessments of colonic transit madewith radiopaque markers are comparable to thosemade with scintigraphy. The radiopqaue markertechnique is simpler and more widely available.However, with scintigraphy, colonic transit canbe assessed in 48 hours, compared with 5 to 7 daysfor radiopaque markers. Moreover, gastric, smallintestinal, and colonic transit can be assessed simul-taneously with scintigraphy.

Constipation

DefinitionA committee of experts developed symptom-basedcriteria (the Rome criteria) for diagnosing func-tional gastrointestinal disorders. These criteria areessential for clinical trials and research studies butare also useful in clinical practice. By convention,these symptom criteria need to present for at least

3 months, with a total symptom duration of 6months or longer. Functional constipation is definedby two or more of the following symptoms: 1)fewer than three defecations per week, 2) straining,3) lumpy or hard stools, 4) sensation of incompleteevacuations, 5) sensation of anorectal obstructionor blockage, and 6) manual maneuvers to facilitatedefecation. For symptoms 2 through 6 to be con-sidered present, they should occur with one-fourthof defecations. Constipation-predominant irritablebowel syndrome is defined by abdominal discomfortand at least two of the following three symptoms: 1)abdominal discomfort associated with change instool form, 2) abdominal discomfort associatedwith change in stool frequency, and 3) abdominaldiscomfort relieved by defecation.

Clinical AssessmentClinical assessment should focus on identifying 1)secondary causes of constipation (Tables 1 and 2),2) inadequate dietary intake of calories and fiber,3) a history of physical, emotional, or sexual abuse,and 4) obstructive defecation. Bowel diaries aremore accurate than self-reporting for character-izing bowel habits, particularly stool frequency.Extremes of stool form, that is, hard small pebblesor watery stools, characterized by the Bristol stoolform scale, correlate strongly with delayed andaccelerated colonic transit, respectively. In con-trast to stool frequency recorded by diaries, fre-quency based on recall alone does not correlatewith colonic transit. Certain symptoms (prolonged

Constipation and Disorders of Pelvic Floor Function 259

Fig. 1. Scintigraphic assessment of colonic transit. Note isotope progression through, A, cecum (1 hour), B,ascending colon (4 hours), and, C, transverse colon (24 hours). D, Numbers represent average isotopedistribution corresponding to a geometric center of 1 to 5. In this patient, the geometric center at 24 hours was1.7 (normal, 1.7-4.0). (From Bharucha AE, Klingele CJ. Autonomic and somatic systems to the anorectum andpelvic floor. In: Dyck PJ, Thomas PK, editors. Peripheral neuropathy. Vol 1. 4th ed. Philadelphia: Elsevier; 2005.p. 279-98. Used with permission.)

A B C D

1 hour 4 hours 24 hours

straining, sense of anorectal blockage, a tendencyto facilitate defecation by assuming different posi-tions, difficulty in evacuating soft stool, and digitalmaneuvers to facilitate defecation) are suggestivebut not diagnostic of functional defecatory disor-ders. The examination may demonstrate anismus,inadequate perineal descent, or, conversely, bal-looning of the perineum with excessive descent.

Practical Classification of ConstipationAfter secondary causes of constipation are excluded,colonic transit and anorectal functions should beassessed in patients with constipation that does notrespond to dietary fiber supplementation (Table 3).This approach facilitates the management of chronicconstipation. Normal-transit constipation includesirritable bowel syndrome and functional consti-pation. In irritable bowel syndrome, abdominal

pain is associated with defecation or a change inbowel habits (ie, harder or less frequent stools).Patients with functional constipation may also haveabdominal pain, but by definition the pain is notrelieved by defecation or associated temporally withharder or less frequent stools. Pelvic floor functionshould be assessed in refractory constipationbecause symptoms alone cannot distinguish amongconstipation resulting from pelvic floor dysfunc-tion, normal transit, and slow transit. Most patientswith obstructive defecation also have delayedcolonic transit. Consequently, delayed colonic transitdoes not imply slow-transit constipation.

Colonic inertia refers to severe colonic motordysfunction that is identified by reduced coloniccontractile responses to a meal and stimulants suchas bisacodyl or neostigmine, as assessed with intra-luminal measurements of pressure activity or tone.

Management of Constipation

PrinciplesReassurance and education about normal bowelhabits, the need for adequate caloric intake anddietary fiber supplementation, and the absence of a“serious disorder” are vital. Deficient caloric intakecan cause or exacerbate constipation, whereasrefeeding may restore colonic transit.

Medical TherapyDietary fiber supplementation either in foods oras a fiber supplement increases stool weight andaccelerates colonic transit. Fiber intake should beincreased gradually to 12 to 15 g daily: psyllium(Konsyl, Metamucil), daily with fluid, or methyl-cellulose (Citrucel), 1 tsp up to 3 times daily;Konsyl, 2 tsp twice daily; calcium polycarbophil(FiberCon), 2 to 4 tablets daily; bran, 1 cup daily.Fiber supplements are more effective in normal-transit or “fiber-deficiency” constipation than inslow-transit constipation or pelvic floor dysfunc-tion. Fiber supplementation should start at a smalldose administered twice daily (AM and PM) withfluids or meals, increasing the dose gradually after7 to 10 days. Patients should be reassured thatalthough fiber supplements may increase gaseous-ness, this often subsides with time. A response tofiber supplements is evident over several weeks,not over days, as with a laxative. Bloating may be

260 Colon

Table 1. Common Secondary Causes ofConstipation

Structural—colonic or anorectal (eg, coloncancer or stricture, large rectocele)

Endocrine—diabetes mellitus, hypothyroidismMetabolic—hypokalemia, hypercalcemia,hypocalcemia, uremia

Infiltrative—scleroderma, amyloidosisNeurologic—Parkinson’s disease, spinal corddisease, autonomic neuropathy, multiplesclerosis

Psychologic—anorexia nervosa

Table 2. Common Medications That CauseConstipation

Analgesics—opiates, nonsteroidalantiinflammatory drugs

Antihypertensives—calcium channel blockers,α2-agonists, diuretics (↓ potassium)

Antacids containing aluminum, calciumAnticholinergics, antidepressants,

antihistaminics, antiparkinsonian agentsLong-term laxative useOthers—iron, cholestyramine

reduced by gradually titrating the dose of dietaryfiber to the recommended dose or by switching toa synthetic fiber preparation such as methylcellu-lose. Bran impairs absorption of iron and calcium.Fiber supplements are contraindicated for patientswith intestinal obstruction, fecal impaction, orsevere vomiting.

• Dietary fiber content should be increasedgradually to 12 to 15 g daily for patients withconstipation.

• In normal-transit constipation, 80% of patientshave a symptomatic response to dietary fibersupplementation.

Hyperosmolar agents, sorbitol or lactulose (15to 30 mL once or twice daily), are nonabsorbabledisaccharides metabolized by colonic bacteria intoacetic and other short-chain fatty acids. Sorbitol andlactulose accelerate proximal colonic transit inhealthy subjects. Both agents may cause transientabdominal cramps and flatulence. They are equallyeffective for treating constipation in the elderly.However, lactulose ($1.32-$2.65 per dose) isextremely sweet and more expensive than sorbitol($0.14-$0.27 per dose). A controlled study showedthat polyethylene glycol (Miralax), 17 g daily for6 months, is superior to placebo for improvingsymptoms in chronic constipation. Oral sodiumphosphate solution is used for bowel cleansing,occasionally by patients with severe constipation.However, acute phosphate nephropathy (acutenephrocalcinosis), a type of acute renal failure, rarelyprogressing to chronic renal impairment and long-term dialysis, has been reported in patients whotook oral sodium phosphate. Renal tubular injuryoccurs from the deposition of calcium phosphate

crystals in the distal tubules and collecting ducts,as shown histologically. Crystals form because of anabnormally high concentration of calcium phos-phate from oral sodium phosphate-induced dehy-dration, decreased intravascular volume, andhyperphosphatemia, which is compounded fur-ther by reabsorption of water from renal tubules.Risk factors for acute phosphate nephropathyinclude advanced age (greater severity for patients57 years and older), decreased intravascular volume(eg, congestive heart failure, cirrhosis, or nephroticsyndrome), acute or chronic kidney disease, andconcomitant use of drugs that affect renal perfu-sion or function (diuretics, angiotensin-convertingenzyme inhibitors, angiotensin receptor blockers,and possibly nonsteroidal antiinflammatory drugs).

Saline laxative, milk of magnesia (15-30 mLonce or twice daily), draws fluid osmotically intothe lumen, stimulates the release of cholecys-tokinin, and accelerates colonic transit. It may causehypermagnesemia, particularly in patients withrenal insufficiency.

• Patients with slow-transit constipation can takesaline laxatives or hyperosmolar agents dailyand stimulant laxatives on an as-needed basis.

• Sorbitol is as effective but less expensive andless sweet than lactulose.

• Oral sodium phosphate solution should beused with care because rarely it can cause acutephosphate nephropathy and renal failure.

Stimulant laxatives affect mucosal transportand motility and include surface-active agents(docusate sodium [Colace], 100 mg orally twicedaily), diphenylmethane derivatives, ricinoleicacid, anthraquinones, glycerin (suppository), and


Table 3. Classification of Functional Constipation

Feature Normal Delayed Normal/delayed

Pelvic floor function Normal Normal AbnormalCategory Normal-transit Slow-transit Obstructive defecationManagement Fiber supplementation Fiber supplementation Biofeedback therapy

LaxativesSurgery

bisacodyl (10-mg tablet or suppository). Stoolsofteners such as docusate sodium are of limitedefficacy. Glycerin and bisacodyl, taken up to onceevery other day, work by inducing colonic high-amplitude propagated contractions. Bisacodyltablets take effect in 6 to 8 hours, and suppositoriesshould be administered 30 minutes after eatingto maximize synergism with the gastrocolicreflex. Of the diphenylmethane derivatives, phe-nolphthalein was withdrawn from the US marketafter animal studies suggested that it may be car-cinogenic; however, no epidemiologic evidencesupports this claim. The anthraquinone com-pounds may cause allergic reactions, electrolytedepletion, melanosis coli, and cathartic colon.Melanosis coli refers to brownish black colorectalpigmentation of unknown composition associatedwith apoptosis of colonic epithelial cells. Catharticcolon refers to altered colonic structure observedon barium enema studies and associated withlong-term use of stimulant laxatives. The alteredstructure includes colonic dilatation, loss of haus-tral folds, strictures, colonic redundancy, andwide gaping of the ileocecal valve. Early reportsimplicating laxative-induced destruction ofmyenteric plexus neurons in cathartic colon havebeen disputed. Although anthraquinones mayinduce colorectal tumors in animal models, sev-eral cohorts and a recent case-control study failedto find an association between anthraquinonesand colon cancer.

• Bisacodyl and glycerin facilitate defecation byinducing colonic high-amplitude propagatedcontractions.

• Melanosis coli indicates recent laxative use.The evidence linking anthraquinones to coloncancer and destruction of the myenteric plexusis inconclusive.

Tegaserod maleate is a partial 5-HT4 receptoragonist that accelerates small-bowel transit andtends to accelerate colonic transit in patients withconstipation-predominant irritable bowel syndrome.Tegaserod was approved for treating constipation-predominant irritable bowel syndrome in womenand chronic constipation in patients younger than65 years. In clinical trials of constipation-predom-inant irritable bowel syndrome, data from weekly

self-administered questionnaires indicatedresponse rates of 46% for tegaserod and 34% forplacebo. For chronic constipation, the primary endpoint was an increase in one complete (feeling ofcomplete evacuation), spontaneous (not precededby laxative use within 24 hours) bowel movementper week during the first 4 weeks compared withbaseline. For this end point, the response rates at 4and 12 weeks were 25% and 28% for placebo,respectively, 39% and 38% for tegaserod 2 mg twicedaily, and 43% and 45% for tegaserod 6 mg twicedaily. Differences between tegaserod 6 mg twicedaily and placebo were significant at 4 and 12weeks; for tegaserod 2 mg twice daily, differenceswere significant at 4 weeks only. Subgroupanalyses did not show significant therapeutic ben-efit for patients older than 65 years. The main sideeffect was diarrhea (6.6% for tegaserod 6 mg twicedaily compared with 3% for placebo); tegaserodwas not associated with a higher incidence ofabdominal surgery or ischemic colitis than placebo.In 2007, tegaserod was withdrawn from the marketbecause a review of the clinical trial data showeda higher incidence (P=.024) of cardiovascularischemic events (myocardial infarction, unstableangina pectoris, and stroke) in patients whoreceived tegaserod than in those who receivedplacebo (13 per 11,614 patients [0.11%] vs. 1 per7,031 patients [0.01%], respectively). All patientswho had cardiovascular ischemic events had pre-existing cardiovascular disease or cardiovascularrisk factors.

Lubiprostone is a novel bicyclic fatty acidderivative that promotes intestinal secretion byactivating intestinal chloride channels. Lubiprostoneaccelerates colonic transit in healthy subjects, andstudies, which have been published mainly inabstract form only, suggest that it improves symp-toms in chronic constipation. The only phase IIstudy published in full suggested that lubipros-tone improved stool consistency and frequencyand self-reported severity of constipation.However, effects on abdominal bloating, dis-comfort, and straining were less impressive.Lubiprostone is well tolerated; nausea andheadache are the most common side effects. Inclinical trials, 33% of patients reported nausea,which generally was mild and could be reducedby taking medication with meals.

262 Colon

• Lubiprostone stimulates intestinal secretion byactivating chloride channels; it also improvesstool consistency and relieves constipation.

Other pharmacologic approaches that havebeen used to manage constipation include colchicineand misoprostol (Cytotec). Colchicine, 0.6 mgorally 3 times daily, and misoprostol, 1,200 μg daily,cause diarrhea. Colchicine should be used cau-tiously, if at all, for treating constipation, becauselong-term use may be associated with neuromy-opathy. Other side effects include hypersensitivityreactions, bone marrow suppression, and renaldamage. Misoprostol should not be used to treatconstipation because it is expensive, may causemiscarriage in pregnant women, and may exacer-bate abdominal bloating. Moreover, its beneficialeffects appear to decrease with time.

• Colchicine and misoprostol are unproven,potentially deleterious agents for treatingslow-transit constipation.

Enemas, including mineral oil retention enema,100 to 250 mL daily per rectum, phosphate enema(Fleet), 1 unit per rectum, tap water enema, 500 mLper rectum, and soapsuds enema, 1,500 mL perrectum, are especially useful in patients with fecalimpaction in the rectosigmoid colon, as may occurin obstructive defecation. All the preparations arecontraindicated for patients with rectal inflamma-tion, and phosphate enemas are contraindicated forpatients with hyperphosphatemia or hyperna-tremia. Mineral oil taken orally is associated withlipid pneumonia, malabsorption of fat-soluble vit-amins, dehydration, and fecal incontinence.

• Enemas may be used judiciously on an as-needed basis for constipation.

Surgical TherapySubtotal colectomy with ileorectal anastomosis iseffective and occasionally indicated for patientswith medically refractory severe slow-transitconstipation, provided that pelvic floor dysfunc-tion has been excluded or treated. In patients withmegarectum, the rectum is also resected. Post-operative ileus and delayed mechanical small-bowel obstruction each occur in approximately

10% of patients. Diarrhea is common shortly afterthe operation but tends to resolve with time. Theimportance of identifying and treating pelvic floordysfunction with biofeedback therapy preopera-tively in patients with slow-transit constipationcannot be overemphasized.

• Subtotal colectomy is necessary and beneficialfor patients with slow-transit constipation whodo not have a response to medical management.

DISORDERS OF PELVIC FLOORFUNCTIONDisorders of pelvic floor function include func-tional defecatory disorders and fecal incontinence. Fecalincontinence, or involuntary leakage of stool fromthe anus, is a common symptom, particularly inthe elderly. In community-based surveys, theprevalence of fecal incontinence among women50 years or older approaches 15%. The prevalenceamong nursing home residents is as high as 40%.The prevalence of functional defecatory disordersin the community is unknown. At Mayo Clinic,50% of patients with chronic constipation had acomponent of pelvic floor dysfunction.

Physiology of DefecationRectal distention evokes the desire to defecate andinduces relaxation of the internal anal sphincterby an involuntary reflex (Fig. 2). Defecation iscompleted by adoption of a suitable posture, con-traction of the diaphragm and abdominal musclesto increase intra-abdominal pressure, and relax-ation of the puborectalis muscle and external analsphincter, both striated muscles. Relaxation of thepuborectalis muscle allows widening and low-ering of the anorectal angle, with perineal descent(Fig. 3). The coordination between abdominalcontraction and pelvic floor relaxation is crucialto the process. Although colonic high-amplitudepropagated contractions may precede defecation,the contribution of rectal contraction to defecationis unclear.

Functional Defecatory Disorders Functional defecatory disorders (also calledobstructive defecation, pelvic floor dyssynergia,and pelvic floor dysfunction) are characterized by


disordered defecation caused by functionalobstruction that results from impaired relaxationof the external anal sphincter, impaired relaxationof the puborectalis muscle, or inadequate propul-sive forces (ie, intrarectal pressure), or some com-bination of these. Although certain symptoms areconsidered suggestive of obstructive defecation(eg, frequent straining, a sensation of incompleteevacuation, dyschezia, and digital evacuation offeces), symptoms alone are not sufficiently specific

for distinguishing between functional defecatorydisorders and other causes of constipation (ie,normal-transit and slow-transit constipation). Athorough digital rectal examination with assess-ment of anal resting tone and anorectal motionwhen subjects contract (ie, squeeze) and simulateevacuation is useful for identifying defecatorydisorders. Anal resting pressure is gauged by theresistance to the insertion of a finger in the analcanal. When patients squeeze, the anal sphincter

264 Colon

Fig. 2. Physiology of defecation. HAPC, high-amplitude propagated contraction. (From Bharucha AE, CamilleriM. Physiology of the colon. In: Zuidema GD, Yeo CJ, editors. Shackelford’s surgery of the alimentary tract. VolIV. 5th ed. Philadelphia: WB Saunders Company; 2002. p. 29-39. Used with permission.)

Fig. 3. Magnetic resonance fluoroscopic images of the pelvis at rest (A) and during simulated defecation (B).Defecation is accompanied by opening of the anorectal junction (arrow), pelvic descent, and widening of theanorectal angle from 101° at rest to 124° during defecation. The rectum was filled with ultrasound gel.

A B

and puborectalis muscles contract; the latter lifts thepalpating finger toward the umbilicus. Conversely,simulated evacuation should be accompanied byperineal descent (2–4 cm) and relaxation of thepuborectalis muscle. In patients with functionaldefecatory disorders, digital rectal examinationmay show increased resting pressure and/orincreased or decreased perineal descent. Whenrectal prolapse is suspected, patients should beexamined in the seated position on a commode.

TestsAnorectal tests are necessary because defecatorydisorders cannot be identified by clinical featuresalone. Anorectal manometry and rectal balloonexpulsion tests usually are sufficient to confirm orexclude functional defecatory disorders. In selectedpatients, defecography with barium or magneticresonance imaging (MRI) may be necessary.

Anorectal manometry—This test may indicatea high resting anal sphincter pressure (>90 mmHg) or a reduced rectoanal pressure gradient (orboth) during simulated defecation (Fig. 4). Normalvalues for anal pressures measured with manom-etry are technique-dependent and influenced byage, sex, and perhaps parity. Anal pressures arelower in women than in men and decrease withage, even in asymptomatic subjects.

Rectal balloon expulsion test—Rectal expulsioncan be evaluated by asking patients to expel fromthe rectum balloons filled with water or air. Oneapproach is to measure the time required to expela rectal balloon while the patient is seated on acommode chair behind a privacy screen. Dependingon the technique, subjects with normal pelvic floorfunctions can expel a rectal balloon within 3 to 5minutes. An alternative method is to measure, withthe patient in the left lateral decubitus position,the traction required to expel a balloon connectedover a pulley to a series of weights. Patients withpelvic floor dysfunction require more external trac-tion to expel a balloon (Fig. 5). The rectal balloonexpulsion test is highly sensitive and specific(>85%) for identifying functional defecatory dis-orders. Moreover, an abnormal result on the rectalballoon expulsion test predicts the response topelvic floor retraining by biofeedback therapy.

Barium or magnetic resonance (MR) proc-tography—During dynamic (ie, barium or MR)

proctography, anorectal anatomy and pelvic floormotion are recorded with the patient at rest,coughing, squeezing, and straining to expel bariumfrom the rectum. The anorectal angle and positionof the anorectal junction are tracked during thesemaneuvers, as are the retention and evacuation ofcontrast material. Dynamic imaging can identifyinadequate or excessive perineal descent, internalrectal intussusception, rectoceles, sigmoidoceles,and enteroceles. Also, puborectalis muscle dys-function can be characterized during squeeze andevacuation. MR proctography is preferred to bariumproctography because 1) it does not entail radiationexposure, 2) it is easier to visualize the bladder anduterus together with the anorectum, and 3) the bonylandmarks (pubis and sacrococcygeal junction) nec-essary to measure anorectal descent are visualizedmore distinctly during MRI. Therefore, measure-ments of anorectal motion are more reproduciblewith MR proctography than barium proctography.However, proctography findings need to be inter-preted in the overall clinical context. For example,rectoceles are particularly common in multiparoussubjects. Clinically important rectoceles are gener-ally large (>3 cm) or fail to empty completely duringdefecation. Moreover, women with clinically impor-tant rectoceles often apply posterior vaginal pressureto facilitate defecation. Rectoceles usually are due toinadequate pelvic floor relaxation rather than to theprimary abnormality.

Colonic transit—Up to 70% of patients withpelvic floor dysfunction have delayed colonic transit.Thus, the finding of slow colonic transit does notexclude the diagnosis of obstructive defecation.

• Anorectal manometry and the rectal balloonexpulsion test generally are sufficient for diag-nosing functional defecatory disorders; proc-tography is necessary in selected cases only.

• The rectal balloon expulsion test is highly sen-sitive and specific for diagnosing functionaldefecatory disorders, and an abnormal test resultpredicts the response to biofeedback therapy.

• Colonic transit is delayed in the majority of pat-ients who have functional defecatory disorders.

• Because false-positive and false-negativeresults may occur, anorectal function tests needto be interpreted in the context of the clinicalfeatures. For example, in up to 20% of healthy


controls, the anal sphincter paradoxically con-tracts instead of relaxes during evacuation.

TreatmentPelvic floor retraining with biofeedback therapyimproves symptoms in 70% of patients who havea functional defecatory disorder. Biofeedbacktherapy is conducted with sensors that measuresurface electromyographic activity or pressuresin the anorectum. By providing auditory or visualfeedback of this activity, patients are taught to relaxthe pelvic floor and improve coordination betweenabdominal wall and diaphragmatic contractionand pelvic relaxation during defecation. Measuresto contract the pelvic floor muscle (eg, Kegel’s exer-cises) are not appropriate for obstructive defecation.Strong rapport between patients and therapists iscritical for biofeedback therapy. Controlled trialshave shown that pelvic floor retraining is superiorto laxatives for relieving constipation in patientswith obstructive defecation. This symptomaticimprovement has been sustained for 2 years.Biofeedback therapy also normalizes colonic transitand anal relaxation during defecation.

Fecal IncontinenceFecal continence is maintained by anatomical factorsand complex sensory and motor interactions

among the sphincters, the anorectum, central andperipheral awareness, and the physical ability toget to a toilet. Fecal incontinence is defined as theinvoluntary leakage of liquid or solid stool fromthe anus; anal incontinence also includes leakageof gas. Up to 40% of nursing home residents havefecal incontinence, which is also common in thecommunity. Up to 1 in 10 of all women and 1 in 5women 40 years and older in the community havefecal incontinence. Patients with chronic fecalincontinence lead a restricted lifestyle, are afraidof having an embarrassing episode, and often

266 Colon

Normal Dyssynergia Impaired propulsion

Rectum

Anus

100

100

0

0

Fig. 4. Rectoanal pressure profiles during defecation in health and functional defecatory disorders (dyssynergiaand impaired propulsion). In contrast to the normal pattern (left) (ie, increased rectal pressure and analrelaxation) during simulated evacuation, patients with defecatory disorders may either paradoxically contractthe anal sphincters (center) or generate inadequate rectal propulsive forces (right).

Fig. 5. Balloon expulsion test. (From Bharucha AE,Klingele CJ. Autonomic and somatic systems tothe anorectum and pelvic floor. In: Dyck PJ,Thomas PK, editors. Peripheral neuropathy. Vol 1.4th ed. Philadelphia: Elsevier; 2005. p. 279-98.Used with permission.)

miss work. The symptom frequently coexists withurinary incontinence and contributes to institu-tionalization. People with fecal incontinence areembarrassed to admit to their family and physi-cian that they have this condition, even thoughtheir symptoms may affect the quality of life sig-nificantly. Therefore, it is essential to ask patientswith diarrhea or diabetes mellitus whether theyhave incontinence.

EtiologyIn most patients, fecal incontinence is attributableto disordered anorectal continence mechanismscompounded by bowel disturbances, generallydiarrhea. Important diseases that contribute tofecal incontinence include the following:

Sphincter damage—This includes obstetricand surgical (eg, hemorrhoidectomy) damage.Known obstetric risk factors for sphincter damageinclude forceps delivery, median episiotomy, andhigh birth weight.

Pudendal neuropathy—This may be attribut-able to obstetric trauma or diabetes mellitus. Also,patients with constipation may strain excessivelyduring defecation and cause stretch injury to thepudendal nerve, soft tissue laxity, and excessiveperineal descent. Eventually, sphincter weaknessdevelops, predisposing to fecal incontinence.

Neurologic causes—These include multiplesclerosis, Parkinson’s disease, Alzheimer’s disease,stroke, diabetic neuropathy, and cauda equina orconus medullaris lesions. Cauda equina lesions thatcause fecal incontinence usually are accompanied byother neurologic symptoms and signs.

Other local causes—Examples are perianalsepsis, radiation proctitis, and systemic sclerosis.In radiation proctitis, the entry of stool into a non-compliant (stiff) rectum may overwhelm continencemechanisms and cause incontinence. Sclerodermais associated with fibrosis of the internal analsphincter and weak resting pressures.

Diarrhea—Fecal incontinence is a commoncomplication of irritable bowel syndrome, chole-cystectomy, and inflammatory bowel disease.

AssessmentPatients with diarrhea must be asked specificallyabout fecal incontinence because they may not vol-unteer the information. The severity, risk factors,

and circumstances of fecal incontinence and itseffect on lifestyle should be assessed. Patients withurge incontinence generally are incontinent only forliquid or semiformed stools, have a brief warningtime, and are unable to reach the toilet in time. Incontrast, patients with passive incontinence are awareof stool leakage only after the episode. Patientswith urge incontinence have decreased analsqueeze pressure or squeeze duration (or both),whereas those with passive incontinence havereduced anal resting pressure. Some patients withurge fecal incontinence also may have rectal hyper-sensitivity, perhaps from a stiffer rectum. Nocturnalfecal incontinence occurs in patients with diabetesmellitus or scleroderma and is suggestive of weak-ness of the internal anal sphincter. A completephysical examination should include perianalassessment to identify common causes of perianalsoiling, such as hemorrhoidal prolapse, perianalfistula, rectal mucosal prolapse, fecal impaction,anal stricture, and rectal mass. The perianal areamust be inspected closely, both with the patient inthe left lateral decubitus position and seated onthe toilet. A thorough digital examination, asdescribed above, should be performed. Flexiblesigmoidoscopy, with or without anoscopy, is thefinal component in this phase of evaluation.

TestsA combination of tests is necessary to evaluate thevarious components of anorectal anatomy andfunction. For each patient, the intensity of investi-gation depends on the patient’s age, severity offecal incontinence, clinical assessment of risk fac-tors and anal sphincter pressures, and response toprevious therapy (Fig. 6).

Anorectal manometry—Frequently, analresting and squeeze pressures are decreased infecal incontinence. Anal pressures should be com-pared with normal values obtained with the sametechnique in age- and sex-matched asymptomaticsubjects. Among patients with weak or normalanal pressures, other factors (eg, diarrhea or dis-turbances of rectal compliance or sensation) alsomay contribute to fecal incontinence.

Anal ultrasonography—This reliably identifiesanatomical defects or thinning of the internal analsphincter and defects of the external anal sphincterthat often are unrecognized clinically or amenable


to surgical repair (or both). However, comparedwith the interpretation of images of the internalsphincter, the interpretation of images of theexternal anal sphincter is more subjective, operator-dependent, and confounded by normal anatomicalvariations of the external anal sphincter. Resultsof prospective studies have suggested that up toone-third of women develop an external analsphincter defect after a vaginal delivery. Therefore,it can be challenging to interpret the clinical signif-icance of anal sphincter defects, that is, the extent towhich a sphincter defect explains anal weakness.

Evacuation proctography—Dynamic proc-tography is indicated for fecal incontinence whenthere is a high index of suspicion for excessive per-ineal descent, a significant rectocele (eg, in patientswho splint the vagina to facilitate rectal emptying),an enterocele, or internal rectal intussusception.

Sphincter denervation measurements—Thepudendal nerve may be injured (with or withoutdamaging the sphincter) during vaginal deliveryor by repetitive straining in patients with chronicconstipation. Pudendal nerve terminal motorlatency (PNTML) can be measured by placing theexamining finger, covered by a glove containing

stimulating and recording electrodes, as close aspossible to the pudendal nerve as it courses aroundthe pelvic brim. PNTML measures the function ofthe fastest conducting fibers. Initial studies showedprolonged PNTML in fecal incontinence. However,PNTML measurements are operator-dependentand lack adequate sensitivity and specificity foridentifying pudendal nerve damage. Patients withprolonged PNTML may have normal anal canalsqueeze pressures. In contrast to earlier studies,recent data have suggested that prolonged PNTMLdoes not predict success after surgical repair ofsphincter defects. According to a position state-ment from the American GastroenterologicalAssociation, PNTML should not be used to eval-uate fecal incontinence. Needle electromyographicexamination of the external anal sphincter providesa sensitive measure of denervation and usually canidentify myopathic, neurogenic, or mixed injury.

Rectal compliance and sensation—Sensationis assessed by asking subjects to report when theyperceive the first detectable sensation, the desireto defecate (or urgency), and maximal tolerablediscomfort during rectal balloon distention, gen-erally with a handheld syringe. Alternatively, a

268 Colon

Fig. 6. Algorithmic approach to fecal incontinence.

balloon can be inflated at a controlled rate by abarostat, which is a continuous-infusion pump.During distention with a barostat, rectal pressuresand volumes and, thus, rectal compliance (pressure-volume relationships) and capacity also can beassessed. Rectal sensation may be normal, decreased,or increased in fecal incontinence. When rectal sen-sation is decreased, stool may leak before theexternal anal sphincter contracts. By improvingrectal sensation, sensory retraining can restore thecoordinated contraction of the external analsphincter and improve fecal continence. Conversely,other patients with fecal incontinence have exag-gerated rectal sensation, perhaps because of a stifferor smaller rectum.

Pelvic MRI—MRI is a relatively new methodfor imaging anal sphincter anatomy and pelvicfloor motion during defecation and squeezewithout radiation exposure. The anal sphinctersalso can be visualized, preferably with an endoanalMRI coil. MRI is superior to ultrasonography forvisualizing morphologic features, particularlyatrophy, of the external anal sphincter. In contrastto evacuation proctography, dynamic MRI doesnot entail radiation exposure and it directly visu-alizes the pelvic floor, including the anterior(bladder) and middle (uterus) compartments.

TreatmentMuch can be accomplished by regulating bowelhabits in patients with diarrhea or constipation.Diarrhea should be managed by treatment of theunderlying condition (eg, antibiotics for smallintestinal bacterial overgrowth and dietary restric-tion for carbohydrate malabsorption) or withantidiarrheal agents, which must be prescribed inadequate doses. Loperamide hydrochloride (4 mg;maximal dose, 16 mg/day), diphenoxylatehydrochloride with atropine sulfate (5 mg), orcodeine sulfate (30-60 mg) may need to be takenregularly, preferably 30 minutes before meals,perhaps up to several times daily. Loperamide notonly delays gastrointestinal transit but alsoimproves anal resting tone. Similarly, amitrypty-line improves fecal continence by restoring stoolconsistency and reducing rectal irritability. Thebile-acid binding resin cholestyramine is usefulfor patients with post cholecystectomy diarrhea.Scheduled rectal emptying with suppositories or

enemas is often useful for fecal impaction andoverflow incontinence.

The results of uncontrolled studies have sug-gested that biofeedback therapy improves symp-toms in up to 70% of patients with fecal incontinence,particularly those with partially preserved rectalsensation. In a controlled trial, 171 patients withfecal incontinence were assigned randomly to fourgroups: standard medical and nursing care (adviceonly), advice and verbal instruction on sphincterexercises, hospital-based computer-assistedsphincter pressure biofeedback, or hospitalbiofeedback and use of a home electromyographicbiofeedback device. Overall, 75% of patientsreported improved symptoms and 5% were cured.Improvement was sustained at 1 year after therapy,and symptoms and resting and squeeze pressuresimproved to a similar degree in all four groups.These results underscore the importance thatpatients attach to understanding the condition, topractical advice about coping strategies (eg, dietand skin care), and to nurse-patient interaction.However, the usefulness of biofeedback therapyover and above that of other conservative mea-sures was unclear. This question was assessed byanother controlled trial, published in abstract formonly. Thirty-six percent of 168 patients with fecalincontinence responded (21%) or withdrew (14%)after medications, education, and behavioralstrategies for 4 weeks. Of the other 108 patients,adequate relief was reported by 77% of thoseassigned randomly to electromyographic-assistedbiofeedback therapy but by only 41% of thoseassigned randomly to Kegel’s exercises alone.These preliminary data support the use ofbiofeedback therapy for patients with fecal incon-tinence that does not respond to other conserva-tive measures. Poor prognostic factors includetotal absence of rectal sensation, dementia,sphincter denervation, and megarectum. Successis highly dependent on the motivation of thepatient and the rapport between the patient andtherapist. Continence improves in 80% to 90% ofpatients shortly after repair of anal sphincterdefects but deteriorates over time thereafter; lessthan 20% of patients are continent at 5 years afterthe operation. Artificial anal sphincter and dynamicgraciloplasty are associated with considerable mor-bidity, particularly wound infections, and are used


sparingly in the United States. Colostomy is oftenthe last resort for patients with medically refractoryfecal incontinence. Several uncontrolled studieshave suggested that sacral nerve stimulation mayimprove fecal continence, particularly in patientswho have normal sphincter anatomy. Sacral nervestimulation is approved for treating urinary symp-toms but, pending completion of a controlled trial,not for fecal incontinence.

• Conservative measures, including manage-ment of bowel disturbances, often can improvefecal continence.

• Patients who do not benefit from conserva-tive measures alone may benefit from pelvicfloor retraining.

• Fecal continence improves in the short termbut deteriorates over time after surgical repairof anal sphincter defects.

270 Colon

271

Colon


QUESTIONS

Abbreviations used:ALT, alanine aminotransferaseAST, aspartate aminotransferaseBUN, blood urea nitrogenCT, computed tomographyECG, electrocardiographyED, emergency departmentEGD, esophagogastroduodenoscopyELISA, enzyme-linked immunosorbent assayNSAID, nonsteroidal antiinflammatory drug

Multiple Choice (choose the best answer)1. A 51-year-old man presents with a 2-day his-

tory of bloody diarrhea, having experiencedwatery diarrhea for 2 days before the appear-ance of blood. He reports no significantabdominal pain and has not had fever. He hasnot taken antibiotics in recent weeks and doesnot have a recent travel history. On examina-tion, the patient is afebrile, has mild nonspecificabdominal tenderness, and active bowelsounds. Laboratory studies show no evidenceof leukocytosis, and stool testing shows thepresence of many fecal leukocytes. Whatwould you do next?

a. Request stool culture and, on the basis of theresult, decide on the necessity of antibiotics

b. Initiate empiric antibiotic therapy whileawaiting stool culture

c. Initiate empiric antibiotic therapy withoutperforming stool culture

d. Perform flexible sigmoidoscopye. Colonoscopy

2. While making rounds on the hospital service,your resident presents a 65-year-old man whowas admitted through the ED with 5 days ofdiarrhea, which has been bloody for the last 2days. He has remained hemodynamicallystable overnight with intravenous hydrationand is afebrile. Overnight, his diarrhea is nobetter. The laboratory results are as follows:

YesterdayAM in ED This AM

Leukocytes, ×109/L 18 19.5Hemoglobin, g/dL 12.9 10.2Platelets, ×109/L 198 110Na+, mEq/L 143 139K+, mEq/L 4.0 3.6Creatine, mg/dL 1.1 1.5BUN, md/dL 31 45AST, U/L 44 110ALT, U/L 32 31

Which of the following organisms is mostlikely?

a. Yersiniab. Toxigenic Escherichia colic. Norwalk-like virus (Norovirus)

d. Clostridium difficilee. Escherichia coli O157:H7

3. A 24-year-old man comes to the ED withwatery diarrhea. His gastrointestinal symp-toms had begun 48 hours earlier with nauseaand vomiting. After the patient had eaten at aChinese restaurant, he developed nausea andvomiting, which lasted for 12 hours, and thendeveloped watery diarrhea. He has not hadfever, recent antibiotics, or infectious contacts.He has not taken any new medications andhas no significant medical history. On clinicalexamination, he is afebrile and has moistmucous membranes. Abdominal examinationdiscloses hyperactive bowel sounds but is oth-erwise unremarkable. The most likely causeof the patient’s acute diarrhea is:

a. Staphylococcus aureusb. Bacillus cereusc. Clostridium perfringensd. Listeria monocytogenese. Clostridium difficile

4. A 74-year-old woman presents with a 2-weekhistory of watery diarrhea. The patient reportspassing 6 to 8 watery stools daily. She has nothad any bloody stools. She has had nocturnaldiarrhea. There has been associated nauseawithout vomiting. She has not reported fever.The patient has a history of diabetes mellitus(type 2), and treatment was switched recentlyfrom metformin to insulin. Approximately 6weeks before the onset of diarrhea, shereceived a course of ciprofloxacin for a urinarytract infection. On clinical examination, thepatient’s vital signs are normal and abdom-inal examination shows mild nonspecific ten-derness. Stool studies show the presence ofmany leukocytes. A stool sample is negativefor Clostridium difficile toxin by ELISA. Whatwould you do next?

a. Initiate treatment with loperamide andtitrate to symptom control

b. Prescribe prednisone 40 mg dailyc. Prescribe metronidazole 500 mg 3 times

daily for 10 days

d. Prescribe vancomycin 125 mg 4 times dailyfor 10 days

e. Send two additional stool samples forClostridium difficile toxin testing

5. An 80-year-old man is evaluated for bloodydiarrhea, which has been present for 5 days.The patient states that initially he experiencedvague abdominal discomfort associated withlow-grade fever and he felt he may have hada virus. Next, watery diarrhea developed,which initially seemed to improve but subse-quently became bloody diarrhea and has beenpresent for 5 days. He thinks that he may havehad low-grade fever intermittently over thepast 72 hours, but this has not been docu-mented. He has had no recent antibiotictherapy. The patient has been looking after his4-year-old grandson, who attends a local day-care facility and has had a recent febrile illnesswith diarrhea. On clinical examination, thepatient’s vital signs are normal but mucousmembranes are dry. Stool testing shows mul-tiple leukocytes. The most likely cause of thisman’s illness is:

a. Salmonella typhib. Clostridium difficilec. Enteroinvasive Escherichia colid. Shigellae. Giardia lamblia

6. Choose the most accurate statement:

a. Environmental factors contribute to about40% of all cases of colorectal cancer

b. Calcium supplementation likely increasesthe risk of colorectal cancer

c. Body mass index is inversely associatedwith the risk of colorectal cancer

d. Colorectal cancer can be considered atobacco-related disease

7. Choose the most accurate statement:

a. Existing data indicate that regular screeninghas a beneficial effect on fatal, but not inci-dent, colorectal cancer

b. More than one-half of US adults older than

272 Colon

50 years are in adherence with the screeningrecommendations for colorectal cancer

c. Digital fecal occult blood testing should beperformed as part of an annual physicalexamination

d. Screening colonoscopy has been shown inthree randomized, controlled trials toreduce colorectal cancer risk

8. Which of the following is not an endorsedoption for average-risk colorectal cancerscreening?

a. Fecal occult blood test or fecal immuno-chemical test every year

b. Flexible sigmoidoscopy every 5 yearsc. Double-contrast barium enema every 5 yearsd. Flexible sigmoidoscopy + double-contrast

barium enema every 5 yearse. Colonoscopy every 10 years

9. Choose the most accurate statement aboutmalignant polyps:

a. Surgical resection should be pursued inall cases

b. Surgical resection should be pursued ifdysplastic cells have spread through themuscularis mucosae

c. Surgical resection should be pursued if dys-plastic cells have invaded the polyp stalk

d. Endoscopic resection is adequate for somecases

10. A 52-year-old woman has a brother who diedof colon cancer (microsatellite instability-highphenotype) at age 40 years. Her brother under-went gene testing, and a germline mutationwas detected in MLH1. The patient has a neg-ative gene test (no mutation found). Whatscreening does she need?

a. Colonoscopy every 6 monthsb. Colonoscopy annuallyc. Colonoscopy every 3 yearsd. Colonoscopy now and every ten years

11. A 69-year-old woman presents with a 5-monthhistory of watery diarrhea. She has not had

any recent change in her diet, has not traveled,and has not taken any new medications,including antibiotics. She has mild abdominalpain and five bowel movements daily but noweight loss, fevers, or gastrointestinal tractbleeding. The physical examination findingsare unremarkable, and the results of bloodtests are normal. Colonoscopic findings werenormal, but mucosal biopsy specimensshowed collagenous colitis. The diarrhea hasnot responded to loperamide up to 16 mg/dayor mesalamine 4.8 g/day, each given for a 6-week period. What is the appropriate next step?

a. High-dose loperamide (up to 32 mg/day)b. Bismuth subsalicylate (9 tablets/day)c. Sulfasalazine (4 g/day)d. Prednisone (40 mg/day)

12. A 36-year-old man has had ulcerative colitisfor 16 years. It is in remission with a regimenof mesalamine 4.8 g/day. On the last surveil-lance colonoscopy, the mucosa showed onlychanges of quiescent colitis. Three biopsy spec-imens from the descending colon show low-grade dysplasia, which is confirmed by asecond gastrointestinal pathologist. What isthe appropriate next step?

a. Add azathioprine 2 mg/kg dailyb. Prescribe an NSAID for chemopreventionc. Follow-up colonoscopy with intensive

repeat biopsies in 6 to 12 monthsd. Referral to surgeon for left hemicolectomye. Referral to surgeon for total proctocolectomy

13. A 21-year-old woman with terminal ilealCrohn’s disease has abdominal pain and diar-rhea that are refractory to trials of mesalamine,budesonide, and azathioprine. There is nofever and no evidence on CT for abscess orobstruction. She then is treated with inflix-imab, 5 mg/kg. Shortly after the infusion ofinfliximab is initiated, flushing, headache,nausea, chest heaviness, and mild dyspneadevelop. Vital sign changes are also noted(blood pressure of 118/76 mm Hg and pulse of66 at baseline and 101/60 and 88, respectively,currently), but findings on examination of the


heart and lungs are normal, as are ECG find-ings. What would be the appropriate next stepin her management?

a. Reassure her that this is a common infusionreaction and continue infusion

b. Stop the infusion, and monitor symptoms.If they resolve, restart infusion at the stan-dard rate

c. Stop the infusion, administer acetaminophenand diphenhydramine. Administer bolus of500 mL of normal saline. If symptomsresolve, restart infusion at a lower rate

d. Stop the infusion and admit the patient fortreatment and observation

e. Stop the infusion. The patient is allergic toinfliximab; it cannot be used again

14. A 45-year-old man with an 8-year history ofulcerative colitis with multiple exacerbationsbegan his current flare 3 weeks ago whilereceiving treatment with mesalamine, 4.8g/day. After 5 days of treatment with pred-nisone, 40 mg/day, failed, he was admitted tothe hospital and treated with methylpred-nisolone, 60 mg/day intravenously. His vitalsigns and abdominal examination findingsremain stable. However, he has not had aresponse to 5 days of intravenous therapy. Hispast medical history is significant for chronicrenal insufficiency attributed to chronic hyper-tension, which is poorly controlled, with bloodpressure averaging 168/98 mm Hg. Thepatient has no prescription insurance and hasdifficulty paying for his medications.Laboratory results included the following:hemoglobin 10.2 g/dL, leukocytes 13.1 × 109/L(neutrophils 75%), creatinine 2.9 mg/dL,potassium 3.2 mEq/L, magnesium 1.2 mg/dL,cholesterol 105 mg/dL, and albumin 3.4 g/dL.What would you recommend at this point?

a. Increase the dose of methylprednisolone to100 mg/day

b. Intravenous cyclosporine beginning at adose of 4 mg/kg daily

c. Intravenous infliximab at a dose of 5 mg/kgd. Surgical consultation for proctocolectomy

with ileal pouch anal anastomosis

15. A 55-year-old man with a 15-year history ofulcerative pancolitis was found to have dys-plasia, and he underwent proctocolectomywith mucosectomy of all rectal mucosal tissueand the creation of a hand-sewn ileal pouchanal anastomosis. His baseline bowel functionpostoperatively was four to six loose bowelmovements per day without any urgency,bleeding, or abdominal pain. Two years post-operatively, he developed diarrhea with 8 to10 watery bowel movements per day that areassociated with mild rectal bleeding, cramps,and urgency. Endoscopy of his pouch showedinflammation and superficial ulcerationthroughout the pouch. The ileum above thepouch appeared normal. Biopsy specimensfrom the pouch showed mild to moderateacute inflammation without granulomas orcrypt abscesses. What is the most likely expla-nation for this exacerbation?

a. Crohn’s disease b. Ulcerative colitis in residual rectal tissue c. Ischemia of the pouchd. Lymphoma of the pouche. Acute pouchitis

16. A 46-year-old woman is referred by her primarycare physician for further management of col-lagenous colitis. She presented with chronicnonbloody diarrhea associated with a 30-lbweight loss. Flexible sigmoidoscopy andbarium enema findings were normal, but colonbiopsy specimens showed collagenous colitis.Treatment with loperamide and cholestyra-mine were without benefit. After telephoneconsultation with you, the primary care physi-cian prescribed bismuth subsalicylate, 3 tablets3 times daily, and mesalamine, 1,600 mg 3times daily, each for 8 weeks. Neither of thesedrugs had any significant effect in controllingthe patient’s diarrhea, and the patient isreferred to you. The next appropriate step inthis patient’s management would be:

a. Prednisone, 60 mg/dayb. Increase bismuth subsalicylate to 6 tablets

3 times dailyc. Determine the antiendomysial antibody level

274 Colon

d. Budesonide, 9 mg/daye. Colonoscopy

17. A 25-year-old woman has a 4-week history ofrectal pain and tenesmus. Three or four bowelmovements per day are of normal consistencybut usually are blood streaked. Also, she inter-mittently passes blood without a bowel move-ment. She states that she does not have anynotable abdominal pain, nausea, vomiting, orweight loss. Initial laboratory studies are unre-markable except for hemoglobin of 10.2mg/dL. Physical examination findings arenormal other than blood on the examiningfinger on rectal examination. Colonoscopyshows normal mucosa in the distal ileum andthroughout the colon down to the sigmoidcolon. The rectum and sigmoid colon have activecolitis with diffuse inflammation and mucosalulceration. Biopsy findings are consistent withulcerative colitis. Which of the following wouldbe the most appropriate therapy?

a. Mesalamine suppositoriesb. Hydrocortisone enemac. Mesalamine enemad. Oral mesalamine (Pentasa)e. Oral budesonide

18. A 22-year-old woman presents with a 3-monthhistory of increasing right lower quadrantabdominal pain and nonbloody diarrhea. Shehas lost 10 lb and recently had two episodes ofincreased mid abdominal pain, distention, vom-iting, and decreased stool output that resolvedafter 1 or 2 days. She has had two urinary tractinfections, and a recent urine culture grewKlebsiella, Escherichia coli, and yeast. She has notnoticed pneumaturia, fecaluria, vaginal symp-toms, fevers, chills, or sweats. She is a smokerand has a family history of Crohn’s disease (anaunt and a cousin). On physical examination,she is thin and pale but in no acute distress.Tender fullness is noted in the right lower quad-rant without guarding or rebound. Colonoscopicfindings were negative, although the endo-scopist was not able to intubate the terminalileum. Which of the following tests would bemost appropriate for establishing the diagnosis?

a. Small-bowel follow-throughb. Enteroclysisc. Small-bowel capsule enteroscopyd. CT enterographye. EGD

19. A 38-year-old man with ulcerative colitis hasbeen receiving maintenance therapy withmesalamine 4.8 g/day. Although compliantwith this therapy, he developed a severe flare.His symptoms did not respond to prednisone,and he was hospitalized and treated withintravenous methylprednisolone. Stoolstudies at admission showed no infection.After 5 days of intravenous corticosteroidtherapy, his symptoms are resolving andtreatment is switched to oral prednisone. Inaddition to tapering prednisone, which of thefollowing would be most appropriate formaintenance therapy in this patient?

a. Maintain on mesalamineb. Maintain on lowest possible dose of pred-

nisonec. Initiate azathioprine therapyd. Initiate cyclosporine therapye. Initiate methotrexate therapy

20. A 37-year-old woman with distal ileal Crohn’sdisease has been receiving maintenance therapywith mesalamine. For 2 weeks, she has hadincreasingly severe right lower quadrantabdominal pain, with six to eight bowel move-ments per day, nausea, anorexia, and a 10-lbweight loss. She states that she has no bleeding,vomiting, abdominal distention, or fever. Onphysical examination, she appears mildlyacutely ill but without abnormal vital signs. Theabdomen is mildly tender in the right lowerquadrant, without mass, guarding, or reboundtenderness. CT enterography shows inflam-mation in the distal 15 cm of the ileum but noabscess. Colonoscopy shows fissuring ulcersin the distal ileum, with no evidence of colitis.Which of the following would be most appro-priate for acute management of this flare?

a. Balsalazideb. Prednisone


c. Metronidazoled. Budesonidee. 6-Mercaptopurine

21. A 31-year-old man with ileal Crohn’s diseasehas been receiving maintenance therapy withmesalamine (Pentasa), 4 g/day. Four weeksago, he developed increasing right lower quad-rant abdominal pain with nonbloody diarrheaand anorexia. He was treated empirically withprednisone, 40 mg/day by mouth. Over theensuing 2 weeks, he has had worsening of hissymptoms, with low-grade fever but no gas-trointestinal tract bleeding. On physical exam-ination, he appears acutely ill with pallor. Histemperature is 38.0°C, with a pulse rate of 98and blood pressure of 106/50 mm Hg. He hasnormal bowel sounds, with tender fullness inthe right lower abdomen but without guardingor rebound tenderness. The leukocyte countis 15.5 × 109/L, with a predominance of neu-trophils. Treatment with broad-spectrumantibiotics is begun in the emergencydepartment, and the patient is admitted to thehospital. Which of the following would be themost appropriate next step?

a. Flexible sigmoidoscopyb. Colonoscopyc. Abdominal CT scand. Cyclosporinee. Infliximab

ANSWERS

1. Answer aThe patient has presented with an acute biphasicdiarrheal illness: initially watery diarrhea, subse-quently bloody diarrhea. Many fecal leukocyteswere seen on stool analysis. Such a biphasic pre-sentation may be seen with E. coli and Shigellainfections. Most cases of Campylobacter infectiondo not require antibiotic therapy, but Shigellainfection should be treated with antibiotics(highly infectious). Therefore, the optimal strategyis to await stool culture before making a decisionabout the necessity of antibiotics. Flexible sigmoi-doscopy and colonoscopy are not indicated, given

the acute presentation. Were the patient elderly,and at risk for ischemic colitis, endoscopic assess-ment may be reasonable.

2. Answer eThe constellation of symptoms and laboratoryfindings is most suggestive of hemolytic uremicsyndrome complicating an infection with E. coliO157:H7. This occurs more often in the elderly orvery young, and the risk may be increased withthe administration of antibiotic therapy. Shigellais also an invasive pathogen and can cause bloodydiarrhea, but it is not associated with hemolyticuremic syndrome. The other infections listed typ-ically result in watery diarrhea.

3. Answer bIf nausea and vomiting are the predominant ini-tial symptoms in a case of suspected food poi-soning, the most likely cause is Staphylococcusaureus, Bacillus cereus, or Clostridium perfringens. Inthis particular case, the ingestion of Chinese foodmakes Bacillus cereus the most likely cause of thepatient’s symptoms. Listeria monocytogenes maycause an acute gastroenteritis after the ingestionof foods such as soft cheese and lunch meats.Listeria is of particular concern in the case of animmunocompromised host or a pregnant woman.Clostridium difficile is unlikely without previoususe of antibiotics.

4. Answer eThe patient has significant watery diarrhea,including nocturnal diarrhea and fecal leukocytes.With the history of antibiotic use, Clostridium dif-ficile-related diarrhea is most likely. The sensitivityof a single negative ELISA-based C. difficile stooltoxin test is approximately 70%. The sensitivity ofcombining three ELISA-based C. difficile stool toxintests is approximately 95%. Therefore, when C.difficile is suspected, up to three sequential stoolsamples should be sent for analysis, to confirmthe correct diagnosis, before therapy is initiated.

5. Answer dSalmonellaand Giardia infection typically present withnonbloody diarrhea. Shigella, EnterohemorrhagicEscherichia coli, and Enteroinvasive E. coli may allcause bloody diarrhea. However, the biphasic

276 Colon

nature of the patient’s presentation, with waterydiarrhea initially, followed by bloody diarrhea,makes Shigella infection the most likely diagnosis.The fact that this patient was caring for a grand-child attending daycare also makes the diagnosisof Shigella infection more likely.

6. Answer dColorectal cancer can be considered a tobacco-related disease.

7. Answer bMore than one-half of US adults older than 50 yearsare in adherence with the screening recommen-dations for colorectal cancer.

8. Answer dFlexible sigmoidoscopy + double-contrast bariumenema every 5 years.

9. Answer dEndoscopic resection is adequate for some cases.

10. Answer dColonoscopy now and every 10 years.

11. Answer bUncontrolled case series have suggested thatmesalamine is effective in only a small proportionof patients with microscopic colitis, and sul-fasalazine appears to be no more effective. Thediarrhea did not improve with 16 mg of loperamideper day, and there is no reason to expect thatincreasing the dose would be of any benefit.Bismuth subsalicylate (Pepto-Bismol) is one of thefew therapies shown in a controlled trial to be effec-tive in microscopic colitis, with 60% to 70% ofpatients having improvement after 8 weeks.Although budesonide is not an option, it is the beststudied medication in treating collagenous colitisand is highly effective. However, many patientshave relapse after budesonide therapy is stopped;therefore, Pepto-Bismol should be tried beforebudesonide, especially in a patient with mildsymptoms, as in this case. Prednisone is also veryeffective. However, the risk of recurrence is highafter discontinuation of treatment, and the sideeffects of prednisone are likely to be more signifi-cant than those of bismuth or budesonide.

12. Answer eLow-grade dysplasia in the context of chroniculcerative colitis carries a high-risk of coexistingcancer (10%-20%) or progression to high-gradedysplasia or cancer (50%) within the next 5 years.Therefore, many authorities recommend total proc-tocolectomy for a patient with low-grade dysplasia.Because the patient is currently asymptomatic andbiopsy specimens did not show active inflamma-tion, adding immunosuppressive therapy is notindicated. Although NSAIDs likely have a chemo-preventive effect, there is no evidence that theycan prevent progression after dysplasia is present.Furthermore, long-term use of NSAIDs mayincrease the risk of a colitis flare. Partial resectionis almost never performed in patients with ulcerativecolitis and dysplasia. Although there may be lessmorbidity related to hemicolectomy, leaving in placeportions of the colon with chronic colitis is thoughtto carry an unacceptably high risk of exacerbationor further development of dysplasia or carcinoma.

13. Answer cAcute infusion reactions are relatively commonwith infliximab and are usually mild and resolvewith discontinuation of the infusion and treatmentwith acetaminophen and antihistamines and,sometimes, corticosteroids. Intravenous fluids areadministered if hypotension is present; epineph-rine may be used for severe reactions. If symptomsrespond and the reaction was mild, the infusioncan be restarted, typically at a slower rate. Mostmild infusion reactions do not require hospital-ization. It would be inappropriate, however, tocontinue the infusion while the patient is having thereaction. If a patient has an infusion reaction, pre-treatment with acetaminophen and antihistamines,with or without corticosteroids, is typically used forsubsequent infusions.

14. Answer dThe patient has not had a response to an appro-priate course of intravenous corticosteroids. Thereis no evidence that a higher dose would be moreeffective, and there is little evidence that prolongedtreatment would increase his chance of having aresponse. Cyclosporine is effective for steroid-refractory ulcerative colitis. However, this patienthas several contraindications to cyclosporine


therapy, including poorly controlled hypertensionand chronic renal insufficiency. Also, hypocho-lesterolemia and hypomagnesemia both increasethe risk of seizures from cyclosporine. Infliximabis also effective for ulcerative colitis that is refrac-tory to steroid therapy, but this patient lacks pre-scription coverage and infliximab is expensive.Therefore, for this patient, surgery is the most appro-priate next step. He is young and would be expectedto do well with an ileal pouch anal anastomosis.

15. Answer eThe patient’s symptoms are consistent with acutepouchitis or Crohn’s disease of the pouch.Inflammation limited to the pouch is more consis-tent with pouchitis, and inflammation in the ileumabove the pouch would suggest Crohn’s disease.The histologic findings are classic for acute pou-chitis. There is no evidence for granulomas, whichwould suggest Crohn’s disease, and the histologicfindings are not compatible with ischemia or lym-phoma. Residual rectal tissue may be left behindafter a total proctocolectomy with ileal pouch analanastomosis (particularly with a stapled anasto-mosis, less so after mucosectomy, as was done inthis case). Although this residual rectal mucosacan become inflamed because of recurrent ulcera-tive colitis (also called cuffitis), the amount of tissueshould be small and easily distinguished frominflammation of the entire pouch, as in this patient.

16. Answer cThe appropriate treatment algorithm for micro-scopic colitis has not been established completelybecause of the lack of randomized controlled trials.Nonetheless, the patient has received appropriatetreatment trials from her primary care physician.The next option to consider is corticosteroidtherapy, preferably with budesonide rather thanprednisone because of the fewer side effects.However, before corticosteroid therapy is initi-ated, it is appropriate to exclude celiac sprue, whichis associated with collagenous colitis and may beresponsible for lack of response of some patients toinitial therapy. It is particularly important toexclude celiac sprue in the case of this patient whohas had significant weight loss. If the patient doesnot have celiac sprue, budesonide therapy wouldbe appropriate. If the patient does not have a

response to corticosteroid therapy, ileostomy maybe necessary to help control the diarrhea andimprove the quality of life, but this is rarely neededin collagenous colitis. Colonoscopy would not beexpected to add significantly to the informationobtained recently with sigmoidoscopy and abarium enema study.

17. Answer cWith inflammation extending into the sigmoidcolon, suppositories would not be sufficient treat-ment because they deliver the drug only to therectum. For this patient’s proctosigmoiditis,enemas are a good choice for therapy. Mesalamineenemas are superior to hydrocortisone enemas.Oral mesalamine would be an alternative if thepatient did not tolerate or have a response to theenemas. However, the Pentasa formulation beginsdelivering active drug in the small intestine. Fordelivery to the left colon, a formulation thatdelivers drug more distally, such as Asacol, Lialda,or an azo-bond 5-acetylsalicylic acid product,would be more appropriate. Budesonide is absorbedin the distal ileum and proximal colon and wouldnot be appropriate therapy for the patient.

18. Answer dThe patient’s presentation suggests Crohn’s diseasewith two recent episodes of partial small-bowelobstruction. The recurrent urinary tract infectionsand recent polymicrobial infection suggest anenterovesical fistula, and the tender right lowerquadrant fullness suggests a possible abscess. Withnegative colonoscopic findings, the small intes-tine needs to be assessed. Because of the recentobstructive symptoms, capsule enteroscopy is con-traindicated. Small-bowel follow-through andenteroclysis would be reasonable tests to evaluatethe small intestine, but CT enterography providesthe added benefit of looking at structures outsidethe bowel lumen and, in particular, can assess fora fistula or abscess. In the absence of significantupper gastrointestinal tract symptoms, EGD is notindicated at this time.

19. Answer cA severe flare of ulcerative colitis developed in thepatient while he was receiving full-dose mesalaminetherapy. Therefore, attempting maintenance with

278 Colon

mesalamine would likely have a high risk of recur-rent failure. Long-term corticosteroid therapy isneither effective nor safe for maintenance therapy.Similarly, long-term cyclosporine therapy has ahigh risk of toxicity without strong evidence of amaintenance benefit. Azathioprine and 6-mer-captopurine are widely used in this setting formaintenance therapy, with good evidence of ben-efit. There is no evidence of a maintenance effectwith methotrexate in ulcerative colitis.

20. Answer dThe patient presents with a moderately severe flareof Crohn’s disease while taking mesalamine.Evaluation shows disease limited to the ileum. Inthis setting, switching to a 5-aminosalicylate acidproduct that delivers drug to the colon (balsalazide)would not be appropriate. Antibiotics sometimesare used for mild to moderate Crohn’s disease, butefficacy appears to be limited and, if seen, tendsto be only in those with colonic or ileocolonic dis-ease. 6-Mercaptopurine would be a reasonablemedication for long-term maintenance therapy inthis patient, but efficacy is delayed; therefore, this

agent is not appropriate for acute management. Inthis setting, corticosteroid therapy often leads toprompt improvement. Prednisone is effective buthas a risk of side effects. Budesonide is a potent cor-ticosteroid designed to be most active in the terminalileum, with less toxicity than prednisone. Therefore,it is the most appropriate treatment for the patient.

21. Answer cThis patient with a flare of ileal Crohn’s diseasehas not had a response to oral prednisone. He hasworsening symptoms and fever, with tender full-ness in the right lower quadrant, which is worri-some for the development of an abscess. Therefore,before immunosuppressive therapy is initiatedwith cyclosporine or infliximab, CT should be per-formed. It is debated whether intravenous corti-costeroid therapy should also be delayed untilabscess is excluded by a CT study. In the acute set-ting, colonoscopy likely will not provide usefulinformation, and flexible sigmoidoscopy wouldbe even less helpful in this patient with ileal dis-ease and no suggestion of rectal inflammation,such as hematochezia.


SECTION VI

Liver

Gastroenterologists should be able to evaluateliver test abnormalities in an efficient, cost-effectivemanner and to manage appropriately patientswho have acute liver failure. To help gastroen-terologists achieve these goals, this chapterincludes the following:

1. General discussion of commonly used livertests

2. Differential diagnosis and discussion of diseasescharacterized by an increase in hepatocellularenzyme levels

3. Differential diagnosis and discussion of diseasescharacterized by an increase in cholestaticenzyme levels

4. Evaluation of patients who have jaundice5. Diagnostic algorithms for evaluating patients

who have abnormal liver tests6. Management of patients who have fulminant

liver failure

COMMONLY USED LIVER TESTS

Aminotransferases (Alanine andAspartate Aminotransferases)The aminotransferases (also referred to as transam-inases) are located in hepatocytes and, thus, aremarkers of liver cell injury (hepatocellular disease).Injury of the hepatocyte membrane allows theseenzymes to “leak” out of hepatocytes, and withina few hours after liver injury, the serum levels of theenzymes increase. Aminotransferases consist ofalanine aminotransferase (ALT) and aspartate amino-transferase (AST). ALT is relatively specific for liverinjury, whereas AST is found not only in hepato-cytes but also in skeletal and cardiac muscle and inother organs. ALT has a longer half-life than AST;thus, improvements in ALT levels lag behind thoseof AST. Marked muscle injury can produce strikingincreases in AST levels and, to a lesser extent, inALT levels.

283

CHAPTER 21

Approach to the Patient With Abnormal Liver Tests

and Fulminant Liver Failure


Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ERCP, endoscopic retrogradecholangiopancreatography; MRCP, magnetic resonance cholangiopancreatography.

Alkaline PhosphataseAlkaline phosphatase is an enzyme located on thehepatocyte membrane bordering bile canaliculi(the smallest branches of the bile ducts). Becausealkaline phosphatase is found also in bone andplacenta, an increase in its level without other indi-cation of liver disease should prompt furthertesting to discover if the increase is from liver orother tissues. One way of doing this is to deter-mine the concentration of alkaline phosphataseisoenzymes. Another way is to determine the levelof γ-glutamyltransferase, an enzyme of intrahep-atic biliary canaliculi. Other than to confirm theliver origin of an increased level of alkaline phos-phatase, γ-glutamyltransferase is of little use in theevaluation of diseases of the liver because its syn-thesis can be induced by many medications, thusdecreasing its specificity for clinically importantliver disease.

BilirubinBilirubin is the water-insoluble product of hememetabolism that is taken up by the hepatocyte andconjugated with glucuronic acid to form monoglu-curonides and diglucuronides. Conjugation makesbilirubin water-soluble, allowing it to be excretedin bile. The serum concentration of bilirubin ismeasured in direct (conjugated) and indirect(unconjugated) fractions. Diseases characterized byoverproduction of bilirubin, such as hemolysis orresorption of a hematoma, are characterized byhyperbilirubinemia that is 20% or less conjugatedbilirubin. Hepatocyte dysfunction or impaired bileflow produces hyperbilirubinemia that is usually50% or more conjugated bilirubin. Because conju-gated bilirubin is water-soluble and may beexcreted in urine, patients with conjugated hyper-bilirubinemia may note dark urine. In thesepatients, the stools are lighter in color because ofthe absence of bilirubin pigments.

Prothrombin Time and AlbuminProthrombin time and serum albumin are com-monly used markers of liver synthetic function.Abnormalities of prothrombin time and albuminimply severe liver disease and should promptimmediate evaluation. Prothrombin time is a mea-sure of the activity of factors II, V, VII, and X, all ofwhich are synthesized in the liver. These factors

are dependent also on vitamin K for synthesis.Vitamin K deficiency may be produced by antibi-otics, prolonged fasting, small-bowel mucosal dis-orders such as celiac disease, or severe cholestasiswith an inability to absorb fat-soluble vitamins.Hepatocellular dysfunction is characterized by aninability to synthesize clotting factors despiteadequate stores of vitamin K. A simple way todifferentiate vitamin K deficiency from hepato-cellular dysfunction in a patient with a prolongedprothrombin time is to administer vitamin K.Administration of vitamin K improves pro-thrombin time within 2 days in a vitamin K-defi-cient patient but has no effect if the prolonged pro-thrombin time is due to liver disease with poorsynthetic function.

Because albumin has a half-life of 21 days,decreases due to liver dysfunction do not occuracutely; however, the serum level of albumin candecrease relatively quickly in a patient who has asevere systemic illness such as bacteremia. Thisrapid decrease likely is caused by the release ofcytokines, which accelerate the metabolism ofalbumin. Other causes of hypoalbuminemiainclude urinary or gastrointestinal tract losses, andthese should be considered in a patient who hashypoalbuminemia but not overt liver disease.

HEPATOCELLULAR DISORDERSDiseases that primarily affect hepatocytes aretermed hepatocellular disorders and are characterizedpredominantly by increased levels of amino-transferases. The disorders are best categorized asacute (generally <3 months) or chronic. Acutehepatitis may be accompanied by malaise,anorexia, abdominal pain, and jaundice. Commoncauses of acute hepatitis are listed in Table 1.

The pattern of increase in aminotransferaselevels may be helpful in making a diagnosis. Acutehepatitis caused by viruses or drugs usually pro-duces a marked increase in the levels of amino-transferases, often more than 1,000 U/L. Generally,ALT increases more than AST. Aminotransferaselevels more than 5,000 U/L usually are due toacetaminophen hepatotoxicity, ischemic hepatitis(“shock liver”), or hepatitis caused by unusualviruses, such as herpesvirus. Ischemic hepatitisoccurs after an episode of hypotension and is seen

284 Liver

most often in patients with preexisting cardiac dys-function. Aminotransferase levels improve withina few days. Another cause of a transient increase inaminotransferase levels is transient obstruction ofthe bile duct, usually from a stone. These increasescan be as high as 1,000 U/L, but the levels decreasedramatically within 24 to 48 hours. In patients withpancreatitis, a transient increase in AST or ALT issuggestive of gallstone pancreatitis. Alcoholichepatitis is characterized by more modest increasesin aminotransferase levels, nearly always less than400 U/L, with an AST:ALT ratio greater than 2:1.Patients with alcoholic hepatitis frequently havean increase in bilirubin level out of proportion tothe increase in aminotransferase levels.

Diseases producing sustained (>3 months)increases in aminotransferase levels are includedin the category of chronic hepatitis. The increasein aminotransferase levels generally is moremodest (2-5 times) than that in acute hepatitis.Although patients may be asymptomatic, theyoccasionally complain of fatigue and right upperquadrant pain. The most important and common

disorders that cause chronic hepatitis are listed inTable 2.

Risk factors for hepatitis C include a historyof blood transfusions or intravenous drug use.Patients with hepatitis B may be from an endemicarea such as parts of Asia or Africa or have a historyof illegal drug use or multiple sexual contacts.Patients with nonalcoholic fatty liver disease areusually obese or have diabetes mellitus or hyper-lipidemia. A complete history is needed to helpdiagnose drug-induced or alcohol-induced liverdisease. Autoimmune hepatitis may manifest asacute or chronic hepatitis. Patients usually havehigher levels of aminotransferases than do thosewith other disorders that cause chronic hepatitis.Autoantibodies, hypergammaglobulinemia, andother autoimmune disorders are helpful clues tothe diagnosis of autoimmune hepatitis.

CHOLESTATIC DISORDERSDiseases that affect predominantly the biliarysystem are termed cholestatic diseases. These canaffect the microscopic ducts (eg, primary biliarycirrhosis), large bile ducts (eg, pancreatic cancerobstructing the common bile duct), or both (eg,primary sclerosing cholangitis). In these disorders,the predominant abnormality is generally thealkaline phosphatase level. Although diseases thatproduce increased bilirubin levels are often called“cholestatic,” it is important to remember thatsevere hepatocellular injury, as in acute hepatitis,also produces hyperbilirubinemia because of hepa-tocellular dysfunction. Causes of cholestasis arelisted in Table 3.

Primary biliary cirrhosis usually occurs inmiddle-aged women who may complain of fatigueor pruritus. Primary sclerosing cholangitis has astrong association with ulcerative colitis. Patientswith primary sclerosing cholangitis often areasymptomatic but may have jaundice, fatigue, orpruritus. Large bile duct obstruction often is due tostones or benign or malignant strictures.Remember that acute large bile duct obstructionfrom a stone may produce marked increases inaminotransferase levels. Intrahepatic mass lesionsshould be considered if a patient has cholestaticliver test abnormalities and a history of malignancy.Also, infiltrative disorders such as amyloidosis,

Approach to the Patient With Abnormal Liver Tests and Fulminant Liver Failure 285

Table 1. Common Causes of Acute Hepatitis

Disease Clinical clue Diagnostic test

Hepatitis A Exposure IgM anti-HAVhistory

Hepatitis B Risk factors HBsAg, IgM anti-HBc

Drug-induced Compatible Improvementmedication after

withdrawal ofagent

Alcoholic History of Liver biopsy, hepatitis alcohol excess improvement

AST:ALT >2 withAST <400 U/L abstinence

Ischemic History of Rapid improve-hepatitis severe ment of

hypotension aminotrans-ferase levels

ALT, alanine aminotransferase; AST, aspartateaminotransferase; HAV, hepatitis A virus; HBc,hepatitis B core; HBsAg, hepatitis B surface antigen.

sarcoidosis, or lymphoma should be considered. Aclue to a possible infiltrative disorder is a markedlyincreased alkaline phosphatase level with a normalbilirubin concentration. Any systemic inflamma-tory process such as infection or immune disordermay produce nonspecific liver test abnormalities.The abnormalities usually are a mixed cholestatic(alkaline phosphatase) and hepatocellular (ALTor AST) pattern.

JAUNDICEJaundice is visibly evident hyperbilirubinemiaand occurs when the bilirubin concentration is

more than 2.5 mg/dL. It is important to deter-mine whether the increase is predominantly con-jugated or unconjugated bilirubin. A commondisorder that produces unconjugated hyper-bilirubinemia (but not usually jaundice) isGilbert’s syndrome. Total bilirubin is generallyless than 3.0 mg/dL, whereas direct bilirubin is 0.3mg/dL or less. The level of bilirubin usually ishigher when a patient is ill or fasting. A pre-sumptive diagnosis of Gilbert’s syndrome can bemade in an otherwise well patient who has uncon-jugated hyperbilirubinemia, normal liver enzymevalues, and a normal concentration of hemoglobin(to exclude hemolysis).

286 Liver

Table 2. Common Causes of Chronic Hepatitis


Hepatitis C Risk factors Anti-HCV, HCV RNAHepatitis B Risk factors HBsAgNonalcoholic fatty liver disease Obesity, diabetes mellitus, Ultrasonography, liver biopsy

hyperlipidemiaAlcoholic liver disease History Liver biopsy, improvement

AST:ALT >2 with abstinenceAutoimmune hepatitis ALT 200-1,500 U/L, Antinuclear or anti-smooth

usually female, other muscle antibody, biopsyautoimmune disease

ALT, alanine aminotransferase; AST, aspartate aminotransferase; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus.

Table 3. Common Causes of Cholestasis


Primary biliary cirrhosis Middle-aged woman Antimitochondrial antibodyPrimary sclerosing Association with ulcerative ERCP, MRCPcholangitis colitis

Large bile duct obstruction Jaundice and pain are common Ultrasonography, ERCP, MRCPDrug-induced Compatible medication/timing Improvement after withdrawal of

agentInfiltrative disorder History of malignancy, Ultrasonography, computed

amyloidosis, sarcoidosis tomographyInflammation-associated Symptoms of underlying Blood cultures, appropriate

inflammatory disorder antibody tests

ERCP, endoscopic retrograde cholangiopancreatography; MRCP, magnetic resonance cholangiopancreatography.

Patients with direct hyperbilirubinemia canbe categorized as those with a nonobstructive con-dition and those with an obstructive condition.Abdominal pain, fever, or a palpable gallbladder(or a combination of these) is suggestive of obstruc-tion. Risk factors for viral hepatitis, a bilirubin con-centration greater than 15 mg/dL, and persistentlyhigh aminotransferase levels suggest that thejaundice is due to hepatocellular dysfunction. Inpatients with acute hepatocellular dysfunction,improvement in bilirubin concentration often lagsbehind the improvement in aminotransferaselevels. A sensitive, specific, and noninvasive test toexclude an obstructive cause of jaundice is liverultrasonography. In diseases characterized by largebile duct obstruction, the intrahepatic bile ductsgenerally are dilated, especially if the bilirubin con-centration is more than 10 mg/dL and the patienthas had jaundice for more than 2 weeks. Acutelarge bile duct obstruction, usually from a stone,may not cause dilatation of the bile ducts, and ifthe clinical suspicion is strong for bile ductobstruction despite normal-sized bile ducts onultrasonography, the extrahepatic duct shouldbe imaged with endoscopic retrograde cholan-giopancreatography (ERCP), magnetic resonancecholangiopancreatography (MRCP), or endo-scopic ultrasonography.

GENERAL APPROACH TO ABNORMALLIVER TESTSWhen a patient has abnormal liver tests at pre-sentation, it is helpful to classify the patient’s con-dition as one of the clinical syndromes listed inTable 4, although the overlap among these cate-gories is considerable. Patients with acute hepatitisor cirrhosis often have jaundice. The approach topatients with acute hepatitis, chronic hepatitis,cholestasis, and jaundice is outlined above. Patientswith a “first-time” increase in liver enzyme levelsare usually asymptomatic, and liver test abnor-malities are found incidentally. As long as 1) norisk factors for liver disease are identified, 2) liverenzyme levels are less than three times normal, 3)liver function is preserved, and 4) the patient feelswell, observation is reasonable, with the testrepeated in a few months. If the repeat test resultsare still abnormal, the patient’s condition fits the

category of chronic hepatitis or cholestasis andappropriate evaluation should be initiated. A similarapproach can be taken for patients with inciden-tally discovered abnormal liver tests who are takingmedications that only rarely cause liver disease.

Patients also may present with cirrhosis orportal hypertension. Most patients with portalhypertension have cirrhosis, although occasionallypatients present with noncirrhotic portal hyper-tension that is idiopathic or due to portal veinthrombosis. The evaluation of a patient with cir-rhosis is similar to that of a patient with chronichepatitis and cholestasis (as shown above). α1-Antitrypsin deficiency, genetic hemochromatosis,and alcoholic liver disease frequently have cir-rhosis as the first manifestation of liver disease. Ifa patient has clinical features that strongly suggestcirrhosis, confirmatory liver biopsy is not necessary.

ALGORITHMS FOR EVALUATINGPATIENTS WITH ABNORMAL LIVERTESTSAlgorithms for evaluating patients who haveabnormal liver tests are, at best, guidelines, and, atworst, misleading. Always remember that in eval-uating (or not evaluating) abnormal liver tests, thepatient’s clinical presentation should be considered.Generally, a patient with liver test abnormalities thatare less than twice normal may be followed as longas the patient is asymptomatic and the albumin level,prothrombin time, and bilirubin concentration arenormal. Also, persistent abnormalities should beevaluated. Algorithms for evaluating increased levelsof ALT, alkaline phosphatase, and conjugatedbilirubin are shown in Figures 1 to 3.


Table 4. Abnormal Liver Tests: ClinicalSyndromes

“First-time” increase in liver enzymesAcute hepatitisChronic hepatitisCholestasis without hepatitis or jaundiceJaundiceCirrhosis or portal hypertension

MANAGEMENT OF FULMINANTLIVER FAILURETraditionally, fulminant liver failure has been definedas the presence of acute liver failure, including thedevelopment of hepatic encephalopathy, within 8weeks after the onset of jaundice in a patientwithout a previous history of liver disease. Becausenot all patients with severe acute liver disease meetthis strict definition, some authors have proposedthe term acute liver failure, which encompasses otherclinical scenarios, including fulminant liver failure.About 2,000 cases of fulminant liver failure occurannually in the United States. The overall mor-tality rate of fulminant liver failure without livertransplantation is high. Because many of thepatients are young and previously healthy, theoutcomes of this relatively unusual condition areparticularly tragic. Specific management, includingliver transplantation, is available, and knowledgeof management strategies is important.

Determining the cause of fulminant liverfailure is important for two reasons: 1) specifictherapy may be available, as for acetaminophenhepatotoxicity or herpes hepatitis, and 2) the prog-nosis differs depending on the cause. For instance,the spontaneous recovery rate for fulminant liverfailure due to acetaminophen or hepatitis A is more

than 50%; consequently, a more cautious approachwould be advised before proceeding with livertransplantation. In comparison, spontaneousrecovery from fulminant liver failure due toWilson’s disease is unusual and early liver trans-plantation would be recommended. Also, identi-fying a specific cause may have implications forother patients. The identification of a hepatotoxicagent is helpful in monitoring other patientsreceiving the same drug treatment. Identificationof a viral cause of fulminant liver failure has impli-cations for other patients who have been exposedto the transmissible agent. The US Acute LiverFailure Study Group has coordinated the effort ofseveral centers that have attempted to better definethe causes and outcome of acute liver failure in theUnited States. The most common identifiablecauses are acetaminophen hepatotoxicity, idio-syncratic drug reactions, hepatitis A and B, andischemia (Fig. 4).

The presenting symptoms of fulminant liverfailure are usually those of acute hepatitis,including malaise, nausea, and jaundice. Portalsystemic encephalopathy is a required feature ofthe syndrome, and manifestations may range fromsubtle mental status changes, such as difficultywith concentration, to coma (Table 5). Because

288 Liver

Acute hepatitis Chronic hepatitis

Abnormal ALT level

Persistent increase orpatient symptomatic orimpaired liver function

US, IgM anti-HAVHBsAg, IgM anti-HBcHCV RNA, ANACeruloplasmin if <40 years

US, anti-HCV, HBsAg, ANAIron studies, A1AT phenotypeCeruloplasmin if <40 yearsConsider biopsy

Repeat tests in 3 months

Duration <3 monthsElevation <3-foldNo symptomsGood liver function

Fig. 1. Evaluation of abnormal alanine aminotransferase (ALT) level. A1AT, α1-antitrypsin; ANA, antinuclearantibody; HAV, hepatitis A virus; HBc, hepatitis B core; HBsAg, hepatitis B surface antigen; HCV, hepatitis Cvirus; US, ultrasonography.

encephalopathy in a patient with acute liver diseaseis an ominous sign, the mental status of patientswith acute hepatitis should be assessed frequently.Laboratory features of fulminant liver failure areconsistent with severe liver dysfunction.Aminotransferase levels are variably increased,

although they usually are quite high. FulminantWilson’s disease is characterized by only modestincreases in aminotransferase levels and a normalor only minimally increased alkaline phosphataselevel despite other, more typical laboratory evi-dence of liver failure. Evidence of hepatocellular


ERCP

Dilated ducts Liver mass Normal

Ultrasonography of liver Pursue nonhepatic causes

Alkaline phosphatase increased

Liver fraction or

GGT abnormal

Liver fraction or

GGT normal

Further imaging

Tumor markers

Biopsy

Pursue intrahepatic causes

Antimitochondrial antibody

Careful drug history

Consider biopsy

Fig. 2. Evaluation of increased alkaline phosphatase levels. ERCP, endoscopic retrogradecholangiopancreatography; GGT, γ-glutamyltransferase.

Conjugated hyperbilirubinemia

Normal liver enzymesAbnormal liver enzymes

Persistently high ALT Elevated alkaline phosphataseTransient increase in ALT

SepsisDubin-Johnson syndromeRotor’s syndrome

Pursue causes of hepatitis

Dilated ducts

ERCP

US or CT

Consider biopsy

Normal ducts

MRCP if biliary obstructionis still suspected

Fig. 3. Evaluation of conjugated hyperbilirubinemia. ALT, alanine aminotransferase; CT, computedtomography; ERCP, endoscopic retrograde cholangiopancreatography; MRCP, magnetic resonancecholangiopancreatography; US, ultrasonography.

dysfunction includes a prolonged prothrombintime and high bilirubin concentration.

The encephalopathy associated with fulminantliver failure is likely different from that of chronicliver disease. The major difference is the propen-sity of encephalopathy of acute liver disease toprogress to cerebral edema. The mechanisms forthe development of cerebral edema have not been

clarified but may involve disruption of the blood-brain barrier and interference with mechanismsof cellular osmolarity. Clinically, the encephal-opathy often is associated with an increase in theserum level of ammonia, although alterations inneurotransmitters likely are involved in causingmental status changes.

Cerebral edema is estimated to cause about20% of deaths of patients with fulminant liverfailure. Cerebral edema leads to death by causingbrain ischemia and cerebral herniation.

Hypoglycemia is a frequent manifestation offulminant liver failure, and the glucose level shouldbe monitored carefully in all patients. The hypo-glycemia is likely due to both inadequate degra-dation of insulin and diminished production ofglucose by the diseased liver.

Infections are another common cause of deathof patients with fulminant liver failure. Reasonsfor the infections are multiple but likely reflectsevere illness and the need for numerous interven-tions and monitoring. The clinical features typicalof infection, such as fever and leukocytosis, are notreliable in patients with fulminant liver failure. Ahigh index of suspicion needs to be maintained, andany clinical deterioration should mandate a searchfor infection.

290 Liver

Fig. 4. Cause of fulminant liver failure in the United States, 1998-2001. *Includes autoimmune hepatitis, Wilson’sdisease, Budd-Chiari syndrome, pregnancy-associated, malignancy, heat stroke, sepsis, and giant cell hepatitis.

Acetaminophen39%

Idiopathic17%

Otheridentifiedcause*14%

Ischemia6% Hepatitis A

4%

Hepatitis B7%

Idiosyncraticdrug

reaction13%

Table 5. Stages of Hepatic Encephalopathy

Stage Features

I Changes in behavior, with minimalchange in level of consciousness

II Gross disorientation, gross slownessof mentation, drowsiness, asterixis, inappropriate behavior, able tomaintain sphincter tone

III Sleeping most of the time, arousableto vocal stimuli, marked confusion, incoherent speech

IV Comatose, unresponsive to pain, includes decorticate or decerebrateposturing

A hyperdynamic circulation and decrease insystemic vascular resistance frequently accom-pany fulminant liver failure. These features maybe well tolerated by patients, but occasionallyhemodynamic compromise can develop. Monitoringparameters may mimic sepsis. Fluid resuscitationoften is necessary, although caution is advisedbecause the administration of excessive fluid mayworsen intracranial pressure.

Renal and electrolyte abnormalities occurbecause of underlying disease such as Wilson’sdisease, functional renal failure due to sepsis orhepatorenal syndrome, or acute tubular necrosis.Renal dysfunction may be more common whenfulminant liver failure is due to acetaminophenhepatotoxicity. Monitoring of electrolytes,including sodium, potassium, bicarbonate, mag-nesium, and phosphorus, is important. Lactic aci-dosis also is common in fulminant liver failure,likely because of hypoperfusion and the inabilityof the diseased liver to clear lactate. The presenceof acidosis is a risk factor for poor outcome in ful-minant liver failure and has been incorporated intoprognostic models.

Several models have attempted to predict out-come of fulminant liver failure. These have beendeveloped to facilitate optimal timing of liver trans-plantation before the patient becomes so ill thattransplantation is contraindicated. The most wellknown and widely used are the King’s College cri-teria (Table 6). Liver transplantation likely improvesmortality, but improved outcomes have beenassessed only by comparison with historical controls.

The appearance of encephalopathy precedescerebral edema; therefore, patients with acutehepatitis and evidence of liver failure need to bemonitored carefully for mental status changes.Patients with encephalopathy should receive lac-tulose, although this agent is not as effective inacute liver failure as in chronic liver disease andmay not prevent cerebral edema from developinglater. Patients with stage II encephalopathy usu-ally are admitted to an intensive care unit for closemonitoring of mental status and vital signs. It isespecially important that sedatives be avoided atthis point to allow close monitoring of mentalstatus. Also, at most centers, computed tomographyof the head is performed to exclude an alternativecause of mental status changes.

Patients who reach stage III encephalopathyare at considerable risk for progression to cerebraledema. Because clinical signs and computedtomography are insensitive for detecting increasedintracranial pressure, many centers instituteintracranial pressure monitoring when patientsreach stage III encephalopathy. Endotracheal intu-bation and mechanical ventilation usually precedeplacement of the intracranial pressure monitor.Various such monitors are used, all of which can becomplicated by infection and bleeding. The goalof intracranial pressure monitoring is to allow treat-ment of high pressure and also to identify whichpatient is too ill for liver transplantation because ofa prolonged period of excessively high intracra-nial pressure. Generally, the goal is to maintainintracranial pressure less than 40 mm Hg and cere-bral perfusion pressure (the difference betweenmean arterial pressure and intracranial pressure)between 60 and 100 mm Hg. Excessively high cere-bral perfusion pressures (>120 mm Hg) canincrease cerebral edema.

Maneuvers that cause straining, including tra-cheal suctioning, should be avoided or limited.


Table 6. King’s College Criteria for LiverTransplantation in Fulminant LiverFailure*

1. Fulminant liver failure due to Wilson’sdisease or Budd-Chiari syndrome

2. Acetaminophen-induced if either of thefollowing are met:a. pH <7.3 24 hours after overdoseb. Creatinine >3.4 mg/dL and prothrombin

time >100 seconds and grade 3-4encephalopathy

3. Nonacetaminophen if eithera. INR >6.5 orb. Any three of the following: INR >3.5,

more than 7 days from jaundice to encephalopathy, indeterminate or drug-induced cause, age <10 years, age >40 years, bilirubin >17.5 mg/dL

INR, international normalized ratio.*Any one of the three criteria.

Paralyzing agents and sedatives may be necessary,although they may limit further assessment of neu-rologic status. For intracranial pressure more than20 mm Hg or cerebral perfusion pressure less than60 mm Hg, elevation of the head to 20 degrees,hyperventilation to a PaCO2 of 25 mm Hg, andmannitol (if renal function is intact) are advised.Barbiturate-induced coma or hypothermia canbe used for refractory cases. A prolonged increasein intracranial pressure above mean arterial pres-sure may signify brain death and generally is acontraindication to liver transplantation. Asudden decrease in intracranial pressure mayindicate brain herniation.

The prolonged prothrombin time seen inpatients with fulminant liver failure is a simplenoninvasive measure to follow, and coagulopathyusually is not corrected unless there is bleeding ora planned intervention such as placement of a mon-itoring device. If bleeding occurs or an invasiveprocedure is necessary, fresh frozen plasma usuallyis administered first. Administration of plateletsand fibrinogen may be necessary in certain cir-cumstances. Continuous infusion of 5% or 10%dextrose is used to keep the plasma glucose levelbetween 100 and 200 mg/dL. The plasma glucoselevel should be monitored at least twice daily. Bothbacteremia and fungemia are sufficiently frequentthat periodic blood cultures are advised and pro-phylaxis with antimicrobials may be initiated,although this practice has not been shown toaffect survival.

Liver transplantation has revolutionized themanagement of fulminant liver failure, which isthe indication for 6% of liver transplants in theUnited States. Even though survival with trans-plantation for fulminant liver failure is lower thanthat for transplantation for other indications, out-comes are an improvement over the dismal survivalrates for fulminant liver failure when prognostic cri-teria such as the King’s College criteria indicate a

poor outcome. Transplantation should be performedwhen a poor outcome is anticipated, yet beforethe patient has uncontrolled sepsis or prolongedperiods of increased intracranial pressure thatprevent recovery even with a functioning trans-planted liver.

RECOMMENDED READINGGreen RM, Flamm S. AGA technical review on the

evaluation of liver chemistry tests. Gastro-enterology. 2002;123:1367-84.

Larson AM, Polson J, Fontana RJ, Davern TJ, LalaniE, Hynan LS, et al, Acute Liver Failure StudyGroup. Acetaminophen-induced acute liverfailure: results of a United States multicenter,prospective study. Hepatology. 2005;42:1364-72.

O’Grady JG, Alexander GJ, Hayllar KM, WilliamsR. Early indicators of prognosis in fulminanthepatic failure. Gastroenterology. 1989;97:439-45.

Ostapowicz G, Fontana RJ, Schiodt FV, Larson A,Davern TJ, Han SH, et al, U.S. Acute LiverFailure Study Group. Results of a prospectivestudy of acute liver failure at 17 tertiary carecenters in the United States. Ann Intern Med.2002;137:947-54.

Polson J, Lee WM, American Association for theStudy of Liver Disease. AASLD position paper:the management of acute liver failure.Hepatology. 2005:41:1179-97.

Poterucha JJ. Fulminant hepatic failure. In: JohnsonLR, editor. Encyclopedia of gastroenterology.Vol 2. Amsterdam: Elsevier Academic Press;2004. p. 70-4.

Viggiano TR, Sedlack RE, Poterucha JJ. Gastr-oen-terology and hepatology. In: Habermann TM,editor. Mayo Clinic internal medicine boardreview 2004-2005. Philadelphia: LippincottWilliams & Wilkins; 2004. p. 253-330.

292 Liver

Viral infections are important causes of liver dis-ease worldwide. The five primary hepatitis virusesthat have been identified are A, B, C, D (or delta),and E. Other viruses such as cytomegalovirus orEpstein-Barr virus also can result in hepatitis aspart of a systemic infection. In addition, medica-tions, toxins, autoimmune hepatitis, or Wilson’sdisease may cause acute or chronic hepatitis.

It is useful to divide hepatitis syndromes intoacute and chronic forms. Acute hepatitis can lastfrom weeks up to 6 months and is often accom-panied by jaundice. Symptoms of acute hepatitistend to be similar regardless of the cause andinclude anorexia, malaise, dark urine, fever, andmild abdominal pain. Patients with chronic hepatitisare often asymptomatic but may complain offatigue. Occasionally, they have manifestationsof cirrhosis (ascites, variceal bleeding, orencephalopathy) as the initial presentation ofchronic hepatitis. Each hepatitis virus causes acutehepatitis, but only hepatitis B, C, and D virusescan cause chronic hepatitis.

The purpose of this chapter is to review theprimary hepatitis viruses. A more comprehensive

discussion of acute hepatitis is found in other chap-ters. The primary hepatitis viruses are compared inTable 1, and the effects of the three most importantviruses in the United States are summarized inTable 2.

HEPATITIS A

EpidemiologyThe incidence of acute hepatitis A virus (HAV)infection is decreasing in the United States,although outbreaks still occur and HAV causesabout 5% of cases of fulminant liver failure. Themajor routes of transmission of HAV are inges-tion of contaminated food or water and contactwith an infected person. Groups at particularlyhigh risk include people living in or traveling tounderdeveloped countries, children in day carecenters, homosexual men, and perhaps personswho ingest raw shellfish. Outbreaks of HAV infec-tion in communities are recognized frequently,although an exact source may not be found. Theincubation period for HAV is 2 to 6 weeks.

293

CHAPTER 22

Chronic Viral Hepatitis


Abbreviations: ALT, alanine aminotransferase; anti-HAV, antibody to hepatitis A virus; anti-HBc, antibody to hepatitis Bcore; anti-HBe, antibody to hepatitis B e; anti-HBs, antibody to hepatitis B surface; anti-HCV, antibody to hepatitis C virus;anti-HDV, antibody to hepatitis D virus; HAV, hepatitis A virus; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surfaceantigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HIV, human immunodeficiency virus;PCR, polymerase chain reaction.

Clinical Presentation and Natural HistoryThe most important determinant of the severity ofacute hepatitis A is the age at which infectionoccurs. Persons infected when younger than 6 yearshave nonspecific symptoms that rarely includejaundice. Adolescents or adults who acquire HAVinfection usually have jaundice. Hepatitis A isalmost always a self-limited infection. There maybe a prolonged cholestatic phase characterized bypersistence of jaundice for up to 6 months. Rarely,acute hepatitis A manifests as fulminant hepatitisthat may require liver transplantation. HAV doesnot cause chronic infection and should not be in thedifferential diagnosis of chronic hepatitis.

Diagnostic TestsThe diagnosis of acute hepatitis A is established bythe presence of IgM hepatitis A antibody (anti-HAV),which appears at the onset of the acute phase ofthe illness and disappears in 3 to 6 months. The IgGanti-HAV also becomes positive during the acutephase, but it persists for decades and is a markerof immunity from further infection. A patient with

IgG anti-HAV, but not IgM anti-HAV, has had aninfection in the remote past or has been vaccinated.

Treatment and PreventionThe treatment of acute hepatitis A is supportive.Immune serum globulin should be administeredto all household and intimate (including day care)contacts within 2 weeks after exposure. HepatitisA vaccine should be offered to travelers to areaswith an intermediate or high prevalence ofhepatitis A, men who have sex with men, intra-venous drug users, recipients of clotting factorconcentrates, and patients with chronic liver dis-ease. Widespread vaccination of health careworkers or food handlers has not been advised.

HEPATITIS B

EpidemiologyHepatitis B virus (HBV) is a DNA virus that causesabout 30% of cases of acute viral hepatitis and 15%of cases of chronic viral hepatitis in the United

294 Liver

Table 1. Comparison of the Four Primary Hepatitis Viruses

Feature HAV HBV HDV HCV

Incubation, days 15-50 30-160 Unknown 14-160Jaundice Common 30% of patients Common UncommonCourse Acute Acute or chronic Acute or chronic Acute or chronicTransmission Fecal-oral Parenteral Parenteral ParenteralTest for diagnosis IgM anti-HAV HBsAg Anti-HDV HCV RNA

HAV, hepatitis A virus; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HDV,hepatitis D virus.

Table 2. Clinical Effect of Hepatitis Viruses in the United States*

HAV HBV HCV

New infections per year 24,000 51,000 20,000Fulminant, deaths/year 50 100 RareChronic infections 0 1.25 million 3.2 millionChronic liver disease, deaths/year 0 3,000-5,000 8,000-10,000

HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus.*The Centers for Disease Control and Prevention estimates, 2005.

States. Major risk factors for disease acquisition inthe United States are sexual promiscuity and intra-venous drug use. HBV infection is also commonin Asia and Africa, where it usually is acquiredperinatally or in early childhood. Many infectedimmigrants to the United States from high endemicareas probably acquired HBV by these routes.

Diagnostic TestsA brief guide to serologic markers for hepatitis B isprovided in Table 3. The interpretation of serologicpatterns is found in Table 4. The best serologic test foracute hepatitis B is IgM antibody to hepatitis B core(anti-HBc). Occasionally, a patient with acutehepatitis B (usually with a severe presentation suchas fulminant hepatitis) lacks hepatitis B surfaceantigen (HBsAg) and has only IgM anti-HBc as themarker for recent infection.

