Alcohol consumption is difficult to quantify accurately, and there is no universally acceptable classification system or standard for the safe level of drinking. In 1862, the British established a daily upper limit of 1.5 oz as the safe level of alcohol consumption (O'Brien and Chafetz, 1982). The equivalence in drinks can be calculated from Table 16-1 (Baum-Baicker, 1985a). The Fourth Special Report of the U.S. Congress on Alcohol and Health considered the moderate drinker as one who consumed 0.22 to 0.99 oz of ethanol per day and the light drinker as one who consumed 0.01 to 0.21 oz/day (NIAAA, 1981). Accordingly, Turner et al. (1981) proposed that to qualify as moderate, one's alcohol consumption should not exceed 0.8 g/kg of body weight (bw) per day (an absolute limit of 80 g of alcohol) or an average of 0.7 g/kg bw in a 3-day period, as shown in Table 16-2 (Baum-Baicker, 1985a). People exceeding these limits are considered heavy drinkers (Klatsky et al., 1979). By this standard, 24% of all adults in the United States can be considered moderate drinkers, one-third as light drinkers, 9% as heavy drinkers, and about one-third as abstainers (NIAAA, 1987).
The best indicator of drinking is the blood alcohol level (BAL) at any time. At a BAL of 0.05 (5 parts of alcohol to 10,000 parts of blood), generally reached after one or two drinks, many people experience positive sensations such as relaxation, euphoria, and well-being (Hales and Hales, 1986). Above this mark, a person starts feeling worse and gradually loses control of speech, balance, and emotions. When BAL reaches 0.1, a person is considered to be drunk (i.e., experiences symptoms of frequent headaches, nausea, stomach pain, heartburn, gas, fatigue, weakness, muscle cramps, irregular or rapid heartbeats, dramatic mood swings, and depression and paranoia); at 0.2, some people pass out; at 0.3, some collapse into a coma; and at 0.4, a person can die (Hales and Hales, 1986).
Patterns of Alcohol Consumption in the United States
In 1985, 18 million adults 18 years of age and over had problems with alcohol use (NIAAA, 1986). Forty-one percent of these (7.3 million) were alcohol abusers, defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as drinkers who experienced at least one severe or moderately severe consequence of alcohol abuse, such as job loss, arrest, or illness, during the previous year. The remaining 59% (10.6 million) were alcoholics, defined as drinkers who, during the past year, experienced at least one symptom of alcohol withdrawal or one loss-of-control symptom plus one other symptom of de-
TABLE 16-1 Amount of Ethanol in a Drinka
Unit of Measure
Ethanol in a Drink
Whiskey (80 proof)
1-oz shot (30 ml)
3.5-oz glass (104 ml)
12-oz bottle (355 ml)
a From Baum-Baicker (1985a).
b Most table wines contain 11 to 13% ethanol. Fortified wines, such as sherry and port, contain approximately 20% ethanol.
c Most U.S. brands contain 3.2 to 4.0% ethanol.
pendence. Although alcohol abusers and alcoholics were defined as separate groups, they were not considered to be mutually exclusive. Many alcoholics also reported consequences of alcohol abuse, and some counted as alcohol abusers may have had alcohol dependence.
Alcohol consumption peaks in the 20- to 40-year age group; alcohol abuse is most frequent in youth and middle age. A national study by Schoenborn and Cohen (1986) showed that 70% of people between the ages of 20 and 34 consumed alcohol.
In a 1985 survey, 66% of the high school seniors interviewed reported that they had consumed alcohol in the past month and 5% described themselves as daily drinkers. Thirty-seven percent of them had had five or more drinks on at least one occasion during the 2 weeks before the survey (NIAAA, 1987).
Alcohol use decreases in the elderly. Among those 65 to 74 years of age, 43% consumed alcohol. The percentage fell to 30% after age 75. The national survey of Cahalan et al. (1967) showed that 15% of those under 40 years and 5% of the elderly were heavy drinkers.
The lower percentage of alcoholics among the elderly is believed to be the consequence of attrition, as younger alcoholics die from accidents, cirrhosis, or other medical complications. It is also more difficult to define alcohol abuse among the elderly, because many of the criteria for such a classification (e.g., inability to hold a job, drunken driving, or other consequences of drinking) are less likely to apply to the elderly. Furthermore, family members may underreport excess alcohol use to protect the dignity of their elderly relatives.
Alcoholism affects nearly 18% of the institutionalized elderly (Schuckit and Miller, 1976), who are more likely to have medical problems. As many as 28% of the elderly residents of psychiatric institutions have had problems with alcohol use. Blose (1978) also found that 40 to 60% of nursing home patients had a history of alcohol-related problems. These figures are especially important in light of the increasingly high percentage of older people in the U.S. population.
Males are more likely to drink alcohol (Table 16-3) and to drink more heavily than females. Nevertheless, the proportion of women who drink has increased in the past 25 years. Through the 1970s, more women than men were abstainers and light drinkers, and fewer women were heavy drinkers. By 1981, the percentage of women who were
TABLE 16-2 Upper Limits of Allowable Daily Alcohol Consumptiona
Weight of Individual
0.8 g/kg bw per dayb
0.7 g/kg bwb
80-Proof Spirits (oz)
12% Table Wine (oz)
80-Proof Spirits (oz)
12% Table Wine (oz)
3.6%c Beer (oz)
a From Baum-Baicker (1985a). Conversions: 1 oz = 23.34 g or 29.574 ml.
b Turner et al. (1981) defined moderate intake as no more than 0.8 g/kg bw per day or an average of 0.7 g/kg bw over a 3-day period. See text.
c By weight, or 4.5% volume.
TABLE 16-3 Estimated Numbers of Adult Alcohol Abusers and Alcoholics, 1985a
a From NIAAA (1986).
b See definitions in text.
heavy drinkers and the percentage of women ages 35 to 44 who were drinkers had increased (Wilsnack et al., 1984).
Rates of excessive drinking and self-reported drinking problems for the adult black population are similar to rates in the general U.S. population (NIAAA, 1987). Black youths have higher abstention rates and lower rates of heavy drinking than white youths. Native Americans, on the average, are more likely to be heavy drinkers than the general population. Some tribes have lower percentages of drinking adults than the U.S. population (30% versus 67%), whereas the percentage of drinkers in other tribes reaches 80% (NIAAA, 1987). Little is known about drinking practices or alcohol-related problems among Asian Americans, although they are generally believed to have a lower prevalence than found in other groups (see Chapter 4 of this report).
Genetics and Alcoholism
Studies of families, twins, adoptees, and animals suggest that alcoholism results from an interaction between heredity and environment (NIAAA, 1987). Research is now focused on identifying physiological, psychological, and biochemical markers for susceptibility to alcohol (see Chapter 4).
Cultural Aspects of Alcohol Use
Ancient Egyptians believed that beer (or bouza) was invented by the goddess Osiris (Ghalioungui, 1979). Beer, produced by malting, was considered food and drink and was the beverage of common people at festivals. Wine was also produced in ancient Egypt and used in religious celebrations and as a medicine. In contrast with beer, wine was considered an aristocrat's drink (Ghalioungui, 1979). In Mesopotamia 3000 years B.C., beer was the drink of the cereal-growing south, whereas wine was the choice of the vine-growing north (Ghalioungui, 1979). Accounts of drunkenness in ancient Greece and Rome are well documented (Roe, 1979). Greeks ate cabbage to avoid inebrietya custom later adopted by the Arabs ( Ghalioungui, 1979). In the Bible, however, the beneficial references to drinking appear to be related to unfermented grape juice (Wilkerson, 1978).
In pre-Islamic Arabia, beer, fermented dates, milk, and wine were commonly consumed (Gawad, 1968). Drinking took place in houses, taverns, and dancing places and along caravan routes. With the advent of Islam, abstinence became the rule in Arabia. In other Middle Eastern cities, such as Baghdad, Cairo, Damascus, and Tehran, drinking was not banned but was unpopular, and today it is barely tolerated (Ghalioungui, 1979). Chicha (beer made from maize) played important religious, economic, and political roles in the Andean South American society during the Incan empire (Morris, 1979). Alcohol had a similar place among the Aztecs of Mexico (Paredes, 1975) and the Mayans of Central America (Gonçalves de Lima et al., 1977).
In medieval Europe, drunkenness was prevalent among the lower orders of clergy (Roe, 1979). In medieval England, wine became plentiful after grapes were imported from France at the end of the fourteenth century. Throughout the Middle Ages, drunkenness was largely associated with revelry, feasting, and religious celebrations. Alcoholism did not become a social problem until distilled beverages became available around 1100 A.D. (Singer et al., 1956). Until the sixteenth century, fortified wine was produced only on a small scale in monasteries. Franciscus Sylvius, a seventeenth-century professor of medicine at the University of Leiden, may
be the first to have distilled alcohol from grain and to have named the result aqua vitae (Lucia, 1963). The English, who called it gin, imported it during the reign of William III. By 1700, gin was produced from excess corn (Dorothy George, 1931) to compete with French liquors (Hirsch, 1949). In the first half of the eighteenth century in England, especially 1720 to 1750, lower-income people drank large quantities of alcohol, and the adverse nutritional consequences of alcoholism were first recognized at that time (Roe, 1979). The Gin Act of 1751 imposed a duty on spirits and stopped distillers, chandlers, and grocers from retailing liquor. This legislation brought excessive alcohol consumption under control several years later (Webb and Webb, 1903).
Rum was developed in the Caribbean in 1650 as a by-product of the sugarcane industry and was distributed to the British Royal Navy in 1892. It was believed to confer strength and offer protection against scurvy (Chalke, 1976).
Puritans in the American colonies believed that alcoholic drinks were wholesome and strengthening. In the eighteenth century, when rum and whiskey became available, alcohol abuse became evident. Black slaves and American Indians were considered too irresponsible to be trusted with the alcohol (Roe, 1979), but the colonists nevertheless used alcoholic beverages to appease the Indians and to motivate the slaves to perform unpleasant tasks.
Alcohol and Nutritional Disorders
The relationship between alcohol abuse and nutritional disorders was reported as early as the eighteenth century (Sedgewick, 1725). In the United States, Benjamin Rush observed in 1809 that approximately 4,000 people died annually from the use of rum (Rush, 1818). He described such effects of hard drinking as loss of appetite, jaundice, dropsy, diabetes, redness of face, fetid breath, epilepsy, gout, and madness. Bynuum (1968) observed that the concept of chronic alcoholism as a disease, instead of as a vice or a cause of other diseases, began about the turn of the eighteenth century, when the phrase habitual drunkenness, the equivalent of today's chronic alcoholism, was coined. Fuchs (1848) described alcohol as a poison. Huss (1852) attributed the effects of chronic alcohol abuse to tissue damage and believed that alcohol's toxic effects were similar to those caused by intoxicating foods. Jolliffe (1940) described the role of alcohol in the development of nutritional deficiencies.
Alcohol in Medicine
In the middle of the nineteenth century, alcohol was commonly used to treat certain diseases and to alleviate symptoms (Roe, 1979). In 1864, a committee of the National Academy of Sciences, in response to a request from the Surgeon General of the U.S. Army, recommended that in military hospitals whiskey be replaced with alcohol, medicated with additives appropriate for the intended objective (Parker, 1978). A strong reaction to its use as a drug occurred early in the nineteenth century and paralleled the growth of the temperance movement (Horsley and Sturge, 1915).
