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Conditions

Hereditary pancreatitis

Hereditary pancreatitis is a genetic condition characterised by recurrent episodes of pancreatitis (inflammation of the pancreas).

Overview

Onset of hereditary pancreatitis is usually in late childhood, with repeated episodes of acute pancreatitis. Symptoms include abdominal pain, fever, nausea and vomiting. Recurrent attacks can lead to chronic pancreatitis, with complications including exocrine and endocrine pancreatic insufficiency and pancreatic adenocarcinoma. The most common cause are pathogenic variants in the PRSS1 gene, following an autosomal dominant inheritance pattern with incomplete penetrance. A few further causative genes have been identified and a small gene panel is available for testing.

Clinical features

Onset of symptoms and diagnosis are typically mid- to late childhood.

Clinical features of hereditary pancreatitis include:

  • recurrent episodes of acute pancreatitis, lasting a few days, characterised by:
    • nausea;
    • vomiting;
    • abdominal pain;
    • fever; and
    • raised serum amylase;
  • chronic pancreatitis usually occurs by early adulthood, characterised by:
    • abdominal pain;
    • bloating;
    • flatulence;
    • pancreatic calcifications and ductal abnormalities; and
    • pancreatic pseudocysts;
  • exocrine pancreatic insufficiency, characterised by:
    • steatorrhea (fatty stools);
    • weight loss; and
    • vitamin deficiencies; and
  • endocrine pancreatic insufficiency:
    • type 3c diabetes mellitus.

There is a high risk of pancreatic adenocarcinoma (cumulative risk around 50% by 75 years of age), especially in smokers.

Despite considerable morbidity, it is thought that individuals with hereditary pancreatitis have a life expectancy in line with the general population.

Genomics

Most cases of hereditary pancreatitis are caused by pathogenic variants in the PRSS1 gene, accounting for about 65%–80% of cases.

PRSS1 encodes the enzyme cationic trypsinogen. Gain-of-function pathogenic variants cause elevated levels of trypsin in the pancreas, causing inflammation and tissue damage. Note that loss-of-function variants in PRSS1 do not cause this phenotype.

A few further genes have been implicated as rare causes of the condition, and a small gene panel is available for testing.

Diagnosis

Genomic testing for hereditary pancreatitis should be undertaken in patients where there are no identifiable acquired causes (such as gallstones or a history of excessive alcohol intake) and any of the following apply:

  • a clinical diagnosis of recurrent acute pancreatitis (at least 2 attacks);
  • chronic pancreatitis;
  • the first episode of acute pancreatitis occurring below 18 years of age; or
  • the first episode of acute pancreatitis with a first-degree relative who has had pancreatitis.

Note that a recent study by Niloofar and others identified pathogenic genetic variants in 63% of patients with an unexplained first incidence of acute pancreatitis below 35 years of age. If your patient does not meet the above National Genomic Test Directory criteria but your clinical suspicion remains high, discuss with your local Genomics Laboratory Hub.

For more information about genomic testing for hereditary pancreatitis and how to request it, see Presentation: Patient with unexplained acute or chronic pancreatitis.

Inheritance and genomic counselling

Hereditary pancreatitis caused by pathogenic variants in the PRSS1 gene is inherited in an autosomal dominant pattern.

  • Individuals affected by an autosomal dominant condition have one normal copy of the gene, and one with a pathogenic variant.
  • The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
  • Incomplete penetrance can occur when not everyone who has the variant develops the disease. In the case of PRSS1-related inherited pancreatitis, penetrance is estimated at around 93%.

Pathogenic variants may be inherited from an affected parent, or may arise de novo for the first time in an individual.

Predictive testing for family members of those with confirmed pathogenic variants in PRSS1 is available to identify those who would benefit from screening for pancreatic exocrine and endocrine dysfunction. Predictive testing of children is appropriate in families with early-onset symptoms.

Management

Management of hereditary pancreatitis is multidisciplinary and typically involves gastroenterology, endocrinology and surgery (if needed), as well as referral to a surveillance programme for those at a high risk of pancreatic cancer. Detailed suggested management approaches are available; see the resources section below.

Patients with a confirmed PRSS1 pathogenic variant should be referred to clinical genetics for discussion of cascade testing for family members.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 28/02/2025
  • Next review due: 28/02/2027
  • Authors: Dr Amy Frost
  • Reviewers: Professor Guruprasad P Aithal