Sensitive tests for HBV DNA are now available.Nearly all patients with HBsAg have HBV DNAin serum when measured with a highly sensitivetest such as the polymerase chain reaction (PCR).Commercially available tests now quantify HBVDNA. HBV DNA levels greater than 104 IU/mLgenerally are considered to indicate active viralreplication. Also, lower levels in a patient with cir-rhosis may be clinically important.

Occasionally, patients have IgG anti-HBc asthe only positive hepatitis B serologic marker. Thishas several possible explanations. The mostcommon reason in a low-risk population is a false-positive test (although the test is often repeatedlypositive). Another explanation is a previous,resolved HBV infection in which the antibody tohepatitis B surface (anti-HBs) has decreased below

the limit of detection. This can be documented indi-rectly by demonstrating an anamnestic type ofresponse to hepatitis B vaccine. Rarely, patientswith hepatitis B may have HBsAg levels that arebelow the level of detection, so that IgG anti-HBcis the only marker of infection. Although the sig-nificance of this low-level infection is unclear, thesepatients can be identified by the presence of HBVDNA (sensitive assays such as PCR may be nec-essary) in the serum or liver.

The usefulness of serologic tests obviates theneed for liver biopsy in the diagnosis of hepatitisB; however, liver biopsy is useful for gradinginflammatory activity and determining the stageof fibrosis. Histologic features of hepatitis B areinflammation that is usually around the portal tract,variable fibrosis that initially is also portocentric,and the presence of ground-glass hepatocytes.Ground-glass hepatocytes are hepatocytes withcytoplasm that has a hazy, eosinophilic appearance.With immunostaining, these cells are positive forHBsAg (Fig. 1). Even though liver biopsy is the “goldstandard” for diagnosing cirrhosis, it generally isnot necessary for patients who have other featuresof cirrhosis, such as portal hypertension.

Clinical Presentation and Natural HistoryThe incubation period after HBV infection rangesfrom 30 to 160 days, and the clinical outcome varies.Acute hepatitis B in an adolescent or adult is ictericin about 30% of cases. Complete recovery with sub-sequent life-long immunity occurs in 95% of infectedadults. About 5% of infected adults have persistenceof HBsAg for longer than 6 months and are referredto as chronically infected. Immunosuppressed

Chronic Viral Hepatitis 295

Table 3. Hepatitis B Serologic Markers

Test Significance

Hepatitis B surface antigen (HBsAg) Current infectionAntibody to hepatitis B surface (anti-HBs) Immunity (immunization or resolved infection)IgM antibody to hepatitis B core (IgM anti-HBc) Recent infection or “reactivation” of chronic

infectionIgG antibody to hepatitis B core (IgG anti-HBc) Remote infectionHepatitis B e antigen (HBeAg) and/or HBV DNA Active viral replication (high infectivity)>104 IU/mL

persons with acute HBV infection are more likelyto become chronically infected, presumably becauseof an insufficient immune response against the virus.

Patients with chronic hepatitis B infection maypresent in one of four phases (Fig. 2). An immune

tolerant phase is recognized in many patients whoare infected perinatally. This phase is character-ized by normal levels of alanine aminotransferase(ALT), presence of hepatitis B e antigen (HBeAg),and very high HBV DNA levels. Generally, liver

296 Liver

Table 4. Interpretation of Hepatitis B Serologic Patterns

HBVIgM IgG DNA,

HBsAg Anti-HBs anti-HBc anti-HBc HBeAg Anti-HBe IU/mL Interpretation

+ - + - + - + Acute infection or acuteflare of chronic hepatitisB

- + - + - ± - Previous infection withimmunity

- + - - - - - Vaccination withimmunity

+ - - + - + <105 Hepatitis B inactive carrierstate

+ - - + + - >105 Chronic hepatitis B+ - - + - + >105 HBeAg-negative chronic

hepatitis B (often“precore” or “core promoter” variants)

Anti-HBe, antibody to hepatitis B e; anti-HBs, antibody to hepatitis B surface; HBeAg, hepatitis B e antigen; HBsAg,hepatitis B surface antigen; HBV, hepatitis B virus; IgG anti-HBc, IgG antibody to hepatitis B core; IgM anti-HBc, IgMantibody to hepatitis B core.

Fig. 1. Liver biopsy specimen from patient with hepatitis B. A, Ground-glass hepatocyte (arrow).(Hematoxylin-eosin.) B, Immunostain for hepatitis B surface antigen showing positive staining ofhepatocyte cytoplasm.

BA

biopsy specimens from these patients show min-imal changes except for ground-glass hepatocytes.The immune tolerant phase can last up to the ageof 40 years and generally evolves under immunepressure into the HBeAg-positive chronic hepatitis Bphase, characterized by increased ALT levels, thepresence of HBeAg, and more than 104 IU/mL ofHBV DNA. Active inflammation and often fibrosisare seen in liver biopsy specimens. This phase gen-erally is thought to lead to progressive liverdamage, including cirrhosis and an increased riskof hepatocellular carcinoma. At a rate of about 10%per year, patients mount enough of an immuneresponse to achieve a decrease in ALT levels, clear-ance of HBeAg and development of anti-HBe (sero-conversion), and a decrease in HBV DNA to lessthan 104 IU/mL. The resulting inactive carrier phaseusually is not accompanied by progressive liverdamage. Most patients remain in this phase formany years and have a better prognosis than thosewith active liver inflammation and viral replication.

About one-third of inactive carriers have areactivation of chronic hepatitis characterized byabnormal ALT levels and HBV DNA of more than

104 IU/mL. This may be associated with a recurrenceto the HBeAg-positive state, but more commonly itis due to a precore or core promoter variant thatproduces HBeAg-negative chronic hepatitis B. ThisHBeAg-negative chronic hepatitis B phase is associatedwith progression of liver damage and, perhaps, anincreased risk of hepatocellular carcinoma. Patientswith HBeAg-negative chronic hepatitis B are morelikely to have lower DNA levels and a fluctuatingcourse than patients with HBeAg-positive chronichepatitis B. Also, the patients generally are olderand have more advanced fibrosis because HBeAg-negative chronic hepatitis B tends to occur later inthe course of infection.

Patients with chronic hepatitis B may experi-ence spontaneous flares of disease characterizedby markedly abnormal aminotransferase levels,deterioration in liver function, and often serocon-version of HBeAg. The differential diagnosis foracute hepatitis in patients with chronic hepatitisB is listed in Table 5. Because disease activitychanges in patients with chronic hepatitis B, evenafter years of senesence, periodic monitoring withliver tests and hepatitis B markers is necessary.


Immunetolerance

Positive HBeAgDNA

Normal ALT

HBeAg-positivechronichepatitis

Positive HBeAgDNA

Abnormal ALT

HBeAgseroconversion

HBeAg-negativechronichepatitis

Negative HBeAgDNA

Abnormal ALT

Precoremutation

Inactivecarrier

Negative HBeAgDNA

Normal ALT

Progression tocirrhosis

Fig. 2. Phases of chronic hepatitis B virus infection. White arrows, changes of histopathology; gray arrows,changes in serologic markers between phases. Up- and down-facing arrows, an increase or decrease of DNA level(↑ = low increase; ↑↑ = moderate increase; ↓↓ = moderate decrease; ↑↑↑ = high increase). ALT, alanineaminotransferase; HBeAg, hepatitis B e antigen. (From Pungpapong S, Kim WR, Poterucha JJ. Natural history ofhepatitis B virus infection: an update for clinicians. Mayo Clin Proc. 2007;82:967-75. Used with permission ofMayo Foundation for Medical Education and Research.)

HBsAg clears spontaneously in about 1% of chron-ically infected patients annually, although this rateis lower in endemic areas where HBV is acquiredat a very young age.

Overall, about 15% to 40% of patients withchronic HBV infection develop serious sequelae ofthe disease, either by the development of decom-pensated liver disease or hepatocellular carci-noma. Factors associated with the developmentof cirrhosis are older age, infection with hepatitisC virus (HCV), human immunodeficiency virus(HIV), or hepatitis D virus (HDV), genoype C,longer duration of infection, high HBV DNAlevels, and alcohol abuse. Many of these factors,including HBV DNA level, are associated alsowith an increased risk for the development ofhepatocellular carcinoma.

Patients with chronic hepatitis B and cirrhosisare at high risk for the development of hepato-cellular carcinoma, and surveillance with ultra-sonography and α-fetoprotein every 6 to 12months is advised. Surveillance should be con-sidered also for patients without cirrhosis whomeet one of the following criteria: family historyof hepatocellular carcinoma, Asian male olderthan 40 years, Asian female older than 50 years,black African older than 20 years, and persistentincrease in ALT level together with an HBV DNAvalue of more than 104 IU/mL.

Eight hepatitis B genotypes have been identi-fied. These are labeled A though H. The hepatitis Bgenotype is determined largely by the country in

which infection is acquired. All genotypes have beenidentified in the United States. The clinical signifi-cance of various hepatitis B genotypes is still beingstudied, and, clinically, the hepatitis B genotype is notcommonly used. In Asian patients, genotype B hasa better prognosis than genoytpe C, including ahigher rate of clearance of HBeAg, a slower rate ofprogression to cirrhosis, and a lower likelihood ofthe development of hepatocellular cancer. GenotypesA and B may have a better response to peginterferontherapy than other genotypes.

TreatmentGenerally, hepatitis B is treated if the patient is atrisk for disease progression. This includes patientswho have liver enzyme levels more than twice theupper limit of normal, active viral replication (asdefined by HBV DNA more than 104-5 IU/mL),and active disease identified in liver biopsy spec-imens. Defining a specific HBV DNA level thatwarrants treatment is difficult because somepatients with advanced and active disease haverelatively low levels and others, especially thosein the immune tolerant phase, have very high levelsdespite the lack of disease activity. In general, avalue greater than 20,000 IU/mL is used as an indi-cation for treatment; however, in the presence ofcirrhosis or HBeAg-negative chronic hepatitis, alevel higher than 2,000 IU/mL has been proposedas an indication for treatment.

Liver biopsy is not always necessary but can behelpful in patients who otherwise do not meet clear

298 Liver

Table 5. Causes of Acute Hepatitis in Patients With Chronic Hepatitis B

Cause Clinical clues

Spontaneous “reactivation” of hepatitis B Seroconversion of HBeAg, reappearance of IgManti-HBc

Flare due to immune suppression Chemotherapy, antirejection therapy, corticosteroids

Induced by antiviral therapy Interferon (common), oral agents (rare)Superimposed infection with other viruses, Exposure to hepatitis D (usually due to illicit drug

especially hepatitis D virus use), A, or COther causes of acute hepatitis History of alcohol excess, medications, illegal

drugs

Anti-HBc, antibody to hepatitis B core; HBeAg, hepatitis B e antigen.

criteria for treatment. Liver biopsy also can be usedto diagnose cirrhosis, which could mandate achange in management, such as evaluation foresophageal varices or surveillance for hepatocel-lular carcinoma.

Hepatitis B can be treated with interferon orone of the oral agents (lamivudine, adefovir, ente-cavir, or telbivudine). Peginterferon has replacedstandard interferon because of once-weekly dosingand perhaps better efficacy. Seroconversion mayoccur months or even years after completion oftreatment. Predictors of a greater likelihood ofresponse to peginterferon include higher ALT level,lower HBV DNA level, shorter duration of disease,and female sex. Patients treated with peginterferonmay experience a flare of hepatitis (likely due toimmune system activation) about 4 to 8 weeks afterbeginning treatment. Treatment should be con-tinued despite this flare unless there is clinical orbiochemical evidence of decompensation. Patientswith Child-Pugh class B or C cirrhosis should notbe treated with interferons because of the risk ofprecipitating decompensation with this flare. Sideeffects of peginterferon are common and are con-sidered below (HEPATITIS C).

The oral agents are the drugs prescribed mostfrequently for the treatment of chronic hepatitis B.They are compared in Table 6. These drugs areremarkably free of side effects, although occasionallyadefovir can cause nephrotoxicity. The oral agentsare useful particularly in patients with decompen-sated cirrhosis, because these drugs may improveliver function. The flare of hepatitis that may occurduring interferon therapy is unusual with the oralagents. Treatment with lamivudine or telbivudine iscomplicated by resistant mutations at a rate of about10% to 15% per year. Resistance to adefovir occurs ata rate of about 1% to 4% per year. Resistance to ente-cavir is uncommon unless the patient has previouslydeveloped resistance to lamivudine, although datafor long-term treatment are needed. Adefovir andentecavir are effective against lamivudine-resistantstrains, although adefovir is probably a better choicebecause of a higher rate of resistance when entecaviris given to patients with resistance to lamivudine.For these patients, adefovir should be added tolamivudine. About 15% to 20% of patients treatedwith oral agents have seroconversion of HBeAgafter 1 to 2 years of therapy, and treatment should

be continued for at least 6 months after seroconver-sion. Patients without seroconversion of HBeAgneed to continue treatment indefinitely. Serocon-version of HBsAg with the oral agents occurs onlyrarely and is not a reasonable treatment goal.

The choice of therapeutic agent for hepatitis Bdepends on several factors. As noted above, onlyactive hepatitis should be treated. Peginterferon isreasonable for patients without cirrhosis who havean ALT level greater than 200 U/L and who are ableto tolerate the numerous side effects of the drug. Theoral agents are preferred for patients with cirrhosis,particularly if there is evidence of decompensation.Patients with long-standing hepatitis B, such asadults who acquired the disease in the perinatalperiod, are not likely to have a response to pegin-terferon treatment, and the oral agents are preferred.Oral agents are preferred also for patients who areimmunosuppressed, for example, after organ trans-plantation or infection with HIV. Patients withhepatitis B who need a course of chemotherapy havean increased risk of disease flare, and treatment withone of the oral agents is advised. Treatment shouldbe given not only during the course of chemotherapybut for 6 months after therapy has been completed.

For patients with end-stage liver disease dueto hepatitis B, liver transplantation is advised. Listingfor transplantation is recommended when a patienthas seven Child-Pugh points or hepatocellular car-cinoma complicating cirrhosis. Patients with hepatitisB who have HBeAg or high HBV DNA levels (orboth) before liver transplantation are at particularlyhigh risk for recurrence after transplantation. Forthese patients, oral agents are recommended beforetransplantation and a combination of hepatitis Bimmunoglobulin and an oral agent after transplan-tation. Even in patients without active viral replica-tion, recurrence rates are sufficiently high that bothpreoperative and postoperative therapy with one ofthe oral agents is still given by most transplant groups.

PreventionHepatitis B immunoglobulin should be given tohousehold and sexual contacts of patients withacute hepatitis B. Infants and previously unvac-cinated 10- to 12-year-old children (who arereaching the age when they will be at highest riskfor acquiring disease) should receive hepatitis Bvaccine. The marker of immunity is anti-HBs.


Neonates often acquire hepatitis B perinatally ifthe mother is infected. Because infected neonatesare at high risk for the development of chronicinfection, HBsAg testing should be performed onall pregnant women. If a pregnant woman isHBsAg-positive, the infant should receive bothhepatitis B immunoglobulin and hepatitis B vaccine.

HEPATITIS DHDV (or the delta agent) is a defective virus thatrequires the presence of HBsAg to replicate.Consequently, there is no reason to search for HDVunless HBsAg is present. HDV infection can occursimultaneously with HBV (coinfection) or as asuperinfection in persons with established hepatitisB. Hepatitis D is diagnosed by antibodies to HDV(anti-HDV) and should be suspected if a patienthas acute hepatitis B or an acute exacerbation ofchronic hepatitis B. In the United States, intra-venous drug users are the group of HBV patientsat highest risk for acquiring HDV.

HEPATITIS CHCV is the cause of the most common chronicblood-borne infection in the United States. It has

been estimated that 3 to 4 million Americans areinfected with the virus; about 70% of them haveabnormal ALT levels. Although the number of newcases of HCV infection is decreasing, the number ofdeaths is increasing because of the propensity ofthe virus to cause chronic infection. HCV is a factorin 40% of all cases of chronic liver disease and isthe leading indication for liver transplantation.

Diagnostic TestsAntibodies to HCV (anti-HCV) indicate exposureto the virus and are not protective. The presence ofanti-HCV can indicate either current infection or aprevious infection with subsequent clearance. Evenafter clearance of the infection, only about 10% ofpatients lose anti-HCV. The presence of anti-HCVin a patient who has an abnormal ALT level andrisk factors for acquiring hepatitis C is stronglysuggestive of current HCV infection. The initialtest for identifying anti-HCV is enzyme-linkedimmunoassay. False-positive results for anti-HCVby this test are unusual but can occur in patientswith hypergammaglobulinemia (eg, patients withautoimmune hepatitis). The specificity (but notsensitivity) of enzyme-linked immunoassay foranti-HCV is improved with the addition of therecombinant immunoblot assay for anti-HCV. A

300 Liver

Table 6. Oral Agents for Treatment of Hepatitis B

Agent

Feature Lamivudine Adefovir Entecavir Telbivudine

Cost per month, $US 230 630 720 500HBeAg seroconversion, % 20 12 21 22

of patientsLoss of HBV DNA, % 40 21 67 60

of patientsResistance, patients 20% at 1 year 0 at 1 year Naïve: <1% at 4% at 1 year

2 years70% at 5 years 29% at 5 years Lamivudine 21% at 2 years

resistance:7% at 1 year

Durability of response, % 50-80 90 69 80of responding patients

HBeAg, hepatitis B e antigen; HBV, hepatitis B virus.

guide to the interpretation of anti-HCV tests is pro-vided in Table 7.

The “gold standard” for the diagnosis ofhepatitis C infection is the presence of HCV RNAin serum as determined with PCR. Most referencelaboratories are able to reproducibly perform thisHCV RNA assay with a sensitivity limit of 10 to50 IU/mL. HCV RNA by PCR is now the preferrednext test (bypassing anti-HCV by recombinantimmunoblot assay) for patients with abnormalliver enzyme levels or for those at high risk forHCV infection who are found to be anti-HCV–posi-tive by enzyme-linked immunoassay.

Levels of HCV RNA do not correlate with dis-ease severity or prognosis, and the major use ofquantitative assays is to stratify response totherapy. Patients with viral levels higher than600,000 IU/mL are less likely to have a responseto treatment. The determination of HCV genotypeis helpful in assessing the likelihood of treatmentresponse. Patients with HCV genotype 1 (whichcomprises about 70% of US patients) are less likelyto have a response to therapy than those with geno-type 2 or 3. Liver biopsy is not necessary for thediagnosis of hepatitis C, but it is helpful in assessingthe severity of disease for prognostication and inmaking decisions about treatment and screening.Typical biopsy findings include a mononuclear(predominantly lymphocytic) portal hepatitis withlymphoid follicles and mild steatosis (Fig. 3).

Clinical Presentation and Natural HistoryThe incubation period of HCV ranges from 2 to 23weeks (mean, 7.5 weeks). Infection with HCVrarely presents clinically as acute hepatitis,although retrospective studies have suggested that10% to 20% of patients have an icteric illness withacute infection. Of those who acquire hepatitis C,60% to 85% develop chronic infection (Fig. 4). Oncechronic infection has been established, subsequentspontaneous loss of the virus is rare. Consequently,most patients with hepatitis C present with chronichepatitis, with a mild-to-moderate increase in ALTlevels. For patients with abnormal ALT levels, thedegree of increase correlates poorly with the his-tologic severity of disease. Some patients havefatigue or vague right upper quadrant pain (orboth). Patients also may come to attention becauseof complications of end-stage liver disease or,

rarely, extrahepatic complications such as cryo-globulinemia or porphyria cutanea tarda. Patientswith hepatitis C-associated cryoglobulinemia usu-ally have a vasculitic rash of the lower extremities,but they also may have a membranoproliferativeglomerulonephritis or polyneuropathy. The cryo-globulinemia and its associated complicationsusually respond to the treatment of hepatitis C.Porphyria cutanea tarda is manifested as a rash onsun-exposed areas, particularly the back of thehands. Many patients also have abnormal iron test


Table 7. Interpretation of Anti-HCV TestResults

Anti-HCV

By EIA By RIBA Interpretation

+ - False-positive EIA,patient does nothave true antibody

+ + Patient has antibody*

+ Indeterminate Uncertain antibodystatus

Anti-HCV, antibody to hepatitis C virus; EIA, enzyme-linkedimmunoassay; RIBA, recombinant immunoblot assay.

*Anti-HCV does not necessarily indicate current HCVinfection (see text).

Fig. 3. Biopsy specimen from patient with hepatitisC. Note portal infiltrate, lymphoid follicle (arrow),and mild steatosis.

results. The response of porphyria cutanea tarda toanti-hepatitis C therapy is more uncertain than theresponse of cryoglobulinemia. Phlebotomyimproves the rash of porphyria cutanea tarda andgenerally is considered first-line therapy.

Up to 30% of patients chronically infected withHCV have a persistently normal level of ALT. Thesepatients generally have less aggressive histologicfeatures and a lower risk of disease progression thando patients with hepatitis C and abnormal ALTlevels. The role of liver biopsy and the treatment ofhepatitis C in patients who have normal ALT levelsare debated, but most hepatologists manage patientswho have normal ALT levels similarly to those whohave abnormal ALT levels.

Nearly all mortality and most morbidity asso-ciated with hepatitis C are due to cirrhosis. About20% to 30% of patients with chronic hepatitis Cdevelop cirrhosis over a 10- to 20-year period (Fig.4). Multiple factors have been studied to identifythe subgroup of patients likely to develop pro-gressive liver disease. Important factors are dura-tion of infection, alcohol intake of more than 50 gdaily, steatosis, coinfection with HIV or HBV, andmale sex. Patients with cirrhosis due to HCV gen-erally have had the disease longer than 20 years.

Perhaps the most important predictive factorfor the development of cirrhosis is the severity ofthe histologic features of the liver at presentation.Histologic specimens need to be interpreted with

knowledge of the duration of infection (if known).Patients who have only mild portal hepatitiswithout fibrosis despite 20 years of infection havea significantly lower risk of progression than thosewho have more active disease with a similar dura-tion of infection. Histologic markers of more activedisease include moderate degrees of inflammationand necrosis and the presence of periportal orseptal fibrosis. Liver biopsy should be performedin most patients being considered for treatment ofhepatitis C to assist in decisions about treatment.

TreatmentThe mortality and morbidity of chronic hepatitis Care related largely to cirrhosis. Consequently, treat-ment clearly is indicated for patients who are athighest risk for the development of cirrhosis: ananticipated long duration of hepatitis C, a historyof alcohol use, or active disease with at least peri-portal fibrosis seen in liver biopsy specimens.Patients who have a high probability of having aresponse to treatment, such as those with genotype2 or 3, may be considered candidates for treatmentregardless of liver biopsy findings. Thus, biopsyis not always necessary before treatment. Knowingwhether the patient has cirrhosis is necessary formonitoring for the development of esophagealvarices and hepatocellular carcinoma. For patientswith clear evidence of portal hypertension, biopsyis not needed to confirm cirrhosis. Therapy also

302 Liver

Acute hepatitis C

60%-85%

15%-40%

30%

70%20%-30%

2%-4%/yearChronic infection

Resolution

Normal ALT

Chronichepatitis Cirrhosis

Unusual

HCC

Death

10 years 20 years 30 years

Fig. 4. Natural history of hepatitis C. ALT, alanine aminotransferase; HCC, hepatocellular carcinoma.Percentage values refer to patients.

should be offered to patients who have extrahep-atic manifestations of hepatitis C, such as vasculitisrelated to cryoglobulinemia. In addition, patientswho have an anticipated long lifespan, for example,those younger than 40 years, might be offered treat-ment independently of liver biopsy findings orgenotype. Treatment may be indicated to reducepotential transmission, for example, a health careworker who performs invasive procedures.

Currently, peginterferon in combination withribavirin is the standard of care for patients withhepatitis C who are deemed candidates for treat-ment. This combination therapy, given for 6 to 12months, results in a sustained clearance of HCVRNA from serum in about 55% of patients. Baselinevariables associated with a sustained response tocombination therapy include HCV genotype 2 or3, HCV RNA levels less than 800,000 IU/mL, noor only portal fibrosis, female sex, and age youngerthan 40 years. Patients who receive at least 80% ofthe planned dose of peginterferon and ribavirinfor the duration of therapy are more likely to havea response. Adherence to therapy is particularlyimportant for harder-to-treat patients, such as thosewith genotype 1.

Hepatitis C genotype and viral level shouldbe determined before treatment is initiated. Whentreating patients who have genotype 1 or 4, theHCV RNA level should be determined after 12weeks of therapy (Fig. 5). Patients who do notachieve a 2 log10 decrease in HCV RNA level fromthe pretreatment value have a very low rate of sus-tained response, and treatment may be discon-tinued. Those with a 2 log10 decrease (or are HCVRNA-negative) at 12 weeks should continue toreceive treatment, and HCV RNA level determinedat 24 weeks. Those who are HCV RNA-positive at24 weeks will not achieve a sustained response,and treatment can be stopped. Patients who areHCV RNA-negative at 24 weeks should completea total of 48 weeks of treatment.

Patients with genotype 2 or 3 have a high rateof response, and determining the HCV RNA levelat 12 weeks probably is not cost-effective (Fig. 6).If therapy is tolerated poorly and a decision needsto be made about continuing therapy, the 12-weekstop rule described for genotype 1 may be applied.Otherwise, treatment should be continued for atotal of 24 weeks.

The most troublesome side effects of hepatitisC therapy are hematologic and neuropsychiatric.Anemia is the most common reason for prema-turely discontinuing hepatitis C combinationtherapy. Ribavirin causes a dose-dependent,reversible hemolysis that is evident within 4 weeksafter treatment is initiated. Peginterferon, becauseof its bone-marrow–suppressive effects, interfereswith erythropoiesis that may otherwise compen-sate for the ribavirin-induced hemolysis. Fatigue,dyspnea, or symptoms of cardiovascular diseasemay accompany anemia. Because ribavirin-inducedhemolysis is dose-dependent, dose reduction usu-ally improves the hemoglobin level, but perhaps atthe expense of treatment efficacy.

Erythropoietin has been used to maintainhemoglobin levels (and therefore ribavirin doses)in patients treated for hepatitis C. Whether ery-thropoietin-induced improvements in hemoglobinlevel and ribavirin dosing will lead to improvedhepatitis C response rates has not been demon-strated. Patient age, symptoms associated withanemia, risk factors for or presence of cardiovas-cular disease, and body size should be consideredwhen deciding whether to use erythropoietin.

Neutropenia that occurs during hepatitis Ctherapy is due to peginterferon. An absolute neu-trophil count less than 500 cells/mL is rare. Seriousinfections are extremely rare except perhaps inpatients with other risk factors for infection, forexample, decompensated cirrhosis. Consequently,neutropenia seldom requires intervention inpatients receiving peginterferon therapy.

Most neuropsychiatric side effects of hepatitisC therapy are due to peginterferon, althoughanemia and other side effects of ribavirin maypotentiate symptoms. The prevalence of neu-ropsychiatric side effects among patients withhepatitis C is high even before treatment, and base-line mood status may influence the likelihood ofdose-limiting neuropsychiatric manifestations ofinterferon. Pretreatment education for patientsand family members about the potential for theseside effects is helpful. Reassurance is also importantbecause many patients are able to cope with theneuropsychiatric manifestations by realizing thatthey are related to treatment and will resolve oncetreatment has been discontinued. Nevertheless,30% of patients treated for HCV infection require


the introduction or addition of medications for thetreatment of these side effects.

Patients who develop suicidal ideation whilereceiving treatment should discontinue therapyand be referred to psychiatry. For patients with

notable depression without suicidal ideation, aselective serotonin reuptake inhibitor such ascitalopram can be prescribed. For patients with aprominent anxiety or irritability component ofdepression, a less activating selective serotonin

304 Liver

10 10

mg/day

<2

of treatment at

Fig. 6. Management of HCV genotype 2 or 3. HCV, hepatitis C virus; PEG-IFN, peginterferon.

Liver biopsy More than portal fibrosis

Yes No

Continue therapyObtain qualitative HCV RNA at 24 weeks

Begin PEG-IFN and ribavirin 1-1.2 g/day Consider observation

Obtain HCV RNA level after 12 weeks

Negative or >2 log10

<2 log10

Stop therapy

Continue therapy for 24 more weeks

Negative Positive

Fig. 5. Management of HCV genotype 1. HCV, hepatitis C virus; PEG-IFN, peginterferon.

reuptake inhibitor such as paroxetine, fluvoxamine,or mirtazapine may be helpful. Mirtazapine is alsouseful for patients who have considerable weightloss with interferon therapy. Fluoxetine, sertra-line, venlafaxine, and bupropion are more acti-vating and, thus, may be preferred for patientswho have fatigue or cognitive slowing. Patientswho have persistent depression despite treatmentwith antidepressants are referred to psychiatry.

Patients who are not candidates for treatmentshould be evaluated annually with routine livertests. For those with early-stage disease, a repeatliver biopsy in 3 to 5 years may be indicated toassess for histologic progression. Patients with cir-rhosis are at increased risk for hepatocellular car-cinoma, particularly if they have a history of alcoholexcess. The risk of hepatocellular carcinoma com-plicating hepatitis C with cirrhosis is 1.4% to 4%per year. Screening with α-fetoprotein and liverultrasonography every 6 to 12 months is advisedfor patients with cirrhosis who are candidatesfor treatment of hepatocellular carcinoma withliver transplantation, liver resection, or percuta-neous ablation.

Patients with hepatitis C and cirrhosis (includingthose with hepatocellular carcinoma) should be con-sidered for liver transplantation. Currently, patientswith seven Child-Pugh points are eligible for listingand should be referred for liver transplantation ifthere are no contraindications. For patients whoreceived a liver transplant for hepatitis C, post-transplant viremia is nearly universal and histologicchanges in the allograft due to recurrent disease arecommon. Nevertheless, the survival rate is good,and hepatitis C is the leading indication for livertransplantation in the United States.

PreventionNo vaccine is available for hepatitis C. Transmissionby needlestick injury is unusual, although moni-toring after inadvertent exposure is advised. Baselineanti-HCV testing with subsequent determinationof HCV RNA level 4 weeks after exposure is rec-ommended. Documented acute infections probablyshould be treated to prevent chronic infection.Perinatal exposure is also uncommon, but it maybe more likely if the mother is also infected withHIV. Maternally derived anti-HCV may be foundin the neonate for up to 18 months after birth, thus

limiting the usefulness of serologic assays for diag-nosis; instead, HCV RNA testing should be used.

For patients infected with HCV, donation ofblood is prohibited. Precaution needs to be takenwhen caring for open sores of HCV-infectedpatients. Sexual transmission is unusual, butcondoms are advised for those with multiple sexpartners. For patients in a monogamous long-termrelationship, the partner should be tested and thecouple counseled about the possibility of trans-mission. The decision about the use of condoms isleft to the infected person and partner.

HEPATITIS EHepatitis E causes large outbreaks of acute hepatitisin underdeveloped countries. Physicians in theUnited States are unlikely to have a patient withhepatitis E. Rarely, a patient may become infectedduring foreign travel. Clinically, hepatitis E virusinfection is similar to HAV infection. Resolutionof the hepatitis is the rule, and chronic infectiondoes not occur. Women who acquire hepatitis Eduring pregnancy may present with fulminantliver failure.

VIRAL HEPATITIS AND HIVBecause of shared risk factors, patients with viralhepatitis are also at risk for infection with HIV. About10% to 15% of HIV-infected patients are HBsAg-pos-itive. Patients with HIV infection are at increasedrisk for remaining chronically infected after the acuteinfection compared with HIV-negative patients.HIV-infected patients with HBV infection havehigher HBV DNA levels and increased liver mor-tality than HBV patients without HIV infection.

The response to treatment for HBV infectionwith interferon in HIV-infected patients is verylow, and treatment with oral agents generally isadvised. Lamivudine is a logical choice for patientswho require treatment for HIV infection. The com-bination of tenofovir and emtricitabine is also alogical choice because it has an antiviral effect onboth HIV and HBV. For the rare patient whorequires treatment for HBV but not HIV, lamivu-dine, entecavir, or tenofovir should not be givenas monotherapy because of the risk of resistancedeveloping to later treatment of HIV disease.


About 45% of HIV-infected patients areinfected with HCV. Compared with HCV-infectedpatients without HIV infection, HCV/HIV-infected patients have higher HCV RNA levels,increased risk of vertical and sexual transmissionof HCV, an increased risk of cirrhosis, and anincreased risk of hepatocellular carcinoma.Patients with HCV/HIV should be considered fortreatment. The HIV disease should be controlled,and treatment is generally recommended only ifthe HIV level is less than 1,000 copies/mL andthe CD4 count more than 200 μL. The patientshould have no recent opportunistic infections,and most physicians advocate liver biopsy beforetreatment. Patients with stage 0 or stage 1 fibrosisgenerally can be observed unless they are HCVgenotype 2 or 3.

The doses used to treat hepatitis C inHCV/HIV-infected patients are similar to thoseused for treating HCV infection in patients withoutHIV infection. Twelve months of treatment isbetter than 6 months, even for patients with HCVgenotype 2 or 3. Three-month and 6-month “stop”rules are used to help identify nonresponders.Erythropoietin and antidepressants are often nec-essary to maintain dosing.

RECOMMENDED READINGDienstag JL, McHutchison JG. American

Gastroenterological Association technicalreview on the management of hepatitis C.Gastroenterology. 2006;130:231-64.

Keeffe EB, Dieterich DT, Han SH, Jacobson IM,Martin P, Schiff ER, et al. A treatment algo-rithm for the management of chronic hepatitisB virus infection in the United States: anupdate. Clin Gastroenterol Hepatol. 2006; Aug4:936-62. Epub 2006 Jul 14.

Lok AS, McMahon BJ. Chronic hepatitis B.Hepatology. 2007;45:507-39.

Poterucha JJ. Hepatitis A. In: Johnson LR, editor.Encyclopedia of gastroenterology. Amsterdam:Elsevier Academic Press; 2004. p. 311-5.

Pungpapong S, Kim WR, Poterucha JJ. Natural his-tory of hepatitis B virus infection: An updatefor clinicians. Mayo Clin Proc. 2007;82:967-75.

Russo MW, Fried MW. Side effects of therapy forchronic hepatitis C. Gastroenterology. 2003;124:1711-9.

Strader DB, Wright T, Thomas DL, Seeff LB,American Association for the Study of LiverDiseases. Diagnosis, management, and treat-ment of hepatitis C. Hepatology. 2004;39:1147-71.

306 Liver

The clinical approach to liver mass lesionsrequires attention to the clinical context withinwhich the mass is identified, the symptoms ofthe patient, and the physical examination, labo-ratory tests, and imaging studies. With the adventof frequent ultrasonographic or cross-sectionalimaging of the abdomen for various abdominalsymptoms, many liver mass lesions are now dis-covered incidentally during imaging performedfor unrelated symptoms. It is important to eval-uate fully these incidentally discovered lesionsbecause a significant proportion of them repre-sent malignant or premalignant disease thatrequires appropriate management. This chapterdescribes the overall approach to the evaluationand diagnosis of liver mass lesions and summa-rizes the clinical features and management of themost common benign and malignant liver masses(Table 1).

EVALUATION

HistoryIt is important to obtain a history of potential riskfactors for different types of liver masses to informthe subsequent evaluation and to limit unnecessarytesting. The age and sex of the patient, a history oforal contraceptive use, geographic residence andtravel history, and comorbid illnesses often pro-vide important clues to the diagnosis. A history ofprevious imaging studies should always be soughtbecause information about whether the mass is new,previously seen and stable in size, or enlarging overtime can be highly valuable in the differential diag-nosis of liver masses.

A history of pain can be an important pre-senting symptom. A rapidly enlarging liver masstends to distend the liver capsule and cause rightupper quadrant abdominal pain, whereas a slowly

307

CHAPTER 23

Clinical Approach to Liver Mass Lesions

Lewis R. Roberts, MB,ChB, PhD

Abbreviations: CA19-9, carbohydrate antigen 19-9; CT, computed tomography; ERCP, endoscopic retrogradecholangiopancreatography; HBV, hepatitis B virus; HCV, hepatitis C virus; MELD, model for end-stage liver disease;MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging; PET, positron emissiontomography; PSC, primary sclerosing cholangitis; PTC, percutaneous transhepatic cholangiography; RFA, radiofrequencyablation; TACE, transarterial chemoembolization; TARE, transarterial radioembolization.

growing mass can reach a substantial size thatalmost completely occupies the liver withoutcausing noticeable symptoms. It may only cometo attention when the mass becomes a visibleabdominal protuberance (Fig. 1). Pain associatedwith tumor growth is usually dull, relatively dif-fuse, and persistent. It may or may not be associatedwith tenderness in the epigastrium and right upperquadrant of the abdomen. Subcapsular lesions,whether benign or malignant, frequently cause apleuritic pain syndrome of abdominal pain accom-panied by right shoulder discomfort exacerbatedby breathing. In particular, lesions that have thepropensity for intralesional rupture or hemorrhage

can first appear as the sudden onset of severeabdominal pain. This is most typical of benignhepatic adenomas or hepatocellular carcinomas,which characteristically are extremely vascular. Ifthe rupture involves the liver capsule, it can beassociated with life-threatening intra-abdominalhemoperitoneum, shock, and risk of exsanguination.

A history of an underlying liver disease thatpredisposes to malignancy is often an importantdiagnostic clue. Patients with viral, alcoholic, non-alcoholic steatohepatitis, autoimmune, metabolic,or other causes of cirrhosis are at increased riskfor the development of hepatocellular carcinoma.These patients may have had complications of cir-rhosis, including ascites, spontaneous bacterialperitonitis, bleeding esophageal varices, or hepaticencephalopathy. In addition, patients with long-standing chronic hepatitis B virus (HBV) infectionare at risk for hepatocellular carcinoma even inthe absence of cirrhosis. Consequently, currentrecommendations are for patients with cirrhosisof any cause or who acquired chronic HBV infec-tion at birth or in early life to be entered into aregular program of surveillance with liver ultra-sonography, with or without serum α-fetoproteinmeasurements, every 6 months. Persons born insub-Saharan Africa should be enrolled in a sur-veillance program beginning at age 20 years; forthose born in Asia, surveillance should be initi-ated at age 40 years for men and 50 years forwomen (Fig. 2). Persons with a family history ofhepatocellular carcinoma and those with high HBVviral loads and active chronic hepatitis should alsohave regular surveillance.

Primary sclerosing cholangitis (PSC), whichcan be subclinical in patients with ulcerative colitisor other inflammatory bowel disease, is a majorrisk factor for cholangiocarcinoma. A history ofsudden hepatic decompensation, cholangitis, orthe development of a new dominant stricture in apatient with known PSC can presage the devel-opment of cholangiocarcinoma. More than half ofthe cholangiocarcinomas that occur in patientswith PSC will be diagnosed within 2 years afterthe initial diagnosis of PSC; therefore, this shouldbe a period of heightened surveillance.

General, nonspecific symptoms associatedwith malignancy include fatigue, loss of appetite,unintended weight loss, low-grade fever, and night

308 Liver

Table 1. Clinial Classification of Liver MassLesions

Benign lesions typically requiring no furthertreatment

Cavernous hemangiomaFocal nodular hyperplasiaSimple liver cystsFocal fatty change or focal sparing in a fatty liver

AngiolipomaBenign lesions requiring further follow-up andmanagement

Hepatic adenomaPyogenic liver abscessNodular regenerative hyperplasiaBiliary cystadenomaInflammatory pseudotumorGranulomatous abscessesAmebic liver abscessEchinococcal cysts

Malignant lesions requiring appropriatetherapy

Liver metastasesPrimary hepatocellular carcinomaCholangiocarcinomaMixed hepatocellular-cholangiocarcinomaCystadenocarcinomaHemangioendotheliomatosisEpithelioid angiomyolipomaMixed epithelial and stromal tumorsSarcomas

sweats. A recent history of iron deficiency anemiashould raise suspicion of colorectal cancer withliver metastases; a long-standing history of gas-troesophageal reflux and new-onset dysphagiashould prompt consideration of esophageal ade-nocarcinoma; the recent onset of diabetes mellitusshould elicit a search for pancreatic adenocarcinoma;and a history of breast cancer should be soughtand the breasts should be examined and imaged to

rule out metastatic breast cancer. In the absence ofother localizing symptoms, occult lymphomashould be considered.

Various paraneoplastic syndromes can behelpful in the diagnosis of liver masses. A historyof flushing, hypotension, and diarrhea is classicfor metastatic neuroendocrine tumors such as car-cinoids. Diarrhea alone occurs most frequentlywith hepatocellular carcinoma as a consequenceof the secretion of vasoactive intestinal polypep-tide and gastrin by the tumor. Also, hepatocellularcarcinomas can be associated with hypoglycemiaand erythrocytosis.

Physical ExaminationThe physical examination may provide clues tothe underlying cause of a liver mass. Most fre-quently, patients have stigmata of chronic liverdisease, including temporal muscle wasting, spiderangiomas, palmar erythema, ascites, splenomegaly,and a caput medusa from recanalization of theumbilical vein. The cirrhotic liver may be palpablynodular and often associated with bilobar enlarge-ment of the liver or isolated hypertrophy of thecaudate lobe. Large liver masses may give rise topalpable hepatomegaly, and subcapsular massesmay be palpable if located anteriorly or inferiorlyin the liver. Abdominal lymphadenopathy orperitoneal carcinomatosis may be palpable.Tumors may have associated tenderness in the

Clinical Approach to Liver Mass Lesions 309

Fig. 1. Large cavernous hemangioma with the presentation of an abdominal mass. A, Arterial phase with peripheralnodular enhancement. B, Venous phase with fill-in of contrast from the periphery toward the center of the mass.

Fig. 2. A small 1.3-cm mass (arrow) identified in anat-risk patient during ultrasonographic screening forhepatocellular carcinoma.

A B

epigastrium or right upper quadrant of theabdomen. Vascular masses such as primary hepa-tocellular carcinomas may have an audible vascularbruit on auscultation. Pallor may be due to anemiafrom colon adenocarcinoma with chronic blood lossor from anemia of chronic disease related to othermalignancies. Jaundice may be due to advancedchronic liver disease or to biliary obstruction fromcholangiocarcinoma. Peripheral edema may be asso-ciated specifically with chronic liver disease, withtense ascites causing compression of the inferiorvena cava and loss of intravascular oncotic pressuredue to hypoalbuminemia, or it may be nonspecific,due to general debility. Frequently, cancer is asso-ciated with an acute phase response syndrome, andbecause albumin is a negative acute phase reactant,a cancer-associated hypoalbuminemia typicallycontributes to peripheral edema. Many cancers areassociated with a prothrombotic tendency; conse-quently, it is important to evaluate new-onset lowerextremity edema, particularly if it is unilateral, fordeep vein thrombosis.

Laboratory TestsLaboratory tests often provide evidence of chronicliver disease or of the underlying tumor that ismetastatic to the liver. A complete blood countmay show thrombocytopenia from chronic liverdisease with splenomegaly, or it may show anemiafrom gastrointestinal blood loss related to colonor other primary gastrointestinal cancer. Typically,aspartate aminotransferase and alanine amino-transferase levels are increased in active inflam-matory liver disease or from neoplastic diseasesinfiltrating the liver. An increase in the bilirubinand alkaline phosphatase concentrations usuallyreflects bile duct obstruction from a primary bil-iary tumor or it may be due to mass effect from anintrahepatic mass or from enlarged lymph nodesin the porta hepatis. The serum level of albuminis often low and the prothrombin time increased inpatients with cirrhosis. Tests that identify the spe-cific cause, such as viral markers (anti-hepatitis Cvirus [HCV] antibody or polymerase chain reactionfor HCV RNA), hepatitis B surface antigen, anti-HBcore antibody, and anti-HB surface antibody, canbe useful. Iron levels typically are increased inpatients with hereditary hemochromatosis andlow in those with anemia from colon cancer-related

gastrointestinal blood loss. Tumor markers suchas carcinoembryonic antigen for colon cancer, car-bohydrate antigen 19-9 (CA19-9), and α-fetoproteinare helpful if positive, but they frequently are neg-ative in patients with early-stage cancer. Also, thesemarkers are not entirely specific for the primarysite. For example, the carcinoembryonic antigenlevel is often increased in cholangiocarcinomasand pancreatic cancers, and the α-fetoprotein levelcan be increased in patients with primary cancersof the upper gastrointestinal tract outside the liver,such as esophageal adenocarcinoma. Primaryhepatic lymphomas or secondary lymphomametastases can masquerade as primary liver can-cers; the serum level of lactate dehydrogenaseusually is increased and can be an important clueto the diagnosis. The urine 24-hour 5-hydroxyin-doleacetic acid concentration is helpful in cases ofsuspected carcinoid syndrome.

Imaging StudiesThe imaging studies most frequently helpful inthe differential diagnosis of liver mass lesionsinclude abdominal ultrasonography, cross-sectionalimaging modalities such as computed tomography(CT) and magnetic resonance imaging (MRI), andvarious nuclear imaging studies, including taggedred cell studies (for cavernous hemangiomas), tech-netium 99m sulfur colloid imaging (to distinguishfocal nodular hyperplasias from adenomas),positron emission tomography (PET), and fusedPET-CT (most useful for imaging metastatic dis-ease). More specialized contrast agents arebecoming available, particularly for MRI. Forexample, ferumoxide (Feridex), an injectable solu-tion of superparamagnetic iron oxide, is taken upby reticuloendothelial cells in the liver, whereastissues such as tumors with decreased reticuloen-dothelial cell function retain their signal intensity.Thus, ferumoxide is considered a “negative” con-trast agent (the liver decreases in signal intensity,not the lesion). Another newer paramagnetic MRIcontrast agent, gadobenate dimeglumine(MultiHance), undergoes biliary as well as renalexcretion and behaves as a nonspecific gadoliniumchelate in the first minutes after administrationand as a liver-targeted agent in later delayedphases; this allows further delineation of lesioncharacteristics in MRI scans obtained 60 to 120

310 Liver

minutes after the injection of contrast and can beparticularly helpful in distinguishing between focalnodular hyperplasias and adenomas.

BENIGN LIVER MASSES

Cavernous HemangiomaCavernous hemangiomas are the most commonbenign liver tumors, occurring in 7% of adults inautopsy series. They are seen predominantly inwomen, with a 1.5-5:1 female-to-male predomi-nance, being diagnosed most frequently in multi-parous women in their third to fifth decades.Cavernous hemangiomas are multicentric in upto 30% of cases and frequently coexist with focalnodular hyperplasias.

Histologic FeaturesCavernous hemangiomas are characterized by anextensive network of vascular spaces lined byendothelial cells and separated by thin, fibrousstroma. Large hemangiomas may have areas ofthrombosis, scarring, and calcification.

Clinical FeaturesHemangiomas are most often asymptomatic.Large, subcapsular hemangiomas may causeabdominal pain or discomfort. Giant heman-giomas (>10 cm) may cause systemic features of

inflammation such as fever, weight loss, andanemia. Kasabach-Merritt syndrome may occurwith disseminated intravascular coagulation, mostcommonly in children. Cavernous hemangiomasdo not undergo malignant transformation, andrupture is exceedingly rare.

Imaging CharacteristicsUltrasonography—On ultrasonography, heman-

giomas are well circumscribed, homogeneouslyhyperechoic lesions with smooth margins.

Dynamic contrast-enhanced multiphasic CT—OnCT, there is peripheral nodular enhancementduring the arterial phase, with later filling-intoward the center of the lesion (Fig. 3).

MRI with gadolinium contrast—Hemangiomasare typically homogeneous, with low signalintensity on T1-weighted images and sharplydemarcated, hyperintense lesions on T2-weighted images. Similar to other contrastimaging studies, there is peripheral enhance-ment in the arterial phase, with later fill-intoward the center of the lesion.

Technetium 99m-labeled red blood cell scintig-raphy—This can be used to confirm the diag-nosis in lesions that are atypical on otherimaging studies. There is low perfusion onearly images, and the isotope graduallyaccumulates to a high concentration withinthe lesion on late images.


Fig. 3. Cavernous hemangioma. A, Peripheral nodular enhancement in the arterial phase (arrows, one large andtwo small cavernous hemangiomas). B, Fill-in toward the center of the lesions in the venous phase (arrows,contrast enhancement extending toward the center of the masses, with almost complete enhancement of the twosmall hemangiomas).

A B

BiopsyBiopsy seldom is needed. It may be useful for smalllesions that show uniform enhancement andresemble primary tumors or metastases and alsofor large lesions that have pronounced scarringand atypical imaging features. Biopsy specimensare typically a relatively acellular “dry aspirate,”with occasional vascular elements seen on histo-logic study.

ManagementMost cavernous hemangiomas do not require inter-vention and can be observed. Symptomatic giantcavernous hemangiomas require surgical enu-cleation or resection.

Hepatic AdenomaHepatic adenomas are benign tumors of the liverthat occur predominantly in young womenbetween the third and fourth decades of life.Hepatic adenoma is associated significantly withlong-term use of oral contraceptive pills. The esti-mated relative risk is 2.5 times greater for womenwho have taken oral contraceptive pills for 3 to 5years than for women who have taken them for 1year or less. After 5 years of oral contraceptive use,the risk sharply increases to 25 times greater after9 or more years of use. Hepatic adenomas alsooccur in a familial pattern associated with diabetesmellitus, in patients with glycogen storage diseasetype 1A or 3, and in persons who take the andro-genic hormones methandrostenolone and methyl-testosterone. Adenomas are usually single, butthey may be multiple, especially in patients withglycogen storage disease. The tumors may decreasein size after withdrawal of oral contraceptives, butthey usually do not; sometimes they increase insize. An important feature of hepatic adenomas isthat they can undergo malignant transformation,although this seems to be relatively unusual.Recent evidence suggests that adenomas that stainpositive for increased cytoplasmic or nuclear β-catenin are more likely to transform to hepatocel-lular carcinoma.

Histologic FeaturesAdenomas are characterized by the presence ofsheets of hepatocytes without bile ductules, fibroussepta, portal tracts, or central veins.

Clinical FeaturesHepatic adenomas are most often asymptomatic.Patients may present with pain or discomfort ofthe upper abdomen or the right upper quadrantof the abdomen. Because these tumors have apropensity to rupture, patients may present withintrahepatic hemorrhage and pain or with hemo-peritoneum and shock.

Imaging CharacteristicsAdenomas frequently have nonspecific imagingcharacteristics. Most often, they are heterogeneousbecause of the presence of intralesional necrosisor hemorrhage, but frequently are homogeneouswhen small. The tumors typically take up contrastrapidly in the arterial phase of contrast CT or MRIstudies and then almost immediately become isoin-tense with the surrounding liver in the portalphase. If contrast studies are not optimally timed,this important imaging feature may be missed.Adenomas often cannot be differentiated defini-tively from hepatocellular carcinoma or hyper-vascular metastases with ultrasonography, CT, orMRI. On technetium 99m sulfur colloid scintigraphy,there usually is no uptake because adenomas do notcontain Kupffer cells. This feature also helps to dif-ferentiate adenomas from focal nodular hyperplasiasin the delayed phase after MRI with gadobenatedimeglumine, in which adenomas show decreasedretention of the contrast when compared with thesurrounding liver (Fig. 4).

BiopsyBecause of the frequent uncertainty about the diag-nosis after a thorough noninvasive evaluation,biopsy often is required for diagnosis.

ManagementResection is the treatment of choice because of therisk of rupture and associated malignancy. Patientsgenerally are advised to discontinue the use of oralcontraceptive pills. Most experts advise againstpregnancy until the lesion can be resected,although the evidence that pregnancy is associ-ated with a higher rate of complications is scant.

Focal Nodular HyperplasiaFocal nodular hyperplasia is thought to developas a reaction of the liver to an intrahepatic arterial

312 Liver

malformation. The arterial malformation forms avascular stellate scar that contains connective tissueand bile ductules. The surrounding mass containsa proliferation of hepatocytes separated by fibroussepta. Focal nodular hyperplasia occurs predom-inantly in women of childbearing age. The rela-tionship to oral contraceptive use is controversial,but some studies have suggested an associationwith long-term use. The tumor may be multiple(10% of patients) or associated with cavernoushemangiomas (20% of patients).

Histologic FeaturesFocal nodular hyperplasia is characterized bybenign-appearing hepatic parenchyma, with bileductules in septal fibrosis.

Clinical FeaturesMost patients with focal nodular hyperplasia areasymptomatic. Patients with large lesions maypresent with abdominal discomfort or an abdom-inal mass.

Imaging CharacteristicsUltrasonography—Focal nodular hyperplasias

have a variable sonographic appearance, withlesions being hypo-, hyper-, or isoechoic. Mostcommonly, the tumors are hypoechoic exceptfor the central scar. A color flow Doppler studymay show increased blood flow in the centralstellate scar.

Multiphasic CT—The presence of an avascularcentral scar or a feeding artery to the mass ishighly suggestive of focal nodular hyperplasia.The lesion shows rapid and intense contrastenhancement during the arterial phase andisointensity during the venous phase.

MRI with contrast—There is rapid, intense con-trast enhancement similar to the pattern withmultiphasic CT. Typically, focal nodularhyperplasias are isointense on T1-weightedimages and either isointense or slightly hyper-intense on T2-weighted images. The centralscar is usually hypointense on T1- but hyper-intense on T2-weighted images. Gadobenatedimeglumine contrast concentrates in theimmature bile ductules and Kupffer cells ofthe tumor (Fig. 5).

Technetium 99m sulfur colloid scintigraphy—Incontrast to the hypointensity of adenomas,50% to 60% of focal nodular hyperplasias show


Fig. 4. Hepatic adenoma. A, Arterial phase, withintravenous injection of gadobenate dimeglumineshowing heterogeneous hyperenhancement. B,Venous phase, the adenoma is almost isoenhancingwith the surrounding liver. C, Delayed hepatobiliaryphase, the adenoma excludes contrast and ishypoenhancing compared with the surrounding liver.

A B

C

hyperintense or isointense uptake because ofthe presence of Kupffer cells.

BiopsyIt can be difficult to distinguish between focalnodular hyperplasia and adenoma because fine-needle aspirates from both lesions may show onlybenign-appearing hepatocytes.

ManagementAsymptomatic focal nodular hyperplasias can bemonitored over time, and surgery rarely is indi-cated. Some groups recommend discontinuationof oral contraceptives, although this has not beenshown to result in regression of the tumor.

Simple Liver CystsSolitary or multiple liver cysts are common, usu-ally asymptomatic, and often coexist with othermass lesions in the liver. The female-to-male ratiois 4:1. Liver cysts occur in 3.6% of the population,and the prevalence increases with age.

Histologic FeaturesCysts are thin-walled structures lined by cuboidalbile duct epithelium and filled with isotonic fluid.

Clinical FeaturesCysts are usually asymptomatic unless large, whenthey can cause symptoms through pressure onadjacent structures. Rarely, large cysts may causebiliary obstruction.

Imaging CharacteristicsUltrasonography—This is the best imaging

modality for cysts. Classically, cysts are ane-choic and have smooth, round margins; a dis-tinct far wall; and posterior acoustic enhance-ment (Fig. 6). Ultrasonography clearly showsthe wall thickness and internal septations, ifpresent. Thick-walled cysts with nodularityor irregular septations suggest the diagnosis ofcystadenoma or, rarely, cystadenocarcinoma.

CT—Cysts have the same density as water and donot change with contrast imaging.

MRI—Cysts are hyperintense on T2-weightedimages. Small cysts may be difficult to differ-entiate from a cavernous hemangioma.

BiopsyBiopsy usually is not necessary because of the dis-tinctive imaging characteristics of simple cysts.

314 Liver

Fig. 5. Focal nodular hyperplasia. A, Arterial phaseshowing homogeneous hyperenhancement and acentral scar. B, Venous phase, the tumor is isoenhancingwith the surrounding liver. C, Delayed phase afterintravenous injection of gadobenate dimeglumineshowing that the contrast concentrates within the tumor.

A

B

C

ManagementLarge symptomatic cysts can be treated with sur-gical fenestration or percutaneous aspiration andinstillation of ethanol to ablate the cyst.

Focal Fat or Fat SparingFatty infiltration of the liver is common. Focalfatty infiltration can give the appearance of a masslesion on imaging studies; conversely, focalsparing in a liver with diffuse fatty infiltrationalso can have the appearance of a mass. Fatty infil-tration typically occurs in obese persons and inpatients with diabetes mellitus, high alcohol con-sumption, or altered nutritional status becauseof chemotherapy regimens.

Histologic FeaturesAreas of fatty infiltration show fat-laden cells.

Clinical FeaturesFocal fat or fat sparing is asymptomatic and usu-ally discovered on abdominal imaging performedfor other causes.

Imaging CharacteristicsFocal fat does not distort the contour of the liver. Ifnormal vessels, especially veins, can be seencoursing through the region, the diagnosis of focalfat is likely. Also, focal fat typically occurs in

vascular watersheds, particularly along the falci-form ligament. Skip areas of normal liver in diffusefatty infiltration typically occur adjacent to thegallbladder fossa, in subcapsular areas, or in theposterior aspect of segment 4 of the liver.

Ultrasonography—Areas of fatty infiltration arehyperechoic.

CT—Fat is hypodense compared with the spleen,but because the fat is dispersed in normal tissue,it is not as low in density as adipose tissue.Venous structures coursing through the areasof focal fat are seen on venous phase studies.

MRI—Fat is occasionally hyperintense on T1-and T2-weighted images. Decreased signalintensity on out-of-phase gradient imaging isdiagnostic of focal fat.

BiopsyBiopsy studies can be used to exclude other lesionsif the diagnosis cannot be established confidently.

ManagementNone is needed. Areas of focal fat may resolve ifpatients lose weight or achieve better control ofdiabetes.

MALIGNANT LIVER MASSES

Hepatocellular CarcinomaThe major risk factors for hepatocellular carcinomainclude cirrhosis from chronic HBV or HCV infec-tion, alcohol use, hereditary hemochromatosis,other causes of liver injury such as α1-antitrypsindeficiency, autoimmune hepatitis, primary biliarycirrhosis, and tyrosinema. Fungal aflatoxins thatcontaminate grains and legumes also have a syn-ergistic effect with other causes of liver injury andcontribute to the development of liver cancer inparts of sub-Saharan Africa and Asia. Approx-imately 80% to 90% of hepatocellular carcinomasarise in the context of cirrhosis. The other 10% to20% comprise two groups. The first group includeschronic HBV-infected patients who develop hepa-tocellular carcinoma in the absence of cirrhosis,presumably due to the oncogenic effects of HBVproteins and HBV integration, inherited familialtendency, and, in certain areas of the world, the


Fig. 6. Simple cyst. Ultrasonogram showing thecharacteristic changes of absence of echoes within thelesion, a distinct far wall, and increased echogenicityposterior to the cyst.

synergistic effect of exposure to dietary aflatoxin.These patients are often young, between 20 and 50years old. The second group of noncirrhotic patientsis characterized by older persons living in countrieswith a low incidence of HBV infection who presentwith sporadic onset hepatocellular carcinoma inthe absence of discernible risk factors. Without sur-veillance, most hepatocellular carcinomas are diag-nosed at an advanced stage, when radical treatmentfor cure is no longer feasible. Therefore, it is impor-tant that persons who are at risk for hepatocellularcarcinoma be enrolled in a surveillance programfor early detection of the tumor.

Surveillance and Diagnosis With Imagingor BiopsyThe best outcomes for treatment of hepatocellularcarcinoma are achieved with liver transplantation,surgical resection, or local ablative therapies suchas radiofrequency ablation or percutaneous ethanolinjection. Because these therapies are most effectivewhen applied to early-stage hepatocellular carci-noma, there is strong rationale for emphasizing aregular surveillance program to screen for thetumor in at-risk persons. Current guidelines rec-ommend that persons with cirrhosis have liverultrasonography every 6 months to screen forhepatocellular carcinoma. For those who havechronic hepatitis B without cirrhosis, screeningshould begin at age 20 years for Africans, 40 yearsfor Asian men, 50 years for Asian women, and 50years for whites. Determining the serum α-feto-protein level has low sensitivity for the detectionof early-stage hepatocellular carcinoma, and itsuse is not recommended, except when high-quality ultrasonography is not available. Thehigher basal metabolic index and central obesityof many US patients frequently render full ultra-sonographic visualization of the liver difficult;hence, α-fetoprotein measurement remains partof the de facto standard for surveillance of hepa-tocellular carcinoma.

Once a new mass is identified with ultra-sonography, it is confirmed with cross-sectionalimaging with contrast CT or MRI. The combinationof arterial enhancement with washout in the portalvenous phase is the hallmark of early-stage hepa-tocellular carcinoma and is highly specific (Fig.7). Hepatocellular carcinoma can be diagnosed

noninvasively if a new nodule found during sur-veillance to arise in a cirrhotic liver shows typicalarterial enhancement and venous washout.Current guidelines require that for nodules 1 to 2cm large, these features be shown by two imagingmodalities; for nodules larger than 2 cm, typicalfeatures seen on one contrast imaging study aresufficient to establish the diagnosis. The majorrationale for noninvasive diagnosis is to preventtumor seeding and recurrence after immunosup-pression in patients who receive a liver transplant.Patients who present with newly discovered livermasses in the absence of cirrhosis and who havenot been receiving ongoing surveillance for chronichepatitis B should have a biopsy study to histo-logically confirm hepatocellular carcinoma becauseconditions such as lymphomas and metastasesfrom other primary sites not infrequently mas-querade as hepatocellular carcinoma in a noncir-rhotic liver. Determination of the α-fetoproteinlevel may obviate the need for biopsy if the level ismarkedly increased, but it is important to considerthat malignancies at other primary sites, notablyesophageal and gastric carcinomas, can also beassociated with a high level of α-fetoprotein.

Management

Liver TransplantationLiver resection and transplantation offer thegreatest chance of cure for patients with hepato-cellular carcinoma. The selection of resection versustransplantation is based on a careful evaluation ofthe comorbid conditions of the patient, liver func-tion, tumor size, number of tumors, vascularinvasion, candidacy for transplantation, and organavailability. Transplantation is an effective treat-ment option for hepatocellular carcinoma ofpatients with cirrhosis because it addresses boththe neoplasm and underlying liver disease.Initially, the outcomes of transplantation for hepa-tocellular carcinoma were poor, but with advancesin patient selection, they have improved substan-tially. With the current selection criteria of onetumor smaller than 5 cm or up to three tumorssmaller than 3 cm, the 5-year survival rate is 70%to 80% and the recurrence rate is less than 15%.Despite the favorable results of transplantation,organ availability is less than the demand and up

316 Liver

to 15% of patients listed for transplant will dropout because of tumor progression before an organbecomes available.

SurgeryLiver resection is the preferred treatment for hepa-tocellular carcinoma in patients without cirrhosisand in those with cirrhosis who have well-preservedliver function and little or no portal hypertension.For patients without cirrhosis, major liver resec-tion can be performed with low mortality rates(<5%), with a 5-year survival rate of 30% to 50%.The major causes of perioperative mortality inpatients with cirrhosis who have liver resectionare bleeding and liver failure. Limited liver resec-tions are safe in patients with cirrhosis who havepreserved liver function (Child-Pugh class A) andno portal hypertension. Multiple methods ofassessing liver function, liver reserve, and peri-operative mortality have been described and areimportant in selecting patients for resection. Themodel for end-stage liver disease (MELD) has beenshown to predict perioperative mortality after liverresection. Patients with a MELD score less than 9have a perioperative mortality rate of 0%, com-pared with 29% for those with a score of 9 or more.After liver resection, the tumor recurs in approxi-mately 70% of patients within 5 years and reflectsboth intrahepatic metastases and the developmentof de novo tumors in the diseased liver. Predictorsof recurrence and survival after resection include

tumor size and number and vascular invasion. The5-year survival rate after liver resection is 30% to50%. For ideal candidates (single tumor, preservedliver function, absence of portal hypertension), the5-year survival rate is as high as 50% to 70%.

Local and Locoregional TherapiesLocal modalities for treating hepatocellular car-cinoma include ablative methods such as per-cutaneous ethanol injection and radiofrequencyablation (RFA) and locoregional therapies suchas transarterial chemoembolization (TACE),transarterial radioembolization (TARE), and con-formal beam radiotherapy.

Percutaneous ethanol injection is performedunder ultrasonographic guidance and is used fortreatment of small hepatocellular carcinomas upto 3 cm large in patients who are not candidatesfor liver transplantation or when liver transplan-tation is not available. Ethanol induces tumornecrosis and is particularly effective in the cirrhoticliver because the surrounding fibrotic tissue limitsthe diffusion of the injected ethanol. Two or threeinjection sessions usually are needed for completeablation of the tumor. The low cost of this treatmentmakes it attractive for use in lower income countries.

With RFA, a high-frequency electrical currentis applied to a treatment probe that is inserted intothe tumor. The treatment probes often have mul-tiple small tines that are deployed in a radialfashion within the tumor to increase the size of the


Fig. 7. Hepatocellular carcinoma. A, Arterial phase showing vascular enhancement (arrow). B, Portal phaseshowing venous washout (arrow).

A B

treatment field. The high-frequency currentinduces temperatures of about 60°C in the tumortissue, leading to coagulative necrosis. RFA typi-cally produces complete necrosis of a 3- to 4-cmradius of tissue during a single 10- to 15-minutetreatment. RFA can be applied to overlappingfields to treat lesions larger than 3 cm, but it is notas effective for these lesions. RFA is not effective forthe treatment of tumors close to major blood ves-sels because of rapid conduction of heat away fromthe tumor due to a heat sink effect. Also, RFA candamage the biliary tree if applied too close to majorbile ducts. Several early studies raised concernsabout increased risks of tumor seeding after RFA.Advances in the ablation technique have loweredthis risk substantially. Most often, surface lesionsare approached through the liver parenchymarather than through direct puncture of the liversurface. In addition, the probe track is cauterizedas the probe is being removed; this destroys andprevents dissemination of any residual hepato-cellular carcinoma cells.

Transarterial chemoembolization (TACE)involves the angiographic injection of a combina-tion of chemotherapy agents with gelfoam particlesinto the branch of the hepatic artery that suppliesthe tumor. The goal is to deliver high concentra-tions of antitumor agents and, simultaneously, toinduce tumor necrosis by occluding the arterialsupply to the tumor. TACE is particularly effec-tive in the treatment of hepatocellular carcinomabecause almost all the blood supply to the tumoris from branches of the hepatic artery. In contrast,the benign liver has a dual blood supply, with 70%to 80% of the blood supply provided by the portalvein and 20% to 30% by the hepatic artery.Consequently, occlusion of the branches of thehepatic artery to the tumor can be achieved withoutsubstantially compromising the blood supply tothe surrounding cirrhotic liver. The major con-traindication to TACE is complete obstruction ofthe portal vein, in which case concomitant obstruc-tion of the arterial supply can lead to hepaticischemia and induce liver decompensation. TACEcan be administered to carefully selected patientswho have incomplete occlusion of the portal vein.Randomized controlled trials have shown thatTACE improves survival of patients with unre-sectable intermediate-stage hepatocellular carci-

noma. The chemotherapy agents typically usedfor TACE include cisplatin, doxorubicin, and mit-omycin C. For TACE, some centers use chemo-therapy agents dissolved in iodized oil (Lipiodol);however, this iodinated contrast agent can interferewith subsequent detection of arterial enhancementin residual tumor nodules.

Transarterial radioembolization (TARE)delivers intratumoral radiation by transarterial injec-tion of yttrium-90 radioactive microspheres, fol-lowing the principles of TACE. Currently, oneproduct has been approved in the United States fortreating hepatocellular carcinoma: TheraSphere(MDS Nordion). TARE has not been studied as rig-orously as TACE. Early uncontrolled studies suggestthere is a risk of progressive long-term liver decom-pensation in patients who have more advanced liverdisease at the time treatment is initiated.

Systemic Approaches to TherapyFor patients with advanced multifocal disease inthe liver or at extrahepatic sites, no safe and effec-tive therapy was available until recently. In early2007, a large multicenter study showed that themultitargeting kinase inhibitor sorafenib had sig-nificant efficacy in a population of mostly Child-Pugh class A patients with unresectable hepato-cellular carcinoma, doubling the median time toradiographic progression from 12.3 to 24.0 weeksand increasing overall survival from 34.4 to 46.3weeks. Sorafenib was approved by the US Foodand Drug Administration in late 2007 for treatmentof unresectable hepatocellular carcinoma.

Cholangiocarcinoma Cholangiocarcinomas are malignancies that arisefrom the bile duct epithelium. In Western coun-tries, PSC is the primary identified risk factor forcholangiocarcinoma. In several countries in Asia,liver fluke infestations of the biliary tract are animportant risk factor. Choledochal and other cyticdisorders of the biliary tract also are associatedwith cholangiocarcinoma. Patients with chronicHCV infection with cirrhosis are also at increasedrisk for cholangiocarcinoma. However, mostpatients with cholangiocarcinoma have no knownrisk factors. For patients with PSC, the risk of diag-nosis of cholangiocarcinoma is highest within thefirst 2 years after the diagnosis of PSC, suggesting

318 Liver

perhaps that the development of cancer is the eventthat in some way triggers the diagnosis of PSC.Cholangiocarcinomas are classified as intrahep-atic and extrahepatic tumors. The presentation ofintrahepatic cholangiocarcinomas is typically as alarge intrahepatic mass with or without intrahep-atic or regional lymph node metastases.Extrahepatic cholangiocarcinomas may be peri-hilar tumors, which arise in the distal right or lefthepatic ducts or at the common hepatic duct bifur-cation, or distal bile duct tumors arising in thecommon bile duct. The laboratory test most oftenused to confirm the diagnosis of cholangiocarci-noma is CA19-9. A CA19-9 value more than 100ng/mL is about 65% to 75% sensitive and 85% to95% specific for the diagnosis of cholangiocarci-noma. CA19-9 also can be increased in pancreaticadenocarcinomas and other upper gastrointestinaltract malignancies. CA19-9 values more than 1,000ng/mL usually are predictive of extrahepaticmetastatic disease.

Histologic FeaturesHistologically, cholangiocarcinomas are adeno-carcinomas. This frequently leads to confusionabout the primary site of the tumor. Thus, cholan-giocarcinoma can be misdiagnosed as metastaticadenocarcinoma of unknown primary site.

Clinical FeaturesThe clinical features of cholangiocarcinoma dependon its location. Approximately 60% to 70% of thesetumors are at the bifurcation of the hepatic duct;the rest occur in the extrahepatic (20%-30%) orintrahepatic biliary tree (5%-15%). The mostcommon symptom of extrahepatic cholangiocar-cinoma is painless jaundice due to obstruction ofbiliary ducts. With tumors of the intrahepatic bileducts, patients often have pain without jaundice.With perihilar or intrahepatic tumors, jaundiceoften occurs later in the disease course and is amarker of advanced disease. Other common symp-toms include generalized itching, abdominal pain,weight loss, and fever. Pruritis usually is precededby jaundice, but it may be the initial presentingsymptom of cholangiocarcinoma. The pain associ-ated with cholangiocarcinoma is usually a constantdull ache in the right upper quadrant of theabdomen. Biliary obstruction results in clay-colored

stools and dark urine. Physical signs include jaun-dice, hepatomegaly, or a palpable right upperquadrant mass. Patients with intrahepatic cholan-giocarcinoma most often present with dull rightupper quadrant discomfort and weight loss.

Imaging CharacteristicsAbdominal ultrasonography—Cholangiocar-

cinomas are typically hypoechoic on ultra-sonography and sometimes are first visualizedduring an ultrasonographic examination of theliver for suspected gallstone disease causingright upper quadrant abdominal discomfort.

Multiphasic CT—Intrahepatic cholangiocarcinomasare usually hypodense on noncontrastimaging, often with a rounded, smooth,nodular appearance. During the arterial phase,there is minimal enhancement that progres-sively increases through the venous phase,often more prominent peripherally than cen-trally. Perihilar cholangiocarcinomas that pref-erentially affect one lobe of the liver often leadto unilobar biliary obstruction for an extendedperiod, during which time the patient has anormal bilirubin level because of adequate bil-iary drainage from the unaffected lobe of theliver. Eventually, the affected lobe undergoesatrophy, with prominent biliary dilatation,while the unaffected lobe undergoes com-pensatory hypertrophy. This syndrome iscalled the atrophy-hypertrophy complex (Fig. 8).Cross-sectional imaging is particularly helpfulfor assessing the degree of encasement of thehilar vasculature, a critically important partof the evaluation for surgical resectability.

MRI with gadolinium or ferumoxides—Intrahepaticcholangiocarcinomas are hypointense on T1-and hyperintense on T2-weighted images.There is peripheral contrast enhancement thatprogresses into the venous phase, similar tothe pattern seen with multiphasic CT. Imagingwith ferumoxides can enhance visualizationof small peribiliary cholangiocarcinomas.Magnetic resonance cholangiopancreatog-raphy (MRCP) is performed concomitantlywith MRI and is now recommended as theoptimal initial investigation for assessing theluminal extent and resectability of suspectedcholangiocarcinoma. MRCP is noninvasive


and as accurate as direct cholangiography inassessing the level of biliary tract obstruction.Often, the biliary tract peripheral to a biliarystenosis can be demonstrated better withMRCP than with endoscopic retrogradecholangiopancreatography (ERCP).

Cholangiography—With the advent of MRI andMRCP, direct cholangiography via ERCP andpercutaneous transhepatic cholangiography(PTC) are becoming less important as initial diag-nostic modalities; however, the resolution pro-vided by PTC and ERCP is still better in somecases than that of MRCP. In addition to providingtissue samples by brush cytology or biopsy, PTCand ERCP allow placement of therapeutic stentsfor biliary decompression if needed and also canbe used to deliver photodynamic therapy tounresectable tumors. PTC may be technicallychallenging in patients with PSC because ofperipheral strictures; for these patients, ERCPis the preferred modality. A completely occludeddistal biliary tract may preclude the use of ERCP,and either PTC or a combined approach of PTCand ERCP may be needed for successful pas-sage through a difficult stricture to accomplishinternal biliary drainage, which is preferred toexternal drainage.

Biopsy and CytologyIntrahepatic mass-forming cholangiocarcinomasusually are biopsied under ultrasonographic orCT guidance. Often, ductal cholangiocarcinomasare less amenable to percutaneous needle biopsy.Also, autoimmune pancreatitis with biliaryinvolvement can mimic a malignant biliary stric-ture, rendering the accurate diagnosis of biliarystrictures even more difficult. Pinch forceps biop-sies and cytologic brushings usually are obtainedat ERCP or PTC to help establish the diagnosis.Because many cholangiocarcinomas are highlydesmoplastic, with a prominent fibrous stromalcomponent separating small islands of malignantepithelium, histologic and cytologic confirmationof their malignancy can be challenging. Recently,advanced cytologic tests for chromosomal polysomysuch as fluorescence in situ hybridization havebeen shown to improve substantially the sensi-tivity of brush cytology for diagnosing malignancyin biliary strictures. Cytology samples with cellsthat show polysomy of two or more relevant chro-mosomal loci, typically chromosomes 3, 7, or 17in the current iteration of the Vysis UroVysion flu-orescence in situ probe set that is used, are highlyspecific for cancer (Fig. 9).

Endoscopic ultrasonography—Endoscopic ultra-sonography with an ultrasound probe at thetip of a duodenoscope allows high-resolutionevaluation of the left lobe of the liver and fine-needle aspiration of lymph nodes at the hepatichilum. This technique has proven extremelyuseful for assessing the presence and malig-nancy of regional lymph nodules duringstaging of cholangiocarcinomas.

Management

SurgeryHilar cholangiocarcinoma accounts for two-thirdsof all cases of extrahepatic cholangiocarcinoma.Intrahepatic cholangiocarcinoma is treated withsurgical resection when feasible. Tumors in themid-bile duct can be treated with resection andanastomosis of the bile duct. Distal extrahepaticcholangiocarcinomas are treated with pancreatico-duodenectomy. For hilar cholangiocarcinomas, sur-gical planning is more complex and preoperative

320 Liver

Fig. 8. Cholangiocarcinoma with atrophy-hypertrophy complex. Note cholangiocarcinomawith obstruction of the left biliary ductal system(arrow) and consequent marked dilatation of the bileducts in the left lobe, with associated atrophy of theleft lobe parenchyma. The right lobe showscompensatory hypertrophy.

evaluation of the local and regional extent of thetumor is critical. Cross-sectional imaging andcholangiography (either direct or MRCP) are nec-essary for appropriate patient selection and surgicalplanning. Current criteria that preclude resectioninclude 1) bilateral ductal extension to secondaryradicles; 2) encasement or occlusion of the mainportal vein; 3) lobar atrophy with involvement ofthe contralateral portal vein, hepatic artery, or sec-ondary biliary radicles; 4) peripancreatic (headonly), periduodenal, posterior pancreatoduodenal,periportal, celiac, or superior mesenteric regionallymph node metastases; and 5) distant metastases.The perioperative mortality rate of hepatic resec-tion for hilar cholangiocarcinoma is between 5%and 10% in major centers. The operation of choicefor hilar cholangiocarcinoma is cholecystectomy,lobar or extended lobar hepatic and bile duct resec-tion, regional lymphadenectomy, and Roux-en-Yhepaticojejunostomy. With surgical resection, the5-year survival rate is 20% to 25%.

Liver TransplantationA protocol of neoadjuvant chemoradiation fol-lowed by liver transplant for patients with hilarcholangiocarcinoma or cholangiocarcinoma arisingin association with PSC has been developed atMayo Clinic Rochester. The protocol is limited topatients who have a mass smaller than 3 cm andexcludes patients who have intrahepatic peripheralcholangiocarcinoma, metastases, or gallbladderinvolvement. Endoscopic ultrasonography is

performed with directed aspiration to rule outinvolvement of regional hepatic lymph nodes.Patients are treated initially with preoperativeradiotherapy (40.5-45 Gy, given as 1.5 Gy twicedaily) and 5-fluorouracil. This is followed by 20-to 30-Gy transcatheter irradiation with iridium.Capecitabine is then administered until trans-plantation. Before transplantation, patientsundergo a staging abdominal exploration. Regionallymph node metastases, peritoneal metastases, orlocally extensive disease preclude transplantation.At the time of the last published review of patientstreated since 1993, 71 patients had begun neoad-juvant therapy at Mayo Clinic Rochester and 38(54%) had had favorable findings at the stagingoperation and subsequent liver transplantation.The 5-year actuarial survival for all patients thatbegin neoadjuvant therapy is 58%; the 5-year sur-vival rate for those undergoing transplantation is82%. These results exceed those achieved withsurgical resection even though all the transplantprotocol patients have unresectable cholangiocarci-noma or cholangiocarcinoma arising in associationwith PSC. These results also are comparable to thoseachieved for patients with chronic liver disease whoreceive a liver transplant for other indications.

Systemic ChemotherapyVarious chemotherapy agents have been evalu-ated for the treatment of cholangiocarcinoma, butgenerally there is only a limited response to theseagents. The current standard of care is gemcitabine,


Fig. 9. Fluorescence in situ hybridization for diagnosis of malignancy in biliary strictures. Fluorescent DNAprobes for the centromeres of chromosomes 3 (red), 7 (green), 17 (aqua), and the p16 locus at chromosome 9p21(yellow) are hybridized to brush cytology specimens obtained from biliary strictures at endoscopic retrogradecholangiopancreatography. The normal diploid cell (A) has two copies of each of the probes; the malignantpolysomic cell (B) has multiple copies of chromosomes 3, 7, 9, and 17.

A B

which can be given alone or in combination witheither capecitabine or oxaliplatin. These regimensproduce responses in 25% to 64% of patients, witha median survival rate of 10 to 15 months. It is notclear whether multiagent therapy has any benefitover gemcitabine alone.

Maintenance of Biliary PatencyFor patients with unresectable tumor causing bil-iary obstruction, the maintenance of biliarypatency is required for substantial survival. Thisusually is achieved with the use of plastic endo-biliary stents, which generally remain patent for8 to 12 weeks, or metal stents, which may remainpatent for more than a year. Unilateral drainage isgenerally sufficient for palliation of biliary obstruc-tion and is associated with fewer complicationsthan bilateral stenting. Photodynamic therapy,administered by intravenous infusion of the pho-tosensitizer porfimer sodium (Photofrin) that pref-erentially accumulates in the proliferating tumortissue, followed 48 hours later with endoscopicor percutaneous application of a laser light tunedto the appropriate wavelength, is applied endo-scopically through a glass fiber inserted to the siteof the malignant biliary stricture.

Liver MetastasesLiver metastases from other primary cancer sitesare the most frequent malignant liver masses.Metastases are most commonly from colorectaladenocarcinomas, but also frequently occur inpatients with pancreatic, esophageal, gastric, neu-roendocrine, or breast cancer. Other potential pri-mary tumors include lung cancers, lymphomas,thyroid cancers, and renal cell carcinomas. Mostoften, liver metastases are multiple and distrib-uted throughout both lobes of the liver. They tendnot to have a large dominant lesion with multiplesmaller satellite lesions, a feature that is more char-acteristic of primary liver tumors such as hepato-cellular carcinoma and cholangiocarcinoma. Livermetastases have various imaging characteristics,depending on the degree of vascularity. Mostcommonly, they show persistent enhancementin the portal venous and venous phases of mul-tiphasic cross-sectional CT or MRI studies. Somemetastases also have a characteristic “halo” ofnonenhancing tissue around the nodule. Limited

disease with only a few metastatic nodules can betreated with surgical resection or conformalradiotherapy. For metastases that are more dif-fuse within the liver, locoregional therapy withTARE can be administered in combination withsystemic chemotherapy appropriate for the pri-mary tumor.

SUMMARYA wide range of liver mass lesions initially may ormay not produce symptoms. Many masses arefound incidentally during imaging for nonspecificabdominal symptoms. Accurate differentiation ofbenign from malignant lesions depends onobtaining a complete history, physical examina-tion, and appropriate laboratory tests. Most benignlesions require no intervention, but an importantsubset requires multidisciplinary evaluation, fol-lowed by surgical resection or other treatments.

RECOMMENDED READINGAlberts SR, Gores GJ, Kim GP, Roberts LR,

Kendrick ML, Rosen CB, et al. Treatmentoptions for hepatobiliary and pancreaticcancer. Mayo Clin Proc. 2007; 82:628-37.

Atassi B, Bangash AK, Bahrani A, Pizzi G,Lewandowski RJ, Ryu RK, et al. Multimodalityimaging following 90Y radioembolization: acomprehensive review and pictorial essay.Radiographics. 2008; 28:81-99.

Bioulac-Sage P, Balabaud C, Bedossa P, ScoazecJY, Chiche L, Dhillon AP, et al, Laennec andElves groups. Pathological diagnosis of livercell adenoma and focal nodular hyperplasia:Bordeaux update. J Hepatol. 2007 Mar;46:521-7. Epub 2007 Jan 2.

Choi BY, Nguyen MH. The diagnosis and man-agement of benign hepatic tumors. J ClinGastroenterol. 2005;39:401-12.

El-Serag HB, Rudolph KL. Hepatocellular carci-noma: epidemiology and molecular car-cinogenesis. Gastroenterology. 2007; 132:2557-76.

Forner A, Vilana R, Ayuso C, Bianchi L, Solé M,Ayuso JR, et al. Diagnosis of hepatic nodules20 mm or smaller in cirrhosis: prospective val-idation of the noninvasive diagnostic criteria

322 Liver

for hepatocellular carcinoma. Hepatology.2008; 47:97-104.

Heiken JP. Distinguishing benign from malignantliver tumours. Cancer Imaging. 2007; 7 SpecNo A:S1-14.

Heimbach JK, Gores GJ, Nagorney DM, Rosen CB.Liver transplantation for perihilar cholangio-carcinoma after aggressive neoadjuvanttherapy: a new paradigm for liver and biliarymalignancies? Surgery. 2006; 140:331-4.

La Vecchia C, Tavani A. Female hormones andbenign liver tumours. Dig Liver Dis. 2006 Aug;38:535-6. Epub 2006 Jun 5.

Llovet J, Ricci S, Mazzaferro V, Hilgard P, Gane E,Blanc, JF, et al. Sorafenib in advanced hepato-cellular carcinoma. N Engl J Med. (In PressJuly 2008).

Lopez PM, Villanueva A, Llovet JM. Systematicreview: evidence-based management of hepa-tocellular carcinoma: an updated analysis of

randomized controlled trials. AlimentPharmacol Ther. 2006; 23:1535-47.

Malhi H, Gores GJ. Cholangiocarcinoma: modernadvances in understanding a deadly old dis-ease. J Hepatol. 2006 Dec; 45:856-67. Epub 2006Sep 25.

O’Neil BH, Venook AP. Hepatocellular carcinoma:the role of the North American GI SteeringCommittee Hepatobiliary Task Force and theadvent of effective drug therapy. Oncologist.2007; 12:1425-32.

Valls C, Iannacconne R, Alba E, Murakami T, HoriM, Passariello R, et al. Fat in the liver: diag-nosis and characterization. Eur Radiol. 2006Oct; 16:2292-308. Epub 2006 Feb 14.

Verslype C, Libbrecht L. The multidisciplinarymanagement of gastrointestinal cancer: thediagnostic and therapeutic approach for pri-mary solid liver tumours in adults. Best PractRes Clin Gastroenterol. 2007; 21:983-96.


EPIDEMIOLOGY AND CLINICALSPECTRUM

Public Health Significance Alcoholic liver disease is a major cause of mor-bidity and mortality in the United States. Alcoholis implicated in more than 50% of liver-relateddeaths in the United States, and complications ofalcoholism contribute to a quarter of a milliondeaths annually. Also, alcoholic liver disease is amajor health care cost expenditure, accounting fornearly $3 billion annually.

Clinical SpectrumThe clinical spectrum of alcoholic liver diseaseincludes fatty liver, alcoholic hepatitis, and alco-holic cirrhosis. Fatty liver develops in response toshort periods (days) of alcohol abuse. It is generallyasymptomatic and reversible with abstinence.More advanced liver injury usually requires pro-longed alcohol abuse over a period of years. Ofnote, the majority of people who abuse alcohol forextended periods do not develop more advanced

lesions of alcoholic liver disease. However, approx-imately 20% of these patients do develop alcoholichepatitis or alcoholic cirrhosis (or both).

Risk Factors

Alcohol IngestionAlthough alcoholic fatty liver may develop inresponse to short periods of alcohol abuse, evenonly a few days, more advanced and morbid liverinjury requires prolonged alcohol abuse. In mostcases, the level of ethanol consumption required forthe development of advanced forms of alcoholicliver disease is 60 to 80 g of alcohol daily for men,or the equivalent of 6 to 8 drinks per day for sev-eral years. In women, half of this amount maycause clinically significant alcoholic liver disease.The quantity of alcohol necessary for liver injuryprobably does not depend on the type of alcoholconsumed. However, there is considerable indi-vidual variability in the threshold of alcohol nec-essary for advanced alcoholic liver disease todevelop, and clearly factors other than absolute

325

CHAPTER 24

Alcoholic Liver Disease

Vijay H. Shah, MD

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, γ-glutamyltransferase; HCV,hepatitis C virus; INR, international normalized ratio; MELD, model of end-stage liver disease; MEOS, microsomalethanol oxidizing system; NAD, nicotinamide adenine dinucleotide, oxidized; NADH, nicotinamide adeninedinucleotide, reduced.

ethanol consumption are important in determiningwhich persons develop alcoholic liver disease. Arecently identified risk factor is obesity. Other riskfactors are described below.

Genetic and Hereditary FactorsThe interindividual variability in the correlationbetween alcohol consumption and development ofliver disease highlights the role of genetic factorsthat may predispose a person to alcohol-inducedliver toxicity. Specific genetic polymorphisms havebeen detected in patients who have alcoholic liverdisease, most notably mutations in the tumornecrosis factor promoter and in alcohol-metabo-lizing enzyme systems. In addition to the geneticfactors predisposing certain alcoholic persons toliver disease, there also is strong evidence thatgenetic factors predispose persons to alcoholism.Currently, however, no single genetic polymor-phism has been shown definitively to contribute toalcoholic liver disease.

SexAlthough alcoholic liver disease is observed morecommonly in men than women, women are pre-disposed to the development of this disease anddevelop more severe disease with less alcohol con-sumption than men. The reason for this greaterrisk in women is not clear; however, despite weightadjustment, a similar level of alcohol consumptionresults in higher blood alcohol levels in womenthan in men. Theories to explain this include a rela-tive deficiency of gastric alcohol dehydrogenase inwomen, sex differences in alcohol bioavailability,and female hormone-related effects.

• Alcoholic liver disease encompasses a clini-cohistologic spectrum (fatty liver, hepatitis,and cirrhosis).

• Although there is considerable variabilityamong persons, the toxic dose of alcohol nec-essary for advanced liver injury to develop isprobably 60 to 80 g daily for several years, witha significantly lower threshold for women.

• Genetic factors contribute to alcoholic liverdisease by predisposing a person to alcoholismas well as to alcohol-induced liver injury.

• Although fatty liver occurs nearly uniformlywith excess alcohol consumption, more

advanced liver injury occurs in only 15% to20% of persons who continue to abuse alcohol.

• Alcoholic hepatitis may occur in the presenceor absence of preexisting liver cirrhosis.

ETHANOL METABOLISM ANDPATHOPHYSIOLOGYMore than one enzyme system is capable of metab-olizing alcohol in the liver. Enzymes that havereceived the greatest attention include alcoholdehydrogenase, aldehyde dehydrogenase, andthe microsomal ethanol-oxidizing system (MEOS)(Fig. 1). The relative importance of each of thesepathways is being investigated. When physiologiccircumstances are normal and blood levels ofalcohol are low, the enzyme of major importanceis alcohol dehydrogenase. This enzyme catalyzesthe conversion of alcohol to acetaldehyde, andaldehyde dehydrogenase subsequently catalyzesthe conversion of acetaldehyde to acetate. Alcoholdehydrogenase catalysis changes the oxidation-reduction state in the cell by increasing the ratioof reduced nicotinamide adenine dinucleotide(NADH) to the oxidized form (NAD), which hasimportant implications for other cellular processes,including the generation of free radicals, inhibi-tion of other enzyme systems, and accumulation offat. Also, an isoform of alcohol dehydrogenaseoccurs within the gastric mucosa, although theclinical importance of the gastric component ofalcohol metabolism is debated.

MEOS is localized in the endoplasmic retic-ulum instead of the cytosol, where the alcoholdehydrogenase system operates, and appears tobe important in alcohol metabolism when bloodlevels of alcohol are moderate to high. Undernormal conditions when these levels are low, therole of MEOS is much smaller than that of thealcohol dehydrogenase system. As explained byits enzyme kinetics, MEOS has a greater role incases of chronic alcohol use because it is inducedby alcohol, thereby allowing progressivelyincreased ethanol metabolism in alcoholics. MEOSalso converts alcohol to acetaldehyde, requiringaldehyde dehydrogenase for further metabolism.Importantly, the specific MEOS enzyme CYP2E1is responsible for the metabolism of various othercompounds. The induction of CYP2E1 by alcohol

326 Liver

importantly affects blood levels of these com-pounds and accounts for the increased toleranceof alcoholics to sedatives. Compounds that arerapidly metabolized in alcoholics by this processinclude isoniazid and acetaminophen. Importantly,nearly one-half of Far East Asians are deficient inaldehyde dehydrogenase activity because of theinheritance of a mutant allele. This can result inexcess accumulation of aldehyde, accounting foralcohol-induced flushing symptoms in these per-sons, who may also be more susceptible to alcohol-induced liver injury. A similar flushing syndromeis observed in response to alcohol consumptionwhen a person ingests disulfuram, which is thebasis for its use in the treatment of alcoholism.Although the peroxisomal catalase enzyme also iscapable of ethanol metabolism, its physiologic rolein alcohol metabolism appears to be minor.

Experimental evidence suggests that thealcohol metabolite acetaldehyde may be a toxicmediator of alcohol-induced liver injury. Themechanism by which alcohol and acetaldehydecause liver injury is being investigated. The ini-tiation of fat accumulation within the liverappears to occur in response to the decreasedoxidation and increased accumulation of fattyacids. These events may be linked to changes inthe liver oxidation-reduction state induced byethanol metabolism. Other important physio-logic events that mediate liver injury includeincreased oxidative stress, hepatocyte apoptosisand necrosis, and deposition of collagen, withensuing fibrosis through activation of liver stellatecells. Various cytokines, transcription factors,and intracellular signaling pathways have beenimplicated in these events, including tumornecrosis factor, a cytokine whose blood levels

appear to correlate with the severity of liver diseasein patients with alcoholic hepatitis.

• Alcohol dehydrogenase is the primary alcohol-metabolizing pathway, particularly whenblood alcohol levels are low.

• MEOS is important in alcoholics, especiallywhen blood levels of alcohol are high.Induction of this system importantly affectsthe metabolism of various xenobiotics.

• Diminished activity of aldehyde dehydrogen-ase accounts for the flushing syndromedetected in a large proportion of Asians whoconsume alcohol.

FATTY LIVER

Case PresentationA 22-year-old male college student has a series oflaboratory tests performed during a routinecheckup at the student health clinic. He is asymp-tomatic, and the physical examination findings arenormal. He takes no medications and has no familyhistory of liver disease. He is not sexually activeand says he does not use intravenous or intranasaldrugs, has not traveled recently, and has not hadblood transfusions. Laboratory findings includethe following: aspartate aminotransferase (AST)65 U/L (normal 8-48 U/L), alanine aminotransferase(ALT) 43 U/L (normal 7-55 U/L), γ-glutamyl-transferase (GGT) 336 U/L (normal 9-31 U/L);mean corpuscular volume and total bilirubin andalkaline phosphatase levels are normal. On fur-ther questioning, the patient admits to having had6 to 10 drinks per day over the past week duringstudent orientation.

Alcoholic Liver Disease 327

Alcoholdehydrogenase

Alcohol Acetaldehyde AcetateMEOS

(CYP2E1)Aldehyde

dehydrogenase

Fig. 1. Alcohol metabolism. Alcohol is metabolized to acetaldehyde by alcohol dehydrogenase and CYP2E1. Inmost persons, the alcohol dehydrogenase pathway is dominant; however, in alcoholic persons and those with highblood levels of alcohol, CYP2E1 is induced and has a major role in metabolism. Acetaldehyde derived from boththese pathways is metabolized by aldehyde dehydrogenase to acetate. MEOS, microsomal ethanol-oxidizing system.

This patient has the clinical features suggestiveof alcoholic fatty liver. The diagnosis and treatmentare discussed below.

History and Physical ExaminationFatty liver may develop in response to only a tran-sient alcohol insult, over a period of days. The mostsalient historical feature is an alcohol binge. Thepatient may be asymptomatic or may complain ofmild nonspecific symptoms, including fatigue,malaise, abdominal discomfort, and anorexia. Onphysical examination, tender hepatomegaly maybe prominent. Stigmata of chronic liver disease areabsent, and in many patients, the physical exam-ination findings are normal.

Laboratory and Radiographic FeaturesLaboratory studies may show mild to moderateincreases in the serum levels of aminotransferases,predominantly an increase in AST. Minor increasesin alkaline phosphatase or bilirubin (or both) maybe observed. Prothrombin time is normal. As inthe above case, laboratory abnormalities often arenoted incidentally in an asymptomatic person.

Histologic FeaturesGenerally, liver biopsy is not necessary to establishthe diagnosis of alcoholic fatty liver because thecondition is benign and reversible. However,biopsy may be performed to determine whetherthe patient has more advanced alcoholic liver dis-ease or another condition. The principal feature ofalcoholic fatty liver in biopsy specimens ismacrovesicular steatosis within hepatocytes (Fig.2). There are no inflammatory cells or collagendeposition. Because biopsy specimens frompatients with Wilson’s disease occasionally havethe features of steatosis, Wilson’s disease shouldalways be excluded in young persons who haveabnormal levels of liver enzymes.

Prognosis and Treatment No specific treatment other than abstinence isrequired for management of alcoholic fatty liver.If abstinence is achieved, alcoholic fatty liver isentirely reversible. However, 20% to 30% ofpatients who continue to abuse alcohol chronicallydevelop more advanced forms of alcoholic liverdisease, including alcoholic hepatitis and cirrhosis.

• Alcoholic fatty liver may develop in responseto short periods of alcohol abuse, although itis more common with chronic alcohol abuse.

• Treatment is focused on abstinence or morejudicious consumption of alcohol.

ALCOHOLIC HEPATITIS

Clinical Presentation A 36-year-old man complains of fatigue, darkurine, and abdominal swelling. He admits todrinking a few beers a day since his teen years, buthe has never had a major medical problem.Recently, he has been drinking more heavily whileunemployed. He states that he has not had bloodtransfusions and does not use intravenous drugs.Physical examination findings are remarkable fortachycardia and low-grade fever. Prominent scleralicterus is noted, and the abdominal examinationshows shifting dullness. The liver span is increasedon percussion.

