Review of the evidence linking alcohol consumption with liver disease and atherosclerotic disease

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1 Review of the evidence linking alcohol consumption with liver disease and atherosclerotic disease Norton Spritz, 2 M.D. Introduction and scope of the review of alcohol ingestion and disease This report will deal with the nature of the evidence linking alcohol ingestion to liver disease and to atherosclerotic disease. It is recognized that by limiting this discussion to these two effects of alcohol on health we will exclude from,consideration the major impact of alcohol on our society-the spectrum of social and personal upheavals that, taken together, constitute alcoholism. This committee elected this course of action because it believed that the association between alcohol consumption and liver disease or atherosclerosis had important parallels to the other issues (cholesterol intake, nature of dietary fat, salt intake, etc.) dealt with in this symposium. These are factors that have a less direct relationship to the illnesses to which they are putatively linked than between alcohol and alcoholism. In addition to alcoholism, liver disease, and atherosclerotic disease, alcohol is closely associated with a wide range of disorders. These include hematological abnormalities, cardiomyopathy, peripheral neuropathy, acute and chronic muscle disorders, central nervous system degeneration (particularly of the cerebellum and cortex), chronic pulmonary disease, certain malignancies, particularly of the head and neck, intestinal malabsorption, metabolic disorders (including hypoglycemia, ketosis, as well as hyperuricemia and gout), alterations in drug metabolism, increased susceptibility to infection, and provide a setting in which general malnutrition and specific dietary deficiencies are seen. It is impossible to review the quality of the evidence linking each of these disorders to alcohol, but it can be stated that in most instances the evidence is strong that alcohol plays a direct etiological role. The sum of all these disorders represents in itself an important health hazard for the population. Types of evidence linking alcohol with liver and heart disease Liver disease Epidemiological. The epidemiological evidence linking alcohol ingestion to cirrhosis of the liver includes a wide range of associations. Cirrhosis is seven times as common in alcoholics as in nondrinkers (1). There is a close association among states in the United States between deaths from cirrhosis and alcohol consumption of about 0.5 gallon per capita to 11 to 12/100,000 in those states with consumption exceeding 1.5 gallon per capita (2). During prohibition in the United States as well as during alcohol control programs in Sweden and Denmark there was a striking fall in the occurrence of deaths from cirrhosis concomitant with a decrease in alcohol ingestion. In the United States in 1916 the death rate for cirrhosis was approximately 11/ 100,000 and fell to 7/100,000 from 1920 to 1930 during prohibition. The figure rose again to 11/100,000 after 1932 when prohibition was repealed (3). These types of associations have been well reviewed in a study by Klatskin (1). In a detailed study carried out in Canada of the relationship among the cost of liquor, liquor consumption, and death rate from cirrhosis of the liver, Seeley (4) found that for the years 1920 to 1960 in Canada these three variables related closely to one another. The From the Medical Service, Manhattan Veterans Administration Hospital, and the Department of Medicine, School of Medicine, New York University, New York, New York Chief of the Medical Service and Professor of Medicine. Downloaded from ajcn.nutrition.org at PENNSYLVANIA STATE UNIV PATERNO LIBRARY on September 18, The American Journal of Clinical Nutrition 32: DECEMBER 1979, pp Printed in U.S.A.

