Alcohol 0 probably adequate for most purposes despite the occasional finding of selected nutritional deficiencies. Effect of Alcohol on the Nutritional Status of Nonalcoholics Few investigations have focused on the effects of alcohol on the nutritional status of nonalcoholic persons. In three groups of nonalcoholic individuals who kept a diary of what they ate over a period of 6 to 12 months, 79 percent reported drinking alcoholic beverages during the study (Bebb et al. 1971). Half of these reported consuming alcohol on half or more of the days recorded. For 22 percent of those who drank alcohol, alcohol contributed approximately 10 percent of average daily total calories; for another 23 percent, it contributed from 5 to 10 percent of daily calories. As the proportion of calories from alcohol increased, there was little change in protein intake but a decrease in carbohydrate and fat intake. The overall quality of the diet could not be related to the proportion of energy derived from alcohol. In a recent representative sample of upper-middle-class persons in south- em California, alcohol did not replace calories derived from other nutrients (Jones et al. 1982). Using the 24-hour recall method, the authors recorded that 51 percent of the subjects consumed an average of 30 g or more of alcohol per day. In a group of "moderate drinking" men, who consumed 25 to 49 g of alcohol per day, there was a significantly lower intake of protein, carbohydrate, and fat. Despite a higher energy intake, the drinkers were not more obese than the nondrinkers. Further studies are needed to define the possible effects of mild to moderate alcohol intake on nutrient intake in the general population. If these effects are negligible, as indicated by the two cited studies, public health efforts may be better focused on persons with alcohol abuse or alcoholism problems. Role of Alcohol in Diseases of the Liver Alcohol-related diseases include both the direct toxic effects of alcohol and the indirect effects caused by the nutritional deficiencies found in alco- holics. According to the DSM-III criteria, liver diseases that occur in chronic alcoholics may be found in periodic abusers as well (Task Force on Nomenclature and Statistics 1980). Alcoholic Cirrhosis Research into the etiology of alcoholic cirrhosis has produced many theo- ries of causation, ranging from a strictly nutritional deficiency to a direct toxic effect of alcohol. Until about 20 years ago, it was believed that 651 O Nutrition and Health maintaining normal protein synthesis would allow the liver tissue to return to normal despite continued alcohol ingestion (Leevy 1967), and protein- and vitamin-supplemented diets were recommended for prevention of alcoholic liver disease. In the mid-1960's, a major change in the theory concerning the cause of alcoholic cirrhosis occurred (Lieber 1966). At that time, the calorie-for- calorie substitution of alcohol for carbohydrates in the diets of young nonalcoholic volunteers was shown to produce fatty liver and ultrastruc- tural changes in the liver cells, even though the volunteers' blood alcohol concentration never exceeded 100 mg/lOO ml and the subjects were not malnourished (Rubin and Lieber 1968). This result was consistent with the theory that alcohol produces a direct toxic effect on the liver. The contention that alcohol itself is the primary offender in the develop- ment of cirrhosis was supported by epidemiologic data. The death rate from cirrhosis in the United States decreased in proportion to the reduction in the consumption of alcohol that occurred during Prohibition (Klatskin 1961), and a similar direct relationship between alcohol intake and cirrhosis was observed in France during World War II when wine was rationed and the per capita consumption of wine decreased (Pequignot and Cyralnik 1970). Further evidence to support this contention derives from the obser- vation that countries with the highest per capita alcohol consumption have the highest rate of mortality from cirrhosis (Sherlock 1981). The death rate from cirrhosis in the United States has recently declined (Laforge et al. 1987). The observation that the development of cirrhosis is partly a response to the long-term consumption of large quantities of alcohol (Lelbach 1975) does not explain why cirrhosis develops in only 12 to 15 percent of alco- holics. In addition to the dose of alcohol and duration of consumption, genetic factors or individual differences among people must be involved. The best evidence to date of the direct hepatic toxicity of alcohol has been shown in baboons, where alcoholic liver disease-including fatty liver and cirrhosisdan be produced in about one-third of the experimental animals even though they are consuming a nutritionally adequate diet (Lieber and DeCarli 1974). Despite these studies, the issue of malnutrition in the genesis of alcoholic cirrhosis continues to be raised, especially in the context of the hepatic pathology similar to alcoholic liver disease that occurs in patients who have undergone jejunoileal bypass surgery for obesity (Patek 1979). 652 Alcohol O Alcoholic Hepatitis A relationship between nutritional status and alcoholic hepatitis (alcohol- induced liver inflammation) derives from the Veterans Administration co- operative study that found features of marasmus or kwashiorkor. the clas- sic starvation diseases, among alcoholic men (Mendenhall et al. 1984). The extent of marasmus and kwashiorkor correlated closely with the severity of the liver disease. Interest in the nutritional therapy of alcoholic hepatitis was elicited by the report that parenteral infusions of amino acids reduced the mortality of persons with severe alcoholic hepatitis (Nasrallah and Galambos 1980). Among a group of patients with biopsy-proven alcoholic hepatitis, im- provement (as measured by clinical and biochemical markers) was more rapid in those receiving the amino acid infusion, although no apparent difference in liver pathology remained in the two groups at the end of 1 month of treatment (Diehl et al. 1985). The researchers concluded that the outcome of alcoholic hepatitis is strongly influenced by the metabolic consequences of alcohol consumption and that it is the resolution of these consequences that is most influenced by parenteral amino acid supplemen- tation. The nutritional status of persons with alcoholic hepatitis needs to be recognized and addressed, but unfortunately at present, its role in the etiology and treatment of this condition remains uncertain. Fatty Liver Several mechanisms have been proposed to explain the fatty changes in the liver that occur as a result of alcohol consumption. Oxidation of alcohol results in the production of reducing equivalents, and the acetate from alcohol can be metabolized to acetyl-CoA. This combination results not only in reduced hepatic oxidation of fatty acids but also in increased production of alpha-glycerophosphate, which in turn favors conversion of fatty acids into long-chain fatty acids and triglycerides that can be depos- ited in the liver as fat. In addition, catecholamine release, in response to either intoxicating dosages of alcohol or alcohol withdrawal, can increase the mobilization of fatty acids from muscle and adipose tissue and, there- fore, increase the delivery of fatty acids to the liver. Role of Alcohol in Diseases of the Nervous System Wernicke-Korsakoff's Syndrome Wemicke's encephalopathy is characterized by weakness of eye move- ments, gait disturbance, and confusion, and Korsakoffs psychosis by 653 O Nutrition and Health amnesia, a disordered sense of time, and confabulation. The two conditions probably represent a continuum, and they usually occur together as Wer- nicke-Korsakoff's syndrome. In approximately one-fourth of patients, the memory disturbance is completely reversible. In half of the cases, improve- ment ranges from slight to significant although the memory loss can be incapacitating, but in the remaining one-fourth of the patients, the memory disturbance is completely