This patient has the clinical features typical ofalcoholic hepatitis. The diagnosis and treatmentare discussed below.

History and Physical ExaminationAlthough alcoholic fatty liver is predominantlyan asymptomatic condition, a constellation of clin-ical symptoms, often nonspecific, frequently areobserved in patients with more advanced lesions,such as alcoholic hepatitis. Persons who drinkmore than 60 to 80 g of alcohol daily for a periodof years are at risk for the development of alco-holic hepatitis; the threshold is lower for women.Also, alcoholic hepatitis may develop in the pres-ence or absence of underlying liver cirrhosis. Theclinical presentation of alcoholic hepatitis includesconstitutional symptoms such as weakness,anorexia, and weight loss and other nonspecificsymptoms such as nausea and vomiting (Fig. 3).Severe alcoholic hepatitis may include moreadvanced symptoms related to portal hyperten-sion, including gastrointestinal tract bleeding,ascites, and hepatic encephalopathy. It is impor-tant to identify risk factors for concomitant oralternative forms of acute and chronic hepatitis,such as viral hepatitis, Wilson’s disease, and drug-induced hepatitis.

328 Liver

The diagnosis of alcoholic hepatitis is contin-gent on determining whether the patient is abusingalcohol. This is not always easy because alcoholicpersons and even their family members often min-imize or hide their alcohol use. An independenthistory from multiple family members is often nec-essary to corroborate the patient’s alcohol history,and different caregivers may obtain a different his-tory from the same interviewee because of the typeof relation between the patient and caregiver andthe approach and persistence of different historytakers. Questionnaires have been used to clarifyalcohol use and abuse syndromes; however,because of their length, many of them are limitedto research purposes. The most useful screeningquestionnaire in clinical practice is the CAGE ques-tionnaire, which includes the following inquiries:Has the patient felt the need to cut back on alcoholuse? Has the patient become annoyed with otherpersons’ concerns about his or her alcohol use?Does the patient feel guilty about his or her alcoholuse? Does the patient use alcohol in the morning asan eye-opener? Although two positive responseshave a high sensitivity and positive predictivevalue for alcohol dependency, any positiveresponse to these inquiries requires a more detailedinvestigation and should heighten the suspicionof alcohol abuse.

In patients with alcoholic hepatitis, physicalexamination findings are most notable for tenderhepatomegaly, fever, and tachycardia (Fig. 3).Other findings depend on the severity of liverinsult, the presence or absence of concomitantcirrhosis, and the presence or absence of portalhypertension. These findings may include jaundice,splenomegaly, collateral vessels, hypogonadism,palmar erythema, asterixis, and ascites in patientswith severe alcoholic hepatitis and portal hyper-tension. Evidence for concomitant infection iscommon and may be detected on examination,including signs of spontaneous bacterial peritonitis,pneumonia, or cellulitis.

Laboratory and Radiographic FeaturesLaboratory abnormalities reflect the extrahepaticadverse effects of alcohol as well as alcohol-inducedliver injury (Table 1). Mean corpuscular volumeusually is increased, reflecting the adverse effect ofalcohol on erythrocytes. The levels of triglyceridesand uric acid also are frequently increased. Patientsare prone to ketoacidosis. Peripheral polymor-phonuclear leukocytosis is prominent, and in somecases, a leukemoid reaction also may be observed.Aminotransferase levels usually are increased lessthan 5 to 10 times normal, but they may be higherwith concomitant acetaminophen toxicity. Also,


Fig. 2. Histopathologic features of alcoholic liver disease. A, Fatty liver. Note macrovesicular steatosis and lackof inflammation and collagen deposition. B, Alcoholic hepatitis. Note polymorphonuclear infiltrates, hepatocytenecrosis, steatosis, Mallory bodies, and variable amounts of fibrosis. C, Alcoholic cirrhosis. Note characteristicmicronodular cirrhosis, although a mixed nodularity pattern is often observed. Frequently, there is prominentsecondary hemosiderosis. (From Kanel GC, Korula J. Liver biopsy evaluation: histologic diagnosis and clinicalcorrelations. Philadelphia: WB Saunders Company; 2000. p. 39, 89, 94. Used with permission.)

A B C

the level of AST almost always is higher than thatof ALT, which is opposite to that in nonalcoholicsteatohepatitis, in which the ALT level is oftenhigher than the AST level. Both the modest increasein aminotransferase levels and the greater increasein AST than in ALT help to differentiate alcoholichepatitis from alternative diagnoses. Some labo-ratory abnormalities reflect the severity of thealcohol-induced liver injury and are prognosti-cally useful, including prothrombin time andbilirubin concentration. In moderate to severe casesof alcoholic hepatitis, prothrombin time andbilirubin concentration are increased, and, in con-trast to aminotransferase levels, prothrombin timeand bilirubin concentration have prognostic utility.Several groups have attempted to use bilirubinconcentration and prothrombin time as well asother laboratory variables to assess the prognosisof patients with alcoholic hepatitis. The mostwidely used of these assessments is the Maddreydiscriminant function analysis:

Discriminant function = 4.6 (prothrombin time –control) + serum bilirubin concentration

(mg/dL)

A discriminant function greater than 32 effec-tively identifies patients whose risk of death is higherthan 50%. The model of end-stage liver disease(MELD) score also predicts survival in patientswith alcoholic hepatitis. MELD score and corre-sponding 90-day survival can be calculated onthe basis of the patient’s creatinine, internationalnormalized ratio (INR), and bilirubin values atthe following Web site: http://www.may-oclinic.org /girst/mayomodel7.html. Other fre-quently observed laboratory abnormalities thatmay cause diagnostic confusion or suggest mul-tifactorial liver disease include increases in ironsaturation indices and ferritin, hepatitis C virus(HCV) antibody positivity, and increased levelsof autoimmune markers such as antinuclear anti-body and anti–smooth muscle antibody. Ratherthan reflecting the concomitant presence of hered-itary hemochromatosis or autoimmune hepatitis,increases in iron indices and autoimmune markersmore commonly reflect the pathogenic role of irondeposition and autoimmunity in the developmentof alcoholic hepatitis. In cases in which the alcoholhistory is questionable, a Doppler ultrasonographicstudy is useful to exclude alternative diagnoses

330 Liver

Hepatomegaly

Jaundice

Spider Nevi

Ascites

Palmar Erythema

Fever

Portal Encephalopathy

Collateral Abdominal Veins

Peripheral Edema

Splenomegaly

Infections

Hepatorenal Syndrome

GI Bleeding

Diarrhea

Nausea & Vomiting

Abdominal Pain

Weight Loss

Anorexia

Weakness

Physical Signs Clinical Symptoms

Fig. 3. Clinical features of alcoholic hepatitis. Clinical symptoms of alcoholic hepatitis are often nonspecific andinclude weakness, anorexia, and abdominal pain. In more severe cases, complications of portal hypertensionpredominate, including gastrointestinal (GI) tract bleeding and renal dysfunction. Physical examination findings aremost notable for hepatomegaly and jaundice. Additional findings depend on the presence of portal hypertension orliver cirrhosis (or both), including stigmata of chronic liver disease and collateral vessels. Numbers refer topercentage of patients with the feature. (From Mendenhall CL. Alcoholic hepatitis. In: Schiff L, Schiff ER, editors.Diseases of the Liver. Vol 2. 7th ed. Philadelphia: JB Lippincott Company; 1993. p. 862. Used with permission.)

such as cholecystitis, biliary obstruction, andhepatic vein thrombosis, which may manifest in amanner similar to alcoholic hepatitis. The falsediagnosis of gallstone disease can be catastrophicbecause of the high surgical morbidity and mor-tality of patients with alcoholic hepatitis.

Because of the inherent difficulties in obtaininga reliable history of alcohol use, various biochem-ical markers have been evaluated for the detectionof surreptitious alcohol abuse. Many of the tradi-tional serologic tests of alcohol abuse are based onindirectly assessing alcohol abuse by examiningsuch markers of liver injury as AST, ALT, the ratioof AST to ALT, and GGT. However, because thesetests assess alcohol abuse indirectly by detectingliver injury, their sensitivity and specificity gener-ally are less than 70%. Mean corpuscular volumealso indirectly assesses alcohol abuse by evaluatingbone marrow toxicity of alcohol; it can be helpfulas an adjunctive test. Newer tests include carbohy-drate-deficient transferrin and mitochondrial AST.Carbohydrate-deficient transferrin reflects the desia-lylation of transferrin that occurs in response to high

alcohol use, and mitochondrial AST is a specificisoform of the enzyme that is released from hepa-tocytes injured by alcohol. However, these testshave not been shown universally to be more effectivethan the less expensive AST-to-ALT ratio, GGT, andmean corpuscular volume.

Histologic FeaturesWith advances in noninvasive liver diagnosticcapabilities over the past decade, the diagnosisof alcoholic hepatitis often is made without liverbiopsy. However, liver biopsy is indicated if thediagnosis is in question after noninvasive evalu-ation. In particular, histologic examination may beuseful in distinguishing coexisting or alternativeliver disorders such as hereditary hemochro-matosis in persons with high iron saturation,Wilson’s disease in younger persons with low tolow-normal ceruloplasmin levels, autoimmunehepatitis in persons with high titers of autoim-mune markers, and hepatitis C in persons withHCV antibody positivity. Liver biopsy, if pur-sued, often requires a transjugular rather than apercutaneous route, depending on the degree ofcoagulopathy and thrombocytopenia. In alcoholichepatitis, liver biopsy specimens demonstrateseveral characteristic features, including cen-trilobular and sometimes periportal polymor-phonuclear infiltrates, centrilobular hepatocyteswelling, ballooning degeneration, macrovesic-ular steatosis, and Mallory bodies (Fig. 2). Often,pericentral and perisinusoidal fibrosis is detectedwith a trichrome stain. The terminal hepaticvenules frequently are obliterated, and indeedthe zone 3 region of the liver acinus shows themost prominent injury. Mallory bodies,eosinophilic-staining condensed cytoskeletalstructures, are not specific for alcoholic hepatitis.However, their presence in association with othersalient biopsy features strongly suggests alcoholichepatitis. Prominent neutrophilic infiltration ofhepatocytes containing Mallory bodies is termedsatellitosis. Giant mitochondria (megamitochondria)are another characteristic feature. In up to 50% ofcases, concomitant cirrhosis may be observed.Importantly, nonalcoholic steatohepatitis cannotbe differentiated reliably from alcoholic hepatitiswith liver biopsy specimens because of the overlapof histologic features.


Table 1. Laboratory Abnormalities inAlcoholic Hepatitis

HematologyMacrocytic anemia (increased MCV)LeukocytosisThrombocytopenia

General chemistryHyperglycemiaHyperuricemiaHypertriglyceridemiaKetosis

Tests of liver function and injuryHypoalbuminemiaHyperbilirubinemiaIncreased prothrombin timeIncreased AST/ALT (ratio of 1.5 to 2.5 and

total increase <10-fold)Increased GGTIncreased alkaline phosphatase (mild)

ALT, alanine aminotransferase; AST, aspartateaminotransferase; GGT, γ-glutamyltransferase; MCV,mean corpuscular volume.

Prognosis and Treatment

AbstinenceAbstinence is an important factor in both short-and long-term survival of patients with alcoholichepatitis. For patients who recover and remainabstinent, the disease may continue to improve(ie, clinical sequelae and laboratory variables) foras long as 6 months. Although the condition of somepatients continues to deteriorate even with absti-nence, the 5-year survival rate for this group is morethan 60%. However, for patients who continue todrink, the 5-year survival rate is less than 30%.

NutritionMalnutrition is almost universal among patientswith alcoholic hepatitis because of concomitantpoor dietary habits, anorexia, and encephalopathy.Although malnutrition was once thought to causealcoholic liver disease, it is no longer considered tohave a major role in the pathogenesis of the disease.However, maintenance of a positive nitrogen bal-ance and provision of adequate energy requirementsthrough nutritional support are a vital supportivetreatment approach. Patients with alcoholichepatitis generally have greater protein and energyneeds because of the stress of illness and under-lying malnutrition. Recommendations include 30to 40 kcal/kg ideal body weight of caloric supple-mentation and 1 to 1.5 g protein/kg ideal bodyweight. Provision of nutrients in excess of calculatedrequirements is unlikely to be of benefit. Everyattempt should be made to provide adequate calo-ries enterally. However, parenteral support may benecessary for some patients. Encephalopathyshould not require protein restriction in mostpatients. For patients with severe encephalopathythat is exacerbated by dietary protein, branchedchain amino acid supplements should be consideredor protein intake should be decreased transiently.Increased use of dietary vegetable protein may bebetter tolerated than animal protein. Other thanfor this scenario, amino acid supplementationprobably does not improve survival sufficientlyfor the added cost.

Portal HypertensionPatients with alcoholic hepatitis may develop com-plications of portal hypertension regardless of the

presence or absence of underlying cirrhosis. Thisclinical observation is supported by studiesdemonstrating that alcohol directly increasesportal pressure, and it emphasizes the impor-tance of the vascular component of intrahepaticresistance and portal hypertension. Hepaticencephalopathy, bleeding esophageal varices,ascites, spontaneous bacterial peritonitis, and hepa-torenal syndrome are complications of portalhypertension commonly encountered in patientswith alcoholic hepatitis. The management of thesecomplications is discussed elsewhere in this book.

InfectionBecause of underlying malnutrition, liver cirrhosis,and iatrogenic complications, infection is one ofthe most common causes of death of patients withalcoholic hepatitis. The patients must be evaluatedcarefully for infections, including spontaneousbacterial peritonitis, aspiration pneumonia, andlower extremity cellulitis. These infections shouldbe treated aggressively with antibiotics. However,fever and leukocytosis are common in patientswith alcoholic hepatitis, even without infection.

CorticosteroidsCorticosteroids have been studied extensively forthe treatment of alcoholic hepatitis. Although manyof the initial controlled trials did not show a benefit,further analysis suggested that patients withencephalopathy and more severe disease may ben-efit. Therefore, follow-up studies focused on therole of corticosteroids in the treatment of patientswho had a discriminant function greater than 32 orhepatic encephalopathy (or both) but not renalfailure, infection, gastrointestinal tract bleeding,or, in some studies, severe diabetes mellitus. Somestudies and meta-analyses that used these criteriashowed that corticosteroid therapy had a survivalbenefit for patients with a discriminant functiongreater than 32 or hepatic encephalopathy (orboth). Currently, the use of corticosteroid therapyfor alcoholic hepatitis varies among experiencedhepatologists.

Other Treatment OptionsAlcohol induces oxidative stress in the liver,resulting in an imbalance between oxidants andantioxidants. To decrease oxygen consumption by

332 Liver

the liver, investigators have studied the role ofpropylthiouracil in treating alcoholic hepatitis.Although a randomized controlled trial showedclinical benefit, the results of follow-up studieshave been inconclusive. Also, because of theinherent hepatotoxicity of propylthiouracil, thisdrug remains experimental. Another putativeantifibrotic agent, colchicine, has been evaluated intreating alcoholic hepatitis. Although an initialtrial suggested that the drug was beneficial fortreating alcoholic liver cirrhosis, no clinical ben-efit has been demonstrated for hepatitis. Otherhepatoprotective compounds, such as S-adenosyl-L-methionine and phosphatidylcholine, may havea small beneficial effect but are not widely usedoutside of research protocols. The results of a recentstudy have suggested that pentoxifylline, aninhibitor of tumor necrosis factor, is of clinical ben-efit. Because the toxicity profile of pentoxifylline islow, its use for alcoholic hepatitis is prevalent; how-ever, confirmatory studies are needed. Ongoingclinical studies are focusing on several differentanticytokine and antioxidant therapies.

• Liver biopsy should be considered if the causeof hepatitis is questioned and specific treat-ments for alcoholic hepatitis other than sup-portive care are contemplated.

• Histologic features cannot reliably differentiatealcoholic hepatitis from nonalcoholic steato-hepatitis. The distinction is made best on thebasis of the clinical history and the pattern ofaminotransferase (ALT and AST) increase.

• For most patients, the treatment of alcoholichepatitis includes abstinence, supportive care,and management of malnutrition, infection,and complications of portal hypertension.

ALCOHOLIC CIRRHOSIS

Clinical PresentationA 56-year-old salesman is admitted to the hospitalwith a 2-hour history of hematemesis and dizzi-ness. His history is remarkable for symptoms offatigue and lower extremity edema. His wife notesthat his memory has been poor recently and he hasbeen a “social drinker” for many years, having afew martinis with clients and during business trips.

Physical examination findings are notable fororthostasis, temporal wasting, spider angiomas onthe chest, and bilateral pitting edema of the lowerextremities. His skin is jaundiced, and a liver edge ispalpable and firm. The tip of the spleen is palpableupon inspiration. Rectal examination shows melenain the vault. There is prominent asterixis.

This patient has the clinical features typical ofalcoholic cirrhosis. The diagnosis and treatmentare discussed below.

History and Physical ExaminationFor persons with a clinical history of marked andprolonged alcohol abuse, only about 20% eventu-ally develop liver cirrhosis. The presence or absenceof symptoms is due largely to the presence orabsence of liver decompensation. Patients withcirrhosis and compensated liver function who areabstinent may have minimal symptoms. The symp-toms of patients with liver decompensation reflectthe severity of portal hypertension, malnutrition,and degree of synthetic liver dysfunction andinclude nonspecific fatigue, weakness, andanorexia. More specific symptoms are related tothe presence of specific complications of cirrhosisand portal hypertension, including gastrointestinaltract bleeding, ascites, encephalopathy, renalfailure, and hepatocellular carcinoma. Physicalexamination may demonstrate stigmata of chronicliver disease (spider angiomas and palmar ery-thema), complications of portal hypertension(ascites, splenomegaly, asterixis, and pedal edema),excess estrogen (gynecomastia and hypogonadism),and systemic alcohol toxicity (peripheral neu-ropathy, dementia, and Dupuytren’s contracture).

Laboratory and Radiographic FeaturesProminent laboratory abnormalities include anincrease in prothrombin time and bilirubin and adecrease in albumin, which are reflected in anincreased Child-Pugh score. Imaging findings maybe suggestive of cirrhosis and ensuing portal hyper-tension, as indicated by heterogeneous liver echo-texture, splenomegaly, collateralization, and asciteson ultrasonography and colloid shift to spleen andbone marrow on liver and spleen scanning.Dynamic triple-phase computed tomography mayshow changes in liver contour, splenomegaly, col-lateralization, or ascites. Patients are at risk for


hepatocellular carcinoma and should be evaluatedbiannually with ultrasonography and the serumα-fetoprotein test, particularly patients who havehad recent clinical decompensation.

Histologic FeaturesTraditionally, alcoholic cirrhosis is classified as amicronodular cirrhosis (Fig. 2). However, in manycases, larger nodules also develop, leading to mixedmicro-macronodular cirrhosis. The earliest collagendeposition occurs around the terminal hepaticvenules, and progression to pericentral fibrosis por-tends irreversible architectural changes. Hemo-siderin deposition is often prominent. In patientswith alcoholic cirrhosis who continue to drinkactively, many of the aforementioned histologic fea-tures of alcoholic hepatitis also are present. Patientsare at risk for hepatocellular carcinoma, particularlythose with coexisting chronic viral hepatitis.

Prognosis and Treatment A good prognosis depends on the absence of liverdecompensation and complications of portalhypertension and the ability to maintain absti-nence. The prognosis for patients with cirrhosiswho are well compensated and able to maintainabstinence is reasonably good, with a 5-year sur-vival rate greater than 80%. Even for patients withdecompensation, the 5-year survival rate withabstinence is greater than 50%. However, patientswho continue to drink have a much worse prog-nosis, with a 5-year survival rate less than 30%.

The only established effective treatment foralcoholic cirrhosis is liver transplantation.Currently, alcoholic liver disease is the secondmost common indication for liver transplantationin adults in the United States. However, fewer than20% of patients with end-stage alcoholic liver dis-ease have transplantation. Despite perceptions tothe contrary, patients who have liver transplanta-tion for alcoholic liver disease have survival ratesafter transplantation comparable to those ofpatients who have transplantation for other indica-tions. Indeed, the risk of cellular rejection is lowerfor persons undergoing transplantation for alcoholicliver disease than for those with other conditions.

A major issue in maintaining excellent out-come for this population focuses on identifyingcandidates with a low risk of recidivism after trans-

plantation. Alcohol relapse after transplantationvaries among centers and is difficult to quantifyaccurately, but it is probably about 15% to 30%.Although detecting surreptitious alcohol use aftertransplantation is often difficult, the low incidenceof graft loss from recurrent alcoholic liver diseasesuggests that most patients who return to drinkingafter transplantation do not drink to the point ofdamaging the graft. However, it must be consid-ered that alcohol abuse after liver transplantationcan cause rapid development of cirrhosis in thegraft, interfere with compliance in taking immuno-suppressive medications, and alter the perceptionof the general public of liver transplantation, thusadversely affecting potential organ donors.Therefore, selecting patients who are appropriatefor liver transplantation requires a team involvinga hepatologist, surgeon, addiction specialist, psy-chiatrist, and social worker. Currently, manytransplant centers require 6 months of abstinenceand appropriate addiction treatment before per-forming a liver transplant. Appropriate family andsocial support is also important. Generally, patientswith active alcoholic hepatitis are not candidatesfor liver transplantation because they have notbeen abstinent for 6 months and they have highperioperative mortality. Also, many of thesepatients will have evidence of marked clinicalimprovement after 6 months of abstinence, therebydelaying or obviating liver transplantation.

• Alcohol is a cause of micronodular cirrhosis,but often mixed micro-macronodular cirrhosisis observed histologically.

• The only curative treatment for alcoholic cir-rhosis is liver transplantation; however, onlya small proportion of patients undergo trans-plantation, partly because of their inability tomaintain prolonged abstinence.

• Transplantation outcomes for alcoholic liverdisease are comparable to those for mostother indications.

SPECIAL CLINICAL SITUATIONS

Alcohol and Hepatitis C The increase in prevalence of HCV infection amongalcoholic persons is 10 times that of the population

334 Liver

at large. Although this may be explained partly byincreased risk factors of HCV transmission in somealcoholic patients, a proportion of these patientshave no identifiable risk factors. Also, patients withHCV infection who are alcoholic or drink in excesshave more aggressive disease, often at a youngerage, and have a worse prognosis than patients whohave only HCV infection. Furthermore, HCV RNAlevels are higher, the histologic features of the liverappear more progressive, and the response totherapy for hepatitis C is worse for patients withHCV infection who drink alcohol in excess.Whether alcohol synergistically damages the liverin patients with HCV infection or, alternatively,facilitates progression of HCV disease throughincreased susceptibility by host immune factors isunclear. Patients with alcoholic liver disease whohave concomitant viral hepatitis have a risk almostfivefold greater for the development of hepato-cellular carcinoma than patients without con-comitant viral hepatitis. Identifying which processis causative in liver injury in patients with bothconditions can be difficult; however, assessing liverbiopsy findings and aminotransferase patterns canbe useful because both of these are different inHCV infection and alcoholic liver injury. Becausethe alcohol threshold necessary to exacerbate thecourse of HCV infection has not been determined,patients with HCV infection should be advisedagainst alcohol use.

Alcohol and AcetaminophenAlcoholic persons are at increased risk for aceta-minophen-induced hepatotoxicity. As little as 2.5to 3 g per day of acetaminophen may result in pro-nounced toxicity. The reason for this is that bothalcohol and acetaminophen are metabolized inpart by cytochrome P-450 2E1, an enzyme inMEOS. With the induction of this enzyme byalcohol, a greater proportion of acetaminophen

is metabolized by this pathway than by the sulfa-tion and glucuronidation detoxification pathways.The byproduct of acetaminophen metabolism byCYP2E1 is N-acetyl-p-benzoquinoneimine, whichis toxic to the liver. The accumulation of this com-pound in conjunction with diminished antioxi-dant defenses in the liver (glutathione) lowers thethreshold of acetaminophen toxicity in alcoholicpersons. Thus, in this population, the clinical pre-sentation of acetaminophen toxicity is distinctfrom that of alcoholic hepatitis. Aminotransferaselevels are markedly increased, often more than1,000 U/L, which is distinctly unusual for alco-holic hepatitis.

RECOMMENDED READINGDegos F. Hepatitis C and alcohol. J Hepatol. 1999;31

Suppl 1:113-8.Imperiale TF, McCullough AJ. Do corticosteroids

reduce mortality from alcoholic hepatitis? Ameta-analysis of the randomized trials. AnnIntern Med. 1990;113:299-307.

Maddrey WC, Boitnott JK, Bedine MS, Weber FL Jr,Mezey E, White RI Jr. Corticosteroid therapyof alcoholic hepatitis. Gastroenterology.1978;75:193-9.

McCullough AJ, O’Connor JF. Alcoholic liver dis-ease: proposed recommendations for theAmerican College of Gastroenterology. Am JGastroenterol. 1998;93:2022-36.

Menon KV, Gores GJ, Shah VH. Pathogenesis, diag-nosis, and treatment of alcoholic liver disease.Mayo Clin Proc. 2001;76:1021-9.

Morgan MY. The treatment of alcoholic hepatitis.Alcohol Alcohol. 1996;31:117-34.

Seeff LB, Cuccherini BA, Zimmerman HJ, AdlerE, Benjamin SB. Acetaminophen hepatotoxi-city in alcoholics: a therapeutic misadventure.Ann Intern Med. 1986;104:399-404.


Vascular diseases of the liver can be divided intodisorders of hepatic inflow (ie, diseases of theportal venous and hepatic arterial inflow) and dis-orders of hepatic venous outflow (Table 1).

For a better understanding of the vascular dis-eases of the liver, a concise review of the vascularanatomy of the liver is important.

ANATOMY OF THE SPLANCHNICCIRCULATIONThe splanchnic circulation comprises the arterialblood supply and venous drainage of the entiregastrointestinal tract from the distal esophagus tothe mid rectum and includes the spleen, pancreas,gallbladder, and liver. The arterial system isderived from the celiac artery and the superiorand inferior mesenteric arteries. The superiormesenteric artery arises from the abdominal aortajust distal to the celiac trunk. For most of its course,this artery lies in the mesentery, with the ileocolicartery being the terminal branch. The superiormesenteric artery gives off three sets of branches:1) several small branches to the pancreas and duo-denum before entering the mesentery, 2) threelarge arteries that supply the proximal two-thirdsof the large bowel, and 3) during its course throughthe mesenteric root, an arcade of arterial branches

to supply the jejunum and ileum. The branchesgiven off in the mesentery form a row of arterialarcades that terminate in the arteriae rectae of thewall of the small bowel. The venous drainage hasa similar pattern, with the venae rectae forming avenous arcade that drains the small bowel. Thesejoin with the ileocolic, middle colic, and right colicveins to form the superior mesenteric vein.

The arterial routes of the splanchnic circulation,except for the hepatic artery, eventually emptyinto the portal venous system through the splenicvein and superior and inferior mesenteric veins.

337

CHAPTER 25

Vascular Diseases of the Liver

Patrick S. Kamath, MD

Abbreviations: HHT, hereditary hemorrhagic telangiectasia; TIPS, transjugular intrahepatic portosystemic shunt.

Table 1. Vascular Diseases of the Liver

Disorders of portal venous inflowAcute mesenteric/portal venous thrombosisChronic mesenteric/portal venous

thrombosisDisorders of hepatic arterial inflow

Hepatic artery thrombosisHepatic arteriovenous fistulaIschemic hepatitis

Disorders of hepatic venous outflowVeno-occlusive diseaseBudd-Chiari syndrome

The portal vein, formed by the convergence of thesplenic and superior mesenteric veins, constitutesthe primary blood supply to the liver. After per-fusing the liver, venous blood reenters the sys-temic circulation through the hepatic veins andsuprahepatic inferior vena cava.

Reminiscent of the lungs, the liver receives adual blood supply. The two sources are portalvenous blood (derived from the mesenteric venouscirculation, including the digestive tract, spleen,and pancreas) and hepatic arterial blood (usuallyfrom the celiac artery). Total hepatic blood flowconstitutes nearly 30% of total cardiac output. Theportal venous inflow comprises 65% to 75% ofhepatic blood inflow, and the hepatic artery sup-plies approximately 25% to 35%. However, approx-imately 50% of the liver’s oxygen requirements isdelivered by hepatic arterial blood.

The hepatic vascular bed is a low-pressuresystem that can maintain a large volume of blood.Sinusoidal blood collects within terminal hepaticvenules and reenters the systemic circulationthrough the hepatic veins and inferior vena cava.The caudate lobe of the liver maintains a separatedrainage of blood, accounting for the compensatoryhypertrophy of this lobe often observed in chronicliver disease associated with outflow obstruction ofthe major hepatic veins (Budd-Chiari syndrome).

DISORDERS OF PORTAL VENOUSINFLOW

Acute Mesenteric Venous ThrombosisAcute mesenteric venous thrombosis is discussedin Chapter 12, “Vascular Disorders of theGastrointestinal Tract.”

Chronic Mesenteric Venous ThrombosisChronic mesenteric venous thrombosis is very dif-ferent from the acute form. Lack of visualization ofthe superior mesenteric vein on computed tomog-raphy or duplex ultrasonography in conjunctionwith extensive collateral venous drainage suggeststhe diagnosis of chronic mesenteric venous throm-bosis. Angiography can help confirm the diagnosisbut rarely is required. Although many patientspresent with nonspecific symptoms of severalmonths’ duration, an increasing proportion are

being identified through imaging studies per-formed for unrelated reasons. These patients maybe asymptomatic with respect to the primary event;hence, the time of the thrombotic event often isunclear. Patients in whom the thrombosis extends toinvolve the portal vein or splenic vein (or both) mayexperience portal hypertension and esophagealvarices, with the attendant complications of varicealbleeding. They also may have splenomegaly andhypersplenism. Chronic mesenteric venousthrombosis should be differentiated from isolatedsplenic vein thrombosis due to pancreatic neo-plasm or chronic pancreatitis. The latter, oftencalled sinistral (or left-sided) portal hypertension, isrelated to a local effect on the splenic vein and isnot usually a disorder of the thrombotic pathway.Thus, anticoagulation for sinistral portal hyper-tension is not warranted.

Patients with isolated chronic mesentericvenous thrombosis often remain asymptomaticbecause of extensive collateral venous drainage.Occasionally, some patients have gastrointestinaltract hemorrhage, and the use of pharmacologicagents such as propranolol is recommended toprevent variceal bleeding. Endoscopic therapy isused both to control active bleeding and to pre-vent rebleeding. Surgical intervention, such as por-tosystemic shunts, is restricted to patients whosebleeding cannot be controlled with conservativemeasures and who have a patent central vein forshunting. When thrombosis is extensive and nolarge vein is suitable for anastomosis, noncon-ventional shunts may be considered, such as anas-tomosing a large collateral vein with a systemicvein. Also, gastroesophageal devascularizationmay be considered. For patients with thrombophilia,anticoagulation may be initiated after the risk ofbleeding has been decreased with surgical stents.

DISORDERS OF HEPATIC ARTERIALINFLOW

Hepatic Artery ThrombosisAside from patients who have had liver trans-plantation, the prevalence of hepatic artery throm-bosis is not certain. Hepatic artery thrombosis isthe cause of considerable morbidity and mortalityin approximately 7% of adults and in perhaps as

338 Liver

many as 40% of pediatric patients undergoingorthotopic liver transplantation. The problem ismore extensive in the pediatric age group becauseof the small caliber of the vessels involved and theprobable greater fluctuation in the concentration ofcoagulation factors.

Several risk factors are related to the develop-ment of hepatic artery thrombosis in adults, withtechnical aspects of the arterial anastomosis beingthe most important risk of early thrombosis. Otherrisk factors are older recipients, clotting abnor-malities, tobacco use, and infections by agents suchas cytomegalovirus. Late hepatic artery throm-bosis has been associated with chronic rejectionand blood-type–incompatible grafts.

The clinical presentation of hepatic arterythrombosis can vary from a mild increase in theserum level of aminotransferases to fulminanthepatic necrosis. The acute presentation, or earlyhepatic artery thrombosis, has a more severe clin-ical course, and late hepatic artery thrombosis gen-erally has a milder course. There is no agreementabout the time point between early and late hepaticartery thrombosis. However, the later that hepaticartery thrombosis develops after liver transplan-tation, the less severe the clinical presentation.

Early hepatic artery thrombosis results in mas-sive injury to hepatocytes and bile duct epithelialcells. Ischemic damage to the bile ducts leads todehiscence of the biliary anastomosis, bile ductstrictures, and intrahepatic abscesses. Thus, bil-iary sepsis may be a common presentation of earlyhepatic artery thrombosis. However, one-third ofepisodes of early hepatic artery thrombosis maybe asymptomatic.

Hepatic artery thrombosis can be diagnosedwith duplex ultrasonography, but visceral angiog-raphy may be necessary to confirm the diagnosis.When hepatic artery thrombosis is detected earlyafter liver transplantation, surgical correction usu-ally is recommended.

Hepatic Artery AneurysmAlthough aneurysm of the hepatic artery (Fig. 1) israre, it is the fourth most common abdominalaneurysm. The aneurysms are usually small (<2cm in diameter) and involve the main hepaticartery. Causes of hepatic artery aneurysms includeatherosclerotic vascular diseases, infections such as

bacterial endocarditis, liver abscess, syphilis, tuber-culosis, and trauma from liver biopsy. The hepaticartery commonly is involved in polyarteritisnodosa, manifested as symptoms related to throm-bosis, rupture, or dissection of the aneurysm.

Most hepatic artery aneurysms are discoveredincidentally. If symptomatic, the first and domi-nating symptom is severe abdominal pain, sug-gesting dissection. Vague abdominal pain in thesepatients is related to compression of surroundingstructures. Rupture of a hepatic artery aneurysmcauses massive intraperitoneal hemorrhage orhemobilia manifested as abdominal pain, jaundice,and gastrointestinal tract bleeding. Hemobilia isusually a manifestation of an intrahepatic aneurysm.

Ruptured hepatic artery aneurysms are asso-ciated with a high mortality rate because, for mostpatients, the diagnosis is made only after rupture.The treatment for a ruptured aneurysm is emer-gency surgery or embolization of the aneurysm inpatients who are not optimal candidates forsurgery. For asymptomatic patients, treatment isdebated. Clearly, aneurysms larger than 2 cm indiameter require treatment, and those between 1and 2 cm in diameter may be treated. Foraneurysms less than 1 cm in diameter, follow-up at6-month intervals is reasonable. Treatmentincludes interventional radiologic approaches toembolize and occlude the aneurysm, ligation atsurgery, or excision and reconstruction of theaneurysm. Intrahepatic aneurysms may be treatedalso with liver resection.

Vascular Diseases of the Liver 339

Fig. 1. Selective hepatic angiogram showing ananeurysm (arrow) of the intrahepatic portion of thehepatic artery.

Hepatic Artery–Portal Vein FistulasHepatic artery–portal vein fistulas are rare causesof portal hypertension. Although fistulas withinthe liver usually are iatrogenic (the result of liverbiopsy), they may be related to neoplasms or hered-itary hemorrhagic telangiectasia (HHT) (Osler-Weber-Rendu disease). A hepatic artery–portal veinfistula should be suspected in a patient who hasacute onset of abdominal pain and ascites, espe-cially if associated with gastrointestinal tractbleeding, because rupture of the artery into theportal vein causes an acute increase in portalpressure. These fistulas may be accompanied byabdominal bruits in most patients. If untreated,a fistula may result in cardiac failure. The besttreatment is embolization and occlusion of thefistula. The usual result is complete cure of theportal hypertension.

Ischemic HepatitisIn patients with congestive heart failure, portalblood flow is minimal; thus, the major contribu-tion of oxygenated blood to the liver is from thehepatic artery. In congestive heart failure, episodesof hypotension, as associated with arrhythmias,diminish hepatic arterial input, resulting inischemic necrosis of the liver. Typical manifesta-tions of ischemic hepatitis are a rapid increase over24 to 48 hours in the serum level of aminotrans-ferases (aspartate aminotransferase and alanineaminotransferase), to several thousand units, some-times more than 10,000 U/L. This value rapidlyreturns to less than 100 U/L in 5 to 7 days. No spe-cific treatment is required other than control of thecardiac condition. Extensive ischemic hepatitismay result in fulminant liver failure.

Other causes of ischemic hepatitis are hypo-volemic shock of any cause and obstructive sleepapnea. Postoperative patients particularly areprone to ischemic liver damage because they oftenhave coexisting arterial hypotension and hypox-emia. Furthermore, hepatic blood flow may bereduced by anesthetic agents. This problem may beof particular concern in patients who have openheart surgery. The typical histologic finding inthese patients with ischemic liver damage is cen-trilobular hepatic necrosis (zone 3). The severityof liver damage is related to the duration ofhypotension and the degree of hypoxemia.

Hereditary Hemorrhagic TelangiectasiaThe criteria for diagnosing HHT include a historyof epistaxis, a family history of HHT, mucocuta-neous telangiectasia, and visceral involvement,which can be hepatic, gastrointestinal, neurologic,or pulmonary. Three of these criteria are requiredfor the diagnosis of HHT.

The vascular malformation within the liver ofpatients with HHT results in fistulae 1) betweenthe hepatic artery and hepatic vein (the mostcommon abnormality), 2) between the hepaticartery and portal vein, or 3) between the portalvein and hepatic vein (or a combination of thesethree). Previously, the most common liver diseasein patients with HHT was transfusion-relatedhepatitis, but currently the most common mani-festation is high-output cardiac failure as a resultof hepatic artery-to-hepatic vein fistulae. Additionalabnormalities include recurrent cholangitis dueto the diversion of hepatic arterial blood, either tothe hepatic vein or portal vein; portal hypertensionas a result of hepatic artery-to-portal vein fistulae,or nodular regenerative hyperplasia; and hepaticencephalopathy because of fistulae between theportal vein and hepatic vein. Embolization of thesefistulae is not recommended because of the highrisk of liver abscesses. This likely is related to mostpatients having some degree of portal vein-to-hepatic vein fistula, and once the hepatic artery isoccluded, there is neither hepatic arterial nor portalvenous blood to the involved segment of the liver.Liver transplantation has been performed to treatHHT and is best indicated for patients who haverecurrent cholangitis.

DISORDERS OF HEPATIC VENOUSOUTFLOW

Veno-occlusive DiseaseVeno-occlusive disease, or sinusoidal obstructionsyndrome, results from occlusion of the centraland sublobular hepatic veins. In the UnitedStates, the most common cause of veno-occlu-sive disease is preconditioning for bone marrowtransplantation. Other causes include radiationto the liver, antineoplastic drugs such as aza-thioprine and 6-mercaptopurine, and ingestion ofalkaloids containing pyrrolizidine.

340 Liver

The following discussion is predominantly onveno-occlusive disease of the liver in relation topatients undergoing bone marrow transplantation.For these patients, the incidence of veno-occlusivedisease is approximately 50%, with a mortality rateof 20% to 40%. Early changes are related to hem-orrhage in zone 3, as seen in liver biopsy speci-mens. Diagnostic criteria include subendothelialthickening of at least one terminal hepatic venulein association with luminal narrowing.

The pathogenesis of veno-occlusive disease isnot well defined. It probably results from a com-bination of endothelial injury and activation ofclotting mechanisms. It has been hypothesized thatthe depletion of glutathione in zone 3 hepatocytesmakes them more prone to damage by antineo-plastic agents such as busulfan. The resulting accu-mulation of oxygen free radicals leads to zone 3necrosis and subsequent endothelial damage.

Clinical criteria for diagnosing veno-occlusivedisease are either the Seattle or the Baltimore cri-teria. The Baltimore criteria reflect more severeveno-occlusive disease and require a weight gainof more than 5% in association with hepatomegalyand ascites. The Seattle criteria require a bilirubinlevel greater than 2 mg/dL in association withhepatomegaly, right upper quadrant pain, and aweight gain of more than 2%. According to boththe Baltimore and Seattle criteria, the criteria shouldbe met within 3 weeks after bone marrow trans-plantation. Bilirubin levels greater than 15 mg/dLare associated with poor outcome.

Treatment of veno-occlusive disease is dif-ficult. Prophylactic strategies have includedadministration of heparin, prostaglandins, orursodeoxycholic acid. Because of the lack of largerandomized studies, it is difficult to determine thebenefits of any of these therapies. The treatmentof established veno-occlusive disease also isdebated. Tissue plasminogen activator and heparinhave been administered to patients at high risk fordying of complications of veno-occlusive disease.If there is no response to thrombolytic therapy,either a surgical shunt or transjugular intrahep-atic portosystemic shunt (TIPS) may be used.Although the initial results with portosystemicshunts may be beneficial, the long-term outcomefor patients who require shunts is poor becausethese patients usually have severe veno-occlusive

disease and intervention generally delays but doesnot prevent a fatal outcome.

Budd-Chiari SyndromeBudd-Chiari syndrome is a heterogenous groupof disorders characterized by obstruction of hepaticvenous outflow. The site of obstruction may be atthe level of small hepatic venules, large hepaticveins, or the inferior vena cava. Obstruction at thelevel of the central and sublobular hepatic venulestraditionally has been called hepatic veno-occlusivedisease. In countries such as Japan and India,obstruction of the inferior vena cava by membranesor webs or segmental narrowing of the vessel alsomay obstruct hepatic venous outflow.

EtiologyThe main causes predisposing to Budd-Chiari syn-drome include a hypercoagulable state, tumorinvasion of the hepatic venous outflow tract, andmiscellaneous causes. In some patients, no clearetiologic factor is discernible. Increasingly, thepresence of multiple underlying disorders thatcause Budd-Chiari syndrome is being recognized.

Hematologic abnormalities are detected in upto 87.5% of patients with Budd-Chiari syndrome,particularly myeloproliferative disorders. Overtpolycythemia vera is the most common disorderencountered. Erythropoietin levels and demon-stration of JAK mutations have been used to diag-nose occult primary myeloproliferative disordersin patients otherwise thought to have idiopathicBudd-Chiari syndrome. Both fulminant andchronic forms of the syndrome have been describedin patients with nocturnal hemoglobinuria.Increasingly, inherited deficiencies of protein C,protein S, and antithrombin are being reported inassociation with the syndrome. Protein C and pro-tein S are vitamin K-dependent proteins that aresynthesized in the liver and endothelial cells andact as fibrinolytic agents. Antithrombin is a vit-amin K-independent protease inhibitor that issynthesized in the liver and neutralizes activatedclotting factors by forming a complex with a spe-cific serine protease. Deficiencies of any of theseproteins can result in both arterial and venousthrombosis, but the correlation between proteinC and protein S levels and the risk of thrombosis isnot precise. In several patients with Budd-Chiari


syndrome, protein C deficiency has been associ-ated also with an underlying myeloproliferativedisorder. The diagnosis is sometimes difficultbecause these proteins can become deficient inpatients with impaired liver function. Normallevels of factors II and VII in patients with Budd-Chiari syndrome or deficiencies of protein C andprotein S in family members may point toward aninherited disorder.

The factor V Leiden mutation has beenreported in approximately 23% of patients withBudd-Chiari syndrome. This mutation, causedby the substitution of an arginine residue by glu-tamine at position 506 in the factor V molecule,abolishes a protein C cleavage site in factor Vand prolongs the thrombogenic effect of factorV activation. The term resistance to activated pro-tein C is another name for this condition.Although about 2.9% to 6% of people of Europeandescent are believed to be heterozygous for thismutation, the relative risk of thrombosis isthought to be low. In addition to being a solecause of Budd-Chiari syndrome, this mutationhas been reported to occur also in combinationwith other prothrombotic disorders.

Clinical ManifestationsThe underlying pathophysiologic abnormality inBudd-Chiari syndrome is an increase in sinusoidalpressure caused by obstruction of hepatic venousoutflow. This results in hypoxic damage to thehepatocytes and increased portal venous pressure.Continued obstruction of hepatic venous outflowleads to further hepatic necrosis, ultimatelyresulting in cirrhosis. Because the caudate lobedrains directly into the inferior vena cava, it is notdamaged. In fact, the caudate lobe hypertrophies,and this may, to various degrees, obstruct the infe-rior vena cava. The clinical presentation of Budd-Chiari syndrome depends on the extent andrapidity of hepatic vein occlusion and whether col-lateral circulation has developed to decompressthe liver. Vague abdominal pain is the mostcommon presenting symptom of the syndrome,and ascites is the most common abnormality notedon physical examination. Some patients withhepatic vein thrombosis are asymptomatic, pre-sumably as a result of occlusion of only one or twohepatic veins and decompression of the portal

system through the development of large intra-hepatic and portosystemic collaterals.

InvestigationsDoppler ultrasonography of the liver is the initialinvestigation of choice in patients with suspectedBudd-Chiari syndrome. It demonstrates thehepatic veins, splenic vein, portal vein, and inferiorvena cava. Necrotic areas are seen better with con-trast-enhanced computed tomography and mag-netic resonance imaging.

Venography or liver biopsy is not necessaryafter Budd-Chiari syndrome has been diagnosedwith noninvasive studies. However, if the clinicalsuspicion of Budd-Chiari syndrome is high, espe-cially in a patient with a fulminant or acute pre-sentation, contrast venography may be necessaryif radiologic imaging is not diagnostic. The char-acteristic appearance of the hepatic veins in Budd-Chiari syndrome is that of a spider’s web with anextensive collateral circulation. Also, the inferiorvena cava may be compressed by an enlargedcaudate lobe or it may show thrombus.

In addition to establishing the diagnosis ofhepatic vein thrombosis, it is important to identify anunderlying cause to determine management strate-gies. An appropriate hematologic work-up shouldbe performed to exclude the various disorders out-lined in Table 2, including demonstrating JAK2mutations to determine if the patient has a myelo-proliferative disorder.

ManagementThe aims of treatment of Budd-Chiari syndrome areto relieve obstruction of the hepatic outflow tract,to identify and treat the underlying cause, and torelieve symptoms. Treatment options include med-ical management, surgical portosystemic shunting,TIPS, and liver transplantation (Table 3). Althoughmost patients who have Budd-Chiari syndrome canbe offered some form of definitive therapy, those inwhom the syndrome is due to extensive malignantdisease are offered only palliative care because ofthe extremely poor prognosis of this condition.

Medical management consists of diuretictherapy for the treatment of ascites, anticoagulationto prevent extension of venous thrombosis, andtreatment of the underlying cause. Approximately20% of patients can be managed with this approach.

342 Liver

If this approach fails, intervention to enhancehepatic venous outflow is the next step. Ideal can-didates for angioplasty include patients with infe-rior vena cava webs or focal hepatic vein stenosis;thrombolytic therapy is used infrequently but isadministered best by direct infusion to the site ofthe clot.

The aim of portosystemic shunting is to usethe portal vein to provide a venous outflow tract forthe liver to reverse hepatic necrosis and to preventchronic sequelae of hepatic venous outflowobstruction. The optimal candidates for surgicalshunting are patients with a subacute presenta-tion in whom ascites is not severe, liver functionis preserved, and the disease course is smoldering.Patients with acute Budd-Chiari syndrome mayneed a less invasive procedure, such as TIPS.Covered stents have increased the long-termpatency of TIPS, making this the preferred methodof performing a portosystemic shunt in mostpatients. Indications for liver transplantation inBudd-Chiari syndrome include 1) end-stagechronic liver disease, 2) fulminant liver failure, and3) deterioration of liver function in spite of por-tosystemic shunting.


Table 2. Causes of Budd-Chiari Syndrome

Common causesHypercoagulable states

InheritedFactor V Leiden mutationProthrombin mutation

AcquiredMyeloproliferative disordersCancerPregnancyOral contraceptive use

Uncommon causesHypercoagulable states

InheritedAntithrombin deficiencyProtein C deficiencyProtein S deficiency

AcquiredParoxysmal nocturnal hemoglobinuria

Antiphospholipid syndromeTumor invasion

Hepatocellular carcinomaRenal cell carcinomaAdrenal carcinoma

MiscellaneousAspergillosisBehçet’s syndromeInferior vena cava websTraumaInflammatory bowel diseaseDacarbazine therapy

Idiopathic

From Menon KV, Shah V, Kamath PS. The Budd-Chiarisyndrome. N Engl J Med. 2004;350:578-85. Used withpermission.

RECOMMENDED READINGGanguli SC, Ramzan NN, McKusick MA, Andrews JC,

Phyliky RL, Kamath PS. Budd-Chiari syndromein patients with hematological disease: a thera-peutic challenge. Hepatology. 1998;27:1157-61.

Garcia-Tsao G. Liver involvement in hereditaryhemorrhagic telangiectasia (HHT). J Hepatol.2007 Mar;46:499-507. Epub 2007 Jan 2.

Kumar S, DeLeve LD, Kamath PS, Tefferi A.Hepatic veno-occlusive disease (sinusoidalobstruction syndrome) after hematopoieticstem cell transplantation. Mayo Clin Proc.2003; 78:589-98.

Kumar S, Sarr MG, Kamath PS. Mesenteric venousthrombosis. N Engl J Med. 2001;345:1683-8.

Menon KV, Shah V, Kamath PS. The Budd-Chiarisyndrome. N Engl J Med. 2004;350:578-85.

Murad SD, Kamath PS. Liver transplantation for

Budd-Chiari syndrome: when is it really nec-essary? Liver Transpl. 2008; 14:133-5.

Norton ID, Andrews JC, Kamath PS. Managementof ectopic varices. Hepatology. 1998;28:1154-8.

Pasha SF, Gloviczki P, Stanson AW, Kamath PS.Splanchnic artery aneurysms. Mayo Clin Proc.2007;82:472-9.

Pastacaldi S, Teixeira R, Montalto P, Rolles K,Burroughs AK. Hepatic artery thrombosis afterorthotopic liver transplantation: a review of non-surgical causes. Liver Transpl. 2001;7:75-81.

Seeto RK, Fenn B, Rockey DC. Ischemic hepatitis:clinical presentation and pathogenesis. Am JMed. 2000;109:109-13.

Sieders E, Peeters PM, TenVergert FM, de Jong KP,Porte RJ, Zwaveling JH, et al. Early vascularcomplications after pediatric liver transplan-tation. Liver Transpl. 2000;6:326-32.

344 Liver

Table 3. Management of Budd-Chiari Syndrome (BCS)

Treatment Indication Advantages Disadvantages

Thrombolytic therapy Acute thrombosis Reverses hepatic necrosis Risk of bleedingNo long-term sequelae Limited success

Angioplasty with and IVC webs Averts need for surgery High rate of restenosiswithout stenting IVC stenosis or shunt occlusion

Focal hepatic vein stenosis

TIPS Possible bridge to trans- Low mortality High rate of shuntplantation in fulminant Useful even with com- stenosisBCS pression of IVC by Extended stents may

Acute BCS caudate lobe interfere with liverSubacute BCS if porta- transplantationcaval pressure gradient <10 mm Hg or occluded IVC

Surgical shunt Subacute BCS Definitive procedure for Risk of procedure-Portacaval pressure many patients related deathgradient >10 mm Hg Low rate of shunt dys- Limited applicability

function with portacaval shunt

Liver transplantation Fulminant BCS Reverses liver disease Risk of procedure-Presence of cirrhosis May reverse underlying related deathFailure of portosys- thrombophilia Need for long-termtemic shunt immunosuppression

IVC, inferior vena cava; TIPS, transjugular intrahepatic portosystemic shunt.From Menon KV, Shah V, Kamath PS. The Budd-Chiari syndrome. N Engl J Med. 2004;350:578-85. Used with permission.

Portal hypertensive bleeding encompasses aspectrum of conditions that include esophageal,gastric, and ectopic varices and portal hypertensivegastrointestinal enteropathy. Esophageal varicealhemorrhage occurs through a combination ofincreased portal pressure and local factors within thevarix itself. Management of esophageal varicesincludes primary prophylaxis of variceal hemor-rhage, treatment of actively bleeding varices, andprevention of variceal rebleeding (secondary pro-phylaxis). Primary prophylaxis is pharmacologictherapy with β-blockers or variceal band ligation ifβ-blocker therapy fails or the therapy is not toler-ated by the patient. Active bleeding is best treatedendoscopically. Either pharmacologic or endoscopictherapy is appropriate for secondary prophylaxis.Surgical shunts or transjugular intrahepatic por-tosystemic shunts (TIPSs) are second-line therapy.

PATHOGENESIS OF PORTALHYPERTENSIONAn increase in the hepatic venous pressure gra-dient—the difference between the wedged hepaticvenous pressure and the free hepatic venous pres-sure—of at least 10 mm Hg is required for the

development of esophageal varices, and a hepaticvenous pressure gradient of 12 mm Hg or more isrequired for the rupture of esophageal varices.

In cirrhosis, portal hypertension occursthrough an increase in resistance to portal venousoutflow early in the disease process. This increaseis due to mechanical factors related to the distor-tion of liver architecture. However, approximately30% of the increase in resistance occurs throughpotentially reversible vascular factors and is thetarget of pharmacotherapy. Portal hypertensionis maintained through the development of a sys-temic hyperdynamic circulation and peripheralvasodilation. The hyperdynamic circulation ischaracterized in the splanchnic circulation byvasodilation and increased flow at the level of thesplanchnic arterioles. This leads to increased portalvenous inflow and exacerbates the existing portalhypertension. Drugs such as octreotide and vaso-pressin reduce splanchnic hyperemia and portalvenous inflow. Portal hypertension results in thedevelopment of collateral circulation, which maydecrease portal pressure. In addition to gastric andintestinal vascular ectasia, esophageal and gastricvarices and portal hypertensive gastropathy occurin patients who have portal hypertension.

345

CHAPTER 26

Portal Hypertension-RelatedBleeding

Patrick S. Kamath, MD

Abbreviation: TIPS, transjugular intrahepatic portosystemic shunt.

ESOPHAGEAL VARICES

PathogenesisLocal factors that determine the risk of hemorrhagefrom esophageal varices include the radius of thevarix, the thickness of the varix wall, and the pres-sure gradient between the varix and the esophageallumen. Factors that determine the severity ofbleeding are the degree of liver dysfunction anddefective coagulation, portal pressure, and the sizeof the rent in the varix. Endoscopic sclerotherapyor band ligation attempts to decrease flow throughthe varix by inducing thrombosis and, ultimately,obliteration of varices.

TherapyThe current recommendations for treatment aresummarized in Table 1.

Primary ProphylaxisAll patients with cirrhosis should have endoscopyto screen for the presence and size of esophagealvarices. In approximately 25% of patients, varicesbleed, usually within the ensuing 2 years. Forpatients with large varices and advanced liver dis-ease, the risk of hemorrhage can be as high as 75%.Thus, prophylactic therapy is indicated for patientswith large varices (>5 mm in diameter). The pres-ence or absence of high-risk endoscopic signs suchas red wales does not influence the decision to ini-tiate therapy. Prophylactic treatment may be con-sidered also for patients with Child-Pugh class Cstatus and small varices. If no varices are detectedat endoscopy, the procedure should be repeatedin 2 or 3 years.

The established primary prophylaxis is treat-ment with nonselective β-adrenergic blockingagents (β-blockers) such as propranolol andnadolol or with endoscopic variceal ligation. It isimportant to use only nonselective agents ratherthan β1-selective agents. β1-Blockade decreasescardiac output and splanchnic blood flow, whereasthe additional β2-blockade allows unopposed α1-adrenergic constriction in the splanchnic circu-lation. This decreases portal blood flow and, con-sequently, portal pressure. Therapy is started at alow dose, with slow upward titration of the doseuntil a resting pulse rate of 55 to 60 beats/minuteis achieved or hypotension develops (systolic blood

pressure <90 mm Hg). A long-acting preparationof propranolol administered as a single dose in theearly evening is preferred. This allows adequateβ-blockade at night, when the risk of bleeding ishigh. With the long-acting preparation adminis-tered in the evening, β-blockade is less during thefollowing day, thus decreasing the side effect offatigue. At the same time, the risk of bleeding islower during the day, and the lesser degree of β-blockade is not deleterious to the patient. Wheneverpossible, the hemodynamic response to pharma-cologic therapy should be measured. The goal oftherapy is to decrease the hepatic venous pressuregradient to less than 12 mm Hg or by 20% whencompared with baseline. Nitrates have no place inprimary prophylaxis, either when administeredas single agents or in combination with β-blockers.

Although sclerotherapy is no longer used as aform of primary prophylaxis, variceal band ligationmay be an alternative approach to primary pro-phylaxis because of the lower rate of esophagealulceration and more effective obliteration ofvariceal structures than with sclerotherapy.Currently, esophageal variceal ligation is recom-mended for patients who have contraindicationsto therapy with β-blockers, who have not had adecrease in the hepatic vein pressure gradient, orwho have experienced side effects from β-blockertherapy. A meta-analysis of all the studies thatcompared β-blockers and endoscopic variceal li-gation showed no significant difference in efficacyor mortality risk between the two treatments. Thus,patient preference may be the factor that bestdetermines which therapy is used.

Control of Esophageal VaricealHemorrhageActive esophageal variceal bleeding is managedbest with endoscopic means, preferably varicealband ligation. After gastrointestinal tract bleedinghas been detected in patients with cirrhosis,immediate initiation of pharmacologic therapyis beneficial—even before endoscopy has demon-strated variceal bleeding. Pharmacologic therapyis continued for up to 5 days after endoscopic treat-ment of varices to reduce the risk of immediaterebleeding. Vasopressin is a potent splanchnicvasoconstrictor that decreases portal venousinflow, thereby decreasing portal pressure, but it

346 Liver

is seldom used. Nitroglycerin is used in conjunctionwith vasopressin to further decrease portal pressureand reduce the ischemic side effects of vasopressin,which are pronounced and limit therapy in up to30% of patients. Octreotide, a long-acting syntheticsomatostatin analogue, is the pharmacologic agentmost commonly used. It appears to decrease portalpressure by inhibiting the release of glucagon andthe ensuing postprandial hyperemia and by havinga direct vasoconstrictive effect on splanchnic arte-riolar smooth muscle. Although octreotide is saferthan vasopressin, the efficacy of the compoundhas not been well established. However, a recentmeta-analysis has suggested that octreotide is ben-eficial for acute bleeding. Octreotide is administeredas an initial bolus of 50 μg, followed by an infu-sion at 50 μg/hour for 5 days in conjunction withendoscopic variceal band ligation.

For treating active bleeding, the use of sur-gical shunts and TIPS is limited to patients withrefractory bleeding or immediate rebleeding aftertwo separate unsuccessful attempts at endoscopicintervention performed within 24 hours.Frequently, TIPS is preferred to surgical inter-vention, particularly in patients with Child-Pughclass B or C status. Also, gastric varices can beobliterated concomitantly with TIPS through theinjection of gel foam or coils into the gastro-esophageal collateral vessels. A surgical shuntshould be considered for patients with Child-Pughclass A status and patients for whom continuedmedical surveillance will be unlikely, because TIPSrequires close ultrasonographic follow-up of theshunt to evaluate for restenosis. The type of sur-gical shunt used depends on institutional expertise

and the patient’s potential as a candidate for livertransplantation.

Supportive and resuscitative care includesairway protection, volume replacement, treatmentof coagulopathy, and vigorous surveillance andtreatment of concomitant infection. Maintenanceof a hematocrit of 25% to 30% is appropriatebecause aggressive transfusion of blood productsmay precipitate further bleeding by increasingportal pressure. Antibiotic prophylaxis for 7 dayswith norfloxacin is recommended to decrease theincidence of bacteremia and spontaneous bacte-rial peritonitis, which commonly accompanyvariceal hemorrhage. Antibiotic therapy is prob-ably the most important reason why the mortalityrate of variceal bleeding has decreased from 50%to about 20%. Lactulose therapy may be institutedto prevent and treat hepatic encephalopathy.

Secondary ProphylaxisSecondary prophylaxis involves therapies to pre-vent rebleeding in patients who have already bledfrom esophageal varices. Intervention is essentialbecause up to 80% of patients who have alreadybled from varices will bleed again within 2 years.Treatments include pharmacotherapy with β-blockers, either alone or in combination with oralnitrates, endoscopic sclerotherapy or band liga-tion, TIPS, and surgical shunts. Either β-blockers orendoscopic therapy is an appropriate treatmentoption for patients who did not receive β-blockersfor primary prophylaxis. Band ligation is the pre-ferred endoscopic treatment because of the lowerincidence of esophageal ulceration and ease oftherapy. After acute bleeding has been controlled

Portal Hypertension-Related Bleeding 347

Table 1. Recommendations for Treatment of Esophageal Variceal Bleeding

Second-lineFirst-line therapy therapy Other

Primary prophylaxis β-Blockers or endoscopic variceal ligation

Control of bleeding Endoscopy + pharmacologic TIPS treatment

Secondary prophylaxis Endoscopy + β-blockers TIPS Liver transplantation

TIPS, transjugular intrahepatic portosystemic shunt.

with variceal ligation, the next ligation session isscheduled in approximately 10 to 14 days.Subsequent sessions are scheduled every 3 or 4weeks. Varices usually can be obliterated over sev-eral weekly sessions. Combination therapy of bandligation and β-blockers may be preferable to eithertreatment used alone.

For patients in whom primary prophylaxiswith β-blockers failed, the addition of oral nitratesto the pharmacologic regimen may furtherdecrease portal pressure and the incidence ofrebleeding. However, concern remains about thelong-term effects of oral nitrates on patient sur-vival; therefore, endoscopic obliteration in com-bination with β-blockers is currently the preferredapproach for secondary prophylaxis for patients inwhom primary prophylaxis with β-blockers failed.TIPS should be used only in patients with recurrentor refractory bleeding despite pharmacologic andendoscopic therapies, especially if they are candi-dates for liver transplantation. There is hesitationin recommending widespread use of TIPS becauseof the risk of worsening encephalopathy, the poten-tial for liver deterioration, and uncertain effectson long-term survival, particularly of patients withadvanced dysfunction of liver synthesis. Surgicalshunts are recommended for patients with excellentliver synthetic function who are unlikely to requireliver transplantation in the near future. All appro-priate patients who have variceal hemorrhageshould be evaluated for liver transplantation.

PORTAL HYPERTENSIVE LESIONS INTHE STOMACHGastric lesions that cause portal hypertensivebleeding include gastric varices, portal hyperten-sive gastropathy, and gastric vascular ectasia.Because no evidence-based management strate-gies are available for gastric sources of portalhypertensive bleeding, therapy often requires anempiric approach.

Gastric VaricesThe most common type of gastric varices isesophageal varices that extend into the cardia ofthe stomach and are readily treated with endo-scopic techniques such as sclerotherapy or bandligation. Varices in the fundus of the stomach,

either as an extension of esophageal varices or asisolated gastric fundal varices, are the mostcommon source of gastric variceal bleeding. Recentdata have suggested that the frequency of bleedingfrom gastric varices is similar to that from largeesophageal varices. Gastric varices are more likelyto be found in patients who have had bleedingfrom esophageal varices than in those who havenot had bleeding. The risk of bleeding from gas-tric varices is related to the size of the varix, liverfunction as determined by the Child-Pugh class,and the presence of red signs on the varix.

β-Blockers are recommended for primary pro-phylaxis of gastric varices. Acute gastric varicealbleeding is treated best endoscopically with injec-tion of cyanoacrylate glue. Currently, however,this is not readily available in the United States.Other options include sclerotherapy withethanolamine oleate or thrombin, but the successrate has varied. Gastric variceal ligation should belimited to varices in the cardia.

Although pharmacologic therapy, for example,β-blockers, may be used to prevent gastric varicealrebleeding, no studies support this practice. Ourpolicy generally has been to consider a portosys-temic shunt for the prevention of rebleeding inpatients with documented gastric fundal varicealbleeding if variceal obturation with cyanoacrylateis not possible. TIPS is reserved for patients withpoor liver function; patients with Child-Pugh classA status should be considered for portosystemicshunt surgery.

Portal Hypertensive GastropathyPortal hypertensive gastropathy is a source of gas-trointestinal tract bleeding in some patients withcirrhosis and portal hypertension. The elementarylesion is a mosaic-like pattern of the gastric mucosa,but this is not specific. The more specific lesion isthe red marking, which may be either a red pointlesion less than 1 mm in diameter or a cherry redspot more than 2 mm in diameter. The presenceof a mosaic-like pattern alone designates mild portalhypertensive gastropathy, whereas red markingssuperimposed on the mosaic pattern suggest severeportal hypertensive gastropathy. Lesions of portalhypertensive gastropathy tend to be more commonin the proximal stomach, in patients with advancedstages of liver disease as noted by the Child-Pugh

348 Liver

classification, in patients with esophageal varices,and in patients who previously have hadesophageal variceal therapy. These lesions also aremore common in patients with gastric varices.Approximately 3% of patients with severe gas-tropathy may present with acute upper gastroin-testinal tract bleeding, and approximately 15%have chronic bleeding.

Anecdotally, acute bleeding from portal hyper-tensive gastropathy has been treated, with a highsuccess rate, with vasoactive drugs such as vaso-pressin, somatostatin, and octreotide. Portosystemicshunts should be considered as rescue treatmentsif vasoactive drug therapy fails. Patients who pre-sent with chronic bleeding may be treated withiron supplementation and β-blockers. For thesepatients, treatment should be continued indefi-nitely or until liver transplantation. Portosystemicshunts may be used as rescue treatment in patientswho continue to be transfusion-dependent in spiteof adequate β-blocker therapy.

Gastric Vascular EctasiaA less common gastric mucosal lesion in portalhypertension is gastric vascular ectasia. In contrastto portal hypertensive gastropathy, gastric vascularectasia is characterized by red markings in theabsence of a mosaic-like pattern. The red markingsmay be arranged in linear aggregates in the antrum,

for which the term gastric antral vascular ectasia (orwatermelon stomach) is used (Fig. 1). If the redmarkings do not have a typical linear arrangement,the lesion is designated diffuse gastric vascular ectasia.The diffuse lesions also may involve the proximalstomach, sometimes making differentiation fromsevere portal hypertensive gastropathy difficult.When the diagnosis is uncertain, gastric mucosalbiopsy, which usually is safe, may be helpful. Liverdysfunction seems to be necessary for the patho-genesis of vascular ectasia because these lesionsmay resolve with liver transplantation.

Treatment of gastric vascular ectasia is diffi-cult. Some patients may be managed only withiron replacement therapy. β-Blockers do not seemto be effective for these lesions, although controlledtrials have not been conducted because of the rarityof gastric vascular ectasia. Thermoablative thera-pies, such as argon plasma coagulation or lasertherapy, may be tried, but the results, especiallyin the diffuse form, are poor. Antrectomy is effective,but the mortality and morbidity related to the oper-ation can be substantial for patients with cirrhosis.These lesions do not respond to portosystemicshunts, either surgical or TIPS, but occasionallymay respond to estrogen-progesterone combi-nations. We typically prescribe a combination ofmestranol, 50 mg, with norethindrone, 1 mg daily,for these patients.

Portal Hypertension-Related Bleeding 349

Fig. 1. A and B, Gastric antral vascular ectasia. Note the linear aggregates of red markings in the antrum andthe absence of an underlying mosaic-like pattern.

BA

RECOMMENDED READINGBosch J, Abraldes JG, Groszmann R. Current man-

agement of portal hypertension. J Hepatol.2003:38 Suppl 1:S54-68.

Boyer TD. Primary prophylaxis for varicealbleeding: are we there yet? Gastroenterology.2005;128:1120-2.

D’Amico G, Morabito A. Noninvasive markers ofesophageal varices: another round, not thelast. Hepatology. 2004;39:30-4.

de Franchis R. Evolving consensus in portal hyper-tension: report of the Baveno IV consensusworkshop in methodology of diagnosis andtherapy in portal hypertension. J Hepatol.2005;43:167-76.

Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W,Practice Guidelines Committee of the AmericanAssociation for the Study of Liver Diseases,Practice Parameters Committee of the AmericanCollege of Gastroenterology. Prevention and

management of gastroesophageal varices andvariceal hemorrhage in cirrhosis. Hepatology.2007;46:922-38.

Groszmann RJ, Wongcharatrawee S. The hepaticvenous pressure gradient: anything worthdoing should be done right. Hepatology.2004;39:280-2.

Kamath PS, Lacerda M, Ahlquist DA, McKusickMA, Andrews JC, Nagorney DA. Gastricmucosal responses to intrahepatic portosys-temic shunting in patients with cirrhosis.Gastroenterology. 2000;118:905-11.

Primignani M, Carpinelli L, Preatoni P, Battaglia G,Carta A, Prada A, et al. Natural history of portalhypertensive gastropathy in patients with livercirrhosis: the New Italian Endoscopic Club forthe study and treatment of esophageal varices(NIEC). Gastroenterology. 2000;119:181-7.

Shah V. Cellular and molecular basis of portalhypertension. Clin Liver Dis. 2001;5:629-44.

350 Liver

The portal hypertension and hepatic synthetic dys-function of cirrhosis cause three main complicationsas liver disease progresses: variceal bleeding, ascites,and hepatic encephalopathy.

ASCITESAscites is the most common major complicationand occurs in about 50% of patients with com-pensated cirrhosis in 10 years. The development ofascites denotes the transition from compensatedto decompensated cirrhosis. It causes increasedmorbidity from abdominal distention and increasedmortality from complications such as spontaneousbacterial peritonitis and renal dysfunction, with amedian survival of 2 to 5 years.

Pathogenesis of AscitesThe hemodynamic changes in chronic liver diseaseand portal hypertension are much better under-stood now and have led to a greater understandingof the pathogenesis of ascites. Increased hydrostaticpressure within hepatic sinusoids occurs fromstructural changes due to architectural distortion

by fibrosis and nodular regeneration (about 70% ofthe increase), with 20% to 30% of the increase fromincreased intrahepatic vascular tone due to vasoac-tive factors. This increase in hepatic sinusoidalpressure appears to be the primary event that leadsto splanchnic (and eventually systemic) vasodi-lation, which in turn causes underfilling of thevascular compartment and baroreceptor-mediatedstimulation of the renin-angiotensin-aldosteronesystem, the sympathetic nervous system, andantidiuretic hormone (ADH). The net result is theretention of renal sodium and water. Nitric oxideappears to be an important factor in the regulationof intrahepatic vascular tone. Considerable evi-dence now shows that, in cirrhosis, the decreasedavailability of hepatic vascular nitric oxide impairsrelaxation and increases hepatic perfusion pressure.However, the splanchnic and systemic vasculatureexhibit marked overproduction of endothelial nitricoxide, which results in arterial vasodilatation and,subsequently, tachycardia, increased cardiacoutput, and decreased arterial pressure.

The hepatic sinusoids are a very low-pressurehydrostatic system, compared with other capillary

351

CHAPTER 27

Ascites, Hepatorenal Syndrome, and Encephalopathy

J. Eileen Hay, MB,ChB

Abbreviations: AASLD, American Association for the Study of Liver Disease; ADH, antidiuretic hormone; CTP, Child-Turcotte-Pugh; MELD, model for end-stage liver disease; PMN, polymorphonuclear neutrophil; PSE, portosystemicencephalopathy; SAAG, serum-ascites albumin gradient; TIPS, transjugular intrahepatic portosystemic shunt.

beds (vascular inflow is partly portal venous bloodthat has a hydrostatic pressure only slightly higherthan systemic venous pressure). In addition, withalbumin freely diffusible across hepatocytes andendothelial membranes, the oncotic pressure gra-dient within the sinusoids is very low and unableto counteract any increase in hydrostatic pressure.Thus, with portal hypertension, increased pressurein the hepatic sinusoids and splanchnic vesselscauses fluid to move into the tissues and to “weep”from the surface of the liver as ascites. A minimumportal pressure gradient of 10 to 12 mm Hg is nec-essary for ascites to develop.

Evaluation of Patients With AscitesThe first step in the diagnostic approach topatients with ascites is to determine the cause(Table 1). In 85% of cases, ascites is due to cir-rhosis and the diagnosis is usually obvious. About15% of cases are due to nonhepatic causes (malig-nancy, tuberculosis, constrictive pericarditis,right-sided heart failure, myxedema, and renalcauses), and these must be differentiated fromcirrhosis and treated appropriately.

Diagnostic paracentesis is mandatory andshould be performed in all patients who presentwith new-onset ascites, who are hospitalized withcirrhotic ascites, or who have cirrhotic ascites andany deterioration in liver function, with fever,worsening encephalopathy, or renal failure. In allcases, ascitic fluid analysis should include a cellcount, both total nucleated and polymorphonuclearneutrophil (PMN) count, and bacterial culture bybedside inoculation of blood culture bottles. Asciticfluid protein and albumin levels are measured

simultaneously with the serum albumin level tocalculate the serum-ascites albumin gradient(SAAG). The albumin concentration in ascitic fluidis inversely proportional to portal pressure. Inmost cases, a SAAG value greater than 1.1 g/dLconfirms, with more than 95% accuracy, the clinicalsuspicion of portal hypertensive-related ascites.The other main cause for a high SAAG value is portalhypertension related to cardiac failure, but in thiscase the total protein concentration in the ascites isusually more than 2.5 g/dL (the value is <2.5 g/dLin cirrhosis-related portal hypertension) (Table 2).

Other tests should be performed only if a specificdiagnosis is suspected clinically. Lactate dehydro-genase and glucose levels should be determined ifsecondary peritonitis is suspected. Other tests toconsider are amylase (>1,000 U/L suggests pan-creatic ascites), cytology (at least at the initial tap),and triglycerides (if the ascitic fluid is cloudy; theconcentration is <100 mg/dL in cirrhosis).Mycobacterial culture should be performed onlyif tuberculosis is strongly suspected. Other asciticfluid indices, for example, lactate and pH, generallyhave been found to offer little or no additionalinformation. Gram staining is rarely ever positive.

352 Liver

Table 1. Diagnostic and TherapeuticAlgorithm for Patients With Ascites

• Does the patient have cirrhosis?• If yes, are there any other complicaitons of cir-

rhosis—spontaneous bacterial peritonitis,portal vein thrombosis, active liver disease,malignancy

• Prognostic factors for therapy—urinarysodium excretion, renal function

• Consideraton of therapeutic options

Table 2. Ascitic Protein and Serum-AscitesAlbumin Gradient (SAAG)

SAAG, g/dL

≥1.1 <1.1

Totalprotein,g/dL

<2.5 Cirrhosis Nephrotic Acute liver syndrome

failure Myxedema≥2.5 Congestive Peritoneal

heart failure carcinomatosisConstrictive Tuberculous

pericarditis peritonitisBudd-Chiari Pancreatic

syndrome ascitesVenoocclusive Chylous ascites

disease

In addition to spontaneous bacterial peritonitis,other cirrhotic complications that may increaseascites, including malignancy, portal or hepaticvenous thrombosis, or active liver disease, shouldbe sought by performing liver tests or imagingstudies. Renal function and renal sodium excretionshould be assessed because they are clinical pre-dictors of a therapeutic response: patients withnormal blood urea nitrogen and creatinine levelsand sodium excretion of more than 10 mEq/L(without taking diuretics) generally are very sensi-tive to sodium restriction and diuretic therapy.Patients with marked sodium retention, particularlythose with abnormal urea and creatinine levels,require much higher doses of diuretics.

Therapy of Cirrhotic Ascites

Sodium Restriction and Diuretic TherapyCirrhotic ascites is perpetuated by renal retentionof sodium and water. Therefore, treatment mustproduce a negative sodium balance, sequentiallyby a low sodium diet and then by diuretics. Onlyabout 10% of patients with cirrhotic ascites havea response to salt restriction alone (with or withoutbed rest). With the initiation of spironolactonetherapy, the ascites will be controlled in 65% ofpatients and in another 25% with the addition of aloop diuretic. Thus, 90% of patients can be managed,often as outpatients, by the sequential introduc-tion of sodium restriction, generally to 2 g/day (88mEq), and then diuretic therapy. Spironolactone,an aldosterone antagonist, is an effective diureticin most patients with nonazotemic cirrhosis withascites and is more effective than furosemide forsingle-agent therapy. Spironolactone is given atan initial dose of 100 mg/day, with 100-mg/dayincrements as appropriate to 400 mg/day, accordingto the clinical response and side effects, particu-larly hyperkalemia. Furosemide is usually startedat a dose of 40 mg/day in combination withspironolactone and increased in 40-mg/day incre-ments to 160 mg/day until the desired effect isachieved or side effects occur. Diuretic therapy istitrated to achieve optimal weight loss withoutcomplications, that is, 1) deterioration in renalfunction, 2) excessive weight loss in relation toascites or edema, 3) orthostatic symptoms, 4)encephalopathy, or 5) dilutional hyponatremia.

Generally, a weight loss of 0.5 to 1.0 kg/day isoptimal to avoid side effects because only 750 to900 mL/day of fluid can be mobilized from theabdomen into the general circulation. After theascites is mobilized by whatever method, diuretictherapy should be adjusted to keep the patient freeof ascites.

Therapeutic ParacentesisIn randomized studies of patients with tense ascitesand avid sodium retention, repeated large-volumeparacentesis (with intravenous infusions ofalbumin), compared with diuretic therapy, is 1)more effective in eliminating ascites; 2) associatedwith a lower incidence of hyponatremia (5% vs30%), renal impairment (3.4% vs 27%), and hepaticencephalopathy (10.2% vs 29%); and 3) associatedwith shorter hospital stay and reduced cost oftherapy without any differences in survival, spon-taneous bacterial peritonitis, or causes of death.

Intravenous infusion of 25% albumin is animportant measure in patients with cirrhosis andtense ascites who are treated with repeated large-volume or total paracentesis, and it has been shownin randomized trials to prevent hyponatremia andrenal impairment. Partial mobilization of ascites,for example, 5 L (at least in edematous patients),can be removed safely without the infusion ofalbumin. However, complete mobilization ofascites without plasma volume expansion causesa deterioration in systemic hemodynamics in allpatients, and 20% will develop hyponatremia orrenal dysfunction that is frequently irreversible.Generally, 8 to 10 g of albumin is infused for every1 L of ascites that is removed. Dextran 70 or polyge-line is less effective than albumin as a plasma volumeexpander. Terlipressin may be an alternative toalbumin, but it is not available in the United States.

Refractory Ascites

DefinitionRefractory ascites is due to avid renal retention ofsodium, which occurs with decompensated cir-rhosis and in 10% to 20% of patients. Clinically,ascites is considered to be refractory when a patienthas adequate sodium restriction and receives max-imal tolerable doses of diuretics without desiredweight loss (24-hour urine sodium is less than

Ascites, Hepatorenal Syndrome, and Encephalopathy 353

intake). Patients who have not had a response to400 mg/day of spironolactone and 160 mg/dayof furosemide generally have ascites refractory tomedical therapy.

Reversible factors that contribute to sodiumretention should be identified and corrected(Table 3).

Treatment OptionsThe long-term prognosis after the development ofrefractory ascites is dismal, with a high 1-yearmortality rate (>70%). Liver transplantation is theonly therapeutic modality capable of improvingboth the quality of life and patient survival.Consequently, liver transplantation should alwaysbe considered in an otherwise acceptable candi-date with ascites that cannot be controlled withadequate sodium restriction and diuretic therapy.

Other therapeutic options for refractory ascitesare repeated therapeutic (large-volume or total)paracentesis or a transjugular intrahepatic por-tosystemic shunt (TIPS). According to the treatmentrecommendations of the American Association forthe Study of Liver Diseases (AASLD), first-linetherapy for refractory ascites is therapeutic para-centesis, and TIPS is reserved for patients whocannot tolerate paracentesis or who require therapyfor more than 2 or 3 months. TIPS is relatively con-traindicated for patients who are older than 70years, have cardiac dysfunction, or have a Child-Turcotte-Pugh (CTP) score higher than 11.

TIPS in Refractory AscitesThe hemodynamic effects of TIPS have been welldescribed. Increased cardiac output and a furtherdecrease in systemic vascular resistance occurstemporarily for 1 to 3 months, but increased uri-nary excretion of sodium starts from 7 to 28 daysafter the procedure, together with a decrease inplasma renin activity and aldosterone levels.

Five randomized trials with 330 patients haveshown that TIPS is effective in reducing ascitesin about 50% of patients at the expense of a 20%higher incidence of encephalopathy. Overallpatient survival is unchanged by TIPS, but insome patients, liver function deteriorates signif-icantly; mortality increases for patients with apre-TIPS CTP score higher than 11 or a model forend-stage liver disease (MELD) score greater than

14. Survival after TIPS for refractory ascites is lessthan survival after TIPS for variceal bleeding.Predictors of worsening encephalopathy are ageolder than 65 years, pre-TIPS encephalopathy, ora TIPS gradient less than 5 mm Hg. Covered stentsmay prove to require less revision and to be asso-ciated with better survival and less encephalopathy.However, the optimal hepatic venous pressure gra-dient for control of ascites is not known.

Hepatic HydrothoraxThis is a complication of cirrhotic ascites in 5% to10% of patients. Management is the same as forascites, with sodium restriction and diuretictherapy. TIPS is effective in some patients.Thoracentesis is recommended only if the diag-nosis is uncertain, if infection is strongly suspected,or for symptomatic relief. Chest tubes and pleu-rodesis should be avoided.

SPONTANEOUS BACTERIALPERITONITISSpontaneous bacterial peritonitis is an infection ofascitic fluid without a known source of infection.It occurs in 10% to 30% of patients with cirrhoticascites and is frequently recurrent (70% recurrencerate in 1 year). In the past, the infecting organismswere normal bowel flora, with 70% of cases causedby gram-negative bacilli (especially Escherichiacoli and Klebsiella) and 30% by gram-positive cocci(mainly Streptococcus and Enterococcus species),with anaerobes being very uncommon (<5% ofcases). Most infections (92% of cases) are causedby a single organism, and 8% are polymicrobial.

354 Liver

Table 3. Reversible Factors for Lack ofResponse to Diuretic Therapy inCirrhotic Ascites

Inadequate sodium restrictionInappropriate use of diureticsNephrotoxic medicationsSpontaneous bacterial peritonitisPortal or hepatic vein thrombosisUntreated active liver disease

The era of norfloxacin prophylaxis has causedepidemiologic changes in bacterial flora, with ashift toward more gram-positive infections. It gen-erally is considered that intestinal bacterial translo-cation is the main pathogenic mechanism leadingto spontaneous bacterial peritonitis, by which bac-teria move from the gut to mesenteric lymph nodesand, hence, into the systemic circulation beforeinfecting the peritoneal cavity.

The clinical presentation and severity ofspontaneous bacterial peritonitis are extremelyvariable, from chills, fever, and abdominal painto no symptoms. The diagnosis may be missedunless paracentesis is performed. Often, the clin-ical picture consists of a single feature, such asfever, abdominal pain, hypothermia, hypotension,diarrhea, lack of response to diuretics, deteriorationin renal function, or worsening portosystemicencephalopathy (PSE). Patients with cirrhosis whoare at particular risk for spontaneous bacterial peri-tonitis are those with advanced cirrhotic-stage liverdisease, a low concentration of ascitic fluid protein

(<1 g/dL), or gastrointestinal tract hemorrhage.Renal impairment is common in these patients anda clinical predictor of poor outcome.

DiagnosisAscitic fluid analysis is essential for the diagnosisof spontaneous bacterial peritonitis (Fig. 1).However, the clinical presentation of this condi-tion can be subtle and easily missed clinically.Diagnostic paracentesis should be performed inall patients hospitalized with cirrhotic ascites andin patients who present with signs of infection,encephalopathy, deterioration of renal function,or gastrointestinal tract bleeding. Bedside inoc-ulation of blood culture bottles with 10 mL ofascitic fluid is essential for confirming that theculture is positive.

A presumptive diagnosis of spontaneous bac-terial peritonitis is made with the finding of morethan 250 PMNs per milliliter of ascitic fluid in apatient with cirrhotic ascites and no secondary sourceof infection. Confirmation is by positive bacterial


Fig. 1. Diagnostic algorithm for spontaneous bacterial peritonitis. CNNA, culture-negative neutrocytic ascites;PMN, polymorphonuclear neutrophil; SBP, spontaneous bacterial peritonitis.

>250 PMNs in ascitic fluid

Bacterial culture

Postitive (not contaminant) Negative

? Antibiotics

Yes No

Other cause for PMNs

Specific diagnosis CNNAPresumed SBPSBP

Yes No

culture of the ascitic fluid; if the bacterial culture isnegative, the diagnosis of culture-negative neu-trocytic ascites is made if there is no recent his-tory of antibiotic therapy and no other cause ofneutrocytic ascites (cholecystitis, pancreatitis,hemorrhage, recent abdominal surgery, or carci-nomatosis). Patients with culture-negative neutro-cytic ascites have clinical and biochemical featuresidentical to those with microbiologically confirmedspontaneous bacterial peritonitis, and they areassumed to represent cases of spontaneous bacte-rial peritonitis missed with current culture tech-niques. Bacterascites is defined by ascitic fluid thatcontains fewer than 250 PMNs per milliliter and apositive bacterial culture. It is usually the transientresidence of bacteria in the ascitic fluid. Patients withbacterascites generally have less severe liver diseasethan those with spontaneous bacterial peritonitis.Although bacterascites may progress to spontaneousbacterial peritonitis, it usually clears spontaneouslywithout antibiotic therapy.

Treatment

Antibiotic TherapyWith the finding of a high PMN count in asciticfluid, empiric therapy for spontaneous bacterialperitonitis must be instituted and directed againstaerobic enteric bacteria. Cefotaxime, 1 to 2 g intra-venously every 8 hours, is the first choice of antibi-otic for empiric therapy and is started when thePMN count in ascitic fluid is more than 250cells/mL. This therapy is more effective (86%)than the combination of ampicillin-aminoglyco-side and is associated with less renal toxicity inpatients with cirrhosis. Aztreonam is less effectivebecause of its lack of activity against gram-positiveorganisms; parenteral amoxicillin-clavulanic acidhas been found to be clinically effective in morethan 80% of cases. After the organism has beenidentified, antibiotic therapy can be adjustedaccordingly. Uncomplicated spontaneous bac-terial peritonitis may be treated effectively in anoutpatient setting with oral ofloxacin, a muchless expensive alternative.

Epidemiologic changes in bacterial infectionshave occurred with norfloxacin prophylaxis, andthese must be considered for each patient. Arecent study of bacterial infections in patients

with cirrhosis who receive norfloxacin prophy-laxis has shown that currently 53% of infectionsare due to gram-positive cocci, especially in noso-comial infections, with invasive procedures, andin patients in intensive care units. In 50% ofpatients receiving norfloxacin prophylaxis andin 16% of those not receiving prophylaxis, spon-taneous bacterial peritonitis is caused by quinolone-resistant gram-negative bacilli; these organismsoften are resistant also to trimethoprim-sul-famethoxazole therapy.

Albumin InfusionsAbout 30% of patients with cirrhosis who havespontaneous bacterial peritonitis develop renalimpairment. This is an important predictor of mor-tality for these patients. A randomized trial hasshown that albumin infusion on day 1 (1.5 g ofalbumin per kilogram) and day 3 (1 g/kg) preventedthis complication. Albumin infusions are now therecommended therapy for spontaneous bacterialperitonitis. However, because of the expense ofalbumin, some physicians argue that perhaps thisapproach should be reserved for patients who arevery ill, especially those with a bilirubin level morethan 4 mg/dL and an increased creatinine level.

Repeat ParacentesisThe usefulness of diagnostic paracentesis after 48hours of antibiotic therapy to observe the PMNresponse is debated. Repeat paracentesis “providesevidence of a satisfactory response to antibiotictherapy and is mandatory” for patients who donot show clinical improvement. If the PMN countis greater than baseline, the patient must be reex-amined carefully for secondary sites of infection,including repeated abdominal radiography forfree air, computed tomography of the abdomen,and surgical consultation.

Differential DiagnosisThe main differential diagnosis for spontaneousbacterial peritonitis is secondary bacterial peritonitis,most commonly from a perforated viscus or, inabout 15% of cases, an abscess. The operative mor-tality rate for patients with cirrhosis who haveinfected ascites is about 85%, but is 100% for patientswith secondary bacterial peritonitis without surgery.Spontaneous bacterial peritonitis and secondary

356 Liver

bacterial peritonitis cannot be distinguished on thebasis of clinical features. Factors that suggest asecondary infection are a high leukocyte count inascites (>10,000/mL), multiple or unusual organ-isms (fungi or anaerobes) in ascitic fluid culture,ascitic fluid glucose level less than 50 mg/dL, lac-tate dehydrogenase level greater than the upper limitof normal for serum, and an increase in the numberof PMNs in ascitic fluid despite antibiotic therapy.

Primary ProphylaxisA disadvantage of antibiotic prophylaxis is theemergence of drug-resistant bacteria, as mentionedabove. Episodes of bleeding in patients with Child’sclass C cirrhosis or recurrent bleeding in patientswith cirrhosis are factors that predict infection andspontaneous bacterial peritonitis, which are oftensevere. Oral or systemic antibodies should be givenfor 7 days to all patients with cirrhosis who have anepisode of gastrointestinal tract bleeding. Whetherantibiotic prophylaxis is beneficial in patients withcirrhosis who have very low levels of protein (<10g/L) in the ascitic fluid is debated, and no con-sensus exists.

Secondary ProphylaxisBecause spontaneous bacterial peritonitis has a 1-year recurrence rate of more than 50%, prophy-lactic measures are warranted for patients whohave survived an episode of this condition. Rarelycan the underlying liver disease be treated (exceptliver transplantation), and only occasionally doesdiuretic therapy completely clear the ascites.Treatment with norfloxacin, 400 mg/day, can beused to eliminate the gram-negative flora (andreduce gram-negative infection), but it will notaffect the other aerobic and anaerobic flora.Trimethoprim-sulfamethoxazole and ciprofloxacinhave also been effective for prophylaxis.

BacterascitesWhen diagnostic paracentesis shows no evidenceof neutrocytic ascites (<250 PMNs/mL) but theascitic fluid culture grows organisms that are notcontaminants, the diagnosis is bacterascites.Paracentesis should be repeated and a decisionabout therapy based on the following: 1) PMNs>250/mL, treat as spontaneous bacterial peritonitis;2) PMNs <250/mL but again culture-positive, treat

with antibiotics; and 3) PMNs <250/mL but neg-ative cultures, no treatment.

RENAL FUNCTION ABNORMALITIESIN CIRRHOSIS AND HEPATORENALSYNDROMEThe hemodynamic changes in chronic liver diseaseincreasingly worsen with the progression fromcompensated cirrhosis, to ascites, to hepatorenalsyndrome. Mild to severe sodium retention by thekidneys, mainly due to increased tubular resorptionof sodium, is a key factor in the pathogenesis ofascites formation in cirrhosis. This occurs with acti-vation of the renin-angiotensin-aldosterone systemand the sympathetic nervous system and increasedsecretion of ADH. As liver disease worsens, theactivity of the renin-angiotensin-aldosterone andsympathetic systems and the secretion of ADHincreases. The increased secretion of ADH eventu-ally impairs water excretion, resulting in increasedtotal body water and dilutional hyponatremia.Splanchnic vasodilatation also continues to increaseas liver disease worsens. As ascites progresses totype 2 hepatorenal syndrome, extrasplanchnicvasoconstriction begins to affect blood flow to thekidneys, brain, liver, and adrenals, hence the renalvasoconstriction of hepatorenal syndrome. Cardiacoutput increases in cirrhosis, but eventually as hemo-dynamic changes worsen, cardiac output decreases,further worsening the blood flow to extrasplanchnicorgans and potentiating renal impairment.

HyponatremiaThe severity of water retention varies considerablyfrom patient to patient, but dilutional hypona-tremia occurs in about 30% of hospitalized patientswith cirrhotic ascites. However, symptoms are rareuntil sodium levels are very low (<110-115 mEq/L).Treatment is fluid restriction. Rarely do patientsneed infusion of hypertonic (3%) saline, and this isadministered only to patients with severe, sympto-matic hyponatremia. The aquaretic drug conivaptan,an antagonist of arginine vasopressin V1A and V2receptors, is available in intravenous form in theUnited States, but it has not been evaluated sys-tematically in cirrhosis. It may be considered forthe patients hospitalized with cirrhosis and severerefractory hyponatremia.


Major Diagnostic Criteria for HepatorenalSyndromeThe International Ascites Club has proposedthat the presence of all the following major cri-teria is necessary for the diagnosis of hepa-torenal syndrome:

• Chronic or acute liver disease with advancedliver failure and portal hypertension

• Low glomerular filtration rate, with theserum creatinine level greater than 1.5mg/dL or creatinine clearance less than 40mL/minute

• Absence of shock, bacterial infection, nephro-toxic drugs, or significant fluid loss

• No sustained improvement in renal functionfollowing diuretic withdrawal or plasmavolume expansion

• Proteinuria of less than 500 mg/dL and noultrasonographic evidence of obstructiveuropathy or parenchymal renal disease

In most cases, the diagnosis is made on the basisof the serum creatinine level, which is a specificbut relatively insensitive index of renal functionin this setting. Additional diagnostic criteria,which may help in making the diagnosis but arenot considered essential, are low urine volume(<500 mL/day), low urine sodium level (<10mEq/L), urine osmolality greater than plasmaosmolality, few urine erythrocytes (<50 per high-power field), and low serum sodium level (<30mEq/L).

Hepatorenal Syndrome Types 1 and 2Type 2 hepatorenal syndrome is moderate renalfailure that is stable over a long time; the mainconsequence is refractory ascites; the creatininelevel is stable at 1.5 to 2.5 mg/dL, generally withan increase of less than 0.5 mg/dL per day. Incomparison, type 1 hepatorenal syndrome israpidly progressive renal failure. It usually occursin patients with type 2 hepatorenal syndromeand results from a precipitating factor such asinfection or gastrointestinal tract bleeding. Thecreatinine level is greater than 2.5 mg/dL or cre-atinine is more than 1.5 mg/dL, with an increaseof 0.5 mg/dL or more per day.

Treatment

PreventionRenal dysfunction in cirrhotic ascites is more easilyavoided than treated. All factors that may poten-tiate renal dysfunction are avoided, includingnephrotoxic drugs, excessive use of diuretics, andlarge-volume paracentesis without intravenousalbumin. Complications such as bacterial infection,gastrointestinal tract bleeding, dehydration, orhypotension must be treated aggressively.Spontaneous bacterial peritonitis should be treatedwith antibiotics and intravenous albumin. Sepsisis a strong risk factor for renal failure in cirrhosisand is associated with arterial underfilling andrenal vasoconstriction.

Renal prostaglandins oppose the renal vasculareffects of vasoconstrictors such as angiotensin IIand epinephrine, and local renal production ofprostaglandins increases in cirrhosis, thus main-taining renal perfusion and sodium excretion. Inadvanced liver disease, renal compensatory mech-anisms are lost (hepatorenal syndrome). Thismechanism explains the nephrotoxicity of non-steroidal antiinflammatory drugs (inhibitors ofprostaglandin production) in cirrhosis.

Treatment The only therapy proven effective for hepatorenalsyndrome is liver transplantation. In type 2 hepa-torenal syndrome, discontinuation of diuretics andplasma volume expansion are usually effective, atleast temporarily. In established hepatorenal syn-drome type 1, patients should undergo plasmavolume expansion with albumin to a normal centralvenous pressure. A further fluid challenge may betried but usually will be ineffective.

There is increasing evidence for the efficacyof vasoconstrictor therapy in combination withplasma volume expansion with albumin (generallya 100-g initial dose, followed by 20-40 g/day) fortype 1 hepatorenal syndrome. Terlipressin is themost widely studied drug and is safe. This hasbeen administered in doses of 0.5 mg/4 hours, upto 12 mg/day, to more than 154 patients, with aresponse rate of 50% to 60%. However, this drug isnot available in the United States. α1-Agonists(midodrine or norepinephrine) also have been

358 Liver

used with some benefit, with albumin, althoughthere have been no randomized trials. In a smallnumber of patients, midodrine and octreotide havesuccessfully reversed the renal failure.

The condition of a small number of patientswith hepatorenal syndrome has improved afterTIPS but, in line with AASLD guidelines, con-trolled trials are required before this treatmentcan be recommended.

HEPATIC ENCEPHALOPATHYHepatic encephalopathy is the one complicationof cirrhosis for which little progress has beenmade in understanding it, diagnosing it, andtreating it. The diagnosis is still clinical, with noconfirmatory laboratory testing. Therapies arevery limited and nonspecific. Furthermore, noweight is given for this complication in the MELDsystem for organ allocation, resulting in consid-erable morbidity.

In chronic liver disease, noxious substances,presumed nitrogenous compounds from proteinbreakdown, are ineffectively detoxified orbypassed (or both) by the diseased liver and affectthe brain, causing a neuropsychometric syndromecalled hepatic encephalopathy. The pathophysiologicmechanism is not well understood, but the majortoxins appear to be ammonia and endogenoussubstances that act at γ-aminobutyric acid-ben-zodiazepine receptors in the brain.

