Chronic Pancreatitis

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Contributor

Mao

Rong Mao, MD, FACMG

Professor of Pathology (Clinical), and Co-Director of Laboratory Genetics and Genomics Fellowship, University of Utah

Medical Director, Molecular Genetics and Genomics, ARUP Laboratories

Chronic pancreatitis includes a number of progressive inflammatory diseases, such as calcifying, chronic obstructive, and steroid-responsive or autoimmune chronic pancreatitis, which lead to pancreatic damage.¹

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.

At its later stages, chronic pancreatitis can result in pancreatic exocrine and endocrine insufficiency and diabetes.^{1

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.} Treatment does not stop disease progression; it serves only to relieve pain and address complications.^{2

Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162.} The pathogenesis of chronic pancreatitis is not fully understood, but episodes of acute pancreatitis are associated with the development of chronic pancreatitis. Alcohol use, smoking, and genetic factors also influence risk.^{1

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.} Although late-stage chronic pancreatitis may be obvious, early-stage chronic pancreatitis presents a diagnostic challenge because pancreatic function may not yet be compromised, and the pancreas might appear normal on imaging.^{1

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.}^{3

Gupte A, Goede D, Tuite R, et al. Chronic pancreatitis. BMJ. 2018;361:k2126.}Definitive diagnosis requires a combination of diagnostic tools, such as clinical examination, imaging, endoscopic procedures, and laboratory tests of pancreatic function.^{2

Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162.}

Quick Answers for Clinicians

How does chronic pancreatitis manifest clinically?

Patients with chronic pancreatitis commonly report episodes of acute pancreatitis or epigastric pain that spreads to the back.³

Gupte A, Goede D, Tuite R, et al. Chronic pancreatitis. BMJ. 2018;361:k2126.

At later stages, they may present with abdominal pain, exocrine insufficiency (often manifesting as steatorrhea), and diabetes (due to endocrine insufficiency).^{1

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.} Pain is observed in up to 85% of patients.^{1

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.} It may be years before exocrine insufficiency and diabetes develop in patients with chronic pancreatitis.^{3

Gupte A, Goede D, Tuite R, et al. Chronic pancreatitis. BMJ. 2018;361:k2126.}

How is pancreatic function testing used in chronic pancreatitis?

Indirect pancreatic function tests are typically used as part of chronic pancreatitis assessment. The fecal elastase-1 test is one of the primary tests used.¹

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.

Diarrheal specimens (watery stool) should be avoided for use in fecal elastase-1 testing because the enzyme in the sample will be diluted, potentially causing a false-positive test result.^{1

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.} The 72-hour fecal fat, serum trypsin, lipase, and amylase tests may also be useful.^{2

Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162.} In addition to indirect function tests, there are direct pancreatic function tests, but these are invasive tests that are neither widely available nor widely used.^{2

Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162.}^{4

Leeds JS, Oppong K, Sanders DS. The role of fecal elastase-1 in detecting exocrine pancreatic disease. Nat Rev Gastroenterol Hepatol. 2011;8(7):405-415.} See Laboratory Testing. Imaging and/or endoscopic procedures are also important in the evaluation of suspected chronic pancreatitis and should be performed in conjunction with laboratory tests and clinical examination.^{1

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.}^{3

Gupte A, Goede D, Tuite R, et al. Chronic pancreatitis. BMJ. 2018;361:k2126.}

What are risk factors for chronic pancreatitis?

It was once thought that all patients with chronic pancreatitis were heavy alcohol users,³

Gupte A, Goede D, Tuite R, et al. Chronic pancreatitis. BMJ. 2018;361:k2126.

but alcohol consumption is now understood as one risk factor among others, and accounts for only 44-65% of chronic pancreatitis cases.^{2

Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162.} Smoking and alcohol use are both dose-dependent risk factors for chronic pancreatitis,^{1

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.} but also work synergistically^{1

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.}^{3

Gupte A, Goede D, Tuite R, et al. Chronic pancreatitis. BMJ. 2018;361:k2126.} and together increase the risk of disease progression.^{2

Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162.} Other risk factors for chronic pancreatitis include recurrent episodes of acute pancreatitis, severe necrotizing acute pancreatitis, obesity, diabetes, and long-term ductal obstruction.^{3

Gupte A, Goede D, Tuite R, et al. Chronic pancreatitis. BMJ. 2018;361:k2126.} However, many patients have idiopathic chronic pancreatitis with no clear cause.^{1

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.}

Which genetic factors are associated with chronic pancreatitis, and when is genetic testing indicated?

A number of genetic variants are associated with chronic pancreatitis, including variants in CFTR, CTRC, PRSS1, SPINK1, CASR, PRSS2, and CLDN2.¹

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.

