Hereditary chronic pancreatitis (ORPHA:676)
A rare gastroenterologic disease characterized by recurrent acute pancreatitis and/or chronic pancreatitis in at least 2 first-degree relatives, or 3 or more second-degree relatives in 2 or more generations, for which no predisposing factors are identified. This rare inherited form of pancreatitis leads to irreversible damage to both exocrine and endocrine components of the pancreas.
Epidemiology
The estimated prevalence of hereditary chronic pancreatitis (HCP) is approximately 1/300,000 people in Europe (1/800,000 in Germany, approximately 1/333,000 in France and approximately 1/175,000 in Denmark).
Clinical description
Onset of HCP is typically early in life, during childhood and adolescence. The clinical presentation is highly variable and includes chronic or intermittent mild to severe abdominal pain associated with exocrine pancreatic insufficiency, leading to maldigestion and/or pancreatic endocrine insufficiency (glucose intolerance progressing to diabetes mellitus type 3c) in some cases. The disease is slowly progressive. The risk of developing pancreatic carcinoma after the age of 50 is elevated in patients with HCP. However, the exact risk increase is difficult to assess.
Etiology
Mutations in the PRSS1 (7q34) gene, encoding cationic trypsinogen, play a causative role in chronic pancreatitis. It has been shown that the PRSS1 mutations increase autocatalytic conversion of trypsinogen to active trypsin and thus probably cause premature, intrapancreatic trypsinogen activation disturbing the intrapancreatic balance of proteases and their inhibitors. Other genes, such as the anionic trypsinogen (PRSS2; 7q34), the serine protease inhibitor, Kazal type 1 (SPINK1; 5q32) and the cystic fibrosis transmembrane conductance regulator (CFTR; 7q31.2) have been found to be associated with chronic pancreatitis (idiopathic and hereditary). Recently, mutations in carboxypeptidase A1 (CPA1; 7q32.2), carboxylesterlipase (CEL; 9q34.13) and pancreatic lipase (PNLIP; 10q25.3) have been found to be associated with HCP and idiopathic chronic pancreatitis with early onset.
Diagnostic methods
Diagnosis of HCP is based on clinical features along with family history of chronic pancreatitis, absence of precipitating factors and a negative workup for known causes of chronic pancreatitis. Imaging (abdominal ultrasound, endoscopic ultrasound, exceptionally with endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance cholangiopancreatography (MRCP) reveals morphological changes like pancreatic calcifications, pancreatic duct changes, pseudocysts, bile duct and duodenal obstruction. The diagnosis might be substantiated by variants in the genes mentioned above.
Differential diagnosis
Differential diagnoses include other forms of chronic pancreatitis mainly alcoholic chronic pancreatitis, idiopathic chronic pancreatitis, autoimmune pancreatitis.
Antenatal diagnosis
Antenatal diagnosis is not encouraged.
Genetic counseling
Genetic testing should only be performed in carefully selected patients by direct DNA sequencing. Mutation in the PRSS1 gene is transmitted in an autosomal dominant manner with incomplete penetrance.
Management and treatment
Mainstays of medical management involve pain control, nutritional support, treatment for diabetes mellitus, and pancreatic enzyme supplementation for exocrine insufficiency. Surgery may be indicated for the management of acute and chronic complications of HCP and includes debridement, drainage, decompression and only very rarely pancreatectomy. Additional risk factors for chronic pancreatitis (smoking, alcohol) should be avoided.
Prognosis
The prognosis of patients with HCP is unpredictable with an increased risk of development of pancreatic carcinoma.

                            Last update: 
                            September 2019


                            - Expert reviewer(s): 
                            Pr Jonas ROSENDAHL