From antiquity, wine, beer, and, later, spirits were considered to be food for the sick when solid foods could not be tolerated (Roe, 1979) and, in many societies, to have nutritional value (Steinkraus, 1979). Although alcohol has been used clinically as an appetite stimulant, as a sedative-hypnotic drug, and as a calorie source for intravenous administration, these uses have not been subjected to controlled medical evaluation (Becker et al., 1974). Ethanol is unusual among drugs in that it has a biphasic impact on the nervous system. In small amounts, it stimulates; but as it accumulates in the body it depresses, and the amount that makes the difference is minute for most people. Many effects of drinking are determined less by the quantity consumed than by one's expectations (Heath, in press).
Transcultural Anthropological Perspective
Alcohol and drinking are perceived differently among Western and non-Western cultures. Some insights into the cultural role of alcohol can be discerned by comparing these cultures.
In Western societies, the frequency of alcoholism is not uniform among various ethnic groups. For example, most Jews drink, but few become alcoholics; ascetic Protestants rarely drink, but those who do so generally drink heavily (Heath, 1975). Bales (1946) explained that Jews regard drinking as a family sacrament, since wine is introduced to children in a sacred ritual context. In contrast, the Irish perceive drinking in a convivial secular context whereby adult men prove their manhood. Since the 1970s, however, Jews have been showing patterns of alcohol abuse (Heath, 1987), presumably because of growing
distance from traditional orthodoxy and from the moral authority of their faith (Douglas, 1987). Comparative ethnic studies also show changes in drinking patterns among Italians, Poles, and Portuguese after they migrated to America (Heath, 1987).
Non-Western Literate Societies
Among non-Western literate societies, there are wide differences in consumption of alcoholic beverages. For example, although prohibition of alcoholic beverages is supposed to characterize the Islamic world, alcohol-related problems are now recognized in Saudi Arabia (Al-Qthami, 1978) and in Bahrein (Alsafar, 1974). In India, some groups of Hindus espouse drunkenness as religious duty, whereas others practice complete abstinence (Heath, 1975).
Among nonliterate societies, the Camba of eastern Bolivia esteem drunkenness and actively pursue it, but there is no alcoholism in the sense that they do not suffer any alcohol-related economic, social, or psychological problems nor do they engage in aggressive behavior (Heath, 1975). Among African tribal societies, beer drinking is an integral part of most social activities among men. Beer is used as an offering to appease the gods, as a pledge of agreement between parties following adjudication, as a reward for help in working one's land in a system of reciprocal labor exchange, and as a medicine. Pathological addiction or aggressive behavior does not occur in these groups (Heath, 1975).
North American Indians also vary widely in their reactions to alcoholic beverages and have changed their attitudes over time. In the first decades of contact with whites, the Iroquois of upstate New York and southeastern Canada consumed distilled liquors in moderation and drinking became an integral part of their religion. In the early eighteenth century, however, aggression became part of their drunken behavior, following the example of white trappers and traders. By 1800, drunkenness had become a serious problem and eventually led to abstinence (Dailey, 1968). Kunitz et al. (1971) suggest that cirrhosis mortality rates are much higher among the Navaho than among the Hopi because the Hopi condemn drinking and reject the drunk, whereas the Navaho expect young men to be heavy drinkers and never force them into isolation or fail to welcome them back into the community.
Some populations show no reactions to alcohol such as hangovers, blackouts, and addiction, even when drunkenness is commonplace, e.g., among the Peruvian Quechua, Bolivian Camba, Salish, Polynesians, and Tarahumara (Heath, 1975). It is not known whether this lack of reaction is due to differences in thresholds to pain, physiological reactions to alcohol, attitudes toward or expected effects of alcohol, or other biologic or cultural factors.
Alcoholic beverages have been used to foster social integration in many societies, such as Finnish Lapps, Bolivian Camba, and many American Indian and South African tribes (Heath, 1975). In other societies, they have been used to appease gods, to pay fines or taxes, to mobilize agricultural labor, to overcome shyness and gain courage, to symbolize social unity, to promote social cohesion or conviviality, to relieve anxieties and pressures due to conflict with a dominant culture, to enhance social status and prestige, to mark personal identity and boundaries between ethnic groups, and to serve as a mode of recreation (Douglas, 1987; Heath, 1975, in press).
Social problems are related more frequently to consumption of alcohol in Western societies than non-Western societies. Alcoholism is rare in non-Western societies, even where most adults of at least one sex drink regularly and where drunkenness is valued (Heath, 1975).
Several generalizations can be derived from cross-cultural studies:
· In most societies, drinking is a social act embedded in a context of values, attitudes, and other norms, all of which influence the expression of effects, regardless of biochemical, physiological, or pharmacokinetic factors.
· Drinking is governed by rules tied to strong emotions and sanctions, determining such things as who may or may not drink, how much of what they may drink, in what context, and with whom.
· Alcohol promotes relaxation and sociability in various populations.
· Physical, economic, psychological, social, or other problems associated with drinking are rare in many cultures.
· When alcohol-related problems occur, they are linked with modalities, attitudes, and norms regarding drinking.
· Attempts at prohibition are not successful unless embedded in sacred or religious values (Heath, 1987).
Evidence Associating Alcohol Consumption with Chronic Diseases
Assessment of Alcohol Consumption
The accurate assessment of alcohol consumption is difficult in population-based studies, and evidence regarding validity and reliability of the estimates has rarely been obtained. Some people are likely to underreport actual consumption, and the frequency of such underreporting varies with the social undesirability of consuming alcohol. In many epidemiologic studies, particularly the earlier ones, participants were simply asked to report an average number of drinks of beer, wine, and liquor or cocktails per day without regard for the complexities of drinking behavior or for the interview techniques needed to obtain information. Investigators have reported alcohol consumption in different units (e.g., number of drinks per day or volume of alcohol per month) and have used different formulas for converting the reported drinking behavior into these units. As a result, it is often difficult to summarize the results of such studies. Some writers have tried to circumvent this problem by using such terms as light, moderate, and heavy drinking, but such descriptive words are not satisfactory for scientific purposes. Where possible, alcohol consumption is reported herein as grams of ethanol per week, but these figures should be considered approximations and interpreted cautiously. Difficulties in assessing published statistics related to alcohol and drug abuse have been highlighted in a recent editorial (Barnes, 1988).
Ethanol may contribute to obesity because, depending on the level of intake, it can serve as an important energy source. The carbohydrate content is negligible for whiskey, cognac, and vodka; however, it is 2 to 10 g of carbohydrate/liter for red or dry white wine, 30 g/liter for beer or dry sherry, and as much as 120 g/liter for sweetened white or port wines (Pekkanen and Forsander, 1977).
National consumption data show that, on the average, alcohol contributes 4.5% of total calories to the energy intake of Americans (Scheig, 1970). The heavy drinker may derive as much as half, or more, of the daily calories from ethanol. Although the combustion of ethanol in a bomb calorimeter yields a value of 7.1 kcal/g, its biologic value may be less when compared in vivo to an equivalent carbohydrate intake. Metabolic ward subjects given additional calories as alcohol failed to gain weight (Lieber et al., 1965). No additional weight was gained by 17 hospitalized alcoholics who were given 1,800 alcohol-derived calories in addition to their 2,600-calorie diet (Mezey and Faillace, 1971). In metabolic ward studies, isocaloric substitution of ethanol for carbohydrates as 50% of total calories in a balanced diet resulted in a decline in body weight, and when given as additional calories, ethanol caused less weight gain than did calorically equivalent carbohydrates or fats (Pirola and Lieber, 1972). Crouse and Grundy (1984) reported variable responses to additional calories given as ethanol: no weight gain in lean individuals and some weight gain in half the obese individuals.
The view that ethanol increases metabolic rate is supported by the observation that ethanol ingestion increases oxygen consumption in normal subjects and that this effect is much greater in alcoholics (Tremolieres and Carre, 1961). Substitution of ethanol for carbohydrates increases the metabolic rate of humans and rodents (Stock and Stuart, 1974; Stock et al., 1973). A 15% increase in thermogenesis was seen in rats fed ethanol for 10 days (Stock and Stuart, 1974). In humans, diet-induced thermogenesis was also increased (Stock and Stuart, 1974). In rats, some, but not most, of the energy wastage was attributable to brown-fat thermogenesis (Rothwell and Stock, 1984). One postulated mechanism of energy wastage is oxidation without phosphorylation by the microsomal ethanol-oxidizing system (Pirola and Lieber, 1972). This pathway was induced by chronic ethanol consumption (Pirola and Lieber, 1975, 1976). Israel et al. (1975) explained energy wastage as the uncoupling of mitochondrial nicotinamide adenine dinucleotide (NADH) reoxidation, perhaps abetted by catecholamine release or a hyperthyroid state. However, the implication of the hyperthyroid state is unresolved (Teschke et al., 1983).
As a calorie source, alcohol is not as efficient as carbohydrates, especially when consumed chronically in large amounts. Thus, ethanol may contribute to excess energy intake, but is not a common primary cause of obesity. Moderate alcohol intake (i.e., 16% of total calories) was associated with a slightly elevated energy intake (Gruchow et al., 1985a). Despite comparable levels of physical activity there was no weight gain, perhaps because of the metabolic considerations discussed above. This and a slightly higher level (23%) of alcohol intake
(Hillers and Massey, 1985) were associated with a substitution of alcohol for carbohydrates as a source of calories. When the percentage of calories from alcohol exceeds 30%, large decreases in protein and fat intake occur.
Because the associations between alcohol consumption and cancer vary by site, the committee considered the evidence separately for each site.
Mortality from oropharyngeal cancer is higher among people in occupations providing ready access to alcohol and among alcoholics, whereas risks are lower among alcohol abstainers such as Seventh-Day Adventists and Mormons in the United States (de Lint and Levinson, 1975; Lyon et al., 1976). In 14,000 Danish brewery workers who were not alcoholics, but who did have an above-average consumption of beer, the incidence of pharyngeal cancer was twice as high as that in the general population (Jensen, 1979).
In a study of 543 men with cancer of the lip, oral cavity, and pharynx and 207 controls, Wynder et al. (1957a,b) found an association of these cancers with alcohol drinking. Rothman and Keller (1972) reanalyzed information on consumption of alcohol and use of tobacco obtained by Keller and Terris (1965). The risk for oropharyngeal cancer increased with increasing alcohol consumption at every level of smoking. In agreement with the findings of Wynder et al. (1957b), the analysis showed multiplicative interactions between alcohol and tobacco in their effects on oral-cavity cancer.
Evidence for the role of alcohol and tobacco in cancer of the oral cavity also comes from a study in France (Schwartz et al., 1962). The average daily consumption of alcohol was significantly increased in patients with cancers of the tongue, buccal cavity, oral pharynx, and hypopharynx. Case-control studies in Puerto Rico (Martinez, 1969) and in the United States (Graham et al., 1977) have confirmed the role of alcohol in cancer of the oral cavity.
Early clinical and occupational studies showed an association between access to alcoholic beverages or heavy alcohol drinking and laryngeal cancer (Kennaway and Kennaway, 1947; Kirchner and Malkin, 1953). Most studies of alcoholics indicate an excess of laryngeal cancer (Monson and Lyon, 1975; Schmidt and de Lint, 1972). The risk of laryngeal cancer among male Danish brewery workers was twice as high as expected (Jensen, 1979).
