Chronic Pancreatitis (LitReview_2009)

8/6/2019 Chronic Pancreatitis (LitReview_2009)

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August 2009

A Supplement to Clinician Reviews

CME

A Case-Based Discussion oChronic Pancreatitis 2

Randall K. Pearson, MD

Evaluation and Diagnosis 9

Rakesh Nanda, MD

Camron Kiafar, DO

Management o ExocrinePancreatic Insufciency 15

Francisco C. Ramirez, MD

Pancreatic Enzyme Therapy 20

Phillip Toskes, MD

Chronic Pancreatitis

Improving Patient Outcomes

This activity is jointly sponsored by Postgraduate Institute

for Medicine and Quadrant Medical Education.

Supported by an educational grant fromSolvay Pharmaceuticals.

Release date: August 2009

Expiration date: August 31, 2010

Estimated time to complete activity: 1.5 hours


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Target Audience: Clinicians with an interest in chronic

pancreatitis.

Statement of Need: The diculty o diagnosing patients

with mild or early chronic pancreatitis contributes to an

underdiagnosis o this condition, which is highlighted by

the act that the delay between onset o symptoms and

diagnosis is oten yearsmost particularly in patients

without a history o alcoholism. However, the serious

nature o the disease, the high risk o complications,and the severe impact o pancreatitis-associated pain

on quality o lie argue or a more concerted eort to

diagnose those with the disease. Use o pancreatic

enzyme therapy can alleviate the complications asso-

ciated with chronic pancreatitis, including malabsorp-

tion and steatorrhea, which can lead to muscle wasting.

Patients with HIV/AIDS may be at greater risk or both

chronic pancreatitis and its complications; recent data

suggest that those in the VA health care system carry

a higher risk or HIV/AIDS than do those in the general

population. It is important that physicians and other

health care proessionals be aware o these conditionsand o the need to initiate appropriate and eective

interventions such as pancreatic enzyme therapy.

Educational Objectives: Upon completion o this

activity, participants will be able to successully:

Explain the epidemiology and pathophysiology o

chronic pancreatitis.

Discuss the symptoms and diagnosis o chronic pan-

creatitis.

State the complications o pancreatic exocrine insu-

ciency (PEI) and malabsorption.

Explain the importance o treating PEI to improvepatient outcomes.

Discuss the role o pancreatic enzyme therapy in

improving nutritional health o patients suering rom

chronic pancreatitisassociated PEI and steatorrhea,

including appropriate dosing o such therapy.

Faculty: James V. Felicetta, MD (Chair), Chairman,

Department o Medicine, Carl T. Hayden VA Medical

Center, Phoenix, Arizona; Proessor o Clinical Medicine,

University o Arizona, Tucson.

Camron Kiaar, DO, FACG, Assistant Chie o Thera-

peutic Endoscopy, Department o Gastroenterology at

Carl T. Hayden VA Medical Center, Phoenix, Arizona.

Rakesh Nanda, MD, FACP, FACG, Assistant Proessor

o Clinical Medicine at the University o Arizona, Tucson;

gastroenterologist on sta at Carl T. Hayden VA Medical

Center, Phoenix, Arizona.

Randall K. Pearson, MD, Associate Proessor, Depart-

ment o Medicine, Division o Gastroenterology and Hep-

atology, Mayo Medical Center, Rochester, Minnesota.

Francisco C. Ramirez, MD, Proessor o Clinical Medicine

at the University o Arizona College o Medicine,

Phoenix; Chie o the Division o Gastroenterology at

Carl T. Hayden VA Medical Center, Phoenix, Arizona.

Phillip Toskes, MD, Proessor o Medicine, University o

Florida College o Medicine, Gainesville, Florida.

Accreditation Statement: This activity has been planned

and implemented in accordance with the Essential Areas

and policies o the Accreditation Council or Continuing

Medical Education (ACCME) through the joint sponsor-

ship o Postgraduate Institute or Medicine (PIM) and

Quadrant Medical Education. PIM is accredited by the

ACCME to provide continuing medical education or

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Credit Designation: Postgraduate Institute or

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Physicians should only claim credit commensurate with

the extent o their participation in the activity.

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The American Academy o Physician Assistants accepts

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Disclosure of Conflicts of Interest: Postgraduate

Institute or Medicine (PIM) assesses confict o interest

with its instructors, planners, managers, and other indi-

CME Ifmi

ChronIC PanCrEatItIs

Impvig Pie oucme tug Ely Ievei d teme


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viduals who are in a position to control the content o

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The facultyreported the ollowing nancial relation-

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related to the content o this CME activity:

James V. Felicetta, MD (Chair), is a member o the

speakers bureaus o Merck, Novartis, and sanoi-

aventis.

Camron Kiafar, DO, FACG, has no nancial arrange-

ments or ailiations with commercial or equipment

companies during the last three years.

Rakesh Nanda, MD, FACP, FACG, has no nancial

arrangements or aliations with commercial or equip-

ment companies during the last three years.

Randall K. Pearson, MD, has no nancial arrange-

ments or ailiations with commercial or equipment

companies during the last three years.

Francisco C. Ramirez, MD, is a member o the speak-ers bureaus o Procter & Gamble and Takeda.

Phillip Toskes, MD, receives grant/research support

rom Axcan, Eurand, Johnson & Johnson, and the

National Institutes o Health and is a member o the

speakers bureau o Axcan.

The ollowing planners and managers, Kelly Eckert,

Linda Graham, RN, BSN, BA, Jan Hixon, RN, BSN, MA,

Trace Hutchison, PharmD, Julia Kirkwood, RN, BSN

and Jan Schultz, RN, MSN, CCMEP hereby state that

they or their spouse/lie partner do not have any nan-

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this activity o any amount during the past 12 months.

Method of Participation: There are no ees or par-

ticipating in and receiving CME credit or this activity.

During the period August 2009 through August 31,

2010, participants must 1) read the learning objec-

tives and aculty disclosures; 2) study the educational

activity; 3) complete the posttest by recording the best

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ation orm on page 25; 4) complete the evaluation orm;

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Any procedures, medications, or other courses o

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Release date: August 2009

Expiration date: August 31, 2010Estimated time to complete activity: 1.5 hours

CHRONIC PANCREATITIS AUGUST 2009 1

This activity is supported by an educational grant rom Solvay

Pharmaceuticals.

Jointly Sponsored by Postgraduate Institute or Medicine and

Quadrant Medical Education.


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CHRONIC PANCREATITIS AUGUST 2009

Case: a Young Woman With PanCreatitis

A 25-year-old white woman presents with an eight-year history o pancreatitis. She had two mild and

sel-limited episodes o well characterized acute pan-

creatitis at age 17. She admitted to drinking alcohol

most weekends, sometimes bingeing, since age 16.

Her clinicians diagnosed alcoholic pancreatitis and

advised abstinence.

The woman was asymptomatic or two years. At age

20 and a junior in college, she had three more discrete

episodes o clinical acute pancreatitis. Ater the second

episode, an empiric cholecystectomy was perormed

or possible microlithiasis, but her episodes persisted.

Her alcohol ingestion was now moderate: three to ourbeers at least three days per week.

The patient was again advised to discontinue alco-

hol, and she complied. She was reerred to a tertiary

care center where an endoscopic retrograde cholan-

giopancreatography with pancreatic sphincterotomies

was perormed. A diagnosis o chronic pancreatitis

(CP) secondary to sphincter o Oddi dysunction was

made. The procedure was complicated by her most se-

vere episode o acute pancreatitis, necessitating a 10-

day hospitalization.

Despite complete alcohol abstinence, the woman

had recurrent attacks o acute pancreatitis requiringhospitalization every other month (on average) or

the next our years. Oten the painul episodes lacked

biochemical evidence o acute pancreatitis (normal

amylase and lipase). For one year prior to reerral to

our medical center, she has had persistent abdominal

pain in between attacks and has required hydrocodone

three days per week. The pain is epigastric with inra-

scapular radiation exacerbated by meals. There is no

evidence o glucose intolerance or history o chronic

diarrhea. She has lost 10 lb unintentionally. Her qual-ity o lie is poor; her requent hospitalizations and

opioid use have resulted in a disability application.

Routine physical exam, blood test, and abdominal

computed tomography results are normal. An endo-

scopic ultrasound demonstrates six criteria or CP: hy-

perechoic strands and oci, parenchymal lobulation,

small shadowing calciications in the pancreatic head,

an echogenic main duct wall, and an irregular main

duct contour. A diagnosis o idiopathic chronic pan-

creatitis (ICP) is established.

This review will ocus on the natural history and

pathophysiology o CP to address questions raised bythis clinical presentation:

Why is this unlikely to be alcoholic pancreatitis?

Is this presentation, with its relatively late diagnosis

(eight years), typical?

Will understanding the natural history help us ad-

vise this patient?

Are there any insights into the mechanisms respon-

sible or idiopathic pancreatitis?

Causes of ChroniC PanCreatitisalclc Cc Pc

Long-term, excessive alcohol ingestion is the mostcommon cause o CP in the developed countries o the

West, accounting or 65% to 80% o all cases (Table 1).1

Thus, the rate o CP depends on alcohol consump-

tion habits and varies rom 3.5 per 100,000 to 27.4 per

100,000.13 Up to 75% o aected individuals are men.1

Most experts estimate that no more than 10% o chronic

alcoholics develop CP; however, epidemiologic studies

to determine environmental, dietary, or genetic coac-

tors have been negative or inconsistent.2,3 Several analy-

ses have suggested that concomitant cigarette smoking

increases the risk or, and accelerates the rate o, progres-

sion o alcoholic chronic pancreatitis (ACP).4

Cc Pca C-Bd Dcrdll K. P, mD

Chronic pancreatitis is a progressive and destructive necroinflammatory disorder of the

pancreas characterized by irreversible fibrosis of the gland with eventual failure of exocrine

and endocrine functions. Flares of inflammation and abdominal pain are dominant clinical

features early in its course. At endstage, parenchymal and ductal calcifications often coincide

with gland failure.

