Investigating the pathobiology of alcoholic pancreatitis

Abstract

Alcohol abuse is one of the most common causes of pancreatitis. The risk of developing alcohol-induced pancreatitis is related to the amount and duration of drinking. However, only a small portion of heavy drinkers develop disease, indicating that other factors (genetic, environmental, or dietary) contribute to disease initiation. Epidemiologic studies suggest roles for cigarette smoking and dietary factors in the development of alcoholic pancreatitis. The mechanisms underlying alcoholic pancreatitis are starting to be understood. Studies from animal models reveal that alcohol sensitizes the pancreas to key pathobiologic processes that are involved in pancreatitis. Current studies are focussed on the mechanisms responsible for the sensitizing effect of alcohol; recent findings reveal disordering of key cellular organelles including endoplasmic reticulum, mitochondria, and lysosomes. As our understanding of alcohol's effects continue to advance to the level of molecular mechanisms, insights into potential therapeutic strategies will emerge providing opportunities for clinical benefit.

Figure 1. The mechanisms of alcoholic pancreatitis

Intracellular events in the pancreatic acinar cell associated with alcohol abuse include dysregulation of calcium signals, protein processing and trafficking, the autophagic, lysosomal and mitochondrial functions; and the induction of inflammatory signals and cell death pathways. These disorders “sensitize” the pancreas so that is in not capable of adapting to stressful stimuli, thus leading to pancreatitis with key pathologic responses of organ inflammation, vascular dysfunction, and parenchymal necrosis. Severe acute pancreatitis can lead to systemic inflammatory response, multiple organ failure, and death. Chronic pancreatitis results from repeated episodes of acute pancreatitis leading to persistent inflammation and fibrosis. The insults of acute and chronic pancreatitis lead to loss of normal function so that exocrine and endocrine pancreatic insufficiency develops.