Specific genetic variants can also increase the risk of secondary pancreatic cancer in patients with chronic pancreatitis.^{3

Gupte A, Goede D, Tuite R, et al. Chronic pancreatitis. BMJ. 2018;361:k2126.} Genetic testing is indicated when the goal is to identify the etiology of chronic pancreatitis and to determine familial risk of the disease. See Genetic Testing.

Indications for Testing

Laboratory testing for chronic pancreatitis can be used to evaluate pancreatic function in patients with suspected chronic pancreatitis,²

Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162.

uncover the genetic cause of hereditary or idiopathic pancreatitis, and monitor patients with an established diagnosis of chronic pancreatitis to guide treatment and assess treatment response.^{1

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.}^{2

Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162.}^{3

Gupte A, Goede D, Tuite R, et al. Chronic pancreatitis. BMJ. 2018;361:k2126.}^{5

Anaizi A, Hart PA, Conwell DL. Diagnosing chronic pancreatitis. Dig Dis Sci. 2017;62(7):1713-1720.}

Laboratory Testing

Diagnosis of chronic pancreatitis is difficult early in the disease course, and the laboratory tests used for chronic pancreatitis have limited sensitivity for early-stage disease.²

Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162.

No single test can be used for diagnosis.^{1

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.}^{3

Gupte A, Goede D, Tuite R, et al. Chronic pancreatitis. BMJ. 2018;361:k2126.}^{5

Anaizi A, Hart PA, Conwell DL. Diagnosing chronic pancreatitis. Dig Dis Sci. 2017;62(7):1713-1720.} Instead, a combination of clinical examination, functional testing, and imaging is typically needed to make a diagnosis.^{5

Anaizi A, Hart PA, Conwell DL. Diagnosing chronic pancreatitis. Dig Dis Sci. 2017;62(7):1713-1720.} Risk factor classification systems for chronic pancreatitis, which account for laboratory and nonlaboratory factors, may help clinicians determine when to proceed with testing.^{5

Anaizi A, Hart PA, Conwell DL. Diagnosing chronic pancreatitis. Dig Dis Sci. 2017;62(7):1713-1720.} The American Pancreatic Association (APA)^{2

Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162.} recommends that indirect pancreatic function tests be used along with imaging to rule out cancer.

Pancreatic Function Tests

Indirect Pancreatic Function Tests

Indirect tests of pancreatic function are used to detect steatorrhea, to assess the extent of exocrine and endocrine insufficiency, and to assist in the diagnosis of chronic pancreatitis.²

Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162.

The tests are discussed in more detail below.

Fecal Elastase-1

The fecal elastase-1 test is a primary test for chronic pancreatitis and measures fecal elastase-1, a pancreatic-specific enzyme and a marker of pancreatic exocrine function. Concentrations <200 µg/g suggest exocrine insufficiency,⁴

Leeds JS, Oppong K, Sanders DS. The role of fecal elastase-1 in detecting exocrine pancreatic disease. Nat Rev Gastroenterol Hepatol. 2011;8(7):405-415.

^{6

Capurso G, Traini M, Piciucchi M, et al. Exocrine pancreatic insufficiency: prevalence, diagnosis, and management. Clin Exp Gastroenterol. 2019;12:129-139.} although levels can be falsely low in patients with diarrhea because the enzyme will be diluted in specimens.^{1

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.} For that reason, watery stool samples should be avoided. The monoclonal assay is considered to be better standardized than the polyclonal assay.^{2

Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162.}^{4

Leeds JS, Oppong K, Sanders DS. The role of fecal elastase-1 in detecting exocrine pancreatic disease. Nat Rev Gastroenterol Hepatol. 2011;8(7):405-415.}

Fecal Fat

A 72-hour fecal fat test, although difficult to perform and not widely available, can be useful in conjunction with other findings when performed appropriately¹

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.

and when small bowel bacterial overgrowth, celiac disease, and inflammatory bowel disease have been ruled out.^{2

Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162.} Values of ≥7 g fecal fat over 24 hours suggest pancreatic exocrine insufficiency.^{2

Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162.}

Serum Trypsin

Serum trypsin levels can also be used to assess pancreatic function; levels <20 ng/mL suggest steatorrhea with a pancreatic etiology.⁵

Anaizi A, Hart PA, Conwell DL. Diagnosing chronic pancreatitis. Dig Dis Sci. 2017;62(7):1713-1720.

Serum Lipase and Amylase

Serum lipase and amylase are used to assess pancreatic inflammation in episodes of acute pancreatitis and will be markedly elevated in that context. Serum lipase increases within 4-8 hours of acute pancreatitis onset and remains elevated for 8-14 days; amylase is initially elevated but returns to normal in 48-72 hours.⁷

McPherson RA, Pincus MR, eds. Henry's Clinical Diagnosis and Management by Laboratory Methods. 23rd ed. Elsevier; 2017.

