Ahmed1995.pdf

Critical Reviews in Toxicology, 25(4):347-367 (1995)

Toxicological Effects of Ethanol on Human Health Farid E. Ahmed*

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Biology Department, Brookhaven National Laboratory, Upton, NY 11973**

*

Recipient of the National Academy of Sciences' Kohelt Fund Grant. Views expressed here do not necessarily represent those of the National Academy

**

of Sciences, National Research Council, National Academy of Engineering, Institute of Medicine, or any of their constituent units. Present address: Dept. of Biochemisby, Rm. 150, Duke University Medical Center, Durham NC 27710

ABSTRACT: Moderate ethanol consumption reduces stress and increases feelings of happiness and well-being, and may reduce the risk of coronary heart disease. Heavy consumption of alcohol, however, may cause addiction and increases all types of injury and trauma. Environmental and genetic factors are involved in susceptibility to alcoholism. Ethanol can lead to malnutrition, and can exert a direct toxicological effect due to its interference with hepatic metabolism and immunological functions. A causal effect has been observed between alcohol and various cancers. Cessation of alcohol consumption and balanced nutrition are recommended primary nonspecific therapeutic measures for alcoholics. Drug therapies for alcoholics suffering from liver injury has resulted in mixed results. In end-stage liver disease, liver transplantation may be considered.

KEY WORDS: chronic diseases, genetics, environmental factors, metabolism, treatment.

1. INTRODUCTION The word alcohol as used throughout this manuscript refers to ethanol. Alcohol is both a food and a drug. Since antiquity, alcohol has been produced and used as a food, a beverage at social events and festivals, and as a medicine. Beer and wine were produced and consumed in ancient Egypt and Mesopotamia 3000 years B.C.' Drunkenness was common in ancient Greece and Rome.2 In pre-Islamic Arabia, beer, fermented dates, milk, and wine were commonly consumed until the advent of Islam.3Alcohol had important religious, economic, and political roles for the cultures of the Andean South Americans, the Aztecs of Mexico, and the Mayans of Central A m e r i ~ aIn .~ medieval Europe, drunkenness was largely confined to revelry, feasting, and religious celebrations, and was prevalent among the lower orders of the clergy;2alcoholism did not become a social

problem until distillation became common around 1100 A.D.3 Puritans in the American colonies considered alcoholic drinks as wholesome and strengthening, and used alcohol to appease the native Indians and to motivate black slaves.2 Alcoholism became a problem in 18th century America, when rum and whiskey became available; approximately 4000 people were reported to have died in the U.S. from consumption of rum.3 Alcohol was used as a medicine in the U.S. military hospitals in the middle of the nineteenth century; however, a strong reaction against its use as a drug occurred during the growth of the temperance movement. North America Indian tribes have reacted variably to alcohol consumption. Some developed a changing attitude toward it; for example, in the first decades of contact with whites, the Iroquois of upstate New York and Southern Canada drank in moderation, and drinking became an integral part of their religion. In the early

Abbreviations: ADH, alcohol dehydrogenase; ALC, alcoholic liver cirrhosis; ATP, adenosine triphosphate; BAL, blood alcohol level; CHD, coronary heart disease; CP, creatinine phosphate; FA, fatty acids; FABP, fatty acid binding protein; FAS, fetal alcohol syndrome; GGTP, gamma-glutamyl transpeptidase; GSH, reduced glutathione; GSSG, oxidized glutathione; HDL, high density lipoprotein; H,O,, hydrogen peroxide; KP, Korsakoff psychosis; MEOS, microsomal ethanol oxidizing system; NADP, nicotinamide dinucleotide phosphate; PLC, primary liver cancer; PUL, polyunsaturated lecithin; RR, relative risk; WE, Wernicke encephalopathy; WKS, Wemicke-Korsakoff Syndrome. 1040-8444/95/$.50

0 1995 by CRC Press, Inc.

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eighteenth century, following the example of white trappers and traders, aggression became part of their drunken behavior, and by 1800 drunkenness became a serious social problem, which led most of them to modify their drinking habits or to abstinence.' Cross-cultural studies have shown alcoholism and its related social problems to be more prevalent in Western societies compared with non-Western ones, and attempts at prohibition were not successful unless embedded in religious beliefs against alcohol cons~mption.~ Comparative ethnic studies have shown change in drinking pattern among Jews, Italians, Poles, and Portuguese after they migrated to the U.S.4 Although moderate consumption of alcohol contributes to feelings of well-being and happiness, and may reduce the risk of some diseases, heavy drinking leads to increase of trauma, and exerts deleterious effects on various body organs. Several reviews on the subject of alcohol and human diseases have appeared in various journals. However, the focus has often been narrowed to a specific disease in a certain organ (e.g., liver). This article, on the other hand, is interdisciplinary in nature, and provides balanced and broad views on topics such as the role of environmental and genetic factors in susceptibility t o alcoholism; beneficial effects of alcohol consumption on human health and chronic diseases, and the developing fetus; nutritional deficiencies resulting from alcohol intake; effects on immune functions; and the effectiveness of dietary interventions and other therapies on alleviating alcohol-related disorders.

Alcohol consumption is difficult to quantify accurately and reliably because different units of measurement are often used (e.g., number of drinks per day or volume consumed per time), complexities of drinking behavior, role of catabolism, and types of questions asked during ~urveying.~ The Fourth Special Report of the U.S. Congress on Alcohol and Health classified drinkers into moderate drinkers (i.e., those who consumed 0.22 to 0.99 oz of alcohol per day) and light drinkers (i.e., those who consumed 0.01 to 0.21 ~ z / d )The . ~ equivalent in drinks can be obtained from Table 1.6 These definitions are arbitrary, and it is important to keep in mind that there is no universally accepted classification system for safe levels of alcohol consumption. It was proposed that moderate alcohol intake should not exceed 0.8 g k g body weight per day, or an average of 0.7 g k g body weight over a 3-day period,' as shown in Table 2.6 Those exceeding these limits were considered heavy drinkers8 Thus, 24% of adults, in the U.S. are considered moderate drinkers, approximately 33% light drinkers, 9% heavy drinkers, and approximately 33% abstainer^.^ Because there is variability in individual tolerance to alcohol consumption, the basis for which is explained in the following sections, this is reflected in a similar variability in upper limits of daily alcohol consumption as presented in Table 2. Drinking in the preceding hours can best be estimated from the level of alcohol in blood (BAL). Sensations of euphoria and well-being have been reported at BAL of

TABLE 1 Amount of Ethanol in a Drink Ethanol content Beverage type

("10)

Whiskey (80 proof) Table wine US. beer

40 12.1a 3.9

a

Unit of measure

Ethanol in a drink [oz and (ml)]

1-02 shot (30 ml) 3.5-02glass (104 mi) 12-02 bottle (355 ml)

0.40 (11.83) 0.42 (12.42) 0.42 (12.42)

Most table wines contain 11 to 13% ethanol. Fortified wines, such as sherry and port, contain approximately 20% ethanol. Most brands contain 3.2 to 4.0% ethanol.

From Baum-Baicker, C.,Drug Alcohol Depend., 15, 207, 1995. With permission.