irreversible (Dreyfus 1979). If Wemicke's en- cephalopathy goes unrecognized, the chances of preventing its progression to Korsakoff's psychosis and resolving its manifestations are reduced. In alcoholics, Wemicke-Korsakoffs syndrome is caused more by thiamin deficiency than by the direct toxic effect of alcohol. The eye manifestations of Wernicke's encephalopathy respond rapidly to thiamin administration, although the associated ataxia and confusion respond more slowly. Brain lesions similar to those found in patients with Wemicke-Korsakoff's syn- drome are found in the brains of animals that are deficient in thiamin (Victor, Adams, and Collins 1971). Alcohol may directly or indirectly affect thiamin intake, absorption, storage, metabolism, and excretion (Hoyumpa 1983). Another possible mechanism includes altered cerebral energy me- tabolism resulting from deficiencies in the function of thiamin-dependent enzymes; these deficits can affect energy production, diminish acet: lcho- line neurotransmission, and impair DNA synthesis (Reuler, Girard, and Cooney 1985). Subclinical thiamin deficiency, as measured by the activity of the thiamin-dependent enzyme erythrocyte transketolase, may occur in as many as one-third of alcoholics suspected of having liver disease (Cami- lo, Morgan, and Sherlock 1981). Because alcohol inhibits active rather than passive transport of thiamin, supplementation of the vitamin in amounts larger than the Recommended Dietary Allowance can overcome the thiamin malabsorption caused by alcohol (Lieber 1983). The variations in clinical presentation and the fact that most persons with thiamin deficiency do not have Wernicke-Korsakoffs syndrome raises the possibility that there may be genetic variants that predispose individuals to its development (Blass and Gibson 1977). For example, a variant of trans- ketolase with a low affinity for the coenzyme thiamin pyrophosphate was found in all of four patients with Wemicke-Korsakoffs syndrome but in none of six control patients. There is considerable evidence that iso- enzymes of human erythrocyte transketolase exist, but the significance of such heterogeneity and its relationship to differential susceptibility to Wernicke-Korsakoffs syndrome has not been determined (Nixon 1984). Because the rate of long-term institutionalization for persons admitted for Korsakoff's psychosis is 30 to 40 percent, some experts have proposed that 6.54 Alcohol Ll thiamin be considered for addition to alcoholic beverages (Centerwall and Criqui 1978). Alcoholic Peripheral Neuropathy Alcoholic peripheral neuropathy, a distal mixed motor sensory net ropathy primarily affecting the lower extremities, is probably the most common neurologic complication of alcoholism, and it occurs in over 80 percent of persons with severe neurologic problems such as Wemicke's encephalopa- thy (Victor, Adams, and Collins 1971). The predominant pathologic abnor- mality is a "dying back" degeneration of nerve axons that affects distal segments of the longest nerve fibers (Behse and Buchthal 1977). Recovery from alcoholic peripheral neuropathy is slow and often incomplete. In the early part of this century, thiamin deficiency was considered to be the cause of alcoholic peripheral neuropathy (Shattuck 1928). That a nutri- tional deficiency plays a role in its development is supported by many factors: the clinical and pathologic features are similar to those seen in beriberi, the classic thiamin deficiency disease; patients with alcoholic peripheral neuropathy have been shown to have deficiencies of thiamin. folic acid, and other B-complex vitamins; improvement may occur with vitamin supplementation; and thiamin deficiency alone can cause a similar type of peripheral neuropathy. Some .vidence suggests that the toxic effects of alcohol alone may cause peripheral nerve damage because some patients with alcoholic neuropathy show no evidence of any nutritional deficiency (Behse and Buchthall977). Other evidence suggests that both diet and alcohol toxicity are at fault. A heavy alcohol intake and a poor diet result in acute axonal degeneration; in persons with chronic neuropathy, a long history of alcohol intake, but a good diet, however, there is little evidence of axonal degeneration and, in fact, considerable evidence of nerve regeneration (Walsh and McLeod 1970). Supplementation with B-complex vitamins and an improvement in overall nutritional status are important in the treatment of this disease, but abstinence from alcohol may be the single most important factor. Alcoholic Dementia The toxic effects of alcohol on the brain have received greater attention since the development of computed tomography (CT). In young alcoholics, cerebral atrophy as measured by CT may be reversed with the cessation of excessive drinking (Ron et al. 1982), but the associated cognitive dysfunc- tion, labeled as alcoholic dementia, may be due in part to nutritional deficiencies. In one study, pathologic examination of alcoholic persons 655 O Nutrition and Health showed changes in the brain consistent with Wernicke's encephalopathy, although clinical signs of the disease were absent (Torvik, Lindboe, and Rogde 1982). The syndrome of alcoholic dementia is also probably due to a combination of thiamin deficiency and the direct toxic effects of alcohol on the brain (Nakada and Knight 1984). Role of Alcohol in Cardiovascular Diseases Alcoholic Cardiomyopathy The adverse effects of alcohol on the heart muscle, or myocardium, have been known since the 1700's when William Withering observed that 10 percent of the patients to whom he administered foxglove (containing digitalis) for heart failure were excessive users of alcohol. Similar observa- tions relating alcohol abuse to heart failure were made by other scientists, such as Steel1 in the late 1800's and Osler in the early 1900's, but these early observations were all but forgotten when beriberi heart disease was de- scribed in thiamin-deficient alcoholics (Weiss and Wilkins 1937). As with many other alcohol-associated conditions, nutritional deficiencies were presumed to be responsible for heart failure in alcoholics, and it was not until the early 1%0's that alcohol was recognized to have a direct toxic effect on the myocardium (Brigden and Robinson 1944). Beriberi heart disease and the congestive cardiomyopathy of alcoholism are now known to be distinctly different entities. The theory that alcoholic cardiomyopathy is caused by the direct toxic effect of alcohol on the myocardium has strong support. The ultrastructural changes seen in the myocardial cells of a person with alcoholic car- diomyopathy, such as fragmentation of myofibrils, clusters of giant mitochondria with distorted membrane folds, dilated sarcoplasmic re- ticulum, and increased glycogen and fat deposits, are similar to those seen in the livers of persons with alcoholic liver disease. Furthermore, thiamin administration and other nutritional therapies alone have produced no benefit in persons with alcoholic cardiomyopathy. The only factor shown to affect recovery significantly is abstinence from alcohol (Demakis et al. 1974). The manner in which alcohol produces its direct toxic effect on cardiac muscle is unclear, although acetaldehyde, the first product of alcohol oxidation, may induce myocardial damage (Schreiber et al. 1972) and has been shown to diminish myocardial protein synthesis (Bing 1978). Changes in cardiac metabolism may also be involved. Alcohol inhibits mitochondri- al respiration and the activity of mitochondrial enzymes in the tricarboxylic 656 Alcohol 0 acid cycle in addition to interfering with mitochondrial calcium binding and uptake. Alcoholics display blood levels of acetaldehyde high enough to inhibit the association of the muscle proteins actin and myosin in vitro and to interfere with mitochondrial protein synthesis (Rubin 1979). Dysrhythmias Another manifestation of the ability of alcohol to produce cardiac toxicity is seen in persons with alcohol-induced dysrhythmia, dubbed "the holiday heart