Several case-control studies have examined the interaction of alcohol and tobacco. Wynder et al. (1957a) reported that the risk of laryngeal cancer increased with the amount of whiskey consumed, even after adjusting for tobacco. Later, Wynder et al. (1976) confirmed the dose-response relationship, although the increase in risk was less than in the earlier studies. Other studies in the United States (Graham et al., 1981), Denmark (Olsen et al., 1985), and Canada (Burch et al., 1981) confirmed the dual role of alcohol and tobacco in increasing the risk of laryngeal cancer. In most of these analyses, the two factors were found to have a synergistic effect.
A high prevalence of alcoholism has been found among patients with esophageal cancer (Piquet and Tison, 1937). Furthermore, the incidence of esophageal cancer was greater among people employed in the production or distribution of alcoholic beverages than in the general population (Jensen, 1979).
Wynder and Bross (1961) reported a dose-response relationship between esophageal cancer and consumption of whiskey and beer by smokers of 16 to 34 cigarettes per day. The risk was approximately 25 times higher among drinkers of seven or more units of whiskey per day than among light whiskey consumers. A dose-response relationship was also found among beer consumers.
In Paris, Schwartz et al. (1962) found that average alcohol consumption was much higher among patients with esophageal cancer than among traffic accident victims. Martinez (1969) reported a clear dose-response relationship between esophageal cancer and daily consumption of alcohol in Puerto Rico. In France, Tuyns et al. (1977, 1979, 1982) found dose-response associations between the consumption of alcohol, after adjusting for tobacco, and the risk of esophageal cancer. Alcohol and tobacco combined had a synergistic effect: There was a very high risk among people who both drank and smoked heavily. Those studies also indicated that the risk of esophageal cancer was pronounced for consumers of apple cider distillates. In a later study, Tuyns (1983) examined the risk associated with alcohol con-
sumption among 74 men and women with esophageal cancer who never smoked. In both sexes, the risk increased with increased daily alcohol consumption. Similar associations were also found in Singapore (De Jong et al., 1974). A case-control study of black men in Washington, D.C., by Pottern et al. (1981) indicated that risk was higher among consumers of hard liquor than among beer drinkers (relative risks of 7.3 and 2.7, respectively).
Although no increased stomach cancer risk was found among Finnish alcoholics or Danish brewery workers (Hakulinen et al., 1974; Jensen, 1979), Sundby (1967) reported a mortality ratio of 1.6 for stomach cancer among alcoholics in Norway. Studies in France (Audigier and Lambert, 1974) and in Japan (Hirayama, 1972) also suggested that alcohol may be associated with cancer at this site. One case-control study showed an association between stomach cancer and wine drinking (Hoey et al., 1981), but other case-control studies have not supported such an association (Acheson and Doll, 1964; Graham et al., 1972; Haenszel et al., 1972; Schwartz et al., 1962; Tuyns et al., 1982).
Breslow and Enstrom (1974) reported an association between beer sales and rectal cancer in 41 states in the United States and in 24 countries. However, when consumption data for fats were taken into account, the correlation with colon cancer disappeared, whereas the positive correlation between beer consumption and rectal cancer remained (Schrauzer, 1976). In Denmark, no increased risk of either colon or rectal cancer was found among brewery workers (Jensen, 1979), but a similar study among brewery workers in Ireland showed a doubling of the risk of rectal cancer (Dean et al., 1979). There was a moderately nonsignificant increased risk of rectal cancer in one case-control study by Tuyns et al. (1982).
In a case-control study conducted in Australia, Kune et al. (1987) found little evidence of an association of any alcoholic beverages with colon cancer, but beer was a risk factor for rectal cancer. The effect was more marked in males than in females. The relative risk for the highest consumption levels in quartiles compared to the lowest was approximately 2. The risk of rectal cancer varied with beer-drinking patterns in the previous 15 to 20 years. Nevertheless, in other case-control studies, either no association or only a weak association was found between the risk of colorectal cancer, colon cancer, or rectal cancer and the consumption of alcohol or beer (Dales et al., 1979; Graham et al., 1978; Miller et al., 1983). By contrast, in cohort studies conducted in Norway (Bjelke, 1978) and in Hawaii (Pollack et al., 1984), there was a dose-response relationship between risk of rectal cancer and consumption of alcohol, especially with regard to frequency of beer consumption.
Some studies suggest an association between pancreatic cancer and alcohol consumption (Burch and Ansari, 1968; Cubilla and Fitzgerald, 1978); however, most studies of alcoholics have not shown an increased risk for cancer at this site (Hakulinen et al., 1974; Monson and Lyon, 1975). Similarly, no cohort or case-control studies have confirmed an increased risk (Jensen, 1979; MacMahon et al., 1981; Tuyns et al., 1982).
In North America and western Europe, cirrhosis of the liver is related mainly to alcohol consumption, and there is a firm association between cirrhosis of the liver and primary liver cancer (Tuyns, 1982). However, not all studies of alcoholics suggest an increased risk of primary liver cancer (Nicholls et al., 1974; Schmidt and de Lint, 1972). Studies of male Danish brewery workers, however, provide a clear association between primary liver cancer and cirrhosis of the liver (Jensen, 1979). In Finland, a significant excess (p < .05) of primary liver cancer was found among alcohol abusers (Hakulinen et al., 1974). Some studies suggest that primary liver cancer may be increased in alcoholics, even in the absence of cirrhosis (Lieber et al., 1979).
Accumulating evidence links viral hepatitis and hepatocellular carcinoma in alcoholics. Serologic markers of viral hepatitis are more frequent in alcoholics (Chevilotte et al., 1983; Gluud et al., 1982; Hislop et al., 1981; Mills et al., 1979; Orholm et al., 1981). Prevalence of anti-HBV (hepatitis virus B) antibodies was also found to be higher in an unselected outpatient alcoholic population (Gluud et al., 1984). Bréchot et al. (1982) reported that 19 of 51 subjects with various stages of alcoholic liver disease had one or more serologic markers of HBV in their serum. Eight of the 51 subjects had HBV-DNA in their livers. In five of these subjects, the DNA was integrated into the genome. Whether this increased incidence of pos-
itive cases is due to the socioeconomic status of the alcoholic, increased exposure to hepatitis infection from blood transfusions, or enhanced susceptibility to infection remains to be determined.
Bréchot et al. (1982) evaluated 20 subjects with alcoholic cirrhosis and hepatocellular carcinoma for evidence of HBV infection. Only 9 of 16 tested serologically had markers of HBV infection, but in all 20 subjects, HBV-DNA was integrated into the genome of the neoplastic liver cells. However, among alcoholic cirrhotics, Omata et al. (1979) found no difference in the frequency of hepatitis infection between those with and those without hepatocellular carcinoma. Goudeau et al. (1981) reported HBV markers in 31% of 125 asymptomatic alcoholics, 55% of 163 alcoholics with cirrhosis, and 22% of 46 with hepatocellular carcinoma. Yarrish et al. (1980) noted similar rates of HBV infection in both alcoholic and nonalcoholic subjects with hepatocellular carcinoma. Of their alcoholic subjects with hepatocellular carcinoma, 88% were seropositive for HBV markers, compared to 69% of nonalcoholic subjects with hepatocellular carcinoma.
In summary, most studies indicate an increased prevalence of HBV infection among alcoholics with cirrhosis and an association between the infection and a high frequency of liver cell cancer.
Most of the studies conducted on this subject suggest that breast cancer risk is related to alcohol consumption (Graham, 1987; Schatzkin et al., 1987). There was a positive correlation between alcohol consumption and breast cancer in 41 states in the United States, but not in 24 other countries (Breslow and Enstrom, 1974). Breast cancer mortality was twofold higher among 2,070 people admitted to mental hospitals in the United Kingdom with a diagnosis of alcoholism (Adelstein and White, 1976). The Third National Cancer Survey in the United States indicated a relative risk of 1.5 for breast cancer from consumption of hard liquor and wine. There was also a dose-response relationship with total alcohol consumption (Williams and Horn, 1977). In one case-control study, Rosenberg et al. (1982) found increased risk of breast cancer for drinkers compared with nondrinkers; the association was evident for beer, wine, and spirits. In another, conducted in France by Lê et al. (1984), there was an increased risk of breast cancer in subjects who consumed alcoholic beverages with meals. The association was significant for beer (relative risk, 2.2) and for wine (relative risk, 1.5). In a cohort study of more than 96,000 women in a multiphasic health examination program in the United States, breast cancer incidence was increased in those who had reported consuming more than three drinks a day (Hiatt and Bawol, 1984). In a 4-year follow-up study of nearly 90,000 U.S. nurses ages 34 to 59, a significant dose-response relationship was found between alcohol consumption and breast cancer risk (Willett et al., 1987). Among women consuming 5 to 14 g of alcohol daily (about 3 to 9 drinks/week), the age-adjusted relative risk of breast cancer was 1.3 (95% confidence interval, 1.1-1.7). Among those consuming 15 g of alcohol or more per day, the relative risk was 1.6 (range, 1.3-2.0). Adjustment for known breast cancer risk factors (e.g., parity, age at first birth, history of maternal breast cancer, prior breast disease, and relative weight) and a variety of nutritional variables (including estimated consumption of total calories, total fat, saturated fat, polyunsaturated fat, cholesterol, carotene, preformed vitamin A, and vitamin E) did not alter this association.
Several other studies, however, have provided no evidence of an association between alcohol and breast cancer (Byers and Funch, 1982; Webster et al., 1983) or only limited evidence (Begg et al., 1983). These conflicting findings are not easy to reconcile, but could be partly explained by methodological differences. For example, although nutritional variables were evaluated in the study by Willett et al. (1987), the data were obtained from a self-administered questionnaire, and it was not possible to evaluate confounding by variables, which may have masked an association. In that study, therefore, increased alcohol consumption could have been a marker for other factors that increase the risk of breast cancer.
In a detailed review of the epidemiologic findings concerning alcohol consumption and breast cancer, Longnecker et al. (1988) concluded that there was sufficient evidence to support an association.
Over the past 20 years, animal studies have shown that ethanol, either applied topically or administered as part of the diet, has cocarcinogenic effects. Examples of these experiments include the enhanced carcinogenesis of 7,12-dimethylbenzanthracene applied either to the cheek epithelium of young hamsters (Elzay, 1966, 1969) or to the skin of mice (Stenbäck, 1969), esophageal tumors induced in rats by diethylnitrosamine
(DEN) (Gibel, 1967), liver tumors induced by vinyl chloride (Radike et al., 1981), nasopharyngeal cancers initiated in pair-fed hamsters by nitrosopyrrolidine (McCoy et al., 1981), and rectal cancers initiated by dimethylhydrazine in rats (Seitz et al., 1984). However, the simultaneous addition of DEN and ethanol in drinking water (25%) did not modify DEN induction of hepatocarcinogenesis (Habs and Schmähl, 1981), nor did consumption of diets containing ethanol (35% total calories) affect the number of liver tumors induced by dimethylnitrosamine (DMN) (Teschke et al., 1983) or modify the development of preneoplastic hepatic foci by aflatoxin B1 in rats (Misslbeck et al., 1984). Similar results were obtained by Schwarz et al. (1983) using DEN or N-nitrosomorpholin as carcinogens and 10% ethanol in drinking water.
The association of alcohol consumption with cancers at sites that do not come into contact with high ethanol concentrations suggests that mechanisms other than, or in addition to, the direct cytotoxic effects of ethanol play a role in carcinogenesis. These are discussed in the following sections.