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TABLE 2 Upper Limits of Daily Alcohol Consumption 0.8 glkg bw per day Weight of individual

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50 60 70 80 90 100 a

110 132 154 176 198 220

80-proof Ethanol Spirits

40 48 56 64 72 80

4.3 5.1 6.0 6.9 7.7 8.6

12% Table Wine

14 17 20 23 26 29

0.7 glkg bw over a 3-d period

3.6% 80-proof Beerb Ethanol Spirits

38 46 53 61 69 76

35 42 49 56 63 70

3.7 4.5 5.2 6.0 6.7 7.5

12% Table Wine

3.6% Beer

13 15 18 20 23 25

33 40 47 53 60 67

1 oz = 23.34 g or 29.574mi. By weight, or 4.5% by volume.

From Baum-Baicker, C., Drug Alcohol Depend., 15,207,1995.With permission.

0.05% (i.e., 5 parts of alcohol per 10,000 parts of blood); at BAL 0.1%, a person is considered drunk; at 0.2 some people pass out; at 0.3% some collapse into a coma; and at 0.4% death ensue^.^ Alcohol consumption peaks in the 20- to 40-year age group, with alcohol abuse most frequent in youth and middle age.9 Alcohol use decreases in the elderly. Thus, 43% of those between 65 to 74 years of age consumed alcohol when compared with 30% after age 75; this is believed to be due to factors such as attrition as younger alcoholics die from accidents or medical complications, difficulty to define abuse among the elderly, and reluctance of family members to report excess alcohol use by their elderly relatives to protect their dignity 28 to 60% of the and p r i ~ a c y Approximately .~ elderly reported a history of alcohol-relatedproblems, which is quite alarming in view of the increase in percentage of elderly in the U.S3 Although males are likely to drink more heavily than females, the proportion of women who drink has increased steadily in the past 30 years.3 Rates of excessive drinking and associated health problems for the adult black population were similar to those of the general U.S. population, although black youth reported higher abstinence rates and lower rates of heavy drinking than white youth.5 Native American Indians are more likely to be heavy drinkers than the general population, and Asian-Americans are

believed to have a lower prevalence than other groups because of their sensitivity to alcoh01.~

111. ALCOHOL AND HUMAN DISEASES A. Obesity National consumption data indicate that alcohol contributes 4.5% of total energy of the American diet, although heavy drinkers were reported to derive at least half of their daily energy from ethanol.lo Although the carbohydrate content is negligible for whiskey, cognac, and vodka, it is 2 to 10 g of carbohydrate per liter for wine, 30 g/l for beer and dry sherry, and 120 g/l for sweetened wine.3The combustion of ethanol in a bomb calorimeter yielded a value of 7.1 kcal/g, but its biological activity may be less, especially when the dose of ethanol is high or the recipient is a chronic alcohol abuser, or both. In nonalcoholic human volunteers, ethanol was utilized as efficiently as fat or carbohydrate as a source of energy, whereas in alcoholics no weight gain was found when alcohol was utilized as the source of the extra energy.1° Isocaloric substitution of ethanol for carbohydrates of up to 50% of total energy in a balanced diet resulted in less weight gain; when alcohol was given as additional calories, it caused not only less of a weight gain than did calorically equivalent carbohydrates or fats in lean individu349

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als, but also some weight gain in half the obese individual^.^ l o Thus, ethanol may contribute to excess energy intake, but it is not a common cause of obesity. It is believed that ethanol increases metabolic rate Gnce ethanol ingestion in normal people increa4es their oxygen consumption, with a greater effect in alcoholics.'0 Substitution of ethanol for carbohydrates resulted in increased metabolic rate and thermogenesis in humans and rodents, and although some of the energy wastage could be attributed to brown fat thermogenesis in rats, most of it could not be accounted for.3 Several mechanisms were proposed to explain energy wastage. These include ( 1 ) oxidation of ethanol to acetaldehyde without phosphorylation by the microsoma1 ethanol-oxidizing system (MEOS) in the hepatocytes resulting in the production of nicotinamide adenine dinucleotide phosphate (NADP) and heat generation, without formation of high energy compounds [CH,CH20H + NADPH + H+ + CH,CHO + NADP' + 2H20]. This pathway is in contrast to the alcohol dehydrogenase (ADH) pathway in which high energy compound adenosine triphosphate (ATP) is generated [CH,CH20H + NAD, -+ CH,CHO + NADH + H']; (2) uncoupling of mitochondria1NADH oxidation leading to decreased production of ATP, which may be provided by either catecholamine release or a hyperthyroid state (although less certain); (3) increased ATPase activity; and (4) inhibition of glycolysis. which results in decreased ATP levels.'"

B. Cardiovascular Diseases

7. Hypertension and Stroke Epidemiologic evidence indicates that adults in the U.S. population who chronically consume two or more drinks of alcohol daily (>30 ml of ethanol) have higher mean blood pressure and a higher prevalence of hypertension than those who consume lesser quantities.' Similar findings were reported in Australia, Finland, South Africa, France, New Zealand, U.K., Japan, and Germany.3 Case-control studies indicate that heavy drinlung (>3OO g/week) is associated with an increased risk of stroke. The association, however, may be

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due to the confounding effects of cigarette smoking.I3 Cross-sectional studies showed that regular daily consumption of >200 g of alcohol was generally associated with greater blood pressure, which is the major risk factor for hemorrhagic stroke and cerebral infarction.14J5Cross-sectional studies also showed that the association between alcohol consumption and blood pressure was weaker in women than in men because of either less consumption or the modifying effect of female hormones.' A prospective study of 800 middle-aged men of Japanese ancestry in Hawaii showed that even lower levels of alcohol consumption (1 to 14 oz of alcohol per month) resulted in increased risk of hemorrhagic stroke.I4 A similar finding was reported for women but not men in the Farmingham study in Massachusetts.'j On the other hand, recent studies have shown that moderate alcohol drinkers (i.e., <3 drinks per day) have fewer myocardial infarctions and hemorrhagic strokes than abstainers.l6-'*

2. Coronary Heart Disease (CHD) In cross-sectional epidemiologic studies, consumption of alcohol showed a positive association with blood levels of high-density lipoprotein (HDL) cholesterol in the U.S., France, Japan, Norway, Portugal, and China.*' Lifetime abstainers as well as former drinkers who later abstained reported a higher risk of CHD than people who consumed 200 mg/dl. The graded nature of this association, its persistence in various populations, and its consistency after adjustment for confounding factors (e.g., cigarette smoking, increased blood pressure) lend credence to the observation that consuming small amounts of alcohol (between 1 and 99 g weekly) may reduce susceptibility to CHD.lC2OThe mechanism of this protective action was shown to be due to increased levels of HDL, both HDL, and HDL, subfractions. The level of each subfraction was shown to be inversely related to the risk of a The high incidence first myocardial infarction. of CHD among abstainers compared with drinkers is believed to be due to a failure to distinguish between former drinkers at high risk and lifelong I69l7

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abstainers.16 Alcohol could also provide protection against CHD because of its antithrombotic effect. Moreover, epidemiologic evidence indicated that heavy or problem drinkers (e.g., those consuming >500 g/week) are associated with increased risk of CHD, and with increased risk of mortality in many populations.22Certain groups who abstain completely from tobacco and alcohol (e.g., Seventh-Day Adventists in California) showed a 20 to 50% lower death rate from CHD than for age-matched groups in the total population of C a l i f ~ r n i aStudies . ~ ~ conducted in several countries showed that populations with moderate per capita intake of 3 to 5% of calories from alcohol experienced very low or very high rates of mortality from CHD.3,5

ing to liver cirrhosis. These effects are discussed next.

