9 fogel pancreatic disorders
- 1. GI Update, May 2012 What’s New in Pancreatic Disorders and Treatment? Evan L. Fogel, M.D. ERCP Fellowship Director Professor of Clinical Medicine Indiana University Health
- 2. Chronic pancreatitis: clinical features • abdominal pain → 80% • pancreatic insufficiency exocrine endocrine
- 3. Pain Management • Medical • Endoscopic • Surgical
- 4. Surgical Therapy When to consider: • patients who fail medical therapy • when complications are present • to exclude malignancy • Ideal operation should relieve pain and preserve endocrine and exocrine function
- 5. Whipple Puestow Frey Beger
- 6. Total Pancreatectomy with Auto Islet cell Transplantation (TP-AIT)
- 7. Total Pancreatectomy with Auto Islet cell Transplantation (TP-AIT) – Data still accumulating – Risk of DM is related to islet cell yield • 1/2 insulin-independent at 1 year, 1/3 at 10 years • 1/3 partial islet cell function, minimal requirements • 1/3-1/2 diabetic — Pain relief: most have less pain after surgery, 50-80% narcotic independent at 2-4 year follow-up
- 8. Quality of Life Improves for Pediatric Patients after Total Pancreatectomy and Islet Autotransplant for Chronic Pancreatitis • prospective, single center study (U Minn) • 19 children (ages 5-18, mean 14.5) with chronic or acute recurrent pancreatitis – clinical history, CT/MRCP/ERCP/EUS findings • all children had repeated hospitalizations and had required narcotics before surgery (13 daily) Bellin et al., Clin Gastro Hep 2011;9:793-9.
- 9. Pediatric HRQOL after TP-AIT • Health-related quality of life (HRQOL) assessed by SF- 36 health survey prior to TP-AIT and at 3, 6, 12, 24 months after surgery • Physical functioning Bodily pain • General health Social functioning • Vitality Mental health • Role limitations attributed to physical / mental health problems • form the basis of the Physical Component Summary (PCS) and the Mental Component Summary (MCS)
- 10. Results • TP-AIT performed in standard fashion • 1 patient did not receive IAT (insufficient islet cell yield) • Average hospital stay: 20.3 ± 9.8 days • re-operation in 3 patients, percutaneous abscess drainage in 1
- 11. Results • Narcotics: – 14/19 discontinued entirely – 2/19 rare use (few times/year) – 1/19tramadol prn – 2/19daily narcotics, at a reduced dose
- 12. Results • Insulin requirements post AIT: − 7/18 insulin-independent mean 18±8 months post- − 4/18 minimal insulin requirement TP-AIT − 8/18 on basal/bolus insulin (1 pre-op diabetic) − 0/6 with prior drainage procedure were insulin independent
- 13. Normalized score HRQOL after TP-AIT Time relative to TP-AIT Change in MCS: p = .06; Change in PCS: p < .001
- 14. Conclusions • the majority of patients can be weaned off narcotic medications after surgery • insulin independence (or minimal use) can be achieved in over 60% of patients – prior surgical drainage procedure increases diabetes risk • Health-related quality of life (as measured by SF-36) improves after TP-AIT
- 15. Limitations • Few numbers of patients (19 children) • Short-term follow-up (2 years) • Heterogeneous patient population – chronic vs acute recurrent pancreatitis – genetic vs other etiologies • Questionnaires often answered by parents – Only 50 (out of a possible 95) completed
- 17. Acute Pancreatitis -- Etiology • gallstones (includes sludge, microlithiasis): > 50% • alcohol • Idiopathic – pancreas divisum – tumors – sphincter of Oddi dysfunction (SOD) • medications • post-ERCP • hyperlipidemia/hypercalcemia • abdominal trauma • hereditary/genetic • miscellaneous