2 ALCOHOLISM, LIVER AND ATHEROSCLEROTIC DISEASE 2735 correlation between per capita consumption and death rate from liver disease was approximated at In an extensive study of the relationship between alcohol intake and the amount and duration of alcohol abuse, Lelbach (5) came to several conclusions. He found that cirrhosis occurs in between 10 to 20% of heavy drinkers and that the risk for developing the disease based on liver biopsies in current drinkers related directly and linearly both to the duration and magnitude of alcohol intake. He calculates, for instance, that an intake of 180 g/day for 25 years (4200 liters of 100 proof whiskey) resulted in severe liver disease in 50% of the group of German alcoholics whom he studied. Since malnutrition frequently accompanies higher levels of alcohol ingestion, it is possible that the direct relationship between cirrhosis and the amount and duration of alcohol ingestion seen by Lelbach reflects to some extent this effect in addition to the direct effect of alcohol on the liver. In this, and the other epidemiological studies cited, specific dietary information that would help to sort out these two effects is not available. It is important to emphasize, however, that, in man, while severe protein malnutrition may lead to fatty liver and undoubtedly augments the toxic effects of alcohol on the liver, cirrhosis per se is not observed in patients with extremes of protein in total caloric deficiency in the absence of alcohol (6). Animal studies. Effects of alcohol on the liver have been shown in a variety of animal species. The most important demonstration has been that of Lieber and DeCarli (7) that, in baboons, cirrhosis can be produced by administering 50% of calories as alcohol. In these studies, attention was paid to maintaining the nutritional adequacy of the alcoholcontaining diet. Fatty liver, alcohol hepatitis, and cirrhosis were all produced in the animals receiving alcohol. The amount of alcohol administered was large and produced evidence of intoxication and, when withdrawn, withdrawal seizures. The intake levels were, however, comparable to those seen in severe human alcoholics. Human experimentation. In studies carried out under metabolic ward conditions the isocaloric substitution of carbohydrate by ethanol leads to accumulation of triglyceride in liver as demonstrated both by direct chemical measurement and by the production of histologically demonstrable fatty liver (8). This abnormality is completely reversible when alcohol is discontinued and replaced isocalorically by carbohydrate. These changes occur despite adequate protein, mineral, and vitamin ingestion and can even be seen during periods of weight gain. Discontinuation of alcohol ingestion in patients with established cirrhosis probably never can lead to histological regression of the disease. On clinical grounds, cessation of alcohol seems to have little impact on the progression of cirrhosis once evidence of portal hypertension is present (9). However, the other two major manifestations of alcohol-related liver disease-fatty liver and alcohol hepatitis - can reverse completely to normal when alcohol is removed from the diet. This recovery has been demonstrated in metabolic ward studies (8) as indicated above, as well as in clinical experience. Alcoholic and atherosclerosis Epidemiological. A link between alcohol intake and increased risks of atherosclerotic disease have been postulated on the basis of two types of epidemiological studies. The first type includes studies of single populations in which mortality for coronary heart disease has been correlated with alcohol intake. The second type of study determines correlations between individual risk factors for coronary heart disease and alcohol intake. The studies of Klatzky et al. (10) suggested a protective effect of alcohol on coronary heart disease. In their study, they could demonstrate the observed protective effect of alcohol in a convincing way only among nonsmokers. Among this group, the patients with myocardial infarction included more abstainers from alcohol than did those without myocardial infarction (57 versus 40%). Among the smokers with or without myocardial infarction, less than 20% abstained from alcohol and this made difficult the definition of a role for alcohol independent from that for cigarettes. Similarly, Yano et al. (11) concluded that, as with multivariate analysis to correct for the association between smoking and alcohol, there was a strong negative association between moderate alcohol consumption (up to 60 ml/day), mainly from beer, and a risk of

