Chronic Pancreatitis

Transcription

1 Falk Symposium 161 October 12, 2007 Chronic Pancreatitis David C Whitcomb MD PhD Giant Eagle Foundation Professor of Cancer Genetics. Professor of Medicine, Cell biology & Physiology, and Human Genetics Chief, Division of Gastroenterology, Hepatology and Nutrition. University of Pittsburgh

2 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

3 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

4 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

5 Radiographic Improvement with Steroids Prior to treatment - 5/9/07 After 3 weeks steroid treatment- 9/5/06

6 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 pempigus foliaceus and pancreatic adenocarcinoma Hamano et. al. N Engl J Med. 2001;344(10):732-8.

7 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)

8 Histology

9 Chronic Pancreatitis Common features of CP A) Pseudocysts B) Calcifications C) Dilated duct D) Pancreatic atrophy E) BD stenosis-dilation F) Splenic vein thrombosis G) Gastric varices 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.

10 Diagnosis of Chronic Pancreatitis: Histology

11 SF12 CP vs Chronic Dz PCS Physical MCS Mental Norm based scores US RAP CP CAD ulcer DM Amann DDW 2007 * Group Vs control significant

12 Physical QOL Scores: Effect of EtOH 60 Control RAP CP NO EtOH Occasional Low risk High risk Yadav - DDW 2007

13 Mental QOL Scores: Effect of EtOH 60 Control RAP CP NO EtOH Occasional Low risk High risk Yadav - DDW 2007 Yadav - DDW 2007

14 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)

15 Etiology of Chronic Pancreatitis Environment Mechanical /Genetic Histology Low Risk High Risk Scar

16 Risk / Etiology of Chronic Pancreatitis TIGAR-O Toxic-Metabolic Alcoholic Tobacco smoking Hypercalcemia Chronic Renal Failure Idiopathic Tropical Genetic Autosomal Dominant Autosomal Recessive / Polygenic Autoimmune Recurrent and Severe Acute Pancreatitis Associated Chronic Pancreatitis Obstructive Etemad & Whitcomb, Gastroenterology. 2001;120: Etiologies are categorized according to mechanism and frequency. More than one factor can be present in a patient Most risks/etiologies are associated with recurrent exposure / RAP Autoimmune mechanisms triggering inflammation may be trypsinindependent

17 Etiology of RAP Somogyi et al, Gastroenterology, 2001:120: Toxic-metabolic Alcohol Hypertriglyceridemia Hypercalcemia Medicines* Organophosphates Scorpion toxins Methylene chloride Mechanical Choledocholithiasis Periampullary obstruction Congenital malformation Miscellaneous Vascular Infections Hereditary Tropical pancreatitis Atypical CF Suspected SOD Pancreas Divisum Autoimmune Red= etiologies that are difficult to eliminate

18 Hereditary Pancreatitis Pancreas 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. Whitcomb et al, Nature Genetics, 1996

19 Trypsinogen Regulation Trypsin(ogen) The master enzyme controlling all other digestive enzymes Trypsinogen controlled by: SPINK1 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 Trypsin TAP = calcium

20 CFTR and Bicarbonate Secretion Whitcomb DC & Ermentrout DB. Pancreas 2004; 29(2):E30-E40-50 mv Acute Pancreatitis Na + HCO 3 - Cl - X HCO3 - Active Trypsin No Flush PANCREATITIS H 2 O (osmosis) To duodenum CFTR Mutations limit bicarbonate secretion, increasing susceptibility to pancreatitis. Opening of CFTR starts ion secretion Chloride washes out and cannot enter on the basolateral side. Chloride is replace by bicarbonate

21 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:

22 Chronic Pancreatitis is a Process Environment Mechanical /Genetic Histology Low Risk High Risk Scar

23 Epidemiological model of CP Chronic pancreatitis likely requires alterations in three domains: environmental stressors, failure to protect from trypsin injury and an altered immune response that leads to fibrosis Hyperstimulation Alcohol Smoking Metabolic & Environmental stresses RAP CP Inadequate injury protection Mutations in PRSS1 SPINK1 CFTR Altered Immune response Over expression of IL-10, TGFβ, etc

24 Sentinel Acute Pancreatitis Event Model was designed to organize risks, etiologies and inflammatory steps Chronic pancreatitis requires both a trigger and continued injury Alcohol HP CFTR Other Schneider and Whitcomb Schneider and Whitcomb Best Pract Res Clin Gastroenterol 2002 Jun;16(3): Whitcomb - Gut 2004

25 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 SPINK1 Mutation CFTR severe

26 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

27 Fibrosis in RAP and ETOH The 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. Sirius red stain for fibrosis Deng et al. Chronic alcohol consumption accelerates fibrosis in response to cerulein-induced pancreatitis in the rat. Am J Path (in press)

28 Demographics: Controls and Pancreatitis Subjects Interim results presented at DDW 2007 No Alcohol Use Occasional Alcohol Use Low-Risk Alcoholism High-Risk Alcoholism Controls (n = 559): Number (%) Age (years) Gender (% Males) Race (% Whites) (46, 67) (43, 62) (38, 53) (37, 57) RAP (n = 365): Number (%) Age (years) Gender (% Males) Race (% Whites) (40, 61) (41, 59) (35, 53) (37, 57) CP (n = 430): Number (%) Age (years) Gender (% Males) Race (% Whites) (41, 62) (41, 62) (43, 58) (41, 56) Yadav - DDW 2007

29 Pathway model Each person with end-stage disease has a high-risk series of factors connecting the environment with the pathology

30 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.