- 18. Acute Pancreatitis -- Etiology • gallstones (includes sludge, microlithiasis): > 50% • alcohol • Idiopathic – pancreas divisum – tumors – sphincter of Oddi dysfunction (SOD) • medications • post-ERCP • hyperlipidemia/hypercalcemia • abdominal trauma • hereditary/genetic • miscellaneous
- 19. ERCP
- 20. Pancreas divisum • most common congenital abnormality of the pancreas • incidence: 7% overall • main pancreatic duct drains via the minor (accessory) papilla • stenotic minor papilla → impaired drainage → acute/chronic pancreatitis
- 21. Pancreatic ductal anatomy • Conventi • Pancreas onal divisum
- 22. Evidence that Pancreas Divisum Can Cause Pancreatitis • unexplained pancreatitis: incidence 3-10x controls • isolated changes of chronic pancreatitis to dorsal duct with a normal ventral duct • Minor papilla therapy (endoscopic or surgical) → 75-80% symptomatic improvement
- 23. Pancreatitis Genetics • PRSS1 – cationic trypsinogen gene • SPINK1 – serine protease inhibitor, Kazal type 1 • CTRC – Chymotrypsin C • CFTR – cystic fibrosis transmembrane conductance regulator – mutations in any of these genes may result in pancreatitis
- 24. Pancreas Divisum (PD) Is Not A Cause of Pancreatitis by Itself But Acts as a Partner of Genetic Mutations • prospective study • evaluated: – the frequency of PD (using MRCP) in patients with unexplained acute recurrent (ARP) or chronic pancreatitis (CP) – the interaction between PD and PRSS1, SPINK1 and CFTR mutations Bertin et al., Am J Gastroenterol 2012;107:311-17.
- 25. • controls: • patients with alcohol-induced chronic pancreatitis • consecutive patients undergoing MRCP for biliary indications • patients without an evident cause of pancreatitis were tested for gene mutations
- 26. Results • 2000-2008: 143 consecutive patients with ARP/CP – alcohol (n=29) – genetic: PRSS1 (n=19) SPINK1 (n=25) CFTR (n=30) -- Idiopathic (n=40) • 28 patients with PD overall
- 27. Pancreas Divisum and Genetic Mutations in Acute Recurrent/Chronic Pancreatitis No pancreatic Alcoholic Idiopathic PRSS1 SPINK1 CFTR p disease (n=29) (n=40) (n=19) (n=25) (n=30) (n=45) Sex ratio (M/F) 20/25 6/23 18/22 10/9 14/11 16/14 NS Median age 50 (20-79) 48 (35-67) 47 (18-79) 23 (15-75) 38 (20-57) 38 (17-62) < .0001 (range) Pancreas divisum 3; 7% 2; 7% 2; 5% 3; 16% 4; 16% 14; 47% < .0001 (n, %)
- 28. Pancreas Divisum and Genetic Mutations in Acute Recurrent/Chronic Pancreatitis No pancreatic Alcoholic Idiopathic PRSS1 SPINK1 CFTR p disease (n=29) (n=40) (n=19) (n=25) (n=30) (n=45) Sex ratio (M/F) 20/25 6/23 18/22 10/9 14/11 16/14 NS Median age 50 (20-79) 48 (35-67) 47 (18-79) 23 (15-75) 38 (20-57) 38 (17-62) < .0001 (range) Pancreas divisum 3; 7% 2; 7% 2; 5% 3; 16% 4; 16% 14; 47% < .0001 (n, %)
- 29. Summary • the frequency of PD was no different in patients with idiopathic pancreatitis (5%), alcoholic pancreatitis (7%) and controls (7%) • PD frequency was higher in patients with genetic mutations identified: PRSS1 (16%), SPINK1 (16%) and CFTR (47%)
- 30. Conclusions • PD alone should no longer be considered as an independent cause of pancreatitis – acts as a co-factor in patients with genetic mutations • the association of genetic mutations and PD may explain why only a subset of patients with PD develop pancreatitis
- 31. Limitations/Criticisms • % genetic mutations (PRSS1, SPINK1) in control populations is unknown • MRCP is not gold standard for diagnosis of pancreas divisum (no secretin used, no ERCPs done) • co-existence of a genetic mutation with PD should not preclude other therapeutic options (i.e. minor papilla therapy)
- 33. • Lower completion rates and adenoma detection rates have been noted at afternoon colonoscopies – due to fatigue, decreased concentration, monotony?