Clinical FeaturesHepatic encephalopathy is a constellation of neu-ropsychiatric features (dominated by significantpsychomotor slowing) that fluctuate greatly overtime and range from a trivial impairment in cog-nition to frank confusion, drowsiness, and coma.Psychomotor speed, visual perception, and atten-tion often are affected more than verbal ability,especially in “minimal” cases. Studies have nowshown that even minimal PSE can greatly affecta patient’s functioning both at home and at work,and its significance should not be underesti-mated. Also, there is evidence that these patientsare not fit to drive a car.

The four stages of hepatic encephalopathy arewell known:

• Grade 1––Confused, altered mood or behavior,psychometric defects

• Grade 2––Drowsy, inappropriate behavior• Grade 3––Stuporous but with inarticulate

speech and able to obey simple commands,marked confusion

• Grade 4–– Coma, unable to be roused

No laboratory test can confirm the diagnosis, whichrests entirely on clinical grounds in the setting ofestablished chronic liver disease. An early battery oftesting can be useful for “subclinical” cases,including number connection tests, line drawingtest, serial dotting test, and digit symbol test.However, this testing is costly and time consuming.Asterixis is a nonspecific clinical sign, which gen-erally, but not invariably, occurs in the early stagesof encephalopathy. Although associated with anincreased arterial level of ammonia, there is no cor-relation between the degree of encephalopathy andthe ammonia level. Characteristic slow waves occuron the electroencephalogram.

Management

Identification of PrecipitantsHepatic encephalopathy must be differentiatedfrom other causes of encephalopathy in patientswith cirrhosis. Head imaging excludes structuralcauses of coma. Also, well-recognized precipitatingfactors must be sought and treated. To treat oravoid hepatic encephalopathy in patients who haveadvanced cirrhosis, the following general measuresmust be considered:

• Avoidance of analgesics, sedatives, and tranquilizers

• Control of gastrointestinal tract bleeding andpurging of blood from the gastrointestinal tract

• Screening and aggressive therapy for anyinfection

• Correction of acidosis, alkalosis, hypoxia, orelectrolyte abnormalities

• Prevention of constipation and intravascularvolume depletion

• Adequate intake of glucose to treat hypo-glycemia and prevent endogenous proteinbreakdown


• Adequate vitamin supplementation, includingthiamine and folate

Treatment

LactuloseThis is the mainstay of therapy for most patients.Lactulose is a nonabsorbable synthetic disaccharidemetabolized by colonic bacteria to organic acids. Itacts as an osmotic laxative. Lactulose may stimulatebacterial growth, thereby increasing the incorpo-ration of nitrogen, and the low pH of the organicacids may increase peristalsis. The starting doseis 30 mL 2 or 3 times daily, titrated to produce 2 to4 stools daily. In comatose patients, lactulose isgiven by feeding tube or rectally. Excessive therapycan cause dehydration and hypernatremia. Lactitolis equivalent to lactulose but is not available in theUnited States. Lactose is effective in lactase-defi-cient patients.

AntibioticsRifaximin is a new nonabsorbable antibiotic, whichin doses of 400 mg 3 times daily, has shown someefficacy in the treatment of hepatic encephalopathy.It presumably acts by decreasing bacterial floraand, thus, reducing the formation of ammonia andother nitrogenous waste products. It is as effectiveas and safer than neomycin or metronidazole.Neomycin can be absorbed to some extent (1%-3%) and lead to ototoxicity and nephrotoxicity.

Dietary Protein RestrictionTheoretically, increased protein intake increasesPSE, but fewer than 10% of cases of PSE are asso-ciated with increased protein ingestion, and somestudies have shown improvements in PSE inpatients with better nutritional status andincreased protein intake. Most patients with PSEdo not need protein restriction. In advanced coma,protein is withheld for a short time while an ade-quate level of glucose is maintained with intra-venous infusion; the precipitating cause for thePSE can then be identified and lactulose therapyinitiated. It is critical in the long term, however,to maintain a positive nitrogen balance in thesepatients, particularly if they already have musclewasting. Also, a small subset of patients appear tobe “protein-sensitive,” that is, they become

encephalopathic with moderate amounts of pro-tein. Thus, these patients must be given the leastamount of protein necessary to maintain a posi-tive nitrogen balance. Protein intake of 1.0 to 1.2g/kg (based on ideal or dry weight) is essential.Protein is best tolerated if the amount is distrib-uted evenly throughout the day rather than givenin large doses. Also, the composition of the pro-tein may make a difference: vegetable proteinsmay be more beneficial (less ammoniagenic) thananimal proteins. Furthermore, within animal pro-teins, toxicity increases from dairy proteins tofish, to meat, and finally, to blood proteins (redmeat). Despite no proven clinical benefit in trials,some patients appear to tolerate preparations ofbranched chain amino acids better than other pro-teins. For patients who are transplant candidates,mild PSE is tolerated better in the long term thana negative protein balance. For nontransplantcandidates with end-stage liver disease andrefractory PSE, quality-of-life issues predominatewith regard to diet.

Therapies of Indeterminate EfficacyZinc is a cofactor of urea cycle enzymes, and itsdeficiency is implicated in PSE. Trials that studiedzinc therapy in PSE have been inconclusive.Preliminary studies are being conducted withornithine-aspartate, which provides substrate forurea formation and glutamine synthesis (the twomajor routes of ammonia clearance). Benzoate andphenylacetate are used to correct urea cycle defi-ciencies, and some studies have shown benzoate tobe beneficial in PSE. Intravenous flumazenil hasproduced temporary improvement in somepatients with grade 4 coma, but the majority ofpatients probably do not benefit from it.

Portosystemic Encephalopathy After TIPS Most post-TIPS PSE is maximal during the first 3months and can be controlled by the above mea-sures. About 8% of cases are refractory to medicaltreatment, and the options are liver transplantationand occluding the stent or decreasing its diameter.Stent manipulation is not without morbidity (recur-rent variceal bleeding, ascites, and even death) andshould be considered only for severely refractorycases. Decreasing the diameter of the stent is saferthan occluding it.

360 Liver

Liver Support Devices The molecular absorbent recirculating system hasbeen used recently to treat patients who have acutedecompensation of cirrhosis and PSE. It appears tobe safe and has produced some biochemical andhemodynamic improvements.

Liver TransplantationThis is the ultimate therapy for PSE. PSE, which isrecurrent or difficult to treat, is but one manifes-tation of a deteriorating liver and is an indicationto consider orthotopic liver transplantation.Because hepatic encephalopathy is not linkeddirectly to mortality in cirrhosis, its presence car-ries no weight over bilirubin, creatinine, and theinternational normalized ratio in the MELD systemfor organ allocation.

Hepatic Encephalopathy and SpontaneousPortosystemic ShuntsA new area of investigation in PSE has been theidentification of large portosystemic shunts inpatients with recurrent or persistent PSE out ofproportion to the severity of liver disease.Fourteen patients with recurrent or persistentPSE were studied and compared with patientswith cirrhosis of equal severity (same bilirubin,international normalized ratio, albumin, sodium,and creatinine values and MELD score). Asexpected, patients with hepatic encephalopathyhad higher ammonia levels but less ascites andvarices, and, on spiral computed tomography,71% had large portosystemic shunts comparedwith 14% of controls. The conclusion of the studywas that the large shunts clearly decompress theportal circulation but perpetuate the hepaticencephalopathy. As yet, there are no proven ther-apeutic implications of this finding.

PROGNOSTIC INDICATORS FORSURVIVAL IN CIRRHOSISCirrhosis can be considered in four stages. Stage1 is completely compensated cirrhosis withoutvarices or ascites. The 1-year mortality rate isvery low, and about 11% of patients annuallyhave progression to a higher stage. Stage 2 is alsocompensated; however, varices are present but

not ascites; the mortality rate is a little higher and10% of patients have progression to a higherstage. Stage 3 is defined by the presence of ascites,with or without varices, and the mortality rateis 20%, with 7% of patients developing bleedingvarices. Stage 4 is defined by bleeding varices; ithas a higher mortality rate. CTP and MELD scoresboth predict mortality.

RECOMMENDED READINGArroyo V, Terra C, Ginès P. Advances in the patho-

genesis and treatment of type-1 and type-2hepatorenal syndrome. J Hepatol. 2007May;46:935-46. Epub 2007 Feb 27.

Córdoba J, López-Hellín J, Planas M, Sabín P,Sanpedro F, Castro F, et al. Normal protein dietfor episodic hepatic encephalopathy: results ofa randomized study. J Hepatol. 2004;41:38-43.

D’Amico G, Garcia-Tsao G, Pagliaro L. Natural his-tory and prognostic indicators of survival in cir-rhosis: a systematic review of 118 studies. JHepatol. 2006 Jan;44:217-31. Epub 2005 Nov 9.

Fasolato S, Angeli P, Dallagnese L, Maresio G, Zola E,Mazza E, et al. Renal failure and bacterial infec-tions in patients with cirrhosis: epidemiologyand clinical features. Hepatology. 2007;45:223-9.

Festi D, Vestito A, Mazzella G, Roda E, ColecchiaA. Management of hepatic encephalopathy:focus on antibiotic therapy. Digestion. 2006;73Suppl 1:94-101. Epub 2006 Feb 8.

Garcia-Tsao G. Portal hypertension. Curr OpinGastroenterol. 2006 May;22:254-62.

Garcia-Tsao G. The transjugular intrahepatic por-tosystemic shunt for the management of cir-rhotic refractory ascites. Nat Clin PractGastroenterol Hepatol. 2006;3:380-9.

Ginès P. Vaptans: a promising therapy in the man-agement of advanced cirrhosis. J Hepatol. 2007Jun;46:1150-2. Epub 2007 Mar 28.

Moreau R, Lebrec D. The use of vasoconstrictors inpatients with cirrhosis: type 1 HRS andbeyond. Hepatology. 2006 Mar;43:385-94.

Riggio O, Efrati C, Catalano C, Pediconi F, MecarelliO, Accornero N, et al. High prevalence of spon-taneous portal-systemic shunts in persistenthepatic encephalopathy: a case-control study.Hepatology. 2005;42:1158-65.


Metabolic liver disease encompasses a diversegroup of disorders that can cause liver damagethrough various mechanisms. Many are due toinborn errors of metabolism that are relativelyuncommon. The various metabolic liver diseasesare listed in Table 1. This chapter reviews heredi-tary hemochromatosis, Wilson’s disease, and α1-antitrypsin (AAT) deficiency because they are themetabolic liver diseases most gastroenterologistsare likely to encounter. These three disorders arecompared in Table 2.

HEREDITARY HEMOCHROMATOSISHereditary hemochromatosis is an autosomalrecessive disorder associated with increasedintestinal absorption of iron and the deposition ofexcessive amounts of iron in the liver, pancreas,and other organs. It is the most common single-gene, inherited disorder in the US white popula-tion. Approximately 1 in every 200 to 300 whitepersons in the United States is homozygous forthe hemochromatosis mutation, and at least 1 inevery 10 is a heterozygous carrier.

Not all iron overload is due to hereditaryhemochromatosis, which should be distinguished

363

CHAPTER 28

Metabolic Liver Disease


Abbreviations: AAT, α1-antitrypsin; OLT, orthotopic liver transplantation.

Table 1. Metabolic Liver Diseases

Inborn errors of carbohydrate metabolismGlycogen storage disease

Inborn errors of protein metabolismTyrosinemiaUrea cycle defects

Inborn errors of lipid metabolismGaucher’s diseaseNiemann-Pick disease

Inborn errors of bile acid metabolismByler diseaseBenign recurrent cholestasis

Inborn errors of copper metabolismWilson’s disease

Inborn errors of iron metabolismHereditary hemochromatosis

Unclassifiedα1-Antitrypsin deficiencyCystic fibrosis

Modified from Ghishan FK. Inborn errors of metabolismthat lead to permanent hepatic injury. In: Zakim D,Boyer TD, editors. Hepatology: a textbook of liverdisease. 4th ed. Philadelphia: Saunders; 2003. p. 1397-1459. Used with permission.

from iron overload caused by other conditions.Secondary iron overload should be suspected inpatients with chronic anemias who have ineffectiveerythropoiesis or have had multiple blood trans-fusions. Rarely, prolonged iron supplementationcan produce abnormal iron test results and, evenmore rarely, tissue iron overload. A commonlyencountered cause of abnormal iron test results isacute or chronic liver disease. Acute liver diseasemay be accompanied by a high ferritin level usu-ally with a normal transferrin saturation. Chronicliver disease, particularly if advanced, may resultin abnormalities in ferritin and iron saturation thatcan mimic hereditary hemochromatosis. Even hightissue concentrations of iron can be seen in somepatients who have advanced cirrhosis due tocauses other than hereditary hemochromatosis.In secondary iron overload, iron often accumu-lates in Kupffer cells rather than in hepatocytes,as typical of hereditary hemochromatosis.However, severe iron overload from hereditaryhemochromatosis may be indistinguishable fromthat due to secondary causes.

The HFE GeneThe gene associated with hereditary hemochro-matosis is the HFE gene. It is located on the shortarm of chromosome 6. The two commonlyassessed point mutations are C282Y and H63D.Other mutations have been described, but they arerare and not likely to be of major clinical impor-tance. About 90% of patients with iron overloadconsistent with hereditary hemochromatosis havehomozygosity for C282Y.

The greatest risk for iron overload is in personshomozygous for the C282Y mutation. Iron over-load also occurs in a small proportion of personswith other HFE mutations (especially compoundheterozygotes who have one copy of C282Y andone copy of H63D and occasionally H63D homozy-gotes), but it is usually less severe. Approximately1% to 2% of the white population are compoundheterozygotes or H63D homozygotes, and only asmall percentage of these persons develop prob-lems with iron overload. In addition, 20% of theUS population is heterozygous for H63D. A singlecopy of H63D does not appear to be a risk factor for

364 Liver

Table 2. Comparison of Hemochromatosis, Wilson’s Disease, and α1-Antitrypsin Deficiency

Feature Hemochromatosis Wilson’s disease αα1-Antitrypsin deficiency

Inheritance Autosomal recessive Autosomal recessive Autosomal codominantHomozygote 1:200-300 1:30,000 1:2,000

frequencyHeterozygote 1:10 1:100 1:30

frequencyGene HFE ATP7BNumber of 2 (C282Y, H63D) >100

mutations*

Chromosome 6 13 14Diagnosis Transferrin saturation, Ceruloplasmin, slit-lamp α1-Antitrypsin phenotype

ferritin, liver iron exam for Kayser-Fleischerconcentration, HFE rings, urine and liver gene test copper quantification

Treatment Phlebotomy Penicillamine, trientine, None/orthotopic liveror zinc transplantation

*Clinically significant.

the development of iron overload. Also, it shouldbe remembered that clinically important iron over-load can occur in the absence of HFE gene muta-tions. Therefore, a negative HFE gene test does notexclude iron overload.

Novel Genes and ProteinsSeveral other genes and proteins of iron metabolismhave been discovered recently, including ferro-portin, transferrin receptor 2, hemojuvelin, andhepcidin. Ferroportin is an iron exporter locatedon enterocytes, macrophages, and the hepatocytebasolateral membrane, and mutations in its genehave been associated with an autosomal dominantform of iron overload. Transferrin receptor 2 islocated mainly on hepatocytes, and mutations in itsgene TFR2 have led to a rare autosomal recessiveform of iron overload. Hemojuvelin (HJV) is therecently discovered gene for juvenile hemochro-matosis located on chromosome 1q.

Of all the proteins, the one that has generatedthe most interest is hepcidin, a small polypeptideproduced in the liver. Hepcidin inhibits iron absorp-tion in the small intestine and prevents the releaseof iron from macrophages. It may function as a reg-ulator of iron stores. Hepcidin levels are increasedmarkedly in infectious and inflammatory condi-tions. It may be responsible for the development ofanemia of inflammation (anemia of chronic disease).Hepcidin levels are inappropriately low in heredi-tary hemochromatosis, and hepcidin knockout micedevelop iron overload in a pattern similar to that ofhuman hereditary hemochromatosis. Preliminarystudies have found that mutations in hepcidin mayinfluence disease expression in hereditaryhemochromatosis. This has led to reconsideration ofthe pathophysiology of iron metabolism. Previousmodels emphasized the role of enterocyte crypt cellsin sensing body iron stores. It may be that the liveris the primary site for sensing the body iron stores,and it responds by increasing or decreasing theproduction of hepcidin. Future studies of hepcidinand other proteins of iron metabolism undoubtedlywill clarify the pathophysiology of iron metabolismand hereditary hemochromatosis.

Clinical FeaturesPersons with hereditary hemochromatosis absorbonly a few milligrams of iron each day in excess

of the amount needed. Therefore, clinical mani-festations generally occur after the fifth decade,when 15 to 40 g of iron have accumulated (normalbody iron stores are approximately 4 g). Of thosewith C282Y homozygosity, about 30% of malesand 2% to 10% of females have evidence of bio-chemical or clinical iron overload. Clinical expres-sion is influenced by age, sex, iron content of the diet,blood loss as occurs in menstruation and pregnancy,and unknown factors, including mutations in genesother than HFE. Thus women, despite an equal fre-quency of homozygosity, express the disease lessfrequently than men. Other factors such as alcoholand hepatitis C may accelerate disease expression.

The classic description of hereditary hemo-chromatosis is cutaneous hyperpigmentation,diabetes mellitus, and cirrhosis (“bronze dia-betes”). Other clinical manifestations includefatigue, abdominal pain, hepatomegaly, abnormalliver enzyme levels, hepatocellular carcinoma, car-diomyopathy, cardiac conduction disorders,hypothyroidism, hypogonadism, impotence, andarthropathy. An example of hemochromatosisarthropathy is shown in Figure 1.

In the past, hereditary hemochromatosis usu-ally was diagnosed at an advanced stage.Currently, most patients with newly diagnosedhereditary hemochromatosis are asymptomatic.This shift toward earlier diagnosis probably is duepartly to increased physician awareness and thedecision of some providers to screen for diseasewith serum iron tests. The most common symp-toms are fatigue, arthralgias, and impotence. Most,if not all, clinical manifestations are preventable ifthe disease is diagnosed early and treated appro-priately. Some of its manifestations, such as skinbronzing, cardiomyopathy, cardiac conductiondisorders, hepatomegaly, and abnormal liver testresults, frequently are reversible after excess ironstores have been removed. Most of the other clin-ical manifestations are not reversible.

DiagnosisThe diagnosis of hereditary hemochromatosis ismade on the basis of a combination of clinical, lab-oratory, and pathologic criteria, including anincrease in serum transferrin saturation [100 ×(serum iron concentration ÷ total iron bindingcapacity)] and an increase in the serum concentration

Metabolic Liver Disease 365

of ferritin. There is diurnal variation in serum ironvalues, and measurements may be affected by theingestion of food; therefore, if transferrin saturationis increased, the measurement should be repeatedin the early morning with the patient fasting. Anincrease in transferrin saturation is the earliest phe-notype abnormality in hereditary hemochromatosis.

The serum concentration of ferritin usuallyprovides a reasonable estimate of total body ironstores, but it is also an acute phase reactant and isincreased in various infectious and inflammatoryconditions in the absence of iron overload. Ferritinmay be increased in 30% to 50% of patients whohave viral hepatitis, nonalcoholic fatty liver dis-ease, or alcoholic liver disease. For these reasons,ferritin should not be used as the initial screeningtest to detect hereditary hemochromatosis.

A diagnostic algorithm for hereditaryhemochromatosis is provided in Figure 2. The HFEgene test is most useful for surveillance of adultfirst-degree relatives of an identified proband.Screening for the disease in family members is cru-cial because 25% of siblings and 5% of children ofa proband will have the disease. HFE gene testingshould replace the more cumbersome and expen-sive HLA typing previously used to screen forhereditary hemochromatosis in siblings. Also, HFEgene testing is often useful in helping to resolveambiguous cases, such as iron overload associatedwith hepatitis C, alcoholic liver disease, or othercauses of end-stage liver disease. HFE gene testingshould be considered also for siblings of C282Yheterozygotes. Before the HFE gene test is per-formed, the person should be counseled about therisks, benefits, and alternatives of genetic testing.Although rare, the possibility of insurance, employ-ment, or other discrimination based on HFE testresults is a concern. For this reason, HFE genetesting usually is not recommended for anyoneyounger than 18 years. The spouse of an affectedperson may be tested to assess risk to children. Ifthe spouse does not have a mutation for HFE, thechildren will not be affected.

Before the HFE gene test was available, liverbiopsy often was used to confirm the diagnosis ofhereditary hemochromatosis. Hepatic iron maybe assessed with an iron stain such as Perls’Prussian blue. In hereditary hemochromatosis,iron initially accumulates in periportal hepato-cytes, but eventually it is distributed throughoutthe liver. In secondary iron overload, iron often ispresent predominantly in Kupffer cells, which mayhelp distinguish it from hereditary hemochro-matosis. In severe iron overload, this distinctioncannot be made. The histologic features of the liverin hereditary hemochromatosis and secondaryiron overload are shown in Figure 3.

In hereditary hemochromatosis, iron stores inthe liver increase progressively with age. This hasled to the development of the hepatic iron index,which is the hepatic iron concentration in micro-moles/gram dry weight liver divided by thepatient’s age in years. Originally, this index wasintended to distinguish between hereditaryhemochromatosis homozygotes and heterozygotesand persons with alcoholic liver disease. In the

366 Liver

Fig. 1. Hemochromatosis arthropathy. A radiographof the hand shows cartilage loss, marginal sclerosis,and osteophyte formation in the second and thirdmetacarpophalangeal joints (arrows) withoutinvolvement of the fourth and fifth joints. Involvementof the second and third metacarpophalangeal joints ischaracteristic of hemochromatosis arthropathy.Occasionally, calcium pyrophosphate dihydratecrystals may be present (chondrocalcinosis). (Modifiedfrom Riely CA, Vera SR, Burrell MI, Koff RS. Thegastroenterology teaching project, unit 8—inheritedliver disease. Used with permission.)

initial study, the hepatic iron index was greaterthan 1.9 for all homozygotes and less than 1.9 forall heterozygotes or patients with alcoholic liverdisease. A hepatic iron index greater than 1.9 is notdiagnostic of hereditary hemochromatosis becausepatients with severe iron overload of any causemay have an index greater than 1.9. Also, becausehereditary hemochromatosis is increasingly diag-nosed at an earlier stage, not all homozygotes willhave a hepatic iron index greater than 1.9.

TreatmentThe treatment of hereditary hemochromatosis usu-ally is reserved for patients with evidence of ironoverload as indicated by an increase in the serumconcentration of ferritin. Therapeutic phlebotomyis the preferred treatment because it is simple, rel-atively inexpensive, and effective. It begins withremoval of 500 mL of blood weekly. The hemo-globin concentration should be measured justbefore each phlebotomy. Weekly phlebotomy

should continue as long as the hemoglobin con-centration is above a preselected value (usually12-13 g/dL). If the concentration is below the pre-selected value, phlebotomy should not be per-formed. Once the hemoglobin concentrationremains below the preselected value for three con-secutive weeks without phlebotomy, the serumconcentration of ferritin and transferrin saturationshould be determined again. Iron depletion is con-firmed if the ferritin level is not greater than 50µg/L, with a transferrin saturation in the low-normalrange. Once iron depletion has been achieved, mostpatients require four to eight “maintenance” phle-botomies annually to keep the ferritin level lowerthan 50 µg/L.

Generally, iron chelators such as the parenteralagent deferoxamine and oral agent deferasirox arenot used to treat iron overload in hereditaryhemochromatosis. Iron chelators are much lesseffective than phlebotomy in removing excess iron.They are administered sometimes to patients with


Fig. 2. Diagnostic algorithm for hereditary hemochromatosis. AST, aspartate aminotransferase. *Anemias withineffective erythropoiesis, multiple blood transfusions, or oral/parenteral iron supplements. (Modified fromBrandhagen DJ, Fairbanks VF, Batts KP, Thibodeau SN. Update on hereditary hemochromatosis and the HFEgene. Mayo Clin Proc. 1999;74:917-21. By permission of Mayo Foundation for Medical Education and Research.)

Fasting, morning transferrinsaturation >45%

No

No

No

No

No

Yes

Yes

Yes

Yes

Yes

No

Stop

Recheck in 1 year

Treat and recheck

Repeat transferrin saturation and serum ferritin > normal

Secondary iron overload?*

HFE gene testing; C282Y homozygote?

Ferritin <1,000 µg/LNormal AST

Phlebotomy Liver biopsy histology and hepatic ironquantitation consistent with hemochromatosis

Phlebotomy Follow

Yes

iron overload due to hematologic disorders char-acterized by ineffective erythropoiesis and anemia,for which phlebotomy is not an option.

Patients with hereditary hemochromatosisshould refrain from taking iron supplements,including multivitamins with iron, and high-dosevitamin C supplements. A “low iron diet” is notnecessary, but red meat should be consumed inmoderation. Patients also should avoid consuming

raw seafood because of an increased risk of Vibriovulnificus infection. Also, poorly cooked meatshould be avoided, and patients should avoidalcohol or minimize its intake because iron andalcohol are synergistic hepatotoxins.

Despite being common, hereditary hemochro-matosis only rarely causes complications of portalhypertension and is an uncommon indication fororthotopic liver transplantation (OLT), accounting

368 Liver

Fig. 3. Iron deposition in the liver. A, Mild (grade 1 of 4) iron deposition in hepatocytes. B, Moderatehemosiderin deposition in precirrhotic homozygous hemochromatosis. Zone 1 hepatocytes are predominantlyinvolved, biliary hemosiderin is not evident, and fibrosis has not yet occurred—all indicating relatively earlyprecirrhotic disease (liver iron concentration, 10,307 µg Fe/g dry weight; iron index, 3.2). (Originalmagnification x133.) C, Marked hemosiderosis and cirrhosis in homozygous hemochromatosis. Although mostiron is in hepatocytes, some Kupffer cells (arrow) and biliary iron (arrowheads) are also present. (Originalmagnification x133.) D, Kupffer cell hemosiderosis. The presence of hemosiderin in Kupffer cells alone (arrows)is typical of mild transfusion hemosiderosis, is nonspecific, and should not prompt further consideration ofhemochromatosis. (Original magnification x240.) A-D, Perls’ Prussian blue stain. (A from Brandhagen DJ. Livertransplantation for hereditary hemochromatosis. Liver Transpl. 2001;7:663-72. Used with permission. B-D fromBaldus WP, Batts KP, Brandhagen DJ. Liver biopsy in hemochromatosis. In: Barton JC, Edwards CQ, editors.Hemochromatosis: genetics, pathophysiology, diagnosis, and treatment. Cambridge: Cambridge UniversityPress; 2000. p. 187-99. Used with permission.)

A B

C D

for fewer than 1% of all liver transplants performedin the United States. The survival rate of patientswith hereditary hemochromatosis undergoingOLT has improved in recent years and is now sim-ilar to that of OLT for other indications. Manydeaths of liver transplant recipients who havehereditary hemochromatosis are caused by cardiacor infectious complications.

PrognosisFor patients in whom hereditary hemochromatosisis diagnosed and treated before diabetes mellitusand cirrhosis develop, the age- and sex-adjustedsurvival rate is normal. However, when cirrhosisor diabetes develops, survival decreases markedly.Up to one-third of patients with hereditaryhemochromatosis and cirrhosis develop hepatocel-lular carcinoma, which often is the cause of death.The presence of hemochromatosis imparts a 200-foldincreased risk for the development of liver cancer,with most cases involving patients with cirrhosis.

The Role of Liver BiopsyHFE gene testing eliminates the need for liverbiopsy in many patients. Traditionally, liver biopsywas performed in patients with iron overload toconfirm the diagnosis of hereditary hemochro-matosis and to exclude cirrhosis. In patients withiron overload who are C282Y homozygotes, liverbiopsy is not necessary to confirm the diagnosis.However, liver biopsy is still the “gold standard”for assessing the degree of fibrosis. Definitivelyexcluding cirrhosis is important because of theincreased risk of the development of hepatocel-lular carcinoma and the resulting need for sur-veillance. The risk for cancer persists even afterexcess iron stores have been depleted. For patientswith cirrhosis, surveillance with ultrasonographyand α-fetoprotein every 6 months is recommended.

There may be a subset of patients with hered-itary hemochromatosis whose risk of cirrhosis isminimal, and liver biopsy would be unnecessary.Several studies have confirmed that certain non-invasive predictors are accurate in excluding cir-rhosis in C282Y homozygotes. In these studies,there were virtually no cases of cirrhosis in C282Yhomozygotes who had a serum concentration offerritin less than 1,000 µg/L and a normal aspartateaminotransferase value. A serum concentration of

ferritin less than 1,000 µg/L seems to be the bestpredictor of the absence of cirrhosis in C282Yhomozygotes. However, the positive predictivevalue of a serum concentration greater than 1,000µg/L is poor because only about 50% of those withthis value had cirrhosis. Consequently, liver biopsyis advisable for patients who have abnormal levelsof aminotransferases or a ferritin concentrationgreater than 1,000 µg/L (or both) to definitivelyassess for the presence of cirrhosis. Similar infor-mation is not available for non-C282Y homozy-gotes. Liver biopsy may be necessary for this groupof patients to confirm the diagnosis and to excludecirrhosis.

Screening for HemochromatosisCurrently, experts disagree about the usefulnessof screening for the general population. Despitethe disease fulfilling many of the criteria of a con-dition appropriate for population screening, somepublic health experts do not advocate screening.They cite lack of information about the burden ofdisease and disease expression in those with HFEmutations as reasons for not endorsing popula-tion screening. However, the natural history of thedisease in an asymptomatic patient identified bypopulation screening may never be known becausemany would consider it unethical to withhold treat-ment once iron overload develops.

Although the majority of C282Y homozygotesprobably will not develop serious problems withiron overload, the true prevalence of clinically rel-evant disease manifestations in hereditaryhemochromatosis is unknown. With the informationcurrently available, it seems reasonable to screenfor iron overload in persons with a family history ofhereditary hemochromatosis symptoms or signssuggestive of the disease or chronic liver disease.

WILSON’S DISEASEWilson’s disease is an autosomal recessive dis-order characterized by abnormal intrahepaticcopper metabolism and deposition of excess copperin the liver, brain, cornea, and other organs.Approximately 1/30,000 persons are homozygousand 1/100 are heterozygous carriers of a Wilson’sdisease gene mutation. It is likely that about onlyhalf of all persons with the disease have come to


medical attention. Not all cases of copper excessin the liver are due to Wilson’s disease. Patientswith chronic cholestatic biliary disorders such asprimary biliary cirrhosis, primary sclerosingcholangitis, or biliary atresia often have excesscopper levels in the liver, although usually not tothe degree seen in Wilson’s disease.

Copper Metabolism and PathogenesisBody copper homeostasis is achieved through bil-iary excretion. In Wilson’s disease, intestinal copperabsorption is normal but biliary excretion of copperis decreased. Copper toxicity has a major role inthe pathogenesis of the disease. Copper accumu-lates in the liver as a result of an abnormal coppertransport protein and eventually appears in otherorgans, particularly the brain. Excess copper exertsits toxic effect by the generation of free radicalsthat result in lipid peroxidation, similar to themechanism proposed for iron-induced damage inhereditary hemochromatosis. Deficiency of ceru-loplasmin is not the cause of Wilson’s disease;rather, it is an effect of the abnormal cellular traf-ficking of copper.

GeneticsThe gene for Wilson’s disease (ATP7B) was iso-lated in 1993. Located on chromosome 13, it codesfor a copper-transporting P-type adenosinetriphosphatase that is located in the endoplasmicreticulum and possibly the biliary canalicularmembrane. Thus far, more than 100 mutationshave been described. Attempts to correlate geno-type with phenotype have not shown a consistentpattern. From 30% to 40% of North American andEuropean patients have the H1069Q mutation.Unlike hereditary hemochromatosis, in whichapproximately 90% of cases are homozygous forthe C282Y mutation, the majority of cases ofWilson’s disease are compound heterozygotes (onecopy of two different mutations). The number ofclinically important mutations makes genetictesting less useful for this disease than for hered-itary hemochromatosis.

Clinical FeaturesThe variation in the clinical presentation of Wilson’sdisease is tremendous, ranging from asymptomaticpatients to those with crippling neurologic symp-

toms. The usual age range at presentation is 12 to23 years; the disease is extremely rare in patientsolder than 40 years . The five main categories ofclinical presentation include hepatic, neurologic,psychiatric, hematologic, and ophthalmologic. Inone large clinical series, the initial clinical mani-festations were hepatic in 42% of patients, neuro-logic in 34%, psychiatric in 10%, and hematologicin 12%. Wilson’s disease can simulate any syn-drome of liver disease, including fulminant liverfailure, chronic hepatitis, and cirrhosis. Liver man-ifestations tend to be more common in childhood,whereas neurologic symptoms tend to appear inthe second and third decades. Although Wilson’sdisease should be considered in all young patientswith liver disease, it is responsible for fewer than5% of cases of chronic hepatitis in persons youngerthan 35 years. Fulminant liver failure due to Wilson’sdisease is four times more common in females thanmales. Reports of hepatocellular cancer in Wilson’sdisease are rare, even though many patients haveadvanced fibrosis at a young age.

Neurologic syndromes are dominated byextrapyramidal motor symptoms, includingrigidity or spasticity, tremor, ataxia, dysarthria,drooling, and involuntary movements. Dementiaand seizures are rare. Psychiatric problems maybe dramatic, with psychosis or depression, or theymay be subtle and manifested as behavioral prob-lems or declining performance in school.Unfortunately, children often are classified ashaving behavioral problems until progressive andsometimes irreversible neurologic symptoms beginto develop.

Patients may present first with hemolyticanemia, frequently seen in association with acute,severe, or fulminant hepatitis. The constellationof young age, severe liver dysfunction, andhemolytic anemia should be assumed to beWilson’s disease until proved otherwise.Occasionally, the disease is identified because ofincidental eye findings, either brown Kayser-Fleischer rings, representing copper deposition inthe periphery of the cornea, or sunflower cataracts.The cataracts are seen only with a slit lamp and donot interfere with vision. The eye findings inWilson’s disease are shown in Figure 4. Renal man-ifestations include proximal or distal renal tubularacidosis and nephrolithiasis. Another manifestation

370 Liver

is azure lunulae, a blue discoloration of the baseof the fingernails that is an uncommon but char-acteristic finding.

DiagnosisThe differential diagnosis of Wilson’s disease isextensive and depends on the presenting clinicalsyndrome. The disease should be considered inany person younger than 30 years who has liverdisease. Nonalcoholic steatohepatitis, autoimmunehepatitis, and chronic viral hepatitis are the mostfrequently considered alternative diagnoses. Thecombination of liver disease and extrapyramidalmotor abnormalities should strongly suggestWilson’s disease. The combination of severe liverdisease and hemolytic anemia should never bemissed. Traditionally, the diagnosis requires at

least two of the following: 1) Kayser-Fleischer rings,2) low level of ceruloplasmin, 3) typical neurologicsymptoms, and 4) liver copper concentrationgreater than 250 µg/g dry weight.

Kayser-Fleischer rings are seen in manypatients with neurologic symptoms but are notfound frequently in patients who have only liverdisease. These rings have been detected also witha slit lamp in conditions associated with chroniccholestasis, such as primary biliary cirrhosis andsclerosing cholangitis. The serum level of cerulo-plasmin is less than 20 mg/dL in 95% of patientswith Wilson’s disease. Even though the level ofceruloplasmin may be increased nonspecificallyas an acute phase reactant or as a result of estrogenadministration, a level higher than 30 mg/dLessentially excludes the diagnosis of Wilson’s dis-ease except in rare patients presenting with ful-minant hepatitis. Persons who are heterozygousfor the Wilson’s disease gene may have a cerulo-plasmin level less than 20 mg/dL but do notdevelop clinical disease. Almost any chronic liverdisease in which liver synthetic function isdecreased may be associated with a ceruloplasminlevel that is lower than normal. The serum con-centration of copper may be low, normal, orincreased and, thus, is not particularly helpful.Although urinary copper excretion may beincreased in other liver diseases, a value less than100 µg/24 hours in a patient with clinical diseasewould be very unusual in symptomatic Wilson’sdisease. A low urinary copper excretion rate mayindicate acquired copper deficiency. This may beconfusing because cases of severe copper defi-ciency may be associated with neurologic symp-toms. The neurologic syndrome in these cases ismyelopathy with weakness and ataxia.

In most cases, liver biopsy is necessary to con-firm the diagnosis, particularly in those with anormal level of ceruloplasmin or without Kayser-Fleischer rings or neurologic symptoms. Often,steatosis is present, and glycogenated nuclei arecommon. Tissue analysis for copper is the “goldstandard” for confirming the diagnosis of Wilson’sdisease. A normal liver concentration of copper(<35 µg/g dry weight) excludes the diagnosis. Mostpatients with the disease have liver copper con-centrations greater than 250 µg/g dry weight, butthis is not a specific finding and may occur in chronic


Fig. 4. A, Kayser-Fleischer ring (arrow). B, Sunflowercataract. (From Zucker SD, Gollan JL: Wilson’sdisease and hepatic copper toxicosis. In: Zakim D,Boyer TD, editors. Hepatology: a textbook of liverdisease. 3rd ed. Philadelphia: WB Saunders; 1996. p.1405-39. Used with permission.)

A

B

cholestatic conditions or, rarely, in autoimmunehepatitis. Unlike hereditary hemochromatosis, chil-dren with Wilson’s disease may already have markedliver fibrosis; thus, liver biopsy should be stronglyconsidered in children to stage the liver disease.

Biochemical tests often show characteristicpatterns, but they are not consistent enough to beconfirmatory. The alkaline phosphatase level maybe low, and the aminotransferase levels tend to beincreased less than would be expected from othersigns of liver necrosis. In fulminant Wilson’s dis-ease, the uric acid level usually is low or unde-tectable, often because of concomitant proximalrenal tubular acidosis. In fulminant liver failure,a marked increase in the serum level of copperstrongly suggests the diagnosis of Wilson’s dis-ease, although a normal level does not exclude ful-minant Wilson’s disease. A diagnostic algorithmfor Wilson’s disease is provided in Figure 5.Complete gene sequencing is available; this maydisclose a functionally significant mutation in a casein which the results of standard tests are equivocal.

Family ScreeningAs in hereditary hemochromatosis, screeningshould be directed at siblings because each hasabout a 25% chance of having Wilson’s disease. Iftreatment is begun in the presymptomatic phase ofthe disease before cirrhosis is established, it isessentially curative. Because copper metabolismin infancy and early childhood may simulateWilson’s disease, children should not be testedbefore age 5 years. Screening should includeaminotransferase and ceruloplasmin levels and aslit-lamp examination for Kayser-Fleischer rings.If the results are normal, screening should berepeated every 5 years until age 20. If the cerulo-plasmin level is less than 20 mg/dL but there areno Kayser-Fleischer rings or convincing neuro-logic symptoms, liver biopsy may be necessary.Genetic testing generally is used for screening oncethe pattern in the index case is known. This may beof value if standard copper test results are equivocal.

Treatment

“Decoppering” AgentsPenicillamine and trientine were developed asmetal chelators and are approved for the treatment

of Wilson’s disease. Penicillamine is an effectivefirst-line treatment, but up to 20% of patients expe-rience drug toxicity, including hypersensitivityreactions, bone marrow suppression, proteinuria,autoimmune disorders, and dermatologic condi-tions. A starting dose of 250 to 500 mg/day is grad-ually increased to 1 to 2 g/day divided into twoto four doses. The drug should be given with smalldoses of pyridoxine because it can deplete vitaminB6. Treatment response is demonstrated by anacute increase in urinary copper excretion thatgradually plateaus at a lower level over 6 to 12months. Initially, urinary copper output is oftenmore than 2,000 µg daily, decreasing to 400 to 500µg daily in the maintenance phase. The urine andserum levels of copper and the ceruloplasmin levelshould be measured and a complete blood countshould be performed weekly during the firstmonth, then every 1 or 2 months during the first6 months. Patients whose condition is stable canthen be followed annually. The slit-lamp exami-nation should be repeated annually to documentthe disappearance of Kayser-Fleischer rings (ifpresent). As many as 20% of patients with neu-rologic symptoms may experience worsening oftheir symptoms during the first month of treat-ment. This deterioration has been irreversible insome patients.

Trientine was introduced as an alternative topenicillamine and should be the first choice for treat-ment. It is given in doses similar to those for peni-cillamine and also has satisfactory long-term effi-cacy. The cupriuresis is less pronounced than withpenicillamine, but an initial increase is expected.Also, trientine has a lower incidence of adverseeffects and a lower rate of neurologic worsening atthe start of treatment. Occasionally, iron deficiencymay develop because of sideroblastic anemia.

Tetrathiomolybdate has shown promise asan effective decoppering agent, with approvalstill pending.

Inhibition of Copper AbsorptionZinc acetate, 50 mg 3 times daily, is effectivetherapy for presymptomatic patients and preg-nant women. It also is an alternative maintenancetherapy for patients presenting with symptomaticdisease after 6 to 12 months of standard treatmentfor removal of copper. Zinc acetate induces the

372 Liver

synthesis of metallothionein in the intestinalepithelium, which then preferentially bindscopper and prevents its absorption. Treatment ismonitored by checking urinary levels of zinc andcopper. The urinary zinc excretion should be atleast 2,000 µg/day.

For pregnancy, penicillamine is probablysafe, but zinc is a better choice for patients whosecondition is stable. The teratogenicity of trien-tine is unknown, and it should not be givenduring pregnancy.

A problem with medical therapy for patientswith Wilson’s disease is compliance. It is hard toconvince young people, many of whom feel well, of

the need to take medicine 2 to 4 times daily for the restof their lives. The tragedy is that if a patient stopstreatment, the probability of death from fulminantliver failure within 1 to 2 years is very high, even ifthe patient was initially asymptomatic.

TransplantationThe indications for liver transplantation includefulminant liver failure, end-stage liver diseaseunresponsive to medical therapy, and chronic dete-rioration of liver function despite long-termtherapy. Liver transplantation is curative becauseit corrects the metabolic defect in Wilson’s disease.Transplantation is the treatment of choice for


Fig. 5. Diagnostic algorithm for Wilson’s disease. K-F, Kayser-Fleischer. *Genetic testing is performed withinfamilies when diagnosis is already established in one family member, using the index patient DNA as areference. (Modified from Gollan JL, Zakko WF. Wilson disease and related disorders. 2nd ed. In: FriedmanLS, Keeffe EB, editors. Handbook of liver disease. Philadelphia: Churchill Livingstone; 2004. p. 221-35. Usedwith permission.)

Wilson’s disease suspected

Serum ceruloplasmin

>30 mg/dL 20-30 mg/dL <20 mg/dL Slit-lamp exam

Diagnosis excluded Normal 24-hour urine copper Diagnosisconfirmed

Genetic testing*

K-F ringsabsent

Liver biopsycontraindicated

Increased Liver biopsy

Quantitative copper>250 μg/g dry weight

K-F rings present

fulminant liver failure because of the low proba-bility that medical therapy will be effective.Nevertheless, medical therapy should be startedbecause patients occasionally recover. Patientswho received a liver transplant for fulminanthepatic failure have a 1-year survival rate of 73%;among those with chronic liver failure, the rate isabout 90%. There are anecdotal reports of markedneurologic improvement after liver transplanta-tion, but transplantation performed solely forrefractory neurologic symptoms is consideredexperimental because of the limited experienceand uncertain outcome.

α1-ANTITRYPSIN DEFICIENCY

Genetics and FunctionAAT deficiency is an autosomal codominant dis-order characterized by lung and liver injury. AATis a member of the serine protease supergenefamily. It functions to protect tissues from pro-teases such as neutrophil elastase. AAT is encodedby a gene on the long arm of chromosome 14. Thephenotype Pi*MM (Pi, protease inhibitor) is presentin 95% of the population and is associated withnormal serum levels of AAT. For liver disease, theZ allele is the most clinically relevant. Thehomozygote frequency of the Z allele is 1:2,000,with a heterozygote frequency of 1:30. The Pi*ZZphenotype is accompanied by a severe deficiencyin AAT, and the Pi*MZ phenotype leads to inter-mediate deficiency.

Pathogenesis The pathogenesis of liver disease associated withAAT deficiency likely is due to the accumulationof the mutant AAT protein in the endoplasmicreticulum. The abnormally folded protein is unableto exit the endoplasmic reticulum. Unlike the lungs,the liver is not damaged by the uninhibited effectsof elastases and other proteolytic enzymes. Thisis supported by the observation that patients withtwo copies of the rare AAT null allele may developlung disease but do not develop liver disease.

Clinical FeaturesAAT deficiency may cause premature emphy-sema and liver disease. In the only population-based study performed, the Swedish neonatal

screening study identified 127 AAT-deficientchildren who were followed prospectivelythrough age 18 years. Neonatal cholestasis devel-oped in 11%, and 6% had other liver disease withoutjaundice. Liver test abnormalities developed 1 to 2months after birth and usually normalized by 6months. A small proportion of children devel-oped end-stage liver disease or presented withfulminant liver failure in infancy. Most (83%)AAT-deficient children were healthy throughoutchildhood, although most had liver test abnor-malities in early life. In adolescents and adults,AAT deficiency may cause hepatitis or cirrhosis.It has been estimated that 2% of adults between20 and 50 years old with the Pi*ZZ phenotypewill develop cirrhosis, compared with 19% ofthose older than 50. In adults, hereditaryhemochromatosis is the most common inheritedcause of cirrhosis, but AAT deficiency is the mostcommon metabolic indication for OLT. It isdebated whether persons with the Pi*MZ phe-notype are at risk for the development of chronicliver disease. Several studies have noted anincreased prevalence of the Pi*MZ phenotypeamong those undergoing OLT for cryptogeniccirrhosis compared with those having OLT forother indications. Patients with cirrhosis due toAAT deficiency have a greatly increased risk ofhepatocellular carcinoma, with some studiesreporting a prevalence of primary liver cancerof up to 30%.

DiagnosisThe diagnosis of AAT deficiency is made by AATphenotyping or genotyping. Serum levels of AATshould not be used to diagnose AAT deficiencybecause they may be falsely increased in inflam-matory conditions, malignancies, pregnancy, andwith estrogen supplementation. Unlike lung dis-ease, liver damage does not correlate with serumlevels of AAT. The diagnosis is confirmed by liverbiopsy. The characteristic finding is the presenceof eosinophilic, periodic acid-Schiff–positive, dia-stase-resistant globules in the endoplasmic retic-ulum of periportal hepatocytes. Because these glob-ules may be present also in heterozygotes and inhomozygotes without liver disease, their presencedoes not imply liver disease. Furthermore, becausethe globules may be variably distributed throughout

374 Liver

the liver, their absence does not exclude the diag-nosis of AAT deficiency. The histologic features ofthe liver in AAT deficiency are shown in Figure 6.

TreatmentNo effective medical treatment is available for theliver manifestations of AAT deficiency. As anattempt to decrease the risk of the developmentof emphysema, patients should refrain fromusing tobacco. They also should minimize alcoholconsumption. In some cases of lung disease, AAThas been infused, but it is not helpful for liverdisease. AAT deficiency may be amenable tosomatic gene therapy. Gene therapy probably

would be beneficial only for the lung diseaseunless a method of delivering the corrected geneproduct to the endoplasmic reticulum of hepa-tocytes was available.

OLT is the only definitive treatment for AATdeficiency. It cures the liver disease because therecipient assumes the Pi phenotype of the donor.

ACKNOWLEDGMENTDavid J. Brandhagen, MD (deceased), and John B.Gross, Jr, MD, are gratefully acknowledged asauthors of this chapter in the first edition of thebook (parts of which appear in this edition).


Fig. 6. Histologic features of the liver in α1-antitrypsin deficiency. Characteristic periodic acid-Schiff–positivediastase-resistant globules (arrows) have accumulated in hepatocytes. A, Low-power and, B, high-power views.

A B

RECOMMENDED READING

Hereditary HemochromatosisAdams PC. Review article: the modern diagnosis

and management of haemochromatosis.Aliment Pharmacol Ther. 2006;23:1681-91.

Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T.Penetrance of 845G→A (C282Y) HFE heredi-tary haemochromatosis mutation in the USA.Lancet. 2002;359:211-8.

Morrison ED, Brandhagen DJ, Phatak PD, BartonJC, Krawitt EL, El-Serag HB, et al. Serum fer-ritin level predicts advanced hepatic fibrosisamong US patients with phenotypic hemochro-matosis. Ann Intern Med. 2003;138:627-33.

Pietrangelo A. Hereditary hemochromatosis: anew look at an old disease. N Engl J Med.2004;350:2383-97.

Pietrangelo A. Non-HFE hemochromatosis.Hepatology. 2004;39:21-9.

Yamashita C, Adams PC. Natural history of theC282Y homozygote for the hemochromatosisgene (HFE) with a normal serum ferritin level.Clin Gastroenterol Hepatol. 2003;1:388-91.

Yu L, Ioannou GN. Survival of liver transplantrecipients with hemochromatosis in the UnitedStates. Gastroenterology. 2007 Aug;133:489-95. Epub 2007 Jun 2.

Wilson’s DiseaseAla A, Walker AP, Ashkan K, Dooley JS, Schilsky

ML. Wilson’s disease. Lancet. 2007;369:397-408.Ferenci P. Wilson’s disease. Clin Gastroenterol

Hepatol. 2005;3:726-33.Roberts EA, Schilsky ML, Division of Gastro-

enterology and Nutrition, Hospital for SickChildren, Toronto, Ontario, Canada. A practiceguideline on Wilson disease. Hepatology.2003;37:1475-92.

α1-Antitrypsin DeficiencyAmerican Thoracic Society/European

Respiratory Society Statement. Standardsfor the diagnosis and management of indi-viduals with alpha-1 antitrypsin deficiency.Am J Respir Crit Care Med. 2003;168:818-900.

Perlmutter DH, Brodsky JL, Balistreri WF,Trapnell BC. Molecular pathogenesis ofalpha-1-antitrypsin deficiency-associatedliver disease: a meeting review. Hepatology.2007;45:1313-23.

Sveger T. Liver disease in alpha1-antitrypsin defi-ciency detected by screening of 200,000 infants.N Engl J Med. 1976;294:1316-21.

376 Liver

Cholestatic liver disease in adults without biliaryobstruction encompasses a broad differential diag-nosis. Drug-induced cholestasis may be the mostcommon explanation for cholestasis in thesepatients. Primary biliary cirrhosis is the mostcommon cholestatic liver disease in adults. Primarysclerosing cholangitis is about half as common asprimary biliary cirrhosis. Other cholestatic condi-tions in adults include autoimmune cholangitis(sometimes known as antimitochondrial antibody[AMA]-negative primary biliary cirrhosis), acquiredimmunodeficiency syndrome (AIDS)-associatedcholangiopathy, and miscellaneous conditions.

DIFFERENTIAL DIAGNOSISThe differential diagnosis for cholestasis in adultswithout biliary obstruction is listed in Table 1.

Primary Biliary CirrhosisPrimary biliary cirrhosis has a prevalence ofabout 150 to 300 per million persons, involveswomen in 90% of cases, and is characterized byAMAs in 95% of patients. These patients present

with biochemical features of cholestasis and maybe symptomatic. Fatigue is the most commonsymptom, but it is nonspecific and not useful inestablishing the diagnosis. Pruritus is less common

377

CHAPTER 29

Cholestatic Liver Disease: Primary BiliaryCirrhosis, Primary Sclerosing Cholangitis,

and AIDS-Associated Cholangiopathy

Keith D. Lindor, MD

Abbreviations: AIDS, acquired immunodeficiency syndrome; AMA, antimitochondrial antibody; ERCP, endoscopicretrograde cholangiopancreatography.

Table 1. Differential Diagnosis forCholestasis in Adults Without LargeDuct Biliary Obstruction

Drug-induced cholestasisPrimary biliary cirrhosis

Autoimmune cholangitisPrimary sclerosing cholangitis

Small duct primary sclerosing cholangitisAIDS-associated cholangiopathyIdiopathic adulthood ductopeniaIdiopathic biliary ductopeniaCholestasis of pregnancyCystic fibrosisSarcoidosisGranulomatous hepatitis

AIDS, acquired immunodeficiency syndrome.

but may occur in 30% to 50% of patients.Increasingly, primary biliary cirrhosis is being rec-ognized in asymptomatic patients on the basis ofabnormal liver test results. The alkaline phos-phatase level is prominently increased, but serumlevels of cholesterol and IgM also can be abnormallyhigh. The most characteristic finding is AMAs,which recognize the lipoic acid binding site on anenzyme in the pyruvate dehydrogenase complex.The diagnosis often is established by the finding ofhigh-titer AMA in the appropriate clinical setting.Although liver biopsy helps confirm the diagnosisand provides information about histologic staging,it may not be required in most cases. Cross-sectionalimaging studies such as ultrasonography, com-puted tomography, or magnetic resonance imagingcan help exclude biliary obstruction. Direct cholan-giography is not needed to establish this diagnosis.

Autoimmune CholangitisAutoimmune cholangitis, or AMA-negative primarybiliary cirrhosis, is characterized by clinical and his-tologic features identical to those of primary biliarycirrhosis. However, the patients do not haveAMAs, but 95% have either antinuclear or anti-smooth muscle antibodies. Occasionally, thesepatients are confused with those who have over-lapping autoimmune hepatitis and primary biliarycirrhosis, but the histologic features and biochem-ical profile generally help differentiate autoimmunecholangitis from the overlap between primarybiliary cirrhosis and autoimmune hepatitis.

Primary Sclerosing CholangitisPrimary sclerosing cholangitis is the next mostcommon cholestatic condition in adults. About70% of the patients have inflammatory bowel dis-ease, and, unlike primary biliary cirrhosis, pri-mary sclerosing cholangitis is more common inmen than in women. The age at onset tends to beyounger, around 40 years for primary sclerosingcholangitis compared with 50 years for primarybiliary cirrhosis. AMAs rarely are present (≤2% ofpatients). Liver biopsy can help confirm the diag-nosis. Biopsy specimens may show more fibrosissurrounding the bile ducts and less inflammationthan seen in primary biliary cirrhosis, althoughthese characteristic findings generally are notapparent. Unlike primary biliary cirrhosis, direct

cholangiography is necessary to establish the diag-nosis of primary sclerosing cholangitis. Occasionally,patients have normal cholangiographic findings,but the histologic and clinical features (history ofinflammatory bowel disease) suggest primary scle-rosing cholangitis. These patients are consideredto have small duct primary sclerosing cholangitis.

AIDS-Associated CholangiopathyAIDS-associated cholangiopathy is defined asbiliary obstruction due to infections that lead tobiliary strictures. This was more common in AIDSpatients before highly active retroviral therapywas introduced. The frequency has now decreased.The usual organisms include Cryptosporidiumparvum, microsporida, cytomegalovirus, andCyclospora. The infection due to these organismstypically involves the intrahepatic biliary system.

The condition usually occurs in patients withvery low CD4 counts and may manifest with rightupper quadrant pain and diarrhea; fever and jaun-dice are less common. Alkaline phosphatase levelsusually are inceased. Transaminase levels usuallyare elevated mildly, and jaundice is unusual andgenerally mild. Diagnosis is often made with endo-scopic retrograde cholangiopancreatography(ERCP), with ultrasonography as the initial study.The cholangiographic patterns seen in more thanone-half of the patients are those of papillarystenosis and sclerosing cholangitis. Patterns ofintrahepatic and extrahepatic involvement withoutpapillary stenosis, papillary stenosis alone, or intra-hepatic involvement alone are less common.

Often, treatment against the causative agentis ineffective. Treatment with highly active retro-viral therapy decreases the percentage of patientswith human immunodeficiency virus infectionthat progresses to AIDS and may eventually pre-vent the development of biliary complications. Ifpatients have obstruction, endoscopic therapy withdilation should be considered.

TREATMENT OF SPECIFICCONDITIONS

Primary Biliary CirrhosisCurrently, we prescribe ursodiol at a dose of 13 to15 mg/kg daily, in divided doses, for patients with

378 Liver

any stage of primary biliary cirrhosis who haveabnormal findings on liver tests. Patients who meetminimal listing criteria for liver transplantationshould be referred for evaluation, but there is noharm in initiating ursodiol therapy while awaitinga donor organ. Ursodiol therapy should beapproached gradually over 2 to 3 weeks to avoidprecipitating pruritus, which can occur if the fulldose is given initially. Ursodiol improves survivalfree of transplantation, decreases the risk of thedevelopment of cirrhosis and varices, and lowerslipid levels. Prognostic models valid in the absenceof therapy remain valid when scores are recalcu-lated after 6 months of therapy and can provideuseful information. However, not all patients havea response to ursodiol therapy. Approximately35% of patients have complete biochemical nor-malization, with an excellent clinical response.Once ursodiol therapy is begun, it appears to be alifelong need, and patients should be instructedaccordingly. Side effects are minimal.

Autoimmune CholangitisPatients with autoimmune cholangitis typicallyhave a response to ursodiol therapy, showing theusual response of patients with primary biliary cir-rhosis. Occasionally, these patients have aresponse to corticosteroids or the combinationof ursodiol and corticosteroids. This is particu-larly likely in patients with overlap of primarybiliary cirrhosis and autoimmune hepatitis. Most

clinicians would begin treatment with ursodiol aloneand add corticosteroids if the results of liver bio-chemistry tests did not improve after 3 to 6 months.

Primary Sclerosing CholangitisPrimary sclerosing cholangitis is the most trouble-some of the more common adult cholestatic liverdiseases because no effective therapy is available.Ursodiol in standard doses has inconsistent effects.Patients may have evidence of rapidly progressivejaundice, may suddenly develop pruritus, or mayhave fever with right upper quadrant pain. Whenany of these occur, cholangiography (usuallyERCP) should be considered, although magneticresonance cholangiography is also an alternative(Fig. 1). Cholangiocarcinoma, a biliary stone in thecommon bile duct, or a dominant stricture all canbe responsible for these manifestations and can bedifferentiated best with ERCP. The endoscopicapproach allows biopsy with brushing for suspectedmalignancy, extrication of biliary stones, or dilata-tion of dominant strictures. The role of stentingafter dilatation has not been defined clearly.

MANAGEMENT OF COMPLICATIONSOF CHOLESTASISComplications of cholestasis require management.Malabsorption and deficiency of fat-soluble vita-mins may occur, especially if cholestasis is severe.These patients require periodic monitoring. Levels

Cholestatic Liver Disease 379

Fig. 1. Comparison of the findings of, A, endoscopic retrograde cholangiopancreatography and, B, magneticresonance cholangiography in the same patient with primary sclerosing cholangitis.

A B

of vitamins A, E, and D can be measured in serumdirectly, and the level of vitamin K can be inferredfrom the prothrombin time. Replacement withwater-soluble forms of the vitamins can be offered(vitamin A, 50,000 units twice weekly; vitamin E,200 units twice daily; vitamin D, 50,000 units twiceweekly; and vitamin K, 5 mg daily). Adequacy ofreplacement can be reassessed by measuring levelsafter 6 to 12 months of therapy. Hypercholes-terolemia, common in patients with cholestasis,does not appear to be associated frequently withatherosclerosis. We have not been aggressive inprescribing antihyperlipidemic therapy for thesepatients because some of the agents may be hepa-totoxic; instead, we have usually settled for theantihypercholesterolemic effects of ursodiol whengiven for primary biliary cirrhosis.

PruritusPruritus can be one of the most troublesome symp-toms of patients with cholestasis. The severity of thepruritus does not correlate closely with the severityof the underlying liver disease, and pruritus mayresolve as the disease progresses. Ursodiol reducespruritus in some patients with primary biliary cir-rhosis, but for those who remain symptomatic,antihistamines (ie, diphenhydramine 25-30 mg bymouth at bedtime) may relieve the pruritus andpermit sleep. Cholestyramine (4-g packets 3 or 4times daily) may help relieve itching, but it can beunpleasant to use. Rifampin (150-300 mg twicedaily) has a rapid onset of action and may be usefullong-term, although liver toxicity may develop in15% of patients. Naltrexone (50 mg daily) may beuseful for some patients, although there is lessexperience with this drug than with the others.Liver transplantation is available for patients whohave severe, intolerable pruritus.

Bone DiseaseAlthough the insufficient delivery of bile acids tothe gut lumen in advanced cholestasis may lead tofat-soluble vitamin deficiency, osteomalacia dueto vitamin D deficiency occurs in fewer than 5% ofpatients with osteopenic bone disease andcholestasis. Almost all bone disease evaluated inNorth America in this setting is due to osteo-porosis, which is the result of insufficient bonematrix rather than a mineralization defect as found

in osteomalacia. The cause of the osteoporosis isuncertain. The patients lose bone at a rate abouttwice that of the normal population. About 33%of patients with primary biliary cirrhosis and about20% of those with primary sclerosing cholangitisare osteopenic at the time of diagnosis, and about10% of them experience vertebral fractures withina few years after diagnosis. The management ofthe bone disease includes exercise and adequatecalcium intake with 1.5 g of elemental calciumdaily in combination with vitamin D supplemen-tation, if deficient. Postmenopausal women mayhave a response to hormone replacement therapy,usually given as patch therapy. Calcitonin therapydoes not appear to be effective, but treatment withbisphosphonates has been shown to be effective.

RECOMMENDED READINGAngulo P, Lindor KD, Therneau TM, Jorgensen

RA, Malinchoc M, Kamath PS, et al. Utilizationof the Mayo risk score in patients with primarybiliary cirrhosis receiving ursodeoxycholicacid. Liver. 1999;19:115-21.

Balan V, Dickson ER, Jorgensen RA, Lindor KD.Effect of ursodeoxycholic acid on serum lipidsof patients with primary biliary cirrhosis.Mayo Clin Proc. 1994;69:923-9.

Chen XM, LaRusso NF. Cryptosporidiosis and thepathogenesis of AIDS-cholangiopathy. SeminLiver Dis. 2002;22:277-89.

Crippin JS, Lindor KD, Jorgensen R, Kottke BA,Harrison JM, Murtaugh PA, et al.Hypercholesterolemia and atherosclerosis inprimary biliary cirrhosis: what is the risk?Hepatology. 1992;15:858-62.

Corpechot C, Carrat F, Bahr A, Chretien Y, PouponRE, Poupon R. The effect of ursodeoxycholicacid therapy on the natrual course of primarybiliary cirrhosis. Gastroenterology.2005;128:297-303.

Guañabens N, Parés A, Monegal A, Peris P, PonsF, Alvarez L, et al. Etidronate versus fluoridefor treatment of osteopenia in primary biliarycirrhosis: preliminary results after 2 years.Gastroenterology. 1997;113:219-24.

Jorgensen RA, Dickson ER, Hofmann AF, RossiSS, Lindor KD. Characterisation of patientswith a complete biochemical response to

380 Liver

ursodeoxycholic acid. Gut. 1995;36:935-8.Lacerda MA, Ludwig J, Dickson ER, Jorgensen RA,

Lindor KD. Antimitochondrial antibody-neg-ative primary biliary cirrhosis. Am JGastroenterol. 1995;90:247-9.

Lewis JH. Drug-induced liver disease. Med ClinNorth Am. 2000;84:1275-311.

Lindor KD, Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. Ursodiolfor primary sclerosing cholangitis. N Engl JMed. 1997;336:691-5.

Lindor KD, Jorgensen RA, Therneau TM,Malinchoc M, Dickson ER. Ursodeoxycholicacid delays the onset of esophageal varices inprimary biliary cirrhosis. Mayo Clin Proc.1997;72:1137-40.

Lindor KD, Jorgensen RA, Tiegs RD, Khosla S,Dickson ER. Etidronate for osteoporosis in pri-mary biliary cirrhosis: a randomized trial. JHepatol. 2000;33:878-82.

Menon KV, Angulo P, Weston S, Dickson ER,Lindor KD. Bone disease in primary biliarycirrhosis: independent indicators and rate ofprogression. J Hepatol. 2001;35:316-23.

Michieletti P, Wanless IR, Katz A, Scheuer PJ,Yeaman SJ, Bassendine MF, et al.Antimitochondrial antibody negative primarybiliary cirrhosis: a distinct syndrome of autoim-mune cholangitis. Gut. 1994;35:260-5.

Olsson RG, Boberg KM, Schaffalitzky de MuckadelO, Lindgren S, Hultcrantz R, Folvik G, et al.Five-year treatment with high-dose UDCA inPSC [abstract]. J Hepatol. 2004;40 Suppl 1:161.

Poupon RE, Lindor KD, Cauch-Dudek K, DicksonER, Poupon R, Heathcote EJ. Combinedanalysis of randomized controlled trials ofursodeoxycholic acid in primary biliary cir-rhosis. Gastroenterology. 1997;113:884-90.

Poupon RE, Lindor KD, Parés A, Chazouilleres O,Poupon R, Heathcote EJ. Combined analysis ofthe effect of treatment with ursodeoxycholicacid on histologic progression in primary bil-iary cirrhosis. J Hepatol. 2003;39:12-6.

Rost D, Rudolph G, Kloeters-Plachky P, Stiehl A.Effect of high-dose ursodeoxycholic acid onits biliary enrichment in primary sclerosingcholangitis. Hepatology. 2004;40:693-8.

Rouillard S, Lane NE. Hepatic osteodystrophy.Hepatology. 2001;33:301-7.

Talwalkar JA, Angulo P, Johnson CD, Petersen BT,Lindor KD. Cost-minimization analysis ofMRC versus ERCP for the diagnosis of pri-mary sclerosing cholangitis. Hepatology.2004;40:39-45.

Talwalkar JA, Lindor KD. Primary biliary cirrhosis.Lancet. 2003;362:53-61.

Talwalkar JA, Lindor KD. Primary sclerosingcholangitis. Inflamm Bowel Dis. 2005;11:62-72.

Talwalkar JA, Souto E, Jorgensen RA, Lindor KD.Natural history of pruritus in primary biliarycirrhosis. Clin Gastroenterol Hepatol.2003;1:297-302.

Wolfhagen FH, Sternieri E, Hop WC, Vitale G,Bertolotti M, Van Buuren HR. Oral naltrexonetreatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastro-enterology. 1997;113:1264-9.

Zein CO, Angulo P, Lindor KD. When is liverbiopsy needed in the diagnosis of primary bil-iary cirrhosis? Clin Gastroenterol Hepatol.2003;1:89-95.

Zein CO, Jorgensen RA, Clarke B, Wenger DE,Keach JC, Angulo P, Lindor KD. Alendronateimproves bone mineral density in primary bil-iary cirrhosis: a randomized placebo-con-trolled trial. Hepatology. 2005;42:762-71.

Cholestatic Liver Disease 381

Drug-induced liver injury is common in both inpa-tient and outpatient settings. In one study, the overallincidence of drug-induced liver disease was 13.9per 100,000 population annually. About 5% to 10%of hospitalizations for jaundice are due to drugs,and medications cause about 50% of cases of fulmi-nant liver failure. Drug-induced liver injury is themost common cause of regulatory action for drugs,including withdrawal from the market. Predisposingfactors for drug-induced liver injury are obesity ormalnutrition, extremes of age, female sex, pregnancy,polypharmacy, previous drug-induced liver injury,genetic influences, and preexisting liver disease.

DRUG METABOLISMOrally administered drugs are lipid-soluble, whichallows them to be absorbed into cells and affectbiologic processes. Drug-metabolizing systemsconvert the parent drug into water-soluble com-pounds, which allow excretion into the bile andurine. The metabolizing systems are divided intophase I and phase II reactions. Phase I reactionsinvolve the cytochrome P-450 (CYP) family ofenzymes and include the addition of polar groups

by oxidation, reduction, or hydrolysis. The metabo-lites formed by phase I reactions may be toxic ifnot subsequently excreted or further metabolized.Activity of phase I reactions is influenced by age,other drugs, and toxins (Table 1). The CYP3A sub-family is the most prominent P-450 systeminvolved in drug metabolism.

Phase II reactions further enhance the watersolubility of a compound and generally involveconjugation of glucuronide, sulfate, acetate, glycine,or glutathione to a polar group. Occasionally, phaseII reactions may affect the parent compounddirectly (ie, without a previous phase I reaction).Age, dietary factors, and nutritional status can alterthe activity of phase II reactions. The influence ofalterations in drug-metabolizing systems on drug-induced liver injury is incompletely understood.

MECHANISMS OF DRUG-INDUCEDLIVER INJURYDrug-induced liver injury can be divided broadlyinto direct chemical toxicity and idiosyncratic reac-tions. Direct toxicity is dose related; the mostcommon example is the hepatotoxicity associated

383

CHAPTER 30

Drug-Induced Liver Injury


Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CYP,cytochrome P-450; HIV, human immunodeficiency virus.

with acetaminophen. Direct toxicity usually occursafter a brief exposure. For a given drug, there isconsiderable variability in the dose required tocause toxicity, largely because of individual dif-ferences in drug metabolism. These differencescan be genetic or due to exogenous effectors ofdrug metabolism.

Idiosyncratic reactions, which are unpredictableand unrelated to medication dose, can be due toeither metabolic factors or hypersensitivity. Mostdrug-induced hepatotoxicity is metabolic, whichinvolves the accumulation of toxic metaboliteswithin hepatocytes that leads to necrosis andinflammation. Although genetic influences inmetabolic drug-induced liver injury are probablyimportant, they are incompletely understood.An example of a predictable metabolic druginjury occurs with irinotecan toxicity in patientswith Gilbert’s syndrome, because the metabo-lism of irinotecan is impaired by a deficiency inthe same enzyme that contributes to the conju-gation of bilirubin.

Liver injury from hypersensitivity usually fol-lows 1 to 5 weeks of exposure to the drug and isaccompanied by rash, fever, and eosinophilia andrecurs with rechallenge. Although the features ofhypersensitivity are very suggestive of drug-inducedliver injury, hypersensitivity features are seen inonly about 20% of all cases of idiosyncratic drug-induced liver injury. Examples of drugs that canresult in a hypersensitivity reaction are sulfonamides,amoxicillin-clavulanate, phenytoin, and halothane.

Because the specific mechanism of drug-induced liver injury is not understood in mostcases, predicting this injury usually is not pos-sible. Deficiencies in certain P-450 enzymes,genetic polymorphisms in immune processes ofcertain interleukins, and certain human leukocyteantigen haplotypes have all been associated withdrug-induced liver injury. Perhaps in the future,pharmacogenetic testing will permit the predictionof individual patterns of drug metabolism andassessment of risk factors for drug-induced liverinjury, thus allowing avoidance of the agent bysusceptible persons.

DIAGNOSISThere is no specific test for drug-induced liverinjury. The maxim that “almost any drug can doanything” is important to consider when evalu-ating patients who have abnormal liver test results.Although the time between the initiation of med-ication use and the onset of hepatotoxicity varies,most drug-induced liver injury occurs within ayear after treatment is started with the drug. Drug-induced liver injury should be suspected whenliver injury occurs soon after the initiation of treat-ment with the agent or after an increase in the doseof an agent that had been administered previously.

Generally, the exclusion of other causes of liverdisease is required before the diagnosis of drug-induced liver injury is made. A recent report thatshowed a positive test for hepatitis E (despite anabsence of relevant travel history) in patients pre-viously thought to have drug-induced liver injuryemphasizes the difficulty with diagnosis.Resolution of the injury after withdrawal of treat-ment with the drug is supportive of the diagnosisof drug-induced liver injury, although the timingof improvement after the withdrawal varies. Also,improvement after withdrawal of the agent may becoincidental if the liver injury is due to an identi-fied cause that coincidentally improves as the drugis withdrawn.

Hepatotoxicity due to drugs can be catego-rized by the biochemical pattern of liver injuryaccording to the following equation:

R=ALT (measured in multiples of ULN)/ALP(measured in multiples of ULN)

384 Liver

Table 1. Drugs and Conditions That AffectActivity of the Cytochrome P-450(CYP) System

Inhibit CYP activity Induce CYP activity

Clarithromycin CarbamazepineErythromycin Chronic alcohol useFluconazole PhenobarbitalIncreasing age PhenytoinItraconazole RifampinKetoconazoleRitonavir

where ALP is alkaline phosphatase, ALT is ala-nine aminotransferase, and ULN is upper limit ofnormal. Hepatotoxicity is considered hepatocel-lular when R is more than 5, cholestatic when R isless than 2, and mixed when R is between 2 and 5.Although most drugs have a signature pattern ofhepatotoxicity (Table 2), different biochemical pre-sentations of drug-induced liver injury can occurwith the same agent.

Many drugs cause mild, often insignificant,and transient increases in liver enzyme levels

within a few months. These usually represent anadaptive response to the drug and do not necessitatewithdrawal of the agent. For example, isoniazidincreases the ALT level more than 3 times the upperlimit of normal in 15% of patients, but the enzymelevels usually normalize despite continued treat-ment. Generally, there should be concern aboutclinically significant drug-induced liver injurywhen liver enzyme levels increase more than 5times the upper limit of normal or when impairedliver function is noted.

Drug-Induced Liver Injury 385

Table 2. Patterns of Liver Injury for Certain Drugs

Hepatocellular Mixed (elevated ALP + Cholestatic(elevated ALT) elevated ALT) (elevated ALP)

Acarbose Amitriptyline Amoxicillin-clavulanic acidAcetaminophen Azathioprine Anabolic steroidsAllopurinol Captopril ChlorpromazineAmiodarone Carbamazepine ClopidogrelBaclofen Clindamycin Oral contraceptivesBuproprion Cyproheptadine ErythromycinsFluoxetine Enalapril EstrogensHAART drugs Flutamide IrbesartanHerbals: kava kava and germander Nitrofurantoin MirtazapineIsoniazid Phenobarbital PhenothiazinesKetoconazole Phenytoin TerbinafineLisinopril Sulfonamides TricyclicsLosartan TrazodoneMethotrexate Trimethoprim-sulfamethoxazoleNSAIDs VerapamilOmeprazoleParoxetinePyrazinamideRifampinRisperidoneSertralineStatinsTetracyclinesTrazodoneTrovafloxacinValproic acid

ALP, alkaline phosphatase; ALT, alanine aminotransferase; HAART, highly active antiretroviral therapy; NSAID,nonsteroidal antiinflammatory drug.

From Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354:731-9. Used with permission.

HISTOLOGIC PATTERNS OF DRUG-INDUCED LIVER INJURYHistologic features of centrilobular necrosis,eosinophilic infiltration, and granulomas are sug-gestive of drug-induced liver injury. However,these findings are not specific for diagnosis, andclinical correlation is mandatory. Drug-inducedliver injury may mimic other liver diseases andshould be part of the differential diagnosis of themultiple histologic patterns.

SteatosisDrug-induced liver injury should be consideredin patients with hepatic steatosis. Valproic acidand tetracycline cause acute development ofmicrovesicular steatosis, whereas tamoxifen,amiodarone, methotrexate, and corticosteroidscause steatosis that develops over months and ispredominantly macrovesicular. More recently, thechemotherapeutic agents irinotecan and oxali-platin have been associated with the developmentof steatohepatitis. Chronic liver injury frommethotrexate and amiodarone can lead even to thedevelopment of advanced fibrosis.

Portal and Periportal Hepatitis Certain drugs produce protein adducts that canact as neoantigens, producing clinical features thatmimic those of autoimmune hepatitis. The mostcommon offenders are minocycline and nitrofu-rantoin. Drug-induced autoimmune hepatitis isassociated with more than 6 months of exposure tothe drug, female sex, and the presence of HLAtypes DR3 and DR4. This type of drug-inducedliver injury does not always remit spontaneouslyafter the drug has been withdrawn, and treatmentwith corticosteroids has produced variable results.A histologic pattern that mimics that of primarybiliary cirrhosis can develop after the administra-tion of chlorpromazine.

Sinusoidal Obstruction SyndromeThe sinusoidal obstruction syndrome, or veno-occlusive disease, is due most often to myeloablativetherapy that is given before stem cell transplantation,but it can occur also after the administration ofazathioprine. The presentation is similar to that ofBudd-Chiari syndrome, with ascites present in nearlyall patients. Anticoagulation can be considered for

treatment of sinusoidal obstruction syndrome,although the mortality rate is high, especially afterbone marrow transplantation, in which 15% to 30%of patients die.

EXAMPLES OF DRUG-INDUCED LIVERINJURY

AcetaminophenMost drug-induced liver injury is acute. Drugscommonly implicated in acute hepatitis are aceta-minophen, antituberculosis agents, antibiotics,and antiseizure drugs. The most common causeof fulminant liver failure in the United States andEurope is acetaminophen toxicity. The metabo-lism of acetaminophen is shown in Figure 1.Decreases in glutathione found in patients withchronic liver disease predispose to the productionof the toxic metabolite. Also, patients with chronicexcessive intake of alcohol produce more of thetoxic intermediate because of the induction ofCYP2E1 activity.

Adding to the role of acetaminophen in ful-minant liver failure, acetaminophen adducts (N-acetyl-p-quinoneimine bound to protein) havebeen identified in 20% of cases of “indeterminate”fulminate liver failure. More than half of thesecases have been “therapeutic misadventures,” inwhich patients inadvertently ingested toxic dosesof acetaminophen. Many of these patients havechronic alcoholism, which up-regulates the pro-duction of the toxic metabolites of acetaminophen.

Acetaminophen hepatotoxicity is character-ized by very high levels of aminotransferases, oftenmore than 5,000 IU/mL. Renal failure is alsocommon. The degree of increase in the aspartateaminotransferase (AST) level at the time of pre-sentation following an acetaminophen overdoseis helpful in predicting hepatotoxicity. Patientswith AST levels less than 50 IU/mL at presenta-tion rarely develop hepatotoxicity, whereas 16%of those with AST levels more than 1,000 IU/mL atpresentation die or need liver transplantation.Patients with acetaminophen hepatotoxicity andpoor prognostic markers should be hospitalizedand their condition monitored. The criteria for livertransplantation are listed in Table 6 in Chapter 21.When N-acetylcysteine is administered soon after

386 Liver

acetaminophen has been ingested, it acts byenhancing the conjugation and, thus, the watersolubility and excretion of N-acetyl-p-quino-neimine. When administered later, after liver injuryhas developed, N-acetylcysteine acts by antioxi-dant and antiinflammatory mechanisms that arenot well understood. N-acetylcysteine also mayenhance liver perfusion through inotropic andvasodilatory effects. Although the efficacy of N-acetylcysteine diminishes when it is given morethan 8 hours after acetaminophen has beeningested, it nonetheless should be given up to 24hours after ingestion because of its putative hepato-protective effects.

AntibioticsAntibiotics are the drug class that most commonlycauses nonfulminant liver injury. Amoxicillin-clavulanic acid is the most frequently reportedantibiotic that causes hepatotoxicity. Liver injuryusually manifests within 1 to 4 weeks after treat-ment with the drug has been stopped, but it canoccur even later. This delayed phenomenon makesdiagnosis difficult. Toxicity may be hepatocellularor cholestatic. Similar to other forms of drug-induced cholestatic liver injury, the cholestasis dueto amoxicillin-clavulanic acid may take weeks toresolve and may even result in chronic liver injury.Telithromycin is a ketolide antibiotic that recentlyhas been reported to cause severe hepatotoxicity.

Antiretroviral AgentsDrugs against the human immunodeficiencyvirus (HIV) cause hepatotoxicity in 2% to 18% ofpatients. Drug-induced liver injury may be diffi-cult to diagnose in these patients because mostof them take multiple drugs and may have otherrisk factors for liver disease, such as viral hepatitisor alcoholism. Drug-induced liver injury may bemore common in patients with viral hepatitis,especially hepatitis C. All classes of antiretroviraltherapy can produce liver injury. Of the proteaseinhibitors, ritonavir, especially at high dose, hasthe highest risk of liver toxicity, with an incidenceof 3% to 9%. The newer protease inhibitor tipranavirhas been associated with severe hepatotoxicity,especially when used in combination with riton-avir and particularly in patients with hepatitisB or C.

The major toxic effect of nucleoside reversetranscriptase inhibitors is lactic acidosis. Anasymptomatic increase in lactate level withoutmetabolic acidosis occurs in 8% to 18% of patientsand may be transient. Lactic acidosis syndrome islikely due to mitochondrial toxicity and may beaccompanied by severe liver dysfunction.Histologic examination of the liver usually showssteatosis, and the mortality rate is high. Amongpatients with hepatitis C, the administration ofribavirin to those also receiving didanosine orstavudine has been associated with mitochon-drial toxicity. Ribavirin for hepatitis C in patientstaking zidovudine is associated with an increasedrisk of anemia.

A hypersensitivity reaction due to the nonnu-cleoside reverse transcriptase inhibitor nevirapineoccurs in 2.3% of patients. This develops within afew weeks after the start of therapy and mayinclude hepatotoxicity. Even more common, late-onset toxicity may also occur. Patients who havechronic viral hepatitis are likely at increased risk fortoxicity with nevirapine therapy.

Herbal TherapiesHerbal medications always should be consideredin the differential diagnosis of liver injury. Manypatients do not consider over-the-counter, nutri-tional, or herbal supplements as “medicines;” thus,these agents may not be included when patientsare asked about medicines taken before the episodeof liver injury. Careful, repeated, and directed ques-tioning is required.

Lipid-Lowering AgentsBecause of the frequency with which statins areprescribed, there has been much interest in thepotential liver toxicity of these agents. Deter-mining whether patients receiving statins havedrug-induced liver injury is difficult because mildincreases in liver enzyme levels are commonwithin 1 month after the initiation of statintherapy, but the levels nearly always improvedespite continued administration of these agents.Furthermore, mildly fluctuating liver enzymelevels are seen also in hyperlipidemic patientsnot receiving statin therapy. The presence of non-alcoholic fatty liver disease in many patients whoare candidates for statin therapy further confounds


the issue, although it has been well demonstratedthat statin drugs are safe for patients with nonalco-holic fatty liver disease. In fact, small studies haveshown histologic improvement in these patients.

Serious toxicity from statin agents is rare. Therisk of fulminant liver failure associated withlovastatin, the first of the statins to be approvedfor treatment of hypercholesterolemia, is about 1in 1 million patient-treatment years, a value thatis similar to the rate of idiopathic fulminant liverfailure. From 1990 to 2002, only 3 of more than51,000 liver transplants in the United States wereperformed for presumed statin-induced liverinjury. Nevertheless, monitoring is still recom-mended, usually before treatment is initiated and12 weeks after therapy is initiated. Monitoringshould be considered also after a change in dose orthe administration of a second lipid-lowering

agent. Statins rarely have been associated with thedevelopment of autoimmune hepatitis, althoughthe association may be only coincidental.

Ezetimibe, which blocks the intestinal absorp-tion of cholesterol, has been associated with elevatedliver enzyme levels and, when used in combinationwith statins, may rarely cause clinically significanthepatoxicity. Sustained-release niacin also may pro-duce symptomatic hepatotoxicity.

TREATMENT AND PROGNOSIS OFDRUG-INDUCED LIVER INJURYFor most cases of drug-induced liver injury, treat-ment is withdrawal of the agent and general sup-port. Patients with severe liver dysfunction who arepotential candidates for liver transplantation shouldbe referred to a transplant center. For acetaminophen

388 Liver

HN–C–CH3 HN–C–CH3 HN–C–CH3

SO4

SulfateAPAP

HN–C–CH3

SulfotransferaseGlucuronyltransferase

Glucuronide

O-Gluc OH

O O O= = =

=

= =

P-450 2E1(P-450 1A2)(P-450 3A4)

O

OGSH

transferaseCovalentbinding

NAPQI

OO

OH

Necrosis

HN–C–CH3HN–C–CH3

S-G S-Prot

Mercapluric Acid

Fig. 1. Metabolism of acetaminophen. Most APAP is conjugated to either glucuronide or sulfate. That portionwhich is oxidized to NAPQI is further detoxified by glutathione transferase. If this system is overwhelmed,NAPQI binds to cellular targets leading to hepatocellular necrosis. APAP, acetaminophen; GSH, glutathione;NAPQI, N-acetyl-p-benzoquinoneimine. (From Zimmerman HJ. Acetaminophen hepatotoxicity. Clin Liver Dis.1998;2:527. Used with permission.)

toxicity, N-acetylcysteine should be given.Carnitine may be helpful for valproic acid-induced microvesicular steatosis. Drug-inducedautoimmune hepatitis that does not improvespontaneously can be treated with corticosteroids.

The prognosis of drug-induced acute hepatitisvaries. According to Hy’s rule (named after thehepatologist Hyman Zimmerman), patients withjaundice due to drug-induced hepatocellular injuryhave a 10% mortality rate without transplantation,even if treatment with the drug is discontinuedpromptly. Patients with fulminant liver failure dueto idiosyncratic drug injury have an 80% mortalityrate without transplantation. The histologic fea-tures of drug-induced hepatitis include diffuselobular injury that may be most prominent in zone3 (centrilobular area). The presence of eosinophilsis very suggestive of drug-induced liver injury,but it is not a sensitive marker.

Cholestatic liver injury can mimic large bileduct obstruction both clinically and histologically.Cholestatic liver injury is less likely to be seriousthan hepatocellular drug injury but is more likelyto be prolonged. In addition to the clinical featuresof increased alkaline phosphatase levels and, fre-quently, jaundice, cholestatic drug-induced liverinjury often has a more gradual improvementthan that of drug-induced hepatocellular injury.The mechanism of drug-induced cholestasis isnot well known, but it may involve injury to bileacid transporters. Ursodiol has been used in cases

of drug-induced cholestasis with a prolongedrecovery phase. Responses have been reported,but the lack of controlled data makes it difficult todraw conclusions about the efficacy of ursodiol.

RECOMMENDED READINGBjörnsson E. Drug-induced liver injury: Hy’s rule

revisited. Clin Pharmacol Ther. 2006; 79:521-8.Chang CY, Schiano TD. Review article: drug hepa-

totoxicity. Aliment Pharmacol Ther. 2007;25:1135-51.

Dalton HR, Fellows HJ, Stableforth W, Joseph M,Thurairajah PH, Warshow U, et al. The role ofhepatitis E virus testing in drug-induced liverinjury. Aliment Pharmacol Ther. 2007 Nov;26:1429-35. Epub 2007 Sep 7.

Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E,Hynan LS, et al, Acute Liver Failure Study Group.Acetaminophen-induced acute liver failure:results of a United States multicenter, prospec-tive study. Hepatology. 2005;42: 1364- 72.

Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH.Pathogenesis, natural history, treatment, andprevention of hepatitis C. Ann Int Med.2000;132:296-305.

Navarro VJ, Senior JR. Drug-related hepatotoxicity.N Engl J Med. 2006;354:731-9.

Núñez M. Hepatotoxicity of antiretrovirals: inci-dence, mechanisms, and management. J Hepatol.2006;44(1 Suppl):S132-S139. Epub 2005 Nov 28.


DIAGNOSISAutoimmune hepatitis is a self-perpetuatinginflammation of the liver of unknown cause that isassociated with interface hepatitis seen on histo-logic examination, hypergammaglobulinemia, andautoantibodies. An international panel has codifiedthe diagnostic criteria, and definite diagnosisrequires the exclusion of hereditary (Wilson’s dis-ease, genetic hemochromatosis, and α1-antitrypsindeficiency), viral (hepatitis A, B, and C virus infec-tions), and drug-induced (diclofenac, isoniazid,propylthiouracil, α-methyldopa, minocycline, ornitrofurantoin-related) conditions (Table 1).

The 6-month requirement to establishchronicity has been waived, and an acute, rarelyfulminant, presentation has been recognized thatmay resemble acute viral or toxic hepatitis. Acholestatic form of autoimmune hepatitis is notrecognized, and a marked increase (more thantwofold the upper limit of normal) in the serumalkaline phosphatase level or the presence of pru-ritus suggests another diagnosis. Celiac disease can

be associated with a liver disease that resemblesautoimmune hepatitis, and it should be excludedin patients who have cryptogenic chronic hepatitis.

Interface hepatitis is the histologic hallmarkof autoimmune hepatitis (Fig. 1). The morphologicpattern is nonspecific and occurs in acute andchronic liver disease of diverse causes. Plasma cellinfiltration of the hepatic parenchyma or portaltracts (or both) is apparent in 66% of tissue speci-mens, but its presence is neither specific norrequired for the diagnosis (Fig. 2). A lobular, orpanacinar, hepatitis frequently accompanies inter-face hepatitis (Fig. 3), and a centrilobular (zone 3)necrosis has also been described (Fig. 4). Successiveexaminations of liver tissue have shown transitionof the centrilobular (zone 3) necrosis to interfacehepatitis, and it may be an early form of the disease.

A scoring system that grades individual com-ponents of the syndrome provides an objectivemeans to assess the strength of the diagnosis, accom-modate unusual features, and compare populationsin different geographic regions and treatment trials

391

CHAPTER 31

Autoimmune Hepatitis

Albert J. Czaja, MD

Abbreviations: AIRE, autoimmune regulator; AMA, antimitochondrial antibodies; ANA, antinuclear antibodies; anti-ASGPR, asialogylcoprotein receptor antibodies; anti-LC1, liver cytosol type 1 antibodies; anti-LKM1, liver/kidneymicrosome type 1 antibodies; anti-SLA/LP, soluble liver antigen/liver pancreas antibodies; APECED, autoimmunepolyendocrinopathy-candidiasis-ectodermal dystrophy; AST, aspartate aminotransferase; HCV, hepatitis C virus; IL,interleukin; pANCA, perinuclear antineutrophil cytoplasmic antibodies; SMA, smooth muscle antibodies.

(Table 2). The scoring system has been developed asa research tool to ensure homogeneous populationsin research studies; it usually is not needed for aconfident clinical diagnosis.

392 Liver

Table 1. Criteria for Diagnosis ofAutoimmune Hepatitis (AIH)

Diagnostic criteria

Definite AIH Probable AIH

Normal AAT Partial AATphenotype deficiency

Normal ceruloplasmin Abnormal copper level or ceruloplasmin

level but Wilson’sdisease excluded

Normal iron and Nonspecific iron ferritin levels or ferritin abnor-

malitiesNo active hepatitis A, No active hepatitis

B, or C infection A, B, or C infection

Daily alcohol <25 g Daily alcohol <50 gNo recent hepatotoxic No recent hepato-

drugs toxic drugsPredominant serum Predominant serum

aminotransferase aminotransferase abnormality abnormality

Globulin, γ-globulin, Hypergammaglob-or IgG level ≥1.5 ulinemia of anytimes normal degree

ANA, SMA, or anti- ANA, SMA, orLKM1 ≥1:80 in adults anti-LKM1 ≥1:40 and ≥1:20 in children; in adults; other no AMA autoantibodies

Interface hepatitis— Interface hepatitis—moderate to severe moderate to severe

No biliary lesions, No biliary lesions, granulomas, or granulomas, or prominent changes prominent changessuggestive of suggestive of another disease another disease

AAT, α1-antitrypsin; AMA, antimitochondrialantibodies; ANA, antinuclear antibodies; anti-LKM1,antibodies to liver/kidney microsome type 1; IgG, serumimmunoglobulin G level; SMA, smooth muscleantibodies.

Modified from Czaja AJ. Autoimmune liver disease. In:Zakim D, Boyer TD, editors. Hepatology: a textbook ofliver disease. Vol 2. 4th ed. Philadelphia: Saunders;2003. p. 1163-1202. Used with permission.

Fig. 1. Interface hepatitis. The limiting plate of theportal tract is disrupted by an inflammatoryinfiltrate that extends into the acinus. Interfacehepatitis is a requisite for the diagnosis ofautoimmune hepatitis, but it is not specific for thediagnosis. (Hematoxylin and eosin; ×200.) (FromCzaja AJ. Current concepts in autoimmune hepatitis.Ann Hepatol. 2005;4:6-24. Used with permission.)

Fig. 2. Plasma cell infiltration of the hepaticparenchyma. Plasma cells (arrow) are characterized bya cytoplasmic halo adjacent to a deeply basophilicnucleus. Plasma cells typically are abundant at theinterface and throughout the acinus, but they do nothave diagnostic specificity. (Hematoxylin and eosin;×400.) (From Czaja AJ. Current concepts inautoimmune hepatitis. Ann Hepatol. 2005;4:6-24. Usedwith permission.)

FREQUENCY AND ETHNICDISTRIBUTIONAutoimmune hepatitis afflicts 100,000 to 200,000persons in the United States and accounts for 5.9%of liver transplantations performed in the UnitedStates. Among white northern Europeans, its meanannual incidence is 1.9 per 100,000, and its pointprevalence is 16.9 per 100,000. Its occurrence issimilar to that of primary biliary cirrhosis and pri-mary sclerosing cholangitis and less than that ofchronic viral hepatitis and alcoholic liver disease.Autoimmune hepatitis occurs mainly in women(female-to-male ratio, 3.6:1), and it affects all ages,including infants.

Originally described in white northernEuropeans and North Americans, the occurrenceof autoimmune hepatitis is now recognized to beworldwide. Ethnic background may affect its clin-ical presentation, and African American patientshave a higher frequency of cirrhosis at presenta-tion than white North Americans. Alaskan nativeshave a higher occurrence of acute icteric diseasethan nonnative patients; Arab patients havecholestatic features; Asians tend to have late-onset,mild disease; South American patients are com-monly young children with severe disease; andSomali patients are usually men with cholestaticfeatures and a poor response to corticosteroid treat-ment. These findings suggest that differences in

genetic predisposition or regional differences inetiologic agents may affect the clinical phenotype.

ETIOLOGYThe cause of autoimmune hepatitis is unknown.Multiple agents have been implicated as triggers ofthe disease, including certain viruses (hepatitis A,hepatitis B, hepatitis C, and measles viruses) anddrugs (diclofenac, isoniazid, α-methyldopa,minocycline, nitrofurantoin, and propylthiouracil).Hepatitis A virus infection and minocycline havebeen implicated most often worldwide. Most caseshave no identifiable trigger.

Triggers may share epitopes that resembleself-antigens, and they may break self-toleranceby overcoming antigenic ignorance, mimickingsequestered epitopes, or generating neoepitopes(or a combination of these). Molecular mimicrybetween foreign antigens and self-antigens is themost frequently proposed initiating mechanism.A long lag time between antigenic exposure anddisease expression and the persistence of diseaseafter the disappearance of the triggering event fur-ther complicate efforts to identify an etiologic basis.The target autoantigen responsible for autoimmunehepatitis may have a short epitope that commonly

Autoimmune Hepatitis 393

Fig. 3. Panacinar hepatitis. Cellular infiltrates (thickarrow) line sinusoidal spaces in association with livercell degenerative and regenerative changes. Rosettesof hematocytes (thin arrows) are also present.(Hematoxylin and eosin; ×200.)

Fig. 4. Centrilobular (Rappaport zone 3) necrosis.Inflammatory cells and injured hepatocytes aredistributed mainly in the centrilobular zone 3 (CV)area. (Hematoxylin and eosin; ×200.) (From Czaja AJ,Carpenter HA. Autoimmune hepatitis. In: Burt AD,Portmann BC, Ferrell LD, editors. MacSween’spathology of the liver. 5th ed. London: ChurchillLivingstone; 2007. p. 493-515. Used with permission.)

is shared by other peptides within the patient.Repeated exposures to the triggering antigen, inturn, may trigger autoreactive responses againstthe liver and anatomically distant organs, therebycausing not only autoimmune hepatitis but con-current immune diseases.

CLINICAL FEATURESWomen constitute at least 70% of cases, and 50%are younger than 40 years (Table 3). Onset is usuallybetween the third and fifth decades, but the age atonset may range from infancy to the extremeelderly. Autoimmune hepatitis tends to be moresevere in children than in adults. Children com-monly have cirrhosis at presentation (as many as

50%), and, during therapy, they enter a sustainedremission less often than adults, especially if theyhave antibodies to liver/kidney microsome type 1(anti-LKM1). Cholangiographic abnormalities thathave been designated as autoimmune sclerosingcholangitis can occur in children, and they may notbe accompanied by cholestatic features, inflamma-tory bowel disease, or refractoriness to corticosteroidtreatment. In contrast, adults with autoimmunehepatitis and similar cholangiographic findings typ-ically have inflammatory bowel disease and a poorresponse to corticosteroid therapy.

Elderly patients more commonly have cirrhosisat presentation and concurrent thyroid (Graves’disease or autoimmune thyroiditis) or rheumatic(rheumatoid arthritis, Sjögren’s syndrome, or

394 Liver

Table 2. Revised Scoring System of the International Autoimmune Hepatitis Group for theDiagnosis of Autoimmune Hepatitis*

Factors Score Factors Score

Female sex +2 Hepatotoxic drugsALP:AST (ALT) ratio Yes −4

>3 −2 No +1<1.5 +2 Alcohol use

γ-Globulin or IgG levels <25 g/day +2>2 ULN +3 >60 g/day −21.5-2 ULN +2 HLA-DR3 or HLA-DR4 +11-1.4 ULN +1 Concurrent immune disease +2

ANA, SMA, or anti-LKM1 Other liver-related autoantibody +2>1:80 +3 Interface hepatitis +31:80 +2 Plasmacytic infiltrate +11:40 +1 Rosettes +1<1:40 0 No characteristic features −5

AMA −4 Biliary changes −3Viral markers Other features (fat, granulomas) −3

Seropositive −3 Treatment responseSeronegative +3 Complete +2

Relapse +3

ALP:AST, ratio of serum alkaline phosphatase to aspartate aminotransferase level; ALT, serum alanine aminotransferaselevel; AMA, antimitochondrial antibodies; ANA, antinuclear antibodies; anti-LKM1, antibodies to liver/kidneymicrosome type 1; HLA, human leukocyte antigen; SMA, smooth muscle antibodies; ULN, upper limit of normal.

