© Dr Whitcomb

Chronic PancreatitisChronic Pancreatitis

David C Whitcomb MD PhDGiant Eagle Foundation Professor of Cancer Genetics.

Professor of Medicine, Cell biology & Physiology, and Human GeneticsChief, Division of Gastroenterology, Hepatology and Nutrition. University of Pittsburgh

Falk Symposium 161October 12, 2007

© Dr Whitcomb

Autoimmune Pancreatitis (AIP)

• First described in 1961 by Henri Sarles• A rare benign fibroinflamatory form of chronic

pancreatitis that can mimic pancreatic ductal adenocarcinoma both clinically and radiographically

• Appears to be more common in Japan than the United States

• 47% of patients present in their 60s and 70s, and 95% of patients with AIP are over 45 years age

• There are unique clinical, radiographic, and histopathologic features of AIP

© Dr Whitcomb

Clinical Features

• Pancreatic manifestations– Obstructive jaundice (2/3 of patients with acute

presentation-biliary stricture associated with either a focal pancreatic mass or diffuse enlargement)

– Diabetes– Steatorrhea– Upper abdominal discomfort or less commonly mild

pain– Weight loss– Rarely Acute Pancreatitis

© Dr Whitcomb

AIP: Imaging Studies

• CT Scan – Diffusely or focally enlargement of pancreas with uniform

enhancement and minimal peripancreatic infiltration– With stricturing of main pancreatic duct one can see

upstream dilatation or pancreatic or common bile ducts– Capsule like low density rim surround the pancreas– Calcifications, stones and pseudocysts are typically not seen

• ERCP-Segmental or diffuse irregular narrowing of main pancreatic duct

• MRCP - Skipped, nonvisualized main pancreatic duct lesions • MRI - As in CT scan- decreased T1 signal and increased T2

signal

© Dr Whitcomb

Radiographic Improvement with Steroids

Prior to treatment - 5/9/07 After 3 weeks steroid treatment- 9/5/06

© Dr Whitcomb

Serologic Markers

• Hamano et. al*. examined 20 pts with AIP with 20 controls and 154 patients with pancreatic cancer, chronic pancreatitis, PBC, PSC or Sjögren’s syndrome

• Median IgG4 level in pts with AIP was 663 mg/dL (nl 8 to 140 mg/dL) compared with 51 mg/dL in healthy controls

• Using a cut off of an IgG4 level > 135 mg/dL was 95% sensitive and 97% specific for differentiating AIP from pancreatic ductal adenocarcinoma

• Other studies have shown that between 62 – 94% of those patients with other features of AIP had elevated IgG4 levels

• Non-specific - IgG4 can be elevated atopic dermatitis, asthma, some parasitic diseases, pemphigus vulgaris, and pempigusfoliaceus and pancreatic adenocarcinoma

Hamano et. al. N Engl J Med. 2001;344(10):732-8.

© Dr Whitcomb

Histopathology

• Intense lymphoplasmacytic inflammatory cell infiltrate accompanied by fibrosis around large and medium sized interlobular ducts

• Venulitis which can be obliterative• IgG4 infiltration in tissue seen by

immunohistochemistry (>10 IgG4-possitive cells/hpf)

© Dr Whitcomb

Histology

© Dr Whitcomb

Chronic Pancreatitis

A) PseudocystsB) CalcificationsC) Dilated ductD) Pancreatic atrophyE) BD stenosis-dilationF) Splenic vein thrombosisG) Gastric varices

Common features of CP

Chronic pancreatitis is a hopeless condition in which the pancreas is destroyed by inflammation and fibrosis, and there is no chance of regeneration. Therapeutic options are directed at replacing lost function (e.g. pancreatic enzymes), and attempting to control pain.

www.pancreas.org

© Dr Whitcomb

Diagnosis of Chronic Pancreatitis: Histology

© Dr Whitcomb

SF12 CP vs Chronic DzN

orm

bas

ed s

core

s

* Group Vs control significant

USUS RAPRAP CPCP CADCAD ulcerulcer DMDM

60

50

40

30

20

5456

41

47

36

454447

42

49

38

50

PCS PhysicalMCS Mental

Amann DDW 2007

© Dr Whitcomb

Physical QOL Scores: Effect of EtOH

Yadav - DDW 2007

NO EtOH Occasional Low risk High risk

60

50

40

30

20

ControlRAPCP

© Dr Whitcomb

Mental QOL Scores: Effect of EtOH

Yadav - DDW 2007Yadav - DDW 2007

NO EtOH Occasional Low risk High risk

60

50

40

30

20

ControlRAPCP

© Dr Whitcomb

CP Development: Observations….

