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!