Hereditary Pancreatitis (HP) was first described in 1952 by Comfort and Steinberg but it was not until 1996 that Whitcomb et al isolated the first responsible mutation in the cationic trypsinogen gene (PRSS1) on the long arm of chromosome seven (7q35).

The term "hereditary pancreatitis" is used when a genetic defect is identified, and "familial pancreatitis" used when it is not.

Presentation

HP is characterised by attacks of epigastric pain, which are often associated with nausea and vomiting. Symptoms may start shortly after birth but onset varies greatly, with some individuals not exhibiting symptoms until adulthood. There is usually progression to chronic pancreatitis with endocrine and exocrine failure and an increased risk of pancreatic cancer. Lifetime risk has been variously calculated as 35-54% to the age of 75 years and screening for early pancreatic cancer is being offered to HP sufferers on a research basis.

The natural history of HP follows a similar pattern to alcohol associated chronic pancreatitis, but there are important differences, for example, HP has an earlier age of onset of pancreatitis although malabsorption and diabetes mellitus occur at a later stage in the disease.

Diagnosis

Families are defined as having HP, if the phenotype is consistent with highly penetrant autosomal dominant inheritance. In simple terms, this would require two or more first degree relatives (or three or more second degree relatives) to have unexplained recurrent-acute or chronic pancreatitis in two or more generations. It is an autosomal dominant disease with penetrance that is generally accepted to be ≈80%.

Genetics

The vast majority of the cases of HP are caused by substitutions, at base 365 (c.365G>A) and base 86 of the cDNA (c.86A>T) on the PRSS1 gene. They were discovered in the late 1990’s by conventional linkage analysis and are now known as p.R122H and p.N29I respectively, according to the amino acid substitution and position in the protein sequence.

These mutations are rarely identified in general screens of patients with idiopathic disease and the phenotype of p.R122H and p.N29I is now well characterised with the p.A16V mutation recently characterised for the first time. There are many other rare mutations or polymorphisms of PRSS1 which remain less well understood and not all HP families have had the responsible genetic mutation identified.

The mechanism by which these genetic mutations cause pancreatitis is incompletely understood but is likely to be the result of increased autoactivation or reduced deactivation of trypsinogen (or a combination of the two), although a novel mechanism has recently been identified in a p.R116C kindred.