1. ERCP: A Potential Cause and a Potential Cure of Pancreatitis Grace H. Elta, MD Professor of Medicine Division of Gastroenterology University of Michigan

2. Complications of ERCP General Considerations: Is the indication for ERCP strong enough to warrant the risks? Low suspicion: Alternative imaging Death in 0.4 -0.6% Does the performing physician have adequate case volume?

3. 2.3 0.9 Overall Severe * * * *P <0.05 Case Volume of Endoscopist

4. ERCP Complications Pancreatitis: 6.7%* Perforation: 0.3% Cholangitis: <1% Cardiopulmonary / sedation: <1% Failed procedure *Freeman ML et al GIE 2001

5. Causes of Post-ERCP Pain Pancreatitis Transient Pain Cholangitis Perforation

6. Post-ERCP Pain: What does it mean? Pain at 2 hrs post-ERCP*: 2/3 of pts developed pancreatitis 1/3 of pts who did not get pancreatitis Recovery room pain not very specific 33% of panc. presents >4hrs post-ERCP** Admission required in 12% with >1 risk factor and 4% without any *Gottlieb GIE 1996 **Freeman NEJM 1996

7. Post-ERCP Pancreatitis Definition requires all 3: New or worsened pain amylase 3X ULN > 24 hrs post-ERCP requiring >2 days hospitalization Severity: Mild: <4 days hospitalization Moderate: 4-10 d. hospitalization Severe: >10 d. hospitalization

8. Risk Factors for Post-ERCP Pancreatitis Patient specific risksOdds ratio Prior ERCP-induced pancreatitis5.4 Suspected SOD2.6 Female gender2.5 Absence of chronic pancreatitis1.9 Normal bilirubin1.9

9. Risk Factors for Post-ERCP Pancreatitis Technique specific risksOdds ratio Difficult cannulation3.4 Pancreatic injection (>1)2.7 Sphincter balloon dilation4.5 Pancreatic sphincterotomy3.1

10. Risks for Pancreatitis: Prospective US Multi-Center Study* Multivariate risk factorsOdds Ratio Minor sphincterotomy 3.8 Suspected SOD 2.6 Prior ERCP-pancreatitis 2.0 Age <60 1.6 2 or more pancreatic injections 1.5 Trainee involvement 1.5 Not risk factors: female gender, idiopathic pancreatitis, difficult cannulation, major sphincterotomy, SOM *Cheng AJG 2006

11. Does SOM Increase Procedure-Induced Pancreatitis? Suspected SOD pts: ERCP with SOM vs. ERCP alone—No differences in pancreatitis rates (26%)* Compared to 3% rate in bile duct stone pts Pancreatitis risk increased by ES and pancreatography Conclusion: It’s the diagnosis (suspected SOD) not the manometry that increases risk *Singh GIE 2004

12. Medications to Lower Post-ERCP Pancreatitis Gabexate mesylate Allopurinol Somatostatin Glyceryl trinitrate Octreotide Glucagon IL-10 Calcitonin Nifedipine Heparin Prednisone Beta-carotene Lidocaine spray *Diclofenac / Indomethacin N-acetylcysteine **Ulinastatin *4 positive / 1 negative studies **Single positive study

13. NSAID Meta-analysis 4 RCTs: 879 patients* Diclofenac / indomethacin vs. placebo Relative risk of pancreatitis: 0.35 65% decrease in pancreatitis, 90% decrease in severe pancreatitis NNT to prevent one episode: 15 *Elmunzer Gut 2008

14. Techniques to Lower Post-ERCP Pancreatitis Wire cannulation instead of contrast* Temporary PD stenting Not clearly shown to be helpful: Post-biliary ES botox Pure cut cautery may be safer than blended cut Low osmolality contrast * Lella GIE 2004

15. Temporary Pancreatic Stenting RCT: Stent lowers risk in biliary SOD pts* Used for other high risk cases Single pigtail flangeless 3F stents appear safer and more effective** Spontaneous stent passage: 70-85% Successful placement in 4 studies=88% * Tarnarsky Gastroenterology 1998 ** Rashdan Clin Gastro & Hep 2004

16. Stenting to Minimize Pancreatitis Meta-Analysis Singh P. GIE 2004;60:544.

17. Problems with Prophylactic PD Stent Technical difficulty in placement Small stents require 0.018 guide wire Increased risk in failed stent placement May require repeat endoscopy Increased cost Possible stent-induced damage Lack of expert agreement on methods

