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Proc Natl Acad Sci USA 81:258-261, 1984. Yu, P.H.; Fang, C.-Y.; and Dyck, L.E. Cutaneous vasomotor sensitivity to ethanol and acetaldehyde: Subtypes of alcohol-flushing response among Chinese. Alcohol Clin Exp Res 14(6):932– 936, 1990. Alcohol-Induced Liver Injury Chronic alcohol abuse is unquestionably the single most important cause of morbidity and mortality from liver disease (alcoholic hepatitis and cirrhosis) in the United States (Grant et al. 1988). Alcohol-induced liver disease usually involves three histologically distinct types of lesions: alcoholic steatosis (fatty liver), alcoholic hepatitis and fibrosis, and cirrhosis (Galambos 1972). Alcoholic fibrosis is the replacement of healthy liver tissue with fibrous (scar) tissue; alcoholic cirrhosis is a group of chronic diseases characterized by fibrosis, nodules, and loss of normal structure of the liver tissue accompanied by functional decline. Figure 1 shows a healthy liver compared with a cirrhotic liver. While 90 percent of the heavy consumers of alcohol develop fatty liver, only 40 percent acquire clinical or histologic signs of alcoholic hepatitis, and 15 to 30 percent develop liver cirrhosis. Mortality from cirrhosis in the United States varies significantly with gender, race, and urbanization. In 1988 the highest mortality from cirrhosis occurred in nonwhite males (18.3 per 100,000), followed by white males (12.2), nonwhite females (8.6), and white females (5.1) (Grant et al. 1991). The possible relation of genetic susceptibility to the risk of end-stage disease will be reviewed later in this section. Chronic alcohol abuse is unquestionably the single most important cause of morbidity and mortality from liver disease (alcoholic hepatitis and cirrhosis) in the United States. Factors in Alcoholic Liver Damage Although at one time alcohol-induced liver cirrhosis was believed to arise from nutritional inadequacies common in heavy drinkers, the overwhelming evidence is that alcohol itself is toxic to the liver. Several factors that increase the risk of developing alcoholic liver damage will be discussed below. The quantity of alcohol consumed is more important than the type of alcoholic beverage in the development of liver damage (Lelbach 1975). A relationship between per capita consumption of alcohol and the prevalence of liver injury has been established in several epidemiologic studies (see reviews by Grant et al. 1988; Parrish Figure 1. A healthy liver compared with a cirrhotic liver. Healthy liver Cirrhotic liver Photographs courtesy of Emanuel Rubin, M.D. et al. 1991). Prospective studies of alcoholics indicate that the risk for cirrhosis becomes significant when average intake is at or above 80 grams (6.2 oz.) of alcohol per day for men or 20 grams (1.55 oz.) for women (Grant et al. 1988). Other studies have documented that the majority of individuals with alcoholic cirrhosis have a prolonged duration of drinking; the "average" cirrhotic individual has been drinking heavily for 10 to 20 years (Grant et al. 1988; Parrish et al. 1991). Gender plays a role in apparent susceptibility to alcohol-induced liver damage. Serious forms of alcoholic liver disease are more frequent in women than men, even after women consume lower amounts of alcohol. In a case-control study, a significant increase in the relative risk of liver cirrhosis was observed in women who reported drinking 21 to 40 grams of alcohol per day (Pequignot et al. 1978). Furthermore, the duration of excessive consumption of alcohol at which injury occurs is usually shorter in women than in men (Mezey et al. 1988). Possible factors contributing to the higher risk of alcohol-related diseases in women include higher peak blood alcohol levels due, in part, to alcohol dehydrogenase (Frezza et al. 1990) and a slightly higher rate of hepatic metabolism of alcohol (Mishra et al. 1989) resulting in a higher rate of production of acetaldehyde, which may play a part in alcohol-induced liver injury (see below and also Chapter 7, Biochemical Effects of Alcohol Metabolism). The hypoxia hypothesis of alcoholic liver damage (see below) predicts that women are more susceptible to the development of alcoholic liver injury because women have lower hematocrits, lower hemoglobin levels, and a higher prevalence of anemia than men (Saltatos and Soranno 1991). Viral hepatitis is commonly associated with inflammation that might further aggravate alcohol-induced liver toxicity. Antibodies to hepatitis C virus (HCV) were observed at a high rate in alcoholics with liver disease, in whom antibody formation to HCV was related to the severity of liver damage (Ishii et al. 1992). Although alcohol is now regarded as the primary liver toxin, nutritional deficiencies do still appear to play a role in alcoholic liver damage. Recent studies suggest that relative deficiencies of selected dietary nutrients may participate in the pathogenesis of liver disease in alcoholics (Mendenhall et al. 1986; Mitchell and Herlong 1986). For example, patients with alcoholinduced liver damage have decreased plasma levels of proteins such as albumin, retinolbinding protein, and transferrin. These protein levels are influenced by cytokines such as tumor necrosis factor-a (TNF-α), which is increased in patients with severe alcoholic hepatitis (McClain and Cohen 1989). Diets that are high in fat, particularly unsaturated fatty acids such as linoleic acid, may increase the