Lipase and amylase also have potential as markers of pancreatic function, and low levels may indicate pancreatic exocrine insufficiency associated with chronic pancreatitis.^{2

Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162.}

Direct Pancreatic Function Tests

Direct pancreatic function tests are invasive tests that involve the use of hormones (secretin or cholecystokinin) to stimulate the pancreas; duodenal contents are then aspirated for measurement of pancreatic enzyme levels and bicarbonate concentrations.⁵

Anaizi A, Hart PA, Conwell DL. Diagnosing chronic pancreatitis. Dig Dis Sci. 2017;62(7):1713-1720.

However, these tests are not widely available.^{1

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.}^{2

Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162.}^{4

Leeds JS, Oppong K, Sanders DS. The role of fecal elastase-1 in detecting exocrine pancreatic disease. Nat Rev Gastroenterol Hepatol. 2011;8(7):405-415.} Like indirect tests, direct pancreatic function tests have lower sensitivity for early chronic pancreatitis than for later-stage disease.^{2

Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162.}

Genetic Testing

A number of genetic aberrations are associated with chronic pancreatitis, including variants in CFTR, CTRC, PRSS1, and SPINK1. Additional variants (eg, in CASR, PRSS2, and CLDN2), have also been linked to chronic pancreatitis. CFTR variants are causal for cystic fibrosis, a disease associated with chronic pancreatitis, and coinheritance of SPINK1 and CFTR increases the risk of chronic pancreatitis.¹

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.

The CLDN2 gene variant is associated with an increased risk for alcohol-related pancreatitis,^{1

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.} whereas other variants (eg, in PRSS1) increase the risk of secondary pancreatic cancer.^{1

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.}^{3

Gupte A, Goede D, Tuite R, et al. Chronic pancreatitis. BMJ. 2018;361:k2126.} Genetic testing can be used to determine a genetic cause of chronic pancreatitis. Familial testing may be appropriate in the case of a known familial mutation. Panel tests have been developed for multiple pancreatitis-associated genetic variants. Refer to the Pancreatitis Panel Test Fact Sheet for additional information.

Monitoring

Nutrient Absorption

Maldigestion in chronic pancreatitis can interfere with nutrient absorption, so in patients with an established diagnosis of chronic pancreatitis, baseline concentrations of fat-soluble vitamins (A, D, E, and K) should be determined, and bone density should be assessed.³

Gupte A, Goede D, Tuite R, et al. Chronic pancreatitis. BMJ. 2018;361:k2126.

Continued monitoring of fat-soluble vitamin levels (along with vitamin supplementation) is recommended in patients with pancreatic exocrine insufficiency who are undergoing treatment with pancreatic enzyme replacement therapy (PERT).^{1

Majumder S, Chari ST. Chronic pancreatitis. Lancet. 2016;387(10031):1957-1966.}

Therapeutic Response

Fecal chymotrypsin and 72-hour fecal fat tests can be useful for therapeutic monitoring of patients receiving PERT.²

Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-1162.

^{5

Anaizi A, Hart PA, Conwell DL. Diagnosing chronic pancreatitis. Dig Dis Sci. 2017;62(7):1713-1720.} Some fecal elastase-1 tests use a monoclonal antibody that is specific for human elastase and will not cross-react with porcine enzymatic supplements used for PERT. For that reason, the fecal chymotrypsin test is preferred for therapeutic monitoring. Fasting hemoglobin A1c or glucose tolerance tests should be performed annually in patients with chronic pancreatitis to monitor for diabetes, which can result from pancreatic endocrine insufficiency.^{3

Gupte A, Goede D, Tuite R, et al. Chronic pancreatitis. BMJ. 2018;361:k2126.}

Pancreatic Cancer

Patients with chronic pancreatitis are at greater risk for pancreatic cancer. Weight loss, lingering abdominal pain, and functional decline should prompt further assessment for malignancy using imaging and cancer antigen (CA) 19-9 testing, for example.³

Gupte A, Goede D, Tuite R, et al. Chronic pancreatitis. BMJ. 2018;361:k2126.

Patients with groove pancreatitis (pancreatitis that encompasses the pancreatic head, duodenum, and pancreaticoduodenal groove) may have increased CA 19-9 concentrations as a result of acute inflammation or biliary blockage.^{5

Anaizi A, Hart PA, Conwell DL. Diagnosing chronic pancreatitis. Dig Dis Sci. 2017;62(7):1713-1720.} These patients may require further procedures, such as surgical resection, to rule out pancreatic adenocarcinoma.^{5

Anaizi A, Hart PA, Conwell DL. Diagnosing chronic pancreatitis. Dig Dis Sci. 2017;62(7):1713-1720.}