Cationic trypsinogen mutations and pancreatitis

Nathan Howes, William Greenhalf, Deborah D Stocken, John P Neoptolemos
Clinics in Laboratory Medicine 2005, 25 (1): 39-59
The discovery of PRSS 1 mutations in hereditary pancreatitis and analysis of how the genotype affects the presentation and progression of hereditary pancreatitis has led to a better understanding of the pathophysiology of the disease. Patients with hereditary pancreatitis present with symptoms at an early age and have a significant lifetime risk for the development of endocrine and exocrine insufficiency, albeit at a later stage than patients with either idiopathic or alcoholic chronic pancreatitis. There are distinct phenotypic differences between hereditary pancreatitis and with other types of pancreatitis. As many as 80% of patients with symptomatic hereditary pancreatitis have an underlying causative PRSS1 mutation; there are, however, few significant phenotypic differences between these PRSS1 mutations. TheR122H mutation is the most common PRSS1 mutation observed, and patients with the R122H mutation present earlier. This, however, does not necessarily translate into a more aggressive disease with respect to complications of chronic pancreatitis. Indeed, the age of presentation of symptoms may be a poor surrogate for predicting outcome, as inherited disorders of trypsinogen may cause subclinical attacks of pancreatitis, which ultimately lead to pancreatic destruction and dysfunction. All patients, irrespective of whether they carry a PRSS1 mutation, are at significant risk of developing pancreatic ductal adenocarcinoma. The risk appears to be insignificant below the age of 40 years, but it increases incrementally thereafter. Significantly, the risk of pancreatic cancer is not related to PRSS1 mutation type and does not appear to be related to the mode of inheritance. The role of SPINK1 mutations in modifying the expression of PRSS1mutations is unclear but appears to be of clinical importance. It is unlikely that they act as causative mutations per se, at least in the Western form of the disease. Additionally, they do not appear to have an impact on the penetrance of PRSS1 gene mutations in hereditary pancreatitis.

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