Ethanol may act as a cocarcinogen at remote sites through its capacity to induce the microsomal cytochrome P450-dependent biotransformation system. Ethanol administration to rats increases hepatic benzpyrene hydroxylase (Rubin et al., 1970). Likewise, activation of nitrosopyrrolidine was substantially increased (Farinati et al., 1985a). Ethanol induces microsomal DMN N-demethylase activity, which functions at low DMN concentrations (Garro et al., 1981). This effect contrasts with those of other microsomal enzyme inducers and may be due to the induction by ethanol of a specific form of cytochrome P450 (Koop et al., 1982; Ohnishi and Lieber, 1977), which differentially affects the activation of various carcinogens. Indeed, a selective affinity for DMN has been demonstrated with the ethanol-induced form of cytochrome P450 (Yang et al., 1985), and an active form of this isozyme (now called P450 IIE1 ) has been purified from human liver (Lasker et al., 1987). Furthermore, in studies using microsomes of ethanol-fed animals, enhanced mutagenicity was demonstrated at low DMN concentrations (Garro et al., 1981).
A growing body of evidence indicates that ethanol acts as a cocarcinogen. For example, the combined action of DMN and alcohol increased the incidence of olfactory neuroepitheliomas in mice (Griciute et al., 1981). Takada et al. (1986) noted neoplastic changes in the liver of rats treated with alcohol and DEN or with phenobarbital and DEN, suggesting that ethanol, as well as phenobarbitol, is a promoter of hepatocarcinogenesis.
The intestinal metabolism of xenobiotic substances may also be altered by ethanol consumption. Elevated cytochrome P450 levels and microsomal enzyme activities have been observed in the esophagus (Farinati et al., 1985a) and in the upper small intestine of rats after chronic ethanol ingestion (Seitz et al., 1979). In the Salmonella typhimurium test system, chronic ingestion of ethanol enhanced the capacity of intestinal microsomes to activate benzo[a]pyrene to a mutagen (Seitz et al., 1978) and the capacity of intestinal microsomes to activate 2-aminofluorene and tryptophan pyrolysate (Seitz et al., 1981).
Enhanced activation of benzo[a]pyrene to mutagenic derivatives has been mediated by lung microsomes in ethanol-fed rats (Seitz et al., 1981). Ethanol also enhanced the induction of nasopharyngeal tumors in hamsters treated with nitrosopyrrolidine (McCoy et al., 1981) and increased the activation of nitrosopyrrolidine to a mutagen by microsomes isolated from hepatic, pulmonary, and esophageal tissues (Farinati et al., 1985a; McCoy and Wynder, 1979).
In the rats treated with 1,2-dimethylhydrazine (DMH), chronic ethanol consumption enhanced the appearance of rectal tumors but not tumors in the distal or proximal colon (Seitz et al., 1984). This effect did not relate to the cytochrome P450-dependent oxidizing system in the liver or in the colonic mucosa or to changes in the fecal bile acids. However, colonic mucosal alcohol dehydrogenase (ADH) was increased by 47% in rats fed ethanol, but it is not clear whether this local increase is associated with the observed enhancement of carcinogenesis.
Obe and colleagues reported that acetaldehyde, the first metabolite of ethanol, induces sister chromatid exchanges (SCEs) in cells grown in tissue culture (Obe and Beck, 1979; Obe and Ristow, 1977) and concluded that there is an elevation of chromosome aberrations in alcoholics (Obe and Ristow, 1979). Alcohol may also inhibit the capacity of cells to repair carcinogen-induced DNA damage. O6-methylguanine transferase (O6-MeGT) is the enzyme responsible for repairing O6-methylguanine (O6-MeG) and O6-ethylguanine adducts. After 4 weeks on a diet containing
ethanol as 36% of total calories, O6-MeGT activity was reduced by approximately 40% relative to controls. In other experiments in rats, 50 mM of ethanol, a concentration corresponding to blood levels in alcohol abusers, directly inhibited O6-MeGT activity (Farinati et al., 1985b). Even minute amounts of acetaldehyde noticeably inactivate the enzyme (Espina et al., 1988). Since alkylation at the O6 position of guanine is associated with both mutagenesis and carcinogenesis (Kleihues et al., 1979; Lewis and Swenberg, 1980; Newbold et al., 1980), the apparent decrease in O6-MeGT activity in alcohol-fed rats could be a mechanism of cancer induction.
Some studies failed to detect an effect of dietary ethanol in the repair of DMN-induced O6-MeG adducts (Belinsky et al., 1982; Schwarz et al., 1982). In one of these, however, O6-MeG levels were examined only until 4 hours after DMN administration (Schwarz et al., 1982). The differences in experimental results may be due to differences in feeding protocols.
Ethanol ingestion produced overt tissue damage in the mucosa of the stomach (Dinoso et al., 1976; Eastwood and Kirchner, 1974; Gottfried et al., 1978) and the small intestine (Baraona et al., 1974; Perlow et al., 1977). The damage was followed by cell proliferation when the administration of alcohol was stopped (Baraona et al., 1974; Willems et al., 1971). Ethanol also stimulated cell proliferation in the germinative epithelium of the rat esophagus in the absence of overt mucosal damage (Mak et al., 1987). Stimulation of cell replication would sensitize the esophagus to chemical carcinogens.
In addition to the local effects of ethanol, some congeners (nonalcoholic components) in alcoholic beverages may play an etiologic role in the development of cancer. Esophageal cancer has been produced in animals by administering relatively large amounts of nitrosamines, which may occur as congeners in some alcoholic beverages (Lijinsky and Epstein, 1970; Lowenfels, 1974). Ethanol catalyzes the production of nitrosamines from nitrites and secondary amines under conditions present in the upper gastrointestinal tract (Pignatelli et al., 1976).
Alcoholic beverages contain a variety of carcinogens such as polycyclic aromatic hydrocarbons (e.g., phenanthrene, fluoranthrene, benzanthracene, benzopyrene, chrysene) (Masuda et al., 1966). Asbestos fibers derived from filters have been detected in beer, wine, sherry, and vermouth (Bignon et al., 1977; Biles and Emerson, 1968; Cunningham and Pontefract, 1971).
Ethanol consumption combined with vitamin A deficiency increases the incidence of squamous metaplasia of the trachea (Mak et al., 1984). Drugs that induce liver microsomes decrease hepatic vitamin A (Leo et al., 1984). A similar effect was also observed in baboons and rats given ethanol (Sato and Lieber, 1981) and other xenobiotic substances, including carcinogens, that interact with liver microsomes (Innami et al., 1976; Kato et al., 1978; Reddy and Weisburger, 1980). Similar observations have been made in humans. For example, patients with alcoholic liver disease had very low hepatic vitamin A levels at all stages of their disease (Leo and Lieber, 1982).
Retinol can compete with DMN for its activation (presumably to carcinogens) in liver microsomes (Leo et al., 1986b). Lowering hepatic vitamin A by diminishing this inhibition may indirectly favor chemical carcinogenesis. Ethanol also may exert a direct stimulatory effect on cell proliferation independent of vitamin A status (Mak et al., 1987).
A Plummer-Vinson-like syndrome was observed among female patients with oral cancer (Wynder et al., 1957a). Hyperplasia was observed on the skin of riboflavin-deficient mice (Wynder and Chan, 1970).
Vitamin B6 plays an important role in the production of antibody response to various antigens (Axelrod and Trakatellis, 1964). This effect may influence tumor development indirectly by affecting the consequences of exposure to HBV. Wynder (1976) reported that pyridoxine deficiency is associated with enhanced liver tumor formation.
Vitamin E and other antioxidants, such as butylated hydroxytoluene (BHT), propylgallate, and ethoxyquin, have reduced the induction of tumors by certain carcinogens in several target organs (Ulland et al., 1973; Wattenberg, 1972a,b). The protective effect of BHT against chemically induced carcinogenesis may be offset, at least in part, by its potentiation of ethanol-induced vitamin A depletion (Leo et al., 1987b).
Gabrial et al. (1982) reported that zinc deficiency enhanced esophageal tumor induction by methylbenzyl nitrosamine in rats.
Atherosclerotic Cardiovascular Diseases
Hypertension and Stroke
Epidemiologic studies have usually indicated that people who regularly consume on average two drinks or more of alcohol per day (>30 ml of ethanol) have higher mean blood pressure levels and a higher prevalence of hypertension than do people who drink smaller quantities (Criqui, 1987). This association was observed in a representative sample of the U.S. adult population (Gruchow et al., 1985b; Harlan et al., 1984) and in subgroups of the U.S. adult population (Clark et al., 1967; Criqui et al., 1982; D'Alonzo and Pell, 1968; Dyer et al. 1977; Fortmann et al., 1983; Kagan et al., 1981; Kannel and Sorlie, 1974; Klatsky et al., 1977, 1981a,b, 1986; Wallace et al., 1981). It has also been observed in Australia (MacMahon et al., 1984), Finland (Tuomilehto et al., 1984), South Africa (Steyn et al., 1986), France (Cambien et al., 1985), New Zealand (Jackson et al., 1985), Great Britain (Cruickshank et al., 1985; Shaper et al., 1987), Japan (Ueshima et al., 1984a,b), and the Federal Republic of Germany (Cairns et al., 1984).
In a cross-sectional study in Canada, no association was observed between self-reported consumption of alcohol and blood pressure (Coates et al., 1985), but the sample was small and the highest level of consumption was four or more drinks per day. In London, Bulpitt et al. (1987) found no increase in mean blood pressure in subjects consuming less than seven drinks per day. In Italy, Trevisan et al. (1987) found no significant association (i.e., p > .05) between alcohol consumption and blood pressure among 203 schoolchildrena sample in which 50% of the boys and 39% of the girls reported a mean regular alcohol consumption of 57 g/week and 42 g/ week, respectively, i.e., less than one 4-oz drink of table wine per day.
The incidence of hypertension has rarely been studied in prospective epidemiologic studies. Determining when persistent elevation of blood pressure occurs usually cannot be done well in such studies, and the definitions of hypertension are substantially different from those customarily used in treatment programs. After 8 years of follow-up in the Framingham Offspring Study (Garrison et al., 1987), alcohol consumption was associated with risk of hypertension in women but not in men after adjustment for adiposity and other variables. The reason for the difference between men and women is not clear.
In cross-sectional studies, the association between alcohol consumption and blood pressure is weaker in women than in men (e.g., Fortmann et al., 1983; Jackson et al., 1985; MacMahon et al., 1984), perhaps because women consume less alcohol than men or underreport consumption more frequently or because female sex hormones modify the effect. The association apparently is not due to confounding by age, race, or ratio of body weight to height. The shape of the association between abstainers and people who consume 200 to 300 g of alcohol per week is uncertain. Mean blood pressures for light drinkers may be higher, lower, or the same as those in abstainers. See, for instance, the different results obtained for men and women by age in the Lipid Research Clinics (LRC) Prevalence Study (Wallace et al., 1982).
In cross-sectional studies, regular daily consumption of 200 to 300 g of alcohol or more is generally associated with increases in blood pressure and elevated blood pressure is the major risk factor for hemorrhagic stroke and cerebral infarction. Thus, it is reasonable to expect that habitual alcohol consumption is associated with increased risk of stroke.