- 34. Effect of the Time of Day on the Success and Adverse Events of ERCP Are ERCP success rates similarly affected? Mehta et al., Gastrointest Endosc 2011;74:303-8
- 35. • Retrospective cohort study at a single tertiary referral center (minimum 500 ERCPs experience per MD) • Evaluated patients undergoing ERCP with no previous papillary intervention • Morning group: starting time before 12pm • Afternoon group: starting time after 12pm
- 36. Results 1066 ERCPs reviewed from 11/06 – 11/08 770 excluded (prior papillary intervention, inadequate documentation ) 296 procedures available for analysis 114 AM 182 PM
- 37. Patient Demographics and Procedure Characteristics AM PM p – age, y 58.7 59.4 NS – male sex 52.6% 43.4% NS – biliary alone 85.0% 84.5% NS – pancreatic alone 7.1% 5.5% NS – trainee involved 49.1% 42.3% NS – Gr 3 complexity 20.2% 22.1% NS – procedure time 40.0 min 40.0 min NS
- 38. AM (n=114) PM (n=182) P value Deep cannulation success 112 (98.3%) 171 (94.0%) .08 Procedures completed 107 (93.9%) 171 (94.0%) .97 Need for precut 27 (23.7%) 53 (29.1%) .31 Any adverse event 10 (8.8%) 13 (7.1%) .61 pancreatitis 9 (7.9%) 7 (3.9%) .13 cholangitis 1 (0.9%) 2 (2.1%) .99 bleeding 0 6 (3.3%) .085 perforation 0 0 - death 0 0 -
- 39. % with Cannulation success P = 0.30
- 40. Conclusions • When performing ERCP, the time of day did not influence: – cannulation success rates – procedure completion rates – length of procedures – adverse events • May be attributed to the heterogeneous nature of ERCP (less monotonous than colonoscopy?)
- 41. Limitations • Retrospective study • Single tertiary referral center: generalizable? • Small numbers – over 70% of patients undergoing ERCP (770/1066) were excluded • Limited complexity, mostly biliary (but same as community practice)
- 43. Post-ERCP Pancreatitis (PEP) • Most common major complication • 1-10%, as high as 30% • Varies with: – definition (Cotton et al. GI Endosc 1991) – methods of detection and follow-up – patient-related factors – procedure-related factors
- 44. Post-ERCP Pancreatitis: Risk Factors Patient Procedure • female • difficult cannulation • # of pancreatic injections • suspected SOD • pancreatic sphincterotomy • normal bilirubin • biliary sphincter dilation • history of acute • precut sphincterotomy pancreatitis • acinarization • prior post-ERCP • degree of PD filling pancreatitis • no chronic pancreatitis
- 45. Post-ERCP pancreatitis: Mechanical theory • trauma to the major papilla at ERCP and subsequent edema may lead to pancreatic duct obstruction, resulting in post-ERCP pancreatitis • reducing the pressure gradient across the pancreatic sphincter with a pancreatic duct stent may lower the frequency of this complication • > 30 studies have now addressed this issue
- 46. PEP Prevention • temporary, small diameter PD stents do lower the frequency and severity of post-ERCP pancreatitis in high-risk patients • now considered standard of care Choudhary et al., Gastrointest Endosc 2011;73: 275-82.
