MECHANISMS OF HEPATIC INJURY IN ALCOHOLIC LIVER DISEASE

Essentially all patients with significant alcoholic liver disease (ALD) have clinical manifestations of malnutrition. 101 Work by Lieber and others, however, has demonstrated that ALD can occur despite adequate nutrition. 85,86 This suggests that the liver injury of ALD is attributable to direct toxic effects of alcohol and its metabolites or the consequences of alcohol metabolism. Major research efforts into these areas have uncovered several potential mechanisms that may play a role in the liver injury of ALD. In all likelihood, several mechanisms operate simultaneously to initiate, potentiate, or perpetuate liver injury once it is initiated in clinical ALD. In addition, the initiating events or factors in alcoholic liver injury and the reasons why some individuals are predisposed to ALD are not known. Although interesting data recently were reported on the mechanisms of liver fibrosis in ALD, alcoholic hepatitis (AH) and acute liver injury are the foci of our discussion because most investigators agree that AH is an intermediate but potentially reversible stage of ALD. It is hoped that further knowledge concerning the pathogenesis of AH will allow the development of more effective treatments for this potentially lethal disease. The concepts of liver injury caused by alcohol-related oxidative stress (lipid peroxidation), immune response (cytokines), fatty acid metabolites, acetaldehyde production (protein–acetaldehyde adduct formation), mitochondrial dysfunction, and synergism of viral liver injuries, have been proposed. 81,145 These are the areas that have received major investigative attention over the past decade and are reviewed in this article.