Pancreatitis David C Whitcomb MD PhD AGAF Giant Eagle Foundation Professor of Cancer Genetics Professor of Medicine Cell Biology amp Physiology and Human Genetics Chief Division of Gastroenterology Hepatology and Nutrition ID: 1038668
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1. Autoimmune & HereditaryPancreatitisDavid 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 PittsburghPRINCIPLES OF GASTROENTEROLOGYfor the NURSE PRACTITIONER AND PHYSICIAN ASSISTANT
2. DisclosureProfessor 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.
3. PancreatitisAcute PancreatitisRecurrent Acute Pancreatitis*Chronic Pancreatitis*(Pancreatic cancer)* Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are part of a continuum – the RAP/CP Syndrome
4. Etiology-based Classification of RAP/CPTIGAR-O classificationToxic-metabolicAlcohol useSmokingIdiopathicGeneticAutoimmuneRecurrent or Severe Acute Obstructive Etemad & Whitcomb. Gastroenterology, 2001.
5. Autoimmune PancreatitisType 1Type 2Tests and interpretation
6. Definition of AIPImmunoglobulin 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 organA lymphoplasmacytic infiltrate with IgG4-positive plasma cellsVariable 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
7. Comparison of IAP type 1 & 2Type 1 AIPPeriductal lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative venulitisOlder (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 steroidsType 2 AIPGranulocytic 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 levelsSah, Gastroenterology, 2010.
8. Autoimmune Pancreatitis Case59 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
9. FNA cytology: negative for malignant cellsType 1 AIP Pancreasfest 2009
10. Follow upInitial improvement on steroidsDeveloped extrapancreatic biliary stricturesERCP with stents.Added azathioprine, not toleratedTreated with Mycophenolate Mofetil (CellCept)– resolution of strictures, stents removed From Dhiraj Yadav MD MPH
11. 45 year old man with acute pancreatitis and PEI that did not resolveSerum IgG4 was normal: EUS FNA demonstrated lymphoma.
12. AIP Evaluation and TreatmentStart 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), thenTaper 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)
13. Pancreatic GeneticsMendelian geneticsComplex geneticsGenetic tests and interpretation
14. Genetics – Key PointsPathogenic genetic variants act by:Altering protein expression Altering protein locationAltering protein functionLoss of functionGain of functionChange of function Pathogenic genetic variants cause disease by:Altering normal development (congenital)Altering function (congenital or acquired)Altering responses to stress or injury (acquired)
15. Pancreatitis – Genetic RiskPancreatitis 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 diseaseEarly 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!
16. Mendelian Genetics:cationic trypsinogencystic fibrosis transmemberane conductance regulatorPancreatic Genetics
17. Trypsinogen RegulationThe master enzyme controlling all other digestive enzymesTrypsinogen controlled by:Trypsin(2) Calcium(2)SPINK1Modified from Whitcomb, Hereditary and Childhood Disorders of the Pancreas, Including Cystic Fibrosis. Sleisenger and Fordtran’s Gastrointestinal and Liver Diseases, 7th Edition, 2002NextTAPTrypsin= calciumTrypsin(ogen)CTRC
18. Trypsin/SPINK1Mendelian: autosomal dominantHereditary pancreatitis (HP): multiple large pedigrees Acute Pancreatitis in 80% with the geneChronic Pancreatitis in 50% with acute pancreatitisPancreatic 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
19. Hereditary Pancreatitis – Natural HistoryHowes et al. Clin Gastroenterol Hepatol. 2004;2(3):252-61
20. Sentinel Acute Pancreatitis Event (SAPE)Whitcomb, Gut 1999Whitcomb, Gastroenterology 2013;144:1292–1302
21. CFTR MoleculeKey FeaturesRegulated anion channelLocated in the apical plasma membrane of epithelial cellsExpressed 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
22. Mendelian: recessiveCystic 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 symptomsCFTR-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
23. Complex GeneticsPancreatic Genetics
24. Complex GeneticsPathogenic 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)
25. Genetic Variants Related to TrypsinGenes 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 inhibitorAcinar cellDuct cellAIR = Acute inflammatory response (acute phase protein expression)
26. Genetic tests and interpretationPancreatic Genetics
27. Genetic TestingMendelian 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 resultsComplex 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.