In the Honolulu Heart Programa prospective study of 8,000 middle-aged men of Japanese ancestryalcohol consumption was positively associated with risk of hemorrhagic stroke but not of thromboembolic stroke (Donahue et al., 1986; Kagan et al., 1980, 1981). Age-adjusted relative risks of hemorrhagic stroke were determined during 12 years of follow-up for men who at entry reportedly consumed 1 to 14, 15 to 39, and 40 or more ounces of alcohol per month (1 to 79, 80 to 214, and 215 or more g of alcohol/week ). In comparison to 2,916 abstainers, their risks were 2.2, 2.9, and 4.7, with 95% confidence intervals of 1.1 to 4.2, 1.4 to 5.9, and 2.4 to 9.5, respectively. After adjustment for hypertension status, cigarette smoking, and other variables in addition to age, the relative risks were 2.3, 2.5, and 2.9all significantly greater than unity. The association appeared stronger for subarachnoid than intracerebral hemorrhage. Corresponding age-adjusted relative risks for thromboembolic stroke were 1.0, 1.3, and 1.3, with 95% confidence intervals of 0.9 to 1.5, 0.9 to 1.4, and 0.9 to 1.7, respectively.
Gordon and Kannel (1983) reported a similar finding for women in the Framingham Studyi.e.,
alcohol consumption was positively associated with risk of hemorrhagic stroke but not with thromboembolic stroke, at least in univariate analysesbut they found no association with either category of stroke for men. In a later paper, however, Friedman and Kimball (1986) reported that the data on alcohol consumption used in those earlier studies were seriously faulty, so it is unclear what weight should be given to the reported findings.
Case-comparison studies indicate that recent drinking, particularly heavy drinking (e.g., more than 300 g/week), is associated with increased risk of stroke (Gill et al., 1986; Gorelick et al., 1987; Taylor et al., 1984; von Arbin et al., 1985). Gorelick et al. (1987) concluded that the association is probably due to confounding effects of cigarette smoking, but this has not been established.
In summary, the epidemiologic evidence is generally consistent with the hypothesis that chronic alcohol consumption is associated with increased blood pressure and with increased risk of hemorrhagic stroke but not of cerebral infarction. The latter association appears to be independent of blood pressure. These associations are clearly present at levels of 200 to 300 g of alcohol per week. The shape of the dose-response curves is uncertain, but results from the Honolulu Heart Program indicate an increased risk of stroke even at lower levels of consumption. The evidence also supports the hypothesis that recent heavy alcohol consumption is associated with increased risk of stroke due to cerebral infarction as well as hemorrhage.
In humans, ethanol consumption consistently results in hyperlipidemia. Serum triglyceride concentrations increase the most due to elevation of very low-density lipoproteins (VLDLs) and chylomicrons, but there is also some elevation of serum cholesterol levels. Upon alcohol withdrawal, triglycerides decrease more rapidly than cholesterol and phospholipids. Postprandial hyperlipidemia was greatly exaggerated by fat-containing meals (Wilson et al., 1970). When 300 g of alcohol were administered daily to humans for several weeks, the initial severalfold increase in triglycerides gradually returned to normal (Lieber et al., 1963). Hyperlipidemia is usually absent with severe liver injury (e.g., cirrhosis), whereas hypolipidemia may result (Borowsky et al., 1980; Guisard et al., 1971; Marzo et al., 1970). In hospitalized alcoholics, serum total cholesterol was not significantly increased (Böttiger et al., 1976). However, in approximately 30% of alcoholics seeking medical attention (Johansson and Laurell, 1969), and in 86% of patients after a recent drinking bout (Johansson and Medhus, 1974), plasma high-density lipoproteins (HDL) were increased but returned to normal after about 2 weeks of abstinence (Devenyi et al., 1980; Johansson and Medhus, 1974). The rise in HDL associated with alcohol has been demonstrated experimentally in rats (Baraona and Lieber, 1970; Baraona et al., 1983). It also has been observed in teenagers (Glueck et al., 1981) and in both older and younger men (Barrett-Connor and Suarez, 1982), but only in inactive mennot in runners whose HDL levels were already increased (Hartung et al., 1983).
Alcohol intake was positively associated in cross-sectional epidemiologic studies with blood levels of HDL cholesterol in the United States (Barrett-Connor and Suarez, 1982; Castelli et al., 1977; Donahue et al., 1986; Gordon et al., 1981), France (Jacqueson et al., 1983), Japan (Chiba et al., 1983), and Norway (Brenn, 1986). In samples of Chinese men in Shanghai matched for age, occupation, and body weight, mean HDL cholesterol was slightly higher (60.2 mg/dl) for those who consumed 6 to 30 g of alcohol per day than in those who abstained (58.5 mg/dl), but the difference was not statistically significant (Chen et al., 1983). Alcohol intake was also positively associated with serum levels of apolipoprotein AI (Phillips et al., 1982) and of both Apo AI and AII (Camargo et al., 1985; Donahue et al., 1986; Fraser et al., 1983; Poynard et al., 1986). The increase in HDL after alcohol consumption involved HDL2 (Ekman et al., 1981; Taskinen et al., 1982, 1985). These observations were made in people whose alcohol intake was relatively high. After one 40-g dose of ethanol (equivalent to 4 oz of 86-proof beverage), there was a transient increase in both HDL2 and HDL3 (Goldberg et al., 1984). Haskell et al. (1984) reported that a moderate dose12 to 51 g (0.5 to 2.2 oz) of ethanol per dayraised levels of HDL3 but not HDL2, and that upon abstention, levels of HLD3, but not HDL2, decreased (Haskell et al., 1984). The relationship between alcohol and HDL3 levels at these alcohol intakes was confirmed by two more recent studies (Haffner et al;, 1985; Williams et al., 1985). Williams et al. (1985) reported a correlation between dietary components, such as alcohol and starch, and HDL3 (but not HDL2). With progression of alcoholic liver injury, the HDL fractions decreased and abnormal lipopro-
teins appeared in the blood (Borowsky et al., 1980; Denvenyi et al., 1980; Poynard et al., 1986; Sabesin et al., 1977).
There is some evidence for an inverse association of alcohol intake with the level of low-density lipoproteins (LDL) (Castelli et al., 1977; Hulley and Gordon, 1981). In the LRC Coronary Primary Prevention Trial, change in alcohol intake was associated inversely with change in LDL cholesterol levels among men in the placebo group after adjustment for change in body mass index and dietary lipids (Glueck et al., 1986).
Coronary Heart Disease
Since LDL levels are positively associated with risk of coronary heart disease (CHD) and HDL levels are inversely associated with risk of CHD, the results described above imply that alcohol consumption should be inversely associated with risk of CHD. Investigation of this hypothesis is complicated, however, by the substantial difficulties involved in assessing alcohol intake in population-based studies. Studies based solely on 24-hour recalls, e.g., the Puerto Rico Heart Program (Kittner et al., 1983), have not been included here because a large proportion of drinkers was misclassified as nondrinkers. Studies that did not describe results in sufficient detail, e.g., the London Busmen Study (Morris et al., 1966), were also excluded.
Investigation of this hypothesis has been complicated further by the positive correlations of alcohol with the number of cigarettes smoked (e.g., Friedman and Kimball, 1986), by the level of blood pressure (discussed above), by the many other effects of alcohol on the cardiovascular system, and by the associations of alcohol with risk of death from some cancers, trauma, cirrhosis, and other causes.
Current interest in alcohol and CHD risk began with the observation of Klatsky et al. (1974) that the percentage of teetotalers was larger (32.4%) in a group of 405 patients with first myocardial infarction than in a comparison group (24.7%) matched for 10 coronary risk factors. Since then, the association has been investigated in a number of cohort studies, most of which indicate that middle-aged men who report that they abstain from alcohol have a somewhat higher risk of CHD than those who regularly consume less than 100 g of alcohol per week. These studies include the Honolulu Heart Program (Blackwelder et al., 1980; Kagan et al., 1981; Yano et al., 1977, 1984), the Whitehall Study of British civil servants (Marmot et al., 1981), the Western Electric Study (Dyer et al., 1977), the urban sample from the Yugoslavia Cardiovascular Disease Study (Kozarevic et al., 1982), the Busselton Study (Cullen et al., 1982), the Albany Study of New York civil servants (Gordon and Doyle, 1985), and the British Regional Heart Study (Shaper et al., 1987). In some studies, such as the Western Electric Study and the British Regional Heart Study, the difference was small and not statistically significant, but in several others (e.g., Friedman and Kimball, 1986; Kozarevic et al., 1982; Yano et al., 1984), the association was highly significant and showed a dose response after adjustment for coronary risk factors such as cigarette smoking, serum cholesterol, and blood pressure.
An especially important aspect of the Honolulu Heart Program is its large number of lifetime abstainers (2,744), which provides a stable base against which to compare the effects in 4,026 current drinkers, who were categorized into four groups of about 1,000 men according to usual amount consumed: 1 to 6, 7 to 15, 16 to 39, and 40 or more ounces of alcohol per month (i.e., 1 to 36, 37 to 83, 84 to 209, and 210 or more g/week) (Yano et al., 1977). The 6-year age-adjusted incidence rates of CHD (coronary death, myocardial infarction, coronary insufficiency, and angina pectoris) were 46 per 1,000 for abstainers and 41, 31, 27, and 21 per 1,000 for the four drinking groups in order of increased consumption. The rate for 821 former drinkers was 56 per 1,000. The association was not specific to any particular type of alcoholic beverage, but was noted for wine, beer, and spirits separately. Similar results were obtained in population-based case-comparison studies (Hennekens et al., 1978, 1979; Klatsky et al., 1986; Scragg et al., 1987; Siscovick et al., 1986).
A subsequent report from the Honolulu Heart Program (Kagan et al., 1981) indicated that risk of CHD death was higher in men consuming 60 oz of alcohol or more per month (315 g/week) than in men consuming 40 to 59 oz/month. An increased risk of CHD among heavy drinkers was also observed in the Albany Study (Gordon and Doyle, 1985), in the Western Electric Study (Dyer et al., 1977), and among nonsmokers in the Framingham Study (Friedman and Kimball, 1986). These groups were usually small and the differences not statistically significant. ''Problem" drinking, history of inebriation, and registration with temperance boards have also been associated with increased risk of CHD, coronary death, or sudden coronary death (Dyer et al., 1977; Kozarevic et al.,
1983; Pell and D'Alonzo, 1973; Poikolainen, 1983; Wilhelmsen et al., 1973).
There are few data on the elderly. In a population-based sample of people age 66 years or older (62% females) in Massachusetts, Colditz et al. (1985) observed that the age-adjusted relative risks of CHD death during 5 years of follow-up associated with consuming 0.1 to 8.9, 9 to 34, and >34 g of alcohol per day were 0.3, 0.6, and 1.3, respectively, in comparison to abstainers. The corresponding 95% confidence intervals for the relative risks were 0.2 to 0.8, 0.3 to 1.7, and 0.3 to 4.8.
There are also some data on women. In the Framingham Study (Friedman and Kimball, 1986), a U-shaped association was observed for women smokers, but the trend was not statistically significant. No association was apparent for nonsmoking women. However, statistically significant inverse associations between alcohol consumption and CHD risk were observed among women in at least three case-comparison studies (La Vecchia et al., 1987; Ross et al., 1981; Scragg et al., 1987).
Some inconsistencies have also been observed. The Yugoslavia Cardiovascular Disease Study selected samples of men from two rural areas and two urban areas. The association between alcohol consumption and CHD risk differed greatly among the areas. A strong statistically significant inverse association was observed in the urban areas; a slight negative association was observed in one rural area and a slight positive association in the other, but neither was statistically significant. The rural samples were characterized by low levels of serum cholesterol (186 mg/dl) as compared to 214 mg/dl for the two urban samples. This circumstance might modify an association between alcohol consumption and CHD risk, especially if that association resulted from effects of alcohol on concentrations of blood lipids.