Chronic pancreatitis was defined by autopsy and surgical biopsies

Most of the clinical effort has been directed at identifying the pathology in living subjects (CT, ERCP, PFT)

Molecular studies on pancreatic tissue defined pathology, not mechanism.

Epidemiology studies identified a few, low-risk factors (EtOH, smoking)

© Dr Whitcomb

Etiology of Chronic Pancreatitis

Environment Mechanical /Genetic Histology

Low Risk High Risk Scar

© Dr Whitcomb

Risk / Etiology of Chronic Pancreatitis

Etemad & Whitcomb, Gastroenterology. 2001;120:682-707

TIGAR-OToxic-Metabolic

Alcoholic Tobacco smokingHypercalcemia Chronic Renal Failure

IdiopathicTropical

GeneticAutosomal DominantAutosomal Recessive / Polygenic

AutoimmuneRecurrent and Severe Acute Pancreatitis

Associated Chronic Pancreatitis Obstructive

•Etiologies are categorized according to mechanism and frequency.•More than one factor can be present in a patient••Most risks/etiologies are Most risks/etiologies are associated with recurrent associated with recurrent exposure / RAPexposure / RAP•Autoimmune mechanisms triggering inflammation may be trypsin-independent

© Dr Whitcomb

Etiology of RAP

• Toxic-metabolic– Alcohol– Hypertriglyceridemia– Hypercalcemia– Medicines*– Organophosphates– Scorpion toxins– Methylene chloride

• Mechanical– Choledocholithiasis– Periampullary obstruction– Congenital malformation

Somogyi et al, Gastroenterology, 2001:120:708Somogyi et al, Gastroenterology, 2001:120:708--717717

• Miscellaneous– Vascular– Infections– Hereditary– Tropical pancreatitis– Atypical CF

• Suspected– SOD– Pancreas Divisum– Autoimmune

Red= etiologies that are difficult to eliminate

© Dr Whitcomb

Hereditary Pancreatitis

• Hereditary pancreatitis (HP) is an unusual form of acute and chronic pancreatitis that runs in families following an autosomal dominant pattern. – Acute Pancreatitis in 80% with the gene– Chronic Pancreatitis in 50% with acute pancreatitis– Pancreatic Cancer in >40% with chronic pancreatitis.

• The disease gene is TRYPSINOGEN (PRSS1)• The mutations appear to be “gain of function” by increasing

activation or decreasing inactivation.

PancreasPancreas

Whitcomb et al, Nature Genetics, 1996

© Dr Whitcomb

Trypsinogen Regulation

• The master enzyme controlling all other digestive enzymes

• Trypsinogen controlled by:–– SPINK1SPINK1– Trypsin(2) –

Calcium(2)Modified from Whitcomb, Hereditary and Childhood Disorders of the Pancreas, Including Cystic Fibrosis. Sleisenger and Fordtran’s Gastrointestinal and Liver Diseases, 7th Edition, 2002

TAP

Trypsin

= calcium

Trypsin(ogen)

© Dr Whitcomb

CFTR and Bicarbonate Secretion

Opening of CFTR starts ion secretion

Cl -

HCO3-

Na+

-50 mV

XX HCO3-

H2O (osmosis) To duodenum

Active TrypsinNo Flush

PANCREATITIS

Chloride washes out and cannot enter on the basolateral side. Chloride is replace by bicarbonatebicarbonate

CFTR Mutations limit bicarbonatesecretion, increasing susceptibility to pancreatitis.