D. P is an associate professor in the department ofmedicine, division of gastroenterology and hepatology, at MayoMedical Center, Rochester, Minnesota.


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AUGUST 2009 CHRONIC PANCREATITIS

The amount o ingested alcohol needed to induce

pancreatitis has not been established. However, most

experts would agree that daily ingestion must be sub-

stantial over a long period; at our center, an intake

o 80 g o pure alcohol daily or 10 years is required

or a patient to be irmly placed in the alcoholic co-

hort.5 This equates to one bottle o wine or a six-pack

o beer daily or a decade. Cumulative lietime intake

approaches 1000 L o pure alcohol; thus, the peak

incidence o ACP occurs in the ith decade o lie

(mean age, 44). An important epidemiologic study

rom Europe demonstrated the dose eect o alcohol:

or every 20-g/day increase in consumption, there was

a 1.4-old increase in relative risk or CP.6

In our practice, this patients intermittent alcohol

ingestion or ewer than ive years is insuicient to

make a diagnosis o ACP, although even modest al-cohol intake accelerates disease progression and acute

lares o inlammation.7 I believe, however, that absti-

nence was unlikely to alter signiicantly this patients

disabling symptoms.

idpc Cc PcOnce alcohol and the uncommon causes o CP have been

excluded, the clinician and the patient are aced with the

vexing and unsatisactory idiopathic diagnosis, which

accounts or at least 20% o CP.13 However, many o

these patients have identiiable genetic predispositions to

CP. The epidemiology and natural history o ICP can bedistinguished rom ACP; these are two distinct cohorts,

based on age o onset and clinical presentation.

ely- iCPICP presents nearly 20 years earlier (mean age o onset,

20 years) than ACP and involves both sexes equally.5,8,9

Pain was virtually universal (96%) in the Mayo se-

ries patients5 and is usually punctuated by episodes o

clinical acute pancreatitis early in the disease course.

Pain is moderate to severe in 80% o patients, and

they require pancreatic surgery more requently than

alcoholics (60% vs 30%) in this series.5

L- iCPICP has a bimodal age distribution; the second

peak occurs in the sixth decade (median age, 56).

Approximately 50% o these patients present without

abdominal pain, and only 10% have severe pain.5

The rate o progression to gland ailure rom onset

o disease, oten marked by the appearance o calci-

ication on clinical radiographs, diers signiicantly

between the groups. In ACP, the appearance o calci-

ications averaged 8.7 years, late-onset ICP 19 years,

and early onset ICP 25 years in the Mayo series.5

Rates o appearance o exocrine and endocrine ailure

mirror these observations (Table 2).5,10

a PcThis uncommon disorder, which may account or 3%

to 5% o CP, has been recognized relatively recently,

and its most common variant has a distinct histopath-

ologic pattern.1113 Autoimmune pancreatitis is also

termed lymphoplasmacytic sclerosing pancreatitis.

The condition involves a plasma cell iniltrate around

small ducts and swirling ibrosis around ducts and

veins (storiorm ibrosis), with a distinctive oblitera-tive phlebitis. This disease presents primarily in men

(70% to 85%) in their seventh decade.1013 A landmark

study rom Japan in 2001 reported the association o

this condition with elevated levels o immunoglobulin

subtype 4 (IgG4) in the serum.11 It is now recognized as

a systemic disease with plasma cells bearing IgG4, in-

iltrating the pancreas and other organs including bile

ducts, salivary glands, retroperitoneum, and kidneys.

Because autoimmune pancreatitis is distinct rom

other orms o CP, pain and acute inlammation are

uncommon at presentation. An inlammatory mass in

the head o the pancreas causing obstructive jaundiceand mimicking pancreatic cancer is the most requent

clinical presentation at our center. The unique respon-

siveness o autoimmune pancreatitis to systemic corti-

costeroid therapy dierentiates this disorder rom CP

and pancreatic cancer.

o CIn Asia and parts o India, the highest prevalence o

CP is observed (up to one in 830 persons).14 This orm

o CP has been called tropical pancreatitis; it is dis-

tinguished by early age o onset (mean age, 13), lack

o alcohol exposure, and rapid progression to calciic

Table 1. C Cc Pc

Data extracted from Witt H et al,1 Etemad B et al,2 and DiMagnoMJ et al.3

C fqcy (%)

Alcoholic 6580Idiopathic 1530

ucAutoimmune 35Obstructive 35

rHereditary


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CHRONIC PANCREATITISA CASE-BASED DISCUSSION


disease and gland ailure.14 Speculation about etiology

has centered on the nearly 50% rate o mutation o the

serine peptidase inhibitor, Kazal type 1 gene, SPINK1,

in these cohorts (see section on SPINK1).

Hypertriglyceridemia and hypercalcemia due to pri-mary hyperparathyroidism are important to recognize

due to their reversibility, but they account or much

less than 1% o cases.1-3

Pancreatic duct obstruction will lead to atrophy, i-

brosis, ductal abnormalities, and parenchymal calciica-

tions upstream rom the block, whether the obstruction

results rom neoplasia or benign strictures (eg, iatrogenic

rom pancreatic duct stenting). Intraductal papillary

mucinous neoplasia, especially o the main duct, can

present in an indolent ashion with all the eatures o ad-

vanced CP due to tumor obstruction or secreted mucin,

including ductal and parenchymal calciication.15 Therisk o invasive malignancy that complicates this disor-

der dictates surgical resection in a subset o patients.

Hereditary pancreatitis (HP), an autosomal domi-

nant disease that was irst recognized by Comort and

Steinberg in 1952, is rare but provides crucial insights

into the pathophysiologic mechanisms responsible or

CP.16,17 Hereditary pancreatitis recapitulates the more

common ACP and ICP clinical presentation, with early

attacks o acute pancreatitis (oten in children younger

than age 10), progression o ibrosis and ductal deects,

and chronic pain, eventuating in gland calciication

and ailure.

Mutations in

the cationic tryp-

sinogen gene,

PRSS1, have been

identiied as re-

sponsible or the

majority o HP

kindreds. This

discovery has in-

tensiied investi-

gation o the role

o premature acti-

vation o trypsin

in the acinar cell

as critical in ini-

tiating pancreatic

injury.18

The mostcommon mutation

(aecting about

50% o kindreds)

inPRSS1 is R122H

or histidine or ar-

ginine.17,18 Figure

1 illustrates how

this gain-o-unction mutation leads to autodiges-

tion by activating the enzyme cascade in the acinar

cell.2 Recently, a transgenic mouse model expressing

mutantPRSS1 displayed both acute inlammation and

progressive ibrosis over time, reproducing the clinicaleatures o CP with a single amino acid substitution in

trypsin.19

Pathogenesis of ChroniC PanCreatitisBy the time ACP is recognized clinically, both acinar

and ductal elements o the exocrine pancreas are ir-

reversibly distorted and injured. Thus, it is no surprise

that multiple theories on the cellular pathogenesis o

alcohol-mediated injury have emerged; these are sum-

marized below and in two recent reviews.2,20

Oxidative stress. Similar to hepatocytes, acinar cells

metabolize alcohol, including an oxidative pathway,capable o damaging lipid membranes including

lysosomes and zymogen granules. However, while

oxidative stress is almost certain to contribute to i-

brogenesis, it has never been shown to be capable o

initiating the process.

Toxic-metabolic. Alcohol appears to be directly toxic

to acinar cells by altering cellular metabolism that

leads to accumulation o excess cytoplasmic lipid.

It is unclear whether development o a steatopan-

creatopathy (similar to indings in the liver) leads

to inlammation.

Stone and ductal obstruction. Henri Sarles pro-

Table 2. f Cc Pc:idpc, alclc, d a

* Insufficient clinical data or follow-up.

Data extracted from Layer P et al5 and Chari ST et al.10

idpc alclc aely- L-

sx (m/f [%]) 44/56 56/44 72/28 83/17a d

Median age (yr) 19 56 44 63Pain (%) 96 54 77 20Diabetes (%) 0 22 8 40Exocrine failure (%) 8 22 12 *Jaundice (%) 0 0 5 73Calcification (%) 0 2 4 0IgG4 increase (%) 6 6 6 71

sbq c

(ev [%]/md [y])Diabetes 32/28 41/12 38/20 75/*Exocrine failure 44/26 46/17 48/13 *Calcification 56/25 37/19 60/09 0


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PEARSON


posed the ducts as the primary site o deranged me-

tabolism in CP, drawing a clear distinction with

acute pancreatitis, wherein activation o trypsinin the acinar cell has been the central paradigm.21

In this model, CP begins in the pancreatic ductal

system; alcohol directly alters the secretion, avor-

ing protein plugs and stone ormation. While the

lithogenicity model clearly applies as the disease

progresses, protein plugs and obstructed ducts are

not always observed in the early stages o clinical

disease or in animal models.

nc-fb mdlTraditional models o ACP pathogenesis assumed that

the disease was chronic rom the start (ie, by the timeirreversible injury and ibrosis were present).13 The ne-

crosis-ibrosis construct postulates initiation o ACP as

an acute event with progression to a chronic irreversible

stage as the result o repeated acute injury.20 The pro-

posed site o the acute necroinlammatory episode is the

acinar cell, with the underlying mechanism centered on

uncontrolled activation o trypsin. Clinical and experi-

mental evidence have accumulated rapidly to support

the necrosis-ibrosis model. These data include:

