Autoimmune & Hereditary Pancreatitis
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Autoimmune & HereditaryPancreatitis
David C Whitcomb MD PhD AGAF Giant Eagle Foundation Professor of Cancer Genetics.
Professor of Medicine, Cell Biology & Physiology, and Human GeneticsChief, Division of Gastroenterology, Hepatology and Nutrition. University of Pittsburgh
PRINCIPLES OF GASTROENTEROLOGYfor the NURSE PRACTITIONER AND PHYSICIAN ASSISTANT
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Disclosure
Professor Whitcomb has served as a consultant for Abbvie, Chicago, IL; Millennium Pharmaceuticals, Cambridge, MA, USA; SMART-MD, Pittsburgh, PA and Novartis, Basal, Switzerland. He is Editor, Pancreatic Diseases for UpToDate, Waltham, MA. He owns stock in Ambry Genetics and equity in SMART-MD. His research is supported by the Department of Defense, the National Institutes of Health, the National Pancreas Foundation, and the Wayne Fusaro Pancreatic Cancer Research Fund.
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Pancreatitis
• Acute Pancreatitis• Recurrent Acute Pancreatitis*• Chronic Pancreatitis*• (Pancreatic cancer)
* Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are part of a continuum – the RAP/CP Syndrome
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Etiology-based Classification of RAP/CP
• TIGAR-O classification– Toxic-metabolic
• Alcohol use• Smoking
– Idiopathic– Genetic– Autoimmune– Recurrent or Severe Acute – Obstructive
Etemad & Whitcomb. Gastroenterology, 2001.
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Autoimmune Pancreatitis
Type 1Type 2
Tests and interpretation
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Definition of AIP• Immunoglobulin G4-related disease (IgG4-RD) is a
syndrome of lymphocyte dysfunction comprised of a collection of disorders that share specific pathologic, serologic, and clinical features.– Tumor-like swelling of the involved organ– A lymphoplasmacytic infiltrate with IgG4-positive plasma
cells– Variable fibrosis with a “storiform” (swirling) pattern.– Elevated serum IgG4 levels in the majority of patients (60-
70%)• IgG4-RD of the pancreas = AIP type 1
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Comparison of IAP type 1 & 2Type 1 AIP• Periductal lymphoplasmacytic
infiltrate, storiform fibrosis, and obliterative venulitis
• Older (62 +/- 14 years)• Common elevated IgG4* (80%)• Other organ involvement (60%):
– proximal biliary,– retroperitoneal,– renal, – salivary disease.
• Inflammatory bowel disease (6%)• High relapse rate after steroids
Type 2 AIP• Granulocytic epithelial lesions
(GEL)
• Younger (18 +/- 19 years)• Rare elevated IgG4* (17%)• Other organ involvement (0%):
• Inflammatory bowel disease (16%) • Relapse is rare
*Up to 7% of pancreatic ductal adenocarcinoma cases have elevated IgG4 levels
Sah, Gastroenterology, 2010.
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Autoimmune Pancreatitis Case
59 yr retired coal miner, presents with 2 week history of
painless jaundice, dark urine, and 16 lb weight loss.
Past History: Diabetes for 8 years (uncontrolled in past few months), OsteoarthritisFamily History: UnremarkableSocial History: Does not drink or smokeMedications: Insulin, occasional analgesicsPhysical Exam: Icteric sclera, enlarged submandibular glands, otherwise normal.Labs: Total bilirubin - 4.2, Direct bilirubin - 3.1,
ALT - 306, AST - 140, ALP - 264, CA 19-9 – normal From Dhiraj Yadav MD MPH
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FNA cytology: negative for malignant cells
Type 1 AIP
Pancreasfest 2009
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Follow up
• Initial improvement on steroids• Developed extrapancreatic biliary strictures• ERCP with stents.• Added azathioprine, not tolerated• Treated with Mycophenolate Mofetil
(CellCept)– resolution of strictures, stents removed
From Dhiraj Yadav MD MPH
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45 year old man with acute pancreatitis and PEI that did not resolve
Serum IgG4 was normal: EUS FNA demonstrated lymphoma.
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AIP Evaluation and Treatment• Start prednisone 40 mg/day for 4 weeks. • After 4 weeks, assess response by clinical evaluation,
radiology, and serology (IgG4 levels).• If clinical, serologic, or radiographic response was
documented (and dramatic), then– Taper prednisone 5 mg/wk until gone.
• If limited response, consider biopsy and/or cancer evaluation.
• If AIP documented and recurrent, then consider adding immunosuppression (e.g. azathioprine)
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Pancreatic Genetics
Mendelian geneticsComplex genetics
Genetic tests and interpretation
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Genetics – Key Points• Pathogenic genetic variants act by:
– Altering protein expression – Altering protein location– Altering protein function
• Loss of function• Gain of function• Change of function
• Pathogenic genetic variants cause disease by:– Altering normal development (congenital)– Altering function (congenital or acquired)– Altering responses to stress or injury (acquired)
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Pancreatitis – Genetic Risk• Pancreatitis is a complex genetic disease:
– Strong underlying genetic risk of recurrent acute pancreatic injury (susceptibility).