18. Survey on PD Stents: Who should get one? Which one? Agreed upon indications: SOD Pancreatic sphincterotomy (minor & major) Ampullectomy Indications according to some: Pre-cut sphincterotomy (71%) Prior post-ERCP pancreatitis (64%) Suspected SOD / normal or no manometry (60%) Traumatic or difficult cannulation (44%) No agreement on stent size and length, how long stents left, and retrieval methods *Brackbill GIE 2006

19. Post-ERCP Pancreatitis: Conclusions Most common complication, 1/3 pts. take > 4hrs to present Patient-related and technique-related risk factors are major determinants of risk Limit pancreatic injection / wire for cannulation Temporary PD stenting for high risk pts

20. Endotherapy for the Pancreas Indications: Acute idiopathic pancreatitis Chronic pancreatitis pain

21. Idiopathic Acute Pancreatitis: Possible Etiologies Microlithiasis / missed stones in GB / ducts Pancreas divisum Sphincter of Oddi dysfunction Neoplasms Subtle chronic pancreatitis Autoimmune / genetic pancreatitis Missed diagnosis of hypertriglyceridemia or hypercalcemia

22. Idiopathic Pancreatitis: Possible Additional Labs Cystic fibrosis genotype Positive in 20% (range: 4-37%) CA19-9 in suspected cancer ANA and IGG4 subtype Ionized serum calcium / parathormone FH: trypsinogen gene and Spink1 Repeat non-fasting triglyceride

23. Idiopathic Pancreatitis: Diagnostic Choices Diagnostic Choices Wait for second episode EUS MRCP +/- secretin stimulation ERCP with manometry Empiric cholecystectomy Factors affecting choice Age= >40 years: 21% had neoplasm* Absent gallbladder *Choudhari AJG 1998

24. What is the role of Microlithiasis? Microlithiasis: small (1-2 mm) stones Sludge: Collection of crystals, mucin, glycoproteins, and cellular debris Sludge may contain microlithiasis: terms used interchangeably clinically

25. Microlithiasis in IAP: Gallbladder in Situ High incidence (60-80%) centers of IAP due to microlithiasis Low incidence (6-8%) centers Evaluation/Rx options: Empiric cholecystectomy / trial of Urso Bile crystal analysis: sensitivity 66% EUS: Superior to crystal analysis* *Dahan Gut 1996

26. Does Microlithiasis cause IAP Post Cholecystectomy? Bile crystals rare in biliary SOD* No biliary crystals in IAP pts** Conclusion: Bile duct Stones / microlithiasis are very rare cause of IAP post-cholecystectomy, best diagnosed by EUS*** *Quallich GIE 2001 **Law GIE 2002 ***Scheiman AJG 2001

27. Acute Idiopathic Pancreatitis Diagnostic Tests EUS Accurate for P. divisum, tumors, bile duct or gallbladder stones Pro: Safe Con: Not therapeutic, miss SOD MRCP Accurate for P. divisum, variable accuracy for tumors and missed stones, miss SOD + Secretin: Improve image quality but value of P. duct dilation / flow is controversial

28. Diagnostic Yield of EUS in IAP *Yusoff GIE 2004 EUS Finding No cholecystec. (n=246) Post-cholecystec. (n=124) Stones (GB or BD)7%3% GB Sludge11%- Pancreas division5%11% IPMN/neoplasm2.8%4.8% Chronic pancreatitis (≥5 criteria) 31%27% Other4.8%

29. Chronic Pancreatitis Presenting as IAP “Small duct” or minimal change Difficult diagnosis EUS: need > 5 criteria for certainty Panc func tests: Also has accuracy issues Treatment options: Medical therapy first ? Value to endoscopic therapy Surgery relegated to resection

30. EUS Diagnostic Accuracy in Chronic Pancreatitis Number of EUS criteria only weakly correlated with fibrosis score* >3 criteria: 80% sensitive & specific EUS true cut and FNA also have poor specificity (65%) Only moderate interobserver agreement on individual criteria** *Chong GIE 2007 **Wallace GIE 2001

31. EUS in IAP Patient

32. Endotherapy for P. Divisum

33. Pancreas Divisum Treatment Pancreas divisum as cause of IRP Rx outcome: 127 pts in 8 series  81% no further episodes in mean f/u of 27 mo Long term (61 mos) f/u of 28 IRP pts* 23 cured, 5 better, 3 repeated ERCP NK vs traction sphincterotome?** Restenosis rate: 13% NK vs 25% TS *Alsolaiman T1528 GIE 04 **Berkes T1532 GIE 04