syndrome" because it occurs more frequently around holidays such as New Year's Eve when alcohol intake is generally highest (Ettinger et al. 1978). Individuals with unexplained acute atria1 fibrillation have been shown to have a significantly higher rate of heavy alcohol consumption than control persons (Rich, Siebold, and Campion 1985). Alcoholics with evi- dence of myocardial dysfunction are more sensitive to the depressant effects of alcohol on the heart and to atria1 and ventricular dysrhythmias following the acute administration of alcohol. Serious dysrhythmias have been observed in patients consuming as little as 7 oz of vodka (Singer and Lundberg 1972). Hemodynamic Effects Acute alcohol ingestion produces complex changes in cardiovascular phys- iology, including dilation of peripheral blood vessels and diminished blood return to the heart. Recent studies have shown that acute alcohol ingestion in normal subjects has a depressant effect on heart muscle action (Lang et al. 1985), but in one group of patients with congestive heart failure, a single intoxicating dose of alcohol significantly reduced pumping efficiency with- out causing any significant deterioration in cardiac performance (Green- berg et al. 1982). It is well established from both animal and human studies that chronic alcohol use injures the heart muscle, depresses ventricular function, and impairs cardiac performance. Over time, alcohol abuse may lead to irreversible damage to the heart muscle and cause congestive heart failure or cardiac arrhythmias. Hypertension Most studies have indicated that a self-reported average consumption of three to four alcoholic drinks per day causes a measurable increase in both the systolic and diastolic blood pressures. These studies suggest that as much as 11 percent of hypertension in men may be attributable to consump- tion of alcohol at this level (MacMahon 1986). O Nutrition and Health Hypertriglyceridemia The most common lipid abnormality associated with alcohol abuse and alcoholism is hypertriglyceridemia. In such persons, the very low density lipoprotein (VLDL) levels are high, corresponding to what would tradition- ally be classified as hyperlipidemia type IV. In more severely affected individuals, there may be an accompanying elevation of chylomicrons, which is consistent with hyperlipidemia type V. Because VLDL particles contain some cholesterol, the serum cholesterol may also be elevated as a result. The effect of alcohol intake on triglyceride levels is often overlooked. Among patients referred to lipid clinics, only diabetes is more important as a secondary cause of hyperlipidemia. Typically, persons with alcohol- induced hyperlipidemia do not respond to dietary or drug intervention unless alcohol intake is limited (Janus and Lewis 1978). Indeed, the alcohol intake of all persons with hypertriglyceridemia should be assessed. In a light to moderate drinker especially, awareness of this effect of alcohol may provide sufficient motivation to lower intake. In the alcoholic person, this awareness might lead to the identification and treat- ment of the alcoholism. Severe hypertriglyceridemia may cause and/or result from pancreatitis (Geokas 1984). Because pancreatitis is more common in alcoholics than in nonalcoholics, all individuals presenting with pancreatitis or otherwise unexplained recurrent upper abdominal pain should be evaluated for hyper- triglyceridemia and history of alcohol use. In alcoholics, extreme forms of hyperlipidemia have been described in which excessive alcohol intakes were associated with jaundice, severe hyperlipidemia, and hemolytic anemia (Zieve 1958). Liver biopsies in such patients showed fatty infiltration with minimal to moderate portal cirrhosis. Fortunately, this syndrome appears to be rare. Elevated Serum Cholesterol Levels Several population studies have suggested that light to moderate drinkers (by self-report) have a lower risk for coronary artery disease than do nondrinkers (Yano, Rhoads, and Kagan 1977; Blackwelder et al. 1980). The observation that alcohol intake tends to increase high density lipoprotein (HDL) cholesterol was originally thought to be consistent with these epidemiologic findings, especially because HDL cholesterol appears to be inversely related to the risk for coronary artery disease. However, more Alcohol O recent studies have shown that the HDL cholesterol can be subdivided into fractions. The HDL, fraction is thought to protect against coronary artery disease but is affected relatively little by moderate alcohol ingestion. Alcohol elevates the HDL, fraction, which appears to have no association with coronary artery disease. In alcoholics, however, the reports to date regarding HDL cholesterol level have been variable and appear to depend on a variety of factors such as level of alcohol intake. the degree of hepatic microsomal enzyme induction, and the severity of alcoholic liver disease (Hurt et al. 1986). Because of the association of reduced levels of apolipo- proteins AI and AI1 (apo AI and AII) with coronary artery disease (Kottke et al. 1986), the effect of alcohol on apo AI and AI1 is also of interest and ap- pears to parallel its effect on HDL cholesterol. In alcoholic men, however. the apo AI levels have been observed to be lower than in nonalcoholic con- trols (Hurt et al. 1986). The epidemiologic findings, therefore, await further confirmation as well as elucidation of a biologic mechanism to explain the apparent protective effect of alcohol. Coronary Heart Disease Some evidence suggests that the ingestion of two to three alcoholic drinks per day reduces the rate of nonfatal myocardial infarction and mortality from coronary heart disease (Yano, Rhoads, and Kagan 1977; Blackwelder et al. 1980). Whether these epidemiologic observations are mediated by effects of alcohol on HDL levels is unknown at present (Ernst et al. 1980). The effects at various levels of alcohol intake, the presence of liver disease, and effects of exercise on HDL cholesterol levels in alcoholics require further study. It appears that the benefits of consuming two to three drinks per day do not increase in persons who drink more. On the contrary, mortality from other diseases increases markedly when alcohol consump- tion exceeds those levels (Blackwelder et al. 1980; Marmet et al. 198 1). Role of Alcohol in Reproductive Disorders The relationship between maternal alcoholism and adverse fetal effects has been known for centuries, but interest was revived after publication of a report on this relationship in the early 1970's (Jones et al. 1973). Fetal alcohol syndrome is characterized by a triad of features: (1) facial malfor- mations, (2) prenatal and postnatal growth deficiencies, and (3) central nervous system disorders, including mental retardation, with the effect occurring as early as the time of conception (Ernhart 1987). Although the initial observations were made of the children of severe alcoholics with longstanding, high-volume alcohol use, fetal abnormalities have now been associated with lesser quantities of alcohol intake during pregnancy O Nutrition and Health (Streissguth et al. 1980), and there appears to be a dose-response relation- ship in which abnormalities increase in proportion to the dose of alcohol (AMA 1983; Emhart 1987). The observation that the fetal alcohol syn- drome occurs in disproportionately larger numbers of American Indians, in patients of lower socioeconomic background, and in children of older mothers might be explained on the basis that the rate of alcohol abuse and alcoholism is higher among these groups (Streissguth 1978). Although most authorities view the syndrome as a direct toxic effect of alcohol on the fetus, malnutrition may also play a role in its development. Acute and chronic alcohol consumption in the rat can significantly reduce the placenta1 uptake of a variety of amino acids (Henderson et al. 1982). However, because of substantial structural differences in the placenta from species to species, extrapolation of these results to humans