Hereditary pancreatitis is due most commonly to

a mutation in trypsinogen that results in a protein

with enhanced intra-acinar activation and impaired

degradation (gain o unction).18

Postmortem studies in atal, acute alcoholic pancre-

atitis have shown no evidence o chronic changesin the pancreas in 53% o cases.22

A prospective study o a cohort o alcoholics dem-

onstrated that progression o ACP correlated most

closely with the requency o recurrent clinical

acute pancreatitis.7,23

Pancreatic ibrosis in animal models can be in-

duced by repeated episodes o necroinlammation

using a variety o methods, including supraphysi-

ologic doses o cerulein, inhibition o superoxide

dismutase, and endotoxin administration coupled

with chronic alcoholic eeding.2427

This paradigm shit in our understanding o the initia-tion o CP requires a reconciliation with the long-held

clinical observation that common causes o acute pan-

creatitis (eg, biliary) are sel-limited and do not lead to ir-

reversible injury. The identiication o pancreatic stellate

cells (PSCs) is a crucial development in understanding the

evolution o acute injury to irreversible ibrogenesis.28

PanCreatiC steLLate CeLLsIn the liver, stellate cells are established as a key regula-

tor and source o collagen deposition in hepatic ibrosis

and progression to cirrhosis. The discovery o these

vitamin-A storing cells a decade ago in the human

Figure 1. rl typ acv Pc

(A) Normal pancreas. Autoactivation of trypsin f rom trypsinogen within the pancreatic acinar cell zymogen granule is inhibited initially by SPINK1 and then

degraded by mesotrypsin and CTRC. This defense mechanism prevents trypsin from activating the enzyme cascade leading to autodigestion, acinar cell death,

and clinical pancreatitis. (B) Hereditary pancreatitis. Mutant PRSS1 demonstrates enhanced autoactivation kinetics and the most common mutant allele (R122H) is

less susceptible to degradation. This enhanced trypsin activity leads to intra-acinar enzyme cascade activation, autodigestion, and inflammation due to necrosis.

(C) Idiopathic pancreatitis. The effects of trypsin autoactivation in the acinar cell can also be enhanced by impaired defense mechanisms including loss of function

mutations in SPINK1 and CTRC. The mechanism by which CFTR mutations (present on ductal cells) enhance intraparenchymal activation of trypsin is not known but

may involve alterations in the balance of proteases and antiproteases due to defective trafficking (relative secretory block) or acidification effects.

AP = activation peptide; CFTR = cystic fibrosis transmembrane conductance regulator gene; CTRC= chymotrypsin C gene; PRSS1 = cationic trypsinogen gene; SPINK1 = serine proteaseinhibitor, Kazal type 1 gene.Adapted from Witt H et al.1

a nl pc hdy

B pc idpc

C pcTrypsinogen

Trypsin

CFTR

AP

SPINK1 MesotrypsinCTRC

Trypsinogen

Trypsin

CFTR

AP


Trypsinogen

Trypsin

CFTR

AP


Enzyme cascade

Autodigestion Pancreatitis Autodigestion Pancreatitis

Enzyme cascade

+


8/28



pancreas was a major advance.28 In the quiescent state,

they are triangular-shaped, perivascular cells contain-

ing lipid-laden vacuoles. Activated PSCs lose their lipid

droplets, morphologically transorm into a ibroblast-

like phenotype, and migrate into periacinar regions.

Once activated, PSCs synthesize and secrete the com-

ponents o early pancreatic ibrogenesis, especially

type I and III collagen.

Considerable experimental and clinical evidencesupports a central role or these cells in generating

the excessive extracellular matrix protein essential or

initiation and progression o CP.2,20,25,29 Furthermore,

two distinct pathways o activation have been iden-

tiied linking PSC activation with alcoholic toxicity.

Proinlammatory cytokines released during acute epi-

sodes o necroinlammation have been observed to acti-

vate PSCs in vitro.2,20 Activated PSCs are also capable o

expressing these same cytokines, setting up the milieu

or autocrine activation and perpetuation o excessive

collagen deposition ater the initial injury has resolved.

Secondly, alcohol and its metabolites (especially acetal-

dehyde) activate PSCs directly and via oxidative stress

mechanisms, bypassing the need or acute injury. This

pathway o activation suggests that pancreatic ibrosis

secondary to alcohol may not be absolutely dependent

on acute inlammation. Figure 2 shows a current work-

ing model or ACP pathogenesis.2

genetiCs anD ChroniC PanCreatitis

Recent advances in genetics have identiied the ollow-ing major groups o mutations predisposing to CP:

PSerine protease 1 gene, PRSS1. As previously dis-

cussed, autosomal dominant HP is due to identiiable

gain-o-unction mutations in the trypsinogen gene

in 75% o kindreds.18,30 Because penetrance o CP in

mutation carriers is high (80%), most patients can be

readily identiied by amily history.18,30 However, sub-

jects harboring a new or spontaneous mutation would

be missed. Patients younger than 25 years o age with

idiopathic acute or CP should undergo genetic testing;

Figure 2. Wk mdl aCP P

In the necrosisfibrosis concept, the acinar cell is the site of initiation. Direct toxicity of alcohol and its metabolites have a variety of effects on acinar cell function,

including increased expression of digestive enzymes, perturbed lipid metabolism, oxidant stress, and destabilized zymogen and lysosomal membranes. The net

effect is enhanced activation of trypsin and, with an appropriate trigger, enzyme cascade activation, necrosis, and inflammation. Inflammation recruits cytokines

that activate stellate cells to deposit excessive extracellular matrix. Stellate cells are also directly activated by alcohol and its metabolites, leading to further collagen

deposition and fibrosis. Finally, perturbed glandular architecture and function cause protein precipitation in the small ductules potentiating the disease process (eg,

a secretory block at the apical surface of the acinar cell).

ACP = alcoholic chronic pancreatitis; CE = cholesteryl esters; FAEE = fatty acid ethyl esters; mRNA = messenger RNA.

Adapted from Witt H et al.1

Acinar

cell Secretory block

Ductule

Protein plug

Acetaldehyde

Oxidant stress

Stellate cell

activation

Cytokines

Necrosis


9/28

PEARSON


in one series, 5% o this cohort had PRSS1 mutations

in the absence o a amily history.30

Chymotrypsin C gene,CTRC. A recent study ound

variants in this protease to be associated with both he-

reditary and idiopathic CP.31 The detected mutations

were loss-o-unction mutations, consistent with the

role o this protease in degrading activated trypsin.

Thus, loss o CTRC would reduce trypsin-degrading

activity in the acinar cell, enhancing trypsin activity

and autodigestion.31

Serine protease inhibitor, Kazal type 1 gene,

SPINK1. Considering the central role o trypsin acti-

vation in pancreatitis, SPINK1 is a logical candidate

gene. A potent protease inhibitor coexpressed in the

acinar cell, it is a irst-line deender in the zymogen

granule against activated intrapancreatic trypsin. In

2000, a germline mutation in the coding region oSPINK1 (N34S) was ound to be strongly associated

with tropical pancreatitis (~50%) and early onset ICP

(~20%).32,33 However, the high prevalence (~2%) o

this genetic polymorphism in the general population

suggests that this mutation predisposes rather than

causes pancreatitis. Furthermore, the mechanism

o impaired protease inhibition has been diicult

to prove; the N34S mutant is a unctional inhibi-

tor.34 Nevertheless, overexpression o native SPINK1

in transgenic models protects against pancreatitis.35

SPINK1 knockout mice die shortly ater birth with

acinar cell degeneration, conirming the importanceo this protein in pancreatitis protection as well as in

acinar cell integrity.36 Figure 1 illustrates a conceptual

model o mutations in trypsin and its inhibitors in

the pathogenesis o acinar cell injury.2

Cystic fibrosis transmembrane conductance reg-

ulator gene, CFTR. Cystic ibrosis (CF) is the most

common autosomal recessive disease among whites.

It is caused by mutations in CFTR, leading to dei-

cient chloride secretion.37 More than 1000 mutations

in CFTR have been identiied with a variable impact

on unction o the protein.38 When CFTR unction is

severely impaired by two mutations causing near com-plete loss o chloride channel activity (including in the

pancreatic ductal cell), overt CF is present with pan-

creatic insuiciency and chronic lung disease, which

are cardinal eatures contributing to premature death.

Milder impairment in CFTR unction has been recog-

nized with a less severe phenotype including suicient

pancreatic unction; ironically, these CF patients are at

risk or clinical episodes o acute pancreatitis.38

In 1998, two groups identiied an almost 6-old in-

crease in CFTR mutations in patients with ICP who oth-

erwise lacked any clinical eatures o CF.39,40 Several series

have conirmed that about 20% to 25% o patients with

ICP (especially early onset) harbor at least oneCFTRmuta-

tion.41,42 Some are true compound heterozygotes with two

mutated alleles, but one mutation mildly impairs CFTR

unction, leaving enough residual chloride channel activ-

ity to avoid overt CF. Thus, ICP is part o a growing list o

monosyndromatic disorders due to impaired CFTR unc-

tion (eg, congenital bilateral absence o the vas deerens

[male inertility] and pulmonary bronchiectasis). Given

the high rate oCFTR mutations in the general popula-

tion (~3%), a single CFTR mutation is likely to be a predis-

posing, permissive actor rather than causative or most

subjects.41,42

genetiCs anD aLCohoLiC PanCreatitisAttempts to link germline mutations to a risk or al-

coholic pancreatitis have been inconsistent and in-

conclusive. Increased CFTR and SPINK1 mutations inACP have been observed in some but not all studies.3

Preliminary studies also suggest that CTRC loss is over-

represented in ACP.31 A recently described polymor-

phism in the anionic trypsinogen gene,PRSS2, protects

against pancreatitis but has not been tested in sui-

ciently large populations to know its role in the 10%

penetrance o ACP in chronic alcoholism.43

Case: Diagnosis anD reCommenDationsOur patient was diagnosed with early-onset ICP.