3 2736 SPRITZ nonfatal myocardial infarction and death from coronary heart disease. In contrast Kannel and Woosley (12) in the Framingham study report that alcohol intake related in neither a positive nor negative way to the risk of coronary disease when analyzed independently of associated risk factors. Pell and D Alonzo (13) and Dyer et al. (14) both reported an increased risk of coronary artery disease in problem drinkers, although in the latter study the difference in coronary heart disease did not reach statistical significance when compared to the control group. In both studies there was an increase in cigarette smoking and hypertension among the drinkers, but an independent negative effect of alcohol ingestion was evident even when these risk factors were accounted for. In addition to the strong relationship cited above between alcohol ingestion and cigarette smoking, alcohol has been related to three other risk factors for coronary heart disease-hypertension, alterations in plasma lipid, and obesity. Alcohol and blood pressure Two studies indicate that men with greater than average alcohol consumption have approximately double the prevalence of blood pressure levels above 160/95 (15, 16). These findings seem to be limited to Caucasians in these studies and reveal a threshold effect in that the effect was not evidenced at the lower levels of alcohol intake. In general these studies indicate that the association between alcohol and blood pressure greater than 160/95 cannot be explained by associations between a heavy drinking pattern and other factors such as sex, age, body weight, cigarette use, or level of education. Alcohol and plasma lipids In a recently published cooperative study (17) involving 3500 men in five American cities, alcohol ingestion was shown to correlate positively in a linear fashion to the triglyceride concentration and also with high density lipoprotein (HDL) cholesterol. In this investigation a negative association with low density lipoprotein cholesterol was found. Other investigators have found little effect of alcohol when administered in short term studies (18, 19) in subjects with normal levels of plasma lipids. When alcohol was administered to patients with hypertriglyceridemia, significant worsening of the hypertriglyceridemia often occurred. Other studies also tend to indicate that there are, within the general population, patients susceptible to marked hypertriglyceridemic effect of alcohol (20). This effect was seen with moderate levels of blood alcohol in these individuals and the effect disappeared when alcohol had been discontinued under control study conditions. While positive correlation between alcohol and triglyceride or very low density lipoproteins would suggest a deleterious influence of alcohol and risk of cardiovascular disease, the positive association between alcohol and HDL would imply the opposite (2 1-23). It is important to point out, however, that while there seems to be a strong inverse relationship between HDL levels and risk of coronary artery disease, the nature of this interplay is not well understood. In preliminary findings, for instance, one group of investigators has reported (23) that in alcoholics the increase in HDL reflected a variety of patterns among the subclasses of that lipoprotein group (HDL2 and HDL3). In many instances, these patterns differ markedly from those found in other population groups in which HDL has been correlated with a protective effect against coronary artery disease. The authors correctly question whether elevations of HDL of differing chemical composition all have the same relationship to protection against coronary heart disease. Alcohol and obesity It has been estimated that, on the average, alcohol accounts for 210 cal/day per person in the United States and in studies of heavy drinkers it was found to account for 36% of caloric intake in men and 22% in women for sustained periods of intake (24). In a study (13) involving 83,000 subjects, alcohol correlated with obesity only in one population segment (white men), and in this group, this effect was seen only in those ingesting six or more drinks per day. Other studies also provided relatively unconvincing data directly relating to alcohol consumption and obesity (10). This small impact of ethanol ingestion on the development of obesity may relate to its relative inefficiency as a source of calories,

4 ALCOHOL1SM, LIVER AND ATHEROSCLEROTIC DISEASE 2737 particularly at high levels of ingestion. Pirola and Lieber (25) showed in both rats and in man that isocaloric (7.1 kcal/g) replacement of caloric intake by alcohol led to weight loss, and when added to a diet with a caloric intake that maintained body weight constant, did not produce weight gain. This effect was noted in studies with human subjects under metabolic ward conditions even when 2000 kcal/day of alcohol were added to a base-line isocaloric diet of 2200 kcal/day. Animal studies Studies of the effect of alcohol on experimental atherosclerosis have been limited and variable in their fmdings. In a recent study using the Carneau pigeon, a fowl susceptible to spontaneous vascular lesions, ethanol feeding for 6 months led to increased aortic cholesterol content but not to gross atherosclerotic lesions (26). Similar findings have been noted in the cholesterol fed rabbit (27), but not in the chicken (28). Human experimentation There have been no controlled studies in which the effect over a long period of the cessation of drinking alcohol on the development of atherosclerotic disease has been evaluated. Autopsy studies in man in which atherosclerotic disease has