DOMMR

1. DOMMR Week of 9/7-9/11

2. Objectives Discuss the pathogenesis, etiology, and diagnosis of chronic pancreatitis Discuss autoimmune pancreatitis focusing on Presentation Radiologic findings Laboratory values Treatment

3. MKSAP #32 A 37y F has a 1 week history of fatigue, jaundice, and slight fever. She has hypothyroidism for which she takes synthroid for the last 10 yrs. She traveled to Mexico 5 months ago and received a dose of hepatitis A vaccine before the trip. Exam discloses mild jaundice and hepatomegaly. CBC: Normal TSH: Normal AST: 310 ALT: 455 Alk Phos: 180 Total bili: 2.3 Which of the following studies will most likely help establish the diagnosis? A. Antimitochondrial antibody B. Antinuclear antibody and anti smooth muscle antibody C. IgM antibody to hepatitis A virus D. Serum acetaminophen E. ERCP

4. Chronic Pancreatitis Irreversible morphologic changes as a response to progressive inflammation Strictures, calculi, dilation of pancreatic duct (PD) Patchy, focal mononuclear infiltrates and fibrosis Leads to loss of pancreatic endocrine and exocrine function Verses Acute Pancreatitis: More chronic, less associated with acute pain Amylase/Lipase often normal Chronic pancreatitis is a patchy, focal disease Significant fibrosis decrease the amount of enzymes

5. Chronic Pancreatitis – Pathogenesis Proteinaceous ductal plugs Protein hypersecretion “plugs” the ducts, acting as a nidus for calcification ? stone formation Chronic inflammation causes scarring of the ducts Ischemia Leads to chronic inflammatory changes Doesn’t initiate, but exacerbates the disease Nutritional deficiency Specifically in antioxidants such as selenium, Vitamin C, Vitamin E, methionine Antioxidant deficiency in stressed cells ? free radicals ? lipid peroxidation, cell impairment

6. Chronic Pancreatitis - Etiology Chronic alcohol abuse Ductal obstruction Hereditary Tropical Systemic Diseases Idiopathic Autoimmune

7. Chronic Pancreatitis - Etiology Alcohol abuse: Alters zymogen activation 50% of cases in Western countries >150g of alcohol daily for > 6yrs, although great variability in sensitivity to alcohol Only 5-10% of alcoholics develop chronic pancreatitis (Pancreatic) Ductal Obstruction: Strictures, pseudocysts, stones, tumors Sphincter of Oddi obstruction Pancreas divisum (although most with this condition are not affected by pancreatitis)

8. Chronic Pancreatitis - Etiology Hereditary: Autosomal dominant with only 80% penetrance Associated with the trypsinogen genes, trypsin inhibitor gene, and CFTR gene Symptoms appear by age 20 High association with pancreatic adenocarcinoma Some mutations may be protective against pancreatitis Systemic diseases: SLE, cystic fibrosis, primary hyperparathyroidism

9. Chronic Pancreatitis - Etiology Tropical Seen in South India (most common cause of chronic pancreatitis) Affects children Often die in early adulthood Idiopathic: Most common cause after alcohol abuse Consider: Concealed alcohol consumption or hypersensitivity to small amounts of alcohol Gene mutations Unreported pancreatic trauma

10. Chronic Pancreatitis – Diagnosis Classic triad of: Steatorrhea, pancreatic calcifications, DM Signs/Symptoms Chronic abdominal pain radiating to the back Labs Normal amylase, lipase Secretin stimulation test Measures pancreatic function by monitoring its response to secretin Secretin normally causes the pancreas to release digestive enzymes

11. CHRONIC PANCREATITIS – DIAGNOSIS Imaging CT Calcifications (common with alcohol induced), ductal dilitation, enlarged pancreas, fluid collections ERCP when CT is normal Irregular narrowing of the main PD with side branches EUS Lobular architecture, dilation of PD, side branches Similar to pancreatic cancer

