What’s New in Pancreatic Disorders

and Treatment?Evan L. Fogel, M.D.ERCP Fellowship Director

Professor of Clinical MedicineIndiana University Health

GI Update, May 2012

Chronic pancreatitis:clinical features

• abdominal pain → 80%• pancreatic insufficiency

exocrineendocrine

Pain Management

• Medical • Endoscopic • Surgical

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

Whipple

BegerFrey

Puestow

Total Pancreatectomy with Auto Islet cell Transplantation (TP-AIT)

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

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.

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)

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

Results

• Narcotics:–14/19 discontinued entirely–2/19 rare use (few times/year)–1/19tramadol prn–2/19daily narcotics, at a reduced dose

Results

• Insulin requirements post AIT:− 7/18 insulin-independent− 4/18 minimal insulin requirement− 8/18 on basal/bolus insulin (1 pre-op

diabetic)− 0/6 with prior drainage procedure were

insulin independent

mean 18±8 months post-

TP-AIT

HRQOL after TP-AITN

orm

aliz

ed s

core

Time relative to TP-AIT

Change in MCS: p = .06; Change in PCS: p < .001

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

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

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

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

ERCP

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

Pancreatic ductal anatomy

• Conventional

• Pancreas divisum

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

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

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.

• 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

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

Pancreas Divisum and Genetic Mutations in Acute Recurrent/Chronic Pancreatitis

No pancreatic

disease (n=45)

Alcoholic (n=29)

Idiopathic (n=40)

PRSS1 (n=19)

SPINK1 (n=25)

CFTR (n=30)

p

Sex ratio(M/F) 20/25 6/23 18/22 10/9 14/11 16/14 NS

Median age (range)

50 (20-79) 48 (35-67) 47 (18-79) 23 (15-75) 38 (20-57) 38 (17-62) < .0001

Pancreas divisum (n, %)

3; 7% 2; 7% 2; 5% 3; 16% 4; 16% 14; 47% < .0001

Pancreas Divisum and Genetic Mutations in Acute Recurrent/Chronic Pancreatitis

No pancreatic

disease (n=45)

Alcoholic (n=29)

Idiopathic (n=40)

PRSS1 (n=19)

SPINK1 (n=25)

CFTR (n=30)

p

Sex ratio(M/F) 20/25 6/23 18/22 10/9 14/11 16/14 NS

Median age (range)

50 (20-79) 48 (35-67) 47 (18-79) 23 (15-75) 38 (20-57) 38 (17-62) < .0001

Pancreas divisum (n, %)

3; 7% 2; 7% 2; 5% 3; 16% 4; 16% 14; 47% < .0001

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%)

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

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)

• Lower completion rates and adenoma detection rates have been noted at afternoon colonoscopies–due to fatigue, decreased concentration,

monotony?

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

• 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

Results

1066 ERCPs reviewed from 11/06 – 11/08

296 procedures available for analysis

114 AM 182 PM

770 excluded (prior papillary intervention, inadequate documentation )

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

AM (n=114) PM (n=182) P valueDeep 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 -

P = 0.30 %

with

Can

nula

tion

succ

ess

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?)

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)

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

Post-ERCP Pancreatitis: Risk Factors

Patient• female• suspected SOD • normal bilirubin• history of acute

pancreatitis• prior post-ERCP

pancreatitis• no chronic

pancreatitis• younger age (<40)

Procedure• difficult cannulation• # of pancreatic injections• pancreatic sphincterotomy• biliary sphincter dilation• precut sphincterotomy • acinarization• degree of PD filling

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

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.

Pharmacologic Prevention of Post-ERCP Pancreatitis

• ERCP provides a unique opportunity to administer a prophylactic therapy prior to the potential pancreatic injury

Pharmacologic Interventions:Mechanisms

• Reduce sphincter spasm• Prevent infection• Reduce contrast toxicity• Decrease pancreatic secretion• Block enzyme-activated inflammatory

cascade• Reduce inflammatory mediators

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

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

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

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

ResultsUdenafil 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 .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

• 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

Conclusion

• Udenafil was not effective for prevention of post-ERCP pancreatitis in this study

The search continues!

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

NSAIDs

• Inexpensive• Easily administered• Favorable risk-profile when

administered as a one-time dose

Rectal NSAIDs and PEP Prevention Study Inclusion

CriteriaIntervention % PEP

Placebo NSAIDp

Murray 2003(Scotland)

ERPSOD

100 mg diclofenac in

recovery

15.4% (17/110)

2 mod/sev

6.3% (7/110)

0 mod/sev0.049

Sotoudehmanesh 2007(Iran)

All-comers 100 mg indomethacin prior to ERCP

6.8% (15/221)5 mod/sev

3.2% (7/221)

0 mod/sev0.06

Khoshbaten 2007(Iran)

ERP 100 mg diclofenac in

recovery

26% (13/50)

0 mod/sev

4%(2/50)

0 mod/sev< 0.01

Montario Loza 2007(Mexico)

Suspected bile duct

obstruction

100 mg indomethacin prior to ERCP

16% (12/75)

0 mod/sev

5.3% (4/75)

0 mod/sev0.034

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.

Conclusions

• Meta-analysis results support the use of NSAIDs in the prevention of PEP

• Further prospective multicenter trials are needed

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

Inclusion Criteria

• Major Criteria (one or more)

Suspicion of SODHistory of PEPPancreatic sphincterotomyPrecut sphincterotomy>8 cannulation attemptsIntact biliary sphincter dilationAmpullectomy

• Minor Criteria (two or more)

Age < 50 and female sexRecurrent pancreatitis (≥ 2)≥ 3 pancreatic duct injections (with at least one to the tail)AcinarizationPancreatic brush cytology

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)

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

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.

Results

• Interim analysis at 400 patients: – PEP rate – adverse events

• Interim analysis after 600 patients

↓

significant benefit of indomethacin

p > 0.005

Results

• 2/09 – 7/11: 602 patients were enrolled– 164 Michigan– 413 Indiana– 22 Kentucky– 3 Ohio

• 295 patients: indomethacin• 307 patients: placebo

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

Post-ERCP PancreatitisAll Sites

Pat

ient

s (

%)

p = 0.005

p = 0.03

Adverse EventsN

o. o

f Adv

erse

Eve

nts

• 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

Heterogeneity in Treatment Effects

Risk score: 1 point per major criterion, 0.5 points per minor criterion

Post-ERCP PancreatitisAll Sites

Pat

ient

s (

%)

p = 0.005

p = 0.03

Post-ERCP PancreatitisOther Sites vs IU

Pat

ient

s (

%)

Pancreatic Stent PlacementN

o. o

f Pat

ient

s

60%

Trainee InvolvementN

o. o

f Pat

ient

s

76%

Odds ratio of PEP

0.39 (p<0.001) if ERCP @ IU

0.30 (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)

Possible explanations

• Outcome adjudication (blinded – central)

• Quality/uniformity

• Technical skill

• Equipment (stent length, wires, etc.)

Summary

• prophylactic rectal indomethacin significantly reduced the incidence and severity of post-ERCP pancreatitis in high-risk patients

Future study

• Repeated dosing of indomethacin?• Addition of a second drug ?• Role in low-risk patients?

– Safe, cheap, easy

Thank-you!