Alcohol abstinence, high-dose pancreatic enzyme

supplements, and pharmacologic doses o antioxidantsdid not prevent urther attacks o acute pancreatitis.

Ater inormed consent, a series o genetic tests were

perormed. No disease-causing mutations in PRSS1

were identiied. Screening or the 100 most common

CFTR mutations and SPINK1 showed the patient to be a

transheterozygote: CFTR508 and SPINK1 N34S. This

combination o mixed mutations has been shown to

be overrepresented in ICP in other studies.42

Given the long course expected with early onset ICP

and the dominance o recurrent lares o acute pancre-

atitis, the patient was reerred or consideration o total

pancreatectomy with islet-cell autotransplantation.

ConCLusionChronic pancreatitis due to any cause is a vexing clini-

cal problem or clinicians and patients. A long delay in

diagnosis, recurrent acute pancreatitis, chronic pain, and

long-term morbidity associated with ailed exocrine and

endocrine unction are normal. Improved understanding

o the initial insult o necroinlammation at a biochemi-

cal and cellular level (intra-acinar activation o trypsin),

coupled with the identiication o PSC as the source o

collagen deposition, should lead to more speciic and e-

ective therapies and improve long-term prognoses.


10/28



referenCes1. Witt H, Apte MV, Keim V, Wilson JS. Chronic pancreatitis:

Challenges and advances in pathogenesis, genetics, diagnosis,and therapy. Gastroenterology. 2007;132(4):15571573.

2. Etemad B, Whitcomb DC. Chronic pancreatitis: Diagnosis,classifcation, and new genetic developments. Gastroenterology.

2001;120(3):682707.3. DiMagno MJ, DiMagno EP. Chronic pancreatitis. Curr Opin Gas-

troenterol. 2006;22(5):487497.4. Maisonneuve P, Lowenels AB, Mllhaupt B, et al. Cigarette

smoking accelerates progression o alcoholic chronic pancre-atitis. Gut. 2005;54(4):510514.

5. Layer P, Yamamoto H, Kaltho L, Clain JE, Bakken LJ, DiM-agno EP. The dierent courses o early- and late-onset idio-pathic and alcoholic chronic pancreatitis. Gastroenterology.1994;107(5):14811487.

6. Durbec JP, Sarles H. Multicenter survey o the etiology o pan-creatic diseases. Relationship between the relative risk o de-veloping chronic pancreatitis and alcohol, protein and lipidcomposition.Digestion. 1978;18(5-6):337350.

7. Mllhaupt B, Truninger K, Ammann R. Impact o etiology onthe painul early stage o chronic pancreatitis: A long-term pro-spective study. Z Gastroenterol. 2005;43(12):12931301.

8. Lankisch PG, Lhr-Happe A, Otto J, Creutzeldt W. Naturalcourse in chronic pancreatitis. Pain, exocrine and endocrinepancreatic insufciency and prognosis o the disease.Digestion.1993;54(3):148155.

9. Ammann RW, Akovbiantz A, Largiader F, Schueler G. Courseand outcome o chronic pancreatitis. Longitudinal study o amixed medical-surgical series o 245 patients. Gastroenterology.1984;86(5 pt 1):820828.

10. Chari ST, Smyrk TC, Levy MJ, et al. Diagnosis o autoimmunepancreatitis: The Mayo Clinic experience. Clin GastroenterolHepatol. 2006;4(8):10101016.

11. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concen-trations in patients with sclerosing pancreatitis. N Engl J Med.2001;344(10):732738.

12. Yadav D, Notahara K, Smyrk TC, et al. Idiopathic tumeactivechronic pancreatitis: Clinical profle, histology, and natural his-tory ater resection. Clin Gastroenterol Hepatol. 2003;1(2):129135.

13. Finkelberg DL, Sahani D, Deshpande V, Brugge WR. Autoim-mune pancreatitis. N Engl J Med. 2006;355(25):26702676.

14. Balakrishnan V, Nair P, Radhakrishnan L, Narayanan VA. Tropi-cal pancreatitisA distinct entity, or merely a type o chronicpancreatitis?Indian J Gastroenterol. 2006;25(2):7481.

15. Zapiach M, Yadav D, Smyrk TC, et al. Calciying obstructivepancreatitis: A study o intraductal papillary mucinous neo-plasm associated with pancreatic calcifcation. Clin Gastroen-terol Hepatol. 2004;2(1):5763.

16. Comort MW, Steinberg AG. Pedigree o a amily with hereditarychronic relapsing pancreatitis. Gastroenterology. 1952;21(1):54-63.

17. Teich N, Rosendahl J, Tth M, Mssner J, Sahin-Tth M. Muta-tions o human cationic trypsinogen (PRSS1) and chronic pan-

creatitis.Hum Mutat. 2006;27(8):721730.18. Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancre-

atitis is caused by a mutation in the cationic trypsinogen gene.Nat Genet. 1996;14(2):141145.

19. Archer H, Jura N, Keller J, Jacobson M, Bar-Sagi D. A mousemodel o hereditary pancreatitis generated by transgenic expressiono R122H trypsinogen. Gastroenterology. 2006;131(6):18441855.

20. Stevens T, Conwell DL, Zuccaro G. Pathogenesis o chronic pan-creatitis: An evidence-based review o past theories and recentdevelopments.Am J Gastroenterol. 2004;99(11):22562270.

21. Sarles H. Alcoholism and pancreatitis. Scan J Gastroenterol.1971;6(3):193198.

22. Renner IG, Savage WT III, Pantoja JL, Renner VJ. Death dueto acute pancreatitis. A retrospective analysis o 405 autopsycases.Dig Dis Sci. 1985;30(10):10051018.

23. Ammann RW, Muellhaupt B. Progression o alcoholic acute to

chronic pancreatitis. Gut. 1994;35(4):552556.

24. Matsumura N, Ochi K. Ichimura M, Mizushima T, Harada H,Harada M. Study on ree radicals and pancreatic fbrosisPancreatic fbrosis induced by repeated injections o superox-ide dismutase inhibitor.Pancreas. 2001;22(1):5357.

25. Apte MV, Wilson JS. Experimental models o pancreatic fbrogen-

esis and the role o stellate cells. In: Buchler MFH, Uhl W, Maler-theiner P, eds. Chronic PancreatitisNovel Concepts in Biology andTherapy. Berlin, Germany: Blackwell Science; 2002:113133.

26. Perides G, Tao X, West N, Sharma A, Steer ML. A mouse model o eth-anol dependent pancreatic fbrosis. Gut. 2005;54(10):14611467.

27. Vonlauen A, Xu Z, Daniel B, et al. Bacterial endotoxin: a trig-ger actor or alcoholic pancreatitis? Evidence rom a novelphysiologically relevant animal model. Gastroenterology.2007;133(4):12931303.

28. Bachem MG, Schneider E, Gross H, et. al. Identifcation, cul-ture, and characterization o pancreatic stellate cells in rats andhumans. Gastroenterology. 1998;115(2):421432.

29. Apte MV, Pirola RC, Wilson JS. Molecular mechanisms o alco-holic pancreatitis.Dig Dis. 2005;23(34):232240.

30. Howes N, Lerch MM, Greenhal W, et al; European Registryo Hereditary Pancreatitis and Pancreatic Cancer (EUROPAC).Clinical and genetic characteristics o hereditary pancreatitis inEurope. Clin Gastroenterol Hepatol. 2004;2(3):252261.

31. Rosendahl J, Witt H, Szmola R, et al. Chymotrypsin C (CTRC)variants that diminish activity or secretion are associated withchronic pancreatitis. Nat Genet. 2008;40(1):7882.

32. Witt H, Luck W, Hennies HC, et al. Mutations in the gene en-coding the serine protease inhibitor, Kazal type 1 are associatedwith chronic pancreatitis. Nat Genet. 2000;25(2):213216.

33. Chandak GR, Idris MM, Reddy DN, Bhaskar S, Sriram PV, SinghL. Mutations in the pancreatic secretory trypsin inhibitorgene (PSTI/SPINK1) rather than the cationic trypsinogen gene(PRSS1) are signifcantly associated with tropical calcifc pan-creatitis.J Med Genet. 2002;39(5):347351.

34. Kuwata K, Hirota M, Shimizu H, et al. Functional analysis o re-combinant pancreatic secretory trypsin inhibitor protein with

amino-acid substitution.J Gastroenterol . 2002;37(11):928934.35. Nathan JD, Romac J, Peng RY, Peyton M, Macdonald RJ, Lid-dle RA. Transgenic expression o pancreatic secretory trypsininhibitor-I ameliorates secretagogue-induced pancreatitis inmice. Gastroenterology. 2005;128(3):717727.

36. Ohmuraya M, Hirota M, Araki M, et al. Autophagic cell deatho pancreatic acinar cells in serine protease inhibitor Kazal type3-defcient mice. Gastroenterology. 2005;129(2):696705.

37. Riordan JR, Rommens JM, Kerem B, et al. Identifcation o thecystic fbrosis gene: Cloning and characterization o comple-mentary DNA. Science. 1989;245(4922):10661073.

38. Durno C, Corey M, Zielenski J, Tullis E, Tsui LC, Durie P. Geno-type and phenotype correlations in patients with cystic fbrosisand pancreatitis. Gastroenterology. 2002;123(6):18571864.

39. Cohn JA, Friedman KJ, Noone PG, Knowles MR, Silverman LM,Jowell PS. Relation between mutations o the cystic fbrosis gene

and idiopathic pancreatitis. N Engl J Med. 1998;339(10):653658.40. Sharer N, Schwarz M, Malone G, et al. Mutations o the cystic

fbrosis gene in patients with chronic pancreatitis. N Engl J Med.1998;339(10):645652.