13. AUTOIMMUNE PANCREATITIS (AIP) First described in 1995 to explain a chronic pancreatitis associated with autoimmune manifestations Defined as a type of chronic pancreatitis characterized by autoimmune inflammatory process where lymphocyte infiltration and associated fibrosis cause organ dysfunction A heterogeneous disorder known by many names: sclerosing pancreatitis, nonalcoholic destructive pancreatitis, tumefactive pancreatitis

14. AIP - EPIDEMIOLOGY Occurs in 5-6% of cases of chronic pancreatitis Incidence is higher in the Far East, where most of the studies on AIP have been done Frequency is increasing in Western nations – perhaps because of increased awareness More common in women Usually diagnosed in > 50yrs, although wide age variation

15. AIP – PATHOPHYSIOLOGY Increased circulating CD4+ and CD8+ T cells bearing HLA-DR4 CD4+ cells subdivided into Th1 and Th2 cell Th1 cells involved in induction and maintenance Th2 cells involved in disease progression Suggests an autoimmune mechanism causing inflammation Often associated with other autoimmune disorders: PSC, PBC, Retroperitoneal fibrosis, RA Sarcoidosis, Sjogrens, IBD (Ulcerative colitis > Crohns)

16. AIP - PRESENTATION Can have a wide variety of symptoms – although typically less severe than acute pancreatitis Abdominal pain, weight loss, jaundice, obstructive pattern of LFTs Presents similar to acute/chronic pancreatitis and pancreatic carcinoma Extrapancreatic manifestations: Lungs: nodules, infiltrates, adenopathy Kidneys: mild renal insufficiency, renal lesions

18. Diagnosis Signs/Symptoms suggestive of pancreatic and biliary duct disease in a patient with a history of autoimmune disorders Radiographic imaging Labs studies Response to steroids Biopsy

19. RADIOGRAPHIC IMAGING CT/MRI: Pancreas appearance: “Sausage shaped”, diffuse enlargement, homogenous attenuation Minimal pancreatic stranding or peripancreatic fluid Lack of pancreatic calcifications Peripheral rim of hypoattenuation “halo” Focal involvement typically in head of pancreas May appear as pancreatic mass Pancreatic-duct narrowing (highly diagnostic) Abdominal U/S Rarely helpful, similar to other types of pancreatitis

20. Endoscopic Imaging ERCP: Irregular narrowing or stricture of the main pancreatic duct Narrowing of the intrapancreatic part of the CBD Irregular narrowing of hepatic bile ducts EUS: Diffuse pancreatic enlargement Diffusely hypoechoic parenchyma

21. Histologic Characteristics, Including a Periductal Collar of Lymphoplasmacytic Inflammation CT Scan: Diffuse Enlargement of the Pancreaswith Homogeneous Attenuation and the Peripheral Rim of a Hypoattenuation “Halo” (Arrow)Histologic Characteristics, Including a Periductal Collar of Lymphoplasmacytic Inflammation CT Scan: Diffuse Enlargement of the Pancreaswith Homogeneous Attenuation and the Peripheral Rim of a Hypoattenuation “Halo” (Arrow)

22. AIP – DIAGNOSTIC CRITERIA IgG4 Cutoff of >135 ? SN=95%, SP=97% May not be elevated initially Other conditions cause IgG4 elevated: Atopic dermatitis, asthma, pemphigus vulgaris, certain parasitic diseases Usually accompanied by elevated IgE Antilactoferrin antibody (ALA) Anticarbonic anhydrase II antibody (ACA II) Anti-smooth muscle antibody (ASMA) Antinuclear antibody (ANA) Rheumatoid Factor (RF)

23. AIP - BIOPSY Ultimately confirms the diagnosis Done when imaging and labs do not establish a diagnosis (or if treatment fails) Periductal collar of lymphocytes and plasma cells “Lymphocytoplasmic infiltrate” Dense fibrosis

