Recurrent Acute Pancreatitis: Can We Really Fix These Patients?

Transcription

1 BRIGHAM AND WOMENS HOSPITAL Recurrent Acute Pancreatitis: Can We Really Fix These Patients? Darwin L. Conwell, MD, MS Professor of Medicine Director, Division of Gastroenterology, Hepatology and Nutrition The Ohio State University Wexner Medical Center Charles Austin Doan Chair in Medicine The Ohio State University College of Medicine Columbus, Ohio Underlying Hypotheses RAP / ARP / IARP Etiologies Pancreatico-biliary Imaging Specific diseases /conditions Working Algorithm What I do Pearls Future Research Directions Finale Outline 2 Page 1 of 19

2 SAPE Hypothesis Step A: Acinar cell stimulation Alcohol, gallstone, TG, oxidative stress Step B: Sentinel Event Early: pro-inflammatory respone Late: Stellate cells, pro-fibrotic response Step C: Removal of stimulus Abstinence, cholecystectomy, lipid lowering agents Step D: Recurrent stimulation Stellate cell mediated periacinar fibrosis Stevens T, Am J Gastroenterol 2004; 99:2256 Whitcomb D, Best Prac and Res in Clin Gastro 2002; 16:347 Acute Pancreatitis: CT Scan Page 2 of 19

3 Recurrent Acute Pancreatitis: Pancreas Imaging CT Scan (DIAGNOSTIC) Chronic pancreatitis Pancreatic neoplasm Pancreatic cyst IPMN MRI and MRCP (DIAGNOSTIC) Pancreatic duct abnormalities, tumors IPMN Biliary tract abnormalities EUS (DIAGNOSTIC) Ampullary tumor, chronic pancreatitis Gallbladder disease IPMN Pancreas neoplasm Chronic pancreatitis Further evaluation of CT findings ERCP (DIAGNOSTIC AND THERAPEUTIC) Sphincter of Oddi manometry Sphincterotomy Acute Pancreatitis: Etiology Mechanical Gallstones, BILIARY SLUDGE, ascariasis, periampullary diverticulum, PANCREATIC / PERIPANCREATIC CANCER, ampullary stenosis, duodenal stricture or obstruction, IPMN Toxic ETHANOL, methanol, scorpion venom, organophosphate poisoning Metabolic HYPERLIPIDEMIA (types I, IV, V), hypercalcemia, AUTOIMMUNE Drugs Didanosine, pentamidine, metronidazole, stibogluconate, tetracycline furosemide, thiazides, sulfasalazine, 5-ASA, L-asparaginase, azathioprine, valproic acid, sulindac, salicylates, calcium, estrogen Infection Viruses-mumps, coxsackie, hepatitis B, CMV, varicella-zoster, HSV, HIV, Bacteria-mycoplasma, Legionella, Leptospira, salmonella, Fungiaspergillus, Parasites-toxoplasma, cryptosporidium, Ascaris Page 3 of 19

4 Acute Pancreatitis: Etiology Trauma (REMOTE) Blunt or penetrating abdominal injury, iatrogenic injury during surgery or ERCP (sphincterotomy) Congenital BILIARY ANOMALIES, PANCREAS DIVISUM, SPHINCTER OF ODDI Vascular Ischemia, atheroembolism, vasculitis (polyarteritis nodosa, SLE) Miscellaneous Post ERCP, pregnancy, renal transplantation, alpha-1-antitrypsin deficiency, CHRONIC PANCREATITIS Genetic CFTR and OTHER GENETIC MUTATIONS IDIOPATHIC Occult gallstones Hypertriglyceridemia Anatomical ampulla, bile duct, pancreatic duct Tumors ampulla, pancreas cancer Sphincter of Oddi dysfunction Autoimmune Inflammatory / Alcohol Genetic Idiopathic Recurrent Acute Pancreatitis: Etiology Page 4 of 19

5 : Microlithiasis viscous suspension in gallbladder bile that may contain small stones (<5 mm in diameter) formed by modification of hepatic bile by gallbladder mucosa mobile, low-amplitude echo on ultrasound that layers in the most dependent part of the gallbladder and is not associated with shadowing Microlithiasis Cholestrol monohydrate crystals, calcium bilirubinate granules commonly found in patients with acute pancreatitis with no obvious cause results of two uncontrolled studies suggest that biliary sludge can lead to pancreatitis, and that these patients with pancreatitis may benefit from intervention Lee SP, NEJM 1992; 326(9): Ros E, Gastroenterology 1991; 101(6): Page 5 of 19