41. Audrzet MP, Chen JM, Le Marchal C, et al. Determinationo the relative contribution o three genesthe cystic fbrosistransmembrane conductance regulator gene, the cationic tryp-sinogen gene, and the pancreatic secretory trypsin inhibitorgeneto the etiology o idiopathic chronic pancreatitis.Eur JHum Genet. 2002;10(2):100106.

42. Noone PG, Zhou Z, Silverman LM, Jowell PS, Knowles MR,Cohn JA. Cystic fbrosis gene mutations and pancreatitis risk:Relation to epithelial ion transport and trypsin inhibitor genemutations. Gastroenterology. 2001;121(6):13101319.

43. Witt H, Sahin-Tth M, Landt O, et al. A degradation-sensitiveanionic trypsinogen (PRSS2) variant protects against chronic

pancreatitis. Nat Genet. 2006;38(6):668673.


11/28


Chronic pancreatitis (CP) is a challenging di-

agnosis, aecting many patients or years

beore being recognized. The chronic pain

associated with the disease and the poten-

tial or opioid abuse magniy the social cost, as well

as the inancial burden on the amily and the healthcare system. Known causes range rom alcohol abuse,

which is responsible or more than 80% o the CP in

North America, to heredity, although many cases are

idiopathic.

The clinicians index o suspicion determines the

aggressiveness with which the diagnosis is pursued.

From onset o symptoms to diagnosis, the average time

lag is 62 months, but or patients without a history o

alcoholism, the delay rom onset o symptoms to diag-

nosis averages 81 months.1,2 Early diagnosis with inter-

vention, including alcohol cessation when applicable,

oten slows progression or reduces complications.This article discusses symptoms that might point to-

ward a diagnosis o CP in its early stages, classic symp-

toms that present in its late stages, and the laboratory

indings and imaging studies used to diagnose CP. Two

case histories demonstrate the subtle and not-so-subtle

characteristics o the disease.

Two Typical casesc 1: abdmn pn wth wght lA 65-year-old man is reerred by his primary care phy-

sician to a gastroenterology practice or evaluation

o chronic abdominal pain o 3 years duration. Hispain occurs daily, without relie, typically radiating

rom the epigastrium to the back. Eating aggravates

the pain, and he has lost 20 lb over the preceding

6 months. He reports consuming no alcohol and no

recreational drugs. Physical examination reveals mild

temporal muscle wasting. The patient is anicteric and

has no abdominal masses or tenderness.

Laboratory data show that hemoglobin, liver unc-

tion tests, electrolytes, blood glucose, glycosylated

hemoglobin, and serum amylase are normal. Esopha-

gogastroduodenoscopy (EGD), abdominal ultrasound,

and an abdominal computed tomographic (CT) scanare also normal.

When patients present with chronic abdominal

pain and weight loss, the dierential diagnosis is vast

encompassing common conditions such as CP, peptic

ulcer disease, gallstones, endocrine diseases, ischemic

bowel, and even pancreatic carcinoma. What should

be the clinicians next step?

c 2: er stt, Drrh, nd wght lA 66-year-old attorney who has atrial ibrillation and

takes wararin or anticoagulation is reerred or EGD

and colonoscopy. He has reported a loss o appetite, in-creased requency o bowel movements, and a weight

loss o 20 lb over 6 months. Are his symptoms sug-

gestive o CP?

pReseNTaTioN cHalleNGesOur ability to diagnose CP in its early stages is limited:

while pancreatic unction is still within physiologic

limits, there may be no symptoms other than pain

and pain is absent in more than 10% o patients with

pancreatic damage.3 No current physiologic tests can

aid clinicians in making a deinitive, early diagnosis,

and ew tests help in staging the disease, especially inits early stages. Direct pancreatic secretory assessment,

once considered a gold standard or diagnosing pan-

creatic insuiciency, is very cumbersome to perorm

and is now used in very ew centers.4 Histologic test-

ing is diicult to perorm saely and may not provide

reliable inormation regarding pancreatic unction.

Conirmation o pancreatitis requires radiographic

imaging and, like initial laboratory tests, such images

oten reveal no abnormality in early disease.

For these reasons, a strong clinical suspicion o early

(minimal change) CP should be pursued vigorously

with specialized testing to conirm the diagnosis.

evutn nd Dgn fchrn pnrttRkh Nnd, MD, nd cmrn Kfr, Do

In early chronic pancreatitis, there may be no symptoms other than pain, which is absent in more

than 10% of cases. Here, some subtle clues that should raise a clinicians index of suspicion.

Dr. Nnd is assistant professor of clinical medicine at theUniversity of Arizona, Tucson, and a gastroenterologist on staff atCarl T. Hayden VA Medical Center, Phoenix.Dr. Kfr is assistant chief of therapeutic endoscopy in thedepartment of gastroenterology at Carl T. Hayden VA MedicalCenter, Phoenix.


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EvAluATION ANd dIAgNOSIS Of CHRONIC PANCREATITIS

10 CHRONIC PANCREATITIS AUGUST 2009

Moreover, a thorough and meticulous patient history

may be useul, particularly i it uncovers any signii-

cant period o alcohol abuse.

siGNs aND syMpToMsThe earliest symptom o CP, abdominal pain, may be

quite variable. Its etiology is unclear and may be mul-

tiactorial, with common causes including pancreatic

or neural inlammation.5

The classic disease triadpancreatic calciication,

diabetes mellitus, and clinically signiicant malab-

sorptionemerges only in advanced disease, oten

accompanied by complications such as pseudocysts,

bile duct or duodenal obstruction, ascites, splenic vein

thrombosis, or pancreatic cancer, which also require

evaluation and management.6 Frequently, more than

90% o the pancreas has been destroyed by the timesuch maniestations occur.7

c pn pttrnThe nature o the patients pain may help rule out

other common causes o abdominal discomort, and

the patients age at presentation may provide clues as

to the etiology o the pancreatitis. The pain o heredi-

tary and tropical pancreatitis tends to present early,

between ages 10 and 30. Alcohol-related pancreatitis

usually presents between ages 30 and 50. Late-onset

idiopathic pancreatitis produces no pain in 50% o

cases, but when pain is present, it tends to emergebetween ages 50 and 70.8

In CP, two pain patterns have been described: con-

tinuous and intermittent. When pain is intermittent,

episodes may be separated by pain-ree intervals o

months or years. In one study, 44% o patients with CP

had short episodes o pain, usually less than 10 days

duration, separated by pain-ree intervals o months

to years, and 56% had episodes o continuous pain,

ranging rom daily to 2- to 3-days per week or at least

2 months.9

Classically, pancreatic pain is elt in the epigastrium

or upper abdomen, with penetration to the back orradiation to the let intercostal region. The patient may

ind relie in crouching down, lying curled up in bed

with thighs pressed against the abdomen, or bending

over the edge o a chair or a bed.10

The intensity o pain may range rom mild to debili-

tating and chronic. The latter may precipitate opioid

dependence or continued alcohol abuse as a means o

providing analgesia. It is essential to assess the pains

severity and eect on the patients quality o lie. It

has been suggested that, as the disease progresses and

the pancreas is destroyed, the pain may subside or

disappear altogether, while symptoms o endocrine

and exocrine insuiciency predominate.9,11 This may

explain the indings o one study in which 45% o

alcoholic subjects had not reported having had pain

despite maniestations o CP at autopsy.12

Mbrtn nd Dbt MtuWith advancing disease, patients develop exocrine in-

suiciency and thus lose the ability to digest protein

and at. Fat malabsorption results in steatorrhea, signi-

ied by the production o large-volume stools that tend

to be oul-smelling, greasy, and hard to lush, possibly

leaving a rim o at in the toilet bowl. Patients may re-

port weight loss with diarrhea. There may be associated

malabsorption o vitamin B12 and at-soluble vitamins

(A, D, E, and K), which might help an astute dietitian

diagnose the condition at an early stage, thereby allow-

ing or more eective intervention. Since malnutritionimpairs immunity, incidence o inection is likely to

rise among aected patients. In a population o veter-

ans, CP related to alcohol abuse is also associated with

drug abuse, hepatitis C viral inection, HIV/AIDS, and

cirrhosis,13 conditions that urther compromise the nu-

tritional status and overall health o the patient.

With the destruction o insulin-producing pancre-

atic cells (endocrine insuiciency), the patient may

develop diabetes mellitus. By the time the patient

maniests malabsorption and diabetes mellitus, the

pancreas has been irreversibly damaged, and the dis-

ease is in its very late stages. At that point, the thirdclassic sign o CP, calciication, may be apparent on

abdominal radiographs and CT scans.

DiaGNosTic TesTiNGAlthough there is no single test that is diagnostic or

early CP, laboratory testing during painul episodes

may be helpul in some patients with acute exacerba-

tion o their CP, since pancreatic enzyme levels are

typically elevated more than 3 times the upper limits

o normal. However, in chronic pancreatitis, serum

concentrations o amylase and lipase may be mildly

elevated but are usually normal or the ollowing rea-sons: (1) signiicant pancreatic ibrosis requently re-

duces the level o these enzymes within the pancreas;

and (2) CP tends to be a patchy, ocal disease that

only minimally increases pancreatic enzymes in the

blood.6

The complete blood count and electrolytes are typi-

cally normal in the absence o signiicant vomiting

and poor oral intake. Elevation o liver enzymes may

point to coexistent liver disease or cholestasis because

o compression o the intrapancreatic portion o the

common bile duct rom edema, ibrosis, or pancreatic

cancer.14


13/28

NANdA an kIAfAR

AUGUST 2009 CHRONIC PANCREATITIS 11

st TtSteatorrhea, i suspected, can be assessed qualitatively

by Sudan staining o eces. Since the qualitative test is

airly insensitive, unless the patient has gross steator-

rhea, it needs to be perormed with the patient on a

high-at diet. Steatorrhea also can be assessed quanti-

tatively by determining ecal at excretion in 24 hours

with the patient ollowing a 100-g at diet. Such tests

are usually perormed over 72 hours, with excretion o

more than 7 g o at per day considered diagnostic o

malabsorption. (Patients with steatorrhea oten excrete

more than 20 g o at per day.) In the proper clinical

setting (typical abdominal pain), conirmation o ste-

atorrhea may be suicient to diagnose CP.

pnrt Funtn Tt

Pancreatic unction tests (PFTs) can be helpul in diag-nosing patients who experience recurrent abdominal

pain but have normal imaging and laboratory tests.