*Pretreatment score: definite diagnosis, >15; probable diagnosis, 10-15. Posttreatment score: definite diagnosis, >17;probable diagnosis, 12-17.

Modified from Czaja AJ: Autoimmune hepatitis. In: Feldman M, Friedman LS, Sleisenger MH, editors. Sleisenger &Fordtran’s gastrointestinal and liver disease: pathophysiology/diagnosis/ management. Vol 2. 7th ed. Philadelphia:Saunders; 2002. p. 1462-73. Used with permission.

systemic lupus erythematosus) disorders thanyoung adult patients. Elderly white patients fromNorth America or northern Europe have HLA-DRB1*04 more often and HLA-DRB1*03 less fre-quently than young adult patients with a similarethnic background, and they respond well to cor-ticosteroid therapy. These findings suggest thatelderly patients have triggering events that aredifferent from those of young adults or that theirgenetic phenotype is associated with a less vig-orous immune response. Aging alters immuneresponsiveness (immunosenescence) by decreasingthe expression of HLA class II molecules and

reducing stimulation and proliferation of antigen-stimulated T cells. These effects may attenuate thepathogenic mechanisms in the elderly and renderthese patients more responsive to treatment.

Forty percent of patients have an abrupt onsetof symptoms, and a fulminant presentation ispossible, especially in the young. Autoimmunehepatitis also may have an indolent clinical coursethat exacerbates spontaneously and resemblesacute hepatitis. Features of chronic liver disease,including hypergammaglobulinemia and fibrosisor cirrhosis seen on histologic examination, arecommon in these patients. In others with an acutepresentation, the findings are indistinguishablefrom those of severe acute hepatitis; the histologicfeatures include interface and lobular hepatitiswithout fibrosis or cirrhosis. The acute severe andfulminant presentations of autoimmune hepatitisare important to recognize because the institutionof corticosteroid therapy can be beneficial in 36%to 100% of these patients.

Autoimmune hepatitis is asymptomatic in 25%to 34% of patients at presentation. Symptomaticand asymptomatic patients have similar histologicfeatures, including the occurrence of cirrhosis.Many asymptomatic patients (26%) have inactivecirrhosis, and their survival is not enhanced withcorticosteroid treatment. Similarly, asymptomaticpatients without cirrhosis who have mild inflam-matory activity can have 10-year life expectanciesthat exceed 80% without treatment. In theseinstances, the absence of symptoms is associatedwith stable inactive or minimally active disease,and treatment is not warranted. Asymptomaticpatients commonly become symptomatic (26%-70%), and they must be monitored regularly for pro-gressive disease activity. The absence of symptomsis not a justification for withholding treatment frompatients who otherwise have active disease.

Symptomatic patients typically have easy fati-gability. Other symptoms include myalgia,arthralgia, anorexia, jaundice or dark urine, and,less commonly, cosmetic changes (facial rounding,hirsutism, or acne), delayed menarche or amen-orrhea, obscure fever (rarely as high as 40°C), andright upper quadrant discomfort. Pruritus andweight loss are unusual, and they suggest an alter-native diagnosis or a disease complicated by biliaryobstruction or hepatocellular cancer.


Table 3. Typical Features of AutoimmuneHepatitis

Feature Patients, %

Clinical featuresFemale sex 70Younger than 40 years 50Acute onset 40Asymptomatic 25-34

Common symptomsFatigue 85Arthralgia 30Myalgia 30Develop later from asymptomatic 26-70

presentationFrequent physical findings

Normal 80Hepatomegaly 20

Typical laboratory findingsIncreased serum levels of AST 100

and ALTIncreased serum levels of 90

γ-globulin and IgGMild hyperbilirubinemia (bilirubin 83

<3 mg/dL)Serum alkaline phosphatase 67

increased <2-fold ULNANA, SMA, or anti-LKM1 87

ALT, alanine aminotransferase; ANA, antinuclearantibodies; anti-LKM1, antibodies to liver/kidneymicrosome type 1; AST, aspatate aminotransferase; SMA,smooth muscle antibodies; ULN, upper limit of normal.

Familial occurrences are rare, but autoimmunehepatitis has been reported in siblings, parents,and grandparents of afflicted persons. First-degreerelatives may have abnormal serum levels ofimmunoglobulin (47%), autoantibodies (42%), andhypergammaglobulinemia (34%). In one series, 3of 55 families (5%) had more than one familymember with chronic liver disease. The rarity offamilial clustering, the uncertain pathogenesis ofthe disease, and the variable phenotype of theillness do not justify family screening.

PHYSICAL FINDINGSMost patients with autoimmune hepatitis havenormal physical examination findings despitesevere inflammatory activity (Table 3).Hepatomegaly is the most common physicalfinding. Ascites and hepatic encephalopathy areindicative of advanced liver disease and cirrhosis,and they usually are not noted at presentation.Hyperpigmentation and xanthelasmas are incom-patible with the diagnosis. The clinical features ofacne, hirsutism, obesity, and amenorrhea in youngwomen that originally constituted the syndrome of“lupoid hepatitis” are now rarely seen.

LABORATORY FEATURESAbnormalities in serum aminotransferase levelsare essential for the diagnosis of autoimmunehepatitis (Table 3). The serum γ-globulin level istypically, but not invariably, increased, and thediagnosis is suspect without this finding. In mostinstances, the serum aminotransferase level at pre-sentation does not exceed 500 U/L (range, 150 U/Lto >1,000 U/L), and the γ-globulin level rangesfrom 2 to 3 g/dL. A polyclonal increase in serumimmunoglobulin concentrations is typical, and theIgG fraction predominates.

Hyperbilirubinemia is present in 83% ofpatients with severe inflammatory activity, butthe serum bilirubin concentration exceeds 3 mg/dLin only 46%. Similarly, an abnormal increase in theserum level of alkaline phosphatase can be demon-strated in 81% of patients, but it is more thantwofold the upper limit of normal in only 33% andmore than fourfold the upper limit of normal inonly 10%.

Antinuclear antibodies (ANA), smooth muscleantibodies (SMA), and anti-LKM1 are the con-ventional serologic markers of autoimmunehepatitis. None is pathogenic or has prognosticvalue, and they may not be present in all patientswith the disease. Many patients who are seroneg-ative for the conventional autoantibodies subse-quently have these autoantibodies, as shown withrepeated testing during the course of the illnessand its treatment. Other patients may have sero-logic reactivities that are outside the standardrepertoire or are still undiscovered.

HLA-DRB1*03, HLA-DRB1*04, and HLA-DRB1*03–DRB1*04 are the principal risk factorsfor autoimmune hepatitis in white North Americanand northern European patients, and they arefound in 85% of cases (Table 4). HLA-DRB1*13 isfound mainly in South American children. HLA-DRB1*07 and DQB1*02 are the risk factors associatedwith the disease characterized by anti-LKM1. HLA-DRB1*03 is associated with early-age onset, dimin-ished response to corticosteroids, and frequentrequirement for liver transplantation. HLA-DRB1*04 is associated with disease onset at age 45years or older, female sex, and frequent concurrentimmune diseases. HLA typing has not beenendorsed as a diagnostic or prognostic tool, but itmay prove useful in determining etiologic factorsand populations at risk for the disease.

CONCURRENT IMMUNE DISEASESConcurrent immune diseases are present in 30% to48% of patients with autoimmune hepatitis (Table5). Adults have mainly autoimmune thyroiditis,Graves’ disease, ulcerative colitis, or synovitis, andchildren have mainly vitiligo, insulin-dependentdiabetes mellitus, or autoimmune sclerosingcholangitis. Elderly patients (>60 years) frequentlyhave autoimmune thyroiditis or rheumatic con-ditions (eg, rheumatoid arthritis or Sjögren’s syn-drome). Celiac sprue may be asymptomatic andpresent in 3% of patients; multiple immune diseasesoccur in 6% of patients. Ulcerative colitis suggeststhe possibility of primary sclerosing cholangitis, andit justifies the performance of cholangiography. Ofthe patients who have autoimmune hepatitis andulcerative colitis, 59% have normal cholangiogramsand respond well to corticosteroid treatment. The

396 Liver

other 41% have primary sclerosing cholangitis andare refractory to corticosteroid treatment.

Autoimmune hepatitis is present in 15% ofpatients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Thissyndrome is characterized by ectodermal dys-plasia, mucocutaneous candidiasis, and multipleendocrine organ failure (parathyroid, ovarian, andadrenal failure). A single gene defect on chromo-some band 21q22.3 has been identified as the basisfor the syndrome, and the disease is inherited inmendelian fashion. The APECED gene encodes fora transcription factor called the autoimmune regulator(AIRE), which modulates clonal deletion of autore-active T cells. APECED does not have HLA-DRassociations or female predominance.

AUTOANTIBODIESANA, SMA, and anti-LKM1 are the serologicmarkers of autoimmune hepatitis, and they shouldbe measured in all patients with suspected disease(Table 6). They are not pathogenic, and theirbehavior does not have important clinical impli-cations. Serum titers do not have prognostic sig-nificance, and low titers should not dissuade thediagnosis if other features implicate the disorder.The conventional autoantibodies may be absentin some patients at presentation; serum titers canfluctuate during the course of illness; and theautoantibodies at presentation may not be the sameones expressed later. As floating variables, themajor clinical value of autoantibodies is to supportthe diagnosis.


Table 4. Genetic Predispositions for Autoimmune Hepatitis

Genetic risk factor Pertinence Associations

HLA-DRB1*03 Principal risk factor in white Type 1 autoimmune hepatitisNorth Americans and northern Young age at onsetEuropeans Treatment failure is more common

Liver transplant is more frequentHLA-DRB1*04 Secondary and independent risk Type 1 autoimmune hepatitis

factor in white North Americans Older patientsand northern Europeans Women

Frequent immune diseasesGood response to treatment

DRB1*0301 Principal susceptibility allele in Pertienent allelic component of white North Americans and HLA-DRB1*03 responsible for northern Europeans disease effects

DRB1*0401 Secondary susceptibility allele in Pertinent allelic component ofwhite North Americans and HLA-DRB1*04 responsible fornorthern Europeans disease effects

HLA-DRB1*07 Susceptibility factor in type 2 Associated with anti-LKM1 in auto-autoimmune hepatitis immune hepatitis and chronic

hepatitis CDRB1*1301 Principal susceptibility allele in Type 1 autoimmune hepatitis

South America (Brazil and Mainly in childrenArgentina) Favors protracted hepatitis A infection

DRB1*1501 Protective allele in white northern Low frequency of type 1 autoimmuneEuropeans hepatitis

DQB1*02 Susceptibility factor in type 2 auto- May be responsibile for type 2 diseaseimmune hepatitis and not anti-LKM1

Anti-LKM1, antibodies to liver kidney microsome type 1; HLA, human leukocyte antigen.

Other autoantibodies that support the diagnosisof autoimmune hepatitis and whose assay gener-ally is available are perinuclear antineutrophilcytoplasmic antibodies (pANCA), which occur in50% to 90% of patients with type 1 autoimmunehepatitis. pANCA may be useful in the evaluationof seronegative (“cryptogenic”) chronic hepatitis.In this same fashion, IgA antibodies to tissue trans-glutaminase or endomysium are useful for excludingthe liver disease associated with celiac disease.

Antibodies that promise to enhance diagnosticand prognostic value but which have not beenincorporated into a conventional diagnostic algo-rithm (nonstandard antibodies) are antibodies toactin (anti-actin), soluble liver antigen/liver pan-creas (anti-SLA/LP), asialoglycoprotein receptor(anti-ASGPR), chromatin, and liver cytosol type 1

(anti-LC1) (Table 6). Anti-ASGPR, anti-chromatin,and anti-SLA/LP are associated with relapse aftertreatment withdrawal, and anti-actin and anti-LC1identify young patients who have aggressive dis-ease. The nonstandard antibodies may emerge asprognostic markers. Anti-SLA/LP have the mostpromise in this regard because they identifypatients who have disease relapse after withdrawalof corticosteroid therapy, have severe diseaseactivity, and possess HLA-DRB1*03.

Cryptogenic chronic hepatitis may be reclas-sified as autoimmune hepatitis by repeat testingfor the conventional autoantibodies or testing forthe nonstandard markers (pANCA or anti-SLA/LP).Conventional autoantibodies that are absent at pre-sentation may be expressed later during the courseof the disease. Anti-SLA/LP may be present in18% of patients who are seronegative by the con-ventional battery, and pANCA may also supportthe diagnosis in otherwise seronegative patients.Determination of IgA antibodies to tissue trans-glutaminase or endomysium may indicate celiacdisease in patients with cryptogenic disease.

Antimitochondrial antibodies (AMA), includingthose against the M2 antigens associated with pri-mary biliary cirrhosis, occur in 8% to 20% ofpatients with autoimmune hepatitis. Assays basedon indirect immunofluorescence may mistake anti-LKM1 for AMA because the diagnostic patternsof indirect immunofluorescence on the murinekidney tubule can be confused. Other patients mayhave an overlap syndrome with primary biliarycirrhosis, early-stage primary biliary cirrhosis,or coincidental collateral autoantibody produc-tion. In patients with otherwise classic autoim-mune hepatitis, AMA have not been associatedwith a cholestatic clinical syndrome, heraldedthe emergence of a different disease, or affectedtreatment response.

The typical autoantibodies of autoimmunehepatitis also can occur in chronic hepatitis B andC. They are usually low titer, background reactivi-ties that should not alter diagnosis or management.Anti-LKM1 have been found in as many as 10% ofEuropean patients with chronic hepatitis C. Theseantibodies are different from the anti-LKM1 foundin classic autoimmune hepatitis. Homologies havebeen described between the antigenic target ofanti-LKM1 and the genome of the hepatitis C virus

398 Liver

Table 5. Immune Diseases Associated WithAutoimmune Hepatitis

Autoimmune scleros- Intestinal villous ing cholangitis* atrophy

Autoimmune Iritisthyroiditis† Lichen planus

Celiac disease Myasthenia gravisCoomb’s-positive Neutropenia

hemolytic anemia PericarditisCryoglobulinemia Peripheral neuropathyDermatitis herpeti- Pernicious anemia

formis PleuritisErythema nodosum Pyoderma gangren-Fibrosing alveolitis osumFocal myositis Rheumatoid arthritis†

Gingivitis Sjögren’s syndromeGlomerulonephritis Synovitis†

Graves’ disease† Systemic lupusIdiopathic thrombo- erythematosus

cytopenic purpura Ulcerative colitis†

Insulin-dependent Urticariadiabetes* Vitiligo*

*Mainly in children.†Most common associations.Modified from Czaja AJ. Autoimmune liver disease. In:

Zakim D, Boyer TD, editors. Hepatology: a textbook ofliver disease. Vol 2. 4th ed. Philadelphia: Saunders;2003. p. 1163-1202. Used with permission.

(HCV), and this molecular mimicry may result incross-reacting antibodies in some patients. ANAand SMA can occur in acute and chronic hepatitisof diverse causes, including alcoholic and nonalco-holic fatty liver disease. Autoantibodies, regardlessof titer or type, expand the differential diagnosis, butthey never establish the true nature of the disease.

SUBCLASSIFICATIONSTwo types of autoimmune hepatitis have been pro-posed on the basis of serologic markers (Table 7).The International Autoimmune Hepatitis Group

has not endorsed these subclassifications becauseeach type lacks a specific etiologic agent, distinctiveclinical behavior, or requirement for a particulartreatment. Nevertheless, the designations havebecome useful clinical descriptors.

Type 1 Autoimmune HepatitisType 1 autoimmune hepatitis is characterized bythe presence of ANA and SMA (Table 7). It is themost common form of the disease worldwide,especially in white Northern Europeans and NorthAmericans. Seventy percent of the patients arewomen younger than 40 years, and more than 30%


Table 6. Autoantibodies Associated With Autoimmune Hepatitis (AIH)

Autoantibody Target Clinical value

Standard repertoireAntinuclear anti- Centromere Diagnosis of type 1 AIH

bodies RibonucleoproteinsSmooth muscle Actin, tubulin, vimentin, Diagnosis of type 1 AIH

antibodies desmin, skeletin Anti-LKM1 CYP2D6 Diagnosis of type 2 AIH

Supplemental repertoirepANCA Possible nuclear membrane Diagnosis of type 1 AIH

lamina Reclassification of cryptogenichepatitis

IgA antibodies to Recombinant or red blood Celiac disease and cryptogenictissue transglutaminase cell-derived tissue trans- hepatitis

glutaminaseIgA endomysial antibody Endomysium from monkey Celiac disease and cryptogenic

esophagus or human hepatitisumbilical cord

Investigational repertoireAntibodies to actin Microfilaments Diagnosis of type 1 AIHAnti-SLA/LP Cytosolic transfer Relapse and DRB1*03

Ribonucleoprotein complex Reclassification of cryptogenic hepatitis

Anti-ASGPR Asialoglycoprotein receptor Histologic activity and relapseAntibodies to Octomeric chromatin ANA-positive disease

chromatin molecule RelapseAnti-LC1 Formiminotransferase Diagnosis of type 2 AIH

cyclodeaminase Prognostic value

ANA, antinuclear antibodies; anti-ASGPR, antibodies to asialoglycoprotein receptor; anti-LC1, antibodies to liver cytosoltype 1; anti-LKM1, antibodies to liver/kidney microsome type 1; anti-SLA/LP, antibodies to soluble liver antigen/liver-pancreas; CYP2D6, cytochrome monooxygenase 206; pANCA, perinuclear antineutrophil cytoplasmic antibodies.

have concurrent immune diseases, especiallyautoimmune thyroiditis, synovitis, or ulcerativecolitis. The onset of symptoms is acute in 40% ofpatients; rarely, the disease may have a fulminantpresentation. Twenty-five percent of patients havecirrhosis at presentation, indicating that type 1autoimmune hepatitis has an indolent, subclinicalstage that is aggressive. The target autoantigen oftype 1 autoimmune hepatitis is unknown.

Type 2 Autoimmune HepatitisType 2 autoimmune hepatitis is characterized bythe presence of anti-LKM1 (Table 7). Type 2autoimmune hepatitis is predominantly a diseaseof children (ages 2-14 years) in Europe. Amongwhite North American adults with autoimmunehepatitis, only 4% have anti-LKM1. The targetautoantigen is the cytochrome monooxygenase2D6 (CYP2D6), which is an important drug-metab-olizing enzyme. Patients with type 2 autoimmune

hepatitis have a high frequency of concurrentautoimmune diseases, especially insulin-depen-dent diabetes mellitus, vitiligo, and autoimmunethyroiditis, and cholangiography may showautoimmune sclerosing cholangitis. The patientsalso commonly have organ-specific autoantibodies,such as antibodies to parietal cells, islets ofLangerhans, and the thyroid. One-third of patientswith anti-LKM1 express anti-LC1. In contrast totype 1 autoimmune hepatitis, patients with type2 disease do not have pANCA. Type 2 autoim-mune hepatitis responds as well to corticosteroidtherapy as does type 1 disease, and it also mayhave an acute, occasionally fulminant, presenta-tion that must be recognized and treated promptly.

GENETIC PREDISPOSITIONSType 1 autoimmune hepatitis has a strong geneticpredisposition, and 85% of white northern European

400 Liver

Table 7. Comparison of Types 1 and 2 Autoimmune Hepatitis

Autoimmune hepatitis

Feature Type 1 Type 2

Characteristic autoantibodies ANA, SMA Anti-LKM1Associated autoantibodies pANCA Anti-LC1

Anti-SLA/LP Anti-ASGPRAnti-actinAnti-ASGPR

Age at onset All ages Mainly pediatric (2-14 years)Common concurrent immune Autoimmune thyroiditis Vitiligo

diseases Synovitis Type 1 diabetesUlcerative colitis Autoimmune thyroiditis

Implicated genetic factors DRB1*0301 (N. Europe) DQB1*02DRB1*0401 (N. Europe) DRB1*03DRB1*1501 (protective)DRB1*1301 (S. America) DRB1*07

Autoantigen Uncertain CYP2D6Treatment Corticosteroids Corticosteroids

ANA, antinuclear antibodies; anti-ASGPR, antibodies to asialoglycoprotein receptor; anti-LC1, antibodies to liver cytosoltype 1; anti-LKM1, antibodies to liver/kidney microsome type 1; CYP2D6, cytochrome monooxygenase 2D6; pANCA,perinuclear antineutrophil cytoplasmic antibodies; SMA, smooth muscle antibodies.

Modified from Czaja AJ. Autoimmune liver disease. In: Zakim D, Boyer TD, editors. Hepatology: a textbook of liverdisease. Vol 2. 4th ed. Philadelphia: Saunders; 2003. p. 1163-1202. Used with permission.

and North American patients have HLA-DRB1*03,HLA-DRB1*04 or both DRB1*03 and DRB1*04(Table 4). Susceptibility resides within the DRB1gene. DRB1*0301 is the principal susceptibilityallele, and DRB1*0401 is a secondary, but inde-pendent risk factor. HLA-DRB1*03 and HLA-DRB1*04 are associated with different clinicalexpressions and treatment outcomes. Patients withHLA-DRB1*03 (DRB1*0301) are younger andrespond less well to corticosteroid therapy thanpatients with HLA-DRB1*04 (DRB1*0401).Remission occurs less frequently; treatment failureoccurs more often; and death from liver failure orrequirement for liver transplantation is morecommon in these patients. In contrast, patientswith HLA-DRB1*04 (DRB1*0401) are older, moreoften women, have a greater occurrence of otherimmune diseases, and have a higher frequency ofremission during corticosteroid treatment. HLA-DRB1*15 (DRB1*1501) protects against type 1 autoim-mune hepatitis in white northern European patients.

Different ethnic groups have different sus-ceptibility alleles, and HLA-DRB1*13 (DRB1*1301)is the principal susceptibility factor in SouthAmerica, especially among children (Table 4).These variations in genetic susceptibility mayreflect region-specific differences in the indige-nous agents that trigger the disease. Furthermore,different manifestations of autoimmune hepatitismay have different genetic associations. Type 2autoimmune hepatitis is associated with HLA-DQB1*02, whereas the expression of anti-LKM1 isassociated with HLA-DRB1*07 and the produc-tion of anti-LC1 is associated with HLA-DRB1*03.These findings suggest that certain nonpathogenicantibodies may or may not be expressed,depending on the patient’s genetic predisposition.

Genetic modifiers of the autoreactive responseexist outside the major histocompatibility complex.These modifiers lack disease specificity, and theywork alone, in various combinations, or in synergy(epistasis) with other principal drivers of the dis-ease to influence the clinical phenotype and diseasebehavior in individual patients. Polymorphisms ofthe vitamin D receptor gene (VDR), point mutationof the tyrosine phosphatase CD45 gene, poly-morphisms of the Fas gene (tumor necrosis factorreceptor super family), mutations of the autoim-mune regulator gene (AIRE), and polymorphisms

of the interleukin (IL)-1, IL-6, and IL-10 promotergenes are part of a burgeoning catalogue of autoim-mune modifiers that will continue to expand withthe application of gene microarrays.

TREATMENT REGIMENSPrednisone alone or a lower dose of prednisone incombination with azathioprine is effective in thetreatment of all forms of autoimmune hepatitis.Each regimen induces clinical, laboratory, and his-tologic remission in 65% of patients within 18months and in 80% within 3 years. Each schedulealso enhances survival expectations. The lifeexpectancy of treated patients exceeds 80% after20 years of observation, and it is similar to that ofage- and sex-matched normal persons from thesame geographic region. Also, treatment with cor-ticosteroids may reduce hepatic fibrosis.Improvement in hepatic fibrosis occurs in con-junction with reductions in liver inflammation,and corticosteroids may facilitate the disappearanceof fibrosis by suppressing inflammatory activity.Also, small case studies have suggested that cir-rhosis can disappear during treatment, but thispossibility must await confirmation by assays morereliably reflective of cirrhosis than conventionalneedle biopsy.

The absolute and relative indications for treat-ment are based on degrees of severity as assessedby clinical, laboratory, and histologic findings(Table 8). Patients with inactive cirrhosis, portalor mild interface hepatitis and no symptoms, ordecompensated inactive cirrhosis with ascites,encephalopathy, or gastrointestinal tract bleeding(or a combination) do not warrant immunosup-pressive therapy. The diagnosis of autoimmunehepatitis does not compel the institution of treat-ment, nor does the absence of symptoms precludethe need for therapy.

The preferred treatment schedule is pred-nisone in combination with azathioprine (Table9). The combination schedule uses a lower dose ofprednisone, and it is associated with fewer corti-costeroid-related side effects. It is especially usefulin patients with obesity, acne, menopause, labilehypertension, brittle diabetes, emotional lability,or osteopenia (or a combination of these). The pred-nisone-alone schedule is useful for patients with


severe, preexistent cytopenia, pregnancy or con-templation of pregnancy, or active malignancy.Both regimens are similarly effective and differonly in the frequency of side effects. Azathioprinehas been teratogenic in animals, but its clinical usein transplantation and inflammatory bowel diseasehas not documented this complication. Nevertheless,because azathioprine is not essential for treatingautoimmune hepatitis, it can be avoided duringpregnancy. Alternate-day corticosteroids in titrateddoses have not improved histologic features, andthis regimen has been abandoned in adults.

LIVER TRANSPLANTATIONLiver transplantation is effective in the treatmentof decompensated disease that is unresponsive toconventional therapies. The 5-year survival rateof patient and graft ranges from 83% to 92%, andthe actuarial 10-year survival after transplantationis 75%. No findings at presentation predict prog-nosis and need for transplantation, and the decisionto transplant should be made after a trial of corti-costeroid therapy. Failure of the laboratory indicesof liver inflammation and function to improve(especially the hyperbilirubinemia) within 2 weeksafter the start of corticosteroid therapy is associ-ated with a high early mortality rate. High MELD(model of end-stage liver disease) scores (≥12points) may identify these patients early.

Autoimmune hepatitis recurs in at least 17%of patients after liver transplantation, but recur-rent disease is typically mild and managed by

adjustments in the immunosuppressive regimen.Progression to cirrhosis and graft failure is possible,and the condition of patients should be monitoredclosely for this possibility, especially if corticosteroidtherapy is discontinued after transplantation.Patients who have recurrent disease typically haveHLA-DRB1*03, but recurrence is not related to amismatch of HLA markers between donor andrecipient. Transplant recipients with autoimmunehepatitis also may have a higher frequency of acuteand chronic cellular rejection, and they may be moredifficult to wean from corticosteroid therapy.

Autoimmune hepatitis can develop de novoin children and adults who undergo transplanta-tion for nonautoimmune liver disease. Immunosup-pression with cyclosporine or tacrolimus may affectthe negative selection of autoreactive immunocytesby the thymus or inhibit their apoptosis. Treatmentwith prednisone and azathioprine usually is effectivein suppressing disease activity. De novo autoim-mune hepatitis after transplantation is rare, occur-ring in 2.5% to 3.4% of allografts, but it can resultin graft loss if not treated with corticosteroids.The possibilities of recurrent or de novo autoim-mune hepatitis after liver transplantation compelconsideration of this disease in all patients withacute or chronic allograft dysfunction.

RELAPSERelapse connotes the exacerbation of diseaseactivity after drug withdrawal, and it is characterizedby an increase in the serum level of aspartate

402 Liver

Table 8. Treatment Indications for Autoimmune Hepatitis

Absolute Relative None

Serum AST level >10-fold Symptoms (fatigue, No symptoms and mild interface upper limit of normal arthralgia, jaundice) or portal hepatitis

Serum AST level >5-fold Serum AST and/or Inactive upper limit of cirrhosisnormal and γ-globulin level γ-globulin < Decompensated inactive cirrhosis> twice normal absolute criteria

Bridging necrosis or multi- Interface hepatitislobular necrosis in liver tissue

AST, aspartate aminotransferase.

aminotransferase (AST) to at least threefold normal.From 50% to 86% of patients have disease relapseafter remission, most often during the first 6months after the termination of therapy (50%). Thehigh frequency of relapse should not discouragedrug withdrawal if a complete resolution of clin-ical, laboratory, and histologic abnormalities hasbeen sustained. Therapy should not be institutedwith the preconception that it will be indefinite.

Normalization of the serum levels of AST, γ-globulin, and IgG in conjunction with histologicresolution decreases the relative risk of relapseafter drug withdrawal by 3- to 11-fold. The nor-malization of tests and tissue does not ensure asustained remission, and 60% of patients who haveachieved this result still have disease relapse.Nevertheless, the pursuit of an idealized end pointduring initial therapy is justified because repeatedrelapse and re-treatment can be associated withprogression to cirrhosis, liver failure, or need forliver transplantation.

Histologic improvement lags behind clinicaland laboratory resolution by 3 to 8 months, andtherapy should be continued for at least 3 monthsbeyond this point of improvement. A liver biopsyassessment performed before initial withdrawalof drug therapy is the only means of confirminghistologic resolution. In Europe, treatment is main-tained for at least 2 years before withdrawal ofdrug therapy is considered. The frequency withwhich corticosteroid treatment can induce reso-lution of the disease is unclear, and the pursuit ofan idealized end point must be tempered againstthe patient’s tolerance of the medication.

Relapse justifies re-treatment with the originaldrug schedule, and patients usually enter anotherremission. Patients who have had disease relapseshould be considered for long-term, low-doseprednisone or indefinite azathioprine therapy. Thelow-dose prednisone strategy requires a carefuldecrease in the daily maintenance dose until thelowest level is achieved to prevent symptoms andmaintain serum AST levels below threefold theupper limit of normal. Indefinite azathioprinetherapy requires induction of clinical and labora-tory remission with conventional treatment andthen gradual corticosteroid withdrawal as the doseof azathioprine is increased to 2 mg per kg daily.

Relapse does not preclude permanent dis-continuation of medication late in the course of thedisease. Twenty-eight percent of patients who havedisease relapse and are re-treated eventuallydevelop inactive disease and drug therapy can bewithdrawn. The possibility of permanent with-drawal of drug therapy justifies periodic attemptsat dose reduction.

SUBOPTIMAL RESPONSESThe condition of 9% of patients deteriorates despitecompliance with the drug regimen (treatmentfailure); 13% of patients develop intolerable sideeffects and must stop taking the medication pre-maturely (drug toxicity); and 13% improve but notto a degree that satisfies remission criteria (incom-plete response). High-dose prednisone (60 mgdaily) or prednisone (30 mg daily) in conjunctionwith azathioprine (150 mg daily) is the treatment


Table 9. Conventional Treatment Schedules

Combination therapyNo. of weeks Prednisone therapy,administered Prednisone, mg daily Azathioprine, mg daily mg daily

1 30 50 601 20 50 402 15 50 30

Maintenance untilend point 10 50 20

failure regimen that induces laboratory remissionin 75% of patients within 2 years. Only 20% ofpatients achieve histologic remission, and patientsremain at risk for progression of the disease andthe development of treatment-related complications.

OTHER TREATMENTSCyclosporine, mycophenolate mofetil, and budes-onide are empiric therapies that have been usedsuccessfully in a small number of patients withdisease intolerant or recalcitrant to conventionalregimens. These medications are representativeof an emerging repertoire of immunosuppressiveagents that have site-specific actions (immunocyteactivation, differentiation, and proliferation) orunique qualities (high first-pass hepatic clearance,low toxicity) (Table 10). Most clinical experiencehas been with cyclosporine and mycophenolatemofetil. Budesonide is the only medication thathas been tested in a clinical trial, but the resultsof the trial have not yet been published. None ofthese medications has been incorporated intostandard treatment algorithms or been endorsedas salvage therapy.

Cyclosporine has been administered as initialtherapy, especially to children, and as salvagetherapy to children and adults, but its advantage

over standard regimens as first-line or rescue treat-ment has not been established. According to threesmall clinical experiences, mycophenolate mofetilhas been an effective substitute for azathioprineand a means of eliminating corticosteroids. Theseexperiences have been countered by the results ofanother small study in which 5 of 8 patients hadlaboratory improvement but not resolution, andcorticosteroid therapy could not be withdrawnfrom any of them. Budesonide has been able toinduce complete or partial laboratory resolutionin patients with mild disease. It is being evaluatedin Europe as a frontline therapy. It has not beeneffective as salvage therapy for patients with severedisease for which corticosteroid therapy failed orfor patients dependent on this medication.Furthermore, budesonide has been associated withside effects in patients with cirrhosis. A standarddrug with a new application is 6-mercaptopurine(1.5 mg/kg daily). Limited clinical experience hasindicated its value in treating patients whose con-dition has deteriorated with conventional corti-costeroid regimens (treatment failure).

LONG-TERM SURVEILLANCEFollow-up must be lifelong to assess tolerance ofthe medication, progression to cirrhosis, late

404 Liver

Table 10. Promising New Immunosuppressive Drugs for Autoimmune Hepatitis

Drug Dose Empiric uses

Cyclosporine 5-6 mg/kg daily First-line therapy for children and adultsCorticosteroid failureCorticosteroid intolerance

Tacrolimus 4 mg twice daily Corticosteroid failureMycophenolate mofetil 2 g daily Treatment failure

Corticosteroid intoleranceUrsodeoxycholic acid 13-15 mg/kg daily Variant syndrome with serum ALP level

>2-fold ULNCorticosteroid intoleranceIncomplete response to standard therapy

Budesonide 3 mg twice daily First-line therapy for mild diseaseOngoing clinical trial in Europe

Mercaptopurine 1.5 mg/kg daily Treatment failure

ALP, alkaline phosphatase; ULN, upper limit of normal.

relapse after remission, treatment failure duringindefinite therapy, and malignant transformation.Prognosis remains excellent despite histologic cir-rhosis, probably because liver synthetic function ispreserved and complications of portal hyperten-sion are rare. Hepatocellular cancer can developin patients with cirrhosis for at least 5 years, but itis rare (1 per 965 patient-years of observation).Recommendations for cancer screening have notbeen codified. The risk of extrahepatic malignancyis 1.5 times normal for patients receiving long-termimmunosuppression, and tumors have diverse celltypes. Standard health maintenance screening pro-tocols should be applied.

VARIANT SYNDROMESPatients with features of autoimmune hepatitisand another liver disease (overlap syndrome) orfindings that are similar to but atypical of classicdisease (outlier syndrome) constitute the variantsyndromes (Table 11). Retrospective analyses havesuggested that 18% of cases of autoimmune liverdisease can be reclassified as a variant form.Standardized diagnostic criteria are lacking; naturalhistory remains uncertain; and treatment algorithmshave not been validated. The principal variant syn-dromes are autoimmune hepatitis with features ofprimary biliary cirrhosis and autoimmune hepatitiswith features of primary sclerosing cholangitis.

Mixed hepatitic and cholestatic features arethe most important clues to the presence of avariant form. AMA, serum levels of alkaline phos-phatase increased to more than twofold normal,concurrent inflammatory bowel disease, histologicevidence of destructive cholangitis or ductopenia,and recalcitrance to corticosteroid therapy justifyconsideration of variant forms. Cholangiographyis indicated for excluding primary sclerosingcholangitis in all adults who have autoimmunehepatitis and unexplained cholestatic clinical orbiochemical features, ulcerative colitis, or refrac-toriness to corticosteroid treatment.

Treatment is empiric and includes prednisone,prednisone in combination with azathioprine,ursodeoxycholic acid, or prednisone and ursodeoxy-cholic acid (Table 11). The serum level of alkalinephosphatase at presentation identifies patientswith variant syndromes who may have a response

to corticosteroid therapy. Patients with serum alka-line phosphatase levels less than twice the upperlimit of normal can experience improvement withcorticosteroid therapy; these patients typicallyhave overlapping features of autoimmune hepatitisand primary biliary cirrhosis (AMA positivity andhistologic evidence of bile duct injury). Serum alka-line phosphatase levels more than twofold theupper limit of normal and the presence of destructivecholangitis (florid duct lesion) seen on histologicexamination justify treatment with prednisone andursodeoxycholic acid.

Therapy is based on the predominant mani-festations of the disease, and regimens appropriatefor hepatitic, cholestatic, or equally mixed hepatiticand cholestatic features are administered (Table11). Histologic resolution is unusual in these patients,especially in those with autoimmune hepatitis andprimary sclerosing cholangitis, and the indicationsfor therapy and the nature of treatment are directedmainly by the severity of symptoms.

Features of autoimmune hepatitis can be pre-sent in chronic hepatitis C, and HCV viremia can bepresent in autoimmune hepatitis. Interferon therapyin patients with autoimmune hepatitis can exacerbatethe autoimmune manifestations, and corticosteroidtherapy in patients with chronic hepatitis C willincrease the viral load. Most patients have chronichepatitis C and autoimmune features that shouldbe treated in the same way as a chronic viral hepatitis.Rare patients have classic autoimmune hepatitis,including the characteristic histologic changes, andcoincidental HCV infection. The chronic hepatitis Cin these patients is probably a background finding,and corticosteroid therapy can improve the pre-dominant autoimmune disease.

SUMMARYAutoimmune hepatitis has a global distributionand affects all age groups. Its diagnosis has beencodified by an international panel, and its ability tomanifest as an acute or fulminant disease is rec-ognized. Subclassifications by serologic markersdo not connote different causes or outcome, andthe designations are controversial. Autoantibodiesare diverse and nonpathogenic. Implicatedautoantigens have been cytosolic enzymes capableof transforming self-proteins or foreign proteins


into antigenic peptides. The disease has a stronggenetic predisposition, and it is closely associatedwith HLA-DRB1*03 and HLA-DRB1*04 in whiteNorth Americans and northern Europeans. Theserisk factors affect susceptibility, clinical expression,and treatment outcome. Patients with HLA-DRB1*03are young and therapy fails or liver transplantationis required more often than for patients with HLA-DRB1*04. Corticosteroid therapy is effective for allforms of the disease, and liver transplantation issalvage therapy for decompensated disease.

RECOMMENDED READINGAlvarez F, Berg PA, Bianchi FB, Bianchi L,

Burroughs AK, Cancado EL, et al. InternationalAutoimmune Hepatitis Group report: reviewof criteria for diagnosis of autoimmunehepatitis. J Hepatol. 1999;31:929-38.

Czaja AJ. Autoantibodies in autoimmune liverdisease. Adv Clin Chem. 2005;40:127-64.

Czaja AJ. Autoimmune hepatitis after liver

transplantation and other lessons of self-intol-erance. Liver Transpl. 2002;8:505-13.

Czaja AJ, Doherty DG, Donaldson PT. Geneticbases of autoimmune hepatitis. Dig Dis Sci.2002;47:2139-50.

Czaja AJ, Freese DK. Diagnosis and treatment ofautoimmune hepatitis. Hepatology. 2002;36:479-97.

Heathcote J. Variant syndromes of autoimmunehepatitis. Clin Liver Dis. 2002;6:669-84.

Krawitt EL. Autoimmune hepatitis. N Engl J Med.2006;354:54-66.

Montano-Loza AJ, Carpenter HA, Czaja AJ.Consequences of treatment withdrawal intype 1 autoimmune hepatitis. Liver Int. 2007;27:507-15.

Montano Loza AJ, Czaja AJ. Current therapy forautoimmune hepatitis. Nat Clin PractGastroenterol Hepatol. 2007;4:202-14.

Vergani D, Choudhuri K, Bogdanos DP, Mieli-Vergani G. Pathogenesis of autoimmunehepatitis. Clin Liver Dis. 2002;6:727-37.

406 Liver

Table 11. Varient Syndromes of Autoimmune Hepatitis (AIH) and Empiric Treatments

Variant syndrome Salient features Empiric treatment strategies

AIH and primary AMA positivity Corticosteroids if serum ALP is biliary cirrhosis Cholestatic and hepatitic tests ≤ twice ULN

Increased serum IgM and IgG Add ursodeoxycholic acid if serumlevels ALP is > twice ULN and/or florid

duct lesions in liver tissueAIH and primary Ulcerative colitis Corticosteroids and ursodeoxycholic

sclerosing cholangitis Pruritus acidCholestatic and hepatitic testsALP:AST >1.5Abnormal cholangiogram

AIH and cholangitis Fatigue Prednisone, ursodeoxycholic acid, (possibly AMA- Pruritus or both, depending on hepatitic negative primary Cholestatic and hepatitic tests and cholestatic componentsbiliary sclerosis) AMA negative

ANA and/or SMA positiveNormal cholangiogram

ALP, serum alkaline phosphatase; AMA, antimitochondrial antibodies; ANA, antinuclear antibodies; AST, serumaspartate aminotransferase; SMA, smooth muscle antibodies; ULN, upper limit of normal.

Nonalcoholic fatty liver disease (NAFLD) refersto the accumulation of fat (mainly triglycerides)in hepatocytes that results from insulin resistance.NAFLD is recognized as the most common chronicliver disease in the Western world. NAFLD encom-passes a wide spectrum of disease from bland hepaticsteatosis, which is generally benign, to nonalcoholicsteatohepatitis (NASH), which may progress to cir-rhosis and liver failure. Hence, distinguishingbetween hepatic steatosis and NASH has importantprognostic and management implications.

NAFLD may be categorized as primary or sec-ondary, depending on the underlying pathogenesis(Table 1). Primary NAFLD is more common andassociated with insulin-resistant states, such asobesity, type 2 diabetes mellitus, and dyslipidemia.Other conditions associated with insulin resistance,such as polycystic ovarian syndrome and hypopi-tuitarism, have also been described in associationwith NAFLD, although its exact prevalence andsignificance in these conditions is not clear. Thedifferentiation of primary NAFLD from secondarytypes is important because they have differenttreatments and prognosis. Primary NAFLD has

reached epidemic proportions in many countries,as demonstrated by several population-basedstudies. In the United States, 34% of the population30 to 65 years old and 9.6% of the population 2 to19 years old have hepatic steatosis. If these figuresare extrapolated to the 2007 US population, morethan 55 million Americans have NAFLD. Theprevalence of NAFLD in the general populationin the United States is almost 14-fold higher thanthe prevalence of hepatitis C virus (HCV) infection,which affects about 4 million people. It also isalmost threefold higher than alcohol-induced liverdisease (about 20 million people in the UnitedStates have some degree of alcohol-induced liverdisease). However, this high prevalence of NAFLDcontrasts with the relatively small proportion ofpatients with NAFLD who show evidence of dis-ease progression or develop complications ofend-stage liver disease, as described below.

CLINICAL MANIFESTATIONSThe clinical, laboratory, histologic, and diagnosticfeatures of NAFLD are listed in Table 2. Patients

407

CHAPTER 32

Nonalcoholic Fatty Liver Disease

Paul Angulo, MD

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CT, computedtomography; HCV, hepatitis C virus; HDL, high-density lipoprotein; MRI, magnetic resonance imaging; NAFLD,nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.

may complain of fatigue or malaise and a sensationof fullness or discomfort in the right upperabdomen. Hepatomegaly and acanthosis nigricansare common physical findings in children,although stigmata of chronic liver disease sug-gestive of cirrhosis are uncommon. The effect ofNAFLD on health-related quality of life is beingevaluated. Several studies have found a significantdetrimental impact on health-related quality oflife of the several comorbidities that conform themetabolic syndrome and often cluster with NAFLD.

The most common clinical scenario leading tothe diagnosis of NAFLD is an asymptomaticincrease in the serum levels of aminotransferases

(alanine aminotransferase [ALT] and aspartateaminotransferase [AST]) not due to viral hepatitis,iron overload, or alcohol abuse. When these otherliver diseases are ruled out, NAFLD is the likelycause in the majority of cases. Aminotransferaselevels, however, are increased in only 20% of thegeneral population with NAFLD. The AST/ALTratio is usually less than one, but this ratio increasesas fibrosis advances. Fatty infiltration of the liveras detected with ultrasonography is also likely tobe due to NAFLD in the majority of cases.However, these findings by themselves are notsufficient to make a diagnosis of NAFLD.Supportive clinical, serologic, and, sometimes, his-tologic evidence is also required.

NAFLD also should be considered as a possibledifferential diagnosis in cases of “cryptogenic”cirrhosis. The prevalence of metabolic risk factorssuch as diabetes mellitus and obesity is similaramong patients with cryptogenic cirrhosis andNASH. In addition, prevalence rates of these riskfactors are higher when compared with patientswith cirrhosis of other causes, suggesting thatNASH accounts for a substantial proportion ofcases of cryptogenic cirrhosis. Hepatic steatosisalso has been observed to disappear over time inpatients with NASH-related cirrhosis, potentiallymasking the diagnosis. Despite this, histologic fea-tures consistent with NASH are still found in up toone-third of explant livers at transplantation forcryptogenic cirrhosis. Rarely, NASH is a consid-eration in patients with subacute liver failure,having been observed among those who have hadsilent progression to cirrhosis before an unknownstimulus precipitates liver failure.

Clinical Features Associated WithNonalcoholic Fatty Liver DiseaseThe most common clinical features associated withNAFLD are the components of metabolic syn-drome. Metabolic syndrome is defined as three ormore of the following: fasting glucose of 100mg/dL or more, central obesity with a waist cir-cumference larger than 102 cm (40 inches) in menand more than 88 cm (35 inches) in women, bloodpressure of 130/85 mm Hg or higher, fastingtriglyceride level of 150 mg/dL or more, and a lowlevel of high-density lipoprotein (HDL) choles-terol (<40 mg/dL in men and <50 mg/dL in

408 Liver

Table 1. Causes of Nonalcoholic Fatty LiverDisease

Cause Examples

Primary Obesity, glucose intolerance,type 2 diabetes, hypertri-glyceridemia, low HDL cholesterol, hypertension

SecondaryNutritional Protein-calorie malnutrition,

rapid weight loss, gastro-intestinal bypass surgery, total parenteral nutrition

Drugs Glucocorticoids, estrogens, tamoxifen, amiodarone, methotrexate, diltiazem, zidovudine, valproate, aspirin, tetracycline, cocaine

Metabolic Lipodystrophy, hypo-pituitarism, dysbetalipo-proteinemia, Weber-Christian disease

Toxins Amanita phalloides mushroom,phosphorus poisoning, petrochemicals, Bacillus cereus toxin

Infections Human immunodeficiency virus, hepatitis C, small-bowel diverticulosis with bacterial overgrowth

HDL, high-density lipoprotein.

women). Of patients with NAFLD, 90% have abody mass index (BMI) of at least 25 kg/m2, 50%are obese (BMI ≥30 kg/m2), 28% have type 2 dia-betes mellitus, 55% have dyslipidemia (hyper-triglyceridemia, hypercholesterolemia, or low levelof HDL-cholesterol alone or in combination), and60% have hypertension. Almost half of the patientswith NAFLD have metabolic syndrome (ie, at leastthree features of the syndrome) (Fig. 1). Also, about75% of lean patients (BMI <25 kg/m2) with NAFLDhave at least one feature of metabolic syndrome.Therefore, the presence of metabolic abnormali-ties increases the likelihood of NAFLD, but thesefeatures are common in the general populationand not specific for the diagnosis.

Most patients with NAFLD who have a BMI of35 kg/m2 or more also meet the criteria for centralobesity, as defined above. It has been demonstratedthat fat with an intra-abdominal (visceral) locationis metabolically different from fat with a moreperipheral or subcutaneous location. The presenceand severity of NAFLD correlates more strongly

with central obesity than with the BMI. Somepatients with NAFLD may have a BMI less than35 kg/m2 and still have central obesity, whereasmany persons with a high BMI do not haveNAFLD. Body fat distribution differs among ethnicgroups, and this may be one of the factors thatexplains the differences in the prevalence ofNAFLD among ethnic groups in the United States.For example, the prevalence is higher among adultHispanics (45%) than among adult whites (33%)and adult African Americans (24%). In the UnitedStates, a difference in prevalence between adultmen and women is found only among whites (42%men vs 24% women).

Biochemical FeaturesSerum liver enzyme abnormalities are oftenrestricted to an increase in the level of ALT or AST(or both), usually less than fivefold normal.Aminotransferase levels in patients with NAFLDfluctuate; at any one time, 78% of patients havenormal levels, but increased levels are detected in

Nonalcoholic Fatty Liver Disease 409

Table 2. Principal Clinical, Laboratory, Histologic, and Diagnostic Characteristics ofNonalcoholic Fatty Liver Disease

Feature Characteristics

Clinical Usually asymptomatic, sometimes mild right upper quadrant discomfort,hepatomegaly, acanthosis nigricans, “cryptogenic” cirrhosis

Often associated with features of metabolic syndrome: diabetes mellitus, obesity,dyslipidemia (hypertriglyceridemia, low HDL cholesterol,hypobetalipoproteinemia)

Biochemical Increased levels of AST and ALT (usually <5-fold normal)Increased levels of alkaline phosphatase and γ-glutamyltransferase (usually <3-fold

normal) AST/ALT ratio <1Hyperinsulinemia and insulin resistanceDyslipidemia, increased ferritin level

Histologic Steatosis (fatty infiltration >5% hepatocytes)Necroinflammation (lobular or portal inflammation, Mallory bodies, ballooning)Fibrosis (perisinusoidal, perivenular, bridging, cirrhosis)

Imaging Imaging indicative of fatty infiltration of the liver (ultrasonography, computedtomography, magnetic resonance imaging, magnetic resonance spectroscopy)

Exclusion of Alcohol intake <140 g/week (women) or <210 g/week (men)Liver disease of viral, autoimmune, genetic origin

ALT, alanine aminotransferase; AST, aspartate aminotransferase; HDL, high-density lipoprotein.

more than 20% of these patients if the measurementis repeated several times during follow-up.Alkaline phosphatase and γ-glutamyltransferaselevels may be increased modestly (generally lessthan threefold normal) in one-third of patients butrarely is the level of one or both of these enzymesincreased without an increase in aminotransferaselevels. Hyperbilirubinemia, low albumin levels,or an increase in the international normalized ratiousually indicates decompensated cirrhosis.

Serum iron tests are commonly abnormal, andferritin levels are increased in up to 50% of patientsand transferrin saturation is increased in up to10%. These findings potentially may lead to con-fusion about a diagnosis of hemochromatosis.Whether the prevalence of heterozygous HFE genemutations is increased among patients withNAFLD is debated; however, the presence of thesegene mutations does not appear to be associatedwith hepatic iron loading or liver fibrosis. Testingfor antinuclear or antismooth muscle antibodies(or both) is recommended for screening for autoim-mune hepatitis in patients with chronicallyincreased enzyme levels. However, serum autoan-tibodies are present in 23% to 36% of patients withNAFLD and may rarely signal coexistent autoim-mune liver disease. In one series of 225 patientswith NAFLD, 8% of autoantibody-positive patientsalso had coexistent features of autoimmune

hepatitis as seen in liver biopsy specimens, but theliver biopsy features help to exclude the diagnosisof autoimmune hepatitis in most patients withNAFLD who test positive for antinuclear or anti-smooth muscle antibodies (or both).

Other laboratory abnormalities commonlyfound in patients with NAFLD are hyperglycemia,hyperinsulinemia, and increased levels of triglyc-erides and cholesterol and decreased levels ofHDL-cholesterol.

Imaging FeaturesUltrasonography, computed tomography (CT),and magnetic resonance imaging (MRI) can beused to noninvasively diagnose fatty infiltrationof the liver. Hepatic steatosis causes increasedechogenicity on ultrasonography, which can becontrasted with the lower echogenicity of thespleen or renal cortex (Fig. 2). A similar patterncan be seen with diffuse fibrosis, giving rise to theterm fatty-fibrotic pattern, although the echoshadows tend to be coarser in the presence of purefibrosis. The sensitivity and specificity of ultra-sonography for detecting hepatic steatosis varyfrom 60% to 94% and 88% to 95%, respectively.However, the sensitivity of ultrasonographydecreases with lower degrees of fatty infiltration.In the presence of 30% or more of fatty infiltra-tion, the sensitivity of ultrasonography is 80%

410 Liver

Metabolic syndromeObesity Type 2 diabetes Dyslipidemia Hypertension

70

60

50

40

30

20

10

0

Pat

ient

s, %

Fig. 1. The prevalence of features of metabolic syndrome among patients with nonalcoholic fatty liver disease.

compared with a sensitivity of 55% when liver fatcontent is 10% to 19%. Similarly, the sensitivity andspecificity of ultrasonography decrease in the pres-ence of morbid obesity to 49% and 75%, respectively.

On noncontrast CT images, hepatic steatosishas a low attenuation and appears darker than thespleen (Fig. 3). The sensitivity of CT for detectinghepatic steatosis of more than 33% is as high as93%, with a positive predictive value of 76%. Bothmagnetic resonance phase contrast imaging tech-niques and magnetic resonance spectroscopy arereliable for detecting steatosis and offer good cor-relation with the volume of liver fat. A liver fatcontent of more than 5% apparent on magneticresonance spectroscopy indicates steatosis.However, the routine application of MRI is limitedby cost and lack of availability.

Histologic FeaturesHistologically, NAFLD is indistinguishable fromthe liver damage that results from alcohol abuse.Liver biopsy features include steatosis, mixedinflammatory cell infiltration, hepatocyte bal-looning and necrosis, glycogen nuclei, Mallory’shyaline, and fibrosis. The presence of steatosisalone or in combination with the other featuresaccounts for the wide spectrum of NAFLD (Fig. 4).Steatosis is present predominantly as macrovesic-ular fat, although some hepatocytes may show an

admixture with microvesicular steatosis. Whenmild, fatty infiltration is concentrated typically inacinar zone 3, moderate to severe fatty infiltrationshows a more diffuse distribution. The inflamma-tory infiltrate usually consists of mixed neutrophilsand lymphocytes and predominates in zone 3.

Ballooning degeneration of hepatocytes resultsfrom the intracellular accumulation of fluid andis characterized by swollen cells typically noted inzone 3 near the steatotic hepatocytes. Mallory’shyaline is found in about half of the adult patientswho have NAFLD and usually is located in bal-looned hepatocytes in zone 3, but it is neitherunique nor specific for NAFLD. The pattern offibrosis is one of the characteristic features ofNAFLD. Collagen is laid down first in the peri-cellular space around the central vein and in theperisinusoidal region in zone 3. In some areas, thecollagen fibers invest single cells in a patternreferred to as chicken-wire fibrosis, as described inalcohol-induced liver damage. This pattern offibrosis helps to distinguish NAFLD and alcoholicliver disease from other forms of liver disease inwhich fibrosis shows an initial portal distribution.

Portal tracts are relatively spared from inflam-mation, although children with NAFLD may showa predominance of portal-based injury instead ofa lobular pericentral injury. Mallory’s hyaline isnotably sparse or absent in children with NAFLD.


Fig. 2. Ultrasonic findings in hepatic steatosis. A, Normal liver has distinctive vascular features, whereas, B,liver with fatty infiltration has a diffuse bright echotexture and blurring of hepatic vessels.

A B

In some patients with cirrhotic stage NAFLD, thefeatures of steatosis and necroinflammatoryactivity may no longer be present.

The histologic distinction between hepaticsteatosis and NASH with high-grade inflammationand fibrosis is relatively clear; however, differen-tiating more subtle changes in the middle of thespectrum can be difficult. Furthermore, differenthistologic definitions have been used to categorizeNASH. The most widely accepted definition ofNASH requires the presence of zone 3 accentuatedmacrovesicular steatosis in conjunction with mildmixed lobular inflammation and hepatocellularballooning. Although liver biopsy is the “gold stan-dard” for diagnosing NASH and staging fibrosis,sampling variability may underestimate theseverity of liver injury.

DIAGNOSISThe “gold standard” for diagnosing NAFLD isclinicopathologic correlation, based on the confir-mation of steatosis by liver biopsy and appropriateexclusion of other causes (Table 2). It is importantto exclude alcohol abuse as the cause of fatty liver.It is known that a minimal amount of alcohol of20 g/day (1-2 standard drinks) for women and 30g/day (2-3 standard drinks) for men can induce

fatty liver, and these limits are commonly used todistinguish between alcoholic and nonalcoholicfatty liver. Secondary causes of NAFLD such asmedications (eg, prednisolone, tamoxifen, amio-darone, and methotrexate), total parenteralnutrition, cachexia, intestinal bypass surgery,human immunodeficiency virus infection, andlipodystrophy, should be excluded becauseNAFLD associated with these conditions has a dif-ferent course and treatment.

Patients with chronically increased serumlevels of liver enzymes should have other causesexcluded by clinical review and laboratory testing.The extent of laboratory evaluation should be indi-vidualized. Among patients evaluated at referralcenters who have chronically increased levels ofliver enzymes and a negative laboratory evalua-tion, the prevalence of NAFLD is between 66% and90%. Other potential diagnoses for these patientsare drug-related liver injury (7.6%), normal or non-specific changes (5.9%-8.3%), autoimmunehepatitis (1.9%-8.3%), chronic biliary disease (3.1%-11.2%), and granulomatous liver disease (1.7%).Whether the liver should be biopsied to establishthe diagnosis of NAFLD needs to be individual-ized. Liver biopsy may be useful for diagnosingNAFLD when a potential differential diagnosis issuggested by clinical, serologic, or biochemical

412 Liver

Fig. 3. Features of hepatic steatosis visualized with computed tomography. A, Normal liver has no attenuationof the signal compared with the spleen, whereas, B, liver with fatty infiltration has an attenuated signalcompared with the spleen.

A B

testing. These situations include the presence ofautoantibodies or increased iron indices, a historyof recent medication change, or the absence ofdetectable hepatic steatosis on cross-sectionalimaging. Also, the persistence of increased levelsof aminotransferases after 3 to 6 months of lifestyleintervention with appropriate weight loss and con-trol of lipids and glucose levels may suggest anotherdiagnosis and dictate the need for liver biopsy.

STAGINGLiver biopsy is the only investigation that can dif-ferentiate NASH from simple steatosis as well asstage the extent of fibrosis. Imaging studies such as

ultrasonography, CT, and MRI are not able to dis-tinguish between steatosis and NASH, nor are theyable to stage the degree of hepatic fibrosis. Recently,measuring liver stiffness with ultrasound- or mag-netic resonance-based elastography has been pro-posed as potentially useful for quantifying liverfibrosis in patients with a wide range of chronicliver disease; however, further evaluation of thesetechniques is needed in patients with NAFLD.

The potential benefits of liver biopsy must beweighed against the small risk of complications,including pain, bleeding, and death. The decisionto pursue biopsy needs to be discussed and indi-vidualized with each patient. Several clinical andlaboratory features are recognized in association


Fig. 4. Liver biopsy specimens. A, Bland steatosis. Steatosis is present predominantly as macrovesicular fat,although some hepatocytes may show an admixture with microvesicular steatosis. (Hematoxylin-eosin; originalmagnification x100.) B, Nonalcoholic steatohepatitis with steatosis, inflammatory infiltrate, Mallory’s hyaline,and hepatocyte ballooning. (Hematoxylin-eosin; original magnification x100.) C, Pericellular and perisinusoidalfibrosis in zone 3. (Masson’s trichrome; original magnification x400.) D, Cirrhotic stage of nonalcoholic fatty liverdisease. (Masson’s trichrome; original magnification x100.)

A B

C D

with NASH or advanced fibrosis (or both) inpatients with NAFLD, including older age, pres-ence of diabetes, higher BMI, higher AST/ALTratio, and low albumin level and platelet count.These features have been combined in a numer-ical score aimed at predicting the presence orabsence of advanced fibrosis in NAFLD (Table 3).

More recently, advanced fibrosis in patientswith NAFLD has been associated with levels ofnovel serum markers of fibrogenesis, includinghyaluronic acid, propeptide of type III collagen,and tissue inhibitor of matrix metalloproteinase-1.These serum markers have been combined in anumerical score named the Enhanced Liver Fibrosispanel to predict the presence and severity of liverfibrosis in NAFLD. Similarly, the fibrotest, which

has been studied extensively in viral hepatitis topredict the severity of fibrosis, has been evaluatedin NAFLD. In addition, caspase-3-generated cyto-keratin-18 fragments, a marker of apoptosis mea-sured in plasma, has been evaluated in distin-guishing between simple steatosis and NASH.With plasma from 44 patients with NAFLD,Wieckowska et al reported a specificity of 99.9%,a sensitivity of 85.7%, and positive and negativepredictive values of 99.9% and 85.7%, respectively,for a cytokeratin-18 value of 395 U/L for the diag-nosis of NASH. Although all these scores basedon laboratory markers aid in making the decisionabout who should have biopsy, additional vali-dation is required before the markers can be usedroutinely in clinical practice.

414 Liver

Table 3. Clinical and Serum Markers of Fibrogenesis Proposed as Predictors of Advanced (Stage3-4) Fibrosis in Patients With Nonalcoholic Fatty Liver Disease

No. of Sensitivity, Specificity,Author patients Clinical score/serum marker AUC % %

Angulo et al 733 −1.675 + 0.037 × age (years) + 0.880.094 × BMI (kg/m2) + 1.13 ×IGF/diabetes (yes = 1, no = 0)+ 0.99 × AST/ALT ratio − 0.013× platelet (×109/L) − 0.66 × albumin(g/dL)

Score < −1.455 82 77Score > 0.676 51 98

Suzuki et al 79 Hyaluronic acid >46.1 ng/mL 0.89 85.0 79.7Sakugawa et al 112 Hyaluronic acid ≥50 ng/mL 0.80 68.8 82.8

Type IV collagen 7S ≥5 ng/mL 0.82 81.3 71.4Palekar et al 80 Hyaluronic acid >45.3 ng/mL 0.88 85.7 80.3Dos Santos et al* 30 Hyaluronic acid >24.6 ng/mL 0.73 82.0 68.0

Type IV collagen >145 ng/mL 0.80 64.0 89.0Laminin >282 ng/mL 0.87 82.0 89.0

Ratziu et al 267 Fibrotest >0.30 0.88 92.0 71.0Fibrotest >0.70 0.88 25.0 97.0

Guha et al 192 −7.412 + [ln(HA) × 0.681] + 0.93 80.0 90.0[ln(P3NP) × 0.775] + [ln(TIMP1)× 0.494]

ELF = 0.3576

ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUC, area under the receiver operator characteristiccurve; BMI, body mass index; ELF, enchanced liver fibrosis; HA, hyaluronic acid; IGF, insulin-like growth factor; ln,logarithm negative; P3NP, propeptide of type III collagen; TIMP1, tissue inhibitor of matrix metalloproteinase-1.

*Predicting presence of fibrosis vs absence of fibrosis.

PROGNOSISKnowledge of the histologic subtype of NAFLDand the stage of fibrosis is useful in determiningprognosis and may alter clinical management. Thenatural history of uncomplicated hepatic steatosisis relatively benign; follow-up of 239 patients for anaverage of 12 years showed progression to cirrhosisin 3 patients (1.3%) and liver-related death in only2 (0.8%). In contrast, NASH may progress to cir-rhosis in up to 15% of patients within 15 years afterdiagnosis. Therefore, the diagnosis of NASH mayprompt a more aggressive therapeutic approachtoward metabolic risk factors and participation ofpatients in clinical trials of novel agents, if available.The presence of advanced fibrosis or cirrhosisshould initiate screening for hepatocellular carci-noma and esophageal varices, with closer moni-toring for disease-related complications. Histologicstaging is also valuable for tracking disease pro-gression or monitoring response to therapy. It isimportant to recall, however, that changes inaminotransferase levels do not correlate reliablywith histologic changes over time.

TREATMENT

Treatment of Associated ConditionsA large body of clinical and epidemiologic datagathered during the last three decades indicatesthat obesity, type 2 diabetes mellitus, and hyper-lipidemia are major associated conditions or pre-disposing factors leading to the development ofNAFLD. Hence, it is reasonable to believe that theprevention or appropriate management of theseconditions would lead to improvement or arrestof the liver disease (Table 4). Weight loss, particu-larly if gradual, may lead to improvement in thehistologic features of the liver in NAFLD. However,the rate and degree of weight loss required for nor-malization of the histologic features have not beenestablished. Total starvation or very low caloriediets may cause worsening of the histologic fea-tures and, thus, should be avoided. The NationalHeart, Lung, and Blood Institute and the NationalInstitute of Diabetes and Digestive and KidneyDiseases expert panel clinical guidelines for weightloss recommend that the initial target for weightloss should be 10% of baseline weight within 6

months. This can be achieved by losing about 0.45to 0.90 kg (1-2 lb) per week. With success, furtherweight loss can be attempted if indicated throughfurther assessment. The panel recommended losingweight through the use of multiple interventionsand strategies, including lifestyle modification (ie,diet modifications and increased physical activity),behavioral therapy, pharmacotherapy (ie, orlistat,phentermine, or sibutramine) and surgery, as wellas a combination of these treatment modalities.The recommendation for a particular treatmentmodality or combination should be individualized,taking into consideration the BMI and the pres-ence of concomitant risk factors and other diseases.


Table 4. Therapeutic Options forNonalcoholic Fatty Liver Diseaseand Nonalcoholic Steatohepatitis

Lifestyle changes Weight reductionReduce total fat intake to <30% of energy source

Replace saturated with unsaturated fats

Increase fiber intake to >15 g/day

Increase physical activityInsulin-sensitizing Metformin

agents PioglitazoneRosiglitazone

Antioxidants and Vitamins E and C cytoprotective Betaineagents Taurine

N-AcetylcysteineSibilinUrsodeoxycholic acidFibrates and statinsOrlistat, phentermine, sibutramine

Other treatments Anti TNF-α antibodies and future areas Pentoxifylline of research Antifibrotic medications

Angiotensin II receptor antagonists

CB1 receptor antagonistsCaspase inhibitors

CB, cannabinoid; TNF, tumor necrosis factor.

The panel did not make specific recommendationsfor the subgroup of patients with NAFLD; how-ever, with the lack of clinical trials in this area, theoverall panel recommendations may be a usefuland safe first step for obese patients with NAFLD.Similarly, no specific recommendations were madefor monitoring with liver tests during weight loss;but measuring liver enzymes monthly duringweight loss seems appropriate.

Different dietary caloric restrictions have beenused. However, additional studies are needed todetermine the most appropriate content of the for-mula to be recommended for obese or diabeticpatients with NAFLD. In the absence of well-con-trolled clinical trials of patients with NAFLD, itmay be tempting to recommend a heart-healthydiet, as recommended by the American HeartAssociation for those without diabetes and a dia-betic diet as recommended by the AmericanDiabetes Association for those with diabetes.Dietary supplementation with ω-3 polyunsatu-rated and monounsaturated fatty acids mayimprove insulin sensitivity and prevent liverdamage. Saturated fatty acids worsen insulin resis-tance, whereas dietary fiber can improve it.Nevertheless, the effect of such dietary modifica-tions in patients with fatty liver has not been estab-lished. A diet to produce weight loss should alwaysbe prescribed on an individual basis and in con-sideration of the patient’s overall health. Patientswho have obesity-related disease such as diabetesmellitus, hyperlipidemia, or cardiovascular diseaserequire close medical supervision during weightloss to adjust the medication dosage as needed.

Improving insulin sensitivity with lifestylechanges or medications usually improves glucoseand lipid levels in patients with diabetes andhyperlipidemia. Improving insulin sensitivity inthese patients is expected to improve liver disease,but in many diabetic or hyperlipidemic patientswith NAFLD, the appropriate control of glucoseand lipid levels is not always accompanied byimprovement in the liver condition.

Pharmacologic Treatment Because achieving and maintaining appropriateweight control is difficult for most obese patients toaccomplish, the use of medications that can reducedirectly the severity of liver damage independently

of weight loss is a reasonable alternative.Pharmacologic therapy also may benefit patientswho do not have risk factors or associated condi-tions, that is, nonobese, nondiabetic patients andthose with a normal lipid profile. However, phar-macologic therapy directed specifically at the liverdisease has been evaluated only recently in patientswith NAFLD. Most of these studies have beenuncontrolled, open-label studies that lasted 1 yearor less, and only a few of them evaluated the effectof treatment on the histologic features of the liver.The results of pilot studies that evaluated insulinsensitizer medications, antioxidants, lipid-low-ering medications, and some hepatoprotectivemedications suggest that these medications may beof potential benefit, but well-designed controlledtrials are needed before any of the medications canbe recommended for patients with NAFLD.

General RecommendationsA useful first step in the management of patientswith NAFLD is to have them make an attempt atgradual weight loss and make a concerted effortto maintain appropriate control of serum glucoseand lipid levels. Perhaps this, along with appro-priate exclusion of other liver disease, may be theonly treatment recommendation for patients withpure steatosis and no evidence of necroinflam-mation or fibrosis, because these are the patientswho seem to have the best prognosis within thespectrum of NAFLD. Patients with steatohepatitis,particularly those with increased fibrosis seen inliver biopsy specimens, may have a worse prog-nosis and should be monitored closely. Theyshould make a greater effort to achieve adequatemetabolic control and should be offered enroll-ment in well-controlled clinical trials that evaluatethe potential benefit of promising medications.Pharmacologic therapy holds promise, but datafrom well-controlled clinical trials are needed todetermine not only the efficacy but also the long-term safety of the several experimental medica-tions; currently, none of these medications canbe recommended for the treatment of NAFLDoutside of clinical trials.

For patients with cirrhotic stage NAFLD anddecompensated disease, liver transplantation is apotential life-extending therapeutic alternative,although some patients with cirrhotic stage

416 Liver

NAFLD have comorbid conditions that oftenreduce the usefulness of liver transplantation.

PREVENTIONNo studies have been aimed at preventing thedevelopment of NAFLD. However, preventingthe development of insulin resistance and its clin-ical manifestations (ie, metabolic syndrome) isexpected to prevent the development of NAFLD.Weight gain and obesity resulting from anincreased sedentary lifestyle and diets with a highcontent of fat and carbohydrates seem to be keyfactors in the development of insulin resistanceand NAFLD. Thus, achieving and maintainingappropriate weight control would be expected toprevent the development of NAFLD, as would thetreatment of glucose and lipid abnormalities. Thisis supported further by data from the diabetes pre-vention program in the United States whichdemonstrated that both lifestyle intervention andthe insulin-sensitizing drug metformin signifi-cantly decreased the development of metabolicsyndrome, which intuitively would prevent thedevelopment of NAFLD.

RECOMMENDED READINGAdams LA, Angulo P. Treatment of non-alco-

holic fatty liver disease. Postgrad Med J.2006;82:315-22.

Adams LA, Lindor KD, Angulo P. The prevalenceof autoantibodies and autoimmune hepatitisin patients with nonalcoholic fatty liver dis-ease. Am J Gastroenterol. 2004;99:1316-20.

Adams LA, Lymp JF, St Sauver J, Sanderson SO,Lindor KD, Feldstein A, et al. The natural his-tory of nonalcoholic fatty liver disease: a pop-ulation-based cohort study. Gastroenterology.2005;129:113-21.

American Gastroenterological Association.American Gastroenterological Association med-ical position statement: evaluation of liver chem-istry tests. Gastroenterology. 2002;123:1364-6.

Angulo P. GI epidemiology: nonalcoholic fattyliver disease. Aliment Pharmacol Ther.2007;25:883-9.

Angulo P, Hui JM, Marchesini G, Bugianesi E,George J, Farrell GC, et al. The NAFLD fibrosis

score: a noninvasive system that identifies liverfibrosis in patients with NAFLD. Hepatology.2007;45:846-54.

Browning JD, Szczepaniak LS, Dobbins R,Nuremberg P, Horton JD, Cohen JC, et al.Prevalence of hepatic steatosis in an urbanpopulation in the United States: impact of eth-nicity. Hepatology. 2004;40:1387-95.

Caldwell SH, Oelsner DH, Iezzoni JC, HespenheideEE, Battle EH, Driscoll CJ. Cryptogenic cir-rhosis: clinical characterization and risk fac-tors for underlying disease. Hepatology.1999;29:664-9.

Ekstedt M, Franzén LE, Mathiesen UL, ThoreliusL, Holmqvist M, Bodemar G, et al. Long-termfollow-up of patients with NAFLD and elevatedliver enzymes. Hepatology. 2006;44:865-73.

Guha IN, Parkes J, Roderick P, Chattopadhyay D,Cross R, Harris S, et al. Noninvasive markersof fibrosis in nonalcoholic fatty liver disease:validating the European Liver Fibrosis Paneland exploring simple markers. Hepatology.2008;47:455-60.

Kleiner DE, Brunt EM, Van Natta M, Behling C,Contos MJ, Cummings OW, et al, NonalcoholicSteatohepatitis Clinical Research Network.Design and validation of a histological scoringsystem for nonalcoholic fatty liver disease.Hepatology. 2005;41:1313-21.

Marchesini G, Bugianesi E, Forlani G, Cerrelli F,Lenzi M, Manini R, et al. Nonalcoholic fattyliver, steatohepatitis, and the metabolic syn-drome. Hepatology. 2003;37:917-23.

Mottin CC, Moretto M, Padoin AV, Swarowsky AM,Toneto MG, Glock L, et al. The role of ultrasoundin the diagnosis of hepatic steatosis in morbidlyobese patients. Obes Surg. 2004;14:635-7.

Orchard TJ, Temprosa M, Goldberg R, Haffner S,Ratner R, Marcovina S, et al, Diabetes PreventionProgram Research Group. The effect of met-formin and intensive lifestyle intervention onthe metabolic syndrome: the DiabetesPrevention Program randomized trial. AnnIntern Med. 2005;142:611-9. Summary forpatients in: Ann Intern Med. 2005;142:I46.

Ratziu V, Massard J, Charlotte F, Messous D,Imbert-Bismut F, Bonyhay L, et al, LIDO StudyGroup, CYTOL study group. Diagnostic valueof biochemical markers (FibroTest-FibroSURE)


for the prediction of liver fibrosis in patientswith non-alcoholic fatty liver disease. BMCGastroenterol. 2006;6:6.

Saadeh S, Younossi ZM, Remer EM, Gramlich T,Ong JP, Hurley M, et al. The utility of radio-logical imaging in nonalcoholic fatty liver dis-ease. Gastroenterology. 2002;123:745-50.

Schwimmer JB, Deutsch R, Kahen T, Lavine JE,Stanley C, Behling C. Prevalence of fatty liverin children and adolescents. Pediatrics.2006;118:1388-93.

Sorbi D, McGill DB, Thistle JL, Therneau TM, HenryJ, Lindor KD. An assessment of the role of liver

biopsies in asymptomatic patients with chronicliver test abnormalities. Am J Gastroenterol.2000;95:3206-10.

Stranges S, Dorn JM, Muti P, Freudenheim JL,Farinaro E, Russell M, et al. Body fat distribu-tion, relative weight, and liver enzyme levels:a population-based study. Hepatology. 2004;39:754-63.

Wieckowska A, Zein NN, Yerian LM, Lopez AR,McCullough AJ, Feldstein AE. In vivo assess-ment of liver cell apoptosis as a novel bio-marker of disease severity in nonalcoholic fattyliver disease. Hepatology. 2006;44:27-33.

418 Liver

Because most pregnant women are young andhealthy, liver disease is uncommon in this patientpopulation. Also, the presence of liver disease mustnot be confused with some of the physiologicchanges of pregnancy that mimic features com-monly associated with liver dysfunction (Table 1),including spider nevi and palmar erythema in 50%of pregnant women, increased serum level of alka-line phosphatase from placental production, anddecreased serum levels of bilirubin and hemo-globin with expanded blood volume. Increasedlevels of bilirubin and transaminases, hepatomegaly,splenomegaly, liver tenderness, or bruits do notoccur in normal pregnancy, and the clinical findingof jaundice is always abnormal. Abnormalities inliver enzyme levels occur in 3% to 5% of pregnanciesand jaundice in 0.1%, with a clinical significancethat is highly variable from a self-limiting to arapidly fatal condition.

For diagnostic purposes, it is useful to divideliver diseases in pregnant women into three maincategories (Table 2):

419

CHAPTER 33

Liver Disease and Pregnancy


Abbreviations: AFLP, acute fatty liver of pregnancy; ERCP, endoscopic retrograde cholangiopancreatography; HBeAg,hepatitis B e antigen; HELLP, hemolysis, elevated liver tests, low platelets; ICP, intrahepatic cholestasis of pregnancy;LCHAD, long-chain 3-hydroxyacyl-CoA dehydrogenase; UDCA, ursodeoxycholic acid.

Table 1. Physiologic Changes in Liver TestsDuring Pregnancy

Test Change

Bilirubin UnchangedAST, ALT UnchangedProthrombin time UnchangedAlkaline phosphatase Increases 2- to 4-foldFibrinogen Increases 50%Globulin Increases in α- and β-

globulinsα-Fetoprotein Moderate increase,

especially with twinsLeukocytes IncreaseCeruloplasmin IncreasesCholesterol Increases 2-foldTriglycerides IncreaseGlobulin Decreases in γ-globulin

ALT, alanine aminotransferase; AST, aspartateaminotransferase.

1. Liver diseases occurring coincidentally in apregnant woman (viral hepatitis is the mostcommon cause of jaundice in pregnant patients)

2. Pregnancy occurring in a woman with chronicliver disease

3. Liver diseases unique to pregnancy, includinghyperemesis gravidarum, intrahepaticcholestasis of pregnancy (ICP), preeclampsia,HELLP (hemolysis, elevated liver tests, lowplatelets) syndrome, and acute fatty liver ofpregnancy (AFLP)

These liver diseases, unique to pregnancy, can beconsidered liver complications of pregnancy itself,and they have a characteristic timing in relation tothe trimesters of pregnancy. Hepatitis E and herpeshepatitis, although not related etiologically to preg-nancy, characteristically produce a fulminant andoften deadly disease in the third trimester of preg-nancy. Recent data suggest that most liver diseasein pregnancy is pregnancy-related and incidentaland chronic liver diseases are uncommon.

DIAGNOSTIC STRATEGY INPREGNANT PATIENTSOptimal management of pregnant patients whohave abnormal liver tests or jaundice requiresaccurate and often rapid diagnosis. The clinicalpresentation and trimester of pregnancy are diag-nostically important (Table 2). Answers to thefollowing questions help formulate a rationalapproach to these patients:

1. Are there any features of underlying chronicliver disease (including liver transplantation)or risk factors for viral disease?

2. Is the presentation compatible with acute viralhepatitis?

3. Are there any features to suggest biliary disease?4. Is there any history of drugs or toxins?5. Are there any features of Budd-Chiari

syndrome?6. Is there any evidence or risk factors for sepsis?7. Does the presentation fit one of the liver dis-

eases unique to pregnancy?

420 Liver

Table 2. Causes and Timing of Liver Disease During Pregnancy

Trimester of Disease category Specific disease pregnancy

Chronic liver disease/portal Chronic hepatitis B 1-3hypertension Hepatitis C 1-3

Autoimmune disease 1-3Wilson’s disease 1-3Cirrhosis of any cause 1-3Extrahepatic portal hypertension 1-3

Liver disease coincidental with Acute viral hepatitis 1-3pregnancy Budd-Chiari syndrome Postpartum

Gallstones 1-3Drug-induced 1-3

Liver disease unique to pregnancy Intrahepatic cholestasis of pregnancy 2-3Hyperemesis gravidarum 1Preeclampsia 3, late 2HELLP syndrome 3, late 2Acute fatty liver of pregnancy 3

HELLP, hemolysis, elevated liver enzymes, low platelets.

Clinical features and laboratory testing allow adiagnosis in most patients, but for some patients,imaging of the liver, endoscopic retrograde cholan-giopancreatography (ERCP), or liver biopsy is nec-essary. Ultrasonography of the liver and abdomenis safe during all three trimesters of pregnancy andis helpful in the evaluation of biliary tract disease,patency of hepatic and portal veins, AFLP,hematomas, and rupture. To confirm the diagnosisof choledocholithiasis, ERCP can be performedsafely in pregnant women. Radiation exposure forfluoroscopy is well below the fetal safety level.Midazolam, meperidine, and glucagon can begiven safely. If indicated, sphincterotomy and stoneextraction should be performed at the same time.Hepatic venography is necessary to confirm thediagnosis of Budd-Chiari syndrome in patientswho have clinical and ultrasonographic featurescompatible with the syndrome.

LIVER DISEASES OCCURRINGCOINCIDENTALLY IN PREGNANTPATIENTS

Viral HepatitisJaundice in pregnancy may be due to any of themany causes of jaundice in nonpregnant patients.Viral hepatitis (due to hepatitis A, B, C, D, or Evirus; herpes simplex virus; cytomegalovirus; orEpstein-Barr virus) accounts for 40% of cases ofjaundice in pregnant women in the United States.Hepatitis A, B, and C have the same frequency inthe pregnant and nonpregnant populations andduring each of the three trimesters of pregnancy.Acute hepatitis A occurs in 1 per 1,000 pregnantwomen and acute hepatitis B in 2 per 1,000;hepatitis D is rare. Hepatitis E is extremely rare inthe United States but is endemic to large areas ofAsia, Africa, and Central America, where, in thethird trimester of pregnancy, it becomes fulminant,with a high mortality rate that probably is influ-enced by malnutrition. In India, 25% of womenwith fulminant liver failure are pregnant, and inalmost all of them, liver failure is due to acute viralhepatitis. Herpes simplex hepatitis is rare.

Apart from hepatitis E and herpes simplex,the clinical and serologic course of acute hepatitisin pregnant women is the same as in nonpregnant

patients, and the hepatitis does not appear to affectthe pregnant state adversely. Even though herpessimplex hepatitis is rare, it must be diagnosedbecause specific therapy is life-saving. In pregnantwomen, it typically occurs as a primary infectionin the third trimester and has systemic featureswith a prodrome and fever, diffuse vesicular rashand leukopenia, vulvar or oropharyngeal vesicularlesions, and coagulopathy. These patients usuallyare anicteric even with liver failure.

Serologic testing for hepatitis A, B, and Cviruses, Epstein-Barr virus, and cytomegalovirusshould be performed in all cases of acute jaundicein pregnancy. Antibody to hepatitis E virus shouldbe assayed if the patient is from, or has been a recenttraveler to, an endemic area. Testing for hepatitisC virus RNA in the absence of antibody to hepatitisC virus has been positive in several pregnantpatients who subsequently developed hepatitis C.Serologic testing, liver biopsy, and culture may benecessary to diagnose herpes simplex hepatitis.

Management of patients who have acute viralhepatitis is supportive except for herpes simplexinfection in which prompt therapy with acycloviror vidarabine is life-saving and without which 50%of mothers will die. Acute or chronic viral hepatitisis not an indication for the termination of preg-nancy, except in the case of a herpes infection thatdoes not respond to antiviral therapy. Congenitalfetal malformations occur only with earlycytomegalovirus infection. Viral hepatitis is notan indication for cesarean section, and breast-feeding should not be discouraged.

Perinatal transmission of hepatitis B is highestin mothers with acute hepatitis, especially withhepatitis B e antigen (HBeAg)-positivity in thethird trimester (50%-80%), lower in mothers withhepatitis B e antibodies (25%), and lowest in carriers(5%). From 80% to 90% of these babies becomechronic carriers. Transmission of hepatitis B is nottransplacental but occurs at delivery and is pre-ventable in more than 95% of cases by passive-active immunoprophylaxis of the babies at birth(Table 3). Breastfeeding is not contraindicated evenif the mother has active hepatitis B. Vertical trans-mission of hepatitis A and D is rare. The frequencyof mother-to-infant transmission of hepatitis C is1% to 5%, with maternal risk factors being coinfec-tion with human immunodeficiency virus, history

Liver Disease and Pregnancy 421

of intravenous drug abuse, and maternal viremiaof more than 106 copies/mL. Transmission is notaffected by mode of delivery or breastfeeding.Newborns of mothers with hepatitis A in the thirdtrimester should be given passive immunopro-phylaxis with immunoglobulin within 48 hoursafter birth. The benefits of immunoglobulin forbabies of mothers seropositive for hepatitis C virusare unknown, and there is no effective therapy forpreventing hepatitis C.

Gallstones and Biliary DiseaseIncreased lithogenicity of bile and biliary stasisduring pregnancy predispose pregnant women toenhanced formation of biliary sludge and stones.Despite their prevalence, symptomatic gallstonesoccur in only 0.1% to 0.3% of pregnancies andsymptoms usually follow multiple pregnanciesrather than during gestation. The common clin-ical presentations are biliary colic (5% of cases ofjaundice in pregnancy), gallstone pancreatitis (50%of women younger than 30 years with pancreatitisare pregnant) and, least common, acute cholecys-titis. The clinical features of biliary disease andpancreatitis are the same as in nonpregnantpatients, can occur at any time of gestation, andmay recur during pregnancy.

Intractable biliary colic, severe acute chole-cystitis not responding to conservative measures,and acute gallstone pancreatitis are indications forimmediate cholecystectomy despite the pregnantstate. For acute biliary colic or acute cholecystitis,

conservative therapy with bed rest, intravenousfluids, and antibiotics is instituted initially and issuccessful in more than 80% of cases, with no fetalor maternal mortality. However, because symp-toms recur during pregnancy in 50% of patients,cholecystectomy is indicated for all patients withsymptoms in the second trimester. For thesepatients, the operation has very little morbidity ormortality. Indeed, patients who undergo chole-cystectomy have better pregnancy outcomes thanthose treated medically. Surgery is avoided in thefirst 10 weeks of pregnancy because of the risk ofabortion with anesthesia and the potential terato-genic effect of carbon dioxide. In the third trimester,the uterus may impinge into the surgical field;there also is an increased risk of premature labor.Laparoscopic cholecystectomy with added pre-caution for the pregnant state is now the standardof care for these patients. An impacted commonbile duct stone and worsening gallstone pancreatitisare indications to proceed to ERCP, sphincterotomy,and stone extraction under antibiotic coverage.

Other DiseasesBudd-Chiari syndrome is rare and when it occursin pregnancy, it is usually in the postpartumperiod. It has been associated with antiphospho-lipid syndrome, thrombotic thrombocytopenicpurpura, preeclampsia, and septic abortion. Sepsisassociated with pyelonephritis or abortion cancause jaundice in early pregnancy. Severe gram-negative sepsis with jaundice has been describedin the third trimester.

PREGNANT PATIENTS WITHCHRONIC LIVER DISEASEMany women with chronic viral or autoimmunehepatitis or Wilson’s disease are of childbearingage. Chronic hepatitis B is present in 0.5% to 1.5%of pregnancies and chronic hepatitis C in 2.3% ofpregnancies in some indigent populations. Anuncomplicated pregnancy with no disease flare isexpected in patients with mild disease or diseasein remission. In hepatitis C, transaminase levelsmay actually decrease and hepatitis C viral RNAlevels increase during pregnancy, with the reverseoccurring in the postpartum period. Patients withDubin-Johnson syndrome or benign recurrent

422 Liver

Table 3. Prophylaxis Regimen for Babies ofHBsAg-Positive Mothers

IntramuscularPreparation Dose administration

HBIG 0.5 mL At birthHBV vaccine* 0.5 mL (10 μg) At birth (2

days)At 1 monthAt 6 months

HBIG, hepatitis B immunoglobulin; HBsAg, hepatitis Bsurface antigen; HBV, hepatitis B virus.

*Recombinant vaccine.

intrahepatic cholestasis may become more jaun-diced during pregnancy, especially in the secondand third trimesters, but the only significance ofsuch jaundice is the necessity to rule out other pos-sible causes. Gilbert’s syndrome and Rotor syndromeare unaffected by pregnancy.

Autoimmune disease is not expected to flare inpregnancy but is treated with increased doses ofcorticosteroids as necessary; azathioprine therapyin pregnancy has not been associated with increasedfetal risk. Patients with Wilson’s disease must betreated adequately before pregnancy and continuereceiving therapy throughout the pregnancy.Discontinuation of therapy poses the risk of fulmi-nant Wilson’s disease. The best treatment is D-peni-cillamine, but, rarely, it has been associated withcongenital defects; trientine is a safe alternative forfetal health but of less proven efficacy for the mother.

Most patients with advanced cirrhosis areamenorrheic and infertile because of hypothala-mopituitary dysfunction, but if pregnancy occurs,maternal and fetal problems can be expected toincrease. Little is known about the optimal man-agement of pregnant patients with cirrhosis andportal hypertension in the modern era of obstetrics.The main risk to the mother is massive gastroin-testinal tract bleeding (20%-25% of cases), andwomen with known esophageal varices should beconsidered for endoscopic therapy, shunt surgery,or even liver transplantation before pregnancy.Also, all patients, even if they do not have varicesbefore pregnancy, should undergo upper endoscopyin the second trimester for assessment of varices.If large varices are present, β-blocker therapy isinitiated. Whether prophylactic endoscopic therapyfor esophageal varices in early pregnancy is bene-ficial has not been tested. Acute variceal bleedingis managed endoscopically in the same way as fornonpregnant patients, although vasopressin is con-traindicated. Little is known about the use ofoctreotide in pregnancy. Ascites and hepaticencephalopathy are treated in the standard way.

Vaginal deliveries with an assisted, shortsecond stage are preferable because abdominalsurgery is avoided. However, for patients knownto have large varices, cesarean section is recom-mended to avoid labor and, thus, prevent anincrease in portal pressure and the risk of varicealbleeding. Postpartum hemorrhage and bacterial

infections are reduced by correction of coagu-lopathy and antibiotic prophylaxis.

A pregnant liver transplant recipient representsa unique clinical situation requiring specializedcare. With the success of liver transplantation, morepregnancies are being reported in liver recipients,and a carefully planned pregnancy in a stable,healthy patient beyond the first 2 years after ortho-topic liver transplantation can have excellent out-comes for the fetus, mother, and graft. However,this is still a high-risk pregnancy, with increasedfetal prematurity and dysmaturity. Also, there issome risk to the allograft from acute cellular rejec-tion or recurrent viral hepatitis. Consequently, itis imperative to monitor immunosuppressionclosely and to adjust the calcineurin inhibitordoses as needed for the increased blood volumein the second half of pregnancy. Liver functionmust be monitored regularly, and all liver abnor-malities, especially acute cellular rejection, mustbe investigated and treated as aggressively as innonpregnant patients.

LIVER DISEASES UNIQUE TOPREGNANCYLiver diseases unique to pregnancy have character-istic clinical features and timing of onset in relationto pregnancy (Table 2). Although still poorlyunderstood, some interesting advances have beenmade recently in understanding these pregnancy-associated diseases. These diseases belong to oneof two main categories depending on whether ornot they are associated with preeclampsia. Secondonly to viral hepatitis as a cause of jaundice in preg-nant patients is ICP, a disease of severe pruritus,mild jaundice, and biochemical cholestasis limitedto the second half of pregnancy. In the United States,ICP occurs in 0.1% of pregnancies, with jaundicein about 20% of cases. Hyperemesis gravidarum,with an incidence of 0.3%, is intractable nausea andvomiting that occur in the first trimester; hightransaminase levels occur in 50% of patients andoccasionally jaundice develops. ICP and hyper-emesis are not associated with preeclampsia.

The preeclampsia-associated liver diseases arepreeclampsia itself, HELLP syndrome, and AFLP.Preeclampsia occurs in 5% to 10% of pregnancies,but the liver is involved only in a small proportion


of patients. Preeclampsia is the most commoncause of liver tenderness and abnormal liver testsin pregnant patients.

Hyperemesis GravidarumHyperemesis gravidarum is intractable vomitingin the first trimester of pregnancy and is so severethat intravenous hydration is required. It occursin 0.3% of pregnancies. Immunologic, hormonal,and psychologic factors associated with preg-nancy may have an etiologic role. Risk factorsinclude hyperthyroidism, psychiatric illness,molar pregnancy, preexisting diabetes mellitus,and multiple pregnancies.

Clinical Features and DiagnosisVomiting must be severe and intractable to sup-port the diagnosis of hyperemesis gravidarum. Itoccurs in the first trimester of pregnancy, typicallybetween 4 and 10 weeks of gestation, and may becomplicated by liver dysfunction and occasion-ally jaundice. High transaminase levels occur in50% of patients, up to 20-fold above the normalrange. The diagnosis is made on clinical groundsand rests on the presence of intractable, dehydratingvomiting in the first trimester. Uncomplicatedvomiting in pregnancy does not cause liver dys-function. When transaminase levels are high, viralhepatitis serologic testing should be performed.In the rare patient who requires liver biopsy toexclude more serious disease, the histologicappearance of the liver is generally normal butmay show cholestasis with rare cell dropout.Despite high transaminase levels, no inflamma-tion or notable necrosis is observed.

ManagementHospitalization is necessary for hydration and par-enteral nutrition; otherwise, therapy is sympto-matic with antiemetics.

Intrahepatic Cholestasis of PregnancyICP is a specific liver disease unique to pregnancy;it is characterized by severe pruritus, mild jaun-dice, and biochemical cholestasis that appear inthe second half of pregnancy and disappear afterdelivery. These features typically recur in subse-quent pregnancies. ICP is second only to viralhepatitis as a cause of jaundice in pregnant women.

Incidence and CauseICP is identified all over the world but has strikinggeographic, ethnic, temporal, and seasonal varia-tions. In the United States, it occurs in 0.1% of preg-nancies, with jaundice in 20% of cases, but it has amuch higher incidence in some other countries.Recent advances have been made in understandingits cause, which seems to be influenced by genetic,hormonal, and exogenous factors, perhaps of dif-fering importance in different women.

Familial cases and the high incidence in cer-tain ethnic groups (Araucanian Indians of Chile)have long suggested a genetic predisposition toICP. Pedigree analysis of family members of a childwith progressive familial intrahepatic cholestasishas identified a mutation in the MDR3 (ABCB4)gene associated with ICP. MDR3 is the transporterfor phospholipids across the canalicular mem-brane. The association of ICP with MDR3 muta-tions has been confirmed by several investigators,and MDR3 mutations may account for 15% of casesof ICP.

The pathogenesis clearly is related in someway to female sex hormones: the temporal rela-tionship to hormone levels in late pregnancy, theincrease in twin pregnancies, and the fact thatestrogens may cause cholestasis in nonpregnantwomen who develop ICP in pregnancy. Theseand other observations suggest that ICP is dueto a genetically abnormal or exaggerated livermetabolic response to the physiologic increasein estrogens during pregnancy. Impaired sulfa-tion (an important detoxification pathway) hasbeen identified in some patients with ICP.Abnormalities in progesterone metabolism alsohave been seen, some probably genetic, someexogenous. Exogenous progesterone therapyadministered in the third trimester of pregnancyincreases the serum levels of bile acid and ala-nine aminotransferase, and progesterone givento prevent premature delivery can precipitateICP in some women. The role of exogenous fac-tors in ICP is suggested by the fact that it recursin only 45% to 70% of pregnancies and with vari-able intensity. Also, the clear seasonal variabilityof ICP suggests modification of the disease byexogenous factors. Dietary factors such as sele-nium deficiency have been implicated in somestudies from Chile.

424 Liver

Fetal complications in ICP are placental insuf-ficiency, premature labor, and sudden fetal death.The pathogenesis of these complications may bedue to increased fetal levels of bile acid. Normally,fetal bile acid is transported across the placentalmembrane to the maternal circulation, and highlevels are damaging to the fetus. Abnormal pla-cental transport of bile acid from the fetal to thematernal circulation, increased maternal levels ofbile acid, and immaturity of fetal transport systemsmay all contribute to increased fetal levels of bileacid in ICP.

Clinical Features and DiagnosisThe onset of pruritus at about 25 to 32 weeks ofgestation in a patient with no other signs of liverdisease is strongly suggestive of ICP. This is espe-cially true if the pruritus has occured in otherpregnancies and then disappeared immediatelyafter delivery. In a first pregnancy, diagnosis isgenerally made on clinical grounds alone and canbe confirmed only with the rapid postpartum dis-appearance of the pruritus.

The pruritus affects all parts of the body, isworse at night, and may be so severe that thepatient is suicidal. Excoriations are usually obvious,and occasionally the cholestasis is complicated bydiarrhea or steatorrhea. Jaundice occurs in 10% to25% of patients and usually follows the onset ofpruritus by 2 to 4 weeks. Jaundice without pru-ritus is rare. Occasionally, the affected patient willbe receiving progesterone therapy.

Variable levels of transaminases are seen inICP, from mild to 10- to 20-fold increases. The con-centration of bilirubin usually increases less than5 mg/dL. The serum level of alkaline phosphataseis less helpful in pregnancy; the most specific andsensitive marker of ICP is the serum level of bileacid, which is always increased in this condition,can be 100 times above normal, and may correlatewith fetal risk. Liver biopsy is needed only if a moreserious liver disease is strongly suspected clini-cally. In ICP, the liver has a near-normal appear-ance, with mild cholestasis and minimal or nohepatocellular necrosis.