In the Framingham Study (Friedman and Kimball, 1986), the association of alcohol with 24-year risk of coronary death may have been modified by cigarette smoking; no association was apparent for men who smoked less than one pack of cigarettes per day, although an inverse association was observed both for nonsmokers and for heavier smokers. However, it is not clear whether this variation was inconsistent with random sampling error.
In patients undergoing coronary angiography, mean coronary occlusion score was inversely associated with consumption of alcohol (<1, 1 to 6, 6 to 12, 12 to 24, and >24 oz/week) for men as well as women (Anderson et al., 1978; Barboriak et al., 1979a,b). An inverse association between consumption of alcohol and severity of coronary atherosclerosis was observed in one population-based autopsy study (Okumiya et al., 1985), but not in later ones (Reed et al., 1987; Rhoads et al., 1978). In the Rhoads study, however, consumption of alcohol was inversely associated with presence of myocardial scarring (Rhoads et al., 1978).
Some studies indicate that per-capita alcohol consumption is negatively correlated with national CHD death rates (Popham et al., 1983). The contrast between a negative correlation for wine (La Porte et al., 1981; Nanji and French, 1985; St. Leger et al., 1979) and a positive correlation for beer (Nanji and French, 1985), however, suggests that the correlations do not directly reflect causal associations with alcohol per se. In addition, consumption of alcohol among cohorts in the Seven Countries Study was not associated in 15 years of follow up with rates for total mortality (Keys et al., 1986). Cohorts with the highest rates of CHDin Finland, the United States, and the Netherlandsobtained 3 to 5% of calories from alcohol, whereas cohorts with the lowest risksin Japan and Greeceobtained 4 to 8% of their calories from alcohol. In California, CHD death rates among Seventh-Day Adventists, who abstain from both tobacco and alcohol, were 20 to 50% lower than for age-matched groups in the total population of California (Phillips et al., 1978). In the British Regional Heart Study, the proportion of heavy drinkers among 22 communities was positively correlated with CHD mortality (Shaper et al., 1987).
The many biologic, psychological, and social effects of alcohol indicate that no account of the association between alcohol and health would be complete without considering total mortality. A U-shaped association has been observed in many cohorts, e.g., the Honolulu Heart Program (Blackwelder et al., 1980), the Whitehall Study of British civil servants (Marmot et al., 1981), the Western Electric Study (Dyer et al., 1977), the Yugoslavia Cardiovascular Disease Study (Kozarevic et al., 1983), the Framingham Study (Friedman and Kimball, 1986), and the Nutrition Canada Survey (Johansen et al., 1987).
In summary, epidemiologic evidence indicates that people who abstain from alcohollifetime abstainers as well as former drinkershave a somewhat higher risk of CHD than persons who consume 1 to 99 g of alcohol per week, at least in populations with mean serum cholesterol levels over 200 mg/dl. The graded nature of this association, its consistency in many different popula-
tions, and its continued strength after adjustment for potentially confounding factors support the inference that consumption of small amounts of alcoholthat is, 1 to 99 g distributed throughout a weekmay reduce susceptibility to CHD. The mechanism for this has not been determined. Postmortem studies suggest that the effect is not due to an association with severity of coronary atherosclerosis. The evidence also indicates that heavy or so-called problem drinking, e.g., more than 500 g/week, is associated with increased risk of CHD. Moreover, heavy drinking is associated with increased risk of total mortality in many populations. However, the findings in certain religious groups, e.g., Seventh-Day Adventists, indicate that abstaining from alcohol is compatible with low overall risk of CHD. Results from the Seven Countries Study show that populations with moderate per-capita intake, i.e., 3 to 5% of calories from alcohol, may have very low or very high rates of CHD.
Alcohol intake was inversely associated with incidence of intermittent claudication in the Framingham Study, but was not associated with risk of congestive heart failure (Gordon and Kannel, 1983). Segel et al. (1984) described alcoholic cardiomyopathy in people with alcoholism and heart disease. This syndrome is typically found in men ages 30 to 44 years who have been ingesting 30 to 40% of their calories as alcohol for 10 to 15 years and is frequently accompanied by arrhythmias. Coronary artery disease, hypertension, valvular abnormalities, and congenital heart disease must be excluded before this disorder is diagnosed. A recent case-comparison study indicated that consumption of more than 85 g of alcohol per day, regardless of type of beverage, was a strong risk factor for dilated cardiomyopathy (Komajda et al., 1986).
Hyperglycemia and Diabetes
In large population studies, alcohol intake has been correlated with hyperglycemia (Gerard et al. 1977). Aside from patients with chronic pancreatitis and endocrine (insulin) insufficiency, there is no ready explanation for this association. Impairment of glucose tolerance has been suspected (Phillips and Safrit, 1971; Rehfield et al., 1973), but is difficult to prove, because the elevated insulin levels that accompany alcohol intake could reflect insulin resistance due to alcohol or the augmentation of insulin release, which alcohol itself causes (Dornhorst and Ouyang, 1971; Metz et al. 1969; Nikkilä and Taskinen, 1975). Insulin resistance caused by alcohol has recently been demonstrated in healthy subjects by measuring glucose utilization with the insulin clamp technique during glucose infusions at steady blood glucose and insulin levels (Yki-Järvinen and Nikkilä, 1985).
In animals and humans, administration of large doses of alcohol after meals results in hyperglycemia (Forsander et al., 1958; Krusius et al., 1958; Matunaga, 1942), which is caused by the release of glucose from the glycogen reserves of the liver into the blood and is mediated mostly by the adrenal medulla and the sympathetic nervous system (Ammon and Estler, 1968; Matunaga, 1942). Decreased peripheral utilization of glucose may also contribute to the hyperglycemia (Lochner et al., 1967).
After eating, when liver glycogen is abundant, glycogenolysis maintains blood glucose levels. In the fasting state, hypoglycemia following alcohol administration is a normal reaction in humans and in laboratory animals (Field et al., 1963; Freinkel et al., 1965). Hypoglycemia results from decreased reserves of hepatic glycogen and inhibition of hepatic gluconeogenesis from various precursors as a consequence of the increased ratio of NADH to NAD (Krebs et al., 1969). Glucogenesis from amino acids and the formation of glucose from glycerol, lactate, and galactose are slowed down by concomitant metabolism of alcohol (Krebs et al., 1969; Madison et al., 1967). The increase in the ratio of NADH to NAD due to hepatic metabolism of alcohol is partly responsible for these metabolic changes. Changes in the activity of enzymes involved in gluconeogenesis have also been described (Duruibe and Tejwani, 1981; Stifel et al., 1976). Hypoglycemia is an important complication of acute alcohol abuse and may be responsible for some of the unexplained sudden deaths resulting from acute alcoholic intoxication. A prompt diagnosis and initiation of therapy is mandatory in view of the reported mortality rate of 11% in adults and 25% in children (Madison et al., 1967). Hypoglycemia may be present when an alcohol drinker exhibits altered mental state even when fed, especially in children. In clinical practice, however, severe alcoholic hypoglycemia is uncommon.
In several conditions, refractiveness to alcohol-induced hypoglycemia can be demonstrated: in nondiabetic obese subjects (Arky et al., 1968), in some alcoholics with a diabetic serum glucose pattern (Hed and Nygren, 1968), and in subjects undergoing steroid therapy (Arky and Freinkel, 1966). Refractiveness has also been demonstrated in chronic malnourished alcoholics (Salaspuro, 1971a,b). This refractiveness may be due to the attenuation of alcohol-induced hepatic redox changes after chronic alcohol consumption (Salaspuro et al., 1981). Alcohol-induced hypoglycemia can also be suppressed by 4-methylpyrazole (an alcohol dehydrogenase inhibitor) (Salaspuro et al., 1977).
Excessive drinking of alcoholic beverages is associated with acute gouty arthritis (Newcombe, 1972). The hyperuricemia that accompanies bouts of intense alcohol intake occurs in patients without known disorders of uric acid metabolism or renal function (Lieber et al., 1962). An important mechanism leading to hyperuricemia is decreased urinary excretion of uric acid secondary to elevated serum lactate. Alcoholic hyperuricemia can be readily differentiated from the primary variety because of its reversibility upon discontinuation of alcohol use. Alcohol-associated ketosis or starvation may also further promote hyperuricemia (MacLachlan and Rodan, 1967).
An increase in urate production, partly explained by an increase in adenosine nucleotide turnover, caused hyperuricemia in volunteers with gout (Faller and Fox, 1982). Urinary urate clearance was increased, and levels of urinary urate and oxypurines were higher. This effect was observed at serum alcohol levels lower than those in lactate-related renal hyperuricemia and those usually seen in patients with alcohol-related hyperuricemia. The purine content (guanosine) of some beers may also contribute to hyperuricemia and gout in alcoholic subjects (Gibson et al., 1984).
Chronic Renal Disease
Altered renal function in alcoholics with liver disease is attributable primarily to impaired hepatic function (hepatorenal syndrome). Since the majority of patients with liver disease and associated renal dysfunction in the United States are alcoholics (Epstein, 1985a,b, 1986, 1987a,b), the alterations in renal function may be the effects of alcohol.
Most alcoholics with mild liver disease have enlarged kidneys at autopsy, and rats given ethanol develop morphological changes and increased lipid accumulation in the kidneys. Alcohol has been proposed both to induce renal sodium retention and to provoke natriuresis (Kalbfleisch et al., 1963; Nicholson and Taylor, 1938; Ogata et al., 1968). Certain conditions (such as degree of hydration or volume status) determine the response. This area requires additional study.
Ethanol also modulates renin-angiotensin responsiveness in humans. These effects vary with the amount of ethanol administered (Linkola et al., 1979). Alcohol can also render the patients susceptible to acute renal failure through several mechanisms, including rhabdomyolysis and volume contraction (Epstein, in press).
Chronic Liver Disease
Mortality And Prevalence
Most cases of cirrhosis are due to alcohol consumption (Lelbach, 1975; Martini and Bode, 1970). The role of alcohol in liver cirrhosis is more important in North and South America than in Europe (66 and 42%, respectively). In Asia its contribution is only 11% (Lelbach, 1975), although this appears to be rising. Cirrhosis is the third leading cause of death for those 25 to 64 years of age in New York City (Department of Health, City of New York, 1984).
The progression to more severe liver injury is accelerated in women (Rankin, 1977). Wilkinson et al. (1969) found that women were more susceptible than men to alcoholic cirrhosis. In more recent studies, the prevalence of chronic advanced liver disease was higher among women than men with a similar history of alcohol abuse (Maier et al., 1979; Morgan and Sherlock, 1977; Nakamura et al., 1979). Studies by Pequignot et al. (1974, 1978) show that daily intake of alcohol as low as 40 g by men and 20 g by women resulted in an increased incidence of cirrhosis in a well-nourished population.
Relation Of Liver Disease To Alcohol Consumption
Despite the high prevalence of alcoholism and cirrhosis throughout the world, the incidence of cirrhosis among alcoholics is low. Autopsies of alcoholics show that the prevalence of cirrhosis is approximately 18%. In liver biopsies of alcoholics, the range was found to be 17 to 31% (Leevy, 1968; Lelbach, 1966, 1967). Alcoholic cirrhosis is correlated both with the magnitude and the duration of alcohol consumption. Pequignot (1958) and Pequignot et al. (1974) estimated that the average
cirrhogenic alcohol consumption is 180 g of ethanol per day consumed regularly for approximately 25 years; the risk is increased five times at a level of consumption between 80 and 160 g/day and 25 times if daily ethanol consumption exceeds 160 g. A close correlation exists between per-capita alcohol consumption and cirrhosis mortality (Jolliffe and Jellinek, 1941; Lelbach, 1976; Schmidt, 1975, 1977).