Pancreatic unction tests may be indirect (ie, simple

and noninvasive) or direct (ie, invasive). Indirect tests

measure the consequences o pancreatic insuiciency.

These tests are more widely available than direct PFTs,

which are perormed only at a ew specialized centers.

In direct PFTs, the pancreas is stimulated through

the administration o a meal or hormonal secreta-

gogues. Shortly thereater, the duodenal luid is col-

lected and analyzed to quantiy normal pancreatic se-

cretory content. The main problem with many directPFTs is their low sensitivity, especially in mild disease.

A negative PFT, thereore, should not exclude the di-

agnosis o CP (Table 1).

Measurement o ecal elastase has been ound to be

helpul in evaluating pancreatic exocrine dysunction

(malabsorption) in some studies.15,16 Unpublished data

rom the test manuacturer indicate that ecal elastase

values o less than 200 g/g suggest pancreatic insu-iciency.15 Low ecal elastase values, however, are also

seen in 25% to 30% o patients with conditions involv-

ing the small bowel, including celiac disease, Crohns

disease, cow milk protein enteropathy, bacterial over-

growth, short-bowel syndrome, and enteritis17,18; and in

patients with diabetes mellitus, a common complica-

tion o CP. The prevalence o low stool elastase has been

reported to be 46% in patients with type 1 diabetes and

30% in patients with type 2 diabetes.19 Since low ecal

elastase can be seen in a variety o other small-bowel

conditions, it should be not used as a sole diagnostic

tool or CP.Another indirect, minimally invasive test o pancre-

atic exocrine unction is the pancreolauryl test (PLT),

which involves ingesting the compound luorescein

dilaurate, a substrate or the pancreatic enzyme cho-

lesterol esterase, with a standard breakast. Fluorescein

is then absorbed rom the gut and excreted in the

urine. Enzymatic cleavage o this substrate results in

Table 1. pnrt Funtn Tt

T sntvt (%) sft (%)

Tubeless

Fecal elastase 78 94

Pancreolauryl 5085 82

Bentiromide(discontinued) 85 90

Duodenal intubation test

Secretin 7589 8090

Table 2. imgng nd end stud fr th Dgn f chrn pnrtt

Tt sntvt (%) sft (%)

Plain abdominal X-ray NA NA

Ultrasonography 6070 8090

Contrast-enhanced

computed tomography 7590 85

Magnetic resonance

cholangiopancreatography (MRCP) 85 100

Endoscopic ultrasound (EUS) 97 60

Endoscopic retrograde cholangiopancreatography (ERCP) 7595 90


14/28



the release o luorescein in proportion to the activ-

ity o cholesterol esterase. Measurement o luorescein

rom the serum or rom a 24-hour urine collection al-lows or a quantitative estimate o pancreatic exocrine

unction. Studies have noted that the sensitivity o PLT

ranges rom 85% or severe to 50% or mild pancreatic

exocrine insuiciency.20,21 The bentiromide test was

similar in principle to the PLT but is no longer used

since the reagent has been withdrawn rom the market.

In general, the useulness o these tests is limited by

their negative results in early stages o the disease and

by their lack o availability in most centers.

Two hormones have been used to stimulate pan-

creatic secretion, cholecystokinin (CCK) and secretin.

The CCK tests measure the ability o pancreatic acinarcells to secrete digestive enzymes, while the secretin

tests measure the ability o pancreatic ductal cells to

produce bicarbonate. Although advanced pancreatic

insuiciency involves abnormalities o both acinar

and ductal secretions, it is not known which hormone

is more sensitive or early pancreatic unctional de-

cline; this is an area o ongoing debate.

O all available PFTs, the secretin stimulation test

is probably the most studied and thus represents a

reerence standard or direct PFTs.22 There are dier-

ent versions o the test, but its basic principle requires

the continuous collection o duodenal luid or 1 to

2 hours. The luid is then analyzed or bicarbonate

concentration, volume, and total output. Both biologic

and synthetic porcine secretin have been used, but hu-man synthetic secretin is now available and compares

avorably with other agents.23

For this test, a double-lumen tube is inserted through

the patients nose and threaded into the duodenum, or

the sample is collected endoscopically.24 A test dose

is given to determine hypersensitivity to any o the

components in the ormulations. Ater a test dose o 0.2

mg synthetic secretin, duodenal contents are collected

beore and ater IV synthetic secretin, at 15-minute

intervals or 1 hour. A bicarbonate concentration o

less than 80 mEq/L in 4 aliquots represents exocrine

insuiciency (malabsorption). Unortunately, the testis time-consuming (requiring about 1 hour), unpleas-

ant or the patient, and neither sensitive nor speciic

enough to deinitively identiy early CP; there is sig-

niicant overlap o values among patients with and

without CP.20

imgng studIn about 30% percent o patients with CP, plain abdom-

inal ilms reveal calciications within the pancreatic

duct. The calciication is pathognomonic o CP and lo-

cated exclusively within the ductal system, not involv-

ing the parenchyma o the gland. Calcium deposition

Figure 1. end Utrund (eUs) img

EUS images (A and B) show features consistent with the diagnosis of chronic pancreatitis. The parenchyma has increased

echogenic foci, stranding with lobulation. The pancreatic duct has an irregular contour with increased echogenicity of the wall.

a B


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NANdA an kIAfAR


is most commonly seen with alcoholic pancreatitis but

is also seen in hereditary and tropical orms.

Transabdominal ultrasound, CT scan, and mag-

netic resonance imaging can all assist in diagnosis

and management o CP. All o these studies may show

calciications, ductal dilation, pancreatic enlargement,

and luid collections (ie, pseudocysts) adjacent to the

gland. Although endoscopic retrograde cholangiopan-

creatography (ERCP) is used as a reerence standard,

a contrast-enhanced CT scan o the abdomen is the

initial imaging modality o choice because it is rea-sonably sensitive and speciic at a relatively low cost

(Table 2).

ERCP has been deemed the gold standard imaging

procedure or diagnosing CP,6 with beading o the

main pancreatic duct, stones or protein plugs within

the duct, and ecstatic side branches considered diag-

nostic. Based upon ductal changes apparent on ERCP,

the Cambridge classiication system assigns patients

to 1 o 3 categories: equivocal changes (Cambridge I),

mild-to-moderate changes (Cambridge II), and con-

siderable changes (Cambridge III). One study using

this system ound that no patients with normal ducts

on ERCP had unctional impair-

ment, while 50% o patients with

Cambridge II changes had pancre-

atic insuiciency.25 For patients

with suspected CP, however, mag-

netic resonance cholangiopancrea-

tography (MRCP), with or without

secretin, and endoscopic ultrasound

(EUS) have become the modalities

o choice in visualizing pancreatic

ducts. These tests provide diagnos-

tic perormance similar to ERCP26,27

without the potential complica-

tions associated with ERCP (inec-

tion, hemorrhage, peroration, and

most notably, causing or exacerbat-

ing pancreatitis). Today, ERCP israrely used or diagnosis alone but

may be used as part o a therapeutic

intervention.

MRCP has the unique ability to

detect biliary and pancreatic ducts

noninvasively and, when used

with IV secretin, signiicantly im-

proves visualization o the main

pancreatic duct as well as its side

branches.28 Likewise, EUS has been

shown to be more sensitive than

ERCP in patients with early CP.29

While less invasive than ERCP, EUS

provides an opportunity or the clinician to obtain

tissue samples during the same procedure i a mass

is detected. Features considered suggestive o CP on

EUS include stones (which are highly predictive), vis-

ible side branches, cysts, lobularity, an irregular main

pancreatic duct, hyperechoic oci and strands, dilation

o the main pancreatic duct, and hyperechoic margins

o the main pancreatic duct. The presence o our or

more o these eatures is considered to be indicative

o CP.30

case DiscUssioNIn case 1, with help rom the patients son, who ac-

companied the patient at this visit, clinicians elicit

a detailed history, which includes a long period o

alcohol abuse (about 6 beers daily or 20 years) that

ended approximately 8 years ago. Clinicians urther

determine that the patient has regular, nonbloody,

ormed stools.

Given the patients history o long-standing, al-

though remote, alcohol abuse, CP is a possible diag-

nosis. An EUS reveals eatures consistent with CP, in-

cluding a parenchyma with increased echogenic oci,

Figure 2. cmutd Tmgrh (cT) sn

The CT scan shows solitary calcification in the tail of the pancreas, which suggests

chronic calcific pancreatitis.


16/28



stranding with lobulation, a pancreatic duct with an

irregular contour, and increased echogenicity o the

wall (Figure 1).

In case 2, ater much discussion, the patient dis-

closes that he had been a heavy alcohol user or 18

years, rom age 12 until ater he let the army. He

recalls that he stopped drinking ater a severe episode

o abdominal pain that required hospitalization. At the

time, he was told he had swelling o the pancreas. He

has not consumed ethanol since that time, more than

35 years ago. A CT scan reveals solitary calciication

in the tail o the pancreas, suggesting chronic calciic

pancreatitis (Figure 2).