susceptibility of the liver to alcoholinduced damage by activating fat-storing liver cells known as Ito cells (Takahashi et al. 1991). Most rodent and primate models for alcoholinduced liver injury require a high-fat diet (>30 percent of calories) to accentuate the degree of fat deposition (steatosis) and fibrosis (increase in fibrous tissue) due to alcohol. For instance, in one rat model intragastric infusion of alcohol concomitant with a high-fat diet produced inflammation and fibrosis of the liver (Tsukamoto et al. 1986). Most clinical studies have also established a positive correlation between the dietary content of unsaturated fat and the mortality from alcoholic liver disease in Western countries (Lieber 1990). Nanji and French (1986) have speculated that a diet high in unsaturated fat would provide increased amounts of polyunsaturated fatty acids, which may contribute to lipid peroxidation in alcoholic liver injury. These lipid peroxides, rather than the parent fatty acid, may act as the stimulus for Ito cell transformation and collagen synthesis. However, the exact role of fatty diet in pathogenesis of alcoholic liver disease remains to be elucidated. The activity of the alcohol-metabolizing enzyme alcohol dehydrogenase (ADH) is influenced by hormones. For example, in rats, growth hormone increases hepatic ADH activity and the synthesis and release of insulin-like growth factor (IGF-I), which induces the transcription (early process by which genes are deciphered) of ADH enzyme. Testosterone decreases ADH activity and alcohol elimination in experimental animals and in humans; an increase in alcohol elimination was observed in men who underwent orchiectomy (removal of testes) for treatment of advanced prostatic cancer (Mezey et al. 1988). Potential Mechanisms of Alcohol-Induced Liver Damage Free radicals The observation by DiLuzio (1963) that alcohol-induced fatty liver can be prevented in experimental animals by the administration of antioxidants has led to the hypothesis that alcohol, or its metabolites, can produce oxidative stress in the liver and that the protective effects of antioxidants could be due to the inhibition of free-radical-induced reactions (for discussion of formation of free radicals, see chapter 7). Hepatic injury induced by most drugs or following ischemia (deficiency of blood) and reperfusion (resumption of circulation) is due to the formation of reactive oxygen species that initiate lipid peroxidation. Oxygen species include the superoxide anion radical (Bautista and Spitzer 1992) and the hydroxyl radical, which is formed by the reaction of superoxide with hydrogen peroxide. These free radicals can be formed in different parts of the cell, such as microsomes, peroxisomes, mitochondria, and cytosol. Numerous investigators have also reported that chronic alcohol intake increases the generation of superoxide free radicals (Bautista and Spitzer 1992; Ekstrom and Ingelman-Sundberg 1989), hydrogen peroxide (Lieber and DeCarli 1970), and hydroxyl radicals (Dicker and Cederbaum 1987) by isolated microsomes. Most studies implicate cytochrome P450 reductase as a major source of the potentially toxic superoxide anion radical (O2-) that may lead to hydroxyl radicals (Cederbaum 1989b, Nordmann et al. 1992). The participation of cytochrome P450 IIE1 in the formation of hydrogen peroxide has been demonstrated by Ekstrom and IngelmanSundberg (1989). The production of free radicals derived directly from alcohol, together with other free radicals, may contribute to the injury of hepatic microsomal constituents. Hydroxyl radicals generated from hydrogen peroxides in the presence of trace amounts of iron could result in oxidizing alcohol to a 1-hydroxyethyl radical (Reinke et al. 1990). This 1-hydroxyethyl radical is also produced by cytochrome P450 independent of hydroxyl radicals (Krikun and Cederbaum 1985). The hydroxyethanol radical has been demonstrated in vivo in alcohol-fed rats (Reinke et al. 1990, 1991) and in the bile of ADH-deficient deermice (Knecht et al. 1990). Free radicals derived from lipids may also play a role in alcohol-induced liver damage. Chronic alcohol administration results in selective induction of cytochrome P450 IIE1 in the centrilobular region of the liver in rats (IngelmanSundberg et al. 1988) and in humans (Tsutsumi et al. 1989). Cederbaum (1989a) has shown that microsomal alcohol oxidation by P450 reductase (which produces hydroxyl radicals) is important in stimulating lipid peroxidation. Lipid peroxidation starts when free radicals attack polyunsaturated fatty acids. This reaction produces lipid radicals, which react with molecular oxygen to form lipid peroxy radicals. Ultimately, this reaction could damage membrane lipids and compromise the integrity of the plasma or organellar membranes. Nonetheless, it is not clear whether increased lipid peroxidation contributes to or results from the centrilobular localization of alcohol-induced liver injury. Increasingly, iron is recognized as a catalyst in many reactions that cause tissue damage. Chronic alcohol consumption increases the absorption of iron from the gastrointestinal tract (Irving et al. 1988), and its metabolism mobilizes iron from ferritin. Chelation of iron with desferrioxamine has been shown to inhibit lipid peroxidation (Shaw 1989). Shifts in cellular redox state by alcohol metabolism (ADH), together with the superoxide anion radicals generated through non-ADH pathways, lead to mobilization of free |