6 METABOLIC HYPERTRIGLYCERIDEMIA Tsuang W Am J Gastroenterol Apr;104(4): Fortson MR, Am J Gastroenterol 1995;90(12): Clinical Presentations (n=70) Poorly controlled obese DM Alcoholic Drug / diet induced 4% admissions for AP Diabetes mellitus (72%) Lipemia (lactescence) (45%) Volume displacement False low serology (amylase) 1/3 Normal serology Mean TG level 4,5000 ml/dl Biochemical / radiologic AP 15% pancreas necrosis MEDICATIONS Classification AP during, resolves, recurs Other etiologies eliminated German Study: 22/1613 (1.4 %) Swiss Study: 20/7338 (0.3 %) Case reports, antedoctal Mechanism Idiosyncratic response Immune mediated reaction Toxin accumulation over time Prognosis excellent (n=22) 19/22 interstitial No necrosis > 33% No mortality Runzi M, Pancreas 1996;13:100 McArthur K, APT 1996;10:23 Mallory A, Gastro 1980;78:813 Page 6 of 19

7 IPMN (Intraductal Papillary Mucinous Neoplasms) Males, 7 th decade ACUTE RECURRENT PANCREATITIS TUMORS Main duct (75%), branch duct, OR mixed FISH EYE, MUCIN LAKES, Associated with invasive adenocarcinoma 1/3 have Peutz-Jeghers gene (STK11/LKB1) Surgery before development of carcinoma Nature Clinical Practice Gastroenterology & Hepatology (2005) 2, INFLAMMATORY epft Duodenal View 75 patients Serology, U/S, Bile analysis, ERCP, CT, EUS Mean age 32 y Mean attacks 5 Etiology Microlithiasis (13%) Chronic Pancreatitis (47%) Secretin Stimulation Bicarbonate concentration 80 meq/l About 50% develop CP Tropical pancreatitis(?) SAPE Hypothesis Garg PK, Clin Gastro Hep (1):75-9 Page 7 of 19

8 Early Chronic Pancreatitis Stevens T, Gastrointest Endosc 2004;60: ASGE GI Fellow Research Award DDW 2005 EUS Criteria for Diagnosis of Chronic Pancreatitis PARENCHYMAL Hyperechoic foci Hyperechoic strands Lobularity of gland Cysts DUCTAL Main duct dilation Duct irregularity Hyperechoic margins Stones Dilated side branches Total EUS score 3,4 or > 5 is abnormal and suggestive of chronic pancreatitis Page 8 of 19

9 Endoscopic Ultrasound (Chronic Pancreatitis) Parenchyma with hyperechoic foci and strands. Pancreatic duct dilated and irregular with hyperchoic margins* *Trikudanathan G, Am J Gastroenterol Apr;111(4): EUS CP Score vs. Peak Bicarbonate (n=56) BICARBONATE (me ENDOSONOGRAPHY SCORE EUS Results: 33 normal (0-3), 13 equivocal ( 4-5) and 10 definite (>5) Conwell DL, Dig Dis Sci May; 52(5): Page 9 of 19

10 AUTOIMMUNE Diagnostic criteria proposed by the Mayo Clinic include the presence of > or = 1 of the following three: HISORT 1) Diagnostic Histology 2) Characteristic Imaging with elevated Serology - elevated IgG4; and / or Other organ involvement 3) Response to steroid Therapy of pancreatic/extrapancreatic manifestations Chari ST, et al., Clin Gastroenterol Hepatol Aug;4(8): Yang DH, et al., Abdom Imaging Jan-Feb;31(1): Autoimmune Pancreatitis: Executive Summary Chronic pancreatitis (TIGAR-O), obstructive jaundice, IARP/RAP Lymphoplasmocytic infiltrate with fibrosis Dramatic response to steroids HISORT histology, imaging, serology, other organ involvement, response to therapy 2 types: AIP and IDCP AIP: elevated IgG4 in 2/3, pancreas manifestation of systemic disease, [IgG4-RD]; RELAPSE, Type 1 IDCP: pancreas only involvement, 25% IBD (UC); RELAPSE RARE (<10%), Type 2 Imaging diffuse enlargement(30-50%), rim/capsule/halo (30-40%) or focal mass DDx: PDAC, IAP, PSC, CholangioCA Relapses common in AIP; rare IDCP Corticosteroid responsive: 40 mg x 4 weeks; taper 5 mg/ week Corticosteroid resistant: immunomodulator (azathioprine, 6-MP, mycophenolate mofetil) or rituximab (B-cell lymphoma or rheumatoid arthritis dosing protocol) Excellent long term survival; diabetes / atrophy (tobacco, alcohol), no increase cancer risk Hart, PA., et al. Gastroenterology 2015 Page 10 of 19

11 Autoimmune Pancreatitis Characteristic Imaging Rim or Halo Sausage ANATOMICAL (smrcp) Pre-Secretin Pancreas divisum IPMN Post-Secretin Biliary anomalies Pancreas anomalies Trauma Page 11 of 19

