Lieber C S
Mount Sinai School of Medicine (CUNY).
Baillieres Clin Gastroenterol. 1993 Sep;7(3):581-608. doi: 10.1016/0950-3528(93)90003-b.
Until the 1960s, liver disease of the alcoholic patient was attributed exclusively to dietary deficiencies. Since then, however, our understanding of the impact of alcoholism on nutritional status has undergone a progressive evolution. Alcohol, because of its high energy content, was at first perceived to act exclusively as 'empty calories' displacing other nutrients in the diet, and causing primary malnutrition through decreased intake of essential nutrients. With improvement in the overall nutrition of the population, the role of primary malnutrition waned and secondary malnutrition was emphasized as a result of a better understanding of maldigestion and malabsorption caused by chronic alcohol consumption and various diseases associated with chronic alcoholism. At the same time, the concept of the direct toxicity of alcohol came to the forefront as an explanation for the widespread cellular injury. Some of the hepatotoxicity was found to result from the metabolic disturbances associated with the oxidation of ethanol via the liver alcohol dehydrogenase (ADH) pathway and the redox changes produced by the generated NADH, which in turn affects the metabolism of lipids, carbohydrates, proteins and purines. Exaggeration of the redox change by the relative hypoxia which prevails physiologically in the perivenular zone contributes to the exacerbation of the ethanol-induced lesions in zone 3. In addition to ADH, ethanol can be oxidized by liver microsomes: studies over the last twenty years have culminated in the molecular elucidation of the ethanol-inducible cytochrome P450IIE1 (CYP2E1) which contributes not only to ethanol metabolism and tolerance, but also to the selective hepatic perivenular toxicity of various xenobiotics. Their activation by CYP2E1 now provides an understanding for the increased susceptibility of the heavy drinker to the toxicity of industrial solvents, anaesthetic agents, commonly prescribed drugs, 'over the counter' analgesics, chemical carcinogens and even nutritional factors such as vitamin A. Ethanol causes not only vitamin A depletion but it also enhances its hepatotoxicity. Furthermore, induction of the microsomal pathway contributes to increased acetaldehyde generation, with formation of protein adducts, resulting in antibody production, enzyme inactivation and decreased DNA repair; it is also associated with a striking impairment of the capacity of the liver to utilize oxygen. Moreover, acetaldehyde promotes glutathione depletion, free-radical mediated toxicity and lipid peroxidation. In addition, acetaldehyde affects hepatic collagen synthesis: both in vivo and in vitro (in cultured myofibroblasts and lipocytes), ethanol and its metabolite acetaldehyde were found to increase collagen accumulation and mRNA levels for collagen. This new understanding of the pathogenesis of alcoholic liver disease may eventually improve therapy with drugs and nutrients.
直到20世纪60年代，酒精性肝病患者的肝脏疾病仅被归因于饮食缺乏。然而，从那时起，我们对酗酒对营养状况影响的理解经历了逐步演变。酒精由于其高热量含量，起初被认为仅作为“空热量”，取代饮食中的其他营养素，并通过必需营养素摄入量减少导致原发性营养不良。随着人群总体营养状况的改善，原发性营养不良的作用减弱，由于对慢性饮酒引起的消化吸收不良以及与慢性酒精中毒相关的各种疾病有了更好的理解，继发性营养不良受到了重视。与此同时，酒精直接毒性的概念作为细胞广泛损伤的一种解释而凸显出来。一些肝毒性被发现是由乙醇通过肝脏乙醇脱氢酶（ADH）途径氧化相关的代谢紊乱以及所产生的NADH引起的氧化还原变化导致的，这反过来又影响脂质、碳水化合物、蛋白质和嘌呤的代谢。小叶中央静脉周围区域生理上普遍存在的相对缺氧使氧化还原变化加剧，从而导致3区乙醇诱导损伤的加重。除了ADH外，乙醇还可被肝脏微粒体氧化：过去二十年的研究最终在分子水平上阐明了乙醇诱导的细胞色素P450IIE1（CYP2E1），它不仅有助于乙醇代谢和耐受性，还导致各种外源性物质在肝脏小叶中央静脉周围的选择性毒性。CYP2E1对它们的激活现在解释了酗酒者对工业溶剂、麻醉剂、常用处方药、“非处方药”镇痛药、化学致癌物甚至营养因素如维生素A毒性的易感性增加。乙醇不仅导致维生素A缺乏，还增强其肝毒性。此外，微粒体途径的诱导导致乙醛生成增加，形成蛋白质加合物，导致抗体产生、酶失活和DNA修复减少；它还与肝脏利用氧气的能力显著受损有关。此外，乙醛促进谷胱甘肽耗竭、自由基介导的毒性和脂质过氧化。此外，乙醛影响肝脏胶原蛋白合成：在体内和体外（在培养的肌成纤维细胞和脂肪细胞中），乙醇及其代谢产物乙醛均被发现可增加胶原蛋白积累和胶原蛋白的mRNA水平。对酒精性肝病发病机制的这种新理解最终可能会改善药物和营养治疗。
