diagnosis and management of chronic...

Stephen T. Amann, MD, FACG

Diagnosis and Management of Chronic Pancreatitis

Stephen T. Amann, MD, FACGDigestive Health Specialists, PA

Tupelo, MS

CP Evidence based

• APA Practice guideline in CP / Diagnostic1

– 1st US guideline; part 1 of three ; 2014

• PancreasFest– Multidisciplinary meeting – multiple annual

• Address numerous topics to identify current knowledge, gaps and best practice recommendations

• Literature review / multicenter trial data

1. Conwell DL et al. Pancreas 2014;43(8):1143-62.

2016 ACG/LGS Regional Postgraduate Course Copyright 2016 American College of Gastroenterology

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GOALS

• Update new epidemiologic factors in CP• Review pathophysiology and new paradigms• Review diagnostic testing• Review treatment strategies

Chronic pancreatitis

• Chronic inflammation and glandular damage, leading to the clinical symptoms and findings of CP

• “CP SYNDROME”

1. Peery et al. Gastroenterology 2012;143(5);1179-1187.


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CP / Epidemiology

• DEMOGRAPHICS– Men 2x more than women– 200K in US have CP; 5-12/100K incidence annually– 19K admissions, LOS 5.1 D, $29K charges1

– QOL Quality of life in CP2

WORSE than diabetes mellitus, hypertension, rheumatoid arthritis2

1. Peery et al. Gastroenterology 2012;143(5);1179-1187.2. Amann ST et al. Physical and mental QOL in chronic pancreatitis: case control from the NAPS2 cohort. Pancreas 2013;42(2):293-300.

CP/ Etiology/ TIGAR-O• Toxic /metabolic

– Alcohol, Tobacco smoking, hypercalcemia, hyperlipidemia, chronic renal failure, toxins

• Idiopathic– Early, Late, Tropical

• Genetic– PRSS1, CFTR, SPINK1, and others.

• Autoimmune– Isolated, Syndromic

• RAP/SAPE associated – Post necrotic, vascular, post-irradiation

• Obstructive– Pancreas Divisum, SOD, duct obstruction


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CP / Alcohol

• In past felt to be 70% related to etiology• NOW appears to be actually about 45% in the

US– Better classification TIGAR-O

• Incorporate 1 or more risk factors

– Cooperative studies advancing understanding of the epidemiology (NAPS)

CP / Alcohol• Pancreatitis more prevalent in alcoholism • Absolute risk of pancreatitis heavy drinkers

2.5-3%• Threshold of 4-5 drinks /day increases risk of

CP1

• Disease modifier– Injury to pancreas– Modifies the immune response

1. Yadav D, et al.. Arch Intern Med. 2009;169:1035–1045.


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CP / Smoking

Risk ratio increases NS > 1PPD > > over 1PPD

3x more likely to develop CP

Stop smoking reduces risk of CP by 50%

Continued smoking increases risk of disease progression pancreatic cancer

Cote GA et al. Alcohol and smoking as risk factors in an epidemiology study of patients with CP. Clin Gastro Hepatol. 2011;9(3):266-73.

CP / ETOH / Smoking

• APA Guideline Take home:

“Alcohol and smoking are independent risk factors for CP. BOTH are associated with disease progression, and their risks are likely additive”


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CP / Genetics

Nature Genetics1996;14(2):141-5.

Hereditary pancreatitis

Familialpancreatitis

Conwell DL et al. Pancreas 2014;43(8):1143-62.

CP / Genetic

• Variable penetrance• Small proportion of CP with known genetic variants• understanding can lead to “personalized medicine”

• APA Guideline Take Home– “Genetic discoveries are rapidly uncovering new

susceptibility factors. Knowledge of gene and gene-,environment interactions may translate into new diagnostic and treatment paradigms”


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CP / Autoimmune Feature Type 1 LPSP Type 2 IDCP

Age 60 ± 15 yrs 48 ± 19 yrs

Elevate Ig4 Y N

Other organs Y N

IBD associated N Y

Relapse Common Y NLPSP: lymphoplasmocytic sclerosing IDCP: idiopathic duct centric

• Mass in the HOP, generalized edema with “halo” sign or sausage like

• Steroid responsive , relapse common in Type 1• Must Differentiate from pancreatic cancer

Sah RP, Chari ST et al. Differences in clinical profile and relapse rate of type 1 verses type 2Autimmune pancreatitis; Gastroenterology 2010;139(1):140-148.