ManagementWith ICP, the main risk is to the fetus and includespremature delivery (up to 60% of cases), perinatal

death, and fetal distress. For the fetus, this is ahigh-risk pregnancy. Fetal monitoring for chronicplacental insufficiency is essential but does notprevent all fetal deaths. Acute anoxic injury canbe prevented only by delivery as soon as the fetusis mature. A recent Swedish population study ofmore than 45,000 pregnancies with 693 cases ofICP (1.3%) showed that fetal complications corre-lated with the increase in maternal levels of bileacid, and premature delivery, asphyxial events,and meconium staining occurred only whenmaternal bile acid levels were more than 40μmol/L. Whether maternal therapy withursodeoxycholic acid (UDCA) will improve fetaloutcome is not known.

Pruritus and liver dysfunction resolve imme-diately after delivery, with no maternal mortality;however, some patients are severely distressed,even suicidal, because of the pruritus. Managementstrategies for the mother have focused on sympto-matic relief. Withdrawal of exogenous progesteronehas produced remission of the pruritus in somepatients before delivery.

UDCA is the agent of choice for the treatmentof ICP. UDCA, 600 to 1,200 mg/day, is successfulin producing relief from pruritus, with parallelimprovement in liver tests, and it has no adversematernal or fetal effects. In one study, fetal out-come was improved, with fewer premature births.High-dose UDCA, 1.5 to 2.0 g/day, has beenshown recently to relieve pruritus in most cases,to decrease abnormal maternal levels of bile acid,and to be completely safe for the fetus. Moreover,babies born to these mothers had almost normalbile acid levels, as compared with those ofuntreated mothers. In randomized controlled trials,UDCA has been shown to be more effective andsafer than cholestyramine, more effective than dex-amethasone (although the latter has the advantageof promoting fetal lung maturity), and more effec-tive than S-adenosyl-L-methionine. Epomediol andsilymarin have produced symptomatic but not bio-chemical relief in a few patients.

ICP recurs in 45% to 70% of subsequent preg-nancies and occasionally with oral contraceptives.Patients with ICP are subsequently at higher riskthan the general population for the developmentof gallstones and cholecystitis, nonalcoholic pan-creatitis, nonalcoholic cirrhosis, and hepatitis C.


Some rare familial cases of apparent ICP have per-sisted postpartum, with progression to subsequentfibrosis and cirrhosis.

PreeclampsiaPreeclampsia-associated liver diseases includepreeclampsia itself, HELLP syndrome, and AFLP.Preeclampsia is the triad of hypertension, edema,and proteinuria in the third trimester of preg-nancy. It occurs in 5% to 10% of pregnancies, butthe liver is involved in only a small proportion ofpatients. It is the most common cause of liver ten-derness and abnormal liver tests in pregnantpatients. The cause of preeclampsia appears toinvolve defective placentation that leads to gen-eralized endothelial dysfunction.

Clinical FeaturesPatients with preeclampsia may present with rightupper abdominal pain, jaundice, and a tender,normal-size liver. Transaminase levels vary frommild to 10- to 20-fold increases. The bilirubin con-centration is usually less than 5 mg/dL. Involvementof the liver always indicates severe preeclampsia.

ManagementNo specific therapy is needed for the liver involve-ment of preeclampsia, and its only importance isthat it indicates severe disease and the need forimmediate delivery to avoid eclampsia and liverrupture or necrosis. HELLP and AFLP may com-plicate preeclampsia.

HELLP SyndromeSevere preeclampsia is complicated in 2% to 12%of cases (0.2%-0.6% of all pregnancies) by hemol-ysis, elevated liver tests, and low platelet count:HELLP syndrome. Although this syndrome hasbeen recognized for more than 50 years, its diag-nosis, management, and pregnancy outcome arestill matters of controversy.

Clinical Features and DiagnosisNo diagnostic clinical features distinguish HELLPsyndrome from preeclampsia. Most patients withHELLP syndrome present with epigastric or rightupper quadrant pain (65%-90% of patients), nauseaand vomiting (35%-50%), a “flulike” illness (90%),and headache (30%). They usually have edema

and weight gain (60% of patients), right upperquadrant tenderness (80%), and hypertension(80%); jaundice is uncommon (5%). Some patientshave no obvious preeclampsia. Most patients (71%)present between 27 and 36 weeks of gestation, butit can be earlier or up to 48 hours after delivery.HELLP syndrome is more common in multiparousand older patients.

With the presence of microangiopathichemolytic anemia, the characteristic histologicfinding in both HELLP syndrome and preeclampsiais periportal hemorrhage and fibrin deposition.Periportal hepatocytes are necrotic, and thrombimay form in small portal arterioles. Severe diseasemay have diffuse or multiple areas of infarction;hemorrhage dissects through the portal connectivetissue initially from zone 1, then more diffusely toinvolve the whole lobule, leading to large hematomas,capsular tears, and intraperitoneal bleeding. Liverbiopsy is rarely needed for diagnosis.

The diagnosis of HELLP syndrome must beestablished quickly because of the maternal andfetal risk and the necessity for immediate delivery.Diagnosis requires the presence of all three cri-teria: 1) hemolysis with an abnormal blood smear,increased lactate dehydrogenase level (>600 U/L),and increase in indirect bilirubin; 2) aspartateaminotransferase level more than 70 U/L; and 3)a platelet count less than 100,000/mm3 (<100×109/L)and, in severe cases, less than 50,000/mm3

(<50×109/L). These diagnostic criteria, however,are not applied consistently. Prothrombin time,activated partial thromboplastin time, and fibrinogenlevels are usually normal, with no increase in fibrin-split products, but occasionally disseminatedintravascular coagulation may be present. Theincrease in transaminase levels can vary from mildto 10- to 20-fold, and the bilirubin concentration isusually less than 5 mg/dL. Computed tomography(limited views) is indicated in patients with HELLPsyndrome to detect liver rupture, subcapsularhematomas, intraparenchymal hemorrhage, orinfarction (Fig. 1); these abnormalities may corre-late with the decrease in platelet count but not withliver test abnormalities.

ManagementThe first priority in the management of patientswith HELLP syndrome is antepartum stabilization

426 Liver

of the mother, with treatment of hypertension anddisseminated intravascular coagulation and seizureprophylaxis. If possible, the patient should betransferred to a tertiary referral center and com-puted tomography of the abdomen (limitedviews) performed.

Delivery is the only definitive therapy. If thepatient is beyond 34 weeks of gestation or has mul-tiorgan failure, disseminated intravascular coag-ulation, kidney failure, abruptio placentae, or fetaldistress, immediate delivery should be performed,probably by cesarean section, but well-establishedlabor should be allowed to proceed if there are noobstetric complications or disseminated intravas-cular coagulation. Many patients (40%-50%)require cesarean section, especially primigravidaremote from term in whom the cervix is unfavor-able. Half of the patients will require blood or bloodproducts to correct hypovolemia, anemia, or coag-ulopathy. Management remote from term is morecontroversial, especially if the fetal lung is imma-ture and the maternal condition is stable and mild.A National Institutes of Health ConsensusDevelopment Panel has suggested that perinataloutcome at less than 34 weeks of gestation isbetter when corticosteroids (betamethasone ordexamethasone, which cross the placenta) areadministered for 24 to 48 hours, with deliverythereafter. The main benefit of this therapy is fetal

lung maturity, but in some cases it also improvesthe maternal platelet count. Some advocate givingdexamethasone to all women with HELLP syn-drome, starting treatment before delivery butcompleting it postpartum, with no delay indelivery, and corticosteroids may aid maternal sta-bility during the transfer time to a tertiary referralcenter. With longer conservative therapy, the con-dition of most women with HELLP syndrome willdeteriorate in 1 to 10 days after diagnosis, with ahigh risk of fetal loss.

In most patients, HELLP syndrome resolvesrapidly and early after delivery and the plateletcount normalizes by 5 days, but some have per-sisting thrombocytopenia, hemolysis, and pro-gressive increase in bilirubin and creatinine levels.The persistence of signs for more than 72 hours,without improvement or the development of life-threatening complications is usually an indicationfor plasmapheresis. Many different treatmentmodalities have been used, including plasmavolume expansion, antithrombotic agents, corti-costeroids, plasmapheresis, plasma exchange withfresh frozen plasma, and dialysis, but no clinicaltrials have been conducted. Serious maternal com-plications are common, including disseminatedintravascular coagulation (20% of patients),abruptio placentae (16%), acute kidney failure (8%),pulmonary edema (8%), acute respiratory distresssyndrome (1%), severe ascites (8%), and liverfailure (2%). Maternal mortality rates range from1% to 25%. Once delivered, most babies do well.

Serious maternal complications are common inHELLP syndrome: disseminated intravascularcoagulation, abruptio placentae, kidney failure,eclampsia, pulmonary edema, severe ascites, liverfailure, and wound hematomas. Generally, hepatichemorrhage without rupture is managed conserv-atively in hemodynamically stable patients, butpatients need close hemodynamic monitoring in anintensive care unit, correction of coagulopathy,immediate availability of large-volume transfusionof blood and blood products, immediate interventionfor rupture, and follow-up diagnostic computedtomographic studies as needed. Exogenous trauma,including abdominal palpation, convulsions, emesis,and unnecessary transportation, must be avoided.

Liver rupture is a rare, life-threatening com-plication of HELLP syndrome. It usually is preceded


Fig. 1. Computed tomography of the abdomen of a28-year-old woman with severe HELLP syndrome at39 weeks’ gestation. A large subcapsular hematoma(arrow) extends over the left lobe; the right lobe has aheterogeneous, hypodense appearance because ofwidespread necrosis, with “sparing” of the areas of theleft lobe (compare perfusion with the normal spleen).

by an intraparenchymal hemorrhage that pro-gresses to a contained subcapsular hematoma inthe right lobe. The capsule then ruptures, withhemorrhage into the peritoneum. Survivaldepends on rapid and aggressive medical man-agement and immediate surgery, although the bestsurgical management is still debated. The optionsinclude evacuation of the hematoma with packingand drainage, ligation of the hepatic artery, partialhepatectomy, direct pressure, packing or hemo-static wrapping, application of topical hemostaticagents, oversewing of the laceration, and angio-graphic embolization. Preoperatively, aggressivesupportive management of hypovolemia, throm-bocytopenia, and coagulopathy is essential.Maternal mortality from liver rupture is high at50%, and perinatal mortality rates are 10% to 60%,mostly from placental rupture, intrauterineasphyxia, or prematurity.

The risk of recurrence of HELLP syndrome insubsequent pregnancies is difficult to assess fromthe data available; the reported incidence is 4% to25%. Subsequent deliveries by these patients havea significantly increased risk of preeclampsia,preterm delivery, intrauterine growth retardation,and abruptio placentae.

Acute Fatty Liver of PregnancyAFLP is a sudden catastrophic illness that occursalmost exclusively in the third trimester and inwhich microvesicular fatty infiltration results inencephalopathy and liver failure.

Incidence and CauseThe cause of AFLP may involve abnormalitiesin intramitochondrial fatty acid oxidation.Mitochondrial trifunctional protein and its α-subunit, long-chain 3-hydroxyacyl-CoA dehy-drogenase (LCHAD), are two enzymes essentialfor the β-oxidation of fatty acids in liver mitochon-dria. Autosomally inherited genetic mutations ofthese two enzymes are associated most closely withAFLP, especially the G1548C mutation of LCHAD.The mothers of babies with defects in fatty acidoxidation and mothers within families with knowndefects in fatty acid oxidation have a high inci-dence (62% in one series) of maternal liver disease,either AFLP or HELLP syndrome. LCHAD defi-ciency has been identified in 20% of babies of

mothers with AFLP but not in babies of motherswith HELLP syndrome. It has been speculated thatmaternal heterozygosity for LCHAD deficiencydecreases the maternal capacity to oxidize long-chain fatty acids in both the liver and the placenta.This, together with the metabolic stress of pregnancyand fetal homozygosity for LCHAD deficiency,causes potentially hepatotoxic metabolites ofLCHAD to accumulate in the maternal circulation.Perhaps external factors exacerbate this situation.There are reports of maternal liver disease associ-ated with defects of other enzymes involved in fattyacid oxidation, but the role of these other enzymesin causing AFLP is a matter of controversy.

Clinical Features and DiagnosisUnlike HELLP syndrome, 50% patients with AFLPare nulliparous, with an increased incidence intwin pregnancies. AFLP occurs almost exclusivelyin the third trimester, from 28 to 40 weeks, mostcommonly at 36 weeks. In a few patients, the pre-sentation is jaundice in the postpartum period.The presentation can vary from asymptomatic tofulminant liver failure; most patients have jaun-dice. A typical patient has 1 to 2 weeks of anorexia,nausea, vomiting, and right upper quadrant painand looks ill, with jaundice, hypertension, edema,ascites, a small liver (it may be enlarged initially),and various degrees of hepatic encephalopathy.Intrauterine death may occur. About 50% ofpatients with AFLP have preeclampsia.

In AFLP, the serum level of aspartate amino-transferase can vary from near-normal to 1,000U/L, usually about 300 U/L; the bilirubin con-centration is usually less than 5 mg/dL but higherin severe or complicated disease. Other typicalabnormalities are normochromic, normocyticanemia; high leukocyte count; normal-to-lowplatelet count; abnormal prothrombin time, acti-vated partial thromboplastin time, and fibrinogen,with or without disseminated intravascular coag-ulation; metabolic acidosis; kidney dysfunction(often progressing to oliguric kidney failure);hypoglycemia; high ammonia level; and often bio-chemical pancreatitis. Computed tomography ismore sensitive than ultrasonography for detectingAFLP. Liver biopsy is rarely indicated for man-agement but is essential for a definitive diagnosisof AFLP. Microvesicular, and infrequently

428 Liver

macrovesicular, fatty infiltration is most promi-nent in zone 3; this fat consists of free fatty acids.Also, there is lobular disarray, with pleomorphismof hepatocytes and mild portal inflammation withcholestasis, an appearance similar to that of Reye’ssyndrome and tetracycline and valproic acid tox-icity (Fig. 2). Although the histologic features usu-ally are diagnostic of AFLP, occasionally, theycannot be differentiated from those of viralhepatitis or preeclampsia.

For severely ill patients with liver failure inthe third trimester, the differential diagnoses areAFLP, HELLP (Table 4), thrombotic thrombocy-topenic purpura, hemolytic-uremic syndrome, andfulminant viral hepatitis.

ManagementEarly recognition of AFLP, with immediate ter-mination of the pregnancy and intensive sup-portive care, is essential for the survival of boththe mother and the fetus. Recovery before deliveryhas not been reported. Although the inciting injuryceases with delivery, the patient requires supportuntil liver function has time to recover. By 2 to 3days after delivery, the transaminase levels andencephalopathy improve, but intensive supportivecare is needed to manage the many complicationsof liver failure until this recovery occurs. Patientswho are critically ill at the time of presentation,who develop complications (encephalopathy,

hypoglycemia, coagulopathy, or bleeding [or acombination of these]), or whose condition con-tinues to deteriorate despite emergency delivery,should be transferred to a liver center.

Delivery is usually by cesarean section, butthe necessity for this has not been tested in ran-domized trials. Rapid controlled vaginal deliverywith fetal monitoring is probably safer if the cervixis favorable and will decrease the incidence ofmajor intra-abdominal bleeding. It probably is bestto maintain an international normalized ratio ofless than 1.5 and a platelet count of more than50,000/mm3 (>50×109/L) during and afterdelivery and to provide antibiotic prophylaxis.With correction of the coagulopathy, epiduralanesthesia is probably the best choice and willallow a better ongoing assessment of the patient’slevel of consciousness.

Intensive supportive care is the same as for anypatient with fulminant liver failure. Plasmapheresishas been used in some cases, but its benefit isunproven. Corticosteroids are ineffective.Although liver function starts to improve within 3days after delivery, the disease then enters acholestatic phase, with increasing levels of bilirubinand alkaline phosphatase. Depending on theseverity and complications, recovery can occur indays or be delayed for months. It is complete whenthe patient has no signs of chronic liver disease.With advances in supportive management of these


Fig. 2. Histologic appearance of the liver of a 32-year-old primigravida with acute fatty liver of pregnancy. A,Sudan stain (low power) shows diffuse fatty infiltration (red staining) involving predominantly zone 3, withrelative sparing of periportal areas. B, Hematoxylin and eosin stain (high power) shows hepatocytes stuffed withmicrovesicular fat (free fatty acids) and centrally located nuclei.

A B

patients, including early delivery, the maternalmortality rate is currently 10% to 18% and the fetalmortality rate is 9% to 23%. Infectious and bleedingcomplications are the most life-threatening con-ditions. Liver transplantation has a very limitedrole in AFLP because of the great potential forrecovery with delivery, but it should be consid-ered for patients whose clinical course continues todeteriorate with advancing fulminant liver failureafter the first 1 or 2 days postpartum without signsof liver regeneration.

Many patients do not become pregnant againafter AFLP, either by choice, because of the dev-astating effect of the illness, or by necessity,because of the hysterectomy to control post-partum bleeding. Women who are carriers of theLCHAD mutation have an increased risk of therecurrence of AFLP in 20% to 70% of pregnan-cies. All babies of mothers with AFLP are testedfor defects of fatty acid oxidation becausepresymptomatic diagnosis and appropriate earlymanagement reduces morbidity and mortality inthese babies. More extensive neonatal screeningfor defects of fatty acid oxidation is advocated bysome. For mothers without identifiable abnor-malities of fatty acid oxidation, AFLP does nottend to recur in subsequent pregnancies, althoughrare cases have been reported.

RECOMMENDED READINGCh’ng CL, Morgan M, Hainsworth I, Kingham JG.

Prospective study of liver dysfunction in preg-nancy in Southwest Wales. Gut. 2002;51:876-80.

Glantz A, Marschall HU, Lammert F, MattssonLA. Intrahepatic cholestasis of pregnancy: arandomized controlled trial comparing dex-amethasone and ursodeoxycholic acid.Hepatology. 2005;42:1399-405.

Hay JE. Viral hepatitis in pregnancy. Viral HepatitisReviews. 2000;6:205-15.

Ibdah JA. Acute fatty liver of pregnancy: an updateon pathogenesis and clinical implications.World J Gastroenterol. 2006;12:7397-404.

Ropponen A, Sund R, Riikonen S, Ylikorkala O,Aittomäki K. Intrahepatic cholestasis of preg-nancy as an indicator of liver and biliary dis-eases: a population-based study. Hepatology.2006;43:723-8.

Schneider G, Paus TC, Kullak-Ublick GA, MeierPJ, Wienker TF, Lang T, et al. Linkage betweena new splicing site mutation in the MDR3 aliasABCB4 gene and intrahepatic cholestasis ofpregnancy. Hepatology. 2007;45:150-8.

Sibai BM. Diagnosis, controversies, and manage-ment of the syndrome of hemolysis, elevatedliver enzymes, and low platelet count. ObstetGynecol. 2004;103:981-91.

430 Liver

Table 4. Diagnostic Differences Between AFLP and HELLP Syndrome

Feature AFLP HELLP

Parity Nulliparous, twins Multiparous, olderJaundice Common UncommonMean bilirubin, mg/dL 8 2Encephalopathy Present AbsentPlatelets Low-normal LowProthrombin time Prolonged NormalAPTT Prolonged NormalFibrinogen Low Normal-increasedGlucose Low NormalCreatinine High HighAmmonia High NormalComputed tomography Fatty infiltration Hemorrhage

AFLP, acute fatty liver of pregnancy; APTT, activated partial thromboplastin time; HELLP, hemolysis, elevated liverenzymes, low platelets.

Orthotopic liver transplantation (OLT) is highlyeffective for patients with liver failure, restoringnormal health and, hopefully, a normal lifestyle.Patient survival is excellent; nationally, the sur-vival rate is 86% at 1 year after OLT and 78% at 3years. However, the demand for donor organsgreatly exceeds supply. In the United States, about6,500 deceased donor organs and about 300 to 500living donor organs are available annually, butcurrently, more than 17,000 patients are on theliver transplant list. Patient selection and organallocation are two major problems.

INDICATIONS FOR ORTHOTOPICLIVER TRANSPLANTATIONDecompensated cirrhosis is the most common indi-cation for OLT (about 70% of cases) (Table 1). Themost common underlying liver disease that leadsto OLT in the United States is cirrhosis due tohepatitis C (41% of cases), with or without hepato-cellular carcinoma, followed by alcoholic cirrhosis(14%), chronic cholestatic liver disease (primarybiliary cirrhosis and primary sclerosing cholan-gitis) (14%), and cryptogenic (10%) (some cases of

cryptogenic cirrhosis may be due to nonalcoholicfatty liver disease), with all other causes of cir-rhosis being less common. This distribution ofcauses of liver disease that leads to OLT will likelychange over the next decades, with the number ofcases of hepatitis C decreasing but the number ofcases of obesity-related liver disease increasing.

431

CHAPTER 34

Liver Transplantation


Abbreviations: CTP, Child-Turcotte-Pugh; INR, international normalized ratio; LDLT, living donor liver transplantation;MELD, model for end-stage liver disease; OLT, orthotopic liver transplantation.

Table 1. Indications for Orthotopic LiverTransplantation

Cirrhosis of any cause (CTP score ≥7)Cirrhotic complications

Hepatocellular carcinomaHepatopulmonary syndrome

Acute liver failure of fulminant Wilson’sdisease

Primary nonfunction or early (first 7 days) hepatic artery thrombosis of hepatic allograft

Metabolic diseasesHyperoxaluriaFamilial amyloidosis

CTP, Child-Turcotte-Pugh.

The two complications of cirrhosis that areaccepted indications for OLT are hepatocellularcarcinoma and hepatopulmonary syndrome. Thefollowing criteria (the Milan criteria) are used toselect tumors suitable for OLT, that is, those likelyto be cured by OLT: a single tumor 5 cm or less inany dimension or three or fewer lesions each smallerthan 3 cm. For all these tumors, there can be no evi-dence of vascular invasion or extrahepatic spread.

About 5% of all OLTs in the United States areperformed for acute medical emergencies,including acute liver failure, fulminant Wilson’sdisease, or early failure of a liver allograft (pri-mary nonfunction or hepatic artery thrombosiswithin the first postoperative week). Acute liverfailure is an uncommon condition, with about only3,000 cases annually in the United States. The mostfrequent cause is acetaminophen hepatotoxicity(40% of cases), followed by indeterminate causes(20%) and idiosyncratic drug reactions (14%).Primary hyperoxaluria and familial amyloidosis,diseases in which the metabolic defect is in theliver, are also recognized indications for OLT inadults. For children, several other metabolic dis-eases are indications for OLT. Several proposedindications for OLT are a subject of controversy,for example, cholangiocarcinoma after intensiveradiotherapy and chemotherapy, portopulmonaryhypertension, metastatic neuroendocrine tumors,and polycystic liver disease. Occasionally, in someregions of the United States, OLT is performed forthese indications.

ALLOCATION OF ORGANSIn February 2002, the allocation system fordeceased donor livers in the United States waschanged to a system based on short-term mor-tality, that is, an organ is allocated to the patientmost likely to die in the next 3 months (Table 2).The most urgent indication for OLT is acute liverfailure, and these patients are given the highestpriority for urgent organ allocation (status 1patients). Unlike status 1 patients, who should beassigned an organ quickly after activation, patientswith chronic liver disease generally have a two-step process: listing for OLT and allocation of adonor organ. If otherwise suitable to be a trans-plant recipient, a patient with cirrhosis is listed for

OLT when he or she meets minimal listing cri-teria; this is based on a Child-Turcotte-Pugh(CTP) score of 7 or more. However, organ allo-cation is prioritized by patients listed within eachABO blood group, according to their 3-monthexpected mortality, as defined by the model forend-stage liver disease (MELD) system.

The MELD score is based on the creatinine,bilirubin, and international normalized ratio(INR) values and is calculated according to thefollowing formula:

MELD score = 0.957 × Loge(creatinine mg/dL) + 0.378 ×Loge(bilirubin mg/dL) + 1.120 × Loge(INR) + 0.643

The three biochemical variables are placed in acomputer program and the MELD score is calcu-lated (www.unos.org). For MELD scores higher

432 Liver

Table 2. Allocation of Deceased DonorOrgans

Allocation status Disease category

Status 1 Acute liver failureFulminant Wilson’s

diseasePrimary nonfunction

of allograftHepatic artery throm-

bosis (1st week aftertransplant)

MELD Calculated Cirrhosis of anyscore cause

Assigned Hepatocellular carcinoma

Hepatopulmonarysyndrome

HyperoxaluriaFamilial amyloidosisAppeal to regionalreview board*

MELD, model for end-stage liver disease.*Any Transplant Program can appeal to the regional

review board for an assigned MELD score for anypatient to allow the patient to receive an organ.

than 40, the expected 3-month mortality rate forpatients is 80% without OLT; for scores of 20 to 29,the rate is 20% to 25%, and for scores less than 10,patients have no excess short-term mortality.

Hepatocellular carcinoma and hepatopul-monary syndrome are accepted indications forOLT for which mortality is not reflected by theMELD score. Patients with either of these condi-tions are assigned MELD scores to allow OLT in 3to 12 months (called MELD exceptions). In theUnited States, hyperoxaluria and familial amy-loidosis are the other two MELD exceptions foradults. Patients with these criteria are assigned aMELD score to allow for OLT to be performedwithin a reasonable time (eg, for patients withhepatocellular carcinoma, the MELD score is ini-tially 22, then increases to 25, 27, and 29 at 3-monthintervals until OLT).

The only ways for patients to be guaranteedconsideration for allocation of a deceased donororgan is to have status 1, a calculated MELD score,or one of the four MELD exceptions for adults(Table 2). For controversial indications for OLT orfor patients who are more symptomatic than sug-gested by their MELD score, transplant programsmay appeal to the regional review board to begiven an assigned MELD score that will allow earlyOLT. Different review boards have differentphilosophies about which patients will be consid-ered for an assigned MELD score; there are nonational rules for these review boards.

Despite the success of OLT, the procedurehas some absolute and relative contraindications(Table 3). None of the relative contraindicationsare absolute, and their weight may vary in dif-ferent transplant programs; however, addedtogether, they may preclude a patient fromhaving OLT.

IMMUNOSUPPRESSIONFive main groups of immunosuppressive med-ications are used in OLT (Table 4). Each immuno-suppressive drug has its own site of action andside effects. The risk of rejection is highest in thefirst weeks after OLT, at which time immunosup-pression is at its highest level. Tacrolimus hasreplaced cyclosporine as the calcineurin inhibitorof choice in most liver transplant programs.Frequently, corticosteroids with or withoutmycophenolate mofetil are administered in thefirst postoperative weeks. Immunosuppression istapered by 4 months, often to tacrolimus mono-therapy, with lower serum levels. Long-term cal-cineurin inhibitor monotherapy is ideal, but ifnephrotoxicity develops in response to the treat-ment, low-dose calcineurin inhibitor plusmycophenolate mofetil or sirolimus may be used.Overall, the trend now is to tailor immunosup-pression to each patient, depending on the timefrom OLT, rejection history, and side effects fromindividual drugs.

Liver Transplantation 433

Table 3. Contraindications to Orthotopic Liver Transplantation

Absolute Relative

Extrahepatic malignancy unless tumor-free for ≥2 years and low General debilityprobability of recurrence Social isolation

Untreated alcoholism or alcoholic hepatitis Advanced ageHigh-dose or multiple pressors Extensive previousSevere multiorgan failure abdominal surgerySevere psychologic disease likely to affect compliance Extensive portal orSevere pulmonary hypertension mesenteric thrombosisAdvanced cardiopulmonary disease

COMPLICATIONS AFTER ORTHOTOPICLIVER TRANSPLANTATION

Primary Nonfunction of the Liver AllograftThe most dire early complication is primary non-function of the allograft. This starts immediatelywith the appearance of clear bile or no output ofbile, high aminotransferase levels, and then anincrease in bilirubin concentration. The main iden-tified risk factor is high fat content of the allo-graft. Grafts may be biopsied to assess this beforeimplantation. No therapy is available for primarynonfunction, and the patient needs to be reactivatedas status 1 to receive a second graft.

Hepatic Artery Thrombosis Another dreaded early complication of OLT ishepatic artery thrombosis. This is most common inchildren, size-mismatched grafts, and living donorOLT. It usually occurs in the first week after OLT, butit can develop later. The clinical manifestations maybe subtle, and patients may be asymptomatic or

have mild fever or increased aminotransferaselevels. In the majority of adults with hepatic arterythrombosis, the grafts fail because of an abscess orischemic cholangiopathy. When hepatic arterythrombosis occurs in the first 7 days after OLT, thepatient will be listed for retransplantation as status 1.

Cellular RejectionAcute cellular rejection occurs in up to 50% ofliver recipients and usually is associated withmild-to-moderate biochemical abnormalities and,occasionally, fever. Although the diagnosis canbe suspected by the timing in the early weeksafter OLT, definitive diagnosis requires histo-logic examination of the liver, with the followingfindings: 1) portal infiltrates with activated lym-phocytes and some eosinophils, 2) lymphocyticcholangitis, and 3) venous endotheliitis. Ninetypercent of cases of rejection occur in the first 2 post-operative months. Most rejections are treated withintravenous corticosteroids, and 85% of patientswith rejection have a response to corticosteroids.

434 Liver

Table 4. Immunosuppressive Drugs and Their Side Effects

Drug class Drug Side effects

Corticosteroids* Methylprednisone Hypertension, diabetes mellitus, Prednisone neurotoxicity, hyperlipidemia, bone loss,

myopathyPurine antagonists Azathioprine Cytopenias

Mycophenolate Gastrointestinal side effects (mycopheno-mofetil late mofetil only)

Calcineurin inhibitors*† Tacrolimus Nephrotoxicity, hypertension, diabetesCyclosporine mellitus, neurotoxicity

TOR inhibitors Sirolimus/rapamycin Cytopenias, hyperlipidemia, poor woundhealing, hepatic artery thrombosis

Antibody therapy (intravenous)* OKT3 (muromonab- Profound immunosuppression, opportun-CD3) istic infections

Antithymocyte globulin(Thymoglobulin)

TOR, target of rapamycin.*Used for treatment and prevention of rejection (others used only for prevention).†Beware of drug interactions with drugs affecting cytochrome P-450 enzyme system; inhibitors of the cytochrome P-450

system (eg, fluconazole) increase the levels of calcineurin inhibitors; drugs stimulating the cytochrome P-450 system (eg,phenytoin) decrease calcineurin inhibitor levels and thus increase the risk of rejection.

Of the cases of steroid-resistant rejection, 90%respond to intravenous antibody therapy withmuromonab-CD3 (OKT3) or antithymocyte glob-ulin. Acute cellular rejection early after OLT gen-erally has no effect on long-term graft outcome,and very few grafts are lost to chronic rejection.

Biliary Strictures The biliary anastomosis, either duct-to-duct or bil-iary-enteric, is the most common site of biliarystrictures, which usually form in the first month.Most strictures respond to endoscopic dilatation,with or without stents, but occasionally surgicalrevision of the anastomosis is needed.

Nonanastomotic or ischemic-type biliary stric-tures may form at any time, but the median time isabout the eleventh postoperative week. The mostcommon identified cause is hepatic artery throm-bosis, either early or late. Other associations arewith ABO incompatibility, long warm (>90 min-utes) or cold (>12 hours) ischemia time, and pri-mary sclerosing cholangitis. Some of these stricturescan be managed with endoscopic or percutaneousbiliary stenting, although ischemic-type biliarystricturing leads to death or need for retransplan-tation in about 50% of cases.

InfectionsA systemic fungal, viral, or bacterial infectiondevelops in one in five liver transplant recipientsduring the first postoperative month. Cytome-galovirus infection is the most common viralinfection. Its incidence peaks in the first 3 to 5postoperative weeks, and it is rare after the firstyear. Its presence is suggested by fever andleukopenia. Treatment is with intravenous gan-ciclovir or oral valganciclovir. Candida infectionis the most common fungal infection, althoughopportunistic infections can also be seen withAspergillus, Nocardia, Cryptococcus, and Pneumocystis.Some transplant programs provide prophylaxisfor Pneumocystis in the early postoperativemonths when immunosuppression is at itshighest level.

Late ComplicationsThe main late complications after OLT are recurrentdisease, complications of immunosuppression,and de novo malignancies.

When late allograft dysfunction occurs in apatient who is well and receiving stable, therapeuticimmunosuppression, recurrent disease is the mostlikely diagnosis, especially if the underlying cause ofliver disease is hepatitis C. The diagnosis is histo-logic, and liver biopsy is needed. The incidence andpotential severity of recurrent disease in an allograftis greatest for hepatitis C. Recurrent hepatitis C maybe treated with pegylated interferon and ribavirin.Side effects are common, especially anemia, anddose reductions are frequently necessary. Treatmentwith pegylated interferon and ribavirin produces asustained virologic response in about 30% of patientswith recurrent hepatitis C after liver transplanta-tion. Currently, recurrent hepatitis B is preventedin more than 90% of patients by hepatitis Bimmunoglobulin and antiviral therapy. However,most other liver diseases, including primary biliarycirrhosis and primary sclerosing cholangitis, autoim-mune hepatitis, nonalcoholic fatty liver disease, andhepatocellular carcinoma may recur.

Most OLT recipients have normal cardiacfunction, but increasingly patients who are obeseor have diabetes mellitus or hypertension areundergoing OLT. In addition, even in those with nopre-OLT risk factors for coronary artery disease,treatment with immunosuppressive drugs mayproduce an increase in hypertension, diabetes,kidney failure, dyslipidemia, and obesity in a highpercentage of patients (Table 5). This leads to aprofile of high risk for cardiovascular diseases formany OLT recipients, with cyclosporine havingmore metabolic effects than tacrolimus. OLTrecipients must receive adequate screening andtreatment for these risk factors.

Liver Transplantation 435

Table 5. Cardiovascular Risk Factors in LiverRecipients

Complication Recipients affected, %

Hypertension* 50Diabetes mellitus 30 (15 new-onset)Kidney failure* 14-30Dyslipidemia* 30-45Obesity 20-30

*Worse with cyclosporine than with tacrolimus.

Liver transplant recipients have multiplepotential risk factors for cancer: immunosuppres-sion, viruses (hepatitis C virus, hepatitis B virus,human papillomavirus, human herpes virus 6,Epstein-Barr virus), alcohol use, and smoking.Furthermore, many recipients are now older than50 years or even older than 60 at the time of OLTand, thus, have the increased cancer risk of aging.The effect of immunosuppression probably isrelated to the degree of immunosuppression ratherthan to individual agents. The reported overallincidence of cancer varies depending on the series,from 2.9% to 14%; the reported cancer-relatedmortality rate is 0.6% to 8%. Malignancies are animportant cause of long-term mortality.

Malignancies that occur frequently in OLTrecipients are skin cancers, posttransplant lym-phoproliferative disease, and cervical, vulvar, andanal squamous cancers. The incidence of colorectalcancer is increased only for recipients with primarysclerosing cholangitis, likely related to ulcerativecolitis. Increasingly, data show notable mortality at 5to 10 years after OLT from upper aerodigestive can-cers in recipients who continue to smoke and drink.

EXPANSION OF THE DONOR POOLAdult-to-adult living donor liver transplantation(LDLT) uses the right lobe of the donor for implan-tation into the recipient. For pediatric recipients, theleft lobe may be used, depending on size. The major

advantages of LDLT over deceased donors areavailability of the organ and expansion of the donorpool. LDLT produces more vascular and biliaryproblems but no less rejection. The donor mor-bidity rate is 8% to 26%, and the mortality rate is0.4% (1/250). Other ways of expanding the donorpool are the use of older donors (higher rate of pri-mary nonfunction), split livers (higher complicationrate, labor-intensive, and disadvantage to primaryrecipient), marginal donors (eg, fatty liver withincreased risk of primary nonfunction), donationafter cardiac death (increased risk of biliary com-plications), and high-risk donors (high-risk lifestyleor medical history).

RECOMMENDED READINGBrown KA. Liver transplantation. Curr Opin

Gastroenterol. 2005;21:331-6.Burton JR Jr, Rosen HR. Diagnosis and manage-

ment of allograft failure. Clin Liver Dis.2006;10:407-35.

Post DJ, Douglas DD, Mulligan DC. Immunosup-pression in liver transplantation. Liver Transpl.2005;11:1307-14.

Shiffman ML, Saab S, Feng S, Abecassis MI, TzakisAG, Goodrich NP, et al. Liver and intestinetransplantation in the United States, 1995-2004.Am J Transplant. 2006;6(5 Pt 2):1170-87.

Verna EC, Brown RS Jr. Hepatitis C virus and livertransplantation. Clin Liver Dis. 2006;10:919-40.

436 Liver

437

Liver


QUESTIONS

Abbreviations used:ALT, alanine aminotransferaseAST, aspartate aminotransferaseCT, computed tomographyERCP, endoscopic retrograde cholangiopancre-atography

HAV, hepatitis A virusHBc, hepatitis B coreHBcAb, hepatitis B core antibodyHBeAg, hepatitis B e antigenHBs, hepatitis B surfaceHBsAg, hepatitis B surface antigenHBV, hepatitis B virusHCV, hepatitis C virusHDV, hepatitis D virusHIV, human immunodeficiency virusINR, international normalized ratioMCV, mean corpuscular volumeMRCP, magnetic resonance cholangiopancre-atography

Multiple Choice (choose the best answer)1. A 45-year-old woman with left lower quad-

rant abdominal cramps is found to have a livermass. Liver ultrasonography shows a 4-cmmass with uniformly increased echogenicity.The results of liver tests are normal. ContrastCT shows a 4-cm mass with peripheralnodular enhancement in the arterial phase andgradual fill-in of contrast in the later phases.

The rest of the liver appears normal. The mostappropriate management of this mass is:

a. Repeat CT in 4 monthsb. Radiofrequency ablationc. Biopsy to confirm the diagnosisd. Surgical resectione. No further intervention is needed

2. A 28-year-old woman with abdominal pain hasa 4-cm solid liver mass and two 2-cm simpleliver cysts. She has been taking oral contracep-tives for 5 years but has no history of liver dis-ease. On contrast CT, the mass enhances in thearterial phase and is isoattenuating in thevenous phase. The imaging data are thoughtto be consistent with either focal nodular hyper-plasia or adenoma. Biopsy confirms focalnodular hyperplasia. The pain has sinceresolved. The most appropriate management offocal nodular hyperplasia in this patient is:

a. No further intervention is neededb. Radiofrequency ablationc. Chemoembolizationd. Surgical resectione. Discontinuation of oral contraceptives

3. A 35-year-old woman with dyspepsia has a 4-cmliver mass. She has no history of liver disease.

She has taken oral contraceptives for 8 years.On CT with contrast, the mass enhances rapidlyin the arterial phase and is isoattenuating in thevenous phase. It has areas of heterogeneity, con-sistent with regions of hemorrhage and necrosiswithin the mass. The most appropriate man-agement of this mass is:

a. No further intervention is neededb. Radiofrequency ablationc. Chemoembolizationd. Surgical resectione. Orthotopic liver transplantation

4. A 72-year-old woman has sudden onset ofpainless jaundice and increased levels ofbilirubin and alkaline phosphatase. CT of theabdomen shows a large 15- × 11-cm lobulatedcyst in the right lobe of the liver, with masseffect on surrounding structures. Biliaryscintigraphy shows no connection of the cystto the biliary tree. Aspiration yields 950 mL ofcloudy yellow fluid; cytology shows reactivecells, and cultures are negative. The mostappropriate management of this cyst is:

a. No further intervention is neededb. ERCP with stent placementc. Cyst aspiration and ethanol sclerosisd. Surgical resectione. Orthotopic liver transplantation

5. A 67-year-old man with chronic hepatitis C withcirrhosis, a platelet count of 80,000/mm3

(80×109/L), and serum total bilirubin of 1.2mg/dL was referred for evaluation. The α-feto-protein level was 15.2 ng/mL. Recent abdom-inal CT findings were negative. EGD showedmoderate-sized varices in the distal esophagus.Six months later, the α-fetoprotein level hasincreased to 250 ng/mL and ultrasonographyshows a new 4.4-cm mass in the liver. ContrastCT shows arterial phase enhancement of themass, with washout in the portal and venousphases. No other evidence of extrahepatic dis-ease is found. The diagnosis is:

a. Hepatocellular adenomab. Hepatocellular carcinoma

c. Focal nodular hyperplasiad. Diagnosis cannot be made without biopsye. Hemangioma

6. The most appropriate management for thepatient in question 6 is:

a. Surgical resectionb. Radiofrequency ablationc. Percutaneous ethanol injectiond. Transarterial chemoembolizatione. Orthotopic liver transplantation

7. A 46-year-old man presented with a 15-lbweight loss and diarrhea. He states that hehas no abdominal pain or anorexia. Examin-ation findings include a body mass index of18 kg/m2. Laboratory findings are as fol-lows: alkaline phosphatase 264 U/L, ALT 62U/L, hemoglobin 10.5 g/dL, and MCV 72fL. A fecal occult blood test was negative, aswas CT colonography. Liver ultrasonog-raphy showed mild steatosis and no dilatedducts. What would be the next most appro-priate test?

a. Abdominal CTb. Colonoscopyc. MRCPd. Tissue transglutaminasee. Liver biopsy

8. A 63-year-old woman presented with a 4-hourhistory of abdominal pain, fever, and nausea.Physical examination shows fever, jaundice,and mild epigastric tenderness. Laboratory find-ings included the following: leukocyte count,18,000/mm3 (18×109/L) with left shift, bilirubin3.6 mg/dL, alkaline phosphatase 150 U/L, AST745 U/L, and ALT 650 U/L. Ultrasonographyshowed multiple small stones in the gall-bladder, no bile duct dilatation, and a normalpancreas. Although treatment was started withantibiotics, she still had fever the followingday. Laboratory tests were repeated: bilirubin5.8 mg/dL, AST 84 U/L, and leukocyte count25,000/mm3 (25×109/L). Blood cultures werepositive for Escherichia coli. Which of the fol-lowing would you advise next?

438 Liver

a. Doppler study of hepatic vesselsb. Laparoscopic cholecystectomyc. MRCPd. Endoscopic ultrasonographye. ERCP

9. A 23-year-old woman has a 2-week history ofjaundice and a 24-hour history of somnolence.She became sexually active with her boyfriend16 weeks ago, and he is HBsAg positive.Physical examination shows jaundice, disori-entation, and asterixis. Laboratory findingsinclude the following: ALT 1,648 U/L,bilirubin 12.5/7.4 mg/dL, and INR 2.4. HBsAg,anti-HCV, and anti-HAV were all negative.Which of the following would confirm themost likely diagnosis?

a. Serologic studies for herpesb. Ceruloplasminc. IgM anti-HBcd. Anti-HDVe. Antinuclear antibody

10. A 42-year-old woman is receiving peginter-feron and ribavirin therapy for hepatitis C.Pretreatment data included HCV genotype 2and HCV RNA level of 550,000 IU/mL. A liverbiopsy specimen showed periportal (stage II ofIV) fibrosis. She is tolerating therapy well.Four-week HCV RNA was 500 IU/mL. She isnow 3 months into treatment, and her HCVRNA is negative. Which of the followingshould you advise?

a. Continue combination therapy for 9 moremonths

b. Continue combination therapy for 3 moremonths

c. Stop therapy now

11. A 53-year-old man with ascites has a historyof hepatitis B. Ten years ago, liver biopsyshowed cirrhosis. Physical examination find-ings include jaundice, spider angiomas, andascites. Laboratory findings include the fol-lowing: ALT 86 U/L, bilirubin 1.3 mg/dL,albumin 2.9 g/dL, INR 1.3, hemoglobin 11.8g/dL, leukocyte count 3,400/mm3 (3.4×109/L),

platelet count 49,000/mm3 (49×109/L), andcreatinine 1.2 mg/dL. HBsAg, IgG anti-HBc,and HBeAg are positive. HBV DNA is 600,000IU/mL. Which of the following statements ismost correct about this patient?

a. Lamivudine should be administeredb. Peginterferon should be administeredc. Entecavir should be administeredd. Give no further HBV therapy now; proceed

with orthotopic liver transplantatione. Paracentesis is contraindicated because of

coagulopathy

12. A 45-year-old man comes to the emergencydepartment with a 3-day history of fatigueand dull, constant, right upper quadrantpain. He drinks one bottle of wine daily. Heused intravenous drugs 20 years ago and cur-rently uses marijuana. He had taken twoacetaminophen tablets for each of the last 2days. Physical examination shows that thepatient is alert and oriented. Other findingsinclude the following: temperature 37.9°C,pulse 100, blood pressure 100/65 mm Hg, noasterixis, and tender hepatomegaly. Laboratoryfindings include the following: hemoglobin12.5 g/dL, MCV 108 fL, platelet count120,000/mm3 (120×109/L), leukocyte count14,900/mm3 (14.9×109/L) with left shift, AST96 U/L, ALT 45 U/L, bilirubin 2.8 mg/dL, INR1.1, and HCV RNA positive. Ultrasonographyshows a heterogeneous echotexture of the liver,no ascites, no gallstones, and no bile ductdilatation. Which of the following would youadvise now?

a. N-acetylcysteineb. MRCPc. Corticosteroidsd. Chemical dependency counselinge. Peginterferon and ribavirin

13. A 43-year-old man presents with persistentjaundice. Acute hepatitis A developed 3months ago. At that time, ALT was 1,234 U/L,bilirubin was 8.6 mg/dL, and IgM anti-HAVwas positive. He continues to have mild fatigueand pruritus but states that he has no abdominal


pain or fever and is not taking any medication.Physical examination findings are notable onlyfor jaundice. Laboratory values are as follows:ALT 236 U/L, bilirubin 7.8/4.2 mg/dL, alka-line phosphatase 400 U/L, INR 1.3, albumin 3.7g/dL, and γ-globulin 1.3 g/dL. Ultrasono-graphic findings were negative except for asmall amount of gallbladder sludge. Which ofthe following would you do next?

a. ERCPb. MRCPc. Endoscopic ultrasonographyd. Liver biopsye. Serial monitoring of liver blood tests

14. An 80-year-old man with jaundice has a his-tory of ischemic cardiomyopathy with biven-tricular failure. Six weeks ago, routine livertests showed an alkaline phosphatase level of180 U/L. Other liver enzymes at that timewere normal. He was admitted 5 days agoafter having a syncopal episode that wasattributed to sudden-onset atrial flutter.Twelve hours after admission (4 days ago),the following laboratory values wereobtained: AST 1,200 U/L, ALT 1,320 U/L,alkaline phosphatase 180 U/L, and bilirubin1.2 mg/dL. Amiodarone therapy was started4 days ago. He states that he does not haveexcessive alcohol use or other risk factors forliver disease. He says he does not haveabdominal pain. Physical examination showsjaundice, tender and pulsatile liver, mod-erate edema, and no spider angiomas orencephalopathy. Laboratory findings includethe following: AST 54 U/L, alkaline phos-phatase 180 U/L, total bilirubin 4.3 mg/dL,and direct bilirubin 2.6 mg/dL. Ultrasono-graphy shows sludge in the gallbladder butno bile duct dilatation. Which of the fol-lowing would you recommend next?

a. Abdominal CT scanb. Doppler study of hepatic artery and portal

veinc. MRCPd. Treatment of cardiac failuree. Stop amiodarone therapy

15. A 43-year-old asymptomatic Somali womanneeds INH (isoniazid) for latent tuberculosis.Her primary physician asks for advice becauseshe also has hepatitis B. The laboratory valuesare as follows, leukocyte count, 7,500/mm3

(7.5×109/L), platelet count 250,000/mm3

(250×109/L), AST 21 U/L, ALT 19 U/L, albumin4.3 g/dL, INR 1.0, and bilirubin 1.0 mg/dL.HBsAg and anti-HBe are positive; HBV DNAis 1,600 IU/mL. Ultrasonographic findings arenormal. Which of the following would youadvise now?

a. Liver biopsyb. Peginterferonc. Lamivudined. Entecavire. Proceed with INH therapy

16. A 30-year-old man who has had HBV infectionfor 6 years presents with a 2-week history ofanorexia, fatigue, and jaundice. He uses intra-venous drugs and drinks alcohol in excess. Heis not taking any medication. Physical exam-ination shows jaundice and needle marks butno hepatosplenomegaly. The following labo-ratory results were obtained: bilirubin 14mg/dL, ALT 1,579 U/L, AST 1,235 U/L, INR1.5, HBsAg positive, IgG anti-HBc positive,IgM anti-HBc negative, HBeAg negative, HBVDNA 1,000 IU/mL, anti-HCV negative, HCVRNA negative, IgG anti-HAV positive, andIgM anti-HAV negative. Which of the fol-lowing is most likely to establish the diagnosis?

a. Liver biopsyb. Urine screen for acetaminophenc. IgM anti-HDVd. Urine screen for alcohole. α-Fetoprotein

17. A 50-year-old Somali man presents with a 2-week history of anorexia, fatigue, and jaun-dice. He came to the United States just 6months ago. He is not aware of any previousHBV test results. He states that he does nothave a previous history of liver disease, alcoholconsumption, or medication use. Physicalexamination shows jaundice and splenomegaly.

440 Liver

Laboratory findings are as follows: bilirubin14 mg/dL, ALT 864 U/L, AST 637 U/L, INR1.5, HBsAg positive, IgM anti-HBc positive,HBeAg negative, HBV DNA 500,000 IU/mL,anti-HCV negative, IgG anti-HAV positive,and IgM anti-HAV negative. Ultrasonographyshows a small nodular liver, recanalizedumbilical vein, and splenomegaly. Which ofthe following is the most likely diagnosis?

a. Acute hepatitis Bb. Acute flare of chronic hepatitis Bc. Diffuse infiltrating hepatocellular carcinoma d. Acute hepatitis C

18. A 48-year-old man is hospitalized foresophageal variceal bleeding. He underwentsuccessful variceal ligation in the emergencydepartment. He has a 2-month history ofmalaise, fatigue, and abdominal distention.He had unprotected sex with prostitutes 30years ago. Physical examination shows mod-erate ascites and splenomegaly. Laboratoryfindings are as follows: hemoglobin 10.2 g/dL,leukocyte count 3,600/mm3 (3.6×109/L),platelet count 61,000/mm3 (61×109/L), INR1.5, albumin 2.5 g/dL, HBsAg positive, IgGanti-HBc positive, HBeAg positive, HBV DNA275,000 IU/mL, and anti-HCV negative.Which of the following is most appropriate?

a. Liver biopsyb. Peginterferon c. Entecavird. Lamivudinee. Transjugular intrahepatic portosystemic

shunt

19. A 27-year-old Asian woman has HBV infectionand lymphoma. Two weeks ago, she hadsplenectomy and was found to have non-Hodgkin’s lymphoma. The surgeon thoughtthat the liver was normal. She needs chemo-therapy and hematology consults to deter-mine if there are any contraindications tochemotherapy. She has no family history ofhepatocellular carcinoma. Physical exami-nation findings are normal. The laboratoryfindings include normal liver enzymes,

HBsAg positive, anti-HBe positive, and HBVDNA 1,000 IU/mL. Which of the followingwould you advise now?

a. Proceed with chemotherapy, no furthertreatment for HBV infection

b. Lamivudinec. Peginterferond. Peginterferon and lamivudinee. Liver biopsy

20. A 21-year-old prospective nursing studentcomes for evaluation because he was denied asa blood donor. He has no complaints and nosignificant past history. He states that he has norisk factors for viral hepatitis or other liverdisease. He has not previously received HBVvaccine. Physical examination findings arenormal. The complete blood count and liverenzymes are normal. Hepatitis markers: IgGanti-HBc is positive. IgM anti-HBc, HBsAg, anti-HBs, anti-HCV, and anti-HIV are negative.Which of the following would you advise now?

a. Check HBV DNAb. Liver biopsy, with hepatitis B immuno-

staining of specimenc. HBV vaccined. No further testing

21. A 43-year-old man was referred for manage-ment of hepatitis C. He has mild fatigue but isotherwise well. His medical history is notablefor remote alcohol abuse and mild depression,for which he takes paroxetine hydrochloride(Paxil). He abused intravenous drugs 20 yearsago. The body mass index is 33 kg/m2.Otherwise, physical examination findingswere normal. The following laboratory find-ings were obtained: ALT 84 U/L; normalbilirubin, albumin, and prothrombin time;platelet count 185,000/mm3 (185×109/L), HCVgenotype 1b, HCV RNA level 7,000,000 IU/mL.Ultrasonography showed a coarse liver echo-texture and a normal spleen. Which of thefollowing would you do now?

a. Start peginterferon and ribavirin therapyb. Perform liver biopsy


c. Do nothing further now, reevaluate in 6months

d. Arrange a psychiatry consultation

22. A 43-year-old man has hepatitis C genotype1b. His HCV RNA level is 1,000,000 IU/mL.Liver biopsy showed stage II/IV disease(periportal fibrosis). You advise treatmentwith peginterferon alfa 2a 180 μg/week andribavirin 1,200 mg/day. Twelve weeks aftertreatment was initiated, the HCV RNA levelis 100,000 IU/mL. He is tolerating therapywell except that hemoglobin is 12 g/dL (was16 g/dL). Which of the following would youadvise now?

a. Continue therapy, repeat HCV RNA in 12weeks

b. Increase the dose of peginterferonc. Increase the dose of ribavirin, add

erythropoietind. Stop therapy

23. A 43-year-old man has chronic hepatitis C.Laboratory findings included the following:ALT 79 U/L; normal bilirubin, albumin, andprothrombin time; HCV genotype 1b andHCV RNA level 2,000,000 IU/mL. Liverbiopsy showed stage III/IV disease (septalfibrosis). After 6 months of full-dose pegylatedinterferon and ribavirin, ALT is now 35 U/L,and the HCV level is 100,000 IU/mL. Which ofthe following should you advise at this time?

a. Continue combination therapy for 3 moremonths and recheck HCV RNA

b. Stop therapyc. Stop ribavirin therapy, continue treatment

with peginterferon for 6 more monthsd. Continue peginterferon and ribavirin

therapy and add ursodiol

24. A 32-year-old woman is referred for hepatitisC. She used intravenous drugs 10 years ago.Physical examination findings are normal. Thelaboratory findings include the following: hemo-globin 14.4 g/dL, leukocyte count 4,000/mm3

(4×109/L), platelet count 245,000/mm3

(245×109/L), INR 1.0, ALT 93 U/L, bilirubin 1.0

mg/dL, albumin 4.3 g/dL, HCV RNA level150,000 IU/mL, and HCV genotype 2. Ultra-sonographic findings are normal. Which of thefollowing would you advise now?

a. Observationb. Liver biopsyc. Peginterferon and ribavirind. No treatment now, reassess in 3 months

25. A 44-year-old man has had a painful lowerextremity rash for 3 months. It has improvedslightly with topical corticosteroids. His his-tory is notable for ulcer disease 20 years agothat required blood transfusion. Physicalexamination shows a purpuric rash on bothlower extremities. Laboratory findings includeALT 84 U/L and anti-HCV positive. Which ofthe following is most correct?

a. Rheumatoid factor will likely be positiveb. Oral corticosteroids should be givenc. Interferon therapy will not help the rashd. Renal arteriography would likely show the

characteristic changes of polyarteritis nodosae. Patient should have rheumatology

consultation

26. An 18-year-old woman presents with acutejaundice and somnolence. She has no pre-vious medical history and takes no medica-tions. She has jaundice and is sleepy butarousable. Laboratory values are as follows:INR 1.6, AST 240 U/L, ALT 210 U/L, totalbilirubin 8 mg/dL, direct bilirubin 3 mg/dL,hemoglobin 9.4 g/dL, ceruloplasmin 8mg/dL (normal, <22 mg/dL), and 24-hoururine copper 563 μg (normal, <60 μg). Whichof the following would you advise now?

a. Trientineb. Penicillaminec. Urgent liver transplantationd. Intracranial pressure monitoringe. Liver biopsy

27. A 74-year-old man presents with a 6-monthhistory of fatigue and edema. He states thathe does not drink alcohol in excess and does

442 Liver

not have a history of liver disease, diabetesmellitus, or risk factors for viral hepatitis.Physical examination shows anasarca andhepatomegaly. The following laboratoryvalues were obtained: hemoglobin 9.3 g/dL,platelet count 140,000/mm3 (140×109/L), totalbilirubin 1.3 mg/dL, direct bilirubin 0.5mg/dL, alkaline phosphatase 635 U/L, AST64 U/L, protein 9.4 g/dL, albumin 1.8 g/dL,INR 1.0, calcium 11.4 mg/dL, and creatinine2.3 mg/dL; urinalysis shows 3+ protein.Ultrasonography shows hepatomegaly but nomass or bile duct dilatation. Which of the fol-lowing would you advise next?

a. Serum protein electrophoresis b. Liver biopsyc. Angiotensin-converting enzyme leveld. MRCPe. HBsAg

28. A 43-year-old asymptomatic woman hasabnormal liver tests. She drinks one bottle ofwine daily and has a remote history of intra-venous drug abuse. Physical examinationshowed jaundice, spider angiomas, andsplenomegaly. Laboratory findings includedthe following: bilirubin 5.4 mg/dL, AST 121U/L, ALT 58 U/L, INR 1.6, platelet count34,000/mm3 (34×109/L), and HCV RNA pos-itive. Ultrasonography showed gallbladderstones, liver echotexture consistent with fat, apatent umbilical vein, and splenomegaly. Inaddition to cessation of alcohol, which of thefollowing would you advise?

a. Peginterferon and ribavirinb. Liver biopsyc. Splenectomyd. Laparoscopic cholecystectomye. Ultrasonography every 6 to 12 months

29. A 36-year-old asymptomatic man was referredwith a chronically elevated level of bilirubin.He had colectomy 8 years ago for colon cancercomplicating familial adenomatous polyposis.He abused intravenous drugs 15 years ago. Hehas no history of medication or alcohol excess.Physical examination findings were normal.

The following laboratory results were obtained:total bilirubin 2.4 mg/dL, direct bilirubin 0.1mg/dL, ALT normal, alkaline phosphatasenormal, and hemoglobin normal. Ultrasono-graphic findings were normal. Which of the fol-lowing is the most likely diagnosis?

a. Metastatic adenocarcinoma to the liverb. Primary sclerosing cholangitis c. Chronic hepatitis Cd. Gilbert’s syndromee. Adenocarcinoma of the ampulla of Vater

30. A 36-year-old woman presents with confusion.She was found by her boyfriend, who said thatthe patient has been ill recently with an upperrespiratory tract infection. She drinks four tosix glasses of wine daily. Physical examina-tion findings were as follows: temperature37.5°C, heart rate 100 beats/minute, bloodpressure 100/60 mm Hg. The patient wassleepy but arousable, had mild jaundice butno hepatosplenomegaly, ascites, or edema.Laboratory values were as follows: AST 5,487U/L, ALT 5,682 U/L, bilirubin 2.5 mg/dL,alkaline phosphatase 163 U/L, NH3 94μmol/L, and creatinine 2.0 mg/dL. A com-plete blood count was normal. Which of thefollowing would you advise at this point?

a. Pentoxifyllineb. N-acetylcysteinec. Corticosteroidsd. Liver biopsye. Acyclovir

31. A 63-year-old asymptomatic woman wasreferred because of an abnormal ALT value 2months after starting treatment with atorva-statin 20 mg/day. The pretreatment ALT valuewas normal. She has no risk factors for liverdisease. Physical examination shows mild obe-sity. On laboratory testing, AST and ALT areboth 65 U/L and alkaline phosphatase,bilirubin, INR, and albumin values are normal.What would be the next best step?

a. Continue atorvastatin and measure ALTagain in 3 months


b. Liver biopsyc. Liver ultrasonographyd. Stop atorvastatin therapye. Check antimitochondrial antibody, anti-

nuclear antibody, HBsAg, and anti-HCV

32. A 73-year-old man presents with a 1-week his-tory of jaundice. During this week, he also hadmild anorexia and a 5-lb weight loss but saidhe had no abdominal pain. He has no previoushistory of liver disease. He drinks two beersdaily. Four weeks ago, he took amoxicillin-clavulanate for 10 days for sinusitis. Physicalexamination documents jaundice and no fever.Laboratory findings include the following:ALT 105 U/L, alkaline phosphatase 478 U/L,and bilirubin 7.4 mg/dL. A complete bloodcount, INR, and albumin level are normal.Liver ultrasonography is negative. One weeklater, his symptoms and laboratory valueshave not changed, and another ultrasono-graphic study is negative. What would be thebest next step?

a. Observe and repeat laboratory tests in 1 weekb. Liver biopsyc. Abdominal CT scand. Check antimitochondrial antibodye. MRCP

33. A 59-year-old woman presents with fatigue of2 weeks’ duration. She has no history of liverdisease. Her only medical history is hypothy-roidism and chronic urinary tract infections.She drinks one beer daily. Her medicationsinclude estrogen (8 years), nitrofurantoin (1year), and levothyroxine (10 years). Physicalexamination findings are normal. A completeblood count is normal. Other findings includethe following: ALT 533 U/L, alkaline phos-phatase 135 U/L, and bilirubin 2.3 mg/dL;INR and albumin level are normal; antinuclearantibody 1:320, smooth-muscle antibody 1:80,γ-globulin 2.4 g/dL. Ultrasonography showedsmall gallbladder stones and no bile ductdilatation. What is the most likely diagnosis?

a. Autoimmune hepatitisb. Nitrofurantoin-induced liver disease

c. Estrogen-induced liver disease d. Choledocholithiasise. Primary biliary cirrhosis

34. A 35-year-old man presents with abdominaldistention. He has a history of ulcerative co-litis but had been well until the distentionstarted suddenly 1 week ago. He states thathe has no edema, dyspnea, chest pain, or fever.The liver enzyme values were normal 1 monthago. He drinks two beers daily. His medica-tions include azathioprine and mesalamine.Physical examination showed moderateascites. Laboratory values included the fol-lowing: complete blood count normal, alka-line phosphatase 133 U/L, and ALT 85 U/L.Bilirubin, INR, and albumin values are normal.Ultrasonography showed ascites, patenthepatic and portal veins, and no bile ductdilatation. What is the most likely diagnosis?

a. Primary sclerosing cholangitis b. Sinusoidal obstruction syndromec. Hepatic vein thrombosisd. Right heart failuree. Mesalamine-induced liver disease

35. A 43-year-old man is homozygous for C282Y.His serum iron level is 220 μg/dL, percent sat-uration is 88%, and ferritin is 575 μg/L. Livertest results are normal. He is healthy andasymptomatic. He consumes one alcoholicbeverage daily. Physical examination findingsare normal. What would you recommend?

a. No further evaluationb. Liver biopsy c. Phlebotomyd. Stop alcohol and repeat iron tests in 3

months

36. A 45-year-old woman had an increased serumlevel of ferritin and anti-HCV detected duringan evaluation for abnormal liver tests. Physicalexamination showed mild splenomegaly.Laboratory findings included the following:iron 120 μg/dL, percent saturation 35%, fer-ritin 414 μg/L, hemoglobin 13 g/dL, plateletcount 109,000/mm3 (109×109/L), AST 95 U/L,

444 Liver

ALT 134 U/L, and HCV genotype 2. Bilirubin,INR, and albumin values were normal.Ultrasonography showed a coarse liver andsplenomegaly. Esophagogastroduodenoscopyshowed small varices. Which of the followingwould you advise?

a. Liver biopsyb. Phlebotomyc. HFE gene testd. Peginterferon and ribavirin

37. A 55-year-old man presented with increasedserum iron levels. He has diabetes mellitus,arthritis, impotence, and atrial fibrillation. Heconsumes two to three beers each week.Physical examination detected an irregularheart rhythm. Laboratory findings includedthe following: iron 210 μg/dL, percent satu-ration 90%, and ferritin 1,714 μg/L. Liver testsand HFE gene tests were normal, as wereultrasonographic findings. Which of the fol-lowing would you recommend?

a. No additional evaluation b. Therapeutic phlebotomyc. Liver biopsyd. Magnetic resonance imaging to examine

for hepatic iron deposition

38. A 32-year-old asymptomatic man who doesnot have any significant medical history wasreferred because of abnormal liver testresults. Physical examination showed a bodymass index of 28.4 but no stigmata of chronicliver disease. Laboratory findings includedAST 64 U/L, ALT 85 U/L, and normal alka-line phosphatase and bilirubin levels.Ceruloplasmin was 17.5 mg/dL (normal,22.9-43.1 mg/dL). Other tests for chronicliver disease were negative. What would yourecommend?

a. Liver biopsyb. Trial of weight loss and repeat liver testsc. Slit-lamp examination to look for Kayser-

Fleischer ringsd. Check serum free copper levele. Start treatment with penicillamine

39. A 42-year-old woman has a chronic, asymp-tomatic mild increase in AST and ALT levels.Liver function is normal. She has a historynotable for dermatomyositis, for which shetakes prednisone 10 mg/day. She drinks fourglasses of wine daily. Her body mass index is23. Laboratory findings include the following:AST 94 U/L, ALT 56 U/L, alkaline phos-phatase 123 U/L, and bilirubin 1.0 mg/dL.Anti-HCV, HBsAg, creatine kinase, aldolase,and iron studies are negative or normal.Ultrasonography shows a change in liverechogenicity consistent with fat. Which of thefollowing is the most likely diagnosis?

a. Alcoholic liver disease b. Nonalcoholic fatty liver disease c. Celiac diseased. Autoimmune hepatitise. Increased aminotransferase levels from

muscle injury

40. A 47-year-old asymptomatic man presentswith abnormal iron tests. He drinks two beersdaily. Physical examination findings arenormal. Laboratory values are as follows: iron180 μg/dL, percent saturation 88%, ferritin1,075 μg/L, complete blood count normal, andAST 42 U/L. The HFE gene test detected twocopies of the C282Y mutation. Ultrasonographicfindings are normal. What would be the mostappropriate next step?

a. Liver biopsyb. Therapeutic phlebotomyc. Stop alcohol, repeat iron tests in 1 yeard. Magnetic resonance imaging of the liver

41. A 65-year-old man presents for assessment ofhyperbilirubinemia of 3 weeks’ duration. Hehas no history of inflammatory bowel disease,and colonoscopy 1 year ago was negative. TwoERCP studies showed changes consistent withprimary sclerosing cholangitis, with a promi-nent distal bile duct stricture. On both occa-sions, brushings were negative for malignancy.Jaundice and mild muscle wasting weredetected on physical examination. Laboratoryfindings included the following: hemoglobin


12.5 g/dL, leukocyte count 6.4 × 109/L, ery-throcyte sedimentation rate 55 mm/hour,AST 30 U/L, alkaline phosphatase 506 U/L,bilirubin 8.5 mg/dL, CA19-9 <15, prostatespecific antigen 0.5 ng/mL, γ-globulin 3.0g/dL. CT showed dilated bile and pancre-atic ducts and diffuse enlargement of thepancreas. Which of the following would youadvise at this point?

a. MRCPb. Repeat ERCPc. Endoscopic ultrasonography d. IgG4e. Antimitochondrial antibody

42. A 36-year-old man with a history of intravenousdrug use is found to be positive for HIV andHCV infection. He is asymptomatic. Laboratoryfindings included the following: AST and ALTboth 65 U/L; complete blood count, bilirubin,albumin, and INR values normal; HCV geno-type is 2, with a level of 400,000 IU/mL; HIVlevel is 1,000 copies/mL; and CD4 count500/mm3. A liver biopsy specimen showedgrade 2 inflammation and stage III fibrosis. Whatis the most suitable therapy at this point?

a. Simultaneous introduction of antiretroviraltherapy and peginterferon and ribavirin

b. Simultaneous introduction of antiretroviraltherapy and peginterferon

c. Peginterferon and ribavirind. Antiretroviral therapy

43. A 63-year-old woman was referred for evalu-ation of an abnormal AST level. One year ago,the AST value was normal. Three months ago,routine testing showed AST was 84 U/L.Recently, the value was 243 U/L. She has mildfatigue but no other symptoms. She drinks oneglass of wine per week. Her past medical his-tory is notable for breast cancer and hyper-tension. Her medications include atenolol andtamoxifen. Findings include the following:body mass index 28, AST 243 U/L, ALT 263U/L, alkaline phosphatase 93 U/L. Bilirubin,albumin, prothrombin time, and a completeblood count are normal. Ultrasonography

shows changes in the liver consistent with fat.What would you advise now?

a. Stop tamoxifenb. Liver biopsyc. Weight loss and repeat tests in 3 monthsd. CT scan of the livere. Stop drinking alcohol

ANSWERS1. Answer eThe best answer is “e” because the CT descriptionis classic for a cavernous hemangioma, which is abenign lesion that requires no therapy unless it issymptomatic. The symptom of left lower quad-rant abdominal cramps is not the usual symptomfor a subcapsular hemangioma, which typicallycauses a pleuritic type pain that is due to irritationof the diaphragm and is worse with deep inspira-tion. Repeat CT would not be unreasonable to con-firm the diagnosis if it is in doubt or to ensure thatthe lesion is stable, but it is not the best answerbecause the radiologic appearance is classic for thecondition. Radiofrequency ablation is not indi-cated for treatment of cavernous hemangiomas.Biopsy is needed only if the diagnosis is in doubt.Surgical resection is indicated only for sympto-matic hemangiomas.

2. Answer aThe best answer is “a” because this asymptomaticlesion is confirmed histologically to be focal nodularhyperplasia. Radiofrequency ablation is not indi-cated for benign liver masses except when the patienthas a comorbid condition that makes him or her inel-igible for surgical resection. Chemoembolization isnot indicated for benign disease. Surgical resectionis not needed in this now asymptomatic patient. Therole of oral contraceptives in the growth of focalnodular hyperplasias is debated. It is likely that thesensitivity of focal nodular hyperplasias to oral con-traceptives is limited to telangiectatic focal nodularhyperplasias, which are now considered to be avariant of hepatic adenomas.

3. Answer dThe best answer is “d” because this lesion has thetypical radiologic imaging characteristics of a

446 Liver

hepatic adenoma, which carries a risk of futuremalignant transformation (particularly if it stainspositive for cytoplasmic or nuclear β-catenin) orintra-abdominal hemorrhage. “No intervention” isnot appropriate in this setting because of the poten-tial risks. If surgery or another ablative method isnot feasible, periodic radiologic follow-up is indi-cated. Radiofrequency ablation is indicated onlywhen the patient has a comorbid condition thatmakes him or her ineligible for surgical resection.Chemoembolization is not indicated for benigndisease. Orthotopic liver transplantation is indicatedonly rarely for patients with adenomatosis who haveprogressive replacement of the liver parenchyma,who have a high propensity for malignant trans-formation, or who have associated glycogen storagedisease with poor metabolic control.

4. Answer cThe best answer is “c” because it represents theleast invasive means of decompressing the cyst,relieving the obstruction of the central bile ducts,and preventing cyst recurrence. “No intervention”is not appropriate because the cyst is causingsymptomatic biliary obstruction. ERCP with stentplacement would commit the patient to long-termbiliary stenting to maintain biliary patency.Surgical resection is a reasonable alternative butis considered a second-line treatment in this casebecause there are not any features that raise concernabout malignant degeneration of the cyst. Withonly a single large cyst and no substantial com-promise of liver function, liver transplantation isnot needed.

5. Answer bThe best answer is “b” because a new lesion occur-ring in a cirrhotic liver with features of arterialenhancement and portal venous phase washouton cross-sectional contrast imaging meets the cri-teria for noninvasive diagnosis of hepatocellularcarcinoma. Also, the α-fetoprotein has increasedto a level that allows diagnosis of hepatocellularcarcinoma with reasonable specificity. Adenomastypically have heterogeneous early arterialenhancement, with rapid return to the intensity ofthe surrounding liver. Like adenomas, focalnodular hyperplasias typically show early arterialenhancement, with rapid return to the intensity of

the surrounding liver; also, they often have a centralscar. Noninvasive diagnosis of hepatocellularcarcinoma avoids the small but real risks of hem-orrhage or tumor seeding along the needle tract.Hemangiomas typically show early peripheralnodular enhancement, with fill-in toward thelater phases.

6. Answer eThe best answer is “e” because it represents themost definitive treatment of hepatocellular carci-noma that meets the Milan criteria (one nodule upto 5 cm large or two or three nodules up to 3 cmlarge) and occurs in a patient with no evidence ofextrahepatic spread. Surgical resection is not appro-priate because of evidence of clinically significantportal hypertension, reflected by the esophagealvarices, thrombocytopenia, and increased bilirubinlevel. Because of the large size of the mass, the like-lihood of complete ablation is not high. In this con-text, radiofrequency ablation does not have aneffect on the underlying liver disease, which willhave a propensity for the development of newtumors. Like radiofrequency ablation, percuta-neous ethanol injection will not have any effect onthe underlying liver disease. Transarterialchemoembolization can be used to prevent tumorprogression while the patient is awaiting livertransplantation, but it is not the optimal definitivetreatment for a patient who is eligible for livertransplantation.

7. Answer dThis patient presents with symptoms that are con-sistent with malabsorption. He has iron deficiencyanemia without evidence of gastrointestinal tractblood loss. Because it would be important toexclude celiac disease, tissue transglutaminasewould be the most appropriate next test. Liver testsare commonly abnormal in patients with celiacdisease, and a diagnosis of celiac disease shouldbe considered in patients with indeterminateabnormalities of liver tests. Abdominal CT is notlikely to add further information to the CT colonog-raphy and liver ultrasonography. Colonoscopyshould be considered in a patient with iron defi-ciency anemia but is not necessary because of thenegative CT colonography findings and the evi-dence suggesting malabsorption. Similarly, MRCP


is not likely to add anything to the CT and ultra-sonographic studies. Liver biopsy could be consid-ered, but the findings would likely be nonspecificand not contribute to a specific diagnosis.

8. Answer eThis patient presents with abdominal pain, fever,and transient abnormalities of aminotransferaselevels associated with a high bilirubin level. Thesefeatures are suggestive of cholangitis, and thispatient remains ill despite receiving antibiotictherapy. ERCP would be the most appropriate nexttest because it would allow not only for the diag-nosis but also for removal of a common bile ductstone. Transient, marked (up to 1,000 U/L) abnormalaminotransferase levels are common in patientswith acute increases in biliary pressure, as from abile duct stone. Rapid improvement in amino-transferase levels can either indicate passage of astone or, as is likely in this case, the stone floatingback more proximally into the biliary tree. ADoppler study of the hepatic vessels would notlikely add to the ultrasonographic information.Hepatic ischemia could be included in the differ-ential diagnosis, but it generally requires systemichypotension. It would be very unusual forsomeone to develop clots of both the hepatic arteryand portal vein. The patient ultimately will needlaparoscopic cholecystectomy, but this should bedeferred until the infection has been betterassessed. MRCP and endoscopic ultrasonographyare helpful in diagnosing common bile duct stonesbut offer no therapeutic potential. Because bileduct obstruction is highly suspected in this patient,one should proceed directly with a test that offersnot only diagnostic but also therapeutic benefits.

9. Answer cThis woman presents with fulminant liver failure.She has exposure to a person with hepatitis B, andthe suspicion for acute hepatitis B is high. About20% of patients with fulminant liver failure fromhepatitis B are HBsAg negative. It is thought thatthe acute liver injury is due to a prompt and vig-orous immune response to the viral infected hepa-tocytes. Although this may result in clearance ofHBsAg, it can produce severe liver injury, seen inthis case. The recent exposure to hepatitis B couldbe confirmed best with an IgM anti-HBc assay.

Herpes hepatitis characteristically is anicteric andaccompanied by very high aminotransferase levels,often more than several thousand. Acute Wilson’sdisease should be considered, although it would beless likely in this patient who has exposure tohepatitis B. Hepatitis D generally affects onlypeople who are HBsAg positive. Antinuclear anti-body determination can be considered becauseautoimmune hepatitis can occasionally presentacutely. Autoimmune hepatitis is an uncommoncause of fulminant liver failure and would be lesslikely given the patient’s exposure to hepatitis B.

10. Answer bThe patient has hepatitis C with genotype 2. At 4weeks, her HCV RNA is positive; that is, she hasnot achieved a rapid virologic response but is nowHCV RNA negative at 3 months. The recommen-dation would be to continue treatment for a total of24 weeks. A 12- or 16-week course of therapy can beconsidered for patients with genotype 2, but only ifthe patient is HCV RNA negative at 4 weeks. Twelvemonths of therapy for genotype 2 patients is not sig-nificantly more effective than a 24-week course.

11. Answer cThis patient has chronic hepatitis B and has nowdeveloped decompensated liver disease. He hasevidence of active viral replication, with a posi-tive test for HBeAg and an HBV DNA level that ismore than 20,000 IU/mL. This would be consis-tent with HBeAg-positive chronic hepatitis B withevidence of liver decompensation. Treatment isadvised. The treatment administered should resultin rapid improvement in HBV DNA and be accom-panied by a low risk of resistance. Entecavir wouldbe the best treatment for this patient. Lamivudinewould likely produce a rapid decrease in HBVDNA, but it is accompanied by a high rate of resis-tance and generally is not advised for patientswith decompensated cirrhosis. Peginterferon canbe effective for hepatitis B but should not be givento patients with decompensated cirrhosis. Thepatient should certainly be considered for livertransplantation; however, therapy before trans-plantation is advised. Not only might therapyproduce clinical improvement, but even if trans-plantation proves to be necessary, the decreasein HBV DNA would be accompanied by a lower

448 Liver

rate of posttransplant recurrence. Paracentesis isadvised in patients with cirrhosis and the newonset of ascites and is not contraindicated unlesscoagulopathy is severe.

12 . Answer dThis patient presents with strong clinical evidenceof alcoholic hepatitis. Patients with alcoholichepatitis commonly have mild fever and leuko-cytosis, but clearly infection needs to be excluded.As is common in patients with alcoholism, thepatient also is hepatitis C RNA positive. Chemicaldependency counseling would certainly be advisedbecause abstinence may improve the patient’sclinical symptoms. Patients with acetaminophenhepatotoxicity, for which N-acetylcysteine mightbe prescribed, have a marked increase in amino-transferase levels. Although the dose necessary toproduce liver injury in alcoholics is lower than it isin patients who do not consume alcohol chroni-cally, the low dose of acetaminophen taken bythis patient would not produce liver injury.MRCP could be considered if bile duct obstruc-tion were highly suspected; however, given theclinical history and the normal ultrasonographicfindings, it would not be necessary in this patient.Corticosteroids are considered as therapy for acutealcoholic hepatitis. Corticosteroids generally areprescribed for patients who have severe disease,which is defined as having encephalopathy or adiscriminant function higher than 32. In patientswho have a discriminant function less than 32 andhepatitis C, corticosteroids would be best avoided.Peginterferon and ribavirin therapy is less effec-tive for patients who consume alcohol regularlyand should be deferred until the patient is abstinentfrom alcohol. Furthermore, hepatitis C treatmentshould be deferred until infection has beenexcluded completely.

13. Answer eThis patient presents with persistent cholestasisafter hepatitis A infection. This syndrome is seenin 10% of patients who acquire acute hepatitis A.No tests are necessary other than serial monitoringof liver blood tests. Further diagnostic studies suchas ERCP, MRCP, and endoscopic ultrasonographycan be considered if the suspicion for biliary injuryis high. Biliary injury is not likely because of the

absence of bile duct dilatation seen on ultra-sonography and the significantly increased ALTlevel. Liver biopsy is not likely to add to the infor-mation that is available. Further diagnostic studieswould be considered if the patient’s condition doesnot improve with observation.

14. Answer dThis patient presents with jaundice after an episodeof hypotension that resulted in acute transientincreases in aminotransferase levels. This wouldbe consistent with cholestasis after acute liver injurydue to hepatitic ischemia. Because of the dual bloodsupply of the liver, hepatic ischemia generallyoccurs only in patients who have an episode ofhypotension. Patients with chronic heart failurewith an element of hepatic congestion are morepredisposed to hepatic ischemia because they aremore dependent on hepatic arterial flow. For thispatient, treatment would be to try to optimize man-agement of his cardiac failure. Abdominal CTwould not be necessary because the ultrasonographicfindings are negative. A Doppler study of the hepaticartery and portal vein is not necessary becausehepatic ischemia requires systemic hypotension.MRCP can be considered if bile duct obstruction isa consideration. Although transient obstruction of thebile duct by a stone can produce transient abnor-malities in aminotransferase levels, it usually isaccompanied by abdominal pain, which is not seenin this patient. Amiodarone can result in liver toxi-city, but aminotransferase levels started to increasebefore amiodarone therapy was instituted.Amiodarone is an important medication in treatingatrial arrhythmias and would be important in man-aging this patient with severe cardiac disease.

15. Answer eThis patient has normal aminotransferase levels, ispositive for anti-HBe, and has an HBV DNA levelthat is less than 20,000 IU/mL. All this would beconsistent with an inactive carrier phase of hepatitisB, and treatment of hepatitis B would not beadvised. Because the patient is an African womanwith hepatitis B, surveillance for hepatocellularcarcinoma is recommended, but she can proceedwith INH therapy. Liver biopsy usually is not nec-essary for patients in the hepatitis B inactive carrierstate. The patient should be followed with serial


monitoring of liver tests and HBV DNA, becauseabout 5% of patients per year will have reactivationof hepatitis B.

16. Answer cThis patient with chronic hepatitis B presents witha clinical syndrome consistent with acute hepatitis.The most likely cause in a patient who abuses intra-venous drugs is hepatitis D, and testing with IgManti-HDV is advised. The other major diagnosticconsideration in this case is a flare of hepatitis B.Patients with an acute flare of hepatitis B oftenbecome IgM anti-HBc positive and have high HBVDNA levels. Liver biopsy would be a reasonableconsideration, but it is more invasive than sero-logic testing and the findings may be nonspecific.Acetaminophen hepatotoxicity usually producessignificantly higher aminotransferase levels thanreported in this patient. Also, he has no history ofacetaminophen use. Alcoholic hepatitis is charac-terized by an AST:ALT ratio of 2:1 and the ASTlevel is not higher than 400 U/L. Occasionally, dis-seminated hepatocellular carcinoma can produceacute hepatitis, but this is not likely in this patientwho has had hepatitis B for only 6 years.

17. Answer bThis patient presents with an acute hepatitis syn-drome but also with strong evidence of chronicliver disease, including a small nodular liver anda recanalized umbilical vein. This would be sug-gestive of acute-on-chronic disease, likely due tohepatitis B. The IgM antibody to HBc is conven-tionally considered a serologic marker for acutehepatitis B but can also become positive during ahepatitis B flare in someone who has long-standinghepatitis B, which is the case in this patient. Acutehepatitis B is unlikely because of the strong clinicalevidence of portal hypertension. The antibody tohepatitis C does not exclude acute hepatitis C, butit is unlikely because of the evidence of hepatitis B.The patient is certainly at risk for a diffuse infiltratinghepatocellular carcinoma, but this is a relativelyunusual cause of acute hepatitis and is unlikely giventhe lack of ultrasonographic evidence.

18. Answer cThis patient has hepatitis B with cirrhosis and arecent episode of variceal bleeding. He is positive

for HBeAg and has a hepatitis B virus DNA of275,000 IU/mL. Patients with hepatitis B andcirrhosis and any detectable HBV DNA levelshould be treated. Entecavir is the most appro-priate agent. Lamivudine could be prescribed, butit is frequently complicated by the developmentof resistance, which sometimes can be accompa-nied by a clinical flare, which ideally should beavoided in patients with cirrhosis. Pegylated inter-feron is contraindicated for patients with decom-pensated cirrhosis. As long as the patient’s bleedingis controlled with variceal ligation, transjugularintrahepatic portosystemic shunt is not needed.Patients with chronic liver disease and strongclinical evidence of cirrhosis do not require biopsyfor histologic confirmation.

19. Answer bThis patient is an inactive hepatitis B carrier andneeds chemotherapy. The recommendation is thatpatients should be treated with an antiviral agentduring the course of chemotherapy and for 6months afterward to prevent an acute flare ofhepatitis B. Lamivudine would be a good choicebecause the length of treatment will be relativelyshort, which lessens the risk of the developmentof resistance. Pegylated interferon should beavoided if the patient is about to receive cytotoxicchemotherapy. There is no need for liver biopsyin this patient because the liver enzyme levels arenormal and the HBV DNA level is low.

20. Answer cThe reasons for an isolated positivity for anti-HBcinclude acute hepatitis B, previous hepatitis B withdisappearance of anti-HBs, ongoing hepatitis Bwith HBsAg below the level of detectability, and afalse positive test. The fact that the antibody isIgG positive excludes acute hepatitis B. For thispatient who will be a health care worker, hepatitisB immunity needs to be provided, and hepatitis Bvaccine is advised. If the anti-HBc is the result of aprevious infection, the patient will have ananamnestic response, with rapid development ofhigh titers of anti-HBc. If the patient happens tohave hepatitis B and receives the hepatitis B vaccine,there should be no adverse consequences, but immu-nity will not develop. After vaccination, the devel-opment of anti-HBs should be assessed. In a patient

450 Liver

who is at high risk for hepatitis B, checking HBVDNA in the serum before vaccination would be rea-sonable; however, most patients will be negative.Thus, this is not a cost-effective test for someonewithout risk factors. Liver biopsy is not needed. Ifthis patient were not a health care worker, no fur-ther testing would be reasonable, but immunizationshould be ensured for this patient.

21. Answer bThis patient has hepatitis C genotype 1, with a highviral level. There is no definite evidence of cirrhosis.The general recommendation for patients withhepatitis C genotype 1, particularly if there is a rel-ative contraindication to treatment, such as depres-sion, is to proceed with liver biopsy. Patients withmild disease, such as stage 0 or stage 1 fibrosis, canbe observed but those with more advanced diseaseshould be treated unless they have decompensatedliver function. Starting treatment with peginter-feron and ribavirin without performing liver biopsycan be considered in certain patients, particularly ifthey have no contraindications to treatment or ifthey have hepatitis C genotype 2 or 3. Reevaluationin 6 months would not provide any informationthat is not already available. Because the patient’sdepression seems reasonably well controlled, psy-chiatry consultation is not necessary. Psychiatryconsultation can be considered for patients whosedepression is not well controlled.

22. Answer dThis man is being treated for hepatitis C genotype1. Treatment is with standard doses of peginter-feron and ribavirin, and, after 12 weeks, he has hada one-log (tenfold) decrease in treatment. Patientswho have less than a two-log decline at 12 weeks oftreatment are unlikely to have a response to therapy,and discontinuing therapy is advised. This patientis more resistant to therapy because of his genotype1 and perhaps his increased body mass index.Continuing therapy for an additional 12 weeks,increasing the peginterferon dose, or increasing theribavirin is very unlikely to increase the chance of aresponse and is not part of standard care.

23. Answer bThis patient has hepatitis C genotype 1, with stage IIIdisease. After 6 months of full-dose peginterferon

and ribavirin, his HCV RNA remains positive.Because this patient will not have a response totherapy, treatment should be discontinued.Continuing therapy for 3 more months mightreduce the HCV RNA level, but it is exceedinglyunlikely to make him HCV RNA negative and evenmore unlikely to provide a sustained response.Adding ursodiol to the regimen has no role in thetreatment of hepatitis C. Maintenance therapy withpeginterferon has not been shown to be beneficial.

24. Answer cThis patient has hepatitis C genotype 2 and no fea-tures of advanced disease. It is likely that she hashad hepatitis C for only 10 years. Because the like-lihood is very high that this patient will have aresponse, treatment would be advised. Liverbiopsy is not likely to change the management ofthis patient. Liver biopsy might change manage-ment only if she has cirrhosis, and this is veryunlikely because of the short duration of hepatitisC. Observation could be considered if she has con-traindications to therapy, but response rates areso high for hepatitis C genotype 2 that treatmentgenerally is advised. Reassessment in 3 monthswould not change management.

25. Answer aThis patient has hepatitis C and symptoms con-sistent with vasculitis. This is likely a case of cryo-globulinemia. Patients with cryoglobulinemianearly always have a positive rheumatoid factortest. The vasculitic rash typically improves withtreatment of hepatitis C. Oral corticosteroids can beeffective for the rash but usually are reserved forsevere disease that does not respond to hepatitisC treatment. Polyarteritis nodosa typically com-plicates hepatitis B, not hepatitis C. Rheumatologyconsultation could be considered, but it generallyis not necessary for patients with the usual clinicalfeatures of the disease.

26. Answer cThis patient presents with fulminant liver failure.Laboratory tests and copper studies are consistentwith Wilson’s disease. Patients with fulminantWilson’s disease should be given decopperingagents, but the likelihood of avoiding liver trans-plantation is so low that proceeding with immediate


transplantation is advised. This patient wouldbe high priority and likely receive a liver rela-tively soon. Intracranial pressure monitoring isused by some groups but probably is not neces-sary at this point. Liver biopsy would only confirmthe diagnosis of Wilson’s disease and not changeclinical management.

27. Answer aThis patient has anasarca and laboratory test abnor-malities that confirm anemia, hypoalbuminemia,hypercalcemia, and renal insufficiency with pro-teinuria. The liver tests are notable for the highlevel of alkaline phosphatase. This constellationof symptoms and laboratory abnormalities shouldraise the possibility of an infiltrative liver disease.Because multiple myeloma with amyloidosiswould be a strong consideration, serum proteinelectrophoresis should be the next test. Liver biopsycan confirm amyloidosis but would be more inva-sive than serum protein electrophoresis, with orwithout bone marrow biopsy. Knowing theangiotensin-converting enzyme level can be usefulin diagnosing granulomatous diseases such as sar-coidosis, which can cause a high level of alkalinephosphatase. However, sarcoidosis would notaccount for the other clinical features. MRCP is notnecessary because a biliary obstruction would notexplain the other clinical features such as anemiaand hypoproteinemia. Typically, hepatitis B wouldcause a greater increase in aminotransferase levelsthan in the alkaline phosphatase level.

28. Answer eThis patient has excessive alcohol intake and strongclinical evidence of cirrhosis. Biochemical featuressuch as an AST level more than twice the ALT levelis consistent with alcoholic hepatitis; however, thepatient also has hepatitis C. Cessation of alcoholshould produce clinical improvement. This patient,who almost certainly has cirrhosis, should undergosurveillance for hepatocellular carcinoma withperiodic ultrasonographic examinations.Peginterferon and ribavirin would be a consider-ation for treating the hepatitis C but should not beprescribed for a patient who currently drinksalcohol in excess, particularly with evidence ofalcoholic hepatitis and marked thrombocytopenia.Liver biopsy is not necessary for patients with a

clear underlying cause of liver disease and clin-ical evidence of cirrhosis, as in this patient.Splenectomy should be avoided in patients withliver disease because of the high rate of operativemorbidity and mortality. The patient is asympto-matic from the standpoint of gallstones; thus, chole-cystectomy is not advised.

29. Answer dCauses for indirect hyperbilirubinemia includeGilbert’s syndrome, hemolysis, and cirrhosis. Forthis patient, Gilbert’s syndrome is the most likelycause. Metastatic adenocarcinoma to the liver is aconsideration in a patient with a history of coloncancer but that would be exceedingly unusual 8years after colon cancer surgery. Also, the patienthas normal ultrasonographic findings. Primarysclerosing cholangitis can cause an increasedbilirubin level, but it should be a direct hyper-bilirubinemia, and it is nearly always accompaniedby a high level of alkaline phosphatase. HepatitisC would typically have high aminotransferaselevels. The patient is at increased risk for adeno-carcinoma of the ampulla of Vater, but there is noevidence of bile duct obstruction and the alkalinephosphatase level is normal.

30. Answer bThis patient with a history of excess alcohol intakehas evidence of encephalopathy and very highaminotransferase levels. The most commoncauses of aminotransferase levels of more than5,000 U/L are acetaminophen hepatotoxicity,hepatic ischemia, and an unusual virus such asherpes. In this clinical situation, the cause is likelyacetaminophen hepatotoxicity, particularly in analcoholic patient in whom toxicity occurs withlower doses of acetaminophen than it does in anonalcoholic patient. N-acetylcysteine should beadministered regardless of the acetaminophenlevel. Pentoxifylline or corticosteroids can be con-sidered for patients who have acute alcoholichepatitis. Alcoholic hepatitis causes an increase inaminotransferase levels, but nearly always lessthan 400 U/L. Liver biopsy would not add to theclinical impression. Acyclovir could be consid-ered for herpes hepatitis. Herpes hepatitis is char-acterized by very high aminotransferase levels,changes in mental status, and fever. The increased

452 Liver

bilirubin level and the absence of high fever wouldmake herpes hepatitis unlikely; thus, acyclovir isnot necessary.

31. Answer aModest abnormalities on liver tests are commonlyseen after initiation of treatment with statin drugs.These modest abnormalities are nearly always tran-sient and attributed to a period of adaptation.Observation would be reasonable. The decision tostop a potentially offending hepatotoxin usuallyis made when the aminotransferase levels are morethan five times the upper limit of normal. Liverbiopsy is not necessary because the liver enzymeabnormalities are only modest, but it can be con-sidered if follow-up continues to show increasedliver enzyme levels. Liver ultrasonography can bedeferred until there is more evidence of chronicliver disease. The patient could have nonalcoholicfatty liver disease, but knowing this would notchange management at this time. At this point, it isnot necessary to stop atorvastatin therapy.Evaluation for other causes of chronic liver dis-ease should be deferred until evidence of chronicliver injury is obtained.

32. Answer aThis patient has jaundice and a history of exposureto amoxicillin-clavulanate. Laboratory evidenceis consistent with cholestasis, and ultrasonographydoes not show dilated bile ducts. The most likelycause in this case is liver injury due to amoxicillin-clavulanate. This is commonly a cholestatic injury.It typically occurs in older men, and symptomsfrequently start after a course of the drug hasalready been completed. Resolution may takeweeks. The best course would be to observe andfollow the patient’s laboratory test results. Liverbiopsy is likely to demonstrate cholestasis andwould not add to the decision for observation. CTcould be considered if there were more suggestionof biliary obstruction and if a potential causeneeded to be excluded. Testing for antimitochon-drial antibody to diagnose primary biliary cirrhosiswould be a consideration if the patient’s labora-tory test results do not improve. Primary biliarycirrhosis is more common in women. MRCP canbe considered to help exclude biliary obstruction,but the patient has had two ultrasonographic

studies that did not show evidence of a dilated bileduct; therefore, biliary obstruction is not likely.

33. Answer bThis patient has clinical acute hepatitis with fatigueand a high level of ALT. She has a history ofhypothyroidism, and her medications includenitrofurantoin. She does have autoimmunemarkers and hypergammaglobulinemia. The mostlikely diagnoses would include nitrofurantoin-induced liver disease and autoimmune hepatitis.Nitrofurantoin can produce hepatotoxicity thatcan mimic autoimmune disease. Other drugs thatcan produce hepatotoxicity that mimicks autoim-mune hepatitis include minocycline and α-methyl-dopa. Because the patient was exposed to a drugthat can cause liver disease, the most likely diag-nosis is nitrofurantoin-induced liver disease. Thistypically occurs in women who have a history ofautoimmune disorders such as hypothyroidism.Unlike other causes of drug-induced liver disease,a drug-induced autoimmune disease can appearmany months after the initiation of treatment withthe offending medication. Estrogen is a rare causeof abnormal liver tests and typically producescholestatic liver injury. Choledocholithiasis canresult in an acute increase in aminotransferaselevels, but patients usually have abdominal pain.Primary biliary cirrhosis would produce a cholestaticrather than a hepatitic liver enzyme profile.

34. Answer bThis patient has sudden onset of ascites and abackground history of ulcerative colitis that is wellcontrolled with azathioprine and mesalamine. Theliver enzyme levels are minimally increased in arelatively nonspecific pattern. Ultrasonographyshows ascites and patent hepatic and portal veins.In a patient with acute onset of ascites, theobstruction of hepatic venous outflow needs to beconsidered. With this history and patent hepaticveins seen on ultrasonography, the most likelydiagnosis is sinusoidal obstruction syndrome orveno-occlusive disease. Although this occurs mostcommonly after bone marrow transplantation, itcan be seen also with azathioprine therapy, whichis likely the culprit here. Primary sclerosingcholangitis could produce a cholestatic liverenzyme profile or advanced liver disease but


would be an unlikely cause of acute onset of ascites.Right-sided heart failure is less likely in a youngman without any history of cardiac disease.Mesalamine-induced liver disease is rare and typ-ically would produce higher levels of liver enzymeswithout ascites.

35. Answer cThis patient has abnormal iron tests and is homozy-gous for hereditary hemochromatosis. Phlebotomywould be advised. Liver biopsy is necessary onlyif the ferritin level is more than 1,000 μg/L or liverenzyme levels are abnormal. Alcohol excess canproduce abnormal iron tests, but the patient’s con-sumption is not excessive.

36. Answer dThe patient has hepatitis C genotype 2. She hasclinical evidence of cirrhosis but also has slightlyabnormal iron tests with an increased ferritin levelbut normal percent saturation. The most likelydiagnosis is hepatitis C, and because of genotype2 and evidence of advanced disease, treatmentwould be recommended. The increased iron valuesalmost certainly are due to hepatitis C. It wouldbe very unusual for a patient with hereditaryhemochromatosis to have a normal percent satu-ration, so HFE gene testing is not necessary. Liverbiopsy is not necessary because of the evidence ofcirrhosis. Phlebotomy does not seem to affect theeffectiveness of treatment of hepatitis C and wouldnot be advised.

