GI system: Role of alcohol in pancreatitis

Researchers studying the pathogenesis of alcoholic pancreatitis recognize the importance of acinar cells in the disease. Acinar cells constitute an “enzyme factory” that produces millions of digestive enzyme molecules per day. It has been shown in animal models that one of the first events in acute experimental pancreatitis is the premature activation of digestive enzymes within acinar cells by co-segregation of zymogen granules with lysosomal enzymes, especially cathepsin B.

Scientists hypothesize that ethanol, ethanol metabolites, and oxidative stress exert toxic effects on pancreatic acinar cells, which predispose the gland to autodigestive injury. These toxic effects include:

These changes sensitize the cell such that overt injury is initiated (alcoholic acute pancreatitis) in the presence of an appropriate trigger. Cytokines released during alcohol-induced necroinflammation activate pancreatic stellate cells (PSCs). In addition, PSCs are activated directly by ethanol, most likely via its metabolism to acetaldehyde (Ac) and the subsequent generation of oxidative stress. Activated PSCs then synthesize excess amounts of extracellular matrix proteins leading to pancreatic fibrosis.

A summary of these proposed mechanisms is shown in Figure 1.

Figure 1 Hypothesized mechanisms of the pathogenesis of alcoholic pancreatitis

A major piece of evidence for this theory is the effect that alcohol and its metabolites have on fibrogenesis in PSCs. In a study conducted in 2000, pancreatic cell cultures were treated with ethanol and acetaldehyde, a product of ethanol oxidation, and collagen production by PSCs was measured. The results of this study are shown in Figure 2. The vertical axis of the graph, which measures the incorporation of proline into collagen, can be interpreted as a measure of total collagen synthesis.

Figure 2 Effects of ethanol (E) and acetaldehyde (A) at concentrations of 10 mmol/L, 50 mmol/L, 100 mmol/L, and 200 mmol/L on collagen synthesis in pancreatic stellate cells