12 Sphincter Of Oddi Three component muscular structure Fasting: MMC controlled Fed: nutrient driven myoactivity Confluence of distal cbd and pd Both mechanical and functional abnormalities Sphincter of Oddi stenosis Sphincter of Oddi dyskinesia Pancreas: Outflow defect *Rome IV: Functional Biliary Spincter Disorder (FBSD) Cotton P, Gastroenterology epub ahead of print COPYRIGHT 2007 THE JOHNS HOPKINS UNIVERSITY. ALL RIGHTS RESERVED. Sphincter Of Oddi Elevated basal pressure > 40 mm Hg Three Types (Accuracy % predicting SOD): Type I (92%) Elevation of pancreas enzymes (> 1.5 times normal) Dilated pancreatic duct (> 6mm head, >5 mm body) Delayed drainage of contrast (> 9 minutes) Type II (58%) 1 or 2 of the above Type III (35%) None of the above EPISOD Cotton P. JAMA May;311(20): Hogan WJ, Endoscopy 1988; Suppl 1:179 Sherman S, Am J Gastroenterol 1991;86:586 Geenan JE, NEJM 1989;320:82 Page 12 of 19

13 Biliary Scintigraphy Criteria Score Peak Time 0,1 Time of Gallbladder visualization 0,1 Prominence of biliary tree 0, 1, 2 Bowel visualization 0, 1, 2 CBD Emptying 0, 1, 2, 3 CBD to Liver Ratio 0, 1, 2, 3 A score of 5 or greater has a 100% sensitivity / specificity Sostre S, J Nucl Med 1992;33:1216 Persson B, Eur J Nucl Med 1993;20:770 Craig AG, Gut 2003;52:352 Cystic Fibrosis: Genetic Defects Whitcomb D Curr Opin Gastroenterol Sep;29(5): Page 13 of 19

14 Clin Med Insights Gastroenterol. 2016; 9: History Records review Ultrasound SURGERY EUS smrcp Clin Med Insights Gastroenterol. 2016; 9: ERCP Page 14 of 19

15 Recurrent Pancreatitis: What do I do? Is this really a Chronic Pain Syndrome that has been mislabeled RAP?? recent ERCP-induced AP Confirm Diagnosis Review biochemistry / serology lipase 3x ULN Review CT scan any evidence of AP, autoimmune Serology during attacks amylase, lipase, index LFTs, Consider repeat Serial Abdominal Ultrasounds biliary sludge Secretin MRCP anatomical anomalies; indirect sphincter function EUS +/- Pancreatic Function Test chronic pancreatitis (primary or secondary) be selective Biliary Scintigraphy Consider: Celiac sprue, HIV Recurrent Pancreatitis: What I do? Genetic testing (family history, asthma, sterile) Cholecystectomy / UDCA Minor duct, pancreatic, biliary sphincterotomy Art of Medicine: discontinue all smoking / alcohol, anti-oxidants, low fat diet, pancreatic enzymes, SL NTG, hand holding Repeat imaging in 3-6 months Sick days Avoidance of Emergency Room PRAYER Page 15 of 19

16 Prevention of recurrent episodes Get the gallbladder out! CHRONIC PAIN SYNDROME D/C alcohol Repeat serology Secretin MRCP Recurrent Pancreatitis: Pearls Early Chronic Pancreatitis - EUS may be too sensitive and not specific Hepatobiliary Scintigraphy Type II Sphincter of Oddi Rome IV Type I: ERCP with ES Type II: ERCP with SOM Type III: Nothing may it RIP! Consider genetic testing Recurrent Pancreatitis: Pearls Keep track of patient / No loss to follow-up! Repeat CT or smrcp in 6 months Page 16 of 19

17 Current Approach Future Approach First Symptoms Time in years Symptoms Testing for Organ damage Diagnosis made Symptomatic Treatment Testing for Genetic Risk Diagnosis made Preventative Treatment Symptoms Patient is Disabled Whitcomb, D Patient is much better Future: Personalized Medicine Approach Whitcomb, D 34 Page 17 of 19

18 Future: Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer (CPDPC) Kaiser F, UCSF Mayo C Ohio State U U.Iowa Indiana U U.Pittsburgh Stanford U. Cedars Sinai LA U.Florida U.Texas - M.D. Anderson Baylor U. NIH RFA-DK /28 Biomarker discovery, validation and implementation strategy Ohio State University Pancreatic Disorders Network (OSU-PDN) In response to: RFA-DK Page 18 of 19

19 Underlying Hypotheses SAP Hypothesis Finale: Recurrent Acute Pancreatitis RAP / ARP / IARP Potential Etiologies Biliary disease - sludge / microlithiasis; anatomic anomalies Chronic pancreatitis; tumor Pancreatico-biliary Imaging EUS smrcp Working Algorithm What I do with these patients? Pearls Future Directions 37 Page 19 of 19