37. Answer cThe patient has clinical and biochemical evidenceof iron overload disease. He has no clinical fea-tures of advanced liver disease, and HFE gene testfindings are unremarkable. Despite the negativeHFE gene test, the likely diagnosis is hereditaryhemochromatosis. Confirmation would be advised.Magnetic resonance imaging could be considered,but this is still an investigational tool. Because of thehigh ferritin level, it would be advisable to excludecirrhosis; thus, a liver biopsy both for a standardhistologic study and quantification of iron wouldbe the next test. Therapeutic phlebotomy will likelybe advised but should be reserved until a firm diag-nosis is made on the basis of the liver biopsy studyand iron quantification.

38. Answer cThis young man has abnormal liver tests and a lowlevel of ceruloplasmin. In this situation, Wilson’sdisease needs to be excluded. The best next testwould be a slit-lamp examination to search forKayser-Fleischer rings. Their presence would beessentially diagnostic of Wilson’s disease in thisclinical setting. Rarely, Kayser-Fleischer rings canoccur in patients with cholestatic diseases such asprimary biliary cirrhosis, but this is very unlikelyin this clinical situation. Liver biopsy with copperquantification can also help diagnose Wilson’s dis-ease, but it is more invasive than a slit-lamp exam-ination. Even if the patient’s liver test resultsimprove with weight loss, Wilson’s disease needsto be excluded because of the low ceruloplasminlevel. A serum free copper level can be helpful inthe setting of Wilson’s disease, but normal valuesdo not exclude the diagnosis. Treatment withpenicillamine should be initiated only after thediagnosis has been confirmed.

39. Answer aThe patient has a mild increase in liver enzymelevels, both AST and ALT levels. She has a historyof dermatomyositis, which is controlled with pred-nisone. The normal creatine kinase and aldolaselevels mean that the increased aminotransferaselevels almost certainly are of hepatic origin.Because of the history of alcohol excess, the mostlikely diagnosis is alcoholic liver disease. Non-alcoholic fatty liver disease cannot be diagnosed ina woman with this degree of alcohol consumption.Also, she does not have other clinical features con-sistent with nonalcoholic fatty liver disease. Celiacdisease is also a consideration, but it is much lesscommon than alcoholic liver disease. Autoimmunehepatitis would typically produce higher amino-transferase levels, with the ALT level higher thanthe AST level.

40. Answer aThe patient has hereditary hemochromatosis. Thediagnosis is essentially confirmed because ofabnormal iron test results, homozygosity forC282Y, and the absence for any other cause of liverdisease. Even though liver biopsy is not neededfor diagnosis, it would be recommended to excludecirrhosis in this man with a ferritin level greater

454 Liver

than 1,000 μg/L. Although the presence of cirrhosiswould not alter plans for phlebotomy, it wouldmandate screening for hepatocellular carcinoma.The amount of alcohol that the patient drinksshould not cause abnormal iron test results,although this certainly should be curtailed in thesetting of another cause for liver disease. Magneticresonance imaging of the liver can help diagnoseiron overload but is still an investigational tool.

41. Answer dThe patient has evidence of sclerosing cholangitis,with a prominent distal bile duct stricture. Althoughthis may represent primary sclerosing cholangitis,the patient does not have inflammatory bowel dis-ease, and IgG4-associated cholangitis should beexcluded. Therefore, the best next test would beto determine the serum IgG4 level. Should IgG4-associated cholangitis be confirmed, treatmentwith corticosteroids would be advised. MRCP,ERCP, and endoscopic ultrasonography are notnecessary at this point unless the lack of anotherdiagnosis is forthcoming. These studies would beespecially useful if biliary malignancy was a con-cern. Antimitochondrial antibody would be usefulto diagnose primary biliary cirrhosis, a disease thatdoes not produce abnormal ERCP findings.

42. Answer cThe patient has HIV infection and hepatitis C.Currently, the HIV infection is minimally active,

with a viral level that is low and a CD4 count that isreasonably high. In this unusual situation, the bestoption for this patient with relatively advanced stagehepatitis C would be the introduction of treatmentwith pegylated interferon. Antiretroviral therapyusually would be initiated first but is not necessaryin this patient with controlled HIV disease. One ratio-nale for treating the hepatitis C first is to decreasethe risk of hepatotoxicity from antiretroviral therapythat occurs in patients with hepatitis C.

43. Answer aThe patient’s AST level is increasing, and ultra-sonography shows changes in liver echogenicityconsistent with fat. Although this disorder usuallyis merely nonalcoholic fatty liver disease associatedwith metabolic syndrome, the increasing AST levelwould be a bit unusual, and one of the drugs thatcan cause this effect is tamoxifen. Discontinuationof tamoxifen therapy with consideration of analternative agent would be advised. Liver biopsycould be considered, but it would be best to waituntil after a trial to see if the liver enzyme valuesimprove after tamoxifen therapy has been stopped.Liver biopsy is likely to show steatohepatitis butwill not differentiate the specific cause. Weight losswith repeat liver tests is a consideration, but thepatient is not excessively overweight. CT of the liverwould not add much information to that obtainedfrom ultrasonography. The amount of alcohol thepatient consumes would not cause liver disease.


SECTION VII

Pancreas and Biliary Tree

Approximately 210,000 new cases of acute pan-creatitis occur annually in the United States, and itsincidence is increasing in and outside this country.Of the new cases, about 80% are the interstitial(edematous) variety and the other 20% are thenecrotizing variety. Necrotizing pancreatitisaccounts for most of the morbidity and nearly allthe mortality associated with acute pancreatitis.

ETIOLOGYGallstones and alcohol are the most common causesof acute pancreatitis in the United States (Table 1).Gallstones are the most common cause in affluentpopulations and alcohol is in lower socioeconomicpopulations. Other causes include hyperlipidemia,hypercalcemia, medications (Table 2), trauma, post-operative state, infections by various agents, andendoscopic retrograde cholangiopancreatography(ERCP). About 20% of cases of acute pancreatitisare classified as “idiopathic” because no cause isfound even after extensive testing. Debated causesof acute pancreatitis are sphincter of Oddi dys-function and pancreas divisum.

Gallstones are thought to produce acute pan-creatitis because they pass into the common bile ductand obstruct the channel shared by the bile duct andpancreatic duct. Patients with gallstone pancreatitisfrequently have abnormal liver enzyme levels.

PathologyThe two forms of acute pancreatitis defined by inflam-matory changes in the pancreatic parenchyma areinterstitial and necrotizing. In interstitial pancre-atitis, edema and inflammation of the pancreaticparenchyma occur without death of pancreaticacini. In necrotizing pancreatitis, there is extensiveparenchymal destruction, frequently with peri-pancreatic fat necrosis.

CLINICAL PRESENTATIONThe clinical presentation of acute pancreatitisranges from mild, nonspecific epigastric pain to acatastrophic acute medical illness. Occasionally,pain may not be present (especially in the case ofpostoperative acute pancreatitis following kidneytransplant or cardiac surgery), and sometimes

459

CHAPTER 35

Acute Pancreatitis

Santhi Swaroop Vege, MDTodd H. Baron, Sr., MD

Abbreviations: APACHE, acute physiology and chronic health evaluation; CT, computed tomography; ERCP, endoscopicretrograde cholangiopancreatography.

acute pancreatitis is diagnosed only at autopsy.Patients with interstitial acute pancreatitis have aclinically mild presentation.

Patients usually present with epigastric or leftupper quadrant pain that may radiate to the back.Nausea and vomiting are nearly always present. Inthe severe form, the patient is systemically ill withfever, tachycardia, tachypnea, and hypotension.Although the findings of ecchymoses in the peri-umbilical area (Cullen sign) or on the flanks (GreyTurner sign) have received much attention, theyare uncommon.

The differential diagnosis of acute pancreatitisis broad and includes myocardial infarction, pepticulcer disease, symptomatic cholelithiasis, andsmall-bowel ischemia.

SEVERITY STRATIFICATIONSeveral severity-of-illness classifications for acutepancreatitis are used to identify patients at risk forthe development of complications. The Ranson

460 Pancreas and Biliary Tree

Table 1. Causes of Acute Pancreatitis

Most commonCholedocholithiasisEthanolIdiopathic

Less commonEndoscopic retrograde

cholangiopancreatography (especially forsuspected sphincter of Oddi dysfunction)

Pancreatic ductal obstruction (pancreaticcarcinoma, intraductal mucinous papillarytumor)

Hyperlipidemia (types I, IV, and V)HypercalcemiaDrugs (see Table 2)Pancreas divisum (?)Abdominal trauma

Least commonViral infectionParasitic infestation of pancreatic ductHereditary (familial)

Modified from Baron TH, Morgan DE: Acute necrotizingpancreatitis. N Engl J Med. 1999;340:1412-7. Usedwith permission.

Table 2. Drugs Associated With AcutePancreatitis

Likely association Possible associationα-Methyldopa AmiodaroneAsparaginase AmpicillinAzathioprine AnticholinesterasesCimetidine Carbamazepine2′,3′-Dideoxycytidine Cisplatin2′,3′-Dideoxyinosine ColchicineEstrogens CorticosteroidsFurosemide Cyclosporine6-Mercaptopurine CytarabineMetronidazole DelavirdinePentamidine DiazoxideSalicylates DiphenoxylateSulfasalazine EnalaprilSulfonamides ErgotamineSulindac ErythromycinTetracyclines Ethacrynic acidValproic acid Ganciclovir

Gold compoundsIndinavirInterleukin-2IsotretinoinKetoprofenLisinoprilMefenamic acidMetolazoneNelfinavirNevirapineNitrofurantoinOctreotideOxyphenbutazoneParacetamol(acetaminophen USP)

PhenforminPhenolphthaleinPiroxicamProcainamideRanitidineRitonavirRoxithromycinStavudineTretinoinTryptophan

score consists of 11 clinical signs with prognosticsignificance: 5 criteria are measured at the time ofadmission, and 6 criteria are measured betweenadmission and 48 hours later (Table 3). The numberof Ranson signs and the incidence of systemic com-plications and presence of pancreatic necrosis arecorrelated. The Acute Physiology and ChronicHealth Evaluation (APACHE) II score is a gradingsystem based on 12 physiologic variables, patientage, and previous history of severe organ systeminsufficiency or immunocompromised state (Table4). It allows stratification of the severity of illnesson admission and may be recalculated daily. Themain disadvantage of the Ranson score is that it maynot be completed until 48 hours after admission.The APACHE II scoring system has the advantageof being completed at the initial presentation aswell as being repeated daily, but it is cumbersometo use.

The Atlanta classification is the most widelyused clinical system for indicating the severity ofacute pancreatitis. This classification recognizesmild and severe types of the disease, which are syn-onymous with the interstitial and necrotizing types,respectively. It classifies an attack of acute pan-creatitis as severe if any of the following criteriaare met: 1) organ failure with one or more of the

following — shock (systolic blood pressure <90mm Hg), pulmonary insufficiency (PaO2 <60 mmHg), renal failure (serum creatinine level >2 mg/dLafter rehydration), and gastrointestinal tractbleeding (>500 mL in 24 hours); 2) local complica-tions such as pseudocyst, abscess, or pancreaticnecrosis; 3) three or more Ranson criteria; or 4)eight or more APACHE II criteria. Terms such asphlegmon, hemorrhagic pancreatitis, infectedpseudocyst, and persistent pancreatitis wereomitted because of the confusion they caused.

Various biochemical markers used to predictthe severity of acute pancreatitis have been evalu-ated. The “gold standard” for predicting theseverity of acute pancreatitis is C-reactive protein,and a value greater than 150 mg/L is considereddiagnostic of severe acute pancreatitis whenobtained 48 hours after the onset of symptoms.Other potential predictive markers of severitybeing evaluated include hemoconcentration withan admission hematocrit of 44 or more, serumtrypsinogen activation peptide, polymorphonu-clear elastase, carboxypeptidase activation pep-tide, interleukin-6, interleukin-8, and procalcitonin.

LABORATORY FINDINGSThe diagnosis of acute pancreatitis requires one of thefollowing criteria: a serum level of amylase or lipase3 times or more the upper limit of normal for thatparticular laboratory assay, definite findings onabdominal ultrasonography or computed tomog-raphy (CT), or surgical or autopsy confirmation.

The two major pitfalls of the serum amylaseassay are 1) it is a sensitive but not specific test and2) various intra-abdominal diseases included inthe differential diagnosis of acute pancreatitis maycause an increase in the serum level of amylase.Another problem is the falsely low serum amylaselevel in hyperlipidemia. Although the serum lipaseassay was developed in an attempt to have a morespecific test, it does not appear to have a signifi-cantly better sensitivity and specificity.

A threefold or more increase in the serum ala-nine aminotransferase level suggests a biliary originof acute pancreatitis. A fasting triglyceride value ofmore than 1,000 mg/dL or a persistent increase afterthe attack has resolved suggests hyperlipidemia asthe cause and not the effect of acute pancreatitis. It is

Acute Pancreatitis 461

Table 3. Ranson Criteria of Severity

During initial At admission 48 hours

Age >55 years Hematocrit decreases Leukocytes >16 × 109/L >10%Blood glucose >200 Blood urea nitrogen

mg/dL increases >5 mg/dLSerum lactate dehydro- Serum calcium <8

genase >350 IU/L mg/dLSerum aspartate amino- Arterial PaO2 <60

transferase >250 IU/L mm HgBase deficit >4 mEq/LFluid sequestration >6 L

Modified from Banks PA. Practice guidelines in acutepancreatitis. Am J Gastroenterol. 1997;92:377-86. Usedwith permission.


Tab

le 4

.A

PA

CH

E I

IS

cori

ng

Sys

tem

*

Ph

ysio

logy

poi

nts

43

21

01

23

4

Rec

tal t

empe

ratu

re, °

C≥4

1.0

39.0

-40.

938

.5-3

8.9

36.0

-38.

434

.0-3

5.9

32.0

-33.

930

.0-3

1.9

≤29.

9M

ean

bloo

d p

ress

ure,

≥1

6013

0-15

911

0-12

970

-109

50-6

9≤4

9m

m H

gH

eart

rat

e, b

eats

/m

inut

e≥1

8014

0-17

911

0-13

970

-109

55-6

940

-54

≤39

Res

pira

tory

rat

e,≥5

035

-49

25-3

412

-24

10-1

16-

9≤5

brea

ths/

min

ute

Oxy

gena

tion

(kPa

)†

FIO

2≥5

0% A

-aD

O2

66.5

46.6

-66.

426

.6-4

6.4

<26

.6FI

O2

<50

% P

aO2

>9.

38.

1-9.

37.

3-8.

0<

7.3

Art

eria

l pH

≥7.7

07.

60-7

.69

7.50

-7.5

97.

33-7

.49

7.25

-7.3

27.

15-7

.24

<7.

15Se

rum

sod

ium

,≥1

8016

0-17

915

5-15

915

0-15

413

0-14

912

0-12

911

1-11

9≤1

10m

Eq/

LSe

rum

pot

assi

um,

≥7.0

6.0-

6.9

5.5-

5.9

3.5-

5.4

3.0-

3.4

2.5-

2.9

<2.

5m

Eq/

LSe

rum

cre

atin

ine,

≥300

171-

299

121-

170

50-1

20<

50μ

mol

/L

Pack

ed c

ell v

olum

e,≥6

050

-59.

946

-49.

930

-45.

920

-29.

9<

20% Whi

te b

lood

cel

l≥4

020

-39.

915

-19.

93-

14.9

1-2.

9<

1co

unt,

×10

9 /L

* AP

AC

HE

II s

core

= a

cute

phy

siol

ogy

scor

e +

age

poi

nts

+ c

hron

ic h

ealt

h po

ints

.† I

f fra

ctio

n of

insp

ired

oxy

gen

(FIO

2) is

≥50

%, t

he a

lveo

lar-

arte

rial

gra

dien

t (A

-a) i

s as

sign

ed p

oint

s. I

f fra

ctio

n of

insp

ired

oxy

gen

is <

50%

, par

tial

pre

ssur

e of

oxy

gen

isas

sign

ed p

oint

s.O

ther

poi

nts

Gla

sgow

com

a sc

ale:

sco

re is

sub

trac

ted

from

15

to o

btai

n po

ints

.A

ge <

45 y

ears

= 0

poi

nts,

45-

54 =

2, 5

5-64

= 3

, 65-

75 =

5, >

75 =

6.

Chr

onic

hea

lth

poin

ts (m

ust b

e pr

esen

t bef

ore

hosp

ital

adm

issi

on):

chr

onic

live

r di

seas

e w

ith

hype

rten

sion

or

prev

ious

live

r fa

ilure

, enc

epha

lopa

thy,

or

com

a; c

hron

ic h

eart

failu

re (N

ew Y

ork

Hea

rt A

ssoc

iati

on c

lass

IV);

chro

nic

resp

irat

ory

dise

ase

wit

h se

vere

exe

rcis

e lim

itat

ion,

sec

onda

ry p

olyc

ythe

mia

, or

pulm

onar

y hy

pert

ensi

on; d

ialy

sis-

depe

nden

t kid

ney

dise

ase;

imm

unos

uppr

essi

on—

eg, r

adia

tion

, che

mot

hera

py, r

ecen

t or

long

-ter

m h

igh-

dose

cor

tico

ster

oid

ther

apy,

leuk

emia

, acq

uire

d im

mun

odef

icie

ncy

synd

rom

e. 5

poi

nts

for

emer

genc

y su

rger

y or

non

surg

ical

pat

ient

, 2 p

oint

s fo

r el

ecti

ve s

urgi

cal p

atie

nt.

Mod

ified

from

Ban

ks P

A. P

ract

ice

guid

elin

es in

acu

te p

ancr

eati

tis.

Am

J G

astr

oent

erol

. 199

7;92

:377

-86.

Use

d w

ith

perm

issi

on.

important to measure the serum level of calciumafter the attack has resolved because the levels can bespuriously low during an attack and hypercalcemiaas the cause of acute pancreatitis can be missed.

The serum levels of creatinine and glucosemay be increased. Decreases in total serum cal-cium more likely are related to low serum levelsof albumin than to true hypocalcemia, which isreflected in measurements of ionized calcium. Also,hypoxemia may be present.

ABDOMINAL IMAGING STUDIESIn acute pancreatitis, plain abdominal radiographsare frequently normal, but they are useful inexcluding perforation. A nonspecific ileus may bepresent as well as a focally dilated small-bowelloop, the so-called sentinel loop. The colon-cutoffsign refers to the abrupt narrowing of the gas inthe transverse colon seen on a plain film of theabdomen in the vicinity of the body of the pancreas.

Abdominal ultrasonography is frequently non-diagnostic in acute pancreatitis because overlyingbowel gas may obscure the pancreas. However,ultrasonography is sensitive for detecting gall-stones and, thus, adds clinical information aboutthe underlying cause of the pancreatitis.

If the diagnosis is in doubt, the best imagingstudy is abdominal CT. It is imperative that intra-venous contrast be administered unless there is amajor contraindication. Pancreatic perfusion is dis-rupted in the case of pancreatic necrosis and isdetectable only if intravenous contrast is given (Fig.1 and 2). A CT classification system for the severityof acute pancreatitis has been developed on the basisof the degree of necrosis and number of fluid col-lections. High mortality can be expected if the CTseverity index of Balthazar is 7 or more. Patientswith acute pancreatitis who have normal CT find-ings have a good prognosis. The correlation is goodbetween the failure of more than 30% of the pan-creas to enhance on contrast-enhanced CT and thefinding of pancreatic necrosis at surgery or autopsy.As the degree of necrosis increases, there is a corre-sponding increase in morbidity and mortality.

It is not absolutely necessary to obtain abdom-inal imaging studies at presentation of acute pan-creatitis unless the diagnosis is in doubt. If thediagnosis is in doubt, contrast-enhanced CT

rather than ultrasonography should be performed.If the cause is in doubt, ultrasonography is the besttest to confirm gallstones. In definite cases of acutepancreatitis, contrast-enhanced CT can be per-formed after 3 days if the patient is not respondingor earlier if the patient’s condition is deteriorating.Recently, magnetic resonance imaging has beencompared prospectively with CT in the setting ofsevere pancreatitis and found to be a reliablemethod for staging severity, to have predictivevalue for the prognosis of the disease, and to havefewer contraindications than CT. It also can detectdisruption of the pancreatic duct, which may occurearly in the course of acute pancreatitis.

TREATMENTBecause the prognosis of interstitial pancreatitis isdifferent from that of necrotizing pancreatitis, man-agement of the two is discussed separately.

Treatment of Interstitial Acute PancreatitisPatients with interstitial pancreatitis may be man-aged on a general hospital ward, without need forintensive care monitoring. Often, all that is neededis to withhold oral intake and liberally administerintravenous fluids and analgesics. Nasogastrictubes should not be used routinely because theydo not improve disease outcome and add to patientdiscomfort. However, for patients with exceptionalnausea and vomiting and ileus, a nasogastric tubemay help relieve the symptoms. Empiric use ofantibiotics should be avoided in interstitial pancre-atitis because these agents do not alter the outcome.

If laboratory findings (increased levels ofaminotransferases or bilirubin or both) and ultra-sonography indicate that gallstones are the causeof the pancreatitis, cholecystectomy should beperformed before hospital dismissal to preventrecurrent attacks of acute pancreatitis. If the patientis a poor surgical candidate because of severecoexisting medical illness, ERCP with biliarysphincterotomy may be a good alternative tocholecystectomy, especially if ultrasonographydemonstrates only sludge or small stones.

If the cause of pancreatitis is in doubt, theserum levels of lipids should be determined anddrugs that may have caused acute pancreatitisshould be reviewed thoroughly. In addition,


abdominal ultrasonography should be performed.After this, if the cause is still in doubt, abdominalCT should be performed to exclude anatomicalcauses of pancreatic ductal obstruction, such asa pancreatic or ampullary mass lesion, or suggestionof intraductal mucinous papillary tumor, especiallyin patients older than 50 years. For elderly patients,

endoscopic ultrasonography, magnetic resonancecholangiopancreatography, or ERCP should be con-sidered if the CT findings are negative.

Treatment of Acute NecrotizingPancreatitis

Supportive CareThe management of patients with clinically severepancreatitis due to pancreatic necrosis is differentfrom that for patients with interstitial pancreatitis.Aggressive hydration with intravenous fluids isvery important. Patient-controlled analgesia for paincontrol requires fentanyl or morphine. Althoughanimal experiments indicated that morphine causedspasm of the sphincter of Oddi, there is no definitehuman evidence that morphine worsens the dis-ease. Patients should be placed in the intensive careunit. In recent years, the management of thesepatients has shifted from early surgical débridement(necrosectomy) to aggressive intensive medical care.Aggressive medical management, with emphasison the prevention of infection, has allowed theprompt identification of complications and improve-ment in outcome for these patients.

Early mortality (within the first 1 or 2 weeks)is due to multisystem organ failure resulting fromsystemic inflammatory response syndrome.Systemic complications include adult respiratorydistress syndrome, acute renal failure, shock, coag-ulopathy, hyperglycemia, and hypocalcemia. Thesecomplications are managed with endotracheal intu-bation, aggressive fluid resuscitation, fresh frozenplasma, insulin, and calcium, as needed.

AntibioticsThe prevention of infection is critical becauseinfected necrosis develops in 30% to 70% of patientswith acute necrotizing pancreatitis and accounts formore than 80% of deaths due to acute pancreatitis.Early studies on antibiotic therapy for patientswith acute pancreatitis failed to demonstrate animportant benefit because these studies includedboth patients with interstitial-edematous acutepancreatitis and patients with necrotizing acutepancreatitis. In experimental acute necrotizingpancreatitis, pancreatic infection occurs primarilyas a result of bacterial translocation from the colon.Human studies have shown benefits from systemic


Fig. 1. Normal contrast-enhanced computedtomogram of the pancreas. Note that the pancreas(P) has a uniform enhancement intermediatebetween that of the liver (L) and spleen (S).

Fig. 2. Acute necrotizing pancreatitis. The patienthad severe pancreatitis after endoscopic retrogradecholangiopancreatography. Note fluid collection(arrowhead F) near the neck of the pancreas. Thedensity of the necrotic portion of the pancreas(arrowhead N) is less than that of the normal-enhancing pancreas in the tail (arrowhead P).

LP

S

P

F

N

antibiotic therapy and selective gut decontamination.In a prospective trial involving a group of patientswith necrotizing pancreatitis, a significantdecrease in gram-negative pancreatic infectionand late mortality (more than 2 weeks after theonset of pancreatitis) was found in the selectivegut decontamination group. Because selective gutdecontamination antibiotics must be administeredorally and rectally, this regimen may pose prob-lems from a nursing standpoint and has not beenadopted. The more commonly used approach issystemic administration of antibiotics to preventpancreatic infection.

Prospective and retrospective studies haveshown a significant decrease in pancreatic infectionin patients given imipenem-cilastatin (Primaxin)intravenously, although a decrease in mortality ratewas not demonstrated. Fluoroquinolones shouldoffer excellent protection against infection of necrosis.However, the results from two randomized prospec-tive trials of quinolone regimens for patients withsevere pancreatitis suggest that these agents are noteffective prophylaxis for reducing the infectiouscomplications of acute pancreatitis. In a recentlypublished Cochrane Database Systematic Review offour prospective randomized trials in which antibac-terial therapy was evaluated in patients with severeacute pancreatitis associated with pancreatic necrosisproven by intravenous contrast-enhanced CT, therewas strong evidence that intravenous antibiotic pro-phylactic therapy for 10 to 14 days decreased the riskof superinfection of necrotic tissue and mortality.Currently, prophylaxis with intravenously admin-istered antibiotics that have excellent penetration ofpancreatic tissue (imipenem-cilastatin) is recom-mended. A concern with prophylactic antibioticsfor severe acute pancreatitis is the development offungal superinfection. Strategies that have been pro-posed to limit this complication include antibiotictherapy limited to 7 days or prophylactic therapywith antifungal drugs. These need to be studied infuture trials. Therapy should begin as soon as severeacute pancreatitis is diagnosed. Recently, a secondantibiotic (meropenem) in the same class has beenshown to be equally effective for preventing septiccomplications of severe acute pancreatitis. Additionalstudies are needed to determine which subgroups ofsevere acute pancreatitis will benefit from prophy-lactic antibiotic therapy.

Detection of Pancreatic InfectionAlthough sterile and infected acute necrotizing pan-creatitis can be difficult to distinguish clinicallybecause both may produce fever, leukocytosis, andsevere abdominal pain, the distinction is important.Without intervention, the mortality rate for patientswith infected acute necrotizing pancreatitis is nearly100%. The bacteriologic status of the pancreas maybe determined with CT-guided fine-needle aspira-tion of pancreatic and peripancreatic tissue or fluid.This aspiration method is safe, accurate (sensitivityof 96% and specificity of 99%), and recommendedfor patients with acute necrotizing pancreatitis whosecondition deteriorates clinically or fails to improvedespite aggressive supportive care. Ultrasonograph-ically guided aspiration may have a lower sensitivityand specificity, but it can be performed at the bedside.Surveillance aspiration may be repeated on a weeklybasis as indicated clinically.

Role of Endoscopic RetrogradeCholangiopancreatographyERCP with biliary sphincterotomy may improvethe outcome of patients who have severe gallstonepancreatitis. Initial studies in which urgent ERCP(within 72 hours after admission) and biliary sphinc-terotomy were performed in patients with acutegallstone pancreatitis and choledocholithiasisshowed improved outcome for only the group ofpatients presenting with clinically severe acute pan-creatitis. The improvement was attributed to relieffrom pancreatic ductal obstruction produced by animpacted gallstone in the common biliary-pancre-atic channel of the ampulla of Vater. More recentstudies have suggested that improved outcome afterERCP and sphincterotomy in gallstone pancreatitismay be the result of reduced biliary sepsis ratherthan a true improvement in pancreatitis. Therefore,for patients with severe gallstone acute pancreatitis,ERCP should be reserved for those with biliaryobstruction suspected on the basis of hyperbiliru-binemia and clinical cholangitis.

Nutritional Support for Acute NecrotizingPancreatitisTo meet increased metabolic demands and to “rest”the pancreas, total parenteral nutrition has beenused frequently for nutritional support of patientswith acute necrotizing pancreatitis, but it does not


hasten the resolution of acute pancreatitis. In ran-domized prospective studies of severe acute pan-creatitis that compared total parenteral nutritionwith enteral feeding (through a nasoenteric feedingtube placed under radiographic guidance beyondthe ligament of Treitz), patients who received enteralfeeding had significantly fewer total and infectiouscomplications, a threefold decrease in the cost ofnutritional support, and improvement in acutephase response and disease severity scores. A recentmeta-analysis of enteral and parenteral nutrition inpatients with acute pancreatitis found that enteralnutrition was associated with a significantly lowerincidence of infections, reduced number of surgicalinterventions to control pancreatitis, and a decreasedlength of hospital stay. The two groups of patientshad no significant differences in mortality or non-infectious complications. It appears that this form ofenteral feeding is preferable for patients who haveacute necrotizing pancreatitis but not severe ileus.Possibly, nasogastric feeding may be as safe, too,as indicated by a small randomized study that com-pared nasogastric feeding with nasojejunal feeding.

Surgical Therapy for Pancreatic NecrosisThe timing and type of pancreatic intervention foracute necrotizing pancreatitis are debated,although guidelines from the InternationalAssociation of Pancreatology for the SurgicalManagement of Acute Pancreatitis have been pub-lished recently. Because the mortality rate of sterileacute necrotizing pancreatitis is approximately10% and surgical intervention has not been shownto decrease this rate, nonsurgical therapy is rec-ommended. Conversely, infected acute necrotizingpancreatitis is considered uniformly fatal withoutintervention. Aggressive surgical pancreaticdébridement (necrosectomy) is the standard ofcare and may require multiple abdominal reex-plorations. Necrosectomy should be performedsoon after infected necrosis has been confirmed.Surgical débridement of sterile necrosis in patientswith multisystem organ failure unresponsive tomaximal treatment in an intensive care unit is con-sidered an indication for surgery. However,delaying surgical intervention more than 14 daysafter the onset of acute necrotizing pancreatitis,when possible, is currently the recommendation,based on recent evidence. This is related to better

demarcation between viable and necrotic tissue atthe time of operation. The role of delayed necro-sectomy (after multisystem organ failure hasresolved) in sterile acute necrotizing pancreatitis isalso debated. Some investigators advocate débride-ment in patients who are still systemically ill withfever, weight loss, intractable abdominal pain,inability to eat, and “failure to thrive” 4 to 6 weeksafter the onset of acute pancreatitis. Others, how-ever, argue that delayed necrosectomy is unneces-sary as long as the process remains sterile.Frequently, multiple operations are required toremove the necrotic pancreatic and peripancreaticmaterial. Abdominal zipper or open packing of thewound permits repeated explorations. If the necrosisis well contained and organized or if the patient isa poor surgical risk, minimal access necrosectomy,either by the percutaneous route with a nephro-scope or the endoscopic route through the stomach,duodenum, or papilla, is the new approach.Pancreatic or gastrointestinal tract fistulae (or both)occur in up to 40% of patients after surgical necro-sectomy and often require an additional procedurefor closure. The mortality rate after necrosectomy foracute necrotizing pancreatitis is approximately 20%.

Prognosis The overall mortality rate for severe acute pancre-atitis has decreased as a result of improved intensivecare unit therapies, antibiotics, and delay of surgeryand is now approximately 15%. Mortality occurs intwo phases: 1) early deaths (1-2 weeks after the onsetof pancreatitis, approximately 50% of all deaths)are due to multisystem organ failure from the releaseof inflammatory mediators and cytokines and 2)late deaths result from local or systemic infections.As long as acute necrotizing pancreatitis remainssterile, the overall mortality rate is approximately10%. The mortality rate at least triples if infectednecrosis occurs. Patients with sterile necrosis andhigh severity-of-illness scores (Ranson score orAPACHE II score) accompanied by multisystemorgan failure, shock, or renal insufficiency have asignificantly higher mortality rate.

Long-Term Sequelae of Acute NecrotizingPancreatitisDespite the enormous cost of caring for patientswho have acute necrotizing pancreatitis, the mean


quality-of-life outcomes up to 2 years after treat-ment of pancreatic necrosis are similar to those forcoronary artery bypass grafting. The long-termclinical endocrine and exocrine consequences ofacute necrotizing pancreatitis appear to dependon several factors: the severity of necrosis, cause(alcoholic vs nonalcoholic), continued use ofalcohol, and the degree of surgical pancreaticdébridement. Sophisticated exocrine functionstudies have shown persistent functional insuffi-ciency in the majority of patients up to 2 years aftersevere acute pancreatitis. Treatment with pancre-atic enzymes should be restricted to patients withsymptoms of steatorrhea and weight loss due tofat malabsorption. Although subtle glucose intol-erance is frequent, overt diabetes mellitus isuncommon. Follow-up pancreatography fre-quently shows obstruction, disruption, or discon-nection of the pancreatic duct, which may resultin persistence or recurrence of fluid collections.This may require endoscopic treatment or distalpancreatic resection.

RECOMMENDED READINGArvanitakis M, Delhaye M, De Maertelaere V, Bali

M, Winant C, Coppens E, et al. Computedtomography and magnetic resonance imagingin the assessment of acute pancreatitis.Gastroenterology. 2004;126:715-23.

Baillie J. Treatment of acute biliary pancreatitis. NEngl J Med. 1997;336:286-7.

Balthazar EJ, Freeny PC, vanSonnenberg E.Imaging and intervention in acute pancreatitis.Radiology. 1994;193:297-306.

Balthazar EJ, Robinson DL, Megibow AJ, RansonJH. Acute pancreatitis: value of CT in estab-lishing prognosis. Radiology. 1990;174:331-6.

Banks PA. Practice guidelines in acute pancreatitis.Am J Gastroenterol. 1997;92:377-86.

Baron TH, Morgan DE. Acute necrotizing pancre-atitis. N Engl J Med. 1999;340:1412-7.

Bassi C, Larvin M, Villatoro E. Antibiotic therapyfor prophylaxis against infection of pancreaticnecrosis in acute pancreatitis. CochraneDatabase Syst Rev. 2003;(4):CD002941.

Bradley EL III. A clinically based classificationsystem for acute pancreatitis: summary of the

International Symposium on Acute Pancreatitis,Atlanta (GA), September 11 through 13, 1992.Arch Surg. 1993;128:586-90.

Buchler MW, Gloor B, Muller CA, Friess H, SeilerCA, Uhl W. Acute necrotizing pancreatitis:treatment strategy according to the status ofinfection. Ann Surg. 2000;232:619-26.

Dervenis C, Johnson CD, Bassi C, Bradley E, ImrieCW, McMahon MJ, et al. Diagnosis, objectiveassessment of severity, and management ofacute pancreatitis: Santorini consensus con-ference. Int J Pancreatol. 1999;25:195-210.

Eatock FC, Brombacher GD, Steven A, Imrie CW,McKay CJ, Carter R. Nasogastric feeding insevere acute pancreatitis may be practical andsafe. Int J Pancreatol. 2000;28:23-9.

Fan ST, Lai EC, Mok FP, Lo CM, Zheng SS, WongJ. Early treatment of acute biliary pancreatitisby endoscopic papillotomy. N Engl J Med.1993;328:228-32.

Foitzik T, Klar E, Buhr HJ, Herfarth C. Improvedsurvival in acute necrotizing pancreatitisdespite limiting the indications for surgicaldebridement. Eur J Surg. 1995;161:187-92.

Folsch UR, Nitsche R, Ludtke R, Hilgers RA,Creutzfeldt W, the German Study Group onAcute Biliary Pancreatitis. Early ERCP andpapillotomy compared with conservativetreatment for acute biliary pancreatitis. N EnglJ Med. 1997;336:237-42.

Gerzof SG, Banks PA, Robbins AH, Johnson WC,Spechler SJ, Wetzner SM, et al. Early diagnosisof pancreatic infection by computed tomog-raphy-guided aspiration. Gastroenterology.1987;93:1315-20.

He YM, Lv XS, Ai ZL, Liu ZS, Qian Q, Sun Q, et al.Prevention and therapy of fungal infection insevere acute pancreatitis: a prospective clinicalstudy. World J Gastroenterol. 2003;9:2619-21.

Isenmann R, Runzi M, Kron M, Kahl S, Kraus D,Jung N, et al, German Antibiotics in SevereAcute Pancreatitis Study Group. Prophylacticantibiotic treatment in patients with predictedsevere acute pancreatitis: a placebo-controlled,double-blind trial. Gastroenterology. 2004;126:997-1004.

Lobo DN, Memon MA, Allison SP, Rowlands BJ.Evolution of nutritional support in acute pan-creatitis. Br J Surg. 2000;87:695-707.


Manes G, Rabitti PG, Menchise A, Riccio E, BalzanoA, Uomo G. Prophylaxis with meropenem ofseptic complications in acute pancreatitis: arandomized, controlled trial versus imipenem.Pancreas. 2003;27:e79-83.

Marik PE, Zaloga GP. Meta-analysis of parenteralnutrition versus enteral nutrition in patientswith acute pancreatitis. BMJ. 2004 Jun12;328:1407. Epub 2004 Jun 2.

Mier J, Leon EL, Castillo A, Robledo F, Blanco R.Early versus late necrosectomy in severe necro-tizing pancreatitis. Am J Surg. 1997;173:71-5.

Neoptolemos JP, Carr-Locke DL, London NJ,Bailey IA, James D, Fossard DP. Controlledtrial of urgent endoscopic retrograde cholan-giopancreatography and endoscopic sphinc-terotomy versus conservative treatment foracute pancreatitis due to gallstones. Lancet.1988;2:979-83.

Nuutinen P, Kivisaari L, Schroder T. Contrast-enhanced computed tomography andmicroangiography of the pancreas in acutehuman hemorrhagic/necrotizing pancreatitis.Pancreas. 1988;3:53-60.

Rattner DW, Legermate DA, Lee MJ, Mueller PR,Warshaw AL. Early surgical debridement ofsymptomatic pancreatic necrosis is beneficial

irrespective of infection. Am J Surg. 1992;163:105-9.

Rau B, Pralle U, Mayer JM, Beger HG. Role of ultra-sonographically guided fine-needle aspira-tion cytology in the diagnosis of infected pan-creatic necrosis. Br J Surg. 1998;85:179-84.

Schmid SW, Uhl W, Friess H, Malfertheiner P,Buchler MW. The role of infection in acute pan-creatitis. Gut. 1999;45:311-6.

Tsiotos GG, Smith CD, Sarr MG. Incidence andmanagement of pancreatic and enteric fistulasafter surgical management of severe necro-tizing pancreatitis. Arch Surg. 1995;130:48-52.

Uhl W, Warshaw A, Imrie C, Bassi C, McKay CJ,Lankisch PG, et al, International Association ofPancreatology. IAP guidelines for the surgicalmanagement of acute pancreatitis. Pancre-atology. 2002;2:565-73.

Werner J, Hartwig W, Uhl W, Muller C, BuchlerMW. Useful markers for predicting severityand monitoring progression of acute pancre-atitis. Pancreatology. 2003;3:115-27.

Windsor AC, Kanwar S, Li AG, Barnes E, GuthrieJA, Spark JI, et al. Compared with parenteralnutrition, enteral feeding attenuates the acutephase response and improves disease severityin acute pancreatitis. Gut. 1998;42:431-5.


Chronic pancreatitis is an often painful inflam-matory condition of the pancreas characterizedby progressive fibrosis that leads to irreversibledestruction of exocrine and endocrine tissue,resulting eventually in exocrine and endocrineinsufficiency. There is considerable heterogeneityin the presentation and natural history of the con-dition. Chronic pancreatitis is classified broadlyinto chronic calcifying pancreatitis, chronicobstructive pancreatitis, and chronic autoim-mune pancreatitis.

Chronic calcifying pancreatitis is characterized byrecurrent bouts of clinically acute pancreatitis earlyin the course of the disease, with eventual devel-opment of intraductal stones later in the diseasecourse. Eventually, steatorrhea and diabetes mel-litus develop in the majority of patients. This isthe clinical profile of the disease that readilycomes to mind when the term chronic pancreatitisis used in clinical practice.

Chronic obstructive pancreatitis results fromobstruction of the pancreatic duct due to any cause.The disease affects only the organ distal to theobstruction. It generally is not associated withstone formation. Although often asymptomatic,

partial obstruction can lead to recurrent bouts ofclinically acute pancreatitis involving the obstructedpart of the gland. Obstructive pancreatitis is com-monly seen distal to pancreatic tumors (ductal ade-nocarcinoma and intraductal papillary mucinoustumor [IPMT]) and postinflammatory stricturesfollowing acute or traumatic pancreatitis.

Chronic autoimmune pancreatitis is a uniqueform of chronic pancreatitis that can be defined asa systemic fibroinflammatory disease that afflictsnot only the pancreas but also various other organs,including the bile duct, salivary glands, retroperi-toneum, and lymph nodes. Organs affected byautoimmune pancreatitis have a lymphoplasma-cytic infiltrate rich in IgG4-positive cells. Theinflammatory process responds to corticosteroidtherapy. The most common presentation of thisform of chronic pancreatitis is with obstructivejaundice, and it rarely presents with clinically acutepancreatitis. Pancreatic calcification is not common.It is thought to be a systemic autoimmune disorder;its best known serologic marker is an increased levelof IgG4.

The rest of the discussion in this chapter isrelated to chronic calcifying pancreatitis.

469

CHAPTER 36

Chronic Pancreatitis

Suresh T. Chari, MD

Abbreviations: CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopicultrasonography; IPMT, intraductal papillary mucinous tumor; MRCP, magnetic resonance cholangiopancreatography;MRI, magnetic resonance imaging.

Several conditions are associated with chroniccalcifying pancreatitis (Table 1). The pathogenesisof chronic pancreatitis due to these presumed eti-ologic agents is largely unknown. In the West, themost common cause of chronic calcifying pancre-atitis is chronic alcohol abuse.

DIAGNOSISAlthough histologic examination is the “goldstandard” for diagnosis of chronic pancreatitis, itoften is not available. Without histologic study, acombination of morphologic findings on imagingstudies, functional abnormalities, and clinicalfindings is used to diagnose chronic pancreatitis.The diagnosis is relatively straightforward in thelater stages of the disease when calcification andsteatorrhea are present. The diagnosis is difficultwhen pancreatic structure and function are not

unequivocally abnormal. Currently available diag-nostic modalities are not adequate for making a firmdiagnosis of chronic pancreatitis without obviouschanges in structure and function.

Structural EvaluationComputed tomography (CT), endoscopic retrogradecholangiopancreatography (ERCP), endoscopicultrasonography (EUS), magnetic resonanceimaging (MRI), and magnetic resonance cholan-giopancreatography (MRCP) are the imaging pro-cedures commonly used to evaluate for structuralchanges in the pancreas. Pancreatic calcificationsuggestive but not diagnostic of chronic pancreatitiscan be identified on abdominal radiographs.However, CT and EUS can detect small specks ofcalcifications not visible on plain radiographs.

Abdominal CT is a good first test for the evalu-ation of a patient with possible chronic pancreatitis.


Table 1. Causes of Chronic Calcifying Pancreatitis (CP)

Presumed cause Salient features

Alcohol Commonest cause of CP in the WestAbout 5% of alcoholics develop CP, usually after long history of

alcohol abuseHereditary Mutations in cationic trypsinogen gene (R117H, N21I) associated

with high penetrance (80%) autosomonal dominant form of CPPresents at an early age (first and second decades)High risk of pancreatic cancer with time, especially in smokers

Tropical Cause unknownHighest prevalence in South IndiaEarly age at onset (first and second decades)High prevalence (>80%) of diabetes mellitus and calcification at

diagnosisIdiopathic Early (juvenile) and late (senile) forms

Juvenile form associated with mutations in CFTR gene, SPINK1gene, and some other mutations in cationic trypsinogen also associated with CP (probably disease modifiers)

Pain is common feature of early-onset diseaseSenile form may be painless in ~50% of patients

Hypercalcemia Uncommon complication of hypercalcemiaHypertriglyceridemia Seen in children with disorders of lipid metabolism

Associated with types I, II, and V hyperlipidemiaTriglyceride levels >1,000 mg/dL

It is noninvasive, widely available, and has relativelygood sensitivity for diagnosing moderate-to-severe chronic pancreatitis. The findings, however,can be normal in early chronic pancreatitis. Chronicpancreatitis is diagnosed on CT by the identificationof pathognomonic calcifications within the mainpancreatic duct or parenchyma or calcification withinthe dilated main pancreatic duct in combination withparenchymal atrophy. CT is also good for the eval-uation of pain in a patient with known chronic pan-creatitis, because it can identify most complicationsof chronic pancreatitis, including peripancreatic fluidcollections, bile duct obstruction, and bowelobstruction, and can reliably visualize inflamma-tory or neoplastic masses larger than 1 cm.

In the absence of a tissue diagnosis, ERCP isquite sensitive and specific for diagnosing mod-erate to severe pancreatitis. Pancreatic ductalchanges seen on ERCP in chronic pancreatitis arelisted in Table 2. Minor changes in the ducts arehard to interpret and are subject to interobservervariation. False-positive results may be obtained inolder patients who may have benign pancreaticduct changes without pancreatitis and in patientswith recent acute pancreatitis who developreversible or permanent pancreatic duct changes inthe absence of chronic pancreatitis.

Diagnostic ERCP carries a small (2%-5%) riskof causing complications, including pancreatitis.Therapeutic maneuvers have a higher risk of com-plication. ERCP is useful when other methods arenondiagnostic or unavailable, when patients have

a clinical pattern of recurrent acute pancreatitis, orwhen a therapeutic intervention is being considered.

EUS provides high-resolution images of thepancreatic parenchyma and duct. Unlike ERCP,which can provide detailed images of changes inthe pancreatic duct, EUS provides informationabout the pancreatic parenchyma as well as theduct. However, the role of EUS and the diagnosticcriteria for diagnosing chronic pancreatitis withEUS are still being evaluated. Problems with inter-pretation may arise in older patients who havesenile changes in the pancreas, in alcoholics inwhom fibrosis may be present but not pancreatitis,and in patients who had a recent episode of acutepancreatitis. There is also the problem of interob-server variability in interpretation. Currently, thediagnosis of chronic pancreatitis should not bebased on EUS criteria alone.

MRCP is noninvasive, avoids ionizing radi-ation and administration of contrast, and doesnot routinely require sedation, making it a diag-nostic procedure of choice for some groups ofpatients. It avoids the risks associated with ERCP.In combination with conventional abdominalMRI, MRCP can provide comprehensive infor-mation about the pancreas and peripancreatic tis-sues. Major lesions such as grossly dilated ducts,communicating pseudocysts, and even pancreasdivisum can be detected, but small duct changesand calcifications are not readily visualized. Also,the combination of MRI and MRCP does not havetherapeutic potential.

Chronic Pancreatitis 471

Table 2. Endoscopic Retrograde Cholangiopancreatography Grading of Chronic Pancreatitis(Cambridge Classification)

Grade Main duct Side branches Other findings

Normal Normal Normal NoneMild Normal ≥3 Abnormal NoneModerate Abnormal: dilated, strictures ≥3 Abnormal NoneSevere Abnormal: dilated, strictures ≥3 Abnormal >1 Finding:

Large (>10 mm) cavityIntraductal filling defects or calculiDuct obstructionSevere duct dilatation or irregularities

Functional Testing in the Evaluation ofChronic PancreatitisThe pancreas has great functional reserve, so thatit must be damaged severely before functional lossis recognized clinically. For example, 90% of thepancreas has to be destroyed before steatorrheaoccurs. Abnormal results of functional testing aloneare not diagnostic of chronic pancreatitis, and diag-nosis requires additional evidence of structuralalteration seen on imaging studies consistent withchronic pancreatitis. Imaging studies by themselvesusually are diagnostic by the time steatorrheadevelops. Invasive tests of pancreatic function (eg,the “tubed” secretin test) show functional impair-ment even in the absence of steatorrhea.However, these tests are not widely available.Noninvasive pancreatic function tests such asfecal fat estimation have poor sensitivity for thedetection of early disease.

CLINICAL FEATURES AND NATURALHISTORYAbdominal pain is the dominant symptom in theearly part of the natural history of chronic pan-creatitis, and steatorrhea and diabetes are theprominent features of late, end-stage disease. Painis often related to acute inflammatory flares. Someauthors have reported a painless “burn out” of thepancreas in the late stages of the disease, but othershave reported pain occurring even in late stages.Complications can occur after acute flares of pan-creatitis or from chronic fibrosis in and aroundthe pancreas.

The clinical features and natural history ofchronic pancreatitis can differ remarkably in dif-ferent forms of chronic pancreatitis. The age at theonset of pain is much lower (first and seconddecades of life) in the hereditary and tropical formsof chronic pancreatitis. Although pain is a domi-nant feature of most forms of chronic pancreatitis,it may be absent in half of the patients who havelate-onset (senile) idiopathic chronic pancreatitis.Diabetes and calcification are uncommon at diag-nosis in alcoholic pancreatitis, but they are presentat diagnosis in more than 80% of patients withtropical pancreatitis.

In alcoholic chronic pancreatitis, death oftenis related to smoking and nonpancreatic and

alcohol-related complications (especially cancers). Intropical pancreatitis, the most common cause ofdeath is diabetes-related complications, followedby pancreatic cancer. Pancreatic cancer can compli-cate any form of chronic pancreatitis, but it is espe-cially common in the hereditary and tropical forms,probably because of the long duration of disease.

COMPLICATIONS

Diabetes MellitusProgressive decrease in islet cell mass leads todiabetes mellitus in chronic pancreatitis. Whereasdiabetes is common at presentation in the tropicalform of chronic pancreatitis, it is usually a late com-plication in other forms of the disease. The majority(85%) of patients, with or without resection, even-tually develop diabetes, and nonresective surgery,such as ductal drainage, does not prevent it.

SteatorrheaSteatorrhea occurs after more than 90% of the glandhas been destroyed. Treatment involves oral pan-creatic enzyme supplements. These come asuncoated tablets or enteric-coated capsules ormicrospheres with pH-dependent release ofenzymes. Patients with severe steatorrhea require30,000 to 45,000 USP of lipase per meal and lesseramounts with snacks. Enzymes should be givenwith meals to allow proper mixing of food withthe enzymes. Acid suppression may be required toprevent destruction of the enzymes by gastric acid.Fat-soluble vitamin levels should be measured atbaseline and monitored periodically to correct anyconcomitant nutritional deficiencies.

PseudocystIn the early stages of the disease, pseudocysts arethe result of a pancreatic duct leak following anattack of clinically acute pancreatitis. In later stages,ductal dilation can lead to leakage and the forma-tion of pseudocyst from duct “blowout.” Upstreamductal obstruction due to stricture often results inthe reformation of pseudocysts after simple enteraldrainage (eg, endoscopic cyst drainage). This mayrequire concomitant drainage of the main pancre-atic duct (usually surgically) or resection of thediseased portion of the gland (or both).


Biliary ObstructionThis complication could result from edema of thehead of the gland following an acute attack, com-pression from a pseudocyst, bile duct entrapmentin the fibrotic process involving the head of thegland, and complicating pancreatic malignancy inpatients with long-standing disease. Edema of thehead of the gland usually responds to conservativemanagement, and compression of a pseudocystresponds to drainage of the pseudocyst. Fibroticstricturing requires surgical biliary bypass.Pancreatic cancer complicating chronic pancre-atitis can be difficult to diagnose early. Confirmedor suspected malignancy should be treated withresective surgery, if operable.

Duodenal ObstructionPotentially reversible gastric outlet obstructioncan occur during an acute flare of pancreatitis sec-ondary to peripancreatic inflammation involvingthe gastroduodenal region. Nasojejunal feedingmay be required to maintain nutrition during thisperiod. Patients with a fibrotic process involvingthe duodenum require surgical bypass of the gastricoutlet obstruction.

Splenic Vein ThrombosisBecause of the proximity of the splenic vein withthe pancreas, the vein is often affected by pancreaticinflammation or fibrosis. Patients with left-sidedportal hypertension (or sinistral portal hyperten-sion) can present with gastric variceal bleeding,which is treated with splenectomy.

MANAGEMENTAbdominal pain is the most dominant and vexingproblem in the management of patients withchronic pancreatitis. It can vary in severity frommild, intermittent pain to severe, chronic, debili-tating pain. In addition to the addiction to alcoholand tobacco that patients with alcoholic pancre-atitis often have, there is also considerable poten-tial for addiction to narcotics by those with severepain. It is very difficult to assess the true severityof the pain of patients addicted to narcotics, andtherapeutic interventions often are seeminglyunsuccessful because of continued dependenceon narcotics. Apart from these issues, our poor

understanding of the pathogenesis of pain hasmade it difficult to manage rationally abdominalpain in chronic pancreatitis. Despite some opti-mism that pancreatic pain eventually “burns out,”most clinicians agree that the pain may diminishbut it rarely disappears with time.

A stepwise approach to pain management isrecommended. However, the scientific evidenceto support any of the measures taken (medical,endoscopic, or surgical) is scant, and there are veryfew well-defined prospective trials of therapy,either in comparison with no therapy or with com-peting therapy.

An important first step is the assessment of apatient’s pain and its nature, frequency, severity,and effect on quality of life and other activities.Patients with intermittent (eg, episodes once a yearor less), uncomplicated episodes with full func-tion between episodes are probably better offwithout potentially injurious interventions.Regardless of the severity of pain, all patients withchronic pancreatitis should be counseled duringeach visit about abstinence from not only alcoholbut also tobacco use.

Patients who have more significant, frequent,or severe pain and a tendency to use narcotics forpain control need further evaluation. The initialevaluation with imaging studies (eg, CT) shouldbe undertaken to rule out complications of pan-creatitis such as persistent acute inflammation(inflammatory mass) in the pancreas, pancreaticand peripancreatic fluid collections, biliary obstruc-tion, and duodenal stenosis. Other diagnoses to beconsidered in the appropriate clinical context arepeptic ulcer disease, gallbladder disease, and pan-creatic cancer. The presence of any of these shouldlead to appropriate intervention.

In patients without the above conditions,medical, endoscopic, and surgical options havebeen attempted. Medical therapy includes a lowfat diet with abstinence from alcohol and use ofhigh-dose pancreatic enzymes in association withacid suppression. Endoscopic therapy includessphincterotomy, lithotripsy, and pancreatic ductstenting. Currently, the evidence supporting theuse of endoscopic therapy for pain in chronicpancreatitis is preliminary and confined largelyto short-term focused observations. Althoughthese procedures may hold promise, they need

Chronic Pancreatitis 473

to be evaluated further in clinical trials. Celiacplexus block appears to have limited benefit inchronic pancreatitis.

Surgical therapy is an option for patients whoclearly appear to have pancreas-related pain. Thechoice of operation, if elected, should be based onthe morphology of the pancreatic duct. Treatmentoptions include decompressive surgery such aslateral pancreaticojejunostomy for patients witha dilated (>6 mm) pancreatic duct, partial pancre-atic resection for those with a persistent inflam-matory mass, or, for patients with disease unre-sponsive to medical therapy and not suitable forother surgical options, total pancreatectomy. Arecent randomized controlled trial comparing pan-creaticojejunostomy and endoscopic therapy forchronic pancreatitis with dilated ducts showedthat surgery provided superior results, with ahigher proportion of patients reporting pain relief.However, the 20% to 40% failure rate mentioned ineven the most enthusiastic reports and the poten-tial for surgical morbidity and mortality warrantreserving surgical treatment for patients withsevere pain not responsive to lesser tactics.

RECOMMENDED READINGAmerican Gastroenterological Association Medical

Position Statement. Treatment of pain in chronicpancreatitis. Gastroenterology. 1998;115:763-4.

Domínguez-Muñoz JE. Pancreatic enzyme therapyfor pancreatic exocrine insufficiency. CurrGastroenterol Rep. 2007;9:116-22.

Etemad B, Whitcomb DC. Chronic pancreatitis: diag-nosis, classification, and new genetic develop-ments. Gastroenterology. 2001;120:682-707.

Heyries L, Sahel J. Endoscopic treatment of chronicpancreatitis. World J Gastroenterol. 2007;13:6127-33.

Layer P, Yamamoto H, Kalthoff L, Clain JE, BakkenLJ, DiMagno EP. The different courses of early-and late-onset idiopathic and alcoholic chronicpancreatitis. Gastroenterology. 1994;107:1481-7.

Martin RF, Marion MD. Resectional therapy forchronic pancreatitis. Surg Clin North Am.2007;87:1461-75.

Warshaw AL, Banks PA, Fernandez-Del Castillo C.AGA technical review: treatment of pain inchronic pancreatitis. Gastroenterology. 1998;115:765-76.


Exocrine pancreatic neoplasms are of epithelial ornonepithelial origin (Table 1). Of all pancreatic tum-ors, ductal adenocarcinoma is the most important.

PANCREATIC DUCTALADENOCARCINOMACancer of the pancreas is a fatal disease and anincreasing health problem. In the United States,more than 32,000 persons die of pancreatic cancerannually. The overall survival rate with pancreaticcancer is less than 5%, the lowest 5-year survivalrate of any cancer. This is due partly to the lowresectability rate.

Only 10% to 15% of patients are candidatesfor curative resection (stage I and stage II disease),and more than 50% have unresectable stage IV dis-ease with distant metastases (Table 2).

Risk Factors for Development ofPancreatic CancerEarly diagnosis of pancreatic cancer is difficultbecause the tumor frequently is detected at a latestage, and until recent years, risk factors for the

development of pancreatic cancer were unde-fined. However, several risk factors have nowbeen described.

475

CHAPTER 37

Pancreatic Neoplasms

Randall K. Pearson, MD

Abbreviations: CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopicultrasonography; FNA, fine-needle aspiration; 5-FU, 5-fluorouracil; MDCT, multidetector computed tomography; MRI,magnetic resonance imaging.

Table 1. Exocrine Pancreatic Tumors

EpithelialCystic

Microcystic (serous) cystadenomaMacrocystic (mucinous) cystadenomaIntraductal papillary mucinous tumorSolid-cystic (solid and papillary) tumor

SolidVariants of ductal adenocarcinoma*

Adenosquamous, anaplastic, acinar cellNonepithelial

Connective tissue originLeiomyosarcomaLiposarcomaRhabdomyosarcomaMalignant neurolemmoma

Malignant lymphomas

*Most important.

Environmental FactorsAromatic amines appear to be responsible for theincreased risk of pancreatic cancer associated withenvironmental factors. Thus, cigarette smoking isthe most important risk factor and increases therelative risk by a factor of 1.5- to 3-fold. Furthermore,in hereditary pancreatic cancer kindreds as well

as hereditary chronic pancreatitis, smoking lowersthe age at onset of pancreatic cancer by 10 years.Persons working in the chemical, petrochemical, orrubber industries and hairdressers have a greaterrisk of pancreatic cancer, which may be related toexposure to aromatic amines. Furthermore, animalstudies indicate that aromatic amines may causepancreatic cancer.

Hereditary PancreatitisTwo mutations of the trypsinogen gene have beendescribed in hereditary pancreatitis. There is a highincidence of pancreatic cancer among patients withhereditary pancreatitis, but this likely is due to theduration of chronic pancreatitis rather than beingrelated specifically to the gene mutation. The esti-mated cumulative risk of pancreatic cancer at age70 is 40% (70- to 100-fold increased relative risk).Possibly in the future, methods will be availablefor identifying patients at risk for pancreatic cancer,but currently no established screening techniqueshave proven value.

Chronic PancreatitisAccording to a multinational study, patients withchronic pancreatitis have a cumulative risk of 2%per decade and a relative risk (the ratio ofobserved-to-expected cases) of 16. However,chronic pancreatitis is relatively uncommon anddoes not contribute significantly to the populationof patients with pancreatic cancer.

Intraductal Papillary Mucinous Tumors(see “Cystic Pancreatic Tumors”)This disease was recognized first in Japan in 1982and increasingly is recognized in the United States.At Mayo Clinic, this condition has been identifiedin more than 100 patients. In about 25% to 50% ofpatients, invasive cancer is found at surgery (insome patients, it is not suspected preoperatively).Therefore, intraductal papillary mucinous tumoris a premalignant lesion, and surgical excision atpresentation is the treatment of choice.

Diabetes MellitusMore than 50% of patients who present with pan-creatic cancer have diabetes mellitus, and in mostpatients, diabetes is diagnosed within 2 years ofthe diagnosis of cancer. Some but not all of the


Table 2. Staging of Pancreatic DuctalAdenocarcinoma

Definition of TNMPrimary tumor (T)

TX Primary tumor cannot be assessedT0 No evidence of primary tumorTis In situ carcinomaT1 Tumor limited to pancreas, ≤2 cm in

greatest dimensionT2 Tumor limited to pancreas, >2 cm in

greatest dimensionT3 Tumor extends directly into any of

the following: duodenum, bile duct, peripancreatic tissues, portal or superior mesenteric vessels

T4 Tumor extends directly into any of the following: stomach, spleen, colon, adjacent large arterial vessels

Regional lymph nodes (N)NX Regional lymph nodes cannot be

assessedN0 No regional lymph node metastasisN1 Regional lymph node metastasis

Distant metastasis (M)MX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasis

Stage groupingStage 0 Tis N0 M0Stage I T1 N0 M0

T2 N0 M0Stage II T3 N0 M0Stage III T1 N1 M0

T2 N1 M0T3 N1 M0

Stage IVA T4 Any N M0Stage IVB Any T Any N M1

patients are insulin-dependent, and in some, dia-betes is diagnosed at the same time as pancreaticcancer. The precise risk of pancreatic cancer inpatients with new-onset diabetes is not welldefined, but according to a meta-analysis, the riskof pancreatic cancer developing in patients whohave had diabetes for more than 1 year is doubled.

InheritanceThe evidence is consistent that 6% to 8% of patientswho present with pancreatic cancer have a familyhistory of pancreatic cancer in a first-degree relative,which represents a 13-fold increase over controls.Families with two or more first-degree relativeswith pancreatic cancer have an increased relativerisk of 18- to 57-fold, depending on the numberand ages of the relatives affected. Also, well-defined syndromes are associated with anincreased incidence of pancreatic cancer, includingPeutz-Jeghers syndrome (STK11), mismatch repairgenes (HNPCC), and familial atypical multiplemole melanoma syndrome (p16). Rare kindredshave been identified in whom the pancreatic cancerappears to be inherited in an autosomal dominantmanner. Germline BRCA2 mutations account forapproximately 20% of these families and currentlyare the most common known inherited predispo-sition to pancreatic cancer.

It is not known at what age screening shouldbegin or indeed whether any screening techniquecan detect early pancreatic cancer or improve prog-nosis. General guidelines include performing con-trast-enhanced multidetector computed tomog-raphy (MDCT) or endoscopic ultrasonography(EUS) at regular intervals, but there are no data tosupport this recommendation. Tumor markers,including K-ras and CA19-9, are too insensitiveand nonspecific.

PathologyAbout 70% of pancreatic ductal adenocarcinomasoccur in the head of the pancreas. Histologically,the neoplasms may vary from well-differentiatedtumors that exhibit glandular structures in a densestroma to poorly differentiated tumors that exhibitlittle or no glandular structure or stroma.Lymphatic spread appears to occur earlier thanvascular invasion, which is present in moreadvanced lesions. Metastatic disease occurs mainly

to the liver and lungs but also to the adrenals,kidneys, bone, brain, and skin.

DiagnosisPatients with pancreatic cancer usually presentwith symptoms of pain, jaundice, weight loss (withor without anorexia), and early satiety. The mostcommon symptom is abdominal pain, whichoccurs in up to 80% of patients. The presence ofpain, particularly pain radiating through to theback, is associated with advanced lesions with apoor prognosis, the implication being that thetumor has spread beyond the pancreas.

Jaundice is the second most common presen-tation and occurs in about 50% of patients. Forpatients with cancer of the head of the pancreas,painless jaundice is the symptom most frequentlypredictive of resectability.

Overt steatorrhea is a far less common pre-senting symptom, even in patients with overt weightloss, and, when present alone, it has been associ-ated with longer survival. An important smallpercentage of patients (approximately 5%) presentwith otherwise unexplained acute pancreatitis.

Tumor Markers for DiagnosisVarious tumor markers are increased in pancre-atic cancer, but all lack sufficient sensitivity andspecificity to be used as either diagnostic orscreening tests. CA19-9 has the greatest sensitivity(about 70%) and specificity (about 87%) when thecutoff value is 70 U/mL. If a lower cutoff value isused, sensitivity is higher, without much effect onspecificity. However, the test is not useful if thebiliary tract is obstructed, because even benign bil-iary tract obstruction can cause a marked increasein CA19-9. Approximately 5% to 10% of the pop-ulation do not express Lewis antigens; thus, CA19-9 would not be detectable in this subgroup, fur-ther compromising the test for general screening.Also, CA19-9 levels are more likely to increase asthe disease advances and becomes metastatic. Forearly-stage or resectable pancreatic cancer (stagesI and II), the sensitivity of an elevated CA19-9 valueis reported as low as 50%, missing half of thepatients with disease at the stage appropriate forpresymptomatic screening.

Genetic markers are present in patients withpancreatic cancer. The most common of these are

Pancreatic Neoplasms 477

the K-ras mutation in 90% of patients, p53 tumorcell suppressor gene in 50% to 70%, and reducedexpression of the DCC gene in about 50%. Othergene deletions are less common.

Although the K-ras mutation can be detectedin pancreatic or duodenal juice or stool frompatients with pancreatic cancer, it is present lessfrequently than in the tumor itself and, thus, is nota useful test because of low sensitivity. Furthermore,lack of specificity is an important issue because K-ras can be detected in chronic pancreatitis.

Islet amyloid polypeptide, a hormonal factorsecreted from pancreatic beta cells, is increasedin patients with pancreatic cancer who have glu-cose intolerance. Currently, it has no proven clin-ical application.

Imaging Testing for DiagnosisMDCT with arterial and portal venous phase con-trast enhancement (“pancreas protocol CT” [com-puted tomography]) should be the primaryimaging study for the evaluation of patients withsymptoms suggestive of pancreatic cancer. It is theappropriate study because it is not only diagnosticbut it also can be used to stage the tumor. Theincrease in sensitivity (about 85%) of dual-phaseMDCT is an important improvement over theability of conventional CT (about 50%-60%) to diag-nose pancreatic tumors. This sometimes leads tomisconceptions about the role of dual-phase CTwhen researching the older literature about theimportance of CT in diagnosis. For tumors smallerthan 15 mm in diameter, however, the sensitivityof MDCT probably is still less than 80%.

Most studies would support a role for EUS inthe setting of a small cancer not detected withMDCT. The sensitivity of EUS for identifying apancreatic mass is reported to be as high as 97%.EUS has been described as the most accurateimaging test for diagnosing pancreatic cancer,being more accurate than transabdominal ultra-sonography or CT. However, MDCT with pan-creas protocol contrast enhancement has “alteredthe equation,” and currently the role of EUS is inidentifying small tumors and in performing fine-needle aspiration (FNA) of the primary tumor orlymph nodes. Although EUS-guided FNA is a safeand effective method to diagnose pancreaticcancer, we rarely perform FNA in patients with

evidence of resectable pancreatic cancer becausethe results do not affect our clinical decision to pro-ceed with surgery. Thus, the role for EUS FNA islimited mainly to patients with unresectablelesions, and whether it should be performed needsto be balanced against obtaining histologic mate-rial by percutaneous biopsy assisted by either ultra-sonography or CT.

Staging Pancreatic TumorsCT should be the initial test not only for diagnosisbut also for staging of pancreatic cancer becauseit may provide evidence of distant metastases orclear vascular involvement, making further stagingunnecessary (Fig. 1 and 2). On contrast-enhancedMDCT images, ductal adenocarcinoma typicallyappears as an irregular, hypodense lesion.Magnetic resonance imaging (MRI) may be as accu-rate as MDCT, but generally it is not as readilyavailable and there is not the same expertise ininterpreting the findings. EUS may be the mostaccurate method for staging the local extent (Tstaging) (Fig. 3) and nodal status (N staging).Correct interpretation of both CT and EUS imagesregarding resectability varies depending on thestudy. For EUS, operator experience and the sizeof the tumor are important variables. Specifically,


Fig. 1. Computed tomogram showinghyperattenuating lesion in the body of the pancreas(arrow). Primary pancreatic adenocarcinoma is usuallyhypoattenuating. This lesion would also be consistentwith an islet cell tumor. The right kidney is absent.This lesion is a metastatic renal cell carcinoma.

the area of interest relative to vascular invasionrequires imaging through the entire extent of thetumor, and with current equipment (either radialor curved linear scanning transducers), resolutionprogressively deteriorates with increasing depth ofimaging. Whether advances in EUS technologywill improve its ability to determine resectabilitywhen CT (or MRI) findings are equivocal is unclear.

Small liver or peritoneal metastases usuallyare not seen on preoperative imaging studies.Laparoscopy has been recommended by someauthors for viewing the liver and peritoneal sur-faces preoperatively. About 10% to 15% of patientshave these small metastases. Most centers do notroutinely perform laparoscopy during preopera-tive assessment, but it can be argued thatlaparoscopy is indicated when the likelihood ofunresectability is high. This would include allpatients with cancer of the pancreatic body or tail,which has a very low chance of being resected andvirtually no chance of cure, or patients with ascites,which usually is related to peritoneal metastases.

Treatment

SurgeryMost patients who undergo surgical resection forpancreatic cancer ultimately die of the disease, butthe only chance of cure, albeit slim, is resection.For this reason, most major centers continue toendorse the surgical approach.

Preoperative biopsy or FNA of a pancreaticmass is not required in most instances because thefindings do not alter the decision to resect. Of thepatients who have the typical clinical presentationand preoperative imaging results, about 95% havepancreatic cancer at surgery. The other 5% usually


Fig. 2. Computed tomogram showing pancreaticcancer. A small hypoattenuating lesion is seen inthe head of the pancreas (arrow). The superiormesenteric vessels are not involved by the tumor,which is resectable.

Fig. 3. A, Endoscopic ultrasonogram of the pancreatic head shows a poorly defined hypoechoic mass thatimpinges on the portal vein for a distance of 11 mm (see markers). Surgical resection confirmed invasion of theportal vein. B, Fine-needle aspiration of mass shown in A.

A B

have chronic pancreatitis, but it is not possible toconfidently exclude tumor preoperatively. Thus,it is appropriate to perform a Whipple procedure.An important exception to this rule is autoimmunepancreatitis; this condition can mimic the presen-tation of pancreatic cancer and has characteristicclinical features that should alert astute clinicianspreoperatively (see Chapter 36, “Chronic Pancre-atitis”). In 10% to 15% of patients, pancreatic cancermay produce a desmoplastic response and tumortissue may be difficult to procure with needlebiopsy or FNA.

If surgical resection is not preceded bylaparoscopy, the surgeon usually examines theperitoneal cavity and its contents carefully forobvious small metastases and then assesses vas-cular involvement, which requires mobilizationof the tumor by dissection. The standard opera-tion for pancreatic cancer is pancreaticoduo-denectomy (Whipple procedure), which involvescholecystectomy and removing a portion of thestomach (at least antrectomy), the distal bile duct,head of the pancreas, the duodenum, proximaljejunum, and regional lymph nodes. Reconstructionwith gastrojejunostomy, hepaticojejunostomy, andpancreaticojejunostomy is required. Results aregood and mortality is low when the operation isperformed by an experienced surgeon.

Alternative operations include a pylorus-pre-serving Whipple resection, which has become thesurgical standard of care at most centers. This pre-serves the stomach and is a less extensive opera-tion. It has been assumed that this operation, com-pared with the Whipple procedure, wouldimprove outcome, especially long-term morbidityrelated to dumping syndrome and weight loss.

An extended or radical Whipple resectionhas been reported in the Japanese literature toprovide better results, but these results have notbeen confirmed by studies in the United Statesor Europe; indeed, four prospective, randomizedtrials have failed to find an advantage for the moreextensive procedure.

Surgery is the only chance for cure, but mediansurvival is only about 18 months and the 5-yearsurvival rate is about 10%. Higher survival rateshave been reported, and it appears that the dif-ferent rates depend on tumor size (<2 cm), histo-logic grade, nodal status, and completeness of

resection. For example, patients with tumorssmaller than 2 cm have a reported survival rate of20%, compared with only 1% for patients withtumors larger than 3 cm. The hypothesis that sur-gical treatment of early pancreatic cancer improvesprognosis is based on these data.

At presentation, most patients have pancre-atic cancer that is unresectable because of distantmetastases or local extension. Because biliaryobstruction can be relieved with endoscopicstenting, surgical management of biliary obstruc-tion usually is limited to patients with a concomi-tant gastric outlet obstruction. Biliary diversion isachieved by cholecystenterostomy (but only whenthe cystic duct enters the common bile duct at adistance from the tumor) or by choledochoen-terostomy. Because duodenal obstruction developsin less than 20% of patients before they die, it is ourpolicy—and that of nearly all centers—not to per-form prophylactic gastrojejunostomy. In somepatients, neuropathy due to infiltration of the plexusby tumor, and not obstruction, may cause vomitingand slow gastric emptying; thus, a drainage proce-dure will not be helpful in these patients. Mostpatients who have jaundice and unresectable pan-creatic cancer should have endoscopic stent place-ment. The preferred endoscopic prosthesis for pal-liation is an expandable metal stent, which is lesslikely to become occluded than plastic stents. Thisis especially true for patients with a life expectancyexceeding 3 months. Percutaneous transhepaticstenting has a lower success rate and a higher 30-day mortality rate and is not the procedure of choice.According to recent reports and our experience,endoscopically placed expandable metal prosthesescan successfully alleviate gastric outlet or duodenalmalignant obstruction, but these new proceduresrequire further evaluation before they can be rec-ommended for routine use.

Palliation of pain is a major problem in pan-creatic cancer. Chemical intraoperative splanch-nicectomy or celiac plexus block performed per-cutaneously or with EUS reportedly has reducedpain markedly and, according to one report, hasprolonged survival. The advantage of plexusblock is that it produces fewer complicationsrelated to narcotic use, namely, constipation,nausea, and vomiting. Although no controlledtrial has tested the efficacy of celiac plexus block


against oral pharmacologic therapy, the currentbias is that celiac block provides better pain control.

If oral analgesia is used to control pancreaticcancer pain, the type and dose of medicationshould depend on the severity of pain. Forexample, mild pain may be controlled with anacetaminophen (325 mg)-oxycodone (5 mg) com-bination, one or two tablets every 4 to 6 hours,whereas more severe pain may require a slow-release morphine compound, usually starting ata dose of 30 mg twice daily and increasing to a doseas high as 600 mg twice daily to achieve pain con-trol. A short-acting liquid morphine compoundmay be useful to control breakthrough pain.Alternatively, a fentanyl (Duragesic) patch, 25 to100 μg per hour, is effective for some patients.

Exocrine Pancreatic InsufficiencyPatients with cancer of the pancreatic head whohave weight loss and stools suggestive of malab-sorption should receive treatment with pancreaticenzymes. Available data suggest that pancreaticsteatorrhea can be corrected with pancreaticreplacement therapy. Our practice has been to pre-scribe pancreatin (Viokase), 8 tablets with meals(2 tablets after a few bites, 4 during the meal, and2 at the end of the meal), to correct steatorrhea.

Chemotherapy and Radiotherapy

ChemotherapyNo single or combination chemotherapy is highlyeffective for pancreatic cancer. Only 5-fluorouracil(5-FU) and gemcitabine have been associated withsurvival longer than 5 months. 5-FU has beenadministered as a bolus or short-term continuousinfusion or protracted infusion to treat manytumors. However, protracted infusion of 5-FU incombination with other chemotherapeutic agentsdoes not appear to be advantageous. Gemcitabinehas a low objective response rate and, comparedwith 5-FU, a small statistically significant improve-ment in overall survival (5.7 vs 4.4 months). One-year survival with gemcitabine treatment is 18%,compared with 2% for 5-FU.

RadiotherapyRadiation is used in two situations. 1) It is used as

adjuvant therapy after resection for cure. Untilrecently, the only randomized trial showed thatradiotherapy in combination with 5-FU had a 2-year actuarial survival rate of 43% compared withan 18% rate for the control group (resection only).However, a recently published European studyfound no significant advantage for radiotherapy.Although this was the largest randomized trial inthe postsurgical adjuvant setting (n=541), designflaws of the study led to serious criticism and lim-ited adoption of its conclusion. External beamradiation with 5-FU is the standard of care foradjuvant therapy in most US centers. 2) In unre-sectable locoregional pancreatic cancer, combinedchemoradiation therapy, with 5-FU and radiation,has been shown to be superior to radiation alone,with a median survival of 42 versus 23 weeks.

CYSTIC PANCREATIC TUMORS

Serous CystadenomaClassically, the presentation of these tumors isdescribed as large, sometimes palpable, asympto-matic upper abdominal masses, but in our expe-rience, they more frequently are small lesions inthe head, body, or tail of the pancreas that are dis-covered incidentally on imaging studies (Fig. 4).They occur equally in males and females and con-stitute up to 10% of all cystic lesions of the pancreas.Histologically, the tumors consist of multiple tinycysts that contain watery fluid. When observed onimaging studies, the grapelike clustering of smallcysts led to the name “microscopic” to describeserous cystadenomas. Their cut surface shows atypical stellate scar (which is also evident onimaging). The malignant potential is almost zero(only a few case reports of malignancy have beenpublished), and in elderly asymptomatic patients,these tumors frequently are only observed.

Mucinous Cystadenoma andCystadenocarcinomaThese tumors occur almost exclusively in women40 to 60 years old. They account for 1% to 2% of allpancreatic exocrine tumors. Foci of malignancy inmany of the cysts and reports of patients with osten-sibly benign resected cystadenomas later presentingwith metastatic disease have led to the concept that


these lesions have a moderate malignant poten-tial. Recent surgical series have shown the impor-tance of size: mucinous cystadenomas smaller than5 cm have a low potential for harboring invasivecancer. The tumors consist of multiple cysts (largerthan those in serous cystadenomas and sometimesreferred to as “macrocystic”) containing stickymucus. As with serous cystadenomas, these lesionsare often identified as a small cystic lesion inpatients having CT for another reason.

Intraductal Papillary Mucinous TumorThis group of tumors, originally described in Japan,consists of intraductal papillary growth of mucin-producing columnar epithelium. These changescan occur in the main pancreatic duct or in sideducts and may involve a small portion of the pan-creas or the entire gland. As a consequence of thesechanges, obstructive pancreatitis frequently occurs,with atrophy of the gland. Malignant transformationof the papillary growth occurs in up to 30% to 50%of patients at the time of diagnosis, when the mainpancreatic duct is involved. Because of this highrate of invasive cancer in main-duct intraductalpapillary mucinous tumor, surgical resection isrecommended. Early diagnosis is essential; onceinvasive cancer develops, one-half of the patients

will have local or distant metastases at the time ofsurgical resection. The malignant potential of side-branch intraductal papillary mucinous tumorappears to be much lower, and the long-term riskis unknown. When to recommend surgical resec-tion (especially when a Whipple resection isrequired) is more controversial.

Frequent clinical presentations include recur-rent episodes of pancreatitis, abdominal pain, orsteatorrhea. Jaundice and diabetes mellitus are lesscommon. The diagnosis is suspected when adilated pancreatic duct or side ducts are seen onCT. The chief differential diagnosis is chronic pan-creatitis. At endoscopic retrograde cholangiopan-creatography (ERCP), about one-half of the patientshave the diagnostic finding of a patulous papillaextruding mucus. EUS may be helpful in makingthe diagnosis, and with less risk than ERCP. Inaddition, EUS can help exclude main-duct involve-ment and aid the clinician in assessing the risk ofmalignancy for the patient.

Solid-Cystic (Papillary-Cystic) TumorThis tumor, which has various names, has astriking female predominance and usually occursin adolescence. The histogenesis is unclear, buthistologically, pseudopapillary and microcysticchanges are present. Most patients present withabdominal pain. The treatment for these often largetumors is excision. The prognosis is good, and mostof the tumors can be considered benign, but occa-sionally metastatic disease occurs.

Approach to Small, Incidentally ObservedCystic Tumors of the PancreasWhen cystic tumors of the pancreas are small, CTand ultrasonography may not be able to resolvethe nature of the cyst. The differential diagnosisincludes benign congenital cysts, small pseudocysts,intraductal papillary mucinous tumor (especiallybranch duct), mucinous cystadenoma, serous cys-tadenoma, and degenerating endocrine or ductaladenocarcinomas. EUS has an important role indefining its structure. For example, what mayappear to be a unilocular simple cyst on CT may beseen on EUS to be a complex cyst with septations.Although aspiration of the cyst is a simple proce-dure, it is not clear whether analysis of the cysticfluid for carcinoembryonic antigen or mucin and


Fig. 4. Computed tomogram showing a serous cyst.The mass lesion in the head of the pancreas consistsof multiple small cystic lesions (arrow). The findingsare typical of serous cystadenoma.

cytologic examination for malignancy alter thedecisions about management for most patients.

Generally, if the nature of a cyst cannot be deter-mined precisely, the practice is to observe the cystand to perform imaging studies at regular intervalsto ensure that it is not rapidly increasing in size.Many of these incidentally found cysts meet theclinical and imaging criteria for branch-duct intra-ductal papillary mucinous tumor. Recently, an inter-national consensus on management was publishedand recommended careful follow-up with imagingfor asymptomatic peripheral cysts 3 cm or smaller.

ACKNOWLEDGMENTJonathan E. Clain, MD, is gratefully acknowledgedas author of this chapter in the first edition of thebook (parts of which appear in this edition).

RECOMMENDED READINGAlexakis N, Halloran C, Raraty M, Ghaneh P,

Sutton R, Neoptolemos JP. Current Standardsof Surgery for Pancreatic Cancer. Br J Surg2004;91:1410-27.

Brugge WR, Lauwers GY, Sahani D, Fernandez-delCastillo C, Warshaw AL. Cystic neoplasms ofthe pancreas. N Engl J Med. 2004;351:1218-26.

DiMagno EP, Reber HA, Tempero MA, AmericanGastroenterological Association. AGA tech-nical review on the epidemiology, diagnosis,and treatment of pancreatic ductal adenocar-cinoma. Gastroenterology. 1999;117:1464-84.

Jacobson BC, Baron TH, Adler DG, Davila RE, EganJ, Hirota WK, et al, American Society forGastrointestinal Endoscopy. ASGE guideline:the role of endoscopy in the diagnosis andthe management of cystic lesions and inflam-matory fluid collections of the pancreas.Gastrointest Endosc. 2005;61:363-70.

Pearson RK, Clain JE, Longnecker DS, Reber HA,Steinberg WM, Barkin JS, et al. Controversiesin clinical pancreatology: intraductal papil-lary-mucinous tumor (IPMT): AmericanPancreatic Association Clinical Symposium.Pancreas. 2002;25:217-21.

Tanaka M, Chari S, Adsay V, Fernandez-delCastillo C, Falconi M, Shimizu M, et al,International Association of Pancreatology.International consensus guidelines for man-agement of intraductal papillary mucinousneoplasms and mucinous cystic neoplasmsof the pancreas. Pancreatology. 2006;6:17-32.

Yang GY, Wagners TD, Fuss M, Thomas CR Jr.Multimodality approaches for pancreaticcancer. CA Cancer J Clin 2005;55:352-67.


Gallstones are extremely common, occurring in 10%to 20% of women and 5% to 10% of men in Westerncultures. They generate an enormous medical andfinancial burden. More than 500,000 cholecystec-tomies are performed each year in the United States.Therefore, an understanding of the physiology, pre-sentation, and efficient approaches to managementis important. Optimal clinical approaches varyconsiderably, depending on the presentation.

BILE PHYSIOLOGYThe major components of bile are water, inorganicsolutes, and organic solutes. The organic solutesinclude miscellaneous proteins, bilirubin, bile acids,and the biliary lipids. Bilirubin is a degradationproduct of heme and usually is present as conju-gated water-soluble diglucuronide. The unconju-gated form of bilirubin precipitates, contributingto pigment or mixed cholesterol stones. Bile acids arebipolar water-soluble molecules synthesized fromcholesterol. When present above the critical micellarconcentration, bile acids self-associate to formmicelles capable of solubilizing hydrophobic lipidmolecules in bile or intestinal chyme. The primary

function of micelles is to facilitate fat digestion andabsorption. The primary bile acids (cholic and chen-odeoxycholic acids) are made in the liver. They areconverted to secondary bile acids (deoxycholic andlithocholic acids) by bacteria in the gut. The majorbiliary lipids, cholesterol and lecithin (phospho-lipid), are insoluble in water. They are secreted intobile as lipid vesicles and are carried in both vesiclesand mixed micelles.

In health, the gallbladder concentrates biletenfold for efficient storage during fasting.Intraduodenal protein and fat release cholecys-tokinin, which stimulates contraction of the gall-bladder, relaxation of the sphincter of Oddi, andflow of bile to the intestine. More than 90% of bileacids are actively absorbed in the terminal ileum.This enterohepatic circulation cycles 4 to 12 timesper day, slowing during fasting and acceleratinggreatly after meals (Fig. 1).

GALLSTONE PATHOGENESIS ANDEPIDEMIOLOGYGallbladder stones are made predominantly ofcholesterol in 80% of patients and of bilirubin

485

CHAPTER 38

Gallstones

Bret T. Petersen, MD

Abbreviations: CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopicultrasonography; MRCP, magnetic resonance cholangiopancreatography.

pigment in 20% (Fig. 2). Cholesterol stones containa mixture of 50% to 99% cholesterol by weight, aglycoprotein matrix, and small amounts of calciumand bilirubin. Development of overt stones requiresthree critical defects related to bile saturation,crystal nucleation, and gallbladder motility.

Cholesterol supersaturation can occur as a resultof deficient secretion of bile acid or hypersecretionof cholesterol. Bile acid secretion may be diminishedbecause of reduced synthesis, as occurs with age orliver disease, or because of reduced enterohepaticcirculation, as occurs with motor disorders, hor-monal defects, and increased gastrointestinal lossesfrom bile acid sequestrant therapy or terminal ilealdisease, resection, or bypass. Cholesterol secretionis increased with hormonal stimuli (female sex,pregnancy, exogenous estrogens, and progestins),obesity, hyperlipidemia, age, chronic liver disease,and sometimes with excessive dietary polyunsatu-rated fats or calorie intake.

In a supersaturated environment, the initialformation of gallstone crystals occurs as a result

of an excess of nucleating versus antinucleatingeffects of the various proteins in bile.

Gallbladder dysmotility results in inadequateclearance of crystals and nascent stones. Motilityis reduced in the presence of supersaturated bileeven before stone formation. Reduced motility is adominant contributing factor to stone developmentduring pregnancy, prolonged total parenteral nutri-tion, somatostatin therapy, or somatostatinoma.

The prevalence of cholesterol gallstones varieswith geography and ethnicity. They are rare inpopulations of Africa and most of Asia, arecommon in most Western populations (15%-20%in women, 5%-10% in men), and occur almost uni-formly in North and South American Indians (70%-90% in women). For all populations, the prevalenceincreases with age and is approximately twice ashigh in women as in men.

Black and brown pigment stones are a result ofincreased amounts of unconjugated insolublebilirubin present in bile, often because of infectionor hepatic secretion. Black stones originate in the


Systemiccirculation

Synthesis(0.2-0.6 g/day)

Urinaryexcretion

(<0.5 mg/day)

Biliary Secretion = Pool x Cycles(12-36 g/day) = (~3 g) x (4-12 /day)

Jejunum

Ileum

Colon

Fecal excretion(0.2-0.6 g/day)

Portal venous return(>95% of biliary secretion)

Fig. 1. Enterohepatic circulation. A pool of 3 g of bile acids cycles 4 to 12 times per day. Ileal absorption returns97% of intraluminal bile acids to the circulation. Ninety percent of bile acids are extracted from the portalsystem on their first pass through the liver. In health, hepatic synthesis of bile acids is equivalent to entericlosses. (Modified from Zucker SD, Gollan JL. Physiology of the liver. In: Haubrich WS, Schaffner F, Berk JE,editors. Bockus gastroenterology. Vol 3. 5th ed. Philadelphia: WB Saunders Company; 1995. p. 1858-1904. Usedwith permission.)

gallbladder. They are small, irregular, dense, andinsoluble aggregates or polymers of calcium biliru-binate. They may occur with cirrhosis or chronichemolysis but usually have no identifiable cause(Fig. 3). Brown pigment stones occur primarily inthe bile ducts, where they are related to stasis andchronic bacterial colonization—as may occur abovestrictures or duodenal diverticuli, after sphinc-terotomy, or in association with biliary parasites.Brown stones are 10% to 30% cholesterol. They aresofter than black pigment stones and may soften ordisaggregate with cholesterol solvents (Fig. 4).

BILIARY IMAGINGNumerous methods are available for imaging thebiliary tree. Some are used primarily to assess thegallbladder or the bile ducts, and others provide amore general assessment of the abdomen, as inpatients with undefined pain.

Abdominal Plain RadiographyAbdominal plain radiography detects only 10% to15% of gallstones, which are calcified sufficiently toappear radiopaque (Fig. 5). Abdominal radiographyalso may detect aerobilia and porcelain gallbladder.

Gallstones 487

Fig. 2. Variations in morphologic findings of cholesterol gallstones. A, Nearly pure 97% cholesterol crystallinestone on a pigmented central nidus. B, Pure 99+% cholesterol stone in the conformation of a mothball. C, Facetedcholesterol stones with an external shell of black pigment and calcification. D, Several morphologic features ofmixed, predominantly cholesterol stones from one patient.

A B

C D

Air within the biliary tree implies the presence ofa previous biliary sphincterotomy, a biliary-entericanastomosis or fistula, or an incompetent sphincter,as may occur with duodenal Crohn’s disease, duo-denal diverticuli, or other periampullary disease.Porcelain gallbladder refers to radiographicallydetectable deposition of calcium within the gall-bladder wall. It has a considerable association withprogression to gallbladder cancer and, thus, is anindication for elective prophylactic cholecystectomy.

Oral CholecystographyOral cholecystography involves standard radio-graphic imaging of the right upper quadrant afteroral administration of a contrast agent (Fig. 6).Normal imaging during oral cholecystographynecessitates ingestion, intestinal absorption, liveruptake, biliary excretion, and gallbladder concen-tration of an iodinated radiodense contrast agent.Sixty to eighty percent of gallbladders opacify aftera single oral dose, and 85% to 90% opacify after asecond or double dose. Nonvisualization of thegallbladder after a reinforced 1- or 2-day study is95% predictive of gallbladder disease. The use oforal cholecystography in clinical practice hasdiminished because it is less sensitive (65%-90%)than ultrasonography for gallbladder stones andit is not indicated when acute cholecystitis is sus-pected. It may be useful when ultrasonographyfails to image the gallbladder or fails to demon-strate stones despite a strong clinical suspicion and

for demonstrating cystic duct patency in potentialcandidates for nonsurgical therapies.

Transabdominal UltrasonographyTransabdominal ultrasonography is the first choicefor evaluation of jaundice and right upper quadrantpain and when cholangitis or cholecystitis is sus-pected, because it is portable, requires no specificpreparation, and uses no radiation (Fig. 7). Theexaminations are analogous to a physical examina-tion and, hence, are somewhat subjective and oper-ator-dependent. They are compromised by obesityand interfering shadows caused by, for example,ribs, scars, and bowel gas. Ultrasonography ishighly sensitive for dilated ducts; however, ductsmay be normal in 25% to 35% of patients withcholedocholithiasis, particularly when the pre-sentation is acute or associated with biliary fibrosis.The sensitivity of ultrasonography for identifica-tion of common duct stones is widely variable(20%-80%). It is most sensitive (90%-98%) for thedetection of gallbladder stones that are identifiedas mobile, intraluminal, echogenic, shadowingparticles. Cholecystitis is identified by gallbladdercontraction or marked distention with surrounding


Fig. 3. Black pigment gallstones are formed primarilyin the gallbladder and made of dense and insolublepolymers of calcium bilirubinate. They constitute20% of gallbladder stones. Although associated withincreasing age, cirrhosis, and hemolysis, they usuallyare idiopathic.

Fig. 4. Brown pigment gallstones are formed in theducts as primary duct stones. They are composed ofcalcium bilirubinate and about 30% cholesterol. Theyare softer and more amorphous than cholesterol orblack pigment stones and are associated with strictures,stasis, duodenal diverticuli, and infection. Here, abrown stone is seen in the lumen of the duodenumafter extraction, with endoscopic retrogradecholangiopancreatography, from the bile duct.

Gallstones 489

Fig. 5. Abdominal plain radiography. A, Radiopaquegallstones; 15% are detected on plain radiography and50% on computed tomography. No relationship tosymptoms. B, Radiopaque bile. So-called milk-of-calcium bile (arrow) is attributed to chronic gallbladderobstruction and is likely related to symptoms whenseen. Here, it is seen below four radiopaqueobstructing stones. C, Aerobilia (arrows), indicative ofpast sphincterotomy or biliary-enteric anastomosis orfistula. It is sometimes seen with Crohn’s disease,diverticula, or other periampullary disease.

A

C

B

Fig. 6. Oral cholecystography. Floating cholesterolgallstones layering at interface of contrast and bile.

fluid or wall thickening. Gallbladder thickeningalso may be due to portal hypertension, ascites,and hypoalbuminemia.

Endoscopic UltrasonographyEndoscopic ultrasonography (EUS) is highly sensi-tive for intraductal stones and slightly less so forgallbladder stones, depending on anatomy. It is anoptimal screening tool when the suspicion for bileduct stones is low to moderate, endoscopic exami-nation of the upper gut is also needed, other extra-luminal questions exist, or the expense and risk ofendoscopic retrograde cholangiopancreatography(ERCP) are unacceptable. Compared with magneticresonance cholangiopancreatography (MRCP) andERCP, EUS is the most cost-effective first study forsuspected stones when the pretest probability is lessthan 55% to 60%. ERCP becomes cost-effective abovethis level, which largely includes only patients withdistinctly abnormal liver enzyme values. EUS alsocan identify gallbladder sludge and microlithiasisin symptomatic patients with negative transab-dominal ultrasonographic findings. Patients must besafe candidates for both endoscopy and sedation.

Radionuclide Biliary ScanningRadionuclide biliary scanning, or hepatobiliaryiminodiacetic acid scanning, involves noninvasivescanning of gamma emissions after intravenousadministration, liver uptake, and biliary excretionof technetium iminodiacetic acid derivatives.Failure to visualize the gallbladder by 4 hours afterinjection is indicative of obstruction of the cysticduct. The primary clinical indication is for the diag-nosis of acute cholecystitis. Nonvisualization ofthe gallbladder is 97% sensitive and 96% specific foracute calculous cholecystitis. False-negative resultsoccur in acalculous cholecystitis, whereas false-positive results occur in chronic cholecystitis, inchronic liver disease, and during total parenteralnutrition or fasting states. The test is also useful

for noninvasive confirmation of intra-abdominalbile leakage.

Abdominal Computed TomographyAbdominal computed tomography (CT) is the bestimaging method for the evaluation of possiblecomplications of biliary stone disease if ultra-sonography is compromised or suboptimal, as inpatients with fever, right upper quadrant pain,and associated jaundice (Fig. 8). Bowel gas andribs do not interfere, and CT is better than ultra-sonography for obese patients, in whom imagingis improved by discrete fat planes. The test is notappropriate for the diagnosis of uncomplicatedstone disease or evaluation of biliary colic, becausehalf of all gallstones are radiolucent on CT.


Fig. 7. Gallbladder ultrasonography. A, Shadowing, mobile, echodense gallstones in a normal lumen. B, Tightlypacked and less discrete stones in a contracted gallbladder. C, Gallbladder sludge composed of cholesterolcrystals and mucus and seen during prolonged gallbladder stasis, as with total parenteral nutrition or duringpregnancy. D, Thick, edematous gallbladder mucosa sometimes seen with acute cholecystitis, portalhypertension, ascites, or hypoalbuminemia.

AB

C D

CholangiographyCholangiography can be performed either inva-sively or noninvasively. The selection of percuta-neous transhepatic cholangiography, ERCP, orMRCP is based largely on institutional expertise,therapeutic goals, and the clinical setting.

Endoscopic RetrogradeCholangiopancreatographyERCP is favored in patients with ascites or coagu-lation defects, suspected periampullary or pan-creatic neoplasia, nondilated ducts, anticipatedneed for therapeutic maneuvers (stone removaland stenting), hypersensitivity to contrast agents,or failure of percutaneous routes (Fig. 9). Purelydiagnostic use is diminishing rapidly because EUSand MRCP serve this purpose more safely in mostpatients. ERCP is successful in more than 95% ofdiagnostic applications, 90% to 95% of sphinc-terotomies and complete stone extraction, and 90%of procedures for stenting of malignant obstruction.The overall risk of the test in patients with suspectedgallstones is 2% to 7% for diagnostic proceduresand 7% to 10% for therapy. Risks include death,pancreatitis, infection, sedation or cardiovascularevents, hemorrhage, and perforation.