Both cases typiy presentations o CP in which a di-

agnosis may be reached ater a taking a detailed, prob-

ing history. The diagnosis o CP was not suspected ini-

tially in either case, and snapshot histories would havemissed important aspects o both patients livessuch

as signiicant, although remote, alcohol abuse. These

cases underscore the need or the clinician-historian to

look at the patients entire lie, keeping in mind that

it is oten more diicult to diagnose CP when alcohol

is not a actor.

ReFeReNces1. Rizk MK, Gerke H. Utility o endoscopic ultrasound in pancre-

atitis: A review. World J Gastroenterol. 2007;13(47):63216326.2. Obideen K, Yakshe P, Wehbi M. Pancreatitis, chronic. eMedi-

cine Web site. http://www.emedicine.com/med/TOPIC1721.

htm. Updated June 16, 2008. Accessed June 24, 2009.3. Lankisch PG, Lhr-Happe A, Otto J, Creutzeldt W. Naturalcourse in chronic pancreatitis. Pain, exocrine and endocrinepancreatic insufciency and prognosis o the disease.Digestion.1993;54(3):148155.

4. Forsmark CE. The early diagnosis o chronic pancreatitis. ClinGastroenterol Hepatol. 2008;6(12):12911293.

5. Dimcevski G, Sami AK, Funch-Jensen P, et al. Pain in chronicpancreatitis: The role o reorganization in the central nervoussystem. Gastroenterology. 2007;132(4):15461556.

6. Steer ML, Waxman I, Freeman S. Chronic pancreatitis. N Engl JMed. 1995;332(22):14821490.

7. Regan PT, Malagelada JR, DiMagno EP, Glanzman SL, Go VL.Comparative eects o antacids, cimetidine and enteric coat-ing on the therapeutic response to oral enzymes in severe pan-creatic insufciency. N Engl J Med. 1977;297(16):854858.

8. Layer P, Yamamoto H, Kaltho L, Clain JE, Bakken LJ, DiM-agno EP. The dierent courses o early- and late-onset idio-pathic and alcoholic chronic pancreatitis. Gastroenterology.1994;107(5):14811487.

9. Ammann RW, Muellhaupt B; Zurich Pancreatitis Study Group.The natural history o pain in alcoholic chronic pancreatitis.Gastroenterology. 1999;116(5):11321140.

10. Haubrich WS. Abdominal pain. In: Berk JE, Haubrich WS, eds.Gastrointestinal SymptomsClinical Interpretation. Philadelphia,PA: BC Decker; 1991:5052.

11. Blackstone MO. Pain in alcoholic chronic pancreatitis. Gastro-enterology. 1999;117(4):10261028.

12. Pitchumoni CS, Glasser M, Saran RM, Panchacharam P,Thelmo W. Pancreatic fbrosis in chronic alcoholics and non-alcoholics without clinical pancreatitis. Am J Gastroenterol.1984;79(5):382388.

13. Wilson NJ, Kizer KW. The VA health care system: An unrecognizednational saety net.Health Aff (Millwood). 1997;16(4):200204.

14. Mergener K, Baillie J. Chronic pancreatitis. Lancet.1997;350(9088):13791385.

15. Keim V, Teich N, Moessner J. Clinical value o new ecal elastasetest or detection o chronic pancreatitis. Clin Lab. 2003;49(5-6):209215.

16. Borowitz D, Baker SS, Duy L, et al. Use o ecal elastase-1 toclassiy pancreatic status in patients with cystic fbrosis.J Pedi-atr. 2004;145(3):322326.

17. Beharry S, Ellis L, Corey M, Marcon M, Durie P. How useul isecal pancreatic elastase 1 as a marker o exocrine pancreaticdisease?J Pediatr. 2002;141(1):8490.

18. Nousia-Arvanitakis S. Fecal elastase-1 concentration: An in-direct test o exocrine pancreatic unction and a maker oenteropathy regardless o cause. J Pediatr Gastroenterol Nutr.

2003;36(3):314315.19. Czak L, Takcs T, Hegyi P, et al. Quality o lie assessment ater

pancreatic enzyme replacement therapy in chronic pancreati-tis. Can J Gastroenterology. 2003;17(10):597603.

20. DiMagno EP. A perspective on the use o tubeless pancreaticunction tests in diagnosis. Gut. 1998;43(1):23.

21. Lankisch PG, Schreiber A, Otto J. Pancreolauryl test. Evaluationo a tubeless pancreatic unction test in comparison with otherindirect and direct tests or exocrine pancreatic unction. DigDis Sci. 1983;28(6):490493.

22. Chowdhury RS, Forsmark CE. Review article: Pancreatic unc-tion testing.Aliment Pharmacol Ther. 2003;17(6):733750.

23. Somogyi L, Ross SO, Cintron M, Toskes PP. Comparison obiologic porcine secretin, synthetic porcine secretin, and syn-thetic human secretin in pancreatic unction testing.Pancreas.2003;27(3):230234.

24. Stevens T, Conwell DL, Zuccaro G Jr, et al. A prospective cross-over study comparing secretin-stimulated endoscopic and Dreil-ing tube pancreatic unction testing in patients evaluated orchronic pancreatitis. Gastrointest Endosc. 2008;67(3):458466.

25. Bozkurt T, Braun U, Leerink S, Gilly G, Lux G. Comparison opancreatic morphology and exocrine unctional impairmentin patients with chronic pancreatitis. Gut. 1994;35(8):11321136.

26. Adler DG, Baron TH, Davila RE, et al; Standards o PracticeCommittee o American Society o Gastrointestinal Endoscopy.ASGE guideline: The role o ERCP in diseases o the biliary tractand the pancreas. Gastrointest Endosc. 2005;62(1):18.

27. Remer EM, Baker ME. Imaging o chronic pancreatitis.RadiolClin North Am. 2002;40(6):12291242.

28. Erturk SM, Ichikawa T, Motosugi U, Sou H, Araki T. Diusion-

weighted MR imaging in the evaluation o pancreatic exocrineunction beore and ater secretin stimulation. Am J Gastroen-terol. 2006;101(1):133136.

29. Kahl S, Glasbrenner B, Leodolter A, Pross M, Schulz HU,Malertheiner P. EUS in the diagnosis o early chronic pan-creatitis: A prospective ollow-up study. Gastrointest Endosc.2002;55(4):507511.

30. Wallace MB, Hawes RH, Durkalski V, et al. The reliability oEUS or the diagnosis o chronic pancreatitis: Interobserveragreement among experienced endosonographers. GastrointestEndosc. 2001;53(3):294299.


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Case: a Middle-aged Man with a historyof alCohol abuseA 56-year-old man with a long-standing history o

alcohol abuse presents to the clinic or management

o chronic diarrhea and weight loss. He has a historyo chronic abdominal pain in the epigastric area that

has increased in intensity over the years. For the past

six to nine months, he has experienced bloating and

diarrhea that is described as oul smelling, pale, bulky,

and greasy in nature, occurs 4 to 6 times per day, and

is associated with a 10-lb weight loss in 6 months. On

physical exam, the mans height was 6'3"; his weight

was 134 lbs; and he was aebrile and well hydrated,

without stigmata o chronic liver disease. There was

no jaundice. Results o cardiovascular and lung exams

were normal. The abdomen was slightly protuberant,

with mild tenderness on deep palpation in the epigas-tric area. No hepatosplenomegaly or intra-abdominal

masses were noted. Extremities ailed to reveal any

pedal edema.

Laboratory work-up revealed a white blood cell

count o 7500/mL with normal dierential; a hemo-

globin level o 12.8 g/dL; mean corpuscular volume

o 100 mm3; and platelet count o 210,000/mL. His

asting serum glucose level was 100 mg/dL; his blood

urea nitrogen, creatinine, and electrolyte levels were

normal. The amylase and lipase levels were normal.

Liver enzymes showed an aspartate aminotranserase

o 54 U/L and an alanine aminotranserase o 36 U/Lwith normal bilirubin and alkaline phosphatase levels.

Plain abdominal ilms revealed calciications in the

midportion o the abdomen; a computed tomographic

scan o the abdomen showed that the calciications

were located in the pancreas with atrophy o the gland

and mild dilation o the entire pancreatic duct. An en-

doscopic ultrasound showed changes compatible with

chronic pancreatitis (CP). The patients stool studies

were negative or ecal leukocytes, occult blood, and

ova and parasite. The Sudan III stain o random stools

was positive. The patient also underwent a quantitative

measurement o ecal at while on a 100-g at diet or3 days and showed a ecal at content o 50 g/day.

PanCreatiC exoCrine insuffiCienCyThe pancreas secretes about 2 L o pancreatic juice

daily; this is composed o water, bicarbonate, and en-

zymes that digest ats, proteins, and carbohydrates.1

The pancreas normally produces more enzymes than

what is needed or the normal digestion o ood, and

this is not clinically compromised until the pancreas

has lost 90% or more o its secretive capacity2; how-

ever, this concept has been challenged.3 The digestive

capacity o the dierent enzymes is aected separatelyby several intraluminal actors where degradation oc-

curs. The loss o enzymatic activity within the intes-

tinal lumen is due, among other actors, to proteolytic

degradation, acid content, and the short hal-lie o

some o the enzymes. Lipase is particularly vulnerable

to all these actors, which explains why maldigestion

o at precedes, and is more severe than, carbohydrate

and protein maldigestion in the setting o exocrine

pancreatic insuiciency.48

The main consequence o pancreatic exocrine in-

suiciency is maldigestion and malabsorption o lip-

ids, leading to a distinct orm o diarrhea character-ized by steatorrhea, weight loss, and malnutrition.