must be cau- tious. Animal studies, on the other hand, appear to support a direct causative effect of alcohol on fetal alcohol syndrome (Randall, Taylor, and Walker 1977). One additional study bears on this point. When pregnant women were separated into alcoholic and nonalcoholic groups by the use of the Michigan Alcoholism Screening Test and by an index of volume of alcohol consumed, pregnant alcoholics were found to have lower plasma zinc levels than nonalcoholic controls, and lower levels of zinc were ob- served in fetal cord blood (Flynn et al. 1981). Although this last study undoubtedly brings attention to possible nutri- tional contributions to the fetal alcohol syndrome, the consensus at present is that the syndrome is due to toxic effects of alcohol and is not a nutritional deficiency syndrome. In addition, a recent study, after controlling for other risk factors, reported lower birth weights among infants born to mothers who consumed as little as one alcoholic drink per day during pregnancy (Mills et al. 1984). Until further information is available, the Surgeon General and the American Medical Association have recognized that com- plete abstinence at the time of conception and during pregnancy is the safest course (DHEW 1979; AMA 1983). Implications for Public Health Policy Dietary Guidance General Public Alcohol has been identified as a dietary factor that increases the risk for diseases of the liver, nervous system, and heart. It also contributes to the 660 Alcohol O development of certain cancers. Although consumption of up to one to two drinks per day has not been associated with disease among healthy male and nonpregnant female adults, evidence that 9 percent of the total popula- tion consumes two or more alcoholic drinks per day suggests that the risk for alcohol-related conditions could be reduced by an overall decrease in alcohol consumption among some segments of the general public. Special Populations Because studies in pregnant women have been unable to identify a thresh- old level of safety for alcohol intake during pregnancy, and because the risk for fetal abnormalities increases with increased alcohol intake during preg- nancy, pregnant women-and women planning to become pregnant- should be advised to avoid drinking alcohol. Persons with alcohol-related liver, nervous system, and cardiovascular conditions (e.g., elevated blood cholesterol and blood pressure levels) should receive advice from health professionals to reduce or eliminate alcohol intake to reverse or to prevent progression of these conditions. Persons with diabetes should also receive counseling on the effects of alcohol on caloric intake and blood glucose control. Adolescents and young adults should be counseled in schools and through the media on the relationship between alcohol intake and motor vehicle and other accidents, suicides, and homicides. Older individuals should be counseled on the relationship between alcohol intake, nutritional deficien- cies, and drug interactions. Nutrition Programs and Services Food Labels Evidence related to the role of alcohol in health suggests that if alcoholic beverage containers are required to bear health warning labels, these labels should carry information warning of hazards to the developing fetus as well as of other health hazards associated with alcohol consumption abuse. Food Services Aside from the special populations noted below, evidence related to the role of alcohol currently holds no special implications for change in policies related to food service programs. 661 O Nutrition and Health Food Products There are no special implications for change in policy related to formula- tion of food products. Special Populations Pregnant women, including those served by the Special Supplemental Food Program for Women, Infants, and Children (WIG) and other maternal and child health programs, should be provided with counseling on avoid- ance of alcoholic beverages. Persons with alcohol-related conditions should be provided with counseling and referrals on the benefits of absti- nence. Research and Suweillance Research and surveillance issues of special priority related to the role of alcohol and health include investigations into: o The levels at which alcohol intake increases risk for chronic diseases and birth defects. o The mechanisms by which alcohol induces fatty changes in the liver. o The mechanisms by which alcohol increases blood pressure, blood cholesterol, blood glucose levels, and other risk factors for chronic disease. o The mechanisms by which low levels of alcohol may reduce risk for coronary heart disease. o The mechanisms by which alcohol increases cancer risk. o The mechanisms by which alcohol damages the nervous system. o The mechanisms by which alcohol intake interferes with nutritional status. o Definition of the physiologic energy value of alcoholic beverages. o The interaction of alcohol intake, nutritional status, socioeconomic status, and health. 662 Alcohol 0 Literature Cied AMA. See American Medical Association. American Medical Association, Council on Scientific Affairs. 1983. Fetal effects of maternal alcohol use. Journal of the American Medical Association 249:2517-21. Badawy, A.A.-B. 1978. The metabolism of alcohol. Clinics in Endocrinology and Metabolism 7~241-71. Baker, H.; Frank, 0.; Letterman, R.K.; Rajan, K.S; ten Hove, W.; and Leevy, CM. 1975. Inability ofchronic alcoholics with liver disease to use food as a source offolates, thiamin, and vitamin Bg. American Journal of Clinical Nutrition 28: 1377-80. Barnes, GM., and Russell, M. 1978. Drinking patterns in western New York State. Journal of Studies on Alcohol 39: 1148-57. Bebb, H.T.; Houser, H.B.; Wits&i, J.C.; Littell, A.S.; and Fuller, R.K. 1971. Calorie and nutrient contribution of alcoholic beverages to the usual diets of 155 adults. American Journal of Clinical Nutrition 24: 1042-52. Behse, F., and Buchthal, F. 1977. Alcoholic neuropathy: clinical, electrophysiological, and biopsy findings. Annals of Neurology 2:95-l 10. Beilin, L.J., and Puddey, I.B. 1984. Alcohol and essential hypertension (editorial). Alcohol and Alcoholism 19: 191-95. Berkelman, R.L. ; Ralston, M. ; Hemdon, J.; Gwinn, M.; Bertolucci, D. ; and Dufour, M. 1986. Patterns of alcohol consumption and alcohol-related morbidity and mortality. Morbidity nnd Mortality Weekly Report 35(2SS):lS!USS. Bing, R.J. 1978. Cardiac metabolism: its contributions to alcoholic heart disease and myocar- dial failwe. Circulation 58:%5-70. Blackwelder, W.C.; Yano, K.; Rhoads, G.G.; Kagan, A.; Gordon, T.; and Palesch, Y. 1980. Alcohol and mortality: the Honolulu Heart Study. American Journal qfhfedicine 68: 164-69. Blass, J.P., and Gibson, G.E. 1977. Abnormality of a thiamine-requiring enzyme in patients with Wemicke-Korsakoff syndrome. New England Journal of Medicine 297: 1367-70. Bonjour, J.P. 1979. Vitamins and alcoholism. I. Ascorbic acid. Internafional Journal for Vitamin Nutrition Research 49~434-41. -. 1980. Vitamins and alcoholism. II. Folate and vitamin B1z. International Journalfor Vitamin Nutrition Research 5096-12 1. Brigden, W., and Robinson, J. 1964. Alcoholic heart disease. British Medical Journal 2: 1283-89. Camilo, M.E.; Morgan, M.Y.; and Sherlock, S. 1981. Erythrocyte transketolase activity in alcoholic liver disease. Scandinavian Journal of Gastroenterology 16:273-79. Centerwall, B.S., and Criqui, M.H. 1978. Prevention of the Wernicke-Korsakoffsyndrome: a cost-benefit analysis. New England Journal sf Medicine 299:285-89. Committee on Diet, Nutrition, and Cancer. 1982. Diet, nutrition, nnd cancer. Washington, DC: National Academy Press. Da&y, W.J. 1979. The nutrient contributions of fermented beverages. In Fermented food beverages in nutrition, ed. C.F. Gastineau, W.J. Darby, and T.B. `Ibmer, pp. 61-79. New York: Academic. 