7. Effects Due to Microsomal Ethanol Oxidizing System (MEOS)

Ethanol is oxidized in the liver by three different enzyme systems: the alcohol dehydrogenase (ADH), the MEOS, and catalase. Figure 1 shows various pathways of ethanol oxidation and metabolism in the hepatocytes. The primary pathway of ethanol metabolism was believed to involve the cytosolic ADH. Another pathway in liver microsomes attributable to H,O,-dependent reaction mediated by peroxisomal catalase is now believed to play a minor role in vivo because H,O, production in the liver is relatively low under ordinary circumstances. In chronic alcoholism, 3. Alcoholic Cardiomyopathy ethanol is believed to increase H,O, in pericentral regions of the liver lobule, in part by elevating Alcoholic cardiomyopathy is a syndrome typirates of peroxisomal P-oxidation of acyl CoA cally found in men between 30 to 45 years of age, corn pound^.^^ An inducible system dependent on who have been chronically receiving 30 to 40% microsomal cytochrome P-450 and specific for of their calories from alcoh01.~Consumption of ethanol oxidation was characterized and desigmore than 85 g/d of alcohol, regardless of the type nated P450IIE1 .31 Because other cytochrome of beverage, was a high risk factor for dilated P-450 isozymes can also contribute to ethanol cardi~myopathy,~~ and lowering overall level of oxidation, the term microsomal ethanol oxidizing alcohol consumption was shown to decrease system has been used.1° The P-450IIE1 gene was mortality due to cardiomyopathy in Australia25 isolated, characterized, and localized on chromoand Seychelles.26 Some mechanisms leading to some 7 in the rat and chromosome 10 in human. cardiomyopathy include accumulation of triglycThe MEOS is involved through sharing with other erides, altered fatty acid composition, membrane microsomal drug-metabolizing systems many alterations with decreased response to Ca2+and properties such as induction of P-450 isozymes, catecholamines, toxicity to striated muscles due NADPH and 0, in various drug, carcinogen, horto interference with oxidative processes as well as mone, and vitamin interactions.1° glycolytic activity with subsequent decrease in Alcoholics exhibited tolerance not only to ATP and creatinine phosphate (CP) levels, and alterations in cardiac protein s y n t h e s i ~ . ~ ~ - ~ ~ ethanol, but also to other drugs such as warfarin, diphenylhydantoin, tolbutamide, and isoniazid leading to increased drug clearance. This tolerance has been attributed to either cenC. Liver Diseases tral nervous system adaptation or to metabolic adaptation.1° Enhanced activity of MEOS can The following sections discuss the effects of result in an adverse effect by converting indusethanol, or its metabolites, on hepatic tissue pathotrial solvents, halothanes, anesthetics, and genesis. Toxic effects of alcohol are due to effects on oxidation of ethanol in the liver by various xenobiotics to hepatotoxic metabolites, as observed in increased CC1, periventricular toxicoxidation pathways, interaction of ethanol with ity, benzene toxicity in the bone marrow, hormones and vitamins, toxic effects of acetaldehalothane-induced centrizonal necrosis in anihyde, and disorders of collagen metabolism lead-

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FIGURE 1. Metabolism of ethanol in the liver. Broken lines indicate pathways that are depressed by ethanol. Repeated arrows represent stimulation or activation. The symbol -[ indicates interference or binding. (From Lieber, C. S., J. Am. Coll. Nutr., 10, 602, 1991. With permission.)

mal\, and increased hepatotoxicity of isoniazid and acetaminophen in alcoholics. u Ethanol affects microsomal metabolism of hormones leading to decreased blood testosterone levels due to enhanced degradation and conversion to estrogen, and to decreased capacity of the testir to synthesize steroids.I0 Moreover, ethanol alters metabolism of structurally similar compounds. such as vitamin D, which may serve as a substrate for the microsomal enzymes, leading to alteration of their oxidative a ~ t i v i t i e s . ~ ~ Alcohol has been shown to contribute to nutritional deficiencies. Hospitalized chronic alcoholic patients had inadequate dietary protein and exhibited symptoms of protein maln~trition.~ Diet high in polyunsaturated fatty acids enhanced the pathogenesis of liver damage due to the induction of i5ozyme cytochrome P-450IIE1 by alcohol ingestion.i4 Hepatic vitamin A levels decreased with progresion of liver injury. Experimental work on rats and baboons suggested that mechanisms such

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as malabsorption of the vitamin in the liver increased its mobilization from the liver and its enhanced catabolism in the liver or other organs may be i n ~ o l v e dIntake .~ of vitamin A was considered normal for Americans consuming up to 400 kcal of ethanol per day (i.e., ~ 2 0 %of total energy). Those getting 24% of their calories from alcohol consumed 75% of the RDA for vitamin A, and those getting 50% or more of their energy from alcohol received a smaller amount of vitamin A.35Drugs such as phenobarbital were found to enhance the catabolism of retinol and exert an inducible effect on the microsomal system, similar to ethanol induction. When both ethanol and phenobarbital were combined in baboons, an additive effect on vitamin A depletion was found. Because alcohol abuse is often associated clinically with drug abuse, this potentiation may have significance for vitamin A depletion in alcoholic abusers. Another microsomal system that converts retinol to polar metabolites (P-45OIIC8) was

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discovered in rats, deermice, and humans (P-45011C8), which lacked the cytosolic retinol dehydrogenase enzyme; it was insensitive to ethanol inhibition and thus may have contributed further to hepatic retinol d e p l e t i ~ nBecause .~~ alcohol consumption potentiates the hepatotoxicity of vitamin A, and the beneficial effect of vitamin A supplementation is achievable only within a narrow therapeutic window, caution should be exercised in selection of a therapeutic dose of vitamin A supplementation for alcoholics.lo Moreover, ethanol also increases the breakdown of other lipid-soluble vitamins, such as a-tocopherol to produce a-tocopherol quinone by free radicals.37 Although experimental studies in rats showed that alcohol interfered with thiamin (vitamin B,) absorption, human jejunal perfusion studies utilizing 5% of total calories as alcohol did not show such an effect, and a 3-year feeding study in baboons in which alcohol contributed 50% of total calories along with a nutritionally balanced diet did not show any effect on the blood or urinary levels of thiamin.1°Nevertheless,profound effects of thiamin deficiency often present in alcoholics and contributeto neurological syndromes, beriberi, and heart disease^.^ Thus, thiamin is given to most alcoholics to guard against its deficiency as thiamin supplementation is easy and safe.lo Folic acid levels are influenced by alcohol consumption. Studies showed that in alcoholics 38% had low serum folate and 18% had low red blood cell folate levels.38Malnourished alcoholics without liver disease absorbed folic acid less efficiently than well-nourished individuals who did not show signs of anemia.3Long-term feeding studies in monkeys suggest that a decrease in hepatic folate is due to a decreased ability to retain folate in the liver or to an increased breakdown due to superoxide and free radical formation. Megaloblastic anemia due to folate deficiency in alcoholics, as in other conditions, was presumed to result from the inhibition of thymidylate synthetase.lo Although alcohol ingestion caused reduced absorption in volunteers after several weeks of intake, alcoholics do not usually suffer from vitamin B 12 deficiency, probably because of the large vitamin stores in the body and the reverse capacity for ab~orption.~ Riboflavin deficiency was seen

when there was a general lack of vitamin B intake. Experimentally, chronic alcohol feeding induced riboflavin deficiency when the intake of the vitamin in monkeys was marginal.1° The role of vitamin C in alcoholic diseases is uncertain, although alteration in ascorbic acid was reported following alcohol ingestion.lo Alcoholics exhibit illnesses related to abnormalities of calcium, phosphorus, magnesium, vitamin D homeostasis and decreased bone density, decreased bone mass, increased susceptibility to fractures, and increased osteonecr~sis.~ Vitamin D deficiency in alcoholic liver disease is believed to be due to decreased vitamin D substrate resulting from poor dietary intake, increased metabolism through P-450 induction, malabsorption due to cholestasis, pancreatic insufficiency, or diminished ~unlight.~ Alcoholics are among Americans with marginal zinc intake. Some instances of night blindness that did not fully respond to vitamin A replacement were shown to respond to zinc treatment.lo

