PRSS1-Related Hereditary Pancreatitis

Excerpt

Clinical characteristics: PRSS1-related hereditary pancreatitis (HP) is characterized by episodes of acute pancreatitis (AP) and recurrent acute pancreatitis (RAP: >1 episode of AP), with frequent progression to chronic pancreatitis (CP). Manifestations of AP can range from vague abdominal pain lasting one to three days to severe abdominal pain lasting days to weeks and requiring hospitalization.

Diagnosis/testing: The diagnosis of PRSS1-related HP is established in a proband with episodes of AP, RAP, and/or CP and a heterozygous pathogenic gain-of-function variant in PRSS1 identified by molecular genetic testing. Note: Because of reduced penetrance, identification of a disease-associated PRSS1 variant in an asymptomatic individual is not sufficient for a clinical diagnosis.

High-penetrance PRSS1 pathogenic variants include p.Asn29Ile and p.Arg122His, and lower-penetrance pathogenic variants include p.Arg16Val, Asp22Gly, p.Lys23Arg, p.Asn29Thr, and p.Arg122Cys. Other PRSS1 pathogenic and risk variants are recognized; these latter variants typically require additional risk factors to cause disease and do not cause autosomal dominant hereditary pancreatitis.

Management: Treatment of manifestations: AP episodes are treated with rapid assessment of severity and fluid resuscitation as needed. Individuals with PRSS1-related HP should be counseled not to delay in being assessed for AP because hypovolemia and shock leads to serious organ dysfunction and failure. For CP, continue strategies to prevent RAP attacks. Antioxidants may have some benefit. Pancreatic enzyme replacement therapy to improve digestion in those with pancreatic insufficiency and bloating, steatorrhea, diarrhea, unexplained weight loss, and/or micronutrient deficiencies (e.g., vitamins A, D, B₁₂). Treatment of glucose intolerance with a regimen typically including metformin and insulin. Management of pain can be challenging but should begin with medical therapy, with endoscopic therapies for obstructions and surgery for more severe pain, including total pancreatectomy with islet autotransplantation, an irreversible procedure with obligate side effects, in select individuals with severe CP.

Prevention of primary manifestations: Avoid smoking and alcohol abuse. A healthy diet that is low in red meat, with multiple small meals if it improves symptoms, good hydration (especially during exercise), vitamins, and antioxidants is recommended. Some individuals report that moderate exercise helps control episodes of pain and reduces pain severity.

Surveillance: Referral to a surveillance program.

Agents/circumstances to avoid: Alcohol and tobacco use; dehydration; physical and emotional stress.

Evaluation of relatives at risk: Molecular genetic testing for the familial PRSS1 pathogenic variant is appropriate in order to identify as early as possible those who would benefit from education regarding lifestyle choices to decrease the risk of pancreatitis and pancreatic cancer and provide screening for pancreatic exocrine and endocrine dysfunction.

Genetic counseling: HP caused by gain-of-function PRSS1 pathogenic variants is inherited in an autosomal dominant manner. Many individuals diagnosed with PRSS1-related HP have an affected parent; some individuals have the disorder as the result of a de novo pathogenic variant. Each child of an individual with PRSS1-related HP has a 50% chance of inheriting the pathogenic variant. Once the PRSS1 pathogenic variant has been identified in an affected family member, predictive testing for at-risk relatives and prenatal/preimplantation genetic testing for PRSS1-related HP are possible.