– Strong underlying genetic risk of progression to fibrosis, pain, diabetes, cancer. (disease modifiers)
– Environmental factors such as alcohol and smoking accelerate and worsen pancreatic disease
• Early knowledge of the basis of increased risk could be used to improve diagnostic certainty, identify syndromes and target therapy.
• Genetics is predicted to change pancreatic disease management from treating end-stage symptoms to minimizing the disease!
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MENDELIAN GENETICS:CATIONIC TRYPSINOGENCYSTIC FIBROSIS TRANSMEMBERANE CONDUCTANCE REGULATOR
Pancreatic Genetics
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Trypsinogen Regulation
• The master enzyme controlling all other digestive enzymes
• Trypsinogen controlled by:– Trypsin(2)
Calcium(2)– SPINK1
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)CTRC
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Trypsin/SPINK1
Mendelian: autosomal dominant• Hereditary pancreatitis (HP): multiple large pedigrees
– Acute Pancreatitis in 80% with the gene– Chronic Pancreatitis in 50% with acute pancreatitis– Pancreatic Cancer in >40% with chronic pancreatitis.
• Gene: cationic trypsinogen (PRSS1)*• Variants: “Gain of function”
– Increase activation – decreasing inactivation.
• HP – illustrated: – Acute Pancreatitis (first) – Chronic Pancreatitis and complications (later) – Suggested a “two hit” CP model (SAPE)**.
* Whitcomb et al, Nature Genetics, 1996** Whitcomb, Gut 1999
R122H
N29I
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Hereditary Pancreatitis – Natural History
Howes et al. Clin Gastroenterol Hepatol. 2004;2(3):252-61
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Sentinel Acute Pancreatitis Event (SAPE)
Whitcomb, Gut 1999Whitcomb, Gastroenterology 2013;144:1292–1302
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CFTR Molecule
Key Features• Regulated anion channel• Located in the apical
plasma membrane of epithelial cells
• Expressed in pancreatic duct cells close to the acinar cells.
• WINK1/SPAK activation changes CFTR from a chloride- to a bicarbonate-preferring channel.
CytoplasmLaRusch. PLoS Genetics, 2014
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Mendelian: recessive• Cystic Fibrosis (of the pancreas)
– Clinical syndrome(s)• Classic CF: pancreatic insufficiency, abnormal sweat chloride,
progressive lung disease, meconium ileus, male infertility (CBAVD), liver disease.
• Atypical CF: like CF but milder symptoms• CFTR-Related Disorders: (CFTR-RD)
– Recurrent acute & chronic pancreatitis (CFTR + SPINK1)*– Pancreatitis, male infertility, chronic sinusitis (CFTR-BD**)
– Genotype: CFTRx/CFTRX (x = CFTRsev, CFTRmv or CFTRBD)***
– Diagnosis: Clinical features, + Sweat chloride or nasal potential difference + abnormal CFTR genotype.
– Consider referral to a CF Center to make the diagnosis.* CFTR/SPINK1 genotypes represents a complex disorder** BD, bicarbonate conductance defective.*** functional effects on CFTR function, sev=severe, mv=mild variable
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COMPLEX GENETICSPancreatic Genetics
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Complex Genetics
Pathogenic genetic variables that are neither sufficient nor necessary to cause a disease, but that come together with other factors (genetic or environmental) to increase susceptibility to a condition, or to modify its clinical features.• Gene x Environment: (e.g. CLDN2 + alcohol)• Gene x Gene: (e.g. CFTR + SPINK1)
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Genetic Variants Related to Trypsin
• Genes linked to CP susceptibility all regulate intra-pancreatic trypsin activity.• Both the acinar cells and duct cells are linked with pancreatitis-causing variations
Whitcomb DC. Annu Rev Med. 2010;61:413-24.
CASR = calcium sensing receptorCTRC = chymotrypsinogen CCFTR = cystic fibrosis trans-membrane conductance
regulatorPRSS1 = cationic trypsinogenSPINK1 = pancreatic secretory
trypsin inhibitor
Acinar cell
Duct cell
AIR = Acute inflammatory response (acute phase protein expression)
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GENETIC TESTS AND INTERPRETATIONPancreatic Genetics
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Genetic Testing• Mendelian Disorders (HP, CF):
– Testing used to confirm or establish a diagnosis in the setting of disease symptoms.
– Genetic counseling is typically recommended prior to ordering the test, and to explain results
• Complex Disorders: (RAP/CP syndromes)*:– Increases or decreases the likelihood that an equivocal pancreatic
structural or functional test, or pancreatitis-like symptoms is a true positive.
– Helps identifies pathogenic pathways leading to RAP, and alters the likelihood that specific complications will occur (e.g. rapid fibrosis).
– May be useful in predictive disease modeling and personalized (individualized) medicine.* These points reflect the personal opinion of the author and have not been
agreed upon by any society or authoritative group.