2. Role of Alcohol Dehydrogenase (AOH) in Pathogenesis Liver ADH is present in various isozyme forms, intra- as well as extrahepatically. However, the extrahepatic form of the enzyme has much lower affinity, and at the level of ethanol in blood it is inactive.1° In the mucosal lining of the stomach wall, at least three different forms of ADH are available. The level of ethanol in the stomach is relatively high after alcohol ingestion, and thus ethanol is effectively metabolized in the stomach and presents a barrier against its systemic effects. This barrier disappears after gastrectomy, and is often decreased in alcoholics due to a decrease in gastric ADH.l0 Medications such as aspirin and some H, blockers such as cimetidine and ranitidine inhibited gastric ADH after moderate intake of alcohol. Women have lower gastric ADH activity than men, which when combined with different body composition (more fat and less water and body weight in women) may explain their increased susceptibility to develop more severe alcohol-related diseases than men. Aging was shown to strikingly decrease in

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vi\~> ethanol metabolism in male rats without major effect on hepatic ADH activity.39 When ethanol is oxidized through the ADH pathway. this results in excess production of hepatic NADH and enhanced NADH to NAD ratio. An elevated NADH/NAD ratio resulted in alteration of the intermediary metabolism of lipids, carbohydrates, proteins. purines, hormones, and porphyrins.53 Increased NADH leads to an increase in the lactate to pyruvate ratio, resulting in hyperlactacidemia, which contributes to acidosis and reduction of the capacity of the kidney to excrete uric acid; this leads to secondary hypeiuricemia. '') Ketosis and enhanced breakdown of purine due to alcohol can also promote the hyperuricemia that leads to aggravating or precipitating gouty attacks3 Increased NADH/NAD ratio increases the concentration of a-glycerophosphate that trap FA leading to accumulation of triglycerides in the liver. In rats and humans, protein deficiency may result in decreased ADH activity, which may lead to metabolic disorders such as inhibition of the citric acid cycle. increase in the ratio of lactate to pyruvate, fasting hypoglycemia, and inhibition of glucose elimination. Moreover, chronic alcohol consumption in combination with protein and a lipocropic-deficient diet resulted in more severe hepatic steatosis than either deficiency alone.3 Studies in animals showed that alcohol consumption accompanied by protein deficiency greatly increased mortality of laboratory animals, without hepatic fat accumulation.' An increased NADH to NAD ratio may exacerbate hypoglycemia by blocking glucogenesis by ethanol in individuals whose glycogen stores have been depleted by either starvation or abnormal carbohydrate metabolism. 10.J1 Alcohol-induced hypoglycemia can be suppressed by the ADH inhibitor 4-methyl pyrazole.' Alcohol may also accelerate rather than inhibit glucogenesis, resulting in hyperglycemia, although the mechanism is not exactly known.'."' Increases in lipoprotein production, hyperlipemia, and ketosis have already been discussed.

3. Toxic Effect of Acetaldehyde All pathways of ethanol oxidation in the liver result in production of acetaldehyde: acetalde354

hyde is further metabolized into acetate. Acetaldehyde dehydrogenase is polymorphic and exists in variable forms in the cytoplasm and mitochondria of most species. This polymorphism explains the intolerance to alcohol and flushing experienced by Asians who have an inactive variant.42 The drug disulfiram inhibits acetaldehyde dehydrogenase, thus raising acetaldehyde levels in the blood after alcohol drinhng, leading to flushing and other adverse effects, which helps in maintaining abstinence.43 Acetaldehyde binds covalently to proteins of liver microsomes of rats in vivo, and selectively forms protein adducts in rat liver microsomes with ethanol-inducible P-450IIE1. Studies in animals and humans have shown that these adducts serve as neoantigens, which generate immune response. Thus, complement-binding acetaldehyde adducts containing immune complex may contribute to the severity of liver disease. Moreover, acetaldehyde binds covalently to other adducts, such as serum albumin, hemoglobin, and cytoskeletal proteins, such as tubulin, the constituent protein of microtubule. An important function of microtubule is promoting the intracellular transport of proteins and their secretion. l o Acetaldehyde has an affinity for sulfhydral groups of cysteine residue, and for lysine, which may alter the capacity of tubulin to polymerize, resulting in impairment of polymerization and alteration of microtubules; this leads to inhibition of secretion of protein, lipoprotein, and glyceroprotein into the plasma and their accumulation in the liver, thus enhancing hepatic damage. In addition, binding to lipoproteins may alter their catabolism. l o Long-term alcohol feeding of ethanol in the diet of rats delayed secretion of export proteins such as albumin and transfenin into the plasma and their retention in the liver, leading eventually to ballooning of the hepatocytes. Another export protein. fatty acid binding protein (FABP), increased by one sixth to one third after ethanol feeding.a However, the increase of FABP may also favor the esterification of FA (mainly as triglycerides) and a modest increase in nonesterified FA, thus preventing accumulation of potentially deleterious nonesterified FA and FA-CoA esters secondary to ethanol-induced inhibition of their 0xidation.4~3~~ Although the mechanism of water retention is not completely clear, a

