Ethanol-Induced Liver Disease

Alcoholism (>5 g of alcohol or about five drinks per day) causes several types of liver injury, including steatosis (fatty liver), alcoholic hepatitis, and cirrhosis. Although almost all people who chronically abuse alcohol develop steatosis, only 10% to 20% develop cirrhosis.^[294] Chronic liver disease is notoriously difficult to detect by a brief history and physical examination. The clinical presentation correlates poorly with hepatic pathology, because physiologic compensatory mechanisms can mask extensive liver disease. Identifying patients with severe alcoholic liver disease is important, as their risk for perioperative morbidity may be increased two- to three-fold.^[295] The most frequent perioperative complications are bleeding, infections, and cardiopulmonary disorders.

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Clinical studies and laboratory experiments have shown that alcoholism produces a multitude of subcellular disturbances, including: (1) acetaldehyde-induced lesions, (2) metabolic perturbations, (3) microvascular hypoxia, (4) increased production of oxygen and nitrogen radicals, and (5) depletion of antioxidant defenses. The metabolism of ethanol plays an integral role in the pathogenesis of alcoholic liver disease.^{[296] [297] [298] [299] [300] [301] [302]} Alcohol dehydrogenase (ADH), a zinc metalloenzyme, catalyzes the rate-limiting step in the ethanol metabolism. Although this enzyme is present in many tissues,^{[300] [303]} more than 95% of ethanol metabolism occurs in the liver. Cytoplasmic ADH is chiefly responsible for oxidizing ethanol to acetaldehyde. However, when ADH activity decreases, as occurs in alcoholic liver disease, microsomal ethanol-oxidizing enzymes (e.g., ethanol-induced CYP2E1) and catalase in peroxisomes become important contributors to ethanol metabolism.^{[304] [305]}

ADH is polymorphic; there are more than 20 different isozymes, with widely varying kinetic properties.^{[294] [306]} It seems likely that genetic polymorphisms of ethanolmetabolizing enzymes affect susceptibility to alcoholic liver disease.^{[306] [307] [308]} Polymorphisms at the ADH2 gene locus (increased frequency of B allele), for example, have been linked to the development of cirrhosis.^[309] Sustained liver injury can diminish the mitochondrial capacity to metabolize acetaldehyde to acetate via aldehyde dehydrogenase (ALDH).^{[305] [307] [310]} When this occurs, acetaldehyde increases in plasma and tissues and probably contributes to the intra- and extra-hepatic toxicities of ethanol.^[311] Acetaldehyde may induce injury in several ways. It forms adducts with intracellular proteins,^[312] binds to glutathione, and depletes the antioxidant pool.^[313] It also triggers the release of chemotactic substances (e.g., leukotriene B₄ ) that attract neutrophils to the liver,^[314] induces changes in plasma membranes to augment superoxide production,^{[315] [316]} and stimulates collagen production and fibroplasia. ^[317]

Similarities in Hepatic Injuries from Hypoxia and Ethanol

There is notable similitude in liver injuries caused by hypoxia and ethanol. Laboratory studies have shown that ethanol markedly increases hepatic oxygen consumption, which is associated with liver injury.^{[294] [318]} The injury is mainly in the centrilobular region (zone 3), where ADH activity is localized, and the oxygen supply is already tenuous.^{[147] [304] [305] [319] [320]} Further, prolonged administration of ethanol increases NO· synthase expression and NO· production. This effect on the NO· pathway, and the resultant vasodilation, may represent a compensatory response to chronic ethanol-induced vasoconstriction in the hepatic microcirculation.^{[321] [322]} Hypoxic liver injury promotes the release of proinflammatory cytokines, tumor necrosis factor-α (TNF-α), and interleukins 1 and 6. These substances increase the expression of adhesion molecules, decrease leukocyte velocity, increase margination and platelet adherence, and reduce hepatic blood flow.^[323] Complement, cytokines, and xanthine oxidase intensify inflammation, and may contribute to pulmonary and cardiac injuries from hepatoenteric ischemia and reperfusion.^{[238] [242] [324] [325]} Similar increases in proinflammatory mediators occur in alcoholic liver disease. ^[326]

There is much evidence, both indirect (lipid peroxidation)^[327] and direct (electron spin resonance data),^[328] that alcoholism causes a significant oxidant stress. Prolonged ethanol intake can simultaneously weaken antioxidant defenses and increase oxidant production; thus the liver damage is progressive.^{[302] [327]} Antioxidants decrease because their consumption increases and/or their synthesis decreases, owing to malnutrition or reduced expression of genes for antioxidant-producing enzymes.^[329] The oxidant stress may involve cytosolic oxidases (aldehyde oxidase, xanthine oxidase) and microsomal ethanol oxidation, which produce superoxide and other reactive species. The activation of inflammatory cells, including Kupffer cells,^[330] can increase nitric oxide synthetase (iNOS) expression in hepatocytes, macrophages, endothelial cells, and vascular myocytes,^[331] and stimulate peroxynitrite formation.^[263] This unstable anion (formed when NO· reacts with O₂ ·^- ) oxidizes sulfhydryl groups as well as nitrating and oxidizing lipids, proteins, and other substances.^{[332] [333] [334] [335] [336] [337]} The depletion of glutathione and α-tocopherol aggravates oxygen radical-mediated ethanol toxicity.^{[327] [338] [339]}