Role of Nutritional Factors in Alcoholic Liver Injury
On the basis of some animal experiments, it was believed until 20 years ago that liver disease among alcoholics was due exclusively to malnutrition and not to direct toxic effects of alcohol itself. Alcoholics undoubtedly suffer from malnutrition for a variety of reasons (Lieber, 1988). Alcohol has a high caloric value, but alcoholic beverages are usually devoid of minerals, vitamins, and proteins. Because alcohol may provide a large portion of the daily caloric intake, high alcohol intake may result in a decreased intake of other nutrients, and maldigestion and malabsorption may contribute to malnutrition. During the past 20 years, however, experiments in animals have shown that ethanol can also affect the liver independently of malnutrition.
The culmination of these studies was the reproduction of the spectrum of alcoholic liver disease, including cirrhosis, in baboons chronically fed a liquid diet containing alcohol and a sufficient amount of protein and other nutrients (Lieber and DeCarli, 1974; Lieber et al., 1975; Popper and Lieber, 1980). In order to quench their thirst or satisfy their hunger, the animals had to ingest the alcohol. The amount of ethanol consumed by baboons was increased to 50% of total energy, and by rats to 36%proportions comparable to heavy alcohol intake by humans. Isocaloric replacement of sucrose or other carbohydrates by ethanol produced a progressive increase in hepatic lipid content during the first month of an experiment in rats (Lieber et al., 1963, 1965). Fatty liver, however, did not develop when ethanol intake was decreased from 36 to 20% of the total dietary energy. It has not been possible to produce more advanced alcohol-induced liver injury in rats because of the short life and lower alcohol intake of the rat compared to the baboon.
Animal experiments and epidemiologic studies demonstrate that ethanol plays a major role in the pathogenesis of alcoholic liver disease. Multiple and often complex nutrient abnormalities in human alcoholics, however, may contribute to such liver disease and many of its complications.
The deleterious effect of alcohol on the liver has also been confirmed in controlled studies with volunteers in metabolic ward studies. Morphologically and biochemically, an increase in hepatic lipid was demonstrated when ethanol was given either as a supplement or as an isocaloric substitute for carbohydrates together with an otherwise nutritionally adequate diet. Hepatic steatosis was produced, even with a high-protein, vitamin-supplemented diet and was accompanied by major ultrastructural liver changes and by elevations of hepatic transaminases in blood (Lane and Lieber, 1966; Lieber et al., 1963, 1965).
If dietary fat was decreased from 35 to 25% of total calories, hepatic triglyceride accumulation greatly decreased (Lieber and DeCarli, 1970). Replacement of dietary triglycerides containing long-chain fatty acids by fat containing medium-chain fatty acids markedly reduced the capacity of alcohol to produce fatty liver in rats (Lieber et al., 1967).
In rats and in humans, protein deficiency may result in decreased hepatic alcohol dehydrogenase activity (Bode et al., 1971), which in turn prevents some acute metabolic effects of alcohol such as the inhibition of the citric acid cycle, the increase in the ratio of lactate to pyruvate (Salaspuro and Mäenpää, 1966), fasting hypoglycemia (Salaspuro, 1971a,b), and the inhibition of galactose elimination (Salaspuro and Kesäniemi, 1973). However, chronic alcohol consumption combined with a protein- and lipotropic-deficient diet led to more pronounced hepatic steatosis than either deficiency alone (Klatskin et al., 1954; Lieber et al., 1969). In other studies, alcohol consumption along with protein deficiency greatly increased the mortality of laboratory animals without demonstrable differences in hepatic fat accumulation (Best et al., 1949; Koch et al., 1968; Porta and Gomez-Dumm, 1968).
Deficiencies in the lipotropic factors (choline and methionine) produced fatty liver and cirrhosis in growing rats (Best et al., 1949), but primates were less susceptible to protein and lipotrope deficiency than were rodents (Hoffbauer and Zaki, 1965). Moreover, fatty liver, as well as fibrosis (including cirrhosis) with major ultrastructural changes (Arai et al., 1984), developed in baboons (Papio papio or Papio hamadryas) despite liberal supplementation with methionine (Lieber and DeCarli, 1974). The capacity of ethanol to produce fatty liver, despite choline and methionine supple-
mentation, was also confirmed in four well-fed macaques (Macaca radiata) by Mezey et al. (1983); but they failed to produce fibrosis. They postulated that ethanol-produced fibrosis in the baboon might be at least partly due to the lower choline content of the baboon diet. However, Rogers et al. (1981), who fed these animals the exact diet given to the baboon, failed to produce cirrhosis or fibrosis in alcohol-fed rhesus monkeys (Macaca mulatta). The amount of lipotrope fed to the baboons was not low enough to account for the absence of cirrhosis. Additional choline failed to prevent the development of fibrosis but caused some liver toxicity (Lieber et al., 1985). Thus, the failure of Mezey et al. (1983) to produce fibrosis in the macaques was probably not due to the higher choline content of the diet, but may have been due to a lower alcohol intake. Because macaques are smaller than baboons and have a higher metabolic rate, the same amount of alcohol does not produce comparable effects in the two species. Furthermore, clinical data from patients with alcoholic liver disease as well as experiments in volunteers have shown the ineffectiveness of lipotropic factors in the prevention of alcohol-associated liver injury (Olson, 1964; Rubin and Lieber, 1968).
Diseases of the Nervous System
The Wernicke-Korsakoff syndrome includes two diseases: Wernicke's encephalopathy, characterized by weakness of eye movements, gait disturbance, and confusion, and Korsakoff's psychosis, a permanent brain disorder characterized by marked abnormalities in cognitive function, particularly the inability to learn new information or to remember recent events. Although severe alcoholics may have both diseases, it is not certain if all Korsakoff patients go through a Wernicke phase (NIAAA, 1987). Avitaminosis, especially of thiamin, is widely regarded as the primary cause of this syndrome, but a direct toxic effect of alcohol has also been implicated in its etiology (NIAAA, 1987). Variations in clinical manifestation, and the finding that most patients with thiamin deficiency do not have the syndrome, suggest that genetic variations may be involved in the etiology of this syndrome (Blass and Gibson, 1977). Since alcohol inhibits the active transfer and not the passive transport of thiamin, it has been postulated that thiamin supplementation in amounts larger than the Recommended Dietary Allowance (RDA) may overcome the thiamin malabsorption caused by alcohol (Lieber, 1983, 1988).
Alcoholic Peripheral Neuropathy
Alcoholic peripheral neuropathy is a mixed motor sensory neuropathy affecting the distal regions, primarily the lower extremities. It occurs in more than 80% of patients with severe neurological disorders, such as Wernicke's encephalopathy (Victor et al., 1971). Recovery from alcoholic peripheral neuropathy is slow and often incomplete. As in the Wernicke-Korsakoff syndrome, thiamin deficiency is regarded as the primary cause of this neuropathy, although the direct toxic effect of alcohol may also play a role (Behse and Buchthal, 1977).
Alcoholic dementia is a cognitive dysfunction associated with alcoholism. It is attributed to a combination of thiamin deficiency and a direct toxic effect of alcohol on the brain (Nakada and Knight, 1984).
Fetal Alcohol Syndrome (FAS)
The deleterious effects of maternal alcoholism on the fetus have been known for centuries. Only since the late 1960s and early 1970s, however, following reports from France (Lemoine et al., 1968) and the United States (Jones and Smith, 1973), has there been wide recognition of the fetal alcohol syndrome (FAS)a distinct pattern of physical and behavioral anomalies characterized by craniofacial, limb, and cardiovascular defects, as well as persistent growth deficiency and developmental delay. The prevalence of FAS varies with the geographic location and the population under study, but a commonly accepted general estimate is 1 to 3 cases per 1,000 live births (NIAAA, 1987).
Epidemiologic surveys show a high prevalence of FAS in some American Indian populations (May et al., 1983), in people from lower socioeconomic backgrounds, and in children born to alcoholic mothers. These results suggest that alcohol abuse may be higher among these subgroups (Streissguth, 1978). Only a small percentage of women who drink abusively during pregnancy deliver babies with FAS-related birth defects, indicating that other factors modify the impact of alcohol on prenatal development. The most relevant factors are persistent drinking during pregnancy, history of excessive alcohol consumption, number of previous deliveries, and race (Sokol et al., 1986). Such factors can increase the probability of FAS by
50%. Alcohol-related neurological and biologic effects have been observed less frequently in subjects with moderate levels of alcohol consumption (NIAAA, 1987). Mills et al. (1984) reported lower than average birth weights for infants whose mothers consumed just one drink a day during pregnancy.
FAS is presently attributed to the toxic effect of alcohol or its metabolites. In one study of pregnant women, it was observed that alcoholics had lower levels of zinc in their serum and fetal cord blood than did nonalcoholic controls (Flynn et al., 1981). This observation suggests that nutritional factors may play a role in the development of FAS.
Contribution to Nutrient Deficiencies
The potential for alcoholism to undermine nutritional status is generally accepted. Iber (1971) estimated that 20,000 alcoholics were suffering major illnesses due to malnutrition in the United States each year, accounting for 7.5 million days of hospitalization. Patients admitted to hospitals for medical complications of alcoholism had inadequate dietary protein (Patek et al., 1975) as well as signs of protein malnutrition (Iber, 1971; Mendenhall et al., 1985). In hospitalized patients, anthropometric measurements indicated impaired nutrition; for example, height-to-weight ratio was lower (Morgan, 1981), muscle mass estimated by creatinine/height index was reduced (Mendenhall et al., 1984; Morgan, 1981), and triceps skinfolds were thinner (Mendenhall et al., 1984; Morgan, 1981; Simko et al., 1982). Continued drinking was associated with weight loss, whereas abstinence was associated with weight gain (World et al., 1984a,b), in patients with and without liver disease (Simko et al., 1982).
Many patients who drink to excess are clearly not malnourished or are malnourished to a lesser extent than those hospitalized for medical problems. Patients with moderate alcohol intake (Bebb et al., 1971), and even those admitted for alcohol rehabilitation (Neville et al., 1968) rather than for medical problems, did not differ nutritionally from controls (matched for socioeconomic and health history), except that alcoholic women had a lower level of thiamin saturation (Neville et al., 1968). When calories from alcohol exceeded 30%, there were large decreases in intakes of protein and vitamins A and C; an intake of thiamin below the RDA (Gruchow et al., 1985a,b); and appreciably lower intakes of calcium, iron, and fiber (Hillers and Massey, 1985). Thiamin levels in the organs are maintained in laboratory animals (Shaw et al., 1981) and in well-nourished alcoholics who take in average or greater-than-average amounts of thiamin (Hoyumpa, 1983). Nevertheless, in the United States, profound effects of thiamin deficiency are very often present in alcoholics and are responsible for the Wernicke-Korsakoff syndrome, beriberi, heart disease, and possibly polyneuropathy.
The folic acid status of alcoholics is compromised when the intensity of drinking increases. Among alcoholics, 38% had low serum folate levels and 18% had low red blood cell folate levels (World et al., 1984b). Malnourished alcoholics without liver disease absorbed folic acid less efficiently than did their better-nourished counterparts (Halsted et al., 1971). In well-nourished alcoholics, folic acid deficiency was only a rare cause of anemia (Eichner et al., 1972).