been related to history of alcohol intake are also inconstant and of questionable interpretation. Earlier studies have suggested an inverse relationship between alcohol ingestion and atherosclerosis but more recent studies as reviewed by Lelbach (5) do not support such fmdings. Autopsy studies are difficult to interpret because of the possible interplay between liver disease that is fatal in many of these patients and factors that affect the progression of atherosclerotic disease. a This background review was prepared in consultation with Drs. Enoch Gordis, Charles S. Lieber, and Frank A. Seixas. References 1. KLATSKIN, G. Alcohol and its relation to liver damage. Gastroenterology 41: 443, JOLIFFE, N., AND E. M. JELLINEK. Vitamin deficiencies and liver cirrhosis in alcoholism VII. Quant. J. Studies Alcohol 2: 544, Vital Statistics ofthe United States, National Office of Vital Statistics. Washington, D.C.: United States Public Health Service. 4. SEELEY, J. Death by liver cirrhosis and the price of beverage alcohol. Can. Med. Assoc. J. 83: 1361, LELBACH, W. K. Cirrhosis in the alcoholic and its relation to the volume of alcohol abuse. Ann. N. Y. Acad. Sci. 252: 85, LIEBER, C. S. Alcohol and malnutrition in the pathogenesis of liver disease. J. Am. Med. Assoc. 233: 1077, LIEBER, C. S., AND L. M. DECARLI. An experimental model of alcohol feeding and liver injury in the baboon. J. Med. Primatol. 3: 153, LIEBER, C. S., D. P. JONES AND L. M. DECARLI. Effects of prolonged fatty liver despite adequate diets. J. Clin. Invest. 44: 1009, SOTERAKIS, J., R. H. RESNICK AND F. 1. IBER. Effect of alcohol abstinence on survival in cirrhotic portal hypertension. Lancet 2: 65, KLATSKY, A. L., C. D. FRIEDMAN AND A. B. SIEGE- LAUB. Alcohol consumption before myocardial infarction. Results from the Kaiser-Permanente epidemiologic study of myocardial infarction. Ann. Internal Med. 81: 294, YANO, K., G. G. RHOADS AND A. KAGAN. Coffee, alcohol and risk of coronary heart disease among Japanese men living in Hawaii. New Engl. J. Med. 297: 405, KANNEL, W. B., AND P. WOOSLEY. Alcohol and cardiovascular risk. Heart disease epidemiology study, Framingham, Massachusetts. Circulation 52: (Suppl. 11) 200, PELL, S. AND C. A. D ALoNzo. A five-year mortality study of alcoholics. J. Med. 10: 344, DYER, A. R., J. STAMLER, P. OGLESBY, D. M. BERK- SON, M. H. LEPPER, H. MCKEAN, R. B. SHEKELLE, M. A. LINDBERG AND D. GARSIDE. Alcohol consumption cardiovascular risk factors and mortality in two Chicago epidemiologic studies. Circulation 56: 1067, KLATSKY, A. L., G. D. FRIEDMAN, A. B. SIEGELAUB AND M. D. GERARD. Alcohol consumption and blood pressure. Kaiser-Permanente multiphasic health examination data. New Engl. J. Med. 296: 1194, D ALoNzo, C. A., AND S. PELL. Cardiovascular disease among problem drinkers. J. Med. 10: 344, CASTELLI, W. P., J. T. DOYLE, T. GORDON, C. G. HAMES, H. C. HJORTLAND, S. B. HULLEY, A. KAGAN AND W. J. ZUKEL. Alcohol and blood lipids, the cooperative lipoprotein phenotyping study. Lancet 2: 153, GINSBERG, H., J. OLEFSKY, J. W. FARQUHAR AND G. M. RAVEN. Moderate ethanol ingestion and plasma triglyceride levels. A study in normal and hypertnglyceridemic persons. Ann. Internal Med. 80: 143, GORDON, T., W. P. CASTELLI, M. C. HJORTLAND, W. B. KANNEL AND T. R. DAWBER. High density lipoprotein as a protective factor against coronary disease. The Framingham Study. Am. J. Med. 62: 707, JOHANSON, B. G., AND A. MEDHUS. Increase in plasma a-lipoproteins in chronic alcoholics after

5 2738 SPRITZ acute abuse. Acta Med. Scand. 195: 273, JoHNSoN, B. G., AND P. NILSSON-EHLE. Alcohol consumption and high density lipoprotein. New Engl. J. Med. 298: 633, NEVILLE, J. N., J. A. EAGLES, G. SAMSON AND R. E. OLSON. Nutritional status of alcoholics. Am. J. Clin. Nutr. 21: 1329, PIROLA, R. C., AND C. S. LIEBER. An experimental model of alcohol feeding and liver injury in the baboon. J. Med. Primatol. 3: 153, SUBBIAH, M. T. R. Ethanol and atherosclerosis: effeet of chronic ethanol ingestion of plasma cholesterol, cholesterol excretion and aortic cholesterol accumulation in spontaneous atherosclerosis-susceptible pigeons. Artery 3: 495, EBERHARD, T. P. Effect of alcohol on cholesterolinduced atherosclerosis in rabbits. Arch. Pathol. 21: 616, NICHoLs, C. W., M.D. SIPERSTEIN, W. GAFFY, S. LINDSAY AND I. L. CHAIKOFF. Does the ingestion of alcohol influence the development of arteriosclerosis in fowls? J. Exptl. Med. 103: 465, 1956.

6 Erratum In the article entitled: Review of the evidence linking alcohol consumption with liver disease and atherosclerotic disease by N. Spritz, (32: , 1979; December supplement), references 17 and 18 were omitted, although they were alluded to in the text. These references are printed below. 17. CASTELLI, W. P., J. T. DOYLE, T. GORDON, L. G. HAMES, H. C. HJORTLAND, S. B. HULLEY, A. KAGAN AND W. J. Zuiuti. Alcohol and blood lipids, the cooperative lipoprotein phenotyping study. Lancet 2: 153, MENDELSON, J. H., AND N. K. MELLO Alcohol-induced hyperlipidemia and beta lipoproteins. Science 180: 1372, The American JournalofClinical Nutrition 33: JULY 1980, p Printed in U.S.A.