463 O Nutrition and Health Demakis, J.G.; Proskey, A.; Rahimtoola, S.H.; Jam& M.; Sutton, G.C.; Rosen, K.M.; Gunner, R.M.; and Tobin, J.R., Jr. 1984. The natural course of alcoholic cardiomyopathy. Annals oflnternal Medicine 80:293-97. DHEW. See U.S. Department of Health, Education, and Welfare. DHHS. See U.S. Department of Health and Human Services. Dickson, B.J.; Delaney, C.J.; Walker, R.D.; Hutchinson, M.; and Buergel, N. 1983. Visceral protein status of patients hospitalized for alcoholism. American Journal of Clinical Nutrition 37:216-20. Diehl,A.M.;Boitnott, J.K.;Herlong,H.E:;Potter,J.J.;VanDuyn,M.A.;Chandler,E.;and Mezey, E. 1985. Effect of parenteral ammo acid supplementation in alcoholic hepatitis. Hepatology 5~57-63. Dreyfus, P.M. 1979. Effects ofalcohol on the nervous system. In Fermentedfood beverages in nutrition, ed. CF. Gastineau, W.J. Darby, and T.B. Turner, pp. 341-57. New York: Academic. Eichner, E.R., and Hillman, R.S. 1971. The evolution of anemia in alcoholic patients. American Journal of Medicine 50:218-32. Emhart, C.B. 1987. Alcohol teratogenicity in the human: adetailed assessment of specificity, critical period, and threshold. American Journal of Obstetrics and Gynecology 15633-39. Ernst, N.; Fisher, M.; Smith, W.; Gordon, T.; Riflcind, B.M.; Little, J.A.; Mishkel, M.N.; and Williams, D.D. 1980. The association of plasma high-density lipoprotein cholesterol with dietary intake and alcohol consumption. Circulation 62(suppl. IV):41-52. Ettinger, PO.; Wu, C.F.; De La Cruz, C., Jr.; Weisse, A.B.; Ahmed, S.S.; and Regan, T.J. 1978. Arrhythmias and the "holiday heart": alcohol associated cardiac-rhythm disorders. American Heart Journal 95:555-62. Flynn,A.;Martier,S.S.;Sokol,R.J.;Miller,S.I.;Golden,N.L.;andDelvillano,B.C.1981. Zinc status of pregnant alcoholic women: a determinant of fetal outcome. Lancer i:572-74. French, S.W. 1971. Acute and chronic toxicity of alcohol. In The biology of afcoholism. Biochemistry, vol. I, ed. B. Kissin and H. Begleiter, pp. 437-511. New York: Plenum. Freinkel, N . ; Arky, R. A. ; Singer, D.L. ; Cohen, A.K. ; Bleicher, S.J. ; Anderson, LB. ; Silbert, C.K.; and Foster, A.E. 1%5. Alcohol hypoglycemia. IV. Current concepts ofitspathogenesis. Diabetes 14:350. Geokas, M.C. 1984. Ethanol and the pancreas. Medical Clinics of North America 68~57-75. Ghaiioungui, P 1979. Fermented beverages in antiquity. In Fermented food beverages in nutrition, ed. C.F. Gastineau, W.J. Darby, and T.B. Turner, pp. 3-19. New York: Academic. Green, P.H.R. 1983. Alcohol, nutrition and malabsorption. Clinics in Gastroenterology 12:563-74. Greenberg, B.H.; Schutz, R.; Grunkemeier, G.L.; and Griswold, H. 1982. Acute effects of alcohol in patients with congestive heart failure. Annals of Internal Medicine 97: 171-75. Gruchow, H.W.; Sobocinski, K.A.; Barboriak, J.J.; and Scheller, J.G. 1985. Alcoholconsump- tion, nutrient intake and relative body weight among U.S. adults. American Journalof Clinical Nutrition 42~289-95. Haisted, C.H.; Robles, E.A.; and Mezey, E. 1971. Decreased jejunal uptake of labeled folic acid (sH-PGA) in alcoholic patients: role of alcohol and nutrition. New England Journal of Medicine 285:7016. 664 Alcohol 0 -. 1973. Distribution of ethanol in the human gastrointestinal tract. American Journal of Clinical Nutrition 26:831-34. Henderson, G.I.; Patwardhan, R.V.; McLeroy, S.; and Schenker, S. 1982. Inhibition of placental amino acid uptake in rats following acute and chronic ethanol exposure. Alcoholism: Clinical and Experimental Research 6:495-505. Herman, C.P., and Polivy, J. 1980. Stress-induced eating and eating-induced stress (reduc- tion)-a response to Robbins and Fray. Appetite 1:135-39. Hillers, V.N., and Massey, L.K. 1985. Interrelationships of moderate and high alcohol consumption with diet and health status. American Journal ofClinical Nutrition 41:35ti2. Hoyumpa, A.M. 1983. Alcohol and thiamine metabolism. Alcoholism: Clinical and Experi- menral Research 7: 11-14. Hurt, R.D.; Higgins, LA.; Nelson, R.A.; Morse, R.M.; and Dickson, E.R. 1981. Nutritional status uf a group of alcoholics before and after admission to an alcoholism treatment unit. American Journal of Clinical Nutrition 34:386-92. Hurt, R.D.; Morse, R.M.; and Swenson, W.M. 1980. Diagnosis of alcoholism with a self- administered alcoholism screening test. Mayo Clinic Proceedings 55:365-70. Hurt,R.D.;Briones,E.R.;Offord,K.P.;~tton,J.G.;Mau,S.J.T.;Morse,R.M.;andKonke, B.A. 1986. Plasma lipids and lipoprotein AI and AI1 levels in alcoholic patients. American Journal of Clinical Nutrition 431521-29. Janus, E.D., and Lewis, B. 1978. Alcohol and abnormalities of lipid metabolism. Clinics in Endocrinology and Metabolism 7:321-32. Jolliffe, N., and Jellinek, E.M. 1941. Vitamin deficiencies and liver cirrhosis in alcoholism. VII. Cirrhosis of the liver. Quarterly Journal of Studies on Alcohol 2:544-83. Jolliffe, N.; Bowman, K.M.; Rosenblum, L.A.; and Fein, H.D. 1940. Nicotinic aciddeficien- cy encephalopathy. Journal of the American Medical Association 114:307-12. Jones, B.R.; Barrett-Connor, E.; Criqui, M.H.; and Holdbrook, M.J. 1982. A community study of calorie and nutrient intake in drinkers and nondrinkers of alcohol. American Journal of Clinical Nutrition 35: 135-39. Jones, K.L.; Smith, D.W.; Ulleland, C.N.; and Streissguth, A.F? 1973. Pattern ofmalforma- tion in offspring of chronic alcoholic mothers. Lancer i:1267-71. Kalant, H. 1971. Absorption. diffusion, distribution, and elimination of ethanol: effects on biological membranes. In The biology of alcoholism. Biochemistry, vol. I, ed. B. Kissin and H. Begleiter, pp. 142. New York: Plenum. Kaunitz, J.D., and Lindenbaum, J. 1977. The bioavailability offolic acid added to wine. Annals of Internal Medicine 87:542-45. Klatskin, G. 1961. Alcohol and its relation to liver damage. Gastroenterology 41:443-51. Kottke, B.A.; Zinsmeister, A.R. ; Holmes, D.R., Jr.; KneUer, R. W. ; Hallaway, B . J. ; and Mau, S.J.T. 1986. Apolipoproteins and coronary artery disease. Mayo Clinic Proceedings 61:313-20. Laforge, R.; Stinson, ES.; Freel, C.G.; and Wiiams, G. 1987. Surveillance report #7: apparent per capita consumption: national, stafe, and regional trends, 1977-85. Rockviue, MD: Division of Biometry and Epidemiology, National Institute on Alcohol Abuse and Alcoholism, September. Landsberg, L., and Young, J.B. 1984. The role of the sympathoadrenal system in modulating energy expenditure. Clinics in Endocrinology and Metabolism 13~475-99. 665 0 Nutrition and Health Lang, R.M.; Borow, K.M.; Neumann, A.; and Feldman, T. 1985. Adverse cardiac effects of acute alcohol ingestion in young adults. Annals oflnternal Medicine 102:742-47. Larkin, E.C., and Watson-Williams, E.J. 1984. Alcohol and the blood. Medical Clinics elf North America 68: 105-20. Leevy, C.M. 1%7. Clinical diagnosis, evaluation and treatment of liver disease in alcoholics. Federation Proceedings 26: 1474-8I. Leevy, C.M.; Tanribilir, A.K.; and Smith, E 1971. Biochemistry of gastrointestinal and liver disease in alcoholism. In The biology ofalcoholism. Biochemistry, vol. I, ed. B. Kissin and H. Begleiter, pp. 307-25. New York: Plenum. Lelbach, W.K. 1975. Cirrhosis in the alcoholic and its relation to the volume c&alcohol abuse. Annals of the New York Academy qf Sciences 252:85-105. Leo, M.A., and Lieber, C.S. 1982. Hepatic vitamin A depletion in alcoholic liver injury. New England Journal of Medicine 307:597-l. Lieber, C.S. 1966. Hepatic and metabolic effects of alcohol. Gastroenterology 50:119-33. -. 1983. Interactions of alcohol and nutrition-introduction to a symposium (editorial). Alcoholism: Clinical and Experimental Research 7~2-3. -. 