Chronic pancreatitis has a small set of well-recognised causes. In adults in the USA, alcohol consumption is the most common, but alcohol alone rarely explains the disease: most people who drink heavily never develop pancreatitis, and a second factor is usually needed for it to progress — the basis of the double-hit theory. Cystic fibrosis is the most common cause in children in the USA, because the defective CFTR protein leaves the gland vulnerable to repeated injury. Cigarette smoking is an independent risk factor, and its effect is dose-dependent: the more a person smokes, the higher the risk, whether or not they also drink alcohol.
Genetic predisposition
Among patients labelled as having idiopathic chronic pancreatitis, about 15% may carry a genetic predisposition. Three genes give the clearest signal, and each contributes to the disease in a different way.
PRSS1 encodes cationic trypsinogen, the inactive precursor of the digestive enzyme trypsin. A mutation here can make trypsinogen activate prematurely inside the acinar cells, because the mutated forms are not inhibited by the intracellular mechanism that normally prevents trypsinogen activation. Trypsin that activates where it should not begins to digest the pancreas itself.
CFTR is the gene mutated in cystic fibrosis. Cystic fibrosis is a monogenic disorder with more than 1700 different mutations that differ from one another genetically and phenotypically: some produce frank cystic fibrosis, while others cause no symptomatic condition. Patients carrying a single or double CFTR mutation are more prone to chronic pancreatitis even without the classic features of cystic fibrosis, such as pulmonary disease, and CFTR mutations are found far more often in the chronic pancreatitis population than in the general population.
SPINK1 encodes a trypsin inhibitor whose job is to mop up any trypsin that activates early. The presence of two mutations in the CFTR gene together with a mutation of the SPINK1 gene has been reported to increase the risk of chronic pancreatitis by 900-fold.