ETIOLOGY AND PATHOGENESIS OF ALCOHOLIC LIVER-DISEASE

被引:24
作者
LIEBER, CS [1 ]
机构
[1] VET AFFAIRS MED CTR, GI LIVER PROGRAM, BRONX, NY 10468 USA
来源
BAILLIERES CLINICAL GASTROENTEROLOGY | 1993年 / 7卷 / 03期
关键词
D O I
10.1016/0950-3528(93)90003-B
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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. © 1993.
引用
收藏
页码:581 / 608
页数:28
相关论文
共 158 条
[1]   IS ALCOHOL HEPATOTOXIC IN THE BABOON [J].
AINLEY, CC ;
SENAPATI, A ;
BROWN, IMH ;
ILES, CA ;
SLAVIN, BM ;
MITCHELL, WD ;
DAVIES, DR ;
KEELING, PWN ;
THOMPSON, RPH .
JOURNAL OF HEPATOLOGY, 1988, 7 (01) :85-92
[2]  
ALLIET J, 1976, OUEST MED, V29, P85
[3]   BIOCHEMICAL AND MORPHOLOGICAL ALTERATIONS OF BABOON HEPATIC MITOCHONDRIA AFTER CHRONIC ETHANOL-CONSUMPTION [J].
ARAI, M ;
LEO, MA ;
NAKANO, M ;
GORDON, ER ;
LIEBER, CS .
HEPATOLOGY, 1984, 4 (02) :165-174
[4]   DECREASED CYTOCHROME-OXIDASE ACTIVITY IN HEPATIC MITOCHONDRIA AFTER CHRONIC ETHANOL-CONSUMPTION AND THE POSSIBLE ROLE OF DECREASED CYTOCHROME-AA3 CONTENT AND CHANGES IN PHOSPHOLIPIDS [J].
ARAI, M ;
GORDON, ER ;
LIEBER, CS .
BIOCHIMICA ET BIOPHYSICA ACTA, 1984, 797 (03) :320-327
[5]   HISTOCOMPATIBILITY ANTIGENS, AUTOANTIBODIES, AND IMMUNOGLOBULINS IN ALCOHOLIC LIVER-DISEASE [J].
BAILEY, RJ ;
KRASNER, N ;
EDDLESTON, ALWF ;
WILLIAMS, R ;
TEE, DEH ;
DONIACH, D ;
KENNEDY, LA ;
BATCHELOR, JR .
BRITISH MEDICAL JOURNAL, 1976, 2 (6038) :727-729
[6]   PATHOGENESIS OF ALCOHOL-INDUCED ACCUMULATION OF PROTEIN IN LIVER [J].
BARAONA, E ;
LEO, MA ;
BOROWSKY, SA ;
LIEBER, CS .
JOURNAL OF CLINICAL INVESTIGATION, 1977, 60 (03) :546-554
[7]   LACK OF ALCOHOL-DEHYDROGENASE ISOENZYME ACTIVITIES IN THE STOMACH OF JAPANESE SUBJECTS [J].
BARAONA, E ;
YOKOYAMA, A ;
ISHII, H ;
HERNANDEZMUNOZ, R ;
TAKAGI, T ;
TSUCHIYA, M ;
LIEBER, CS .
LIFE SCIENCES, 1991, 49 (25) :1929-1934
[8]   RED-BLOOD-CELLS - A NEW MAJOR MODALITY FOR ACETALDEHYDE TRANSPORT FROM LIVER TO OTHER TISSUES [J].
BARAONA, E ;
DIPADOVA, C ;
TABASCO, J ;
LIEBER, CS .
LIFE SCIENCES, 1987, 40 (03) :253-258
[9]  
BARCLAY LRC, 1988, J BIOL CHEM, V263, P16138
[10]   FORMATION OF ACETALDEHYDE ADDUCTS WITH ETHANOL-INDUCIBLE P450IIE1 INVIVO [J].
BEHRENS, UJ ;
HOERNER, M ;
LASKER, JM ;
LIEBER, CS .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1988, 154 (02) :584-590