- 47. Pharmacologic Prevention of Post-ERCP Pancreatitis • ERCP provides a unique opportunity to administer a prophylactic therapy prior to the potential pancreatic injury
- 48. Pharmacologic Interventions: Mechanisms • Reduce sphincter spasm • Prevent infection • Reduce contrast toxicity • Decrease pancreatic secretion • Block enzyme-activated inflammatory cascade • Reduce inflammatory mediators
- 49. Udenafil • a phosphodiesterase type 5 (PDE-5) inhibitor • a smooth muscle relaxant • originally indicated for erectile dysfunction • studied in: – pulmonary hypertension – Raynaud’s phenomenon – hypercontactile esophageal motility disorders – biliary sphincter of Oddi (SO) dysfunction
- 50. Udenafil • PDE-5 inhibitors reduce basal pressure in SO • Udenafil (100 mg) reaches maximal plasma concentration within 2 hrs, time of onset within 1 hr • Administration prior to ERCP may – allow easier cannulation – potentially reduce post-ERCP pancreatitis rates
- 51. Udenafil • multicenter, double-blind RCT • 3 academic medical centers in Seoul, Korea • evaluated both low- and high-risk patients undergoing ERCP, age 20-80 • excluded patients on nitrates or those with significant coronary/cerebrovascular event within 6 months Oh et al., Gastrointest Endosc 2011;74:556-62
- 52. Results • 278 patients randomized – Udenafil 137, placebo 141 • patient demographics, indications for ERCP and therapeutic procedures performed were similar in each group Oh et al., Gastrointest Endosc 2011;74:556-62
- 53. Results Udenafil Placebo p Overall, n 137 141 hyperamylasemia (n, %) 15 (10.9) 19 (13.5) .520 pancreatitis (n, %) 11 (8.0) 11 (7.8) .944 mild/moderate/severe 8/3/0 7/3/1 .587 High-risk patients, n* 60 60 hyperamylasemia (n, %) 14 (23.3) 13 (21.6) .827 pancreatitis (n, %) 11 (18.3) 8 (13.3) .453 mild/moderate/severe 8/3/0 4/3/1 .385 *High-risk patients had > 1 of the following: age < 40, suspected SOD, difficult cannulation, complete pancreatic duct opacification
- 54. • Adverse effects – Udenafil 6 (3 flushing, 3 headache) – placebo 5 (2 headache, 2 sweating, 1 dizziness) • univariate and multivariate analysis: − age < 40, suspected SOD, complete PD opacification and failed cannulation were associated with post-ERCP pancreatitis
- 55. Conclusion • Udenafil was not effective for prevention of post-ERCP pancreatitis in this study The search continues!
- 57. NSAIDs • Inhibit prostaglandins, phospholipase A2 and neutrophil-endothelial interaction – all believed to play an important role in the pathogenesis of acute pancreatitis • Reduce mortality from acute pancreatitis in animal models
- 58. NSAIDs • Inexpensive • Easily administered • Favorable risk-profile when administered as a one-time dose
- 59. Rectal NSAIDs and PEP Prevention Study Inclusion Intervention % PEP p Criteria Placebo NSAID Murray 2003 ERP 100 mg 15.4% 6.3% (Scotland) SOD diclofenac in (17/110) (7/110) 0.049 recovery 2 mod/sev 0 mod/sev Sotoudehmanesh All-comers 100 mg 6.8% (15/221) 3.2% 2007 indomethacin 5 mod/sev (7/221) 0.06 (Iran) prior to ERCP 0 mod/sev Khoshbaten 2007 ERP 100 mg 26% 4% (Iran) diclofenac in (13/50) (2/50) < 0.01 recovery 0 mod/sev 0 mod/sev Montario Loza Suspected 100 mg 16% 5.3% 2007 bile duct indomethacin (12/75) (4/75) 0.034 (Mexico) obstruction prior to ERCP 0 mod/sev 0 mod/sev
- 60. A meta-analysis of rectal NSAIDs in the prevention of PEP • Pooled relative risk reduction for PEP after NSAID administration: 0.36 (95% CI 0.22- 0.60) • NSAID patients: ↓ PEP 64% ↓ mod-sev PEP 90% • NNT: 15 patients Elmunzer et al., Gut 2008;57:1262-7.