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tion of triglycerides in the liver by trapping fatty rise in protein, amino acids and an increase in acids (FA). Moreover, excess NADH may also ions could enhance water retention by osmosis; promote synthesis of FA. Only when very large these increases lead to hypertrophy and balloonamounts of alcohol are consumed, do FA deposit ing of the hepatocytes. This ballooning may favor in the liver.lO Moderate hyperlipemia can be obprogression of liver diseases in alcoholics. lo served in early stages of alcoholic liver injury. In Mitochondria1 impairment leading to defecsome alcoholics, depending on dose and duration tive oxygen utilization, decreased oxidation of of alcohol intake, severe hyperlipemia develops FA, and alteration of oxidative phosphorylation is as a consequence of potentiation of abnormal also hypothesized to result as a consequence of metabolism of lipids or carbohydrates. Hyperacetaldehyde accumulation in alcoholics, rather lipemic response develops progressively and inthan other factors such as maln~trition.~~ volves all lipoprotein classes, including HDL. Acetaldehyde may induce toxicity through Studies on volunteers in metabolic wards demoninterference with enzyme activities, such as by strated an increase in hepatic lipids when ethanol binding to important receptors.84Increased oxywas given either as a supplement or as an isocagen radicals produced by ethanol may also be loric substitute for carbohydrates in an otherwise involved.49 Acetaldehyde binds with cysteine, nutritionally balanced diet. Hepatic steatosis was which is a constituent of glutathione (GSH). This produced, even with a high protein, high vitamin binding may contribute to depression of liver diet and was accompanied by major ultrastrucGSH.'O GSH is important in body defenses betural changes in the liver and by elevated liver cause it acts as a scavenger for toxic free radicals, transaminases in the blood. If dietary fat was particularly reactive oxygen species. Acute ethadecreased from 35 to 25% of total calories, henol administration to rats inhibited GSH and led patic triglyceride accumulation was decreased to an increase in its loss from the liver. Chronic treatment led to a decrease of GSH p e r o x i d a ~ e . ~ ~ dramatically. Replacement of dietary triglycerides that contained long-chain FA with those conA mechanism of ethanol-induced fatty liver in taining medium-chained FA resulted in marked monkeys and humans has been proposed where reduction of the capacity of alcohol to produce severe reduction in GSH favored peroxidation fatty liver in rat~.~JO Another way by which liver and enhanced lipid peroxidation as a result of dispenses excess lipids is through increasing generation of a~etaldehyde.~~ GSH depletion was ketogenesis, which leads to mild ketosis in modexperimentally decreased by administration erate alcoholics and severe ketoacidosis in susChanges of antioxiof S-adenosyl-~-methionine.~* ceptible individuals.1° dants such as vitamin C, GSH, selenium, and vitamin E due to either direct effect of ethanol or malnutrition associated with alcoholism have been 5. Alcoholic Liver Cirrhosis (ALC) reported.1° Free radicals generated during the metabolism of acetaldehyde by aldehyde oxidase are Despite the high prevalence of alcoholism believed to be a major mechanism in the initiation and cirrhosis throughout the world, the inciof alcohol-induced liver injury.53 dence of cirrhosis among alcoholics is relatively low (Le., -18%).3 Thus, individual susceptibility influences development of ALC. 4. Fatty Liver Genetic and environmental factors that may influence this susceptibility include individual The main pathway for ethanol metabolism differences in alcohol metabolism, consumpinvolves the alcohol dehydrogenase (ADH) pathtion patterns, gender, histocompatibility (HLA) way in which alcohol is oxidized to acetaldehyde, antigens, family history of alcoholism, immune which in turn loses hydrogen when it is oxidized response, and poor n ~ t r i t i o n .ALC ~ is correto acetate, most of which is released into the lated with both the magnitude and duration of bloodstream. Ethanol oxidation increases the raalcohol use.54Thus, the average cirrhogenic dose tio of NADH to NAD, which raises the concentrawas estimated to be 180 g ethanol per day for tion of a-glycerophosphate, leading to accumula355

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25 years; the risk increased five times at a dose of 80 to 160 g/day, and 25 times at >160 g/d.55 The role of alcohol in liver cirrhosis was more pronounced in the Americas (66%develop ALC) than in Europe (42%), than in Asia (1 1%), although the percentages seem to be on the rise in Europe and Asia.56Women seem more susceptible than men to this disease as a daily intake of 40 g by men and 20 g by women resulted in an increased incidence of the disease in a well-nourished normal p ~ p u l a t i o n although ,~~ in a normal population a dose of 40 g/d for both men and women was reported to have no observable adverse effect on ALC.” A retrospective case-control study in France showed that a relative risk of liver cirrhosis was positively correlated with alcohol and fat consumption and negatively correlated with carbohydrate and protein intakes.58A reduced content of hepatic a-tocopherol observed in some patients with ALC may play a role in ethanol-induced lipid pero~idation.~~ Patients with ALC experience increased resting metabolic rate and enhanced thermogenesis, resulting in negative energy balance, defective glucose storage, and normal glucose oxidation, which lead to an increased energy need.60 While the rate of malnutrition was relatively modest in alcoholic patients without alcoholic liver disease, it is virtually 100% in patients with alcoholic hepatitis or ALC. Abnormalities in amino acids were observed, depending on the degree of hepatic damage, amount of alcohol consumed, and intake of amino acids. Plasma concentration of branched-chain amino acids, aromatic amino acids, and a-amino-n-butyric acid increased, whereas that of hydroxy amino acids, including alanine and proline, decreased.61 Alteration in the production, site of action, or metabolism of cytokines (regulatory polypeptides secreted during the generation of an immune response by lymphocytes) due to ethanol consumption was observed in alcohol liver injury. Abnormalities in the production of interleukin- 1, interleulun-2, interleukin-6, and tumor necrosis factor-a were related to abnormalities in alcoholic hepatitis, including hepatic tissue damage, and ALC.62-M Severe protein energy malnutrition was shown to adversely affect the production of interleukin- 1 produced by the macrophage-mono-

356

cyte system, resulting in immunosuppression in ALC patients.65 Interference with immunologic functions, such as production of mesangial IgA and deposition, were observed in rats as well as humans.66

6. Disorders of Collagen Metabolism Alcoholic liver cirrhosis was thought to develop as a consequence of alcoholic hepatitis characterized by ballooning of the hepatocytes, extensive necrosis and polymorphonuclear infiltration, and increased deposition of collagen and glycoaminoglycolysis; however, work with baboons has shown that fulminating alcoholic hepatitis is not necessary for the development of cirrhosis.’O It is now believed that alcohol affects the metabolism of collagen, leading to fibrosis by depositing collagen in mesenchymal cells and fat storage cells (lipocytes or Ito cells). Accumulation of collagen could be due to failure of the process of collagen degradation to keep up with its synthesis in the liver.’O Addition of polyunsaturated lecithin (PUL) to transformed lipocytes in vitro appeared to prevent collagen accumulation by stimulating collagenase activity. PUL also attenuated accumulation of collagen after alcohol administration in viva6’ PUL contains the lipotrope choline whose lack may play a role in alcohol liver injury. In rats, ethanol increased choline requirement by enhancing choline oxidation. Primates, however, were much less susceptible to protein and lipoprotein deficiency than rodents as very high doses of choline and methionine treatments in alcoholic patients and baboons suffering from hepatic injury was ineffective. This is probably due to species differences inasmuch as human liver contains much less choline oxidase than that of rats.1° Clinical data from patients with alcoholic liver disease as well as from volunteers showed the ineffectiveness of lipotrophic factors in the production of alcohol-related liver injury.3 Dietary zinc influenced hepatic prolyl hydroxylase activity and collagen deposition in alcoholic rats.6R ALC was associated with decreased thiamin diphosphate concentration and thiamin phosphorylati~n.~~