1984. Metabolism and metabolic effects of alcohol. Medical Clinics oflvorth America 68:3-31. Lieber, C.S., and DeCarli, L.M. 1974. An experimental model of alcohol feeding and liver injury in the baboon. Journal qf Medical Primatology 3:153-63. Lindenbaum, J. 1977. Metabolic effects of alcohol on the blood and bone marrow. In Meta- bolic aspects of alcoholism, ed. C.S. Lieber, pp. 215-47. Lancaster, England: MTP. Losowsky, M.S., and Leonard, P.J. 1967. Evidence of vitamin E deficiency in patients with malabsorption or alcoholism and the effects of therapy. Gut 8:53%3. Lucas, CC.; Ridout, J.H.; and Lumchick, G.L. 1968. Dietary protein and chronic intoxica- tion with ethanol. Canadian Journal qf Physiology and Pharmacology 46~475-85. MacMahon, S.W. 1986. Alcohol and hypertension: implications for prevention and treatment (editorial). Annals oflnternal Medicine 105:12&26. Marks, V. 1978. Alcohol and carbohydrate metabolism. Clinics in Endocrinology and Metab- olism 7:333-49. Marmet, M.G.; Shipley, M.J.; Rose, G.; and Thomas, B.J. 1981. Alcohol and mortality: a U- shaped curve. Lancet i:580-83. McClain, C.J. ; Van Thiel, D.H. ; Parker, S. ; Badzin, L.K. ; and Gilbert, H. 1979. Alterations in zinc, vitamin A, and retinol-binding protein in chronic alcoholics: a possible mechanism for night blindness and hypogonadism. Alcoholism: Clinical and Experimental Research 3:135-41. McDonald, J. 1980. Alcohol and diabetes. Diabetes Care 3:62%37. McDonald, J.T., and Margen, S. 1976. Wine versus ethanol in human nutrition. I. Nitrogen and calorie balance. American Journal of Clinical Nutrition 29: 1093-l 103. Mendenhall, CL.; Anderson, S.; Weesner, R.E.; Goldberg, S.J.; and Crolic, K.A. 1984. Protein-calorie malnutrition associated with alcoholic hepatitis. American Journal qfMedi- tine 76:21 l-22. 666 Alcohol 0 Mezey, E., and Faillace, L.A. 1971. Metabolic impairment and recovery time in acute ethanol intoxication. Journal of Nervous and Mental Diseases 153:445-52. Mills,J.L.;Graubard,B.I.;Harley,E.E.;Rhoads,G.G.;andBerendes,H.W.1984.Matem~ alcohol consumption and birth weight. Journal of the American Medical Association 252: 1875-79. Moore, M.H., andGerstein, D.R., eds. 1981. Alcoholandpublicpolicy: beyond theshadowof prohibition. Washington, DC: National Academy Press. Moore, R.A. 1971. The prevalence of alcoholism in a community general hospital. American Journal of Psychiatry 128:638-39. Morgan, M.Y. 1982. Alcohol and nutrition. British Medical Bulletin 38:21-29. Nakada, T., and Knight, R.T. 1984. Alcohol and the central nervous system. Medical Clinics of North America 68:121-31. Nasrallah, SM., and Galambos, J.T. 1980. Amino acid therapy of alcoholic hepatitis. Loncet ii:l27&77. National Center for Health Statistics. 1986. Health, United States, 1986. DHHS publication no. (PHS) 87-1232. Washington, DC: U.S. Government Printing Oflice. NCHS. See National Center for Health Statistics. Neville, J.N.; Eagles, J.A.; Samson, G.; and Olson, R.E. 1968. Nutritional status of alco- holics. American Journal of Clinical Nutrition 21~132940. Nixon, P.F. 1984. Is there agenetic component to the pathogenesis ofthe Wemicke-Korsakoff syndrome? (editorial). Alcohol and Alcoholism 19:219-21. Orten, J.M., and Sardesai, V.M. 1971. Protein, nucleotide, and porphyrin metabolism. In The biology of alcoholism. Biochemisrry, vol. I, ed. B. Kissin and H. Begleiter, pp. 229-61. New York: Plenum. Passmore, R. 1979. The energy valueofalcohol. InFermentedfood beverages in nutrition, ed. C.F. Gastineau, W.J. Darby, and T.B. nmer, pp. 213-23. New York: Academic. Patek, A.J., Jr. 1979. Alcohol, malnutrition, and alcoholic cirrhosis. American Journal of Clinical Nutrition 32~130442. Patek, A.J., Jr., and Post, J. 1941. `l?eatment of cirrhosis of the liver by a nutritious diet and supplements rich in vitamin B complex. Journal of Clinical Znvestigation 20:481-505. Patek, A.J., Jr.; Toth, LG.; Saunders, M.G.; Castro, G.A.M.; and Engel, J.J. 1975. Alcohol and dietary factors in cirrhosis: an epidemiological study of304 alcoholic patients. Archives of Internal Medicine 135:1053-57. Pennington, J.A.T. and Church, H.N. 1985. Bowes and Church's food values ofportions commonly used. New York: Harper & Row. Pequignot, G., and Cyralnik, F. 1970. Chronic disease due to overconsumption of alcoholic drinks. In International encyclopedia ofpharmacology and therapeutics, vol. II, pp. 375412. Oxford, England: Pergamon. Pirola, R.C. 1978. Drug metabolism and alcohol. Baltimore, MD: Univ. Park Press. Pirola, R.C., and Lieber, C.S. 1972. The energy cost of the metabolism of drugs, including ethanol. Pharmacology 7: 185-%. Polivy, J., and Herman, C.P. 1976a. Effects of alcohol on eating behavior: disinhibition or sedation? Addictive Behaviors 1: 121-25. 667 O Nutrition and Health -. 1976b. Effects of alcohol on eating behavior: influences of mood and perceived intoxication. Journal of Abnormal Psychology 85:601. Randall, CL.; Taylor, W.J.; and Walker, D.W. 1977. Ethanol-induced malformations in mice. Alcoholism: Clinical and Experimental Research 1:219-24. Ravenholt, R.T. 1984. Addiction mortality in the United States, 1980: tobacco, alcohol and other substances. Population and Development Review 10~697-724. Reuler, J.B.; Girard, D.E.; and Cooney, T.G. 1985. Current concepts: Wemicke's encepha- lopathy. New England Journal of Medicine 312: 1035-39. Rich, E.C.; Siebold, C.; and Campion, B. 1985. Alcohol-related acute atria1 fibrillation. Archives of Internal Medicine 145:83@-33. Roe, D.A. 1979. Alcohol and the diet. Westport, CT: AVI. Ron, M.A.; Acker, W.; Shaw, G.K.; and Lishman, W.A. 1982. Computerized tomography of the brain in chronic alcoholism: a survey and follow-up study. Brain 105:497-514. Rothwell, N.J., and Stock, M.J. 1986. Diet-induced thermogenesis. Nutrition International 2(2):95-99. Rubin, E. 1979. Alcoholic myopathy in heart and skeletal muscle. New England Journal of Medicine 301:28-33. Rubin, E., and Lieber, C.S. 1968. Alcohol-induced hepatic injury in nonalcoholic volunteers. New England Journal of Medicine 278:869-76. Rund, D.A.; Summers, W.K.; and Levin, M. 1981. Alcohol use and psychiatric illness in emergency patients. Journal of the American Medical Association 245: 124M1. Russell, R.M.; Rosenberg, I.H.; Wilson, P.D.; Iber, EL.; Oaks, E.B.; Giovetti, A.C.; Otradovec, C.L.; Karwoski, PA.; and Press, A.W. 1983. Increased urinary excretion and prolonged turnover time of folic acid during ethanol ingestion. American Journal of Clinical Nutrition 38:64-70. Schreiber, S.S.; Briden, K.; Oratz, M.; and Rothschild, M.A. 1972. Ethanol, acetaldehyde, and myocardial protein synthesis. Journal of Clinical Investigation 51:2820-26. Shattuck, G.C. 1928. The relation of beri-beri to polyneuritis from other causes. American Journal of Tropical Medicine 83539-43. Shaw, S., and Lieber, C.S. 1983. Alcoholism. In Nutritional support of medicalpractice. ed. H.A. Schneider, C.E. Anderson, and D.B. Coursin, pp. 236-59. 2d ed. Philadelphia, PA: Harper & Row. Sherlock, S. 1981. Diseases of the liver and biliary system, p. 334 6th ed. Oxford, England: Blackwell. Simko, V.; Connell, A.M.; and Banks, B. 1982. Nutritional status in alcoholics with and without liver disease. American Journal of Clinical Nutrition 35: 197-203. Singer, K., and Lundberg, W.B. 1972. Ventriculararrhythmiasassociated with the ingestion of alcohol. Annals of Internal Medicine 77~247-48. Sorrell, M.F.; Baker, H.; Barak, A.J.; and Frank, 0. 1974. Release by ethanol of vitamins into rat liver perfusates. American Journal of Clinical Nutrition 27~743-45. Steinkraus, K.H. 1979. Nutritionally significant indigenous foods involving an alcoholic fermentation. In Fermentedfood beverages in nutrition, ed. C.F. Gastineau, W.J. Darby, and T.B. `Khmer, pp. 35-59. New York: Academic. 668 Alcohol O Streissguth, A.P. 1978. Fetal alcohol syndrome: an epidemiological perspective. American Journal of Epidemiology 107:467-78. Streissguth. A.P.; Barr, H.M.: Martin, D.C.; and Herman. C.S. 1980. Effects of maternal alcohol, nicotine, and caffeine use during pregnancy on infant mental and motor development at eight months. A/coho/ism: C/inica/ and Experimental Research 4: 1.52-64. Sullivan, L.W., and Herbert, V. 1964. Suppression of hematopoiesis by ethanol. Jolrrnal of Clinical Investigation 43:2048-62. Swenson, W.M., and Morse, R.M. 1975. The use of a self-administered alcoholism screening test (SAAST) in a medical center. Mayo Clinic Proceedings 50:204-8. Task Force on Nomenclature and Statistics. 1980. In Diagnostic, and Jtutisrical manuul of mental disorders, pp. 169-70. 