Normal serum B12 levels were common in alcoholic patients with folate deficiency, either with cirrhosis (Herbert et al., 1963; Klipstein and Lindenbaum, 1965) or without cirrhosis (Halsted et al., 1971; Racusen and Krawitt, 1977). The low incidence of clinically significant B12 deficiency is probably due to the large vitamin stores in the body and the reserve capacity for absorption. Alcohol ingestion caused reduced absorption in volunteers after several weeks (as measured by the Schilling test) (Lindenbaum and Lieber, 1975).
The incidence of pyridoxine deficiency, as measured by low plasma pyridoxal-5'-phosphate (PLP), was more than 50% in alcoholics without abnormal hematologic indices of abnormal liver function (Lumeng and Li, 1974). Inadequate intake may not be the only factor contributing to low plasma levels of PLP. PLP is more rapidly destroyed in erythrocytes in the presence of acetaldehyde, the first product of ethanol oxidation, perhaps by displacement of PLP from protein and its exposure to phosphatase (Lumeng, 1978; Lumeng and Li, 1974). Riboflavin deficiency is usually encountered when there is a general lack of vitamin B intake. Its exact incidence in the alcoholic patient is not known, but evidence of deficiency was found in 50% of a small group of alcoholics with medical complications severe enough to warrant hospitalization (Rosenthal et al., 1973).
Vitamin A ingestion was not considerably below normal in Americans who consumed up to a mean of 400 kcal of alcohol per day (or less than 20% of total calories) (Gruchow et al., 1985a), since the vitamin A density of the nonalcoholic portion of the diet approximated that eaten by control populations. Americans consuming 24 to 28% of their
energy as alcohol ingest 75% of the RDA for vitamin A (Hillers and Massey, 1985). Severe alcoholism, in which 50% or more of energy intake is derived from alcohol, is probably associated with even less vitamin A intake in the United States, as shown for wine drinkers in Chile, where consumption of 150 g of alcohol daily was associated with an intake of only 25% of the RDA for vitamin A (Bunout et al., 1983). Elderly American men who consume alcohol regularly had lower vitamin A intakes compared to their abstinent counterparts (Barboriak et al., 1978).
Althausen et al. (1960) reported that alcohol inhibited vitamin A absorption in humans. Vitamin A absorption is reduced even further in the presence of fat malabsorption due to chronic alcoholic pancreatis. In humans with alcoholic liver disease, hepatic vitamin A levels progressively decreased with increasing severity of liver injury (Leo and Lieber, 1982). Enhancement of hepatic vitamin A degradation due to alcohol consumption is a likely explanation for vitamin A depletion. The metabolism of retinoic acid to 4-hydroxy and 4-oxoretinoic acid and other polar metabolites occurs through the action of microsomal enzymes, which are inducible by ethanol consumption (Sato and Lieber, 1982), but they probably do not have sufficient activity to be largely responsible for depleting vitamin A stores.
Newly discovered microsomal pathways for oxidation of retinol to polar metabolites (Leo and Lieber, 1985) and to retinol (Leo et al., 1987a) are also inducible by alcohol (Leo et al., 1986a) and are more likely mechanisms for hepatic vitamin A depletion. In addition, alcohol promotes vitamin A mobilization from the liver (Leo et al., 1986a, 1988). The clinical consequences of altered vitamin A status include the increased incidence of night blindness (xerophthalmia) due to lowered tissue vitamin A levels. Abnormal dark adaptation occurred in 15% of alcoholics without cirrhosis and in 50% of alcoholics with cirrhosis (Bonjour, 1981).
Alcoholics also have illnesses related to abnormalities of calcium, phosphorus, and vitamin D homeostasis as well as decreased bone density (Saville, 1965), decreased bone mass (Gascon-Barré, 1985), increased susceptibility to fractures (Nilsson, 1970), and increased osteonecrosis (Solomon, 1973). Low blood levels of calcium, phosphorus, magnesium, and 25-hydroxy vitamin D have also been reported in alcoholics (Gascon-Barré, 1985). Vitamin D deficiency in alcoholic liver disease probably is due to decreased vitamin D substrate as a result of poor dietary intake, malabsorption due to cholestasis, pancreatic insufficiency, diminished sunlight, or all these conditions.
Vitamin E deficiency is not a recognized complication of alcoholism. In some studies, however, abnormally low blood levels of vitamin E have been reported in alcoholics (Losowsky and Leonard, 1967; Myerson, 1968).
The diet of many Americans is marginal in zinc (Sandstead, 1973), and alcoholics probably are among those with marginal intake. For example, zinc absorption was low in alcoholic cirrhotics, but not in patients with cirrhosis from other causes (Valberg et al., 1985), and alcoholics with (Vallee et al., 1956) and without (Sullivan and Lankford, 1962) cirrhosis had hyperzincuria and reduced zinc levels. Some instances of night blindness not fully responsive to vitamin A replacement responded to zinc replacement (Leo et al., 1988).
The evidence suggests that moderate alcohol consumption reduces stress; increases feelings of happiness, euphoria, and conviviality; decreases tension, depression, and self-consciousness; improves certain types of cognitive performance, such as problem solving and short-term memory; improves psychological well-being; and produces other positive effects, such as increases in HDL levels (Baum-Baicker, 1985a,b). On the other hand, alcohol consumption may lead to addiction (Roe, 1979), and it influences the likelihood of virtually all types of injury: almost half of fatally injured drivers, people killed by falls, drowning, assault, and suicides, and a large percentage of adult passengers and pedestrians killed in motor vehicle crashes have blood alcohol levels of 0.1% or higher (NRC, 1985). Moreover, alcohol can have deleterious effects on the fetus. Attempts to prohibit alcohol consumption through taxation and prohibition have always failed, except when they have been based on religious grounds (Heath, 1975). Thus, prudence suggests a lowering of or abstention from alcohol consumption.
Of the estimated 18 million alcoholics in the United States, 7.3 million (or 41%) are considered abusers and 10.6 million (59%) are considered alcohol dependent. Alcohol consumption peaks in the 20- to 40-year age group and decreases with
advancing age. Although more males than females consume alcohol, the percentage of female drinkers is on the rise. The rate of excessive alcohol consumption among blacks and whites in the general U.S. population is similar. American Indians are three times more likely to be heavier drinkers than the general population, but there is wide variation from tribe to tribe.
Hospitalized alcoholics show signs of protein malnutrition. Those who derive more than 30% of their calories from alcohol have decreases in protein intake; lower calcium and iron intakes; intakes less than the RDAs for vitamins A, C, and thiamin; and deficiencies of pyridoxine and riboflavin. Alcoholics also exhibit abnormalities of calcium, phosphorus, and vitamin D homeostasis as well as reduced zinc absorption. Alcohol consumption, however, is not a primary cause of obesity.
There is consistent evidence that alcohol intake increases the risk of cancer of the oral cavity, pharynx, esophagus, and larynx, where alcohol interacts synergistically with tobacco. There is also a consistent association between alcohol intake and primary liver cancer, although it is unclear whether alcohol increases the risk of primary liver cancer in the absence of liver cirrhosis. Associations have also been found between increasing alcohol consumption and cancers of the pancreas, rectum, and breast. At present, however, there is little or no evidence of a causal relationship. Furthermore, alcoholism is associated with (and perhaps promotes) HBV infection, another factor that independently favors the development of hepatocellular carcinoma. The etiologic role of viruses in the pathogenesis of some tumors has been established. It is conceivable that suppression of immune responsiveness may be important in virus-induced tumors such as hepatocellular carcinoma, which has been associated with HVB infections.
Chronic alcohol abuse may contribute to carcinogenesis through a variety of mechanisms, including the induction of microsomal enzymes that activate procarcinogens, effects on DNA metabolism and DNA repair resulting from alkylation, association with virus hepatitis B, general mechanisms of tissue injury and regeneration, alterations of immune responsiveness, contact-related local effects, the effects of congeners, and the impact of nutritional deficiencies.
Among the dietary deficiencies associated with chronic ethanol abuse, lack of retinoids probably plays a prominent role, because vitamin A depletion favors carcinogenesis in a variety of tissues. This effect is magnified in the liver, where ethanol promotes vitamin A depletion even in the presence of vitamin A-rich diets. Hepatic depletion is due to enhanced catabolism and to mobilization of vitamin A from the liver to peripheral tissues where vitamin A content then increases; these effects are exacerbated when severe vitamin A depletion is superimposed on chronic alcohol consumption. Hepatic vitamin A stores are then depleted to a level precluding extensive mobilization; as a result, there is a general lack of vitamin A in hepatic and nonhepatic tissues.
Epidemiologic studies associate chronic alcohol consumption with high blood pressure and increased risk of hemorrhagic stroke; acute consumption is linked with increased risk of stroke due to cerebral infarction and hemorrhage. Heavy drinking is associated with increased risk of CHD, but light and moderate drinking are generally associated with a CHD risk that is lower than that for abstainers.
Alcohol consumption is associated with hyperglycemia in humans and animals. Alcohol-induced hypoglycemia, although rare, has also been reported, as has refractiveness to this state. Excessive alcohol consumption has also been associated with gouty arthritis and with ketosis, with minimal or no acidosis. Alcohol also affects renal function, as shown by enlarged kidneys in autopsied alcoholic patients with mild liver disease, by modulating renin-angiotensin responsiveness and by rendering patients susceptible to renal failure.
Alcohol is a causative factor in fatty liver, alcoholic hepatitis, and cirrhosis. Most cases of liver cirrhosis are caused by alcohol consumption: 66% of the cases in North America, 42% in Europe, and 11% in Asia. Women are more susceptible than men. Liver diseases can be due either to alcohol-induced malnutrition or to the toxic effects of alcohol on the metabolic processes of the liver leading to disorders such as decreased fatty acid oxidation, hyper- or hypoglycemia, alteration of the cytochrome P450-dependent oxidizing system, increased production of acetaldehyde, and possibly a direct effect on the metabolism of collagen leading to cirrhosis.
Alcohol has also been implicated as an etiologic agent in nervous system diseases such as Wernicke-Korsakoff syndrome, alcoholic peripheral neuropathy, and alcoholic dementia. Thiamin deficiency is, however, suspected to be the primary cause of those syndromes. Pregnant women who consume high levels of alcohol develop fetuses with a distinct pattern of physical and behavioral
abnormalities referred to as fetal alcohol syndrome, characterized by a higher incidence of birth defects.
Moderate alcohol consumption is associated with some beneficial effects. It, however, carries the risk of addictiveness and increases the likelihood of virtually all types of injury, suggesting prudence in alcohol consumption and even abstention.
Directions for Research
· Genetic Determinants of Susceptibility to Alcoholism Certain genetic variations in enzymes involved in alcohol metabolism influence susceptibility to alcohol addiction. Other genetic variations determine the susceptibility of target organs, such as the liver, to the deleterious effects of alcohol. Therefore, further research in the following topics is warranted:
Identification of genes or of markers for genes involved in alcohol metabolism to enable the identification of high-risk individuals for intensive preventive efforts.
Elucidation of the structure and function of these genes and their products to permit more rational and effective means of treating alcoholism and its sequelae. This research is now feasible and is likely to be highly productive.
· Effects of Alcohol on Chronic Diseases There is strong evidence that alcohol influences the risk of CHD, hypertension, stroke, osteoporosis, and some types of cancer.
Investigation of the metabolic mechanisms by which alcohol influences the above diseases would be helpful in planning prevention and treatment strategies. There is sufficient knowledge of the physiological and biochemical processes involved in alcohol metabolism and in the pathogenesis of those diseases to make such research feasible and productive.
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