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7. Nutritional and Toxicological Consequences of Alcoholism Alcohol can cause malnutrition by displacing other nutrients either due to excessive consumption of empty calories, or secondary to maldigestion or malabsorption of nutrients resulting from gastrointestinal complications in chronic consumption of alcohol.70Alcohol can also cause direct toxicity due to its interference with hepatic metabolism. There is an interplay between toxicological and nutritional factors in alcohol processing in the body, especially the liver. Toxicity may exacerbate malnutrition by enhancing nutrient degradation, and malnutrition may adversely affect the alcohol detoxification process in the body.1° Use of a liquid diet in experimental studies overcame the natural aversion of rodents for alcohol and established a causal role of ethanol in the pathogenesis of liver diseases in baboons.71 Individuals with moderate alcohol intake showed little nutritional differences from nondrinkers. In the diet of light drinkers, alcoholic calories were additive to the energy derived from carbohydrates or fats, but in the diets of moderate and heavy drinkers, alcoholic calories replaced other sources of energy (mostly carbohydrates) in a dose-dependent manner. As alcohol intake increases to >41% caloric intake, the percentage of energy derived from protein, fat, and carbohydrate decreases, and intake of vitamins A, C, E, thiamin, calcium, iron, and fiber decreases, and nitrogen loss in the urine increases. Among minerals, zinc and selenium were found to be decreased.lo Chronic alcohol misusers accumulate significant amount of iron due to unregulated increase of intestinal iron absorption via the noncarrier-mediated pericellular route.72Ethanol altered mitochondrial and other liver membranes and their enzymes, such as alkaline phosphatase and gamma-glutamyl transpeptidase (GGTP), in alcoholics and in ethanol-fed rats.1° Chronic ethanol feeding was shown to increase hepatic plasma membrane fluidity, contrary to the homeoviscous changes observed in brain synaptosomes, erythrocytes, liver mitochondria, and microsomes, probably due to the specialized role of the liver in bile excretion, lipoprotein metabolism, and ethanol oxidation.lo This fluidity was associated with de-

creased membrane vitamin A and increased cholesterol esters content.73

0. Cancer An association between alcohol and cancer came primarily from epidemiologic case-control studies that focused on certain cancers and retrospective determination of prior alcohol consumption, and from cohort studies that linked drinking habits of study participants with subsequent cancer-induced fatalities. Additional evidence came from descriptive studies correlating cancer rates with average drinking patterns for various national, regional, and local groups. Total cancer risk was shown to increase with increasing level of alcoholic beverages consumption. Table 3 shows that the relative risk (RR) to nondrinkers of all types of cancer increases with an increase in daily intake of alcohol after adjusting for cigarette smoking. These data, which are typical of several studies of total cancer risk, were derived from a 12-year cohort follow-up study of approximately 276,000 American men.74Risks, however, vary by site of cancer induction as detailed herein. Strong association of cancer with alcohol intake was observed for oral and pharyngeal cancers. Data taken from nearly 1100 patients with these cancers and 1300 controls in four areas of ~ ~presented in Table the U.S. in the m i d - 1 9 8 0 ~and 4 show that RR of oral and pharyngeal cancers as a result of a multiplicative interaction between smoking and drinking increase in each smoking status with an increase of alcohol intake. Approximately 75% of all oral and pharyngeal cancers in the U.S. are caused by interaction between smoking and drinking, resulting in an increased risk of consumers of both products by 37-fold compared with abstainers from both alcohol and t o b a c ~ o . ~Data ~ , ~in * Table 4 strongly indicate that alcohol by itself increased the risk of cancer in nonsmokers and exsmokers, as was reported elsewhere.79However, it is possible that in nonsmokers alcohol interacts with other carcinogens, although the evidence is difficult to evaluate directly in epidemiologic studies because only few of the cancer patients are nonsmokers, which makes it

357

TABLE 3 Relative Risks of Total Cancer Mortality According to Number of Alcoholic Drinks Per Day Alcohol intake (drinkslday) None
a

Number of cancer deaths

RRa

95% Confidence interval

4748 563 1026 458 345 178 44 1

1.o 0.9 0.9 1.I 1.3 1.5 1.6

0.8-1 .O 0.9-1.1 1.o-1.3 1.2-1.5 1.3-1.7 1.5-1.8

All risks relative to nondrinkers and adjusted for cigarette smoking.

From Blot, W. J., Cancer Res., 52 (Suppi.), 21 19s, 1992. With permission.

TABLE 4 Relative Risks of Oral and Pharyngeal Cancer in Males According to Amount of Tobacco Smoking and Alcoholic Beverage Drinking RR

Smoking status


1-4

5-14

15-29

30+

Totalb

Nonsmoker Ex-smoker 1-19/d for 20+ years 20-39/d for 20+ years 40+/d for 20+ years Totald

l.Oc 0.7 1.7 1.9 7.4 1.0

1.3 2.2 1.5 2.4 0.7 1.2

1.6 1.4 2.7 4.4 4.4 1.7

1.4 3.2 5.4 7.2 20.2 3.3

5.8 6.4 7.9 23.8 37.7 8.8

l.Oc 1.1 1.6 2.8 4.4

a

Number of drinkdweek. Risk adjusted for alcohol intake. Data from Reference 75. Risk adjusted for smoking.

From Blot, W., Cancer Res., 52 (Suppi.),2119s, 1992. With permission.

difficult to divide them into yet smaller groups to evaluate other exposure risk fact01-s.'~Drinking is also believed to enhance the risk of developing oral and pharyngeal cancers by either lowering nutritional status due to empty calories, or deprivation of important vitamins, minerals and other ~" data exist on the nutrients, or b ~ t h . ' ~ .Fewer effect of alcohol on cancer induction according to timing and duration of exposure because it is often difficult to accurately identify exdrinkers and assess when they stopped consuming alco-

358

holic beverages. Increased risk of oral and pharyngeal cancers was associated with most types of alcoholic beverages, suggesting that ethanol is associated with cancer development. Differences in the magnitude of risk were reported, however, for various types of beverages.76 That ethanol may be the key ingredient was also suggested by findings of increased risk of oral cancer in users of mouthwash.81In addition, the correlation between mouthwash and oral cancer suggests a topical rather than a systemic route of alcohol in

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cancer induction because few individuals swalSeveral epidemiologic studies correlated low mouthwash.76 breast cancer with alcohol consumption, with Case-control and cohort studies conducted significant excess risk of cancer at doses as low worldwide showed an increased risk of esophas three drinks per day.3,76,82,87 This evidence is, ageal cancer with increased consumption of alhowever, controversial,16 and although the cohol and smoking.82 Alcohol also seemed to mechanism of this association is not clear, alenhance the effect of poor nutrition on esophteration of hormonal status was reported to inageal cancer and vice versa, consistent with a crease breast cancer risk in humans and animultiplicative interaction between the t ~ o . ~ ~ mals.@ , ~ ~ , ~ ~ Variation in risk of esophageal cancer was obSeveral case-control and cohort studies sugserved among various beverages, suggesting that gested an increased risk of cancer of the large in addition to ethanol, congeners or other conbowel, particularly rectal cancers, with contaminants may be responsible for cancer inducsumption of alcoholic beverages, particularly ti~n.~,~~ beer.3,76,82 However, inconsistencies among studA strong correlation was found between ies and the small number of observations cast alcohol and cancer of the larynx, with alcohol doubt about alcohol intake as a risk factor and tobacco having a synergistic interactions3 for large bowel ~ a n c e r . Although ~ ~ , ~ ~ some The risk of alcohol-induced laryngeal cancer epidemiologic studies reported a correlation was shown to vary by anatomic site, with alcobetween alcohol consumption and cancers of hol exerting a great effect on the extrinsic, rather the stomach, pancreas, lung, bladder, and other than the intrinsic larynx,83suggesting that alcosites, the overall evidence does not bolster that hol may act through topical exposure.76 c~ntention.~,~~,~ In North America and western Europe, alSeveral experimental studies in animals cohol is considered the primary cause of liver (e.g., mice, rats, hamsters) did not show any cirrhosis, with deaths from liver cancer increaspositive association between consumption of ing by approximately 50% in alcoholic^.^^^^^ alcohol and direct carcinogenic effect. The numThere is a firm association between liver cirber of animals was, however, small and the rhosis and primary liver cancer (PLC). Howduration of alcohol ingestion was brief.82On the ever, not all studies of alcoholism showed an other hand, in experimental studies, alcohol increased risk of PLCSx5A limited interrelaappeared to enhance the carcinogenic effect of tionship between other liver cancer factors and some carcinogens such as benzo[a]pyrene and alcohol was deduced from epidemiologic stud7,12-dimethyl benzanthracene (i.e., alcohol is a ies, although interactive effects with smoking cocarcinogen), and to promote the hepato(a weak hepatic carcinogen) and hepatitis B and carcinogenic effect of d i e t h y l n i t r ~ s a m i n e . ~ . ~ ~ . ~ ~ C viruses (strong hepatocarcinogens) were When ethanol was given to animals and the f o ~ n d .It~ is~ believed ,~~ that alcohol exerts its intestinal microsomes extracted and used in a effect on liver cancer through induction of cirshort-term test, like the Ames Salmonella rhosis or other liver damage, thus disposing typhimurium system, chronic ingestion of ethanol was shown to enhance the capacity of the susceptible individuals to development of heintestinal microsomes to activate the propatic tumors.76 Alcohol can influence liver carcinogens 2-aminofluorene and tryptophan pymetabolism, particularly alcohol-inducible cytochrome P-450,which catabolizes metabolism r o l y ~ a t eAlcohol .~ and acetaldehyde also interof xenobiotics and alters the ability of liver to fered with the capacity of cells and experimental detoxify compounds with carcinogenic potenanimals to repair carcinogen-induced DNA damage, resulting in alkylation at the O6 position in tial such as nitrosamines.I0 Alcohol may also guanine and a decrease in 06-methyl guanine deplete the liver’s vitamin A stores affecting transferase activity, processes that are associated blood and tissue levels of retinol and its metabolites, which were shown to influence sevwith both mutagenesis and carcinogenesi~.~~ Acetaldehyde induced sister chromatid exchanges, eral types of chemically induced cancer in aniand enhanced chromosomal aberrations in cell mals.10,76 359