CP /Epidemiology / Race

N (%) NAPS2NAPS2-

CVNAPS2-

AA Total

Years 2000-2006 2008-2012 2011-2014 2000-2014Number of

Centers 19 13 8 26

White 458 (85) 453 (87) 0 (0) 911 (76)

Black 58 (11) 56 (11) 134 (100) 248 (21)

Others 23 (4) 12 (2) 0 (0) 35 (3)

• NAPS2 Data set• 248 B 911 W

Wilcox CM et al. Racial Differences in the Clinical profile, Causes and Outcome of Chronic Pancreatitis. Submitted 2016

NEW


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Race 2TIGAR-O Factors N (%) Black (N=248) White (N=911)

Toxic-MetabolicAlcohol*Tobacco*HyperlipidemiaHypercalcemiaMedicationsChronic Renal Failure*Toxins*

198 (79.8)182 (73.4)

18 (7.3)1 (0.4)6 (2.4)8 (3.2)2 (0.8)

401 (44.0)395 (43.4)98 (10.8)

8 (0.9)24 (2.6)11 (1.2)0 (0.0)

Idiopathic* 37 (14.9) 345 (37.9)

Genetic* 6 (2.4) 93 (10.2)

AutoimmuneAutoimmune Pancreatitis*Autoimmune-associated diseases

0 (0.0)2 (0.8)

27 (3.0)27 (3.0)

RAP and SAP associated CP 8 (3.2) 55 (6.0)

Obstructive* Pancreas divisum*Sphincter of oddi*Post-trauma strictureDuct obstruction*Others (CV/AA only)

25 (10.1)12 (4.8)4 (1.6)0 (0.0)6 (2.4)5 (2.6)

189 (20.8)93 (10.2)52 (5.7)6 (0.7)

51 (5.6)24 (5.3)

Miscellaneous (CV/AA only) 19 (10.0) 46 (10.2)

ETOH 80% Vs 44%

Smoke 73 Vs 43%

CP / Race

• Take Home:– As compared to whites, blacks were almost twice

as likely to have alcohol as a cause of disease.– Advanced morphological abnormalities were

significantly more likely in blacks.– Abdominal pain was more common, more severe,

and more likely to result in disability in blacks


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CP / Pathophysiology• 2 hit hypothesis model

– SAPE : sentinel AP event; initiate inflammatory cascade

• Risk factors previously noted

– Second episode of AP or oxidative stress• Fibrosis, ductal and parenchymal changes

– 10% of single AP and 36% RAP progress to CP*

*Sankaran S et al. Frequency and progression from AP to CP and risk factors: A meta-analysis. Gastroenterology 2015; 149:1490-1500

Pancreatic stellate cell

Fibrosis sequence• Complex nature and

interactions• Inflammatory infiltrate

variable• Acinar loss- PEI• Islet loss – pancreatic

diabetes

Hamada, Shin. Masamune, Atsushi. Shimosegawa, Tooru. (2015). Pancreatic fibrosis. Pancreapedia:Exocrine Pancreas Knowledge base, DOI:10.3998/panc.2015.42.


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CP/ Pathophysiology

• APA Guide Take home:– CP is characterized by fibrosis and atrophy with or

w/o chronic inflammation– May be focal, patchy or diffuse– Progressive disease may lead to EXOCRINE or

ENDOCRINE (Type 3c pancreatic diabetes) deficiency

– Autoimmune CP can mimic pancreatic cancer

CP / Diagnosis

• Based on local expertise• All recs in relation to appropriate Hx / patient• No gold standard test for CP syndrome

– Structure, function and access risk


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CP/Diagnosis/ CT

• APA guideline : CT– Best for late findings of CP, limited for early– Ductal calcifications most specific reliable finding

for CP– Help in diagnose complications of CP– Eval other causes of abd pain

CP/Diagnosis / MRI :MRCP

• APA guideline : MRI– MRI is more sensitive imaging tool for diagnosis of

CP• Can pick up parenchymal changes before ductal

changes (Signal intensity and delayed enhancement)