Eicient digestion o triglycerides requires lipase, co-

lipase, and bile salts. CP involves acid-mediated lipase

inactivation and decreased secretion o lipase and

colipase. In the presence o a low luminal pH, bile

acid precipitation and mucosal dysunction also con-

tribute to malabsorption. Fat maldigestion also leads

to malabsorption o at-soluble vitamins (A, D, E, K).

Malabsorption o vitamin B12 also occurs, although

the clinical correlate is unknown. Steatorrhea aects

nutrition and quality o lie negatively.9 The deiciency

in micronutrients, at-soluble vitamins, and lipopro-

Mm ecPcc icc

fcc C. rm, MdExocrine pancreatic insufficiency is characterized by maldigestion and malabsorption of lipids,

leading to steatorrhea, weight loss, and malnutrition. Alcohol abuse is a significant risk factor,

and treatment may include pancreatic enzyme replacement.

d. rm is a professor of clinical medicine at the Universityof Arizona College of Medicine and chief of the division ofgastroenterology at Carl T. Hayden VA Medical Center, both inPhoenix, Arizona.


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mANAgEmENT Of ExOCRINE PANCREATIC INSuffICIENCy


teins has been associated with an increased morbid-

ity secondary to the increased risk or malnutrition-

related complications and cardiovascular (CV) events.10

CV complications arise primarily rom abnormalities

in lipid metabolism; these abnormalities are signiicant

contributors to atherosclerosis, although they may not

be its direct cause. Patients with alcoholic CP exhibit

signiicantly lower levels o total cholesterol, high-

density lipoprotein (HDL), apoprotein A1 (apoA1), and

lipoprotein(a) [Lp(a)] than controls and signiicantly

lower levels o cholesterol, apoA1, apoprotein B (apoB),

and Lp(a) than alcoholics who do not exhibit clinical

evidence o pancreatic or liver disease. Decreased levels

o Lp(a) have been associated with increased risk o

atherogenic CV disease. In addition, a decreased level

o HDL, which is protective against CV disease, urther

increases the risk or pancreatic or liver disease.10

Fat maldigestion is the most common maniesta-

tion o exocrine pancreatic insuiciency, although

protein (azotorrhea) and starch (amylorrhea) mal-

digestion may be rare and late occurrences in the

course o the disease. Bacterial overgrowth, which is

seen in 25% to 50% o patients with exocrine pan-

creatic insuiciency, either contributes to diarrhea or

is responsible or its persistence in patients receiving

adequate pancreatic exocrine supplementation.1113

The exact reason or the association o bacterial

overgrowth with exocrine pancreatic insuiciency is

not well known. In patients with untreated severepancreatic insuiciency, bacterial overgrowth was

seen in 50% o patients.12 In an animal model with

pancreatic duct ligation, however, pancreatic enzyme

replacement reversed bacterial overgrowth. This sug-

gests that pancreatic enzymes may have an important

role in the normalization o luminal conditions that

prevent such overgrowth.14 Bacterial overgrowth may

also give rise to bile acid malabsorption and changes

in intestinal permeability.1516

treatMent of PanCreatiC enzyMeinsuffiCienCyThe indications or pancreatic enzyme replacement

therapy include weight loss, more than 15 g o e-

cal at excretion daily while on a 100-g/day at diet,

and steatorrhea-related relevant symptoms.17 The role

o pancreatic enzyme replacement in persons with

asymptomatic steatorrhea o less than 15 g/day is

controversial; these patients have low circulating lev-

els o prealbumin, erritin, and liposoluble vitamins

that normalize with pancreatic enzyme replacement.

Consequently, some observers advocate its use to pre-

vent related nutrient deiciencies.18

n MmThe nutritional management o pancreatic exocrine

insuiciency includes dietary modiication, such aslimitation o at content in the diet, and administra-

tion o liposoluble vitamins, such as calcium and vi-

tamin B12. Fat-soluble multivitamins can be admin-

istered orally using water-miscible preparations and

water-soluble orms.19 In patients with alcoholic CP

(the most common cause o CP and pancreatic exo-

crine insuiciency), abstinence rom alcohol is asso-

ciated not only with decreased pain but also with an

increase in gastric lipase that may compensate partly

or the loss o pancreatic lipase, helping at digestion.20

Alcohol abstinence may improve at malabsorption by

an indirect mechanism, (ie, by an increase in the se-cretion o gastric lipase). It is not known whether this

increase is clinically signiicant and suicient to pre-

vent at malabsorption and steatorrhea.21

The inding that the lipolytic activity o pancreatic

enzyme replacements is higher when replacements

are taken with high- rather than low-at diets has

led to questions about the beneit o a low-at diet.22

Other dietary modiications include low volume and

requent meals that avoid diicult-to-digest ood, as

well as the use o medium-chain triglycerides (MCTs),

which do not require enzymatic breakdown or absorp-

tion. However, MCTs are primarily used or supple-menting calories in patients with weight loss and to

reduce steatorrhea in patients with a poor response to

pancrelipase.17

Pcc em rpcmThe cornerstone o treatment o pancreatic exocrine

insuiciency is the exogenous replacement o lipase.

To understand the requirements or exogenous oral

pancreatic replacement, it is important to review exo-

crine secretion by a healthy pancreas in response to

nutrients.23 In the asting state, pancreatic secretion

ollows an interdigestive cyclical pattern, which de-

Fat maldigestion is the most

common manifestation of exocrine

pancreatic insufficiency, although

protein (azotorrhea) and starch

(amylorrhea) maldigestion may

be rare and late occurrences in the

course of the disease.


19/28

RAmIREz


pends on upper gastrointestinal motility.24 The mean

secretion o lipase during the interdigestive period is

about 1000 U/min,4,2526 the maximal postprandial

enzyme output is between 3000 to 6000 U/min, and

2000 to 4000 U/min are secreted or a longer period

o time.4,26 Since lipase is the major deiciency, 30,000

IU or more need to be ingested with each meal to

end or prevent steatorrhea. It is crucial, however, to

understand the equivalence/conversion between IU

and units used in dierent countries (in the US, USP

[US Pharmacopeia] units; in Europe, PhEur [European

Pharmacopoeia] units). Thus, since 1 IU is equivalent

to 3 USP units o lipase activity, 30,000 IU is equivalent

to 90,000 USP units. Remembering this dierence is

essential or avoiding undertreatment o patients.27 (A

conversion dose o the three dierent enzyme contents

in the pancrelipase preparations include: 1 PhEur unito amylase = 4.15 USP units o amylase; 1 PhEur unit o

lipase = 1 USP unit o lipase, and 1 PhEur unit o pro-

tease = 62.5 USP units o protease.28,29) Since the goal

o exocrine pancreatic insuiciency treatment is to re-

place lipase, the decision about which ormulation to

use should be based primarily on the lipase activity

content. Keep in mind that the lipase replacement goal

may be diicult to achieve because o gastric acid se-

cretion, nonparallel gastric emptying, and proteolytic

inactivation o lipase.

The timing o administration o the pancreatic en-

zymes may aect therapeutic eicacy. Adequate mix-ing o ood with the pancreatic enzymes and optimal

intestinal motility are crucial or satisactory at diges-

tion.30,31 A commonly reported mistake is giving the

enzymes beore meals rather than with meals, which

increases mixing the enzymes with the chyme. One

recommendation is to administer one quarter o the

dose ater the irst bites o the meal, one hal during

the meal, and the remaining quarter with the last ew

bites.27 A prospective, randomized, three-way crossover

study ound that enzyme replacement therapy appears

to be more eicacious when enzymes are administered

with meals or just ater meals rather than beore eat-ing.32 The study did not use a quantitative ecal bal-

ance to assess the response, however.27 Changes in

malabsorption can be measured using the coeicient

o at absorption (CFA). CFA = dietary at (g/day)

ecal at (g/day)/dietary at (g/day) x 100%. The normal

ecal at amount while on a 100-g at diet is less than

7%. The CFA may be used to calculate this percentage,

but it is more important to ollow up on the response

to therapy and to assess the eicacy o the ormula-

tions compared with placebo or other medication. The

diagnosis o exocrine pancreatic insuiciency is based

on demonstration o more than 7% o ingested at in

the stool, using a 3-day stool collection, while ingest-

ing 100 g o at per day or 3 days. This results in a

CFA o 95% (within normal limits).

Pcc em rpcm fmTwo major pancreatic enzyme (pancrelipase) ormu-

lations are available: uncoated or conventional and

enteric-coated microencapsulated.28 The ormer are

susceptible to excessive inactivation by gastric acid

(pancreatic lipase is irreversibly inactivated at pH lev-

els o less than 4), which is urther enhanced by de-

creased bicarbonate pancreatic secretion.20 Although

uncoated pancreatic enzyme replacement is eective

in reducing steatorrhea, at digestion and absorptiondo not normalize in most patients.3337 To avoid this,

one may increase the dose to counteract the loss. This

high-dose pancrelipase replacement may be associated

with adverse eects, including diarrhea and latulence,

as well as hyperuricosuria in children because o the

high purine content in the ormulations. Alternatively,

one may increase the gastric pH by concomitant use

o bicarbonate, histamine 2 (H2) receptor antagonists,

or proton pump inhibitors.34,3840 Because no head-to-

head comparisons o bicarbonate, H2 receptor antago-

nists, or proton pump inhibitors have been perormed,

the superiority o any one o these medications hasnot been established.41 The pH eect (pH greater than

4) in the duodenum must last at least 90 minutes to

allow time or the enzyme to act and to prevent its

destruction.33 Combination therapy does not seem to

be superior to enteric-coated preparations administered

alone, however.42

The enteric-coated ormulations allow delivery o the

enzymes into the small intestine where they are released

only when the pH is greater than 5.5. In most studies,

but n

Chronic Pancreatitis (LitReview_2009)

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