- 61. Conclusions • Meta-analysis results support the use of NSAIDs in the prevention of PEP • Further prospective multicenter trials are needed
- 63. Study Design • multicenter, RCT • patients enrolled from 4 university- affiliated medical centers (IU, Michigan, Kentucky, Case Western) • Independent data and safety monitoring board reviewed data quarterly
- 64. Inclusion Criteria • Major Criteria (one or • Minor Criteria (two or more) more) Suspicion of SOD Age < 50 and female History of PEP sex Pancreatic Recurrent pancreatitis sphincterotomy (≥ 2) Precut sphincterotomy ≥ 3 pancreatic duct >8 cannulation attempts injections (with at least one to the tail) Intact biliary sphincter dilation Acinarization
- 65. Exclusion Criteria • Active pancreatitis • Contraindication to NSAID use (serum creatinine > 1.4 mg/dl, active ulcer disease) • NSAID use (other than cardioprotective aspirin) within 1 week of ERCP • Anticipated low-risk of PEP (eg. chronic calcific pancreatitis, pancreatic head mass, biliary stent exchange)
- 66. Intervention • Immediately post-ERCP, patients were randomly assigned to receive: – two 50-mg indomethacin suppositories – two identical-appearing placebo suppositories • Randomization schedule was generated centrally at UM, stratified according to study center
- 67. Outcomes • Primary: development of PEP, defined according to consensus criteria – New onset of upper abdominal pain – Amylase/lipase > 3x normal, 24h post-ERCP – Hospitalization for at least 2 nights • Secondary: development of moderate or severe pancreatitis Cotton et al., Gastrointest Endosc 1991;37:383-93.
- 68. Results • Interim analysis at 400 patients: – PEP rate p > 0.005 – adverse events • Interim analysis after 600 patients ↓ significant benefit of indomethacin
- 69. Results • 2/09 – 7/11: 602 patients were enrolled – 164 Michigan – 413 Indiana – 22 Kentucky – 3 Ohio • 295 patients: indomethacin • 307 patients: placebo
- 70. Results • Baseline characteristics were similar in the two study groups • Follow-up for the 1o and 2o endpoints was 100% • 82.3% of patients had clinical suspicion of SOD
- 71. Post-ERCP Pancreatitis All Sites p = 0.005 Patients (%) p = 0.03
- 72. No. of Adverse Events Adverse Events
- 73. • beneficial effect of indomethacin on PEP rate was seen across all risk groups – regardless of whether a PD stent was placed or had a clinical suspicion of SOD
- 74. Heterogeneity in Treatment Effects Risk score: 1 point per major criterion, 0.5 points per minor criterion
- 75. Post-ERCP Pancreatitis All Sites p = 0.005 Patients (%) p = 0.03
- 76. Post-ERCP Pancreatitis Other Sites vs IU Patients (%)
- 77. No. of Patients Pancreatic Stent Placement 60%
- 78. No. of Patients Trainee Involvement 76%
- 79. Odds ratio of PEP 0.39 (p<0.001) if ERCP @ IU 0.30 (p<0.001) when adjusting for risk 0.35 (p<0.001) when adjusting for PD stenting (60% @ UM, 92% @ IU) 0.45 (p<0.001) when adjusting for trainee involvement (76% @ UM, 36% @ IU)
- 80. Possible explanations • Outcome adjudication (blinded – central) • Quality/uniformity • Technical skill • Equipment (stent length, wires, etc.)
- 81. Summary • prophylactic rectal indomethacin significantly reduced the incidence and severity of post-ERCP pancreatitis in high-risk patients
- 82. Future study • Repeated dosing of indomethacin? • Addition of a second drug ? • Role in low-risk patients? – Safe, cheap, easy
- 83. Thank-you!