– Ductal changes specific and reliable (Cambridge)– Stimulation MRI with secretin may improve

diagnostic accuracy – ductal and parenchymal• ? Need for EUS like MRI post secretin staging system…


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CP / Diagnosis / ERCP

• APA Guideline : ERCP– ERCP rarely used for Dx of CP

• therapy predominant

– Correlation of Cambridge criteria and histo is in advanced disease

– Confounders limits interpretation of ductal changes

• IOA, age related, post –AP changes, PanIN branch duct changes

CP / Diagnosis / EUS

• APA Guideline : EUS– Ideal threshold number of EUS criteria to Dx CP not

firmly established• >5 or <2 strongly suggests or refutes CP Dx• Rosemont Classification

– EUS features of CP are not necessarily pathologic• Aging, normal variant, non pathologic fibrosis (alcoholism,

male, obese, smokers…) – Poor IOA for EUS CP features limits accuracy and

utility of EUS for Dx of CP• Early disease


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EUS / Elastogragaphy

• Hue histogram – Qualitative

• Calculated strain ratio– Abnormal Vs normal

unrelated tissue– Compared to Rosemont

and numerical

Guo, Jintao. Sun, Siyu. (2015). Endoscopic Ultrasound for the Diagnosis of Chronic Pancreatitis.Pancreapedia:Exocrine Pancreas Knowledge base, DOI:10.3998/panc.2015.33

NEW

CP /Diagnosis / iPFT

• Indirect PFT – trypsinogen, FPE1, fecal fat, steatocrit

• APA Guideline: iPFT– Sensitive for steatorrhea /exocrine dysfunction– Moderate sensitive for Dx of severe CP– FPE ; polyclonal better, effected by watery stool or

small bowel disease– Fecal chymotrypsin helpful in detecting compliance

with PERT* Imaging to rule out pancreatic CA *


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CP /Diagnosis / PFT

• Direct PFT- secretin PFT, CCK PFT, ePFT– Peak bicarbonate ≈ histology

• APA Guideline : – High sensitivity for late CP; lower for early– Traditional oroduodenal tube test accurate but

not widely used– ePFT correlates well with the traditional testing

• Conwell DL Cleveland Clinic

CP Diagnosis APA Guide Summary

• When CP Dx criteria met no further testing• Imaging to rule out pancreatic cancer

– Local expertise

• Structure Function

• Comprehensive characterization– TIGAR-O; exocrine or endocrine dysfunction or

both


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CP Treatment /Pain

• Primary clinical complaint• Leads to one of the worst QOL scores• Multiple pain patterns, severity• Morphology on imaging does not correlate

with pain; complex

Pain /PancreasFest Multidisciplinary Study Group1

• Etiology of pain– Duct obstruction, strictures, pancreatic fibrosis– Alterations in nociception– Inflammation (mast cells, cytokines, immune cells

in nerves)– Changes in central processing of pain– maldigestion

1. Anderson MA et al. Mechanism, assessment and management of pain in chronic pancreatitis: Recommendations of a multidisciplinary study group. Pancreatology (2015) http://dx.doi.org/10.1016/j.pan.2015.10.2015


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Pain /PancreasFest Multidisciplinary Study Group

• Evaluation– Pain should be evaluated at every visit for

character, frequency and intensity.• Constant pain pattern

– More disability– Hospitalizations– Pain medication use– Lower QOL scores

– QOL– Psychological comorbidities should be addressed


• Treatment: – Medical management of the pain

• Stepwise approach NSAID to narcotic medications for constant severe pain (ibuprofen, tramadol, hydrocodone, morphine…..)

• Long term narcotics warrant pain clinic evaluation• Neuromodulating agent , Pregabalin can be considered

(RCT)*

*Olesen SS et al. Pregabalin reduces pain in patients with chronic pancreatitis in a randomized controlled trial. Gastroenterology 2011;141(2):536-43


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• PERT– Controversial for pain relief– Clearly helps PEI and may help maldigestion

symptoms and QOL; nutritional benefits. • Vit A,D,E,K, osteoporosis: supplement appropriately

• Antioxidants– Controversial and mixed data

• Less effect in EOTH CP, ? combinations unclear

– Not routinely recommended


• Behavior Modification– Strongly recommended that ETOH and smoking

cessation be undertaken and supported– Decrease disease progression and pancreatic cancer risk