Percutaneous TranshepaticCholangiographyPercutaneous transhepatic cholangiography may befavored in patients with more proximal obstruction(hilar or above), surgically distorted gastroduodenal

anatomy (especially Roux limbs, but also Whippleor Billroth II anatomy), and after failure of pre-vious ERCP. It is almost uniformly successful inpatients with dilated ducts and in 75% to 95% ofthose with nondilated ducts. The overall risk is 3%to 8% and includes death, sepsis, bile leaks, andintraperitoneal bleeding.

Magnetic ResonanceCholangiopancreatographyMRCP is favored in frail patients who are not can-didates for conscious sedation and in those withcoagulopathy or a need for concurrent staging orevaluation of the liver parenchyma or other organs,especially when there is little likelihood for thera-peutic intervention.

GALLSTONE CLINICALPRESENTATIONS ANDMANAGEMENTAsymptomatic gallstones are a common incidental dis-covery in the course of various abdominal imagingprocedures. Gallstones remain asymptomatic long-term in 70% to 80% of patients. When gallstoneseventually become symptomatic, only 2% to 3%of patients present initially with acute cholecys-titis or other complications. Asymptomatic stonesgenerally do not require therapy. However, pro-phylactic cholecystectomy should be considered forpatients before extended travel to remote areas (eg,Antarctica) and in American Indian populations, in

Gallstones 491

Fig. 8. Computed tomography of complicated biliary stone disease. A, Thickened gallbladder wall (arrow), asseen in the ultrasonogram in Figure 7 D. B, Emphysematous cholecystitis (arrow) due to Clostridium species andothers presents with toxicity as a medical and surgical emergency.

A B

whom the relative risk for stone-associated gall-bladder carcinoma is 20-fold higher than in thosewithout stones.

Cholecystectomy can be considered duringweight loss operations, even without existingstones, because the subsequent development ofstones can be anticipated. Cholecystectomy is notrecommended for patients with asymptomaticstones who have diabetes mellitus or sickle celldisease if they have usual access to medical care.

Biliary colic is a relatively specific form of painthat usually develops rapidly in the epigastrium orright upper quadrant and lasts longer than 15 min-utes but not longer than 4 to 6 hours. A completehistory is required to differentiate alternativecauses of pain. After symptoms develop, a similarpattern is likely to continue. The likelihood ofpatients experiencing a severe event or complica-tion is approximately 1% per year, prompting therecommendation for surgical therapy of sympto-matic stones. Histologically, most patients withrecurrent biliary colic have chronic cholecystitis.Patients with uncomplicated colic require episodicpain management and dietary moderation empha-sizing self-selection rather than strict exclusion of

fat or other food types. Laparoscopic cholecystec-tomy is now the standard and most widely usedtherapy. There is a “learning curve” of at least 10to 25 procedures, during which time the durationof the procedure and complications are consider-ably greater. The major risk is for serious ductinjuries, which occur in fewer than 1 in 400 cases.Open cholecystectomy is necessary in less than 5%of initial laparoscopic procedures. Conversionitself usually is not considered a complication butan appropriate change in technique based on intra-operative findings. The risk for conversion is higherwith acute cholecystitis.

Nonoperative therapy of gallbladder stonesis largely of historical interest. A general require-ment for all nonsurgical therapies is patency of thecystic duct, as determined with oral cholecystog-raphy or radionuclide biliary scanning. Stones thatare seen to float above a contrast layer during oralcholecystography are high in cholesterol and veryamenable to dissolution (Fig. 6). The major short-coming of all nonsurgical therapies is the potentialfor gallstone recurrence, which occurs in 10% to20% of patients per year and up to 40% to 60%overall for patients with multiple stones. Oral bileacid therapy with ursodeoxycholic acid (7-8 mg/kgper day) dissolves 30% to 80% of radiolucent stonesless than 15 mm in diameter over 6 to 24 months.Repeat cholecystography is performed after 6 to12 months, and therapy is discontinued if no dis-solution is evident or if overt rim calcification hasdeveloped. Side effects of therapy are infrequentand include diarrhea in 3% to 5% of patients.Extracorporeal shock wave lithotripsy is per-formed more commonly in Europe than in theUnited States. One machine has been approvedfor duct stone applications only, and no machinehas been approved in the United States for gall-bladder stones. Extracorporeal shock wavelithotripsy is generally safe and well tolerated.Success depends on fragmentation plus either pas-sage or dissolution of the resulting debris. Optimalresults are achieved with single radiolucent stonesless than 20 mm in diameter, for which clearanceis achieved in 70% to 95% after 12 to 24 monthsof full-dose bile acid therapy. Rapid dissolutionof gallstones over 6 to 12 hours can be accom-plished by delivery of a cholesterol solvent suchas methyl-tert-butyl ether into the gallbladder


Fig. 9. Endoscopic retrograde cholangiography.Contrast-filled bile duct demonstrates Mirizzi’ssyndrome, recognized by the unusual eccentricstricture in the mid duct, with nonvisualization ofthe cystic duct and gallbladder.

through a transhepatic catheter. Cholesterol stonesthat are radiolucent on CT are predictably soluble,independent of their size or number.

Complications of gallstone disease includeacute cholecystitis, Mirizzi’s syndrome, gallbladderperforation, cholecystoenteric fistulas, “gallstoneileus,” and gallstone or biliary pancreatitis.

Acute cholecystitis presents with biliary colic thatusually lasts longer than 4 to 6 hours and spreads toinvolve the parietal surfaces, with evolution from anonspecific visceral character to a more localizedright upper quadrant pain. There may be associatednausea, vomiting, jaundice, fever, and tenderness.The laboratory results are nonspecific and mayinclude leukocytosis and modest increases in amino-transferase, alkaline phosphatase, and amylaselevels. Management of acute cholecystitis includesadministration of antibiotics, hydration, analgesia,nasogastric suction as needed for comfort, andremoval or drainage of the obstructed gallbladder.Gallbladder decompression via percutaneous place-ment of a cholecystostomy tube is efficacious inpatients with substantial operative risk. After daysto weeks of antibiotic therapy and passive drainage,subsequent operative or nonoperative managementcan be pursued electively. Endoscopic drainage alsohas been described.

Mirizzi’s syndrome involves gallbladderobstruction plus obstructive jaundice from stoneimpaction in the distal cystic duct, with inflam-matory compression of the common hepatic duct.The clinical and cholangiographic findings must bedifferentiated from those of other benign andmalignant duct strictures. Treatment is generallysurgical, although endoscopic palliation withstenting and stone removal has been described.

Gallbladder perforation from stone-inducedinflammation generally is contained locally andrarely is free within the abdomen. Perforation withabscess formation occurs especially with minimallysymptomatic smoldering disease in elderly patients.

Cholecystoenteric fistulas can develop as a resultof gallbladder perforation and decompression intoany neighboring viscus. They usually involve theduodenum or the hepatic flexure of the colon.When fistulas develop to the colon, patients maypresent with new onset of watery bile acid diarrheaor cholangitis from colonic contamination of a dis-eased gallbladder.

Gallstone ileus results after the passage of astone through a fistula and subsequent obstruc-tion in a narrow downstream section of gut. Thisis most common in the terminal ileum. Gallstoneileus occurs especially in elderly women. The clin-ical presentation is that of intestinal obstructionwith aerobilia seen on plain radiography or CT.Management is surgical.

Gallstone or biliary pancreatitis manifests acutelyas a result of temporary stone impaction or traversalthrough the sphincter of Oddi. The best indicatorof a biliary cause is an acute increase in amino-transferase values (more than threefold) at initialpresentation. Corroborating findings include adilated bile duct and stones within the gallbladder.

CHOLEDOCHOLITHIASISMost bile duct stones originate in the gallbladder,and 5% to 15% of patients undergoing cholecys-tectomy have concurrent duct stones. Coexistentduct and gallbladder stones generally have thesame composition: 70% are cholesterol stones and30% are pigment stones. Primary duct stones arebrown pigment stones, which differ from thesmaller, harder, black pigment stones found inthe gallbladder.

The presentation of duct stones varies andranges from few or no symptoms to overt cholan-gitis or pancreatitis. The development of secondarybiliary cirrhosis related to ductal pressure rarelyoccurs in the absence of clinical symptoms or lab-oratory abnormalities. Classically, stone-relatedobstruction is recurrent and incomplete. Increasesin bilirubin and alkaline phosphatase levels areless marked than those for fixed malignant obstruc-tion; the bilirubin level usually peaks at 12 to 14mg/dL. Ninety percent of obstructing duct stonesare located distally near the ampulla, where visu-alization with ultrasonography and CT is difficult.Definitive identification requires cholangiography.Once identified, duct stones should be removed,usually through ERCP with sphincterotomy.Extracorporeal shock wave lithotripsy of ductstones is clinically approved and feasible. It usuallyis coupled with ERCP removal of stone debris.Stones identified at operation can be removedthrough percutaneous T-tube tracts 4 to 6 weekspostoperatively. This is successful in 96% of

Gallstones 493

patients, and the morbidity rate is 4%. No primarydissolution therapy is available for common ductstones, although reports of softening or disag-gregation of brown pigment stones occasionallyprompts use of ursodeoxycholic acid beforeERCP is repeated.

Optimal management for healthy patientswith concurrent gallbladder and bile duct stonesis incompletely defined. Currently, the usual prac-tice combines therapeutic ERCP with laparoscopiccholecystectomy. Laparoscopic duct explorationis still not widespread, although data suggest it isassociated with lower morbidity and incurs lowercosts than postoperative ERCP.

Elective management of gallbladder stonesafter resolution of cholangitis and endoscopic clear-ance of duct stones is somewhat controversial.For high-risk patients, clearance of duct stonesalone often is adequate. Experience suggests rela-tive safety for observation alone. Biliary colic orcholecystitis that requires therapy subsequentlydevelops in 15% to 20% of patients. This risk jus-tifies prophylactic elective cholecystectomy inaverage-risk patients.

CHOLANGITISAcute bacterial cholangitis is due to infection inobstructed bile ducts. It is caused most commonlyby obstructing stones and occurs only infrequentlywith benign or malignant strictures. Charcot’s triad(fever and chills, jaundice, and abdominal pain)is present in perhaps 60% of cases. Diagnosis maybe difficult in elderly patients, who may not havejaundice or pain. Acute cholangitis is a medicalemergency when fever exceeds 40°C or is associ-ated with sepsis, hypotension, peritoneal signs, ora bilirubin concentration more than 10 mg/dL. CTor ultrasonography is supportive of the diagnosis.Most episodes are due to coliforms such asEscherichia coli, Klebsiella (70% of episodes),Enterococcus, and anaerobes (10%-15%). Initialtherapy includes empiric use of antibiotics,including broad-spectrum agents such as ampi-cillin plus an aminoglycoside, extended-spectrumpenicillins, or third-generation cephalosporins,with or without the addition of specific anaerobiccoverage. From 85% to 90% of patients have aresponse to initial antibiotic and supportive

therapy before biliary intervention. Biliarydrainage is mandatory, however. Its urgencydepends on the initial response to antibiotics andsupportive care. ERCP with nasobiliary drainplacement, stent, or sphincterotomy and ductclearance is associated with considerably lowermorbidity and mortality than traditional surgicalmanagement. If endoscopy fails to achieve access,subsequent percutaneous or surgical decom-pression should be pursued, depending on theclinical urgency.

Patients with recurrent pyogenic cholangitis, ororiental cholangiohepatitis, present with recur-rent, progressively severe, and frequent attacks ofcholangitis with associated extensive stone dis-ease, especially of the intrahepatic ducts. Secondaryduct dilation, stricture formation, and further stoneformation become self-perpetuating. This form ofcholangitis occurs especially in the Asian-Pacificbasin. The pathogenetic mechanism is not under-stood completely; however, postulated causesinclude primary congenital biliary strictures andcysts, biliary parasitic infection (Ascaris orClonorchis), and chronic intrahepatic bacterial col-onization from unclear sources. Therapy isdirected toward duct decompression, drainage,stone clearance, and occasionally lobar or seg-mental resection for isolated intrahepatic disease.Isolated unilateral intrahepatic involvement ismost common in the left hepatic ductal system.

BILIARY STRICTURESIatrogenic bile duct strictures develop after 1 in 200to 1 in 1,000 cholecystectomies. Presentation maybe months to years after the injury. When ductinjury is recognized intraoperatively, the idealmanagement is primary surgical repair withcholedochojejunostomy. When treated at firstpresentation with a surgical Roux-en-Y hepati-cojejunostomy, 85% to 90% of patients have goodlong-term results. Endoscopic therapy is nowcommon, however, and 75% to 85% of patientshave good results 5 to 10 years later. Recent serieshave reported better results with maximal cal-iber dilation and stenting for 6 to 12 months.Anastomotic bile duct strictures are treated muchlike other iatrogenic lesions, with endoscopic dila-tion and stenting when accessible.


Inflammatory bile duct strictures occur withprimary sclerosing cholangitis and acute orchronic pancreatitis. Those related to chronicfibrotic pancreatitis are best treated surgicallywith a biliary enteric anastomosis. Strictures fromacute pancreatitis usually can be palliated withendoscopic stenting until the acute inflammatoryphase resolves. The optimal management of pri-mary sclerosing cholangitis-related dominantstrictures is debated, but it generally involvesendoscopic balloon dilation with or without stentplacement rather than operation. Intervention isused only for stricture or stone-related clinicaldecline, such as cholangitis, pain, or jaundice.

Currently, most benign strictures of the extra-hepatic ducts are treated, at least initially, with endo-scopic balloon dilation and stenting. Indications forendoscopic or percutaneous treatment of biliarystrictures, in preference to surgery, include recur-rence after operative repair, poor operative risk,portal hypertension, high stricture with little or noproximal extrahepatic duct (type 3 or 4), absence ofproximal dilation, dominant stricture of primarysclerosing cholangitis (potential liver transplanta-tion), and short-term palliation of acute or chronicpancreatitis-induced stricture.

ELUSIVE BILIARY-TYPE PAINSYNDROMESWhen patients present with recurrent right upperquadrant pain, often subsequent to cholecystec-tomy, several potential causes must be considered.

Nonbiliary sources of pain, such as functionalor irritable bowel syndrome, nonulcer dyspepsia,gastroesophageal reflux, pancreatic disease, oreven cardiac disease, may present with featuressuggesting a biliary source. When treated withcholecystectomy, they typically recur. Diagnosisis largely through careful history and selective useof diagnostic testing.

Gallbladder dyskinesia, sometimes termed cysticduct syndrome in the surgical literature, refers to apoorly contractile gallbladder as demonstratedwith cholecystokinin-stimulated radionuclide bil-iary scanning or ultrasonographic volumetricstudies. The pathogenesis of pain is not known,but it may be related to a diseased gallbladder wallor a small duct relative to gallbladder size. Data

suggest that cholecystectomy affords pain reliefto patients with markedly diminished stimulatedejection fractions. Reproducibility of testing hasbeen demonstrated only for gallbladder contrac-tions with the use of weight-based infusions of chole-cytokinin rather than bolus injections or alternativemeans of stimulation.

Microlithiasis refers to the presence and symp-tomatic passage of small crystalline aggregates orstones that go undetected on ultrasonography. Apatient’s stone-forming disposition can be inferredfrom the identification of cholesterol crystals orcalcium bilirubinate aggregates during polarizedmicroscopy of a centrifuged bile pellet (Fig. 10).Positive microscopy findings are considered anindication for cholecystectomy, or for sphinctero-tomy if the gallbladder has already been removed;however, microlithiasis is uncommon in this set-ting. Sludge or microlithiasis may be demonstrablealso with EUS when transabdominal imagingresults are normal.

Sphincter-of-Oddi dysfunction refers to a con-tinuum of stenosing or hypertonic abnormalities ofthe biliary or pancreatic sphincter. It is presump-tively diagnosed on the basis of specific symptomsand laboratory criteria. Type I is sometimes referredto as papillary stenosis. Features include pain,dilated ducts, pain-associated aminotransferaseabnormalities, and delayed drainage duringcholangiography. It can be treated with sphinc-terotomy without previous confirmatory tests.Type II features pain and one or two of the asso-ciated features of type I. Type II is commonlyconfirmed manometrically before therapy by thedemonstration of intercontractile resting sphincterpressures of more than 40 mm Hg. Semiempiricalsphincterotomy probably can be justified forpatients with classic recurrent short-lastingincreases in aminotransferase levels during pain.Presumptive type III is associated with pain aloneand none of the more objective supporting fea-tures. Type III should not be investigated withmanometry before a thorough search is made foralternative causes of pain and trials of medical ther-apies directed toward functional syndromes arecompleted. ERCP should not be performed toexclude stones or other abnormalities without theavailability of manometry. Hence, EUS or MRCPmay be preferable early investigations in most

Gallstones 495

patients. It should not be treated with sphinctero-tomy in the absence of abnormal manometryresults. Manometry results are abnormal in 15%to 60% of patients, depending on selectivity oftesting, and response to sphincterotomy is about70% in patients with abnormal pressures.

BILIARY LOOK-ALIKESIntravenous ceftriaxone may lead to the formationof crystalline biliary precipitates of drug.Ceftriaxone crystals can induce all potential com-plications of small bile duct stones, including biliarycolic and pancreatitis.

Erythromycin hepatotoxicity presents as a syn-drome of pain, fever, and cholestatic hepatitis,which mimics acute cholecystitis. It is importantto elicit an antibiotic history during an evaluationof symptoms. A consistent history and associatedeosinophilia may assist in identifying the syndrome.

Leptospirosis has a severe form termed Weil’ssyndrome, which is characterized by fever, jaun-dice, azotemia, and right upper quadrant pain.The presentation may mimic that of acute bac-terial cholangitis. Clues to the diagnosis include ahistory of exposure risk, myalgias, ocular pain,photophobia, azotemia, and abnormal urinalysisfindings.


Fig. 10. Polarized microscopy of bile. A and B, Microscopic examination of sediment after centrifugation of bileshows birefringent rectangular notched crystals. Their identification confirms stone-forming physiology and thepotential for an association between gallstones and the patient’s symptoms. In B, the amorphous golden materialis aggregated bilirubinate salts, which may occur with cholesterol crystals or alone. They also indicate a stone-forming propensity.

A B

497

Pancreas and Biliary Tree


QUESTIONS

Abbreviations used:ALT, alanine aminotransferaseAST, aspartate aminotransferaseCT, computed tomographyERCP, endoscopic retrograde cholangiopancre-

atographyEUS, endoscopic ultrasonographyMEN, multiple endocrine neoplasiaMRI, magnetic resonance imagingTPN, total parenteral nutrition

Multiple Choice (choose the best answer)1. A 29-year-old man is referred for recurrent

episodes of pancreatitis. His first episode ofpancreatitis occurred at age 10 years. Hisattacks occur once a year and lead to hospi-talization for a week. In between episodes, hedoes not experience any discomfort. So far, hehas not had any complications. On furtherquestioning, he states that his father andpaternal aunt have also had pancreatitis andhave undergone pancreatic surgery. He hassmoked a pack of cigarettes a day for the past10 years, but only occasionally consumesalcohol. ERCP at an outside institution showeda 6-mm pancreatic duct without strictures,with multiple dilated side branches. The mostlikely cause of pancreatitis in this patient is:

a. Cationic trypsinogen gene mutationb. Heterozygous SPINK1 gene mutation

c. Heterozygous CFTR gene mutationd. Von Hippel-Lindau gene mutatione. Gallstone pancreatitis

2. A 40-year-old man who has been drinkingapproximately 5 cans of beer/day for thepast 15 years is admitted with complaints ofnausea, vomiting, and abdominal pain. Onexamination, he is afebrile and in no acutedistress. Abdominal examination shows ten-derness in the upper abdomen. Laboratoryfindings include amylase >10 times the upperlimit of normal. This is his fourth bout of pan-creatitis in 5 years. Which of the followingwould not strongly suggest the diagnosis ofchronic pancreatitis?

a. A dilated pancreatic duct with glandularatrophy

b. Scattered calcification in the body and tailof the pancreas

c. EUS performed 3 months after the attackshowing lobularity of the parenchyma andhyperechoic foci (2 of 9 criteria)

d. Fecal fat estimation on a 100-g fat dietshowing 40 g of fat per day

e. Pancreatic exocrine glandular fibrosis andatrophy found on surgical biopsy

3. A 45-year-old woman who had gastric bypasssurgery 6 months ago presents with complaintsof greasy, oily stools associated with a 20-lbweight loss. She has a voracious appetite but

hesitates to eat because it worsens her diar-rhea. She has no history of pain or pancre-atitis. She has never consumed alcohol orsmoked tobacco. Her family history is non-contributory. A 72-hour stool fat collectionon a 100-g fat diet showed 70 g of fat per day.Serum calcium and triglyceride levels werenormal. Which of the following does notresult in inadequate production or action ofpancreatic enzymes?

a. Severe villous atrophy associated with celiacsprue

b. Autoimmune pancreatitisc. Roux-en-Y gastric bypass surgeryd. Zollinger-Ellison syndromee. α1-Antitrypsin deficiency

4. A 23-year-old female college student pre-sents with severe, constant abdominal pain,nausea, and vomiting which began 3 daysago. She previously has been well. Duringthe last 8 years, her alcohol consumption hassteadily increased to “several drinks a day.”The serum level of amylase is increased morethan 7 times normal. Liver function tests arenormal. The serum triglyceride level isinceased at 620 mg/dL. Which of the fol-lowing statements is most correct?

a. A serum lipase level is needed to confirm thediagnosis of acute pancreatitis

b. Amylase levels more than fivefold normalpredict severe pancreatitis

c. The increased serum triglyceride level sug-gests pancreatitis due to hyperlipidemia

d. Three days from the onset of symptoms,the serum lipase level is more likely to beincreased than the serum amylase level

e. Ultrasonography of the gallbladder thatshows no stone excludes biliary pancreatitis

5. A 46-year-old woman presents with severe,constant upper abdominal pain, fever, vom-iting, and new jaundice. She drinks one ortwo alcoholic beverages a week and neverhas been hospitalized except for the deliv-eries of her five children. Her serum amylase

and lipase levels are increased more than 5times normal. ALT is 412 U/L. She has beenreceiving broad-spectrum antibiotics sinceadmission, but she continues to have pain,fever, and vomiting. Which of the followingis the best course of action?

a. Urgent ERCP if ultrasonography shows acommon bile duct stone

b. Urgent ERCP if ultrasonography shows adilated bile duct

c. Urgent ERCP if a nuclear medicine scandoes not show excretion of contrast intothe duodenum

d. Urgent ERCP if altered mental status developse. Urgent ERCP

6. A 65-year-old man is admitted to the intensivecare unit with severe acute pancreatitis. Whichof the following is most predictive of severity?

a. His ageb. Gallstone pancreatitis as a causec. Persistent organ failured. Pulmonary infiltratese. C-reactive protein level greater than 150

mg/dL at 48 hours

7. A 65-year-old man is admitted to the hospitalwith severe acute necrotizing pancreatitis.After a few days, he is still unable to take ade-quate calories by mouth and still has someabdominal pain. Which of the following ismost likely to help him?

a. Enteral feeding by nasogastric tubeb. TPNc. Somatostatind. Broad-spectrum antibioticse. Enteral feeding by nasoduodenal tube placed

well beyond the pylorus

8. A 68-year-old man has a 3-month history of milddyspeptic symptoms and a 15-lb weight loss.Findings on upper endoscopy were normal. Sixweeks of proton pump inhibitor therapy hasnot produced any improvement. For 3 days, hehas had dark urine and pale stool. He was


brought to the emergency department by hisfamily when they noted scleral icterus. On phys-ical examination, he is comfortable and afebrilewith normal vital signs. He is visibly jaundiced,but the examination findings are otherwisenormal. Biochemical studies show a bilirubinlevel of 10 mg/dL (direct, 6 mg/dL) and athreefold increase in the aminotransferase andalkaline phosphatase levels. Bedside ultra-sonography shows gallstones and a dilated biliarytree. Which of the following is the best option?

a. Immediate admission to the hospital forobservation and blood cultures

b. Urgent ERCP and bile duct decompressionc. Viral serologic testing, stop proton pump

inhibitor therapy, and refer to a hepatologistd. Contrast-enhanced CT of the abdomene. Referral to a surgeon for cholecystectomy

9. Which of the following is most correct aboutneuroendocrine tumors of the pancreas?

a. Nearly all the tumors are associated withMEN 1 syndrome

b. Other features of MEN 1 syndrome includepheochromocytoma

c. The most common peptide expressed ispancreatic polypeptide that causes awatery diarrhea

d. Nonfunctioning islet cell tumors accountfor at least 50% of the tumors

e. Neuroendocrine tumors associated withMEN 1 tend to be solitary and are rarelymalignant

10. A 45-year-old gravida 5 para 5 woman in oth-erwise good health has three discrete episodesof epigastric abdominal pain lasting 1 to 3 hours.Abdominal ultrasonography shows three gall-stones in the gallbladder. Which physiologicalteration most likely is not responsible for thegallstones in this patient?

a. Deficient secretion of bile acidb. Cholesterol supersaturationc. Imbalance of nucleating and antinucle-

ating factors

d. Relative gallbladder dysmotilitye. Excess bilirubin secretion

11. A 30-year-old African American man withsickle trait develops severe right upper quad-rant pain with vomiting. His pain lastsapproximately 4 hours. A plain film of theabdomen shows calcified densities in the gall-bladder. Which of the following statementsabout these densities is most likely correct?

a. They are brown pigmented stonesb. If surgery is not feasible, the patient would

benefit from treatment with ursodeoxy-cholic acid

c. They are black pigment stones, which arecomposed of calcium bilirubinate andaccount for 80% of common duct stones

d. Cirrhosis is a risk factor for these stonesthat contain less than 50% of cholesterol

e. Duodenal diverticula predispose to theformation of these stones

12. A 45-year-old woman has abdominal ultra-sonography for postprandial diarrhea andlower abdominal cramping relieved by defe-cation. Several 8-mm mobile stones are foundin a nondilated gallbladder. The bile ducts andliver function tests are normal. Which of thefollowing is most likely?

a. As she ages, the likelihood of symptomaticbiliary colic developing is 50%

b. Complications occur at a rate of 10% per yearc. Diabetes mellitus in the patient would war-

rant cholecystectomyd. Her lifetime risk of symptoms is 20%e. It is likely that her first presentation will be

pancreatitis

13. A 45-year-old woman undergoes laparoscopiccholecystectomy for classic biliary colic withmultiple gallbladder stones and a normal-cal-iber bile duct. Two days postoperatively, shehas recurrent pain, a tender abdomen,bilirubin 1.9 mg/dL, and normal AST, ALT,and alkaline phosphatase levels. CT shows anew intra-abdominal fluid collection, and


ERCP is “normal.” Which of the followingis the most likely cause of this patient’s post-operative problem?

a. Leaking hepatic segment with anomalousbiliary drainage

b. Acute pancreatitis with pseudocyst formation

c. A retained and now passed common bileduct stone

d. Dropped intraperitoneal gallstonee. Missed common bile duct stone

14. A 25-year-old woman presents with a 2-yearhistory of daily upper abdominal pain. Mostof the symptoms occur postprandially. Sherarely vomits and has had no weight loss.Physical examination findings are normal.An extensive series of studies, includingendoscopy and abdominal imaging withultrasonography and CT, have been nega-tive. Laboratory studies repeated 3 timesduring pain are normal except for a 1.5- to2.0-fold increase in the amylase level withnormal lipase level. Which of the followingis most likely?

a. This is a disease that accounts for 10% ofunexplained chronic abdominal pain

b. The clearance of amylase in the urine wouldbe low

c. A threefold increase in the serum amylaselevel would exclude this condition

d. ERCP would be indicated to diagnose earlychronic pancreatitis

e. The diagnosis of chronic pancreatitis is secure

15. A 29-year-old man presents with recurrentepisodes of pancreatitis that began at age 10years, and occur approximately once a year.He has no symptoms otherwise. His fatherand paternal aunt had pancreatitis thatrequired surgery. He rarely drinks alcohol butsmokes a pack of cigarettes daily. CT of thepancreas shows diffuse calcifications, andERCP shows an 8-mm pancreatic duct withmultiple dilated side branches. Which of thefollowing would be most appropriate?

a. Referral to a surgeon for Puestow procedureb. Genetic counseling and testing for cystic

fibrosis gene mutationsc. ERCP with sphincterotomy and pancreatic

duct stone clearanced. Yearly endoscopic ultrasonography and

CA19-9 testing for cancer screeninge. Genetic counseling and testing for cationic

trypsinogen gene mutations

ANSWERS1. Answer aThe history of early onset of pancreatitis and strongfamily history of pancreatitis are highly suggestiveof hereditary chronic pancreatitis. Mutations in thecationic trypsinogen gene (R117H and N21I) are themost common gene mutations associated with anautosomal dominant pattern of inheritance of pan-creatitis. Mutations in SPINK1 and CFTR genes areassociated with idiopathic pancreatitis. VonHippel-Lindau gene mutations are not associatedwith pancreatitis; these patients may have serouscystadenomas of the pancreas. Gallstone pan-creatitis does not cause chronic diffuse pancre-atic ductal abnormality.

2. Answer cChronic pancreatitis is a histologic diagnosis.However, this “gold standard” is rarely available.Thus, surrogate clinical markers are used to diag-nose chronic pancreatitis. In a patient with recur-rent pancreatitis, all of the following would stronglysuggest the diagnosis of chronic pancreatitis:

1. Histologic study shows features typical of usualchronic pancreatitis

2. Pancreatogram shows marked abnormalities(Cambridge II or III)

3. Calculi in the pancreatic duct are seen onplain radiographs of the abdomen, CT, MRI,or EUS

4. EUS shows ≥5 criteria (<5 criteria are nonspe-cific and cannot be used to diagnose chronicpancreatitis)

5. Pancreatic function is markedly depressed (pan-creatic steatorrhea)


3. Answer eDepressed pancreatic function occurs in severe celiacsprue. This is thought to result from lack of releaseof cholecystokinin from a severely affected duodenalmucosa. Pancreatic function recovers with recoveryof intestinal villous architecture. Autoimmune pan-creatitis is a fibroinflammatory disorder that cancause marked pancreatic atrophy and, consequently,pancreatic insufficiency. Gastric bypass surgery isintended to cause poor mixing of food and pancre-atic enzymes and bile. The common channel wherefood and pancreaticobiliary secretions mix is gen-erally about 100 to 150 cm from the ileocecal valve.The large amount of acid secreted in Zollinger-Ellisonsyndrome inactivates pancreatic enzymes. However,a large volume of gastric and pancreatic secretionsand mucosal injury due to acid overproduction alsocontribute to diarrhea in Zollinger-Ellison syndrome.α1-Antitrypsin deficiency is not known to affect pan-creatic function.

4. Answer dThe diagnosis of pancreatitis does not need to beconfirmed with a serum lipase level because thepresentation is typical and serum amylase level isincreased at least 2- to 3-fold normal. The degree ofincrease in the amylase or lipase level does not pre-dict the severity of acute pancreatitis. Her triglyc-eride level is not even in the range (>1,000 mg/dL)that would be suspicious for pancreatitis due tohyperlipidemia, and it would be necessary to checkit again after the acute pancreatitis resolves,because a modest increase due to pancreatitis fromother causes often improves or normalizes withresolution of the acute episode of pancreatitis.Normal gallbladder findings on ultrasonographynever exclude biliary pancreatitis. With acute pan-creatitis, the serum lipase level remains elevatedlonger than does the serum amylase level.

5. Answer eWith the lack of significant alcohol history, multiplepregnancies (risk for gallstones), and increased ALTlevel, this patient most likely has acute biliary pan-creatitis. Because of persistent fever, pain, and vom-iting as well as jaundice, despite antibiotic therapy, sheneeds urgent ERCP for cholangitis, even if ultra-sonography does not show ductal dilation or a stonein the common bile duct. Because of the acute pan-

creatitis and jaundice, a nuclear medicine scan isunlikely to be helpful. Waiting for further deteriora-tion (altered mental status) in the condition of thispatient, who has cholangitis, before performing ERCPis not justified.

6. Answer cThe cause of acute pancreatitis is not clearly a pre-dictor of severity. Age older than 60 years, a bodymass index greater than or equal to 30, veryincreased level of C-reactive protein, pleural effu-sion, and pulmonary infiltrates are all predictors ofseverity. Persistent organ failure as well as mul-tiple organ failure is among the strongest predictorsof severity.

7. Answer eAt this early stage, and in the absence of docu-mented infection, it is unlikely that antibiotictherapy will be helpful. Somatostatin has not beenshown to be helpful in this setting. Nasogastrictube feeding, similar to oral feeding, is not likely tobe tolerated. Nasojejunal, or (more often in practice)nasoduodenal, feeding is preferred to TPN becauseit is cheaper, helps preserve the gut mucosal bar-rier, and hence reduces the rate of infection, whichis higher with TPN.

8. Answer dThis patient has painless jaundice and does not needurgent ERCP or blood cultures in the absence ofcholangitis. Because the dilated ducts and clinicalpresentation do not support an intrahepatic cause,viral serologic testing is not likely to be helpful.Although ultrasonography shows gallbladdergallstones, the lack of pain argues against chole-docholithiasis as a cause of the jaundice; hence,cholecystectomy is not necessary. CT is likely toshow a mass lesion in the head of the pancreas thatwould account for this presentation, most likely pan-creatic adenocarcinoma.

9. Answer dMost neuroendocrine tumors of the pancreas arenot associated with MEN 1 syndrome, which doesnot include pheochromocytoma. Many neuroen-docrine tumors produce pancreatic polypeptide,but this hormone does not cause watery diarrhea.At least half of all islet cell tumors are nonfunctioning.


With MEN 1 syndrome, neuroendocrine tumorsare more often multifocal and invasive.

10. Answer eThis multiparous woman most likely has choles-terol-rich gallstones and not black (bilirubin) orbrown (pigment) stones. She is unlikely to haveexcessive hepatic secretion of bilirubin. She verywell could have some combination of the fol-lowing: deficient secretion of bile acid, cholesterolsupersaturation, gallbladder dysmotility, and animbalance of nucleating and antinucleating factorsin the bile.

11. Answer dThese calcified densities in the right upper quad-rant likely represent gallstones. In this patient, theyare black pigment stones, which are related tohemolysis as well as to cirrhosis; they form pri-marily in the gallbladder. Brown pigment stones,which calcify, usually form in the bile ducts andare related to stasis (duodenal diverticula) andinfection. Both black and brown stones, as well ascalcified cholesterol stones, do not dissolve readilywith ursodeoxycholic acid treatment.

12. Answer dThis patient’s symptoms are nonspecific and notlikely to be due to her gallstones. Her lifetime riskof symptoms is about 20%, with the risk of a more

serious event (cholecystitis, choledocholithiasis, orpancreatitis) much less than 1% per year. In theabsence of biliary symptoms, diabetes mellitus doesnot merit elective cholecystectomy.

13. Answer aThe clinical scenario and increased bilirubin levelstrongly suggest a bile duct leak, and the normalERCP findings suggest injury to an anomalous bileduct not detected with ERCP, such as a right poste-rior segment duct draining into the extrahepatic treeor near the cystic duct (or both).

14. Answer bThis patient most likely has macroamylasemia, asso-ciated with a low amylase clearance in urine becauseof its association with a macroglobulin in serum.Serum levels of amylase can be more than tenfoldnormal. This is not a common disorder.

15. Answer eThis patient’s history, including his family history,strongly suggests the autosomal dominant disorderof hereditary pancreatitis; hence, genetic counselingand testing for cationic trypsinogen gene mutationshould be performed. Although the risk of pancre-atic cancer is high, there are no effective screeningmethods. Conservative management and smokingcessation would be recommended, given his infre-quent episodes of acute pain.


INDEX

Page numbers followed by “i”

denote illustrations; those fol-

lowed by “t” denote tables

AAcanthosis nigricans, and gas-

tric cancer, 80Acetaminophen

and alcoholic liver disease,335

hepatotoxicity, 386–387metabolism, 388i

Acetylcholine, in gastric secre-tion, 58, 58i

Achalasiabotulinum toxin, 37calcium channel antago-

nists, 37definition, 36diagnosis, 36–37management, 37–38pathophysiology, 36, 36ipneumatic dilatation, 37–38

Achlorhydria, 70, 71, 90and vitamin B12 deficiency,

135Acromegaly, gastrointestinal

manifestations, 178Actinomyces, 152, 157Acute fatty liver of pregnancy

(AFLP), 423, 429iclinical features, 428–429differential diagnosis, 430tmanagement, 429–430

Acute Physiology and ChronicHealth Evaluation(APACHE) II, 461,462t

Adalimumab, inflammatorybowel disease, 205

Addison’s disease, gastroin-testinal manifesta-tions, 178

Adenocarcinomacolorectal cancer sequence,

242, 242iesophagus, 21, 21i, 26, 27pancreatic ductal, 469, 475

staging, 476risk factors, 28–29small-bowel and Crohn’s

disease, 222Adenoma

-carcinoma sequence, 242,242i

hepatic, 312, 313iAdenomatous polyps, 242Adenoviruses, enteric, 224Aerobilia, pancreas radiog-

raphy, 489iAIDS-associated cholan-

giopathy, 378“AIDS gastropathy,” 152Alanine aminotransferase

(ALT), 283acute hepatitis, 284, 285talcoholic hepatitis, 330, 331tautoimmune hepatitis, 394t,

395tchronic hepatitis, 285, 286tdrug-induced liver injury,

385, 385tevaluation, 289thepatitis B, 296, 297, 299hepatitis C, 300, 302nonalcoholic fatty liver dis-

ease, 409tAlcohol

and acute gastritis, 69and acute pancreatitis, 459and chronic calcifying pan-

creatitis, 470, 470tand chronic reactive gas-

tritis, 71dehydrogenase, 326, 327iand peptic ulcer disease, 60

Alcoholic cirrhosis, 325, 329i,333–334

Alcoholic fatty liver, 325,327–328, 329i

Alcoholic hepatitis, 285, 285t,325, 329i, 332–333

clinical features, 329, 330ihistologic features, 331history and physical

examination,328–329

laboratory abnormalities,329–330, 331t

treatment, 332Alcoholic liver disease

abstinence, 328, 332, 334epidemiology, 325histologic features, 328, 329iliver transplantation, 334risk factors, 325–326in women, 326

Alkaline phosphatase (ALP),284, 289i

autoimmune hepatitis, 394tdrug-induced liver injury,

385, 385tAlpha chain disease, 179–180Alpha1-antitrypsin (AAT),

autoimmunehepatitis, 392t

Alpha1-antitrypsin (AAT) defi-ciency, 177–178,364t

diagnosis, 374–375genetics, 374histologic features, 375itreatment, 375

Ambulatory esophageal pHmonitoring

GERD, 13–15indications for, 13tracings, 14i

American Joint Committee onCancer, TNM classi-fication, 80

Aminolevulinic acid (ALA)dehydratase defi-ciency, 179

Aminotransferases, 283, 284,285

Amyloidosis, 120t, 130–131,180

cholestasis, 285, 286tgastrointestinal manifesta-

tions, 182Amyotrophic lateral sclerosis,

gastrointestinalmanifestations, 180

Anal resting pressure, 264–265Anemia

503

504 Index

and IBD, 219megaloblastic, 135, 136pernicious

and gastric cancer, 79and vitamin B12 defi-

ciency, 135–136sickle cell, gastrointestinal

manifestations, 179Anisakiasis, 73Ankylosing spondylitis, and

IBD, 216Anorectal manometry, 265, 267Antacids, peptic ulcer disease,

64Anterior uveitis, and IBD, 216Antibiotics

hepatotoxicity, 387inflammatory bowel dis-

ease, 202in necrotizing pancreatitis,

464–465Antineutrophil cytoplasmic

antibodies(pANCA), autoim-mune hepatitis, 398,399t

Antinuclear antibodies (ANA),autoimmunehepatitis, 392t, 395t,397, 399, 399t

Antireflux surgery, GERD,18–19

Antral G-cell hyperplasiahypergastrinemia, 90and peptic ulcer disease, 59

Argon plasma coagulation,GAVE, 73, 74i

Arthritis, and IBD, 215–216Ascites

diagnosis, 352tevaluation, 352–353hepatic hydrothorax, 354nonhepatic causes, 352pathogenesis, 351–352refractory, 353–354secondary bacterial peri-

tonitis, 352, 356–357therapy, 353transjugular intrahepatic

portosystemicshunt, 354

Aspartate aminotransferase(AST), 283

alcoholic hepatitis, 330, 331tautoimmune hepatitis, 394t,

395tnonalcoholic fatty liver dis-

ease, 409tAspergillus, 152Aspirin, and peptic ulcer dis-

ease, 57Asterixis, 359Astrovirus, diarrhea, 224Atlanta classification, acute

pancreatitis, 461Auerbach plexus, 97Autoimmune

endocrinopathies,70

Autoimmune hepatitis (AIH),285, see alsoHepatitis

autoantibody markers,397–399, 399t

centrilobular necrosis, 391,392i

clinical features, 394–396,395t

concurrent immune dis-eases, 396–397, 398t

diagnosis, 391–393, 392tepidemiology, 393etiology, 393–394genetics, 397t, 400–401immunosuppressive drugs,

404tlaboratory features, 396liver transplantation, 402plasma cell infiltration, 391,

392irelapse, 402–403scoring system, 394tsurveillance, 404–405treatment, 401–402, 402t,

403t, 404types, 399–400, 400tvariant syndromes, 405, 406t

Azathioprinefor autoimmune hepatitis,

401–402, 403tfor inflammatory bowel dis-

ease, 203–204

BBacillus cereus, 233Bacteracites, 357Bacterial overgrowth, 104

risk factors, 132tsyndromes, 131–133and vitamin B12 deficiency,

136Baltimore criteria, veno-occlu-

sive disease, 341Barium proctography, 265Barium swallow

achalasia, 36idiffuse esophageal spasm,

38iBarium upper gastrointestinal

tract series, GERD,12

Barrett’s esophaguscancer risk, 26–27cryotherapy, 28definition, 21epidemiology, 22–26and GERD, 26incidence, 24ilong-segment, 21, 23imucosa, 21i, 22ineoplastic transformation,

26–27pathophysiology, 22photodynamic therapy, 28prevalence, 25irisk factors, 25–26short-segment, 21, 23isurveillance, American

College ofGastroenterology,27–28

Bartonella henselae, 156Basal acid output (BAO), gas-

trin, 90–91Behçet’s syndrome, 167, 173,

181Bernstein test, GERD, 15Bile

acid(s)critical micellar concen-

tration, 485primary, 485secondary, 485

duct strictures

Index 505

iatrogenic, 494inflammatory, 495

milk-of-calcium, 489iphysiology, 485, 486ireflux, 6

and acute gastritis, 69and chronic reactive gas-

tritis, 70–71Biliary

colic, 492disease, and pregnancy, 422disorder mimics, 496imaging, 487–491obstruction, in chronic pan-

creatitis, 473pancreatitis, 493strictures, 494–495

cholangiocarcinomas,320, 321i

liver transplantation, 435Bilirubin, 284, 485Billroth I and II operations

and gastric cancer, 78–79retained antrum, 59, 59i

Biofeedback therapyfecal incontinence, 269functional defecatory disor-

ders, 266Blastocystis hominis, 156, 232Bleeding. See also Upper gas-

trointestinal tractbleeding

benign rectoanal disease,164

beta blockers, and portalhypertensive, 345,348

diverticular, 163–164esophageal varices, control

of, 346t, 347gastric neoplasms, 162and IBD, 164Meckel’s diverticulum, 164non-upper gastrointestinal

tractcauses, 163–165evaluation, 165and NSAIDs, 159and portal hypertension,

345–348Blue rubber bleb nevus syn-

drome, 176Bone marrow transplantation,


Breakthrough acid production,15

Breath testing, bacterial over-growth, 118,132–133, 133i

“Bronze diabetes,” 365Brooke ileostomy, ulcerative

colitis, 205, 206iBudd-Chiari syndrome (BCS),

290i, 291tcauses, 343tclinical manifestations, 342etiology, 341–342liver transplantation, 342,

344tmanagement, 342–343, 344tpolycythemia vera, 341and pregnancy, 422

Bullous pemphigoid, 176Burton’s hypogammaglobu-

linemia, 177

CCaliciviruses, gastroenteritis,

224Cameron lesions, 161Campylobacter, 153, 155

diarrhea, 225–226, 226t-like organism (CLO) test,

61, 62Candida

esophagitis, HIV, 150species, 72, 151t

Candidiasis, chronic mucocuta-neous, 177

Carbohydrate malabsorption,117–118

Carcinoidappendiceal, 88–89colon, 89crisis, 86rectal, 89syndrome

diagnosis, 89diarrhea, 86–87, 95facial flushing, 86, 95symptoms, 86–87wheezing, 87

tumors, 86

characteristics based onlocation, 87t

diagnosis, 89small intestinal, 88stomach, 87type 1, gastric, 87type 2, gastric, 87–88type 3, gastric, 88Zollinger-Ellison syn-

drome, 87Cardiac transplantation, gas-

trointestinal mani-festations, 177

Cardiovascular disorders, gas-trointestinal mani-festations, 177

Cathartic colon, 262Cavernous hemangioma,

311–312, 311iCeftriaxone, biliary precipi-

tates, 496Celiac artery compression, 173Celiac disease, 120t, 123–127

associated disorders, 125tassociated risk conditions,

126–127complications, 126dermatitits herpetiformis,

124t, 126, 128igenetic markers, 125gluten, 123, 125, 126histologic findings, 126iIgA-based serologic studies,

123, 125tmanifestations, 124tMarsh classification, 127isilent, 123

Chagas’ disease, 36gastrointestinal manifesta-

tions, 180Chicken-wire fibrosis, liver

biopsy, 411Child-Pugh score

alcoholic cirrhosis, 333cirrhosis, 299gastric varices, 348hepatocellular carcinoma,

318Chlamydia, 157Cholangiocarcinoma, 318–319,

320ibiliary patency, 322biliary strictures, 320, 321i

506 Index

biopsy and cytology, 320clinical features, 319imaging characteristics,

319–320management, 320–322and primary sclerosing

cholangitis, 308,318, 320, 321

and ulcerative colitis, 222Cholangiography

gallbladder, 491percutaneous transhepatic,

491Cholangitis, 494, see also

Primary sclerosingcholangitis

autoimmune, 378sclerosing, 394treatment, 379

bacterial, acute, 494Escherichia coli, 494Klebsiella, 494

Cholecystectomy, 492Cholecystitis

acute, 493transabdominal ultrasonog-

raphy, 487–488Cholecystoenteric fistulas, 493Choledochojejunostomy, 494Choledocholithiasis, 493–494Cholelithiasis, and Crohn’s

disease, 219Cholestasis

bone disease, 380causes, 286tcomplication management,

379–380differential diagnosis, 377t

Cholestatic liver disease,285–286, 377–380

differential diagnosis, 377tCholesterol gallstones,

485–486, 487iCHOP (cyclophosphamide,

doxorubicin, vin-cristine and pred-nisone)chemotherapy, 83

Chromium, 138Chronic obstructive pul-

monary disease,gastrointestinalmanifestations, 178

Churg-Strauss syndrome, 173,181

Cirrhosisalcoholic, 325, 329i 333–334ascites, 351–354in autoimmune hepatitis,

395hepatic encephalopathy,

359–361and hepatitis C, 302, 302t,

305and hepatocellular carci-

noma, 308, 315hepatorenal syndrome, 358and hereditary hemochro-

matosis, 365, 369and liver transplantation

allocation, 431–432micronodular, 329i, 334portal hypertension, 345primary biliary, 285, 286t

antimitochondrial anti-body-negative, 377,378

and autoimmunehepatitis, 406t

treatment, 378–379prognostic indicators, 361

Clostridium difficile, 120t, 131,156, 172

-associated diseaseclinical presentation,

234–235diagnostic testing, 235epidemiology, 233–234prevention, 237surgery, 236treatment, 235–236

Clostridium perfringens, foodpoisoning, 233

Cobalamin (vitamin B12), 135Colchicine and misoprostol,

263Colitis. See also Ulcerative co-

litiscytomegalovirus, 156, 156iischemic, 164, 172–173pancolitis, 199pseudomembranous, 233,

234Collagen vascular disease, 70Colocolonic inhibitory reflexes,

258

Coloncarcinoid, 89cathartic, 262HIV infection-related disor-

ders, 155–157Colonic contractile response,

258Colonic flora, 131–132Colonic inertia, 260Colonic motor physiology,

257–259Colonic relaxation, 258Colonic transit, 258–259, 259i

testing, 265–266Colorectal cancer

adenoma-carcinomasequence, 242, 242i

chemoprevention, 248–249definition, 241epidemiology, 243–244familial adenomatous poly-

posis, 245–246hereditary nonpolyposis,

246heritable syndromes,

245–247and IBD, 220–222, 221t, 244Lynch syndrome, 246, 246tpolyps, 242–243presentation, 241–242prevention, 247–249risk factors, 244–245staging, 243, 243tTurcot’s syndrome, 246treatment, 249

Colostomy, refractory fecalincontinence, 270

Congestive heart failure, andliver function tests,176, 177

Conjugated hyperbiliru-binemia, 284, 287

evaluation, 289iConnective tissue disorders,

gastrointestinalmanifestations,180–181

and GERD, 6Constipation, 176

clinical assessment, 259–260colonic motor physiology,

257–259definition, 259

Index 507

in diabetes mellitus, 101functional, 259, 261tmanagement, 260–263mediation-related, 260tnormal-transit, 260in pregnancy, 181secondary causes, 259, 260tslow-transit, 260, 263surgery, 263

Copper, 138metabolism in Wilson’s dis-

ease, 370Corticosteroids

alcoholic hepatitis, 332inflammatory bowel dis-

ease, 202–203and peptic ulcer disease, 60

Cowden disease, 247Crash diets, gastrointestinal

manifestations, 175CREST (calcinosis cutis,

Raynaud phenom-enon, esophagealdysfunction, sclero-dactyly, telangiec-tasias) syndrome

and GERD, 3t, 4, 6UGI bleeding, 162

Crohn’s disease, 122, 193, 197ibiopsy specimens, 68bone and joint manifesta-

tions, 215–216and cholelithiasis, 219clinical presentation, 195colorectal cancer, 220, 221cutaneous, 218differential diagnosis,

197–198epidemiology, 193, 194erythema nodosum, 218genetics, 194medications, 199–205metastatic, 218nephrolithiasis, 219perianal fistula treatment, 210irenal complications, 219serologic markers, 196, 196tand small-bowel adenocar-

cinoma, 222stricturoplasty, 205, 206isurgery, 205, 205isurveillance colonoscopy,

221

treatment, according to indi-cation, 212t

treatment strategies, 207i,207–209, 208i, 209i,210i

types, 199Cronkhite-Canada syndrome,

247Cryptococcus neoformans, 72Cryptosporidium, 149, 153, 155,

156diarrhea, 233parvum, 154i, 378

Cyclooxygenase (COX)-2inhibitors, andpeptic ulcer disease,57–58

Cyclospora, 153, 154, 232, 378Cyclosporine

autoimmune hepatitis, 404,404t

inflammatory bowel dis-ease, 204

Cystadenocarcinoma, 481–482Cystic duct syndrome, 495Cytochrome P-450 (CYP)

system, drugmetabolism,383–384, 384t

Cytomegalovirus (CMV)colitis, 156, 156igastritis, 71–72in HIV, 150, 151t, 154upper gastrointestinal tract

ulceration, 59

DDefecation, physiology, 263,

264iDefecatory disorders

functional, 263–265biofeedback therapy, 266tests, 265–266, 266itreatment, 266

obstructive, 263symptoms, 264

Dermatitis herpetiformis, 124t,126, 128i

Dermatologic disorders, gas-trointestinal mani-festations, 176–177

Diabetes mellitus

in chronic pancreatitis, 469,472

and colorectal cancer, 245diarrhea and malabsorp-

tion, 131fatty liver infiltration, 315gastrointestinal manifesta-

tions, 101, 101t, 104i,178

and hereditary hemochro-matosis, 365, 369

nonalcoholic fatty liver dis-ease, 285, 286t, 407,408, 415, 416

and pancreatic cancer,476–477

recent onset and pancreaticcancer, 309

and somatostatinoma, 94Diarrhea, 176

amyloidosis, 130astrovirus, 224bacterial, 224–231, 225t, 226tcarcinoid syndrome, 86–87,

95celiac disease, 124tchildhood infectious,

223–224Clostridium difficile, 233–237diabetes mellitus, 131and fecal incontinence, 267food poisoning, 232–233,

233tHIV infection, 153, 155infectious

antibiotic therapy, 224tbacterial, 225–231clinical features, 225tepidemiology, 223parasitic, 231–232viral, 223–224

mechanism, 120osmotic, 121, 122tparasitic, 225t, 231–232in pregnancy, 181rotovirus, 223–224scleroderma, 131secretory, 121, 122tshortened small bowel, 121SIBO, 132traveler’s, 232tropical sprue, 128viral, 223–224, 225t

508 Index

Whipple’s disease, 127Diet

and gastric cancer, 78and peptic ulcer disease, 60

Dietary fiber supplementation,260–261

Dieulafoy’s lesion, 163Direct hyperbilirubinemia,

284, 287Disaccharidase deficiencies,

118Distal gastric cancers, 80Diverticular disease

classification, 237clinical features, 237–238treatment, 238

Dubin-Johnson syndrome,422–423

Duchenne’s muscular dys-trophy, gastroin-testinal manifesta-tions, 180

Duodenal ulcersgastrinomas, 89, 90imaintenance therapy, 65

Dysentery, 227t, 228Dysmotility

cerebral palsy, 180cerebrovascular disease, 180gastric, in Epstein-Barr virus

infection, 101medications, gastric,

105–106in multiple sclerosis, 101in Parkinson’s disease,

100–101systemic sclerosis, 104i

Dyspepsiadefinition, 107and diet, 60functional, 107–108

causes, 107tevaluation and therapy,

109pathophysiology,

108–109Dysphagia

definition, 33management algorithm, 40i

Dysplasiahigh-grade, 27–28IBD cancer risk, 221low-grade, 27

and neoplastic transforma-tion, 27

EEating disorders, gastroin-

testinal manifesta-tions, 175

Ehlers-Danlos syndromegastrointestinal manifesta-

tions, 182UGI bleeding, 162, 173

Encephalitozoon intestinalis, 153,154

Endocrine disorders, gastroin-testinal manifesta-tions, 178–179

Endometriosis, gastrointestinalmanifestations, 182

Endoscopic retrograde cholan-giopancreatog-raphy (ERCP), 287,320

chronic calcifying pancre-atitis, 470, 471, 471t

evaluation, 289igallbladder, 491, 492i, 493,

494gallstone pancreatitis, 463,

465Endoscopic therapy

GERD, 19UGI bleeding, 160–161

Endoscopic ultrasonography(EUS)

chronic calcifying pancre-atitis, 470, 471

gallbladder, 489, 490igastric cancer, 81gastric lymphoma, 82

Enemas, 263Enhanced Liver Fibrosis panel,

scoring, 414Entamoeba histolytica, 154

diarrhea, 231–232Enteric neuropathic disorders,

101–102Enteritis

HIV infection, 153radiation, 122

Enterohepatic circulation, 486iEpidermolysis bullosa, 176Epilepsy, gastrointestinal man-

ifestations, 180Epstein-Barr virus infection

and gastric cancer, 79gastric dysmotility, 101

Erythropoietic protopor-phyria, 179

Escherichia coli, 155, 156, 172cholangitis, 494enteroaggregative (EAEC),

229, 230tenterohemorrhagic

(O157:H7) (EHEC),226t, 228–229, 230t

enteroinvasive (EVEC), 229,230t

enteropathogenic (EPEC),229, 230t

enterotoxigenic (ETEC), 229,230t

gastroenteritis, 228–229spontaneous bacterial peri-

tonitis, 354Esophageal cancer, 28–29

adenocarcinoma, 21, 21i, 26,27

Barrett’s esophagus, 26–27diagnosis and staging, 29,

30tintestinal metaplasia of

cardia, 27signs and symptoms, 29T and N staging, 29, 31i

Esophageal manometry, 6, 7i,36i, 39i, 40i

Esophageal motor abnor-mality, nonspecific,39

Esophageal spasm, diffuse, 38,38i, 39i

Esophageal varices, 345bleeding control, 347, 346themorrhage control,

346–347pathogenesis, 346primary prophylaxis, 346,

347tsecondary prophylaxis,

347–348, 347ttreatment, 347t

Esophagectomy, 27–28Esophagitis

Candida, in HIV, 150eosinophilic, 39–40

Index 509

erosive, 12iin HIV, 151

gastrinomas, 89, 90ireflux, 4, 5i

Esophagus. See also Barrett’sesophagus

and GERD, 4HIV infection, 150–152motility disorders, 35–38,

35tnormal motor function, 35inutcracker, 38–39resection, endoscopic

mucosal, 28spastic disorders, 38–39vascular disease, 167

Ethanol metabolism, 326–327,327i

Extracorporeal shock wavelithotripsy, 492, 493

Extrinsic neuropathic disor-ders, 99–101

FFamilial adenomatous poly-

posis (FAP), andcolorectal cancer,245–246

Familial visceral myopathy,type II, 102

Fasting gastroduodenalmanometry, 98, 99i

Fat malabsorption, 118–119Fat sparing liver infiltration,

315Fatty-fibrotic pattern, liver

ultrasonography,410

Fecal fat excretion, 119Fecal incontinence, 263,

266–267assessment, 267, 268ietiology, 267pelvic MRI, 269tests, 267–269treatment, 269–270

Ferritinin hereditary hemochro-

matosis, 366in NAFLD, 410

5-aminosalicylates (5-ASA),

ulcerative colitis,199, 200t, 201–202

5-HT (5-hydroxytryptamine;serotonin), 258

5-HT4 receptor agonist, consti-pation, 262

Focal fatty liver infiltration, 315Focal nodular hyperplasia,

312–314, 314iFolic acid, 136Food poisoning, 232–233, 233t

Blastocystis hominis, 232Clostridium perfringens, 233Listeria monocytogenes, 233Staphylococcus aureus, 233

GGallbladder

dyskinesia, 495perforation, 493porcelain, 488

Gallstonesand acute pancreatitis, 459asymptomatic, 491–492black pigment, 486–487,

487i, 488ibrown pigment, 487, 488,

488icholesterol, 485–486, 487iclinical presentation,

491–493epidemiology, 485imaging, 487–488, 489ipathogenesis, 485–487and pregnancy, 422

Gamma (γ-) glutamyltrans-ferase (GGT), 284,289i

alcoholic hepatitis, 331, 331tGastric acid

and GERD, 4–6hypersecretion, 58–59

Gastric adenocarcinomaclinical features, 79–80diffuse type, 80, 81iepidemiology, 77–78pathogenesis, 78prognosis, 81–82risk factors, 78–79staging, 80–81, 81ttreatment, 81

tumor features, 80Gastric biopsy protocol, 68, 69iGastric bypass surgery, and

vitamin B12 defi-ciency, 136

Gastric emptying, 98, 99iGastric lymphoma

clinical features, 82epidemiology, 82prognosis, 84risk factors, 82rituximab, 84staging, 83, 83ttumor features, 82–84

Gastric motility, 98, 99iGastric mucosal defense mech-

anisms, 56iGastric neoplasms, 77

bleeding, 162frequency, 77t

Gastric pacing therapy, 107Gastric ulcers

follow-up, 65maintenance therapy, 65

Gastric varices, 348Gastrin, in gastric secretion, 58,

58iGastrinomas, 59, 89

triangle, 89, 90iGastritis

acute, 67, 69atrophic, 69–70

autoimmune, 69–70multifocal, 70

chronic, 69–72and hypertrophic gas-

tropathy, 74reactive, 70–71

classification, 68tdefinition, 67, 74eosinophilic, 72–73granulomatous, 72histopathology, 67–68infectious

bacterial, 71fungal, 72

lymphocytic, 72, 73iSydney system, classifica-

tion, 67, 68tsyphilitic, 72viral infectious, 71–72, 223

Gastroenteritis

510 Index

caliciviruses, 224eosinophilic , 120t, 130Escherichia coli, 228–229Giardia lamblia, 232Salmonella, 226–228, 226t

Gastroenteropancreatic neu-roendocrine tumors(GNETs), 86

management, 94–95, 95iof pancreatic origin, 89

clinical features, 89–90,90i

diagnostic tests, 90–91treatment, 91

Gastroesophageal reflux dis-ease (GERD)

acid clearance, 4acid-suppressive therapy,

10, 10t, 11, 15, 16talarm symptoms, 12antireflux surgery, 18–19atypical symptom diag-

nosis, 11barium upper gastroin-

testinal series, 12and Barrett’s esophagus, 26Bernstein test, 15chest pain

esophageal, 8–9, 97functional, 17–18

and connective tissue disor-ders, 6

contributing factors, 4–6coronary ischemia, 9definition, 3diagnosis, 10–11empiric trials, 10, 10tendoscopy, 11–12, 11tepidemiology, 6–8, 8ietiology, 3t, 3–4, 4iextraesophageal symptoms,

6, 9–10gastric refluxate, 4i, 5igrading systems, 12laryngeal stenosis, 6, 7ilifestyle modification, 15,

16tLos Angeles classification,

12, 12iin pregnancy, 181presentation, 8–10prokinetics, 16t, 17quality of life, 7, 9i

symptom index, 13symptoms, 8, 9i, 10itesting, 11–15treatment, 15–19, 16t

Gastrointestinal motor func-tion, 97–98

Gastrointestinal stromaltumors (GIST)

clinical features, 84epidemiology, 84KIT gene mutation, 84, 85pathogenesis, 84prognosis, 85staging, 85, 85itreatment, 85tumor features, 84–85

Gastroparesisclassification, 100tclinical features, 102–103diagnosis flow diagram,

105iinvestigation, 103–104management, 102–104treatment, 104–107

Gastropathy, 67, 73–74“AIDS,” 152hypertrophic, 73–74portal hypertensive, 73vascular, 73, 162–163

Geneticsalcoholic liver disease, 326alpha1-antitrypsin (AAT)

deficiency, 374dysmotility, 99gastric cancer, 79hereditary hemochro-

matosis, 364IBD, 194pancreatic cancer, 477–478Wilson’s disease, 370

Giant migrating complex, 98Giardia, 177

lamblia, 154gastroenteritis, 232

Gilbert’s syndrome, 286Glucagonoma, 93

clinical features, 93diagnosis, 93–94pathogenesis, 93treatment, 94

Gluten, in celiac disease, 123,125, 126

Graft-vs-host disease, gastroin-


Gynecologic disorders, gas-trointestinal mani-festations, 182

HHead injury, acute, gastroin-


Heartburndefinition, 8functional, 14

Helicobacter pylori, 56–57antibiotic resistance, 63diagnostic tests, 61, 62tand extranodal marginal

zone B-cell lym-phoma, 82–83

and functional dyspepsia,107t, 108

and gastric cancer risk, 79gastritis, 67, 71, 120tand GERD, 6and intestinal metaplasia of

cardia, 26multifocal atrophic gastritis,

70and NSAIDs, 58in peptic ulcer disease, 55,

56regimens, American College

ofGastroenterology,63t

stool antigen assay, 61–62treatment, 63, 63tand UGI bleeding, 161urease breath test, 62

HELLP (hemolysis, elevatedliver tests, lowplatelets) syn-drome, 423, 427i

clinical features, 426differential diagnosis, 430tmanagement, 426–428

Hematochezia, 163Hematologic disorders, gas-


Hemolytic uremic syndrome(HUS)

Index 511

and EHEC, 229gastrointestinal manifesta-

tions, 179and S. dysenteriae, 228

Henoch-Schönlein purpura,173

Hepatic artery aneurysm, 339, 339iinflow disorders, 338–340-portal vein fistulas, 340thrombosis, 338–339

liver transplantation, 434Hepatic encephalopathy, 288,

290, 291clinical features, 359management, 359–360stages, 290ttreatment, 360–361

Hepatic hydrothorax, 354Hepatic iron index, 366–367Hepatic venous outflow disor-

ders, 340–343Hepatitis

acute, 284, 293causes, 285tin chronic hepatitis B

patients, 297, 298talcoholic, 285, 285t, 325,

329i, 332–333clinical features, 329, 330ihistologic features, 331history and physical

examination,328–329

laboratory abnormalities,329–330, 331t

treatment, 332autoimmune, 219, 285

alpha1-antitrypsin, 392tantimitochondrial anti-

body, 392t, 398, 406tantiliver/kidney micro-

some type 1 (anti-LKM1) antibodies,397, 398

autoantibody markers,397–399, 399t

centrilobular necrosis,391, 392i

clinical features, 394–396,395t

concurrent immune dis-

eases, 396–397, 398tdiagnosis, 391–393, 392tepidemiology, 393etiology, 393–394genetics, 397t, 400–401immunosuppressive

drugs, 404tlaboratory features, 396liver transplantation, 402overlap syndrome, 405plasma cell infiltration,

391, 392iprednisone, 401, 403trelapse, 402–403scoring system, 394tsmooth muscle anti-

bodies (SMA), 392t,395t, 397, 399, 399t

surveillance, 404–405treatment, 401–402, 402t,

403t, 404types, 399–400, 400tvariant syndromes, 405,

406tchronic, 285, 293

causes, 286tinterface, 391, 392iischemic, 284–285, 285t, 340panacinar, 391, 392iportal, drug-induced liver

injury, 386viral. See also Hepatitis A, B,

C, D, and Eorganisms causing, 293and pregnancy, 421–422

Hepatitis A (HAV), 285t, 294tepidemiology, 293–294

Hepatitis B (HBV), 285, 285t,286t, 294t

acute flares, 297, 298chronic phases, 296–298,

297iHBeAg-negative, 287HBeAg-positive, 287

clinical presentation,295–298

diagnostic tests, 295epidemiology, 294–295hepatocellular carcinoma

risk, 298and HIV, 305liver biopsy specimen, 296i

liver transplantation, 299oral agents, 299, 300tperinatal transmission, 421,

422tprevention, 299–300serologic markers, 295t, 296ttreatment, 298–299

Hepatitis C (HCV), 285, 286tand alcohol, 334–335anti-HCV test, 300, 301tand autoimmune hepatitis,

393, 405biopsy specimen, 301iclinical presentation,

301–302diagnostic tests, 300–301and HIV, 206liver transplantation, 305management, 304inatural history, 302tneuropsychiatric side

effects, 303–305in pregnancy, 421, 422prevention, 305treatment, 302–305

Hepatitis D, 300Hepatitis E, 305Hepatocellular carcinoma,

308t, 309, 309i,315–316, 317i

diagnosis, 316and hepatitis B, 298and hepatitis C, 302tliver resection, 317liver transplantation,

316–317management, 316–318

transarterial chemoem-bolization (TACE),318

transarterial radioem-bolization (TARE),318

Hepatocellular disorders,284–285

Hepatorenal syndromediagnostic criteria, 348prevention, 358treatment, 358–359types, 358

Hepatotoxicityacetaminophen, 386–387

512 Index

antibiotics, 387antiretroviral agents, 387erythromycin, 496herbal therapies, 387lipid-lowering agents,

387–388liver injury pattern, 384–385,

385tstatins, 387–388

Hereditary angioedema, 177Hereditary coproporphyria,

179Hereditary hemochromatosis,

363–369, 364tarthropathy, 366iclinical features, 365diagnosis, 365–367, 367iHFE gene, 364–365, 366iron metabolism proteins,

365screening, 369treatment, 367

Hereditary hemorrhagictelangiectasia(HHT), 340

Herpes simplex virus (HSV)HIV, 150–151, 152iupper gastrointestinal tract

ulceration, 59Hiatal hernia

and Barrett’s esophagus, 22and GERD, 3, 4

Highly active antiretroviraltherapies(HAARTs), gas-trointestinal sideeffects, 149–150

Hirschsprung disease, 99Histamine, in gastric secretion,

58, 58iHistamine2 (H2) receptor

blockersGERD, 15peptic ulcer disease, 64

Histoplasmosis, 152 Hodgkin’s disease

and liver function tests, 176liver manifestations, 179

Human immunodeficiencyvirus (HIV) infec-tion, 149

colon, 155–157esophagus, 150–152

opportunistic infection, 149oral lesions, 150, 151tpancreas, 157small bowel, 152–155stomach, 152and viral hepatitis, 305–306

Hy’s rule, drug-induced liverinjury, 389

Hyperbilirubinemiaautoimmune hepatitis, 396conjugated, 284, 287

evaluation, 289idirect, 284, 287jaundice, 286

Hypercortisolism, gastroin-testinal manifesta-tions, 178

Hyperemesis gravidarum, 181,424

Hypergastrinemiaand achlorhydria, 90type 2 gastric carcinoids, 87,

88Hyperosmolar agents, consti-

pation, 261Hyperparathyroidism, gas-


Hyperthyroidism, gastroin-testinal manifesta-tions, 178

Hypocoagulable states, gas-trointestinal mani-festations, 179

Hyponatremia, 357Hypoparathyroidism, gas-


Hypothyroidism, gastroin-testinal manifesta-tions, 178–179

IIatrogenic bile duct strictures,

494Idiosyncratic reactions, drug-

induced liverinjury, 384

Ileus, gallstone, 493Imaging

abdominal computedtomography, gall-

stones, 490abdominal plain radiog-

raphy, gallstones,487–488, 489i

acute pancreatitis, 463, 464aerobilia, pancreas radiog-

raphy, 489ianal ultrasound, 267–268barium proctography, 265biliary, 487–491cholangiocarcinoma,

319–320cholangiography, gall-

bladder, 491endoscopic retrograde

cholangiopancre-atography (ERCP),287, 320

chronic calcifying pancre-atitis, 470, 471, 471t

evaluation, 289igallbladder, 491, 492i,

493, 494gallstone pancreatitis,

463, 465endoscopic ultrasonog-

raphy (EUS)chronic calcifying pancre-

atitis, 470, 471gallbladder, 489, 490gastric cancer, 81gastric lymphoma, 82

gallstones, 487–488, 489igastroesophageal scintig-

raphy, 15liver mass lesions, 310–311magnetic resonance cholan-

giopancreatog-raphy (MRCP), 287,319–320

chronic calcifying pancre-atitis, 470, 471

evaluation, 289igallstones, 491

proctographybarium, 265evacuation, 268magnetic resonance, 265

NAFLD, 410–411, 411i, 412ipancreatic cancer, 478, 478i,

479ipelvic MRI, fecal inconti-

nence, 269

Index 513

radionuclide biliary scan-ning, 490

scintigraphy, colonic transit,259i

“thumbprinting,” abdom-inal radiograph,169, 172

transabdominal ultrasonog-raphy, cholecystitis,487–488

Imatinib, GISTs, 85Immunologic disorders, gas-


Immunosenescence, 395Inborn errors of metabolism,

363, 363tInfection

alcoholic hepatitis, 332liver transplantation, 435non-UGI bleeding, 165

Infiltrative disorders,cholestasis, 285,286t

Inflammatory bile duct stric-tures, 495

Inflammatory bowel disease(IBD). See alsoCrohn’s disease,Ulcerative colitis

anemia, 219anterior uveitis, 216arthritis, 215–216bleeding, 164cardiopulmonary complica-

tions, 220, 220tclinical presentation,

195–197colorectal cancer, 220–222,

221tdermatologic manifesta-

tions, 217–218, 217tdiagnosis, 194–195differential diagnosis,

197–198, 198tepidemiology, 193–194erythema nodosum, 217, 218genetics, 194hematologic complications,

219, 220thepatobiliary manifesta-

tions, 218–219, 218t

medications, 199–205adalimumab, 205infliximab, 204–205mercaptopurine, 203–204methotrexate, 204tacrolimus, 204

ocular manifestations,216–217, 217t

osteopenia, 219osteoporosis, 219pyoderma gangrenosum,

217–218renal complications, 219,

220trheumatologic manifesta-

tions, 215–216, 216tscleritis, 216thromboembolism, 220, 220t

Infliximab, inflammatorybowel disease,204–205

Insulinoma, 92Interdigestive migrating motor

complex, 98, 99iInterstitial cells of Cajal, 98, 99,

102Intestinal lymphangiectasia,

130, 130iprimary, 130secondary, 130

Intestinal metaplasia of cardiaBarrett’s esophagus, 26esophageal adenocarci-

noma, 27with goblet cells, 21–22, 22i,

23iIntestinal pseudo-obstruction

classification, 100tdecompression, 106diagnosis flow diagram,

105imanagement, 102–104treatment, 104–107

Intestinal type gastric adeno-carcinoma, 80

Intraductal papillary mucinoustumor (IPMT), 469,476, 482

Intrahepatic cholestasis ofpregnancy (ICP),423, 424–425

clinical features, 425

management, 425–426Iron, 137

index, hepatic, 366–367metabolism

hepcidin, 365proteins, 365

overload, hereditaryhemochromatosis,363–364

secondary, 364Irritable bowel syndrome (IBS)

and constipation, 260constipation-predominant,

259definition, 251diagnostic criteria, 251t, 253diarrhea-predominant, 254epidemiology, 252management, 253–255, 254ipain-predominant, 255pathogenesis, 252–253postinfectious, 252psychiatric disorder, 252,

255risk factors, 252

Isospora belli, 154

JJaundice, 176, 286–287

KKaposi’s sarcoma, 151t, 155,

156, 157Kasabach-Merritt syndrome,

311Kegel’s exercises, 266, 269

LLactase deficiency

congenital, 117–118primary, 118secondary, 118

Laparoscopic surgicalmyotomy, acha-lasia, 38

Leishmania, 152, 156, 157Leptospirosis, 496Lesar-Trelat sign, and gastric

514 Index

cancer, 80Leukemias, gastrointestinal

manifestations,179–180

Lichen planus, 177Linitis plastica lesion, 80Listeria

monocytogenes, food poi-soning, 233

species, 155Liver cysts, 314–315, 315iLiver disease

alcoholic, 325–334cholestatic, 377–380chronic, and pregnancy,

420, 420t, 422–423coincidental, in pregnancy,

420, 421–422causes and timing, 420

complications, 351drug-induced, 285, 285t,

383–389inborn errors of metabolism,

363, 363tmetabolic, 363tand pregnancy, 419–430renal function abnormali-

ties, 357–359TPA-induced, 107vascular, 337t

Liver failureacute, 288fulminant, 288–292, 291t,

373–375and acetaminophen, 386causes, 288, 290icerebral edema, 290, 291liver transplantation, 291,

291tsymptoms, 288

hypoglycemia, 290Liver injury

drug-induceddirect toxicity, 383–384Hy’s rule, 389

patternalcohol-induced vs.

NAFLD, 411specific drugs, 385t

Liver mass lesionsabdominal mass presenta-

tion, 309ibenign, 311–315

clinical classification, 308tevaluation, 307–309hepatocellular carcinoma,

308t, 309, 309i,315–318, 317i

imaging studies, 310–311laboratory tests, 310malignant, 315–322metastases, 322paraneoplastic syndromes,

309physical examination,

309–310Liver tests, 283–284

abnormal results, 176clinical syndromes, 287tevaluation, 287, 288i, 289i

Liver transplantation. See alsoOrthotopic livertransplantation

alcoholic liver disease, 334recidivism, 334

cellular rejection, 434–435drug-induced liver injury,

388, 389fulminant liver failure, 291,

291t, 292, 373–375hepatic encephalopathy, 361hepatitis B, 299hepatitis C, 305hepatocellular carcinoma,

316–317hereditary hemochro-

matosis, 368–367living donor (LDLT), 436pregnancy in recipients, 423Wilson’s disease, 373

Long-chain 3-hydroxyacyl-CoA dehydroge-nase (LCHAD), andAFLP, 428, 430

Lower esophageal sphincter(LES)

anatomy and physiology,33, 34

and Barrett’s esophagus, 22and GERD, 4normal motility, 35i

Lubiprostone, 262Lung transplantation, gas-


Lymphoma. See also Gastric

lymphomacholestasis, 286diffuse large B-cell

(DLBCL), 83partial gastrectomy, 83

enteropathy-associated T-cell (EATL), 126

extranodal marginal zone B-cell (ENMZL),82–83

H. pylori, 82–83 gastrointestinal manifesta-

tions, 179–180and IBD, 222Mantle cell, 180mucosa-associated lym-

phoid tissue, 82non-Hodgkin, 155

Lynch syndrome, and colo-rectal cancer, 246,246t

MMMaddrey discriminant func-

tion analysis, 330Malabsorption, 117

carbohydrate, 117–118fat, 118–119mechanisms, 118tprotein, 119–120

Maldigestion, 117Malignant melanoma, stomach

metastatic disease,96

Mallory bodies, liverhistopathology,329i, 331

Mallory-Weiss tear, UGIbleeding, 161

Malnutrition, alcoholichepatitis, 332

Manganese, 138Marsh lesions, celiac disease,

124, 126i, 127iMastocytosis, gastrointestinal

manifestations, 179Meckel’s diverticulum,

bleeding, 164Median arcuate ligament syn-

drome, 173Megamitochondria, alcoholic

hepatitis, 331

Index 515

Meigs’ syndrome, 182Meissner plexus, 97Melanosis coli, 262Ménétrier’s disease, 74, 120tMesalamine

Crohn’s disease, 201ulcerative colitis, 199, 200t

Mesenteric ischemia, 167artery thrombus, 170chronic, 172embolus, 169i, 169–170evaluation, 169history, 168–169nonocclusive, 170, 170iprimary, predisposing con-

ditions, 167, 168tsecondary, predisposing

conditions, 167, 167tvenous thrombosis,

170–171, 171iMesenteric venous thrombosis,

170–171, 338chronic, 338risk factors, 171t

Metabolic syndromedefinition, 408–409features in NAFLD, 410i

Microlithiasis, 495, 496iMicrosomal ethanol-oxidizing

system (MEOS),326, 327

Microsporida, HIV, 149, 153,154i

Migraine, gastrointestinalmanifestations, 180

Minerals, 137–138Mirizzi’s syndrome, 492i, 493Mitochondrial neurogastroin-

testinalencephalomy-opathy, 102

Model for end-stage liver dis-ease (MELD)system, 432t,432–433

alcoholic hepatitis, 330hepatic encephalopathy,

359, 361hepatocellular carcinoma,

317Molybdenum, 138Motility disorders, 97, 100t

enteric neuropathy, 101–102extrinsic neuropathy,

99–101genetic defects, 99management, 102–104neuropathic vs. myopathic,

103, 104ipathogenesis, 98–99smooth muscle disturbance,

102treatment, 104–107

Mucinous cystadenoma,481–482

Mucosa-associated lymphoidtissue (MALT) lym-phoma, 82

Muir-Torre syndrome, and col-orectal cancer, 246

Multiple endocrine neoplasia(MEN1) syndrome

and gastrinomas, 89and GNETs, 86

Multiple myeloma, gastroin-testinal manifesta-tions, 180

Multiple sclerosisdysmotility, 101gastrointestinal manifesta-

tions, 180Muscular dystrophy

gastrointestinal manifesta-tions, 180

oculogastrointestinal, 102oculopharyngeal, gastroin-


Myasthenia gravis, gastroin-testinal manifesta-tions, 180

Mycobacteriumavium-intracellulare, 72, 127,

152, 153, 154tuberculosis, 154–155

NNNausea and vomiting, 175Necrotizing pancreatitis, 456,

464ilong-term sequelae, 466–467necrosectomy, 466

parenteral nutrition,465–466

surgery, 466treatment, 464–465

Neoplasmscolon, 164gastric, 77, 77t, 162pancreas, 475–481upper gastrointestinal tract,

162Neuromuscular disorders, gas-


Niacin (vitamin B3), 136Nissen fundoplication, 40iNodular regenerative hyper-

plasia, gastroin-testinal manifesta-tions, 181

Non-Hodgkin’s lymphoma,155

Nonalcoholic fatty liver dis-ease (NAFLD), 285,286t

biochemical features, 409t,409–410

causes, 408tclinical manifestations,

407–408, 409tdiagnosis, 412–413epidemiology, 407fibrogenesis markers, 414,

414tfibrosis scoring, 414, 415histology, 411–412, 413ihyperlipidemia, 409, 415hypertension, 408t, 409, 415imaging, 410–411, 411i, 412iinsulin resistance, 407metabolic syndrome fea-

tures, 410iprevention, 417primary, 407, 408tsecondary, 407, 408tstaging, 413–414treatment, 415–417, 415t

Nonalcoholic steatohepatitis(NASH), 407, 412,415

Nonsteroidal antiinflamma-tory drugs(NSAIDs)

516 Index

and acute gastritis, 69and chronic gastritis, 71and H. pylori, 58non-upper gastrointestinal

bleeding, 65and peptic ulcer disease, 57,

65, 66toxicity, American College

ofGastroenterology,57

and upper gastrointestinalbleeding, 159

Nutcracker esophagus, 38–39Nutritional disorders

mineral deficiencies,137–138

vitamin deficiencies,135–137

OOObesity

gastrointestinal manifesta-tions, 175

and NAFLD, 408, 409, 415Obstructive sleep apnea

GERD, 3and ischemic hepatitis, 340

Ogilvie’s syndrome, 258Olsalazine, 200t, 201, 202Oncologic disorders, gastroin-

testinal manifesta-tions, 179–180

Oral cholecystography, 488,489i

Oropharyngeal disorders,34–35

treatment, 35Orthotopic liver transplanta-

tion (OLT), 431. Seealso Liver transplan-tation

allocation of organs, 432t,432–433

cardiovascular risk, 435tcomplications, 434–436contraindications, 433timmunosuppression, 433,

434tindications for, 431t,

431–432living donors, 436

Osler-Weber-Rendu disease,162, 340

PPPain

abdominal, 176chest, and GERD, 17–18in chronic pancreatitis, 472,

473–474in pancreatic cancer,

480–481syndrome

elusive biliary-type,495–496

epigastric, 108Panacinar hepatitis, 391, 392iPancolitis, 199Pancreas

HIV infection-related disor-ders, 157

small cysts, 482–483Pancreatic cancer

diagnosis, 477environmental factors, 476genetic markers, 477–478imaging, 478, 478i, 479ipathology, 477risk factors, 475–477tumors, 478–479

cystic, 481–483exocrine, 475tstaging, 478–479

treatment, 479–481Whipple procedure, 480

Pancreatic cystsbenign, congenital, 482small, 482–483

Pancreatic insufficiencyexocrine, 481

Pancreatic lipase, 119Pancreatitis

acute, 459Atlanta classification, 461causes, 460tclinical presentation,

459–460drugs associated with,

460tetiology, 459imaging, 463, 464ilaboratory findings, 461,

463

severity classifications,460–461, 461t, 462t

treatment, 463–466autoimmune, chronic, 469biliary, 493calcifying, chronic, 469

causes, 470tclinical features, 472complications, 472–473diagnosis, 470evaluation, 470–472management, 473–474

chronic, 469duodenal obstruction,

473and pancreatic cancer,

476splenic vein thrombosis,

473steatorrhea, 469, 472

gallstone, 495hereditary, 476in IBD, 220, 220tinterstitial acute, 463obstructive, chronic, 469

Papillary stenosis, 495Papillary-cystic pancreatic

tumor, 482Paracentesis, 352Paraneoplastic syndromes,


Parietal gastric cell, 58iParkinson’s disease

dysmotility, 100–101gastrointestinal manifesta-

tions, 180Pelvic floor function disorders,

263–265. See alsoFecal incontinence,Defecatory disor-ders

dyssynergia, 263tests, 265–266, 266itreatment, 266

Pemphigus vulgaris, 176Peptic ulcer disease (PUD), 55i

antacids, 64antiplatelet agents, 60antisecretory treatment,

64–65aspirin, 57clinical features, 61

Index 517

complicated, 61, 65cyclooxygenase (COX)-2

inhibitors, 57–58epidemiology, 55and gastrinoma, 89Helicobacter pylori, 56–57, 58Helicobacter pylori eradica-

tion, 62, 63, 63tlifestyle modifications, 65maintenance therapy, 65misoprostol, 64–65nonsteroidal antiinflamitory

drugs, 57–58pathophysiology, 55–61in pregnancy, 181prevention, 65–66psychologic factors, 61and radiation injury, 60risk factors, 60–61systemic mastocytosis, 59testing, 61–62treatment, 62–65

Peritonitis, bacterialEscherichia coli, 354secondary, 352, 356–357Spontaneous, 354–355

diagnosis, 355–356, 355idifferential diagnosis,

356–359treatment, 356

Pernicious anemiaand gastric cancer, 79and vitamin B12 deficiency,

135–136Peutz-Jeghers syndrome

and colorectal cancer, 247and pancreatic cancer, 477

Pneumocystis carinii (now P.jiroveci), 155

Polyarteritis nodosa, 173, 181Polycystic kidney disease, gas-


Polymyositis, gastrointestinalmanifestations, 181

Polyposisfamilial adenomatous

(FAP), 245–246attenuated (AFAP), and

colorectal cancer,246

hamartomatous syndromes,247

juvenile syndrome, 247MutYH-associated, 247

Polypsadenomatous, 242in colorectal cancer, 242–243hamartomatous, 243

Porphyriaacute intermittent, 179cutanea tarda, 179gastrointestinal manifesta-

tions, 179Portal hypertension

alcoholic hepatitis, 332bleeding, 345–348gastric lesions, 348–349left-sided, 338liver tests, 287sinistral, 338

Portal venous inflow disor-ders, 338

Portosystemic encephalopathy(PSE), 355, 360, 361

post-TIPS, 360Post-fundoplication motor dis-

orders, 40Postprandial distress syn-

drome, 108Postprandial gastroduodenal

manometry, 98, 99iPouchitis, 205Preeclampsia, in pregnancy,

423–424, 426Pregnancy

appendicitis, 181coincidentally-occurring

liver disease, 420,421–422

gastrointestinal manifesta-tions, 181–182

and inflammatory boweldisease, 194

and liver disease, 419–421causes and timing, 420tunique to pregnancy, 420,

423–430liver tests in, 419tpreclampsia, 423–424, 426volvulus, 181and Wilson’s disease, 373,

422, 423Primary nonfunction of liver

allograft, 434Primary sclerosing cholangitis

(PSC), 378and autoimmune hepatitis,

406t

and cholangiocarcinoma,308

and IBD, 218treatment, 379and ulcerative colitis, 285

Proctographybarium, 265evacuation, 268magnetic resonance, 265

Prostaglandins, gastric secre-tion inhibition, 58,58i

Proteinmalabsorption, 119–120restriction, PSE, 360

Protein-losing enteropathies,120

causes, 120tProthrombin time, 284

fulminant liver failure, 292Proton pump inhibitors (PPI)

and acute gastritis, 69empiric trials for GERD, 10tGERD treatment, 15, 16–17,

17iulcer healing, 64

Proximal gastric lesions, 90Pruritus, cholestasis, 380Pseudo-obstruction

classification, 100tdiagnosis flow diagram,

105imanagement, 102–104treatment, 104–107

Pseudoachalasia, 37Pseudocyst, in chronic pancre-

atitis, 472Psoriasis, gastrointestinal man-

ifestations, 177Pudendal nerve terminal

motor latency(PNTML), 268

Pulmonary disorders, gas-trointestinal mani-festations, 177–178

Pyridoxine (vitamin B6), 136

RRRadiofrequency ablation

(RFA), hepatocel-lular carcinoma,317–318

518 Index

Ranson criteria, acute pancre-atitis, 460–461, 461t

Reactive atypia, vs. dysplasia,27

Rectal balloon expulsion test,265, 266i

Rectal compliance and sensa-tion, 268–269

Rectoanal pressure gradient,265, 266i

Rectoceles, 265Reflux

of acid, definition, 13disease, refractory, 17, 18t

Rehydration, gastric dys-motility, 105

Renal disorders, gastroin-testinal manifesta-tions, 178

Renal transplantation, gas-trointestinal mani-festations, 178

Resistance to activated proteinC, 342

Retained antrum syndrome,59, 591

Retroperitoneal adenopathy,M. tuberculosis, 155,155i

Rheumatologic disorders, gas-trointestinal mani-festations, 180–181

Riboflavin (vitamin B2), 136Rome criteria

constipation, 259irritable bowel syndrome,

251Rotovirus, diarrhea, 223–224

SSSalmonella

enteritidis, 155, 226species, 153

clinical syndromes, 227tgastroenteritis, 226–228,

226tpredisposing conditions

for infection, 227tSarcoidosis

liver manifestations, 178,286

and peptic ulcer disease, 60Satellitosis, hepatocytes, 331Scleroderma

diarrhea and malabsorp-tion, 131

eosinophilic gastritis, 73and esophageal hypo-

motility, 39, 39igastrointestinal manifesta-

tions, 180and gastrointestinal

motility, 102and GERD, 3t, 4, 6

Seattle criteria, veno-occlusivedisease, 341

Secretin stimulation test, 91,91i

Selective IgA deficiency, 177Selenium, 138Seronegative spondy-

loarthropathies,gastrointestinalmanifestations, 181

Serotonin, and motor/sensorycolonic function,258

Serous cystadenoma, 481, 482iSerum albumin, 284Serum-ascites albumin gra-

dient (SAAG), 352,352t

Shigella dysenteriae, 228Shigella species, infection, 228Short bowel resection, 121Short bowel syndrome,

122–123Shy-Drager syndrome, gas-


Sickle cell anemia, gastroin-testinal manifesta-tions, 179

Sinusoidal obstruction syn-drome, 386

Sitophobia, 172Sjögren’s syndrome, gastroin-


Small boweladenocarcinoma and

Crohn’s disease, 222bacterial overgrowth,

132–133

biopsy specimens, 126idiseases, 123–131HIV infection-related disor-

ders, 152–155ischemia, 169motility disorders, 103, 104inormal flora, 131obstruction in pregnancy,

181shortening and diarrhea,

121transplantation, 107villous atrophy, 127t

Small cell carcinoma of thelung, gastroin-testinal manifesta-tions, 180

Small intestinal bacterial over-growth (SIBO), 118,120t, 132–133, 133i

treatment, 133Smoking

and gastric cancer, 78and peptic ulcer disease, 60,

65Smooth muscle disorders, 102Solid-cystic pancreatic tumor,

482Somatostatin, gastric secretion

inhibition, 58, 58iSomatostatinoma, 94Sphincter-of-Oddi dysfunc-

tion, 495–496Spinal cord injuries, gastroin-


Splanchnic artery aneurysms,173

Splanchnic circulation, 337–338Squamous cell carcinoma

and achalasia, 38esophagus, 28risk factors, 28

Staphylococcus aureus, food poi-soning, 233

Steatosisdrug-induced liver injury,

386hepatic, 410, 411i, 412iNAFLD, 411, 413i

Stimulant laxatives, 261–262Stomach

Index 519

HIV infection-related disor-ders, 152

metastatic disease, 95, 96watermelon, 73, 163

Stool antigen assay, H. pylori,61–62

Streptococcus bovis, 156Subtotal colectomy with ileo-

rectal anastomosis,263

Superior mesenteric artery,169i

embolus, 169, 169ithrombus, 170

Swallowing, 33anatomy, 33physiology, 33–34

Sydney system, gastritis classi-fication, 67, 68t

Systemic disease, gastroin-testinal manifesta-tions

cardiovascular, 177dermatologic, 176–177endocrine, 178–179gynecologic, 182hematologic, 179immunologic, 177neuromuscular, 180oncologic, 179–180pregnancy, 181–182pulmonary, 177–178renal, 178rheumatologic, 180–181symptoms and signs,

175–176Systemic lupus erythematosus,


TTTherapeutic paracentesis, 353Therapeutic phlebotomy, 367Thiamine (vitamin B1), 136Thrombotic thrombocytopenic

purpura (TTP)and EHEC, 229gastrointestinal manifesta-

tions, 179TNM classification

colorectal cancer, 243t

esophageal cancer, 29, 31i,30t

gastric adenocarcinoma, 80pancreatic cancer, 476t

Torulopis glabrata, 72Transaminases, 283Transient lower esophageal

sphincter relax-ations (TLESRs), 3, 4

Transjugular intrahepatic por-tosystemic shunt(TIPS)

ascites, 354hepatic venous outflow, 341,

342, 343portal hypertension, 345,

347, 348Traveler’s diarrhea, 232Treponema pallidum, 72Trimethoprim-sulfamethoxa-

zole (TMP-SMX),227, 228, 230, 231

Tropheryma whippelii, 127Tropical sprue, 128–129

acute, 128chronic, 128

Tuberous sclerosis, 247Turcot’s syndrome, and col-

orectal cancer, 246Tylosis, 177Typhoid fever, 226, 227, 227t

UUUlcerative colitis, 193, 197i

Brooke ileostomy, 205, 206iand cholangiocarcinoma,

222clinical presentation, 195colorectal cancer, 220differential diagnosis,

197–198epidemiology, 193, 1945-ASA, 199, 200–202, 200tgenetics, 194Kock pouch, 205, 206ileft-sided, 199medications, 199–205, 201tand primary sclerosing

cholangitis, 218, 285serologic markers, 196, 196tsulfasalazine, 199, 200t, 201

surgery, 205, 206isurveillance colonoscopy,

221treatment according to indi-

cation, 211ttreatment strategies,

205–207Ulcerative proctitis, 199Ulcerative proctosigmoiditis,

199Ulcers. See Duodenal ulcers,

Gastric ulcers,Peptic ulcer disease

Uncomplicated peptic ulcerdisease, mainte-nance therapy, 65

Upper esophageal sphincter(UES), anatomy andphysiology, 33, 34

Upper gastrointestinal tract(UGI) bleeding, 159

angiographic embolization,161, 163

aortoenteric fistula, 162clinical factors, 160CREST syndrome, 162Ehlers-Danlos syndrome,

162, 173endoscopic findings, 160evaluation, 159–160and H. pylori, 161hematobilia, 162hemosuccus pancreaticus,

162Mallory-Weiss tear, 161mucosal erosive disease, 161neoplasms, 162and NSAIDs, 159, 161peptic ulcers, 160–161portal hypertensive gas-

tropathy, 161–162vascular anomalies, 162–163

Upper gastrointestinal tractulceration, viral59–60

Urease breath test, H. pylori, 62

VVVaricella-zoster virus, and

achalasia, 36Variegate porphyria, 179

About the book…

Written by an experienced and dedicated team of Mayo Clinic gastroenterologists and hepatologists, this newly expanded and updated Third Edition of the best-selling Mayo ClinicGastroenterology and Hepatology Board Review is the go-to comprehensive resource for acomplete scope of essential knowledge in all areas of gastroenterology and hepatology and inthe related areas of pathology, endoscopy, nutrition, and radiology.

The new edition is an easy-to-use, case-based text expertly designed for those preparing to takethe gastroenterology board examination and for gastroenterologists in need of recertification.Medical students and residents in the areas of internal medicine and gastroenterology, gastroen-terology fellows, and physicians seeking a practical and comprehensive review of gastroenterologyand hepatology will also benefit from this stand-alone guide.

New features in the Third Edition include:

• Several new multiple-choice questions and answers addressing the growing areas of concernin gastroenterology and hepatology

• 12 substantially updated and revised chapters by new authors who provide fresh, cutting-edge perspectives

• A new chapter on drug-induced liver injury• Increased emphasis on case-based learning, which is critical to superior diagnostic and thera-

peutic approaches to patient care• The addition of more than 100 high-quality color photographs• Content that is organized by subspecialty areas, including esophageal, gastroduodenal, and

colonic disorders, small-bowel disease and nutrition, pancreaticobiliary and liver diseases,and other miscellaneous disorders

• An abundance of additional new material appropriate for the board review and practice

About the editors...

STEPHEN C. HAUSER, MD, is Consultant, Division of Gastroenterology and Hepatology,Mayo Clinic, Rochester, Minnesota; Assistant Professor of Medicine, College of Medicine,Mayo Clinic

DARRELL S. PARDI, MD, is Consultant, Division of Gastroenterology and Hepatology,Mayo Clinic, Rochester, Minnesota; Associate Professor ofMedicine, College of Medicine, Mayo Clinic

JOHN J. POTERUCHA, MD, is Consultant, Division ofGastroenterology and Hepatology, Mayo Clinic, Rochester,Minnesota; Associate Professor of Medicine, College ofMedicine, Mayo Clinic


Board Review

Third Edition




MAYO CLINIC SCIENTIFIC PRESS

Mayo C

linic Gastroenterology and H

epatology Board R

eview

ThirdEdition

Hauser

HauserSpread 8/5/08 12:25 PM Page 1

Mayo Clinic Gastroenterology and Hepatology

Documents

Transcript of Mayo Clinic Gastroenterology and Hepatology