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. This is the basis of the double-hit theory.
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.
In children in the USA, cystic fibrosis is the most common cause, because the defective CFTR protein leaves the gland vulnerable to repeated injury. The CFTR gene is one of several genes that also matter in people with no obvious cause.
Genetic predisposition
Chronic pancreatitis is called idiopathic when no cause can be identified. 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 (the enzyme-producing cells of the pancreas), 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.
SPINK1 encodes a trypsin inhibitor whose job is to mop up any trypsin that activates early.
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.
These variants can act together: 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.