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• Endoscopic Treatment– Important role in CP pain therapy

• Duct obstruction in HOP• Pseudocysts, fistula/leaks, PD stones

– Reduces pain in 65-84% PD stents for strictures• No RCT, sham controlled studies

– Varied techniques (single/multiple stents), ESWL– EXPERIENCE counts


• Neurolytic therapy– EUS guided CPB not routinely recommended as

only 50% responders and short lived effect– Surgical division of the splanchnic system similar

results


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CP/Treatment/Surgical

• Goal is pain relief and preserve tissue• Procedure type is patient specific• Pain relief: 80% immediate

40-50% long-term• Employed, no ETOH, family support• mortality <5%, complications 10-25%• Surgeon/Hospital volume a factor


• Surgical TAKE HOME– Can be first line therapy

• Heavy stone burden body/tail• Inflammatory mass

– Indicated with resection or drainage for persistent pain Ø response to medical or endoscopic

– Resection or drainage should not be done in setting of candidate for TPAIT if available


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• TPAIT– Potential management option for intractable pain

in CP, and to impact risk of pancreatic cancer in high risk patients

– Multidisciplinary team

Bibliography1. Conwell et al. APA Practice guidelines in Chronic Pancreatitis; Evidence based report on

Diagnostic guidelines. Pancreas 2104;43(8):1143-622. Whitcomb DC et al. Multicenter approach to recurrent acute and Chronic Pancreatitis in

the United States: The North American Pancreatitis Study 2. Pancreatology 2008;8:520-531.

3. Frulloni L et al. Italian Consensus guidelines for Chronic Pancreatitis. Digestive and Liver Disease 2010;42S(6):S381-406.

4. Mullady DK, Yadav D, Amann ST, et al. Type of pain, pain-associated complications, quality of life, disability and resource utilization in chronic pancreatitis: a prospective cohort study. Gut. 2011;60:77–84.

5. Yadav D, Hawes RH, Brand RE, et al. Alcohol consumption, cigarette smoking, and the risk of recurrent acute and chronic pancreatitis. Arch Intern Med. 2009;169:1035–1045.

6. Andriulli A, Botteri E, Almasio PL, et al. Smoking as a cofactor for causation of chronic pancreatitis: a meta-analysis. Pancreas. 2010;39:1205–1210

7. Yadav D, Hawes RH, Brand RE, et al. Alcohol consumption, cigarette smoking, and the risk of recurrent acute and chronic pancreatitis. Arch Intern Med. 2009;169:1035–1045.

8. Sankaran S, Xiao A, Wu L et al. Frequency and progression from AP to CP and risk factors: A meta-analysis. Gastroenterology 2015; 149:1490-1500


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Bibliography9. Mounzer R, Whitcomb DC. Genetics of acute and chronic pancreatitis. Curr Opin Gastroentrol

2013;29:544-51. 10. Amann ST , Yadav D et al. Physical and mental quality of life in CP: case control study from the

NAPS2 cohort. Pancreas 2012;42(2):293-300.11. Anderson MA , Akshintala V, Albers, K, Amann ST et al. Mechanism, assessment and management

of pain in chronic pancreatitis: Recommendations of a multidisciplinary study group. Pancreatology (2015) http://dx.doi.org/10.1016/j.pan.2015.10.2015 In press.

12. Olesen SS et al. Pregabalin reduces pain in patients with chronic pancreatitis in a randomized controlled trial. Gastroenterology 2011;141(2):536-43.

13. Kaufman M et al. Efficacy of endoscopic ultrasound-guided celiac plexus block and celiac plexus neurolysis for managing abdominal pain associated with chronic pancreatitis and pancreatic cancer. J Clin Gastroenterol 2010;44(2):127-34.

14. Buscher HC et al. Limited effect of thoracoscopic splanchnicectomy in the treatment of severe pancreatitis pain: a prospective long-term analysis of 75 cases. Surgery 2008;143(6):715-22.

15. Bellin M et al. Total pancreatectomy and islet autotransplantation in chronic pancreatitis: Recommendations from PancreasFest. Pancreatology 2013;14;27-35.

16. Chandrasekhara V et al. The role of endotherapy in benign pancreatic disease. Gastrointest Endosc 2015;82(5):203-15.


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