3rd ed. Washington. DC: American Psychiatric Association. Thomson. A.D. 1978. Alcohol and nutrition. Clinics in Endocrinology und Metabolism 71405-28. Tomaiolo, P.P., and Kraus, V. 1980. Nutritional status of hospitalized patients. Journal of Purenteral and Enteral Nutrition 4: l-3. Torvik, A.; Lindboe, C.F.: and Rogde, S. 1982. Brain lesions in alcoholics: a neu- ropathological study with clinical correlations. Journal of Neurological Scienre 56:233-48. USDA/DHHS. See U.S. Department of Agriculture and U.S. Department of Health and Human Services. U.S. Department of Agriculture and U.S. Department of Health and Human Services. 1985. Nutrition and your health: dietary guidelines for Americans. Home and Garden Bulletin no. 232. Washington, DC: U.S. Government Printing Gffice. U.S. Department of Health, Education, and Welfare. 1979. Healthy people: the Surgeon General's report on health promotion and disease prevention. Stock No. 017-001-00416-2. Washington, DC: U.S. Government Printing G&e. U.S. Department of Health and Human Services. 1980. Promoting health/preventing disease: objectives for the nation. Washington, DC: U.S. Government Printing Office. -. 1983. Promoting health/preventing disease: Public Health Service implementation plans for attaining the objectives for the nation. Public Health Reports 98(5, suppl.). -. 1985 Report of the Secretary's Task Force on Biack and Minority Health. Vol. I: Executive Summary. Washington, DC: U.S. Government Printing Gf?ice. -. 1986. The 1990 health objectivesfor the nation: a midcourse review. Public Health Service. DHHS publication no. 87-4753. Washington, DC: U.S. Government Printing GfJice. -. 1987. Sixrh special report to the U.S. Congress on alcohol and health from the Secretary of Health and Human Services. DHHS publication no. (ADM) 87-1519. Washing- ton, DC: U.S. Government Printing GfBce. Vestal, R.E.; McGuire. E.A.; Tobin, J.D.; Andres, R.; Norris, A.H.; and Mezey, E. 1977. Aging and ethanol metabolism. Clinical Pharmacology and Therapeutics 21:343-54. Victor, M.; Adams, R.D.; and Collins, G.H. 1971. The Wernicke-Korsakoffsyndrome. Phila- delphia, PA: Davis. Walsh, J.C., and McLeod, J.G. 1970. Alcoholic neuropathy: an electrophysiological and histological study. Journal of Neurological Science 10:457-69. Wechsler, H.; Demone, H.W.; and Gottleib, N. 1978. Drinking patterns of greater Boston adults. Journal of Studies on Alcohol 39: 1158-65. Cl Nutrition and Health Weiss, S., and Wilkins, R.W. 1937. The nature of the cardiovascular disturbances in nutri- tional deficiency states (beriberi). Annals oflnfernal Medicine 11:104-48. Wheeler,P.G.;Smith,T.;Gollindano,C.;Alam,A.N.;Willrinson,S.P.;Edmonds,C.J.;and W-s, R. 1977. Potassium and magnesium depletion in patients with cirrhosis on mainte- nance diuretic regimens. Gu? 18683-87. Wharton, J.C. 1982. Crusaders forfitness: the history ofAmerican he&h reformers. Prince- ton, NJ: Princeton Univ. Press. Wickramsinghe, S.N.; Gardner, B.; and Barden, G. 1987. Circulating cytotoxic protein generated after ethanol consumption: identification and mechanism of reaction with cells. Lancer ii: 122-26. Williams, H.E. 1984. Alcoholic hypoglycemia and ketoacidosis. Medical Clinics of North America 68333-38. Williamson, D.F.; Forman, M.R.; Binkin, N.J.; Gentry, EM.; Remington, P.L.; and Ttowbridge, FL. 1987. Alcohol and body weight in United States adults. AmericanJournalof Public Health 71:1324-30. World, M.J.; Ryle, P.R.; Pratt, O.E.; and Thomson, A.D. 1984. Alcohol and body weight (editorial). Alcohol and Alcoholism 19: l-6. Yano, K.; Rhoads, G.G.; and Kagan, A. 1977. Coffee, alcohol and risk of coronary heart disease among Japanese men living in Hawaii. New England Journal of Medicine 297:405-9. Zieve, L. 1958. Jaundice, hyperlipemia and hemolytic anemia: a heretofore unrecognized syndrome associated with alcoholic fatty liver and cirrhosis. Annals of Internal Medicine 48:471-96. 670 Chapter 18 Drug-Nutrient Interactions . . . the suffering was caused by digestion itself. . . vitiated by so long a use of opium. Thomas De Quincey Confessions of an Opium Eater (182 1) Introduction Drugs are chemical agents used to prevent or treat disease. They interact with foods and nutrients in several ways. Drugs can interfere with appetite or with nutrient digestion, absorption, metabolism, or excretion. Similarly, both nutritional status and diet can affect the action of drugs by altering their metabolism and function, and various dietary components can have pharmacologic activity under certain circumstances. Such interactions raise concerns that drugs might impair nutritional status and induce nutri- tional deficiencies or that inappropriate dietary intake might impair or enhance drug activity. This chapter reviews these issues. More complete discussion of individual topics may be found in comprehensive reviews and monographs (Hathcock and Coon 1978; Young and Blass 1982; Smith and Bidlack 1982; Roe 1984; Roe 1985; Hathcock 1987a, 1987b). Historical Perspective Throughout history, treatments for injuries and diseases have often in- cluded manipulations of the diet and the use of remedies prepared from plants, animals, and minerals. The earliest surviving written records de- scribe the ancient Sumerians' medicinal uses of laurel, caraway, and thyme. The first Chinese herb book, written in 2700 B.C., listed 365 medicinal plants and included ma-huang, the source of ephedrine. In 1000 B.C., the Egyptians were using garlic, opium, castor oil, coriander, mint, indigo, and other herbs as medicines, foods, and dyes (Young 1978). Hippocrates advocated the use of a few simple herbal drugs along with fresh air, rest, and proper diet to help the body's "life force" eliminate health problems (Lust 1974). Galen recommended large doses of drug mixtures to correct the 67: 0 Nutrition and Health imbalances that he believed caused diseases. Descriptions of the properties and medicinal uses of about 500 plants in De Mareria Medica, compiled in the first century A.D. by the Greek physician Dioscorides, remained an authoritative reference until the 17th century. Some of these plants from earlier writings are sources of modern drugs, including quinine from cinchona bark, morphine from the opium poppy, digitalis from foxglove, and reserpine from rauwolfia (Lust 1974). In the 16th and 17th centuries, a school of scientists known as iatrochemists believed that chemistry's proper function was to assist physicians to im- prove health care (ACS 1977). Their teachings led in the 18th and 19th centuries to the use of minerals such as arsenic, iron, and sulfur to treat acute infections, a practice that may be said to be the beginning of chemo- therapy. The purges and emetics of past medical practice usually were given as short courses of therapy and were unlikely to have a lasting effect on nutritional status. The chronic use of drugs such as opium or alcohol, however, was more likely to impair nutritional status through reduced nutrient intake or, in the case of alcohol, toxic effects on the digestive system (see chapter on alcohol). As the sciences of medicine and nutrition developed, successful therapies tended to occur in areas associated directly or indirectly with the treatment of acute nutrient deficiency states, such as the use of limes to prevent or cure scurvy. Eventually, the use of drugs evolved from an empirical art handed down through the centuries to a rigorous science of pharmacology in which known amounts of pure agents with specific physiologic effects are admin- istered to treat particular conditions. The development of new drugs has the potential for introducing new drug-nutrient interactions, some of which may be beneficial to the patient while others may be deleterious. Thus, present interest in drug-nutrient interactions focuses on prevention of nutrient deficiencies in individuals who take drugs and on minimization of diet-induced impairments of drug function (Hathcock 1987a). Significance for Public Health Because of individual variations in dietary intake and in the use of and response to drug therapies, the effects of interactions between drugs and nutrients are difficult to measure, and no direct information is available on the incidence, prevalence, or health cost of such interactions. Drug-nu- trient interactions are most likely to impair health or nutritional status in persons who take multiple drugs for prolonged time periods. 