ALCOHOLIC LIVER DISEASE: THE ROLE OF INTESTINAL BARRIER

About 4% of global deaths occur due to alcohol ingestion. Alcoholic liver disease encompasses a spectrum ranging from simple steatosis to liver fibrosis, cirrhosis and hepatocellular carcinoma. Alcoholic hepatitis defined as hepatocellular inflammatory syndrome occurring in the setting of recent consumption of large amounts of alcohol can superimpose on any of the mentioned stages of alcoholic liver disease. Ethanol is metabolized in the gastrointestinal tract and liver to acetaldehyde. Both substances induce the following changes in the intestinal tract: bacterial overgrowth; changes in the composition of intestinal microbiota; disruption of tight junctions and adherens junctions composing the essential part of the intestinal barrier and resulting in increase of intestinal permeability, which alongside with reduced clearance of bacterial components by hepatic macrophages lead to bacterial translocation. The latter is characterized by transition of live bacteria or their products (lipopolysaccharides, deoxyribonucleic acids) from intestines to extraintestinal locations, in particular, to mesenteric lymph nodes and systemic circulation. Increased endotoxin levels stimulate lipopolysaccharide signaling system involving lipopolysaccharide-binding protein, toll-like receptors, CD-14 receptors. This activates Kupffer cells, which are sensitized by ethanol to the action of lipopolysaccharide and start to produce pro-inflammatory mediators, most importantly, tumor necrosis factor-alpha, as well as reactive oxygen species. These substances contribute to hepatocellular injury, inflammation, activation of hepatic stellate cells and subsequent fibrosis. When confronted to the endotoxemia resulting from injured intestinal barrier, the liver exploits a sort of feedback mechanism aimed at increasing the protective properties of the mentioned barrier. The B-cell superantigen, Fv-protein, which enhances effector capabilities of secretory immunoglobulin A in the intestine, was found to be increased in the feces of patients with alcoholic liver disease. In conclusion, changes of intestinal barrier function are critical in the pathogenesis of alcoholic liver disease. Increasing our understanding of their delicate mechanisms and developing strategies to improve the protective functions of intestinal barrier components are urgent challenges of current hepatology in search of effective prevention and treatment modalities for alcoholic liver disease.