AcuteAcutePancreatitisPancreatitis

Whitcomb DC & Ermentrout DB. Pancreas 2004; 29(2):E30-E40

© Dr Whitcomb

PSTI-SPINK1

• The pancreatic secretory trypsin inhibitor (PSTI) = Serine Protease Inhibitor Kazal type 1 (SPINK1).

• SPINK1 is an acute phase protein, and is expressed after inflammation is established.

Khalid et al, Gut 2006;55:728–731

© Dr Whitcomb

Chronic Pancreatitis is a Process

Environment Mechanical /Genetic Histology

Low Risk High Risk Scar

© Dr Whitcomb

Metabolic &Environmental

stresses

HyperstimulationAlcoholSmoking Inadequate

injuryprotection

Mutations in PRSS1SPINK1CFTR

AlteredImmuneresponse

Over expression of IL-10, TGFβ, etc

Epidemiological model of CP

RAPRAP

Chronic pancreatitis likely requires alterations in three domains:environmental stressorsenvironmental stressors, failure to protect from trypsin injuryprotect from trypsin injuryand an altered immune responsealtered immune response that leads to fibrosis

CPCP

SentinelAcutePancreatitisEvent

• Model was designed to organize risks, etiologies and inflammatoryinflammatory steps

• Chronic pancreatitis requires both a triggerand continued injury– Alcohol– HP– CFTR– Other

Schneider and WhitcombSchneider and WhitcombBest Pract Res Clin Gastroenterol 2002 Jun;16(3):347-63Whitcomb - Gut 2004

© Dr Whitcomb

Interaction of Trypsin, CFTR and SPINK1

• Trypsinogen (PRSS1) R122H, N29I etc = Injury• CFTR Severe & others = Injury• SPINK1 N34S Modify the response to injury

PRSS1 R122H

CFTR severe

SPINK1Mutation

© Dr Whitcomb

Effect of ETOH on RAP

Deng et al. Chronic alcohol consumption accelerates fibrosis in response to cerulein-induced pancreatitis in the rat. Am J Path. 2005, 166:93-106

© Dr Whitcomb

Fibrosis in RAP and ETOH

Deng et al. Chronic alcohol consumption accelerates fibrosis in response to cerulein-induced pancreatitis in the rat. Am J Path. 2005 (in press)

Sirius red stain for fibrosisThe relative mRNA expression levels of collagen α1 in control and alcohol-treated rats after 1 and 3episodes of pancreatitis*: p < 0.05, **: P<0.01.

© Dr Whitcomb

Demographics: Controls and Pancreatitis SubjectsInterim results presented at DDW 2007

Yadav - DDW 2007

1645 (37, 57)

6693

15.442 (35, 53)

6888

43.350 (41, 59)

3892

25.349 (40, 61)

2691

RAP (n = 365):Number (%)Age (years)Gender (% Males)Race (% Whites)

32.549 (41, 56)

7376

14.350 (43, 58)

7297

3253 (41, 62)

3993

21.250 (41, 62)

2984

CP (n = 430):Number (%)Age (years)Gender (% Males)Race (% Whites)

12.447 (37, 57)

5993

1147 (38, 53)

5390

52.452 (43, 62)

3391

24.255 (46, 67)

2381

Controls (n = 559):Number (%)Age (years)Gender (% Males)Race (% Whites)

High-RiskAlcoholism

Low-RiskAlcoholism

Occasional Alcohol Use

No Alcohol Use

© Dr Whitcomb

Pathway model

• Each person with end-stage disease has a “high-risk” series of factors connecting the environment with the pathology

© Dr Whitcomb

Complications of RAP - Hypothesis

• Factors associated with RAP: – Normal response = healing– Anti-inflammatory immune response (fibrosis) – B-type pain (severe, continuous)– Calcifications (obstructive complications)– Diabetes mellitus– Early Cancer

• Early knowledge of specific risk factors may help prevent serious complications.

• Factors associated with RAP: – Normal response = healing– Anti-inflammatory immune response (fibrosis) – B-type pain (severe, continuous)– Calcifications (obstructive complications)– Diabetes mellitus– Early Cancer

• Early knowledge of specific risk factors may help prevent serious complications.