612 Drug-Nutrient Interactions O One indicator of the potential public health importance of drug-nutrient interactions may be found in the increasing level of use of medications by the general public. Population exposure to prescription drugs, defined as the average per capita number of prescription doses, increased 28 percent between 1971 and 1982. Males obtained 40 percent of the prescriptions, females 60 percent (Baum et al. 1985). In 1984, more than 1.5 billion prescriptions were dispensed from retail pharmacies, a 2 percent increase over 1983 levels. The cost of these prescriptions was $18.4 billion (Anony- mous 1986a). New prescriptions accounted for 51 percent of the total, refills for 49 percent. The increase in prescriptions tilled between 1984 and 1985 was 1.1 percent, largely as a result of increases in refills (Anonymous 1986b), and persons over 50 purchase prescriptions at about twice the rate of the rest of the population (Baum et al. 1985). The proportionate share of prescription drugs taken by older persons increases with increasing age. Persons over age 65, for example, take about 25 percent of the national total of prescribed drugs and about an equal proportion of drugs sold over the counter although they constitute only about IO percent of the population (Chen et al. i985). Surveys show that the majority of elderly people take two to five different drugs daily and experi- ence about two to three times more adverse drug effects than younger individuals (Rikans 1986). The medications most frequently used are drugs for cardiovascular disease, the central nervous system, and constipation, and most of the serious reactions are from cardiovascular and psychoactive agents (Chen et al. 1985). Older persons are thus at increased risk for deleterious drug-nutrient interactions because they take multiple drugs over long periods of time, are more susceptible to nutritional deficiencies (see chapter on aging), and have reduced ability to metabolize drugs (Rikans 1986). Scientific Background: Methodological Issues When interpreting the clinical significance of drug-nutrient interactions, it should be noted that recognized, frequent, serious interactions would result in unacceptable toxicity, and, consequently, in abandonment of the drug before marketing (Anonymous 1986~). Therefore, many drug-nutrient interactions will rarely be manifest clinically and can only be demonstrated in the laboratory. In most cases, excessive or abusive use of a drug is necessary before adverse effects become clinically apparent, and such effects are likely to occur only in vulnerable individuals who are chron- ically malnourished, elderly, or ill. Although it is possible that subclinical effects on health or nutritional status may occur at the usual levels of drug intake, especially when therapy is long term, such effects are difficult to 673 0 Nutrition and Health assess in individuals and are not yet possible to demonstrate in the popula- tion (Roe 1985). The effects of drugs on human nutrition are complex and may not be recognized during routine preclinical toxicity testing in animals. Currently, the potential of a drug to affect adversely nutritional status is evaluated in animals by determination of food intake, body weight gain, and serum chemistry and hematology profiles. Although animal toxicology studies have often revealed adverse effects of drugs on food consumption and body weight gain, such effects are usually seen only at high drug doses and are not thought likely to affect nutritional status at doses typically prescribed (Gilchrist 1981). There are, however, occasions when a drug alters the nutritional status of animals at doses near the human therapeutic range. One such example is the inhibition of bile acids and fat-soluble vitamin absorption in both rats and humans by bile salt sequestrants such as cholestyramine (Harkins, Hager-man, and Sarett 1%5; Hashim, Bergen, and Van Itallie 1%1). The addition of cholestyramine to the diet of weanling rats at concentrations near those that are used in humans has been shown to reduce the normal body weight gain of these animals, perhaps because of vitamin A depletion; the inclusion of additional vitamin A in the diet was shown to prevent the weight loss, although liver stores of vitamin A remained low (Whiteside et al. 1965). Many drugs have been shown to affect serum chemistries or hematologic parameters adversely during animal toxicity studies. In most cases, these changes are due to toxicities unrelated to nutrition. In general, the design of animal toxicology studies rarely allows for an adequate assessment of chronic drug effects on nutrition, but when a nutritional problem is identi- fied in human clinical studies, animal studies can help clarify the mecha- nism of the interaction (Gilchrist 1981). Due to limitations in the doses used, in the number of subjects studied, and in the duration of drug administra- tion, prospective (cohort) studies of drug safety can detect adverse effects on nutritional status only when they occur with high frequency in the study population. Depending on the intended use of the drug, populations at greatest risk for adverse nutritional effectsdhildren, pregnant women, and older persons-may not be studied at all. Key Scientific Issues o Effects of Drugs on Nutritional Status 0 Effects of Diet on Drug Metabolism Drug-Nutrient Interactions 0 o Effects of Drug-Food Incompatibilities o Effects of Drugs Used in Food Production o Effects of Pharmacologic Doses of Nutrients Effects of Drugs on Nutritional Status Drugs can affect nutritional status by altering appetite, food digestion, and nutrient absorption, metabolism, utilization, or excretion. Appetite and Food Intake The regulation of food intake is exceedingly complex and involves the integration by the brain of chemical signals that convey visual, olfactory, and gustatory information as well as many internal signals regarding the quality, palatability, and need for food through multiple neurotransmitters and hormones (Morley et al. 1984; Sullivan and Gruen 1985). Appetite is stimulated, for example, by norepinephrine, opioid peptides, pancreatic polypeptides, growth hormone releasing factor, and gamma aminobutyric acid (GABA). Conversely, appetite is inhibited by factors such as dopamine, epinephrine, serotonin, neurotensin, calcitonin, and cor- ticotropin releasing factor (Leibowitz 1986) and by intestinal hormones such as cholecystokinin, bombesin, somatostatin, and glucagon (Merely and Levine 1985; Sullivan and Gruen 1985). The ways in which anorectic agents might affect appetite regulatory mech- anisms are poorly understood. Amphetamines, fenfluramine, and the over- the-counter phenylpropanolamine (PPA) diet pills have been reported to exert their effects by causing the release from the central nervous system of neurotransmitters that increase feelings of satiety (Hoebel 1977). Other nutrition-related metabolic effects, such as lowering of body weight set points (Stunkard 1982), have been postulated but need confirmation. Al- though some drugs have been shown to induce weight loss in experimental animals, both the safety and efficacy of their use by humans is controver- sial. Certain studies suggest that they induce small but significant weight losses, but others have found them to be ineffective and possibly harmful (Friedman, Kindy, and Reinke 1982). PPA is an example of an amphetamine-like agent with no data on long-term benefits but well-docu- mented side effects, including hypertension, seizures, strokes, headache, nausea, and behavioral disturbances (Pentel 1984). Of considerable current research interest is exploration of the use of narcotic antagonists such as naloxone to block the appetite-stimulating 675