Chronic pancreatitis (CP) describes a wide range of progressive fibroinflammatory diseases of the exocrine pancreas that can lead to damage to the gland. The generalization of the damage causes the insufficiency of the exocrine and endocrine functions of the pancreas, which requires treatment. In this article we will discuss the main risk factors associated with this chronic pathology and how they affect its development.
Alcohol has traditionally been considered the most common risk factor for PC. Epidemiological studies conducted in the USA have indicated alcohol as the causative agent of almost 50% of PC cases. An Italian multicentre study evaluating 893 patients with CP showed that alcohol was the main risk factor in 43% of cases, either alone (34%) or in combination with ductal obstruction (9%).
Recently genetic variants have been identified in the loci of the genes containing CLDN2, which influences the risk of alcohol-related pancreatitis. The frequency of homozygotes for this genetic variant was higher in men than in women (26 vs. 0.07), providing a probable explanation for the variation in the incidence of CP according to sex. The alcoholic CP is little known but believes that chronic alcohol consumption sensitizes acinar cells and injures them interfering with the mechanisms that protect them against stress induced by the endoplasmic reticulum.
Smoking is a risk factor for independent CP. The harmful effects of smoking seem to be synergistic with alcohol consumption. A Danish study identified smoking as the strongest risk factor for the progression from acute to chronic pancreatitis. In vitro studies show that nicotine induces oxidative stress in pancreatic acinar cells. The nicotine metabolite 4- (methylnitrosamino) -1- (3-pyridyl) -1-butanone (NNK) has been implicated in the pathogenesis of tobacco-related pancreatitis.
In the last two decades, several studies have identified specific genes that predispose to PC, either due to premature activation of trypsinogen or lack of inactivation of trypsin during pancreatic inflammation. Researchers have identified gain-of-function mutations in the cationic trypsin gene (PRSS1) that lead to premature activation of trypsinogen as a cause of hereditary pancreatitis.
The inheritance is autosomal dominant with a high penetrance; and the affected individuals usually show signs. The serum protease inhibitor SPINK1 is expressed in pancreatic acinar cells during the inflammatory response and encodes a trypsin inhibitor. Although a mutation in SPINK1 is not an independent PC risk factor, it has disease-modifying properties and has been implicated in the progression of acute pancreatitis to recurrent PC.
Ductal obstruction due to inflammatory narrowing, benign tumors or neoplasms leads to chronic obstructive pancreatitis proximal to the obstruction. Occasionally, in patients with pancreas divisum, PC may be confined to the dorsal pancreas, suggesting a causal role of ductal obstruction in the development of CP in these patients. However, a higher frequency of pancreas divisum has been observed in patients with pancreatitis related to the CFTR mutation but the pathophysiological contribution of ductal obstruction and genetic factors to the development of CP in the pancreas divisum is poorly understood.
In a large proportion of PC cases the cause is not found. Before labeling pancreatitis as chronic idiopathic, a thorough investigation should be done to identify common causes. Tropical pancreatitis, also known as fibrocalculous pancreatic diabetes, is a form of idiopathic CP that starts early in the tropics. The highest prevalence of this form of CP is found in southern India, and is characterized by early onset pain, calcifications in the main pancreatic duct, and the rapid onset of diabetes resistant to ketosis. Although genetic (SPINK1), nutritional and inflammatory factors have been implicated, the pathogenesis of this disease remains largely unknown.
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