cu1tures.l In other studies in rats, acetaldehyde caused nasal and laryngeal carcinoma following its inhalation, and when administered after benzo[a]pyrene ingestion, it enhanced lung tumors. 76 Epidemiologic studies and experimental work support the following hypothesis as potential mechanisms for alcohol-induced cancer:

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1.

2.

3.

4.

360

The presence of congeners, carcinogens, additives, and other contaminants in alcoholic beverages (e.g., N-nitroso compounds found in some beers, polycyclic aromatic hydrocarbons and phenols in whiskeys, tannins in wines, mycotoxins in some wines and beer, inorganic arsenic and other pesticide residues, asbestos fibers in beer, wine, sherry, and vermouth, flavoring agents, preservatives, and other natural products) may influence the carcinogenic p r o ~ e s s . ~ . ~ ~ Modification of metabolism of carcinogenic and other compounds. For example, induction of cirrhosis and other liver damage through inhibition of compounds that modify liver’s clearance function, increased exposure to compounds such as N-nitrosodiethylamine in other organ^,^ generation of metabolites such as acetaldehyde, and induction of enzymes (e.g., cytochrome P450) that catalyze the metabolic activation of some compounds into carcinogens (i.e., metabolism of N-nitrosonicotine of tobacco) possibly leading to a synergistic effect between alcohol and tobacco in cancer of the upper aerodigestive cancers.’ Act as a solvent, leading to increased penetration of other carcinogens as seen in increased cancer risk in tissues topically exposed to alcohol (e.g., mouth, pharynx, esophagus, and extrinsic larynx) and the synergistic effect of tobacco. Alcohol may also influence activation and interaction of carcinogens at the cellular level in certain tissues (e.g.. mouth and throat), and result in increased tissue exposure to oxidants, thereby elevating risk of DNA damage and malignant tran~formation.~.~~ Affecting hormonal level, function, and metabolism resulting in increased exposure

5.

6.

to these compounds in susceptible target organs (e.g ., breast). Suppressing the immune function through its effect on nutritional status, liver, and other body functions. For example, vitamin B,, which plays an important role in the production of antibodies that influence tumor development in the liver indirectly by affecting subsequent exposure to hepatitis B-virus, was reported to be decreased in alcoholic~.~,~~ Reducing intake and bioavailability, and enhancing deficiencies of nutrients that may influence cancer. Ethanol consumption combined with vitamin A and C deficiencies may alter epithelial cell chemistry and function, increasing susceptibility to carcinogens as seen in ethanol-enhanced tracheal metaplasia in ethanol-fed, vitamin A-deficient rats. Alcohol may also decrease delivery to hepatic cells of nutrients and additives that may be protective because of their antioxidant properties (e.g., vitamin E, butylated hydroxytoluene, propylgallate, and ethoxyquine have reduced tumor induction in several target organs). Alcohol may also lead to methyl deficiencies, which caused liver cancer in experimental animals and enhanced the tumorigenic effect of methyl-deficient diets.”76

E. Diseases of the Nervous System Wernicke-Korsakoff Syndrome (WKS) is a combination of two diseases: Wernicke encephalopathy (WE) characterized by paralysis of external eye muscles, ataxia, gait disturbance, and confusion; and Korsakoff psychosis (KP), a permanent brain disorder characterized by marked abnormalities in cognitive and emotional functions, such as the inability to learn new information, to remember and retain recent events (e.g., episodic memory), or to recognize emotions. Chronic heavy alcohol drinking may lead to both diseases, although not all Korsakoff patients go through a Wernicke phase.90 Frontal-lobe dysfunction is believed to produce a disorganization of the retrieval process, which contributes to the temporally extensive retrograde amnesia in

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Korsakoff patients?l Rat brain homogenates incubated with ethanol (0 to 100 mM) for periods up to 60 min showed that acetaldehyde was produced through the action of the enzyme catalase, which may lead to the psychopharmacological effects of It is believed that WK results from a nutritional deficiency, especially vitamin B,, or thiamin, an essential coenzyme in intermediate carbohydrate metaboli~m.~~ Variations in clinical manifestations and the finding that most patients with thiamine deficiency do not have the syndrome suggest that genetic variation may be involved in the etiology of WEe3Variants of the enzyme transketolase, which has reduced affinity for its cofactor thiamin pyrophosphate, were found. Cloned human transketolasecopy DNAs (cDNAs) from these variants showed a single-copy gene producing mRNA of approximately 2100 nucleotides. No specific nucleotide variations in the coding region of the gene were detected in WK patients, suggesting that allelic variants of the transketolase gene cannot account for the biochemically distinct form of the enzyme, and that the underlying mechanism is extragenetic and may be a result of difference in posttranslational processing, or modification of the transketolase pol~peptide.~~ Because alcohol inhibits the active and not the passive transfer of thiamin, supplementation in amounts larger than the RDA for this vitamin are given (i.e., 100 mg of parenteral thiamin), especially when glucose infusions are administered.93 Alcoholic peripheral neuropathy is a mixed motor sensory impairment affecting the distal regions, primarily the legs, and occurs in more than 80% of patients with severe neurological disorders such as WE. Thiamin deficiency is believed to be the main reason for the neuropathy, although the direct toxic effect of alcohol cannot be ruled Alcohol dementia involve severe intellectual deterioration, change in behavior and personality, and cognitive impairment in chronic heavy alcoholic consumption. It is attributed to combination of a nutritional disorder (i.e., thiamin deficiency) and a direct toxic effect of alcohol on the Abstinence from alcohol and proper nutrition are the cornerstones of treatment against alcoholinduced nervous system diseases, although phar-

macological modification of neurotransmitter function and/or enhancement of cerebral metabolism combined with behavioral methods may be beneficial. Serotonergic approaches to improve episodic memory in detoxified alcoholics also may reduce alcohol intake.96