34. Acute pancreatitis can be a neoplastic presentation Ampullary neoplasm Ductal cancer / isolated MPD stricture IPMN Islet cell / metastatic cancer

35. Ampullary Neoplasm

36. Pancreatic Duct Stricture

37. EUS of Case: Early Pancreatic Cancer

38. Intraductal Papillary Mucinous Neoplasm: IPMN

39. SO Anatomy

40. Does SOD cause Idiopathic Acute Pancreatitis? Pro: Present in 30-60% of IAP pts Pts with panc. SOD more likely to get post-ERCP pancreatitis than those with normal SOM (26% vs. 7%)* 60-80% IAP pts improve after sphincter ablation *Tarnasky Gastroenterology 1998

41. Does SOD cause Idiopathic Acute Pancreatitis? Pro: Present in 30-60% of IAP pts Pts with panc. SOD more likely to get post-ERCP pancreatitis than those with normal SOM (26% vs. 7%)* 60-80% IAP pts improve after sphincter ablation *Tarnasky Gastroenterology 1998

42. Contemporary* Classification for Suspected Pancreatic SOD Type I-Pancreatic type pain -Amylase/lipase elevation -Dilated Pancreatic duct Type II-Pancreatic type pain -Either abnormal pancreas enzymes or duct dilation Type III-Pancreatic type pain only *Classic System includes delayed drainage >8 min

43. Why Pancreatic SOD Classification is Not Useful Few Type I pts reported, most IAP pts have normal PD caliber IAP pts fit into Type II category and are primary pts of interest Type III—an uncertain diagnosis

44. Pancreatic SOD Therapy Choices What Type of Sphincterotomy? Biliary ES: Proposed as safer 1 st step* Dual purpose: treats microlithiasis and lowers panc SO pressure somewhat Efficacy is only 28-50% Higher failure rate than panc or dual ES *Levy AJG 2001

45. Pancreatic SOD Therapy Choices What Type of Sphincterotomy? Pancreatic ES alone Treats correct portion of SO Creates small biliary ES Complete dual ES Surgical sphincteroplasty Insufficient data to support clear superiority for any method

46. 65 yo woman, 3 episodes of IARP in one year

47. Idiopathic Acute Pancreatitis ↓ R/0 autoimmune / genetic pancreatitis ↓ EUS → diagnosis/treatment ↓ no diagnosis ERCP with manometry for >1 attack Algorithm for IARP

48. Pancreatic Endotherapy for Chronic Pancreatitis Duct disruptions, pancreatic ascites Pseudocyst drainage Per ampulla-communicating cysts Transluminal stents Treatment of chronic pain Stone clearance Stricture treatment

49. Stent for Duct Disruption Resolution: 60-80% Bridge disruption Less success in AP

50. Rules for Endoscopy of Pancreatic Pseudocysts Symptomatic True PP-not acute fluid collections (<4 wks) EUS to assess wall (<10 mm) & R/O vessels Antibiotic coverage Surgical back-up

51. Endotherapy for Pseudocysts - Outcome* ResolutionComplication Chronic PP92%17% Acute PP74%19% Panc necrosis 72%37% PFC recurrence=16% with 766 d f/u *Baron GIE 2002

52. Endotherapy of MPD Stones & Chronic Pancreatitis Pain Pancreatic duct stones Rx Usually requires ESWL  1.5 sessions / pt Stone clearance:  Complete 40%; partial 40%; failure 20% Pain relief outcome: 75% with complete clearance 40% with partial clearance

53. Endotherapy for Chronic Pancreatitis Pain Case series:Pain relief: 45-74% RCT surg vs endotherapy in 72 pts* Initial success similar 5 yr f/u: Pain relief 86% vs 61% RCT surg vs endotherapy in 39 pts** 2 yr f/u: Pain relief 75% vs 32% *Dite Endoscopy 2003 **Cahen NEJM 2007

54. Complications of Pancreatic Endotherapy

55. Procedure-induced pancreatitis High risk in IAP--odds ratio=1.9 Stenosis of pancreatic ES: 13-25% Risk greater for traction type Stent-induced ductal changes Infect a cyst Misc: bleeding, perforation, sedation

56. Pancreatic Endotherapy Conclusion Acute & chronic pancreatitis indications 50-80% chance of benefit depending on specific indication 15-20% complication rate RCTs needed