9 fogel pancreatic disorders

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9 fogel pancreatic disorders

  1. 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. 2. Chronic pancreatitis: clinical features• abdominal pain → 80%• pancreatic insufficiency exocrine endocrine
  3. 3. Pain Management• Medical• Endoscopic• Surgical
  4. 4. Surgical TherapyWhen 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. 5. Whipple Puestow Frey Beger
  6. 6. Total Pancreatectomy with Auto Islet cell Transplantation (TP-AIT)
  7. 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. 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. 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. 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. 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. 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. 13. Normalized score HRQOL after TP-AIT Time relative to TP-AITChange in MCS: p = .06; Change in PCS: p < .001
  14. 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. 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
  16. 16. 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
  17. 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. 18. ERCP
  19. 19. 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
  20. 20. Pancreatic ductal anatomy• Conventi • Pancreas onal divisum
  21. 21. 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
  22. 22. 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
  23. 23. 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 mutationsBertin et al., Am J Gastroenterol 2012;107:311-17.
  24. 24. • 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
  25. 25. 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
  26. 26. 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 NSMedianage 50 (20-79) 48 (35-67) 47 (18-79) 23 (15-75) 38 (20-57) 38 (17-62) < .0001(range)Pancreasdivisum 3; 7% 2; 7% 2; 5% 3; 16% 4; 16% 14; 47% < .0001(n, %)
  27. 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 NSMedianage 50 (20-79) 48 (35-67) 47 (18-79) 23 (15-75) 38 (20-57) 38 (17-62) < .0001(range)Pancreasdivisum 3; 7% 2; 7% 2; 5% 3; 16% 4; 16% 14; 47% < .0001(n, %)
  28. 28. 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%)
  29. 29. 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
  30. 30. 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)
  31. 31. • Lower completion rates and adenoma detection rates have been noted at afternoon colonoscopies – due to fatigue, decreased concentration, monotony?
  32. 32. Effect of the Time of Day on theSuccess and Adverse Events of ERCP Are ERCP success rates similarly affected?Mehta et al., Gastrointest Endosc 2011;74:303-8
  33. 33. • 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
  34. 34. Results1066 ERCPs reviewed from 11/06 – 11/08 770 excluded (prior papillary intervention, inadequate documentation )296 procedures available for analysis 114 AM 182 PM
  35. 35. 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
  36. 36. AM (n=114) PM (n=182) P valueDeep cannulation success 112 (98.3%) 171 (94.0%) .08Procedures completed 107 (93.9%) 171 (94.0%) .97Need for precut 27 (23.7%) 53 (29.1%) .31Any 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 -
  37. 37. % with Cannulation success P = 0.30
  38. 38. 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?)
  39. 39. 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)
  40. 40. 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
  41. 41. Post-ERCP Pancreatitis: Risk FactorsPatient 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
  42. 42. 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
  43. 43. 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 careChoudhary et al., Gastrointest Endosc 2011;73: 275-82.
  44. 44. Pharmacologic Prevention of Post-ERCP Pancreatitis• ERCP provides a unique opportunity to administer a prophylactic therapy prior to the potential pancreatic injury
  45. 45. Pharmacologic Interventions: Mechanisms• Reduce sphincter spasm• Prevent infection• Reduce contrast toxicity• Decrease pancreatic secretion• Block enzyme-activated inflammatory cascade• Reduce inflammatory mediators
  46. 46. 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
  47. 47. 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
  48. 48. 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 monthsOh et al., Gastrointest Endosc 2011;74:556-62
  49. 49. Results • 278 patients randomized – Udenafil 137, placebo 141 • patient demographics, indications for ERCP and therapeutic procedures performed were similar in each groupOh et al., Gastrointest Endosc 2011;74:556-62
  50. 50. Results Udenafil Placebo pOverall, 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 .587High-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
  51. 51. • 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
  52. 52. Conclusion• Udenafil was not effective for prevention of post-ERCP pancreatitis in this study The search continues!
  53. 53. 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
  54. 54. NSAIDs• Inexpensive• Easily administered• Favorable risk-profile when administered as a one-time dose
  55. 55. Rectal NSAIDs and PEP PreventionStudy Inclusion Intervention % PEP p Criteria Placebo NSAIDMurray 2003 ERP 100 mg 15.4% 6.3%(Scotland) SOD diclofenac in (17/110) (7/110) 0.049 recovery 2 mod/sev 0 mod/sevSotoudehmanesh 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/sevKhoshbaten 2007 ERP 100 mg 26% 4%(Iran) diclofenac in (13/50) (2/50) < 0.01 recovery 0 mod/sev 0 mod/sevMontario 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
  56. 56. 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 patientsElmunzer et al., Gut 2008;57:1262-7.
  57. 57. Conclusions• Meta-analysis results support the use of NSAIDs in the prevention of PEP• Further prospective multicenter trials are needed
  58. 58. 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
  59. 59. Inclusion Criteria• Major Criteria (one or • Minor Criteria (two or more) more)Suspicion of SOD Age < 50 and femaleHistory of PEP sexPancreatic Recurrent pancreatitissphincterotomy (≥ 2)Precut sphincterotomy ≥ 3 pancreatic duct>8 cannulation attempts injections (with at least one to the tail)Intact biliary sphincterdilation Acinarization
  60. 60. 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)
  61. 61. 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
  62. 62. 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 pancreatitisCotton et al., Gastrointest Endosc 1991;37:383-93.
  63. 63. Results• Interim analysis at 400 patients: – PEP rate p > 0.005 – adverse events• Interim analysis after 600 patients↓significant benefit of indomethacin
  64. 64. Results• 2/09 – 7/11: 602 patients were enrolled – 164 Michigan – 413 Indiana – 22 Kentucky – 3 Ohio• 295 patients: indomethacin• 307 patients: placebo
  65. 65. 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
  66. 66. Post-ERCP Pancreatitis All Sites p = 0.005Patients (%) p = 0.03
  67. 67. No. of Adverse Events Adverse Events
  68. 68. • 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
  69. 69. Heterogeneity in Treatment EffectsRisk score: 1 point per major criterion, 0.5 points per minor criterion
  70. 70. Post-ERCP Pancreatitis All Sites p = 0.005Patients (%) p = 0.03
  71. 71. Post-ERCP Pancreatitis Other Sites vs IUPatients (%)
  72. 72. No. of Patients Pancreatic Stent Placement 60%
  73. 73. No. of Patients Trainee Involvement 76%
  74. 74. Odds ratio of PEP0.39 (p<0.001) if ERCP @ IU0.30 (p<0.001) when adjusting for risk0.35 (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)
  75. 75. Possible explanations• Outcome adjudication (blinded – central)• Quality/uniformity• Technical skill• Equipment (stent length, wires, etc.)
  76. 76. Summary• prophylactic rectal indomethacin significantly reduced the incidence and severity of post-ERCP pancreatitis in high-risk patients
  77. 77. Future study• Repeated dosing of indomethacin?• Addition of a second drug ?• Role in low-risk patients? – Safe, cheap, easy
  78. 78. Thank-you!

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