F. Fetal Alcohol Syndrome (FAS) Fetal alcohol syndrome (FAS) causes a distinct pattern of physical and behavioral anomalies characterized by craniofacial, limb, central nervous system, and cardiovascular defects in the fetus in addition to growth delay and mental retardation. The worldwide incidence of FAS is 1.9 cases per 1000 live birth^.^,^^ Direct and indirect biological effects of alcohol exposure in utero seem to work with other factors such as genetic variations, alteration in DNA methylation, nutritional status, impaired placental transport, abnormal muscle organogenesis, pattern of exposure to smoking and use of drugs (e.g., nicotine and cocaine), fetal hypoxia, autoimmune reaction, and alteration in metabolic enzyme activities and cell functions important in cell division and membrane i n t e g ~ i t y . ~The * . ~ ~roles of prostaglandins and hormones are not clearly understood.lW A small percentage of women who drink excessively (>180 g of alcohol per day) deliver babies with mild FAS. Tolerance to alcohol may be due to metabolic or biochemical and structural adaptations at cellular membranes after chronic alcohol consumption.lo* Epidemiologic surveys showed a high prevalence of FAS in some native Americans and in people from lower socioeconomic backgrounds. Factors such as persistent drinking during pregnancy, history of excessive alcohol consumption, number of previous deliveries, and race affect development of FAS and increase the probability of its incidence by 50%. Alcohol-related neurological and biological effects are less frequent among women with moderate level of alcohol con~umption.~ Experimental work showed suppression of immune response, as measured by a decrease in the thymocyte number in splenic T-cell-proliferative response to the hemagglutininhitogen concanavalin A and plasma insulin-like growth fac-

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tor in rats exposed irz utero to e t h a n ~ l . ' ~ ' J ~ ~its intake is the first step in treatment of alcoholic diseases. Thus, balanced nutrition is the first raEpidemiologic and experimental studies have tional nonspecific therapy for alcoholics. Methionlinked ethanol-induced teratogenicity with materine and zinc supplementation have been hypothnal/fetal deficiencies in zinc and methionine. esized to protect fetuses of pregnant alcoholic Moreover, ADH is a zinc metalloenzyme, and mothers.lM If this hypothesis proves to be correct zinc deficiency decreases ADH activity, slowing down the elimination of ethanol. The essential in further testing in animals, then the size of the amino acid methionine is a lipotrope as well, and supplement and the timing of the supplement administration with respect to the timing of alcoserves as a universal methyl donor that is inhol ingestion will need to be worked out before volved in hepatic detoxification.lm clinical applications can be made. Thiamin supplementation has been recommended for alcoholic IV. GENETICS OF ALCOHOLISM patients with diseases of the central nervous sysIn patients with liver disease, tem and liver.93.95Jos Evidence gathered over the last 25 years shows nutritional intervention in the form of parenteral that alcoholism is due to an interaction between or enteral supplementation to correct for energy, environmental and genetic factoms The role of amino acid, and vitamin deficiencies has been genetics in predisposition to alcoholism was deevaluation method p r e ~ c r i b e d . ' ~A ~ Jnutritional '~ rived from studies of adoptees separated from using a correlation between real body weight, their biological parents at an early age, familial lean body mass and arm muscular area was helpstudies, studies on twins, and animal breeding ful in evaluating patients suffering from alcoholic studies.' Studies of adopted children indicated liver disease because of its ability to correct errors that natural sons of alcoholics were more likely to due to the presence of ascites."l Specific therabe alcoholics than natural sons of nonalcoholics, pies for alcoholic hepatitis with corticosteroids, irrespective of whether the sons were raised by cyanidanol, penicillamine, synthetic thyroid antheir alcoholic biological parents or by their nontagonists, hormones, and amino acids have been alcoholic adoptive parents. Twin studies have tried; results were either negative or contradicprovided views that are less clear for the role of tory."? In cirrhotic patients, colchicine treatment genetic factors than adoption studies.' Animal slowed and reduced mortality."* Therapy with studies have shown that alcohol elimination and agents such as the polyunsaturated phosphatidylalcohol consumption are partially determined by choline and S-adenosyl-L-methionine (a precurgenetics. sor of glutathione) for alcoholic hepatitis and cirMany studies have been conducted on identirhosis shows promise but requires further fying neurophysiological (e.g., electrical brain l 3 In end-stage liver disease, investigation.10Ji2J patterns), neuropsychological (e.g., abstracting, orthotropic liver transplantation should be conproblem solving, perception), and biochemical sidered because these patients do as well as other (e.g., genetic variation in alcohol-metabolizing nonalcoholic patients with other forms of endenzymes, especially ADH and aldehyde dehydrogenase) markers of susceptibility to alcoholism.s stage liver disease.los Molecular cloning techniques have identified five human ADH genes on the region q21-25 of VI. DIRECTIONS FOR FUTURE chromosome 4; markers for these genes have also RESEARCH been identified.IMPolymorphism among various ethnic groups may explain variations in their ability to metabolize alcohol.107 Research should be directed to expand and develop the following areas: V. POTENTIAL THERAPIES OF Explore the effect of moderate and excessive CHRONIC ALCOHOLISM ethanol intake on well-being and human health. The mechanism(s) by which alcohol influences Because chronic alcohol consumption affects chronic diseases. the nutritional status of its users, cessation from 362

Genes and genetic markers necessary to identify individual susceptibility for alcoholism. Biochemical, clinical, and immunological markers for diagnoses of alcoholic diseases. Role of nutritional and therapeutic factors in the treatment of alcoholic diseases. Role of environmental factors in the development of alcoholic diseases.

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VII. CONCLUSIONS AND RECOMMENDATIONS Moderate alcohol consumption seems to reduce stress, increases feelings of happiness, wellbeing, and euphoria, decreases tension and depression, improves certain types of cognitive performance, improves psychological well-being, and may reduce the risk of coronary heart disease.5 On the other hand, heavy consumption of alcohol and addiction increase all types of injury and trauma, and induce deleterious effects on various organs and the developing fetus.3Attempts to prohibit consumption of alcohol have usually failed, unless they were based on religious doct r i n e ~Thus, . ~ prudence dictates lowering of alcohol consumption in the general population and abstinence in those with alcohol-related diseases. Environmental and genetic factors are involved in the susceptibility to alcoholism. Alcohol can lead to malnutrition either primarily due to consumption of empty calories, or secondary to maldigestion or malabsorption of nutrients due to gastrointestinal complications. Alcohol can also exert a direct toxicological effect due to its interference with hepatic metabolism. Interferencewith immunological functions was also observed in humans and experimental animals. A causal effect has been observed between alcohol and various cancers (e.g., oropharynx, esophagus, larynx, liver, breast, and large bowel). Alcohol-induced nervous system disorders are believed to be due to depletion of thiamin. Deficiencies in zinc and methionine have been reported in FAS.

ACKNOWLEDGMENTS I express my gratitude to Drs. Charles S. Lieber, Cynthia Baum-Baicker, and William J. Blot for the tables and the figure that they pro-

vided; to members of the NAS Committee on Diet and Health for some of their contributions to the substance of this article; and to the reviewers of this manuscript for their insightful comments.

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