24. AIP – DIAGNOSTIC CRITERIA Japan Pancreas Society Frulloni et al. Aparisi et al. Mayo Clinic Suggest “response to steroids” as a an addition to diagnostic criteria Most important to rule out alcohol-induced chronic pancreatitis or pancreatic ca

26. AIP - TREATMENT Diagnostic findings on imaging with supportive lab results warrants a trial of steroids Rarely, AIP resolves spontaneously Prednisone 40mg/day Taper by 5 mg every 1-2 weeks Dramatic response often seen in 2-4 weeks Monitor response by imaging (labs will also improve) Malignant lesions may respond to steroids, so must confirm complete resolution If response to steroids is poor, consider alternate diagnosis Maintenance therapy needed for only a small group

27. DIFFERENTIATING AIP FROM OTHER DISORDERS PSC is not steroid responsive “Beaded” ducts with PSC Changes in intra/extra hepatic ducts (PSC) vs CBD (AIP) AIP has a more insidious presentation Pancreatic cancer is not steroid responsive Can see some response, but not total Mass in the head of the pancreas more typical of pancreatic cancer Normal IgG4 in pancreatic cancer AIP vs PSC AIP vs Pancreatic Ca

29. MKSAP #32 A 37y F has a 1 week history of fatigue, jaundice, and slight fever. She has hypothyroidism for which she takes synthroid for the last 10 yrs. She traveled to Mexico 5 months ago and received a dose of hepatitis A vaccine before the trip. Exam discloses mild jaundice and hepatomegaly. CBC: Normal TSH: Normal AST: 310 ALT: 455 Alk Phos: 180 Total bili: 2.3 Which of the following studies will most likely help establish the diagnosis? A. Antimitochondrial antibody B. Antinuclear antibody and anti smooth muscle antibody C. IgM antibody to hepatitis A virus D. Serum acetaminophen E. ERCP

30. MKSAP #32 Consider AIP because of co-existent autoimmune disease and elevated LFTs Incubation period for Hepatitis A is 2-6 weeks; also received 1 dose of Hepatitis A vaccine AMA used to diagnose PBC, which has elevated total bilirubin and alk phos, lower AST, ALT Tylenol overdose associated with aminotransaminase levels > 3000 ERCP usually done if concern for obstruction, which is commonly associated with pain

31. Recap of Learning Points –  Chronic Pancreatitis Characterized by patchy, focal infiltrates Triad: Steatorrhea, pancreatic calcification, DM Pathogenesis: Protein plug, ischemia, nutritional (antioxidant) deficiency Etiology: ETOH, idiopathic, ductal obstruction, hereditary, tropical, autoimmune, systemic diseases Imaging: Calcifications, diffusely enlarged pancreas, ductal dilitation

32. RECAP OF LEARNING POINTS - AIP Mild symptoms usually without acute attacks of pancreatitis Association with other autoimmune disorders Labs: Increased levels of IgG4 ANA, ACA-II, ASMA, ALA, RF Imaging: Diffuse enlargement of pancreas Rare calcification Irregular narrowing of the main pancreatic duct “Halo” of hypoattenuation Biopsy: Fibrotic changes with lymphocyte infiltration Therapy: Dramatic improvement with steroid therapy

33. Follow up of Patient Based on biopsy, was a concern for AIP so checked IgG panel (normal, including IgG4), RF (<20), AMSA (negative), ANA (1:40) GI also recommended ALA, ACA-II, but not done Surgery recommend Ca 19-9 (88, normal 1-37) to rule out carcinoma Liver biopsy showed no intrinsic liver disease Subsequent CT showed pancreatic necrosis and wanted to proceed with surgery but patient continue to worsen Developed sepsis, acute respiratory failure requiring intubation, and v.fib arrest, but was resuscitated Taken to the OR for pancreatic necrosis, but expired before surgery began