The possible beneficial effects in general of moderate

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1 Lower Risk for Alcohol-Induced Cirrhosis in Wine Drinkers Ulrik Becker, 1,2 Morten Grønbæk, 1 Ditte Johansen, 1 and Thorkild I. A. Sørensen 1 Although there is a well-known relationship between total alcohol intake and future risk for cirrhosis, other factors such as the type of alcohol consumed are sparsely studied. The aim of this study was to assess the effects of wine compared with other types of alcoholic beverages on risk for alcohol-induced cirrhosis. In 3 prospective studies, 30,630 participants from the Copenhagen area were followed-up for a total observation time of 417,325 person-years. Information on weekly intake of beer, wine, and spirits, and sex, age, body mass index, smoking habits, and education was obtained from questionnaires. The primary outcome measures were first admission or death, with alcohol-induced cirrhosis obtained from death certificates and from the National Hospital Discharge Register. Data were analyzed by means of multiplicative Poisson regression models. We confirmed the increasing risk for cirrhosis with increasing alcohol intake. Individuals who drank more than 5 drinks per day had a relative risk of 14 to 20 for developing cirrhosis compared with non- or light drinkers. However, compared with individuals who drank no wine (relative risk set at 1.0), individuals drinking 16% to 30% wine of their total intake had a relative risk of 0.4 (95% confidence limits, ) and those drinking 51% or more of wine had a relative risk of 0.3 (95% confidence limits, ) for developing cirrhosis. In conclusion, the results suggest that a high intake of all 3 types of alcohol conveys an increased risk for cirrhosis, but wine drinkers are at a lower risk than beer and spirits drinkers. (HEPATOLOGY 2002;35: ) The possible beneficial effects in general of moderate wine intake as compared with beer and spirits intake has been corroborated by a cohort study showing a lower risk for dying from not only cardiovascular but also noncardiovascular causes in moderate wine drinkers. 1,2 Although death from alcohol-induced cirrhosis only constitutes a minor proportion of the noncardiovascular causes of death, a different effect of wine, beer, and spirits drinking on the risk for developing alcoholinduced cirrhosis may contribute to the explanation of the apparent beneficial effects of wine drinking on all-cause From the 1 Copenhagen Centre for Prospective Population Studies (Copenhagen County Centre of Preventive Medicine, Copenhagen Male Study, and Copenhagen City Heart Study), Danish Epidemiology Science Centre at the Institute of Preventive Medicine, Copenhagen University Hospital, Copenhagen; and the 2 Department of Gastroenterology, Division of Medical Gastroenterology, and Alcohol Unit, Copenhagen University Hospital, Hvidovre Hospital, Hvidovre, Denmark. Received May 16, 2001; accepted December 28, Supported by the Danish National Board of Health. The Copenhagen Centre for Prospective Population Studies is funded by The Danish National Research Council, and the Danish Epidemiology Science Centre is funded by the Danish National Research Foundation. Address reprint requests to: Ulrik Becker, M.D., Alcohol Unit 161, Hvidovre Hospital, DK 2650 Hvidovre, Denmark. becker@dadlnet.dk; fax: (45) Copyright 2002 by the American Association for the Study of Liver Diseases /02/ $35.00/0 doi: /jhep mortality. There is evidence showing that an alcohol intake of 3 to 5 drinks per day or more leads to the development of cirrhosis in 2% to 3% of individuals per year. 3,4 Prospective population studies with assessment of alcohol intake at baseline show a relationship between alcohol intake and future risk for development of alcoholinduced cirrhosis. 5 However, other factors may modify the effect of alcohol intake on the risk for development of cirrhosis. It was the aim of this study to assess the effect of wine, beer, and spirits on risk for development of alcohol-induced cirrhosis in a prospective population. Patients and Methods Sample. The Copenhagen Centre for Prospective Population Studies contains pooled data from 3 large population studies from the urban and suburban area of Copenhagen: Copenhagen City Heart Study, Copenhagen Male Study, and Copenhagen County Centre of Preventive Medicine. The latter includes 6 cohorts among which 3 are studies from the World Health Organization Monitoring of Trends and Determinants in Cardiovascular Diseases (MONICA). The cohorts have been described in detail earlier. 6-9 The cohorts providing relevant information on beer, wine, and spirits intake was used in 868

2 HEPATOLOGY, Vol. 35, No. 4, 2002 BECKER ET AL. 869 Table 1. Study Sample and Year of Initial Examination and Re-examination Number of Participants Year of Examination Year of Reexamination(s) Observation Time (person-years) Participation Rate at Initial Examination Copenhagen County Centre of Preventive Medicine 1897 birth cohort , birth cohort , birth cohort 1, , , MONICA I 3, , MONICA II 1, , MONICA III 1, , Copenhagen City Heart Study 17, , , Copenhagen Male Study 3, , Total 30, ,325 this study and comprised a total of 30,630 individuals. Table 1 gives an overview of the study sample and cohorts. Briefly, all population studies included a self-administered structured questionnaire concerning general healthrelated issues. The questionnaires were checked by a trained staff member during a general health examination. Alcohol Intake. Participants of the Copenhagen City Heart Study and the Copenhagen County Centre of Preventive Medicine were asked about their average weekly number of drinks of beer, wine, and spirits, respectively. In the Copenhagen Male Study, participants were asked about their daily intake of beer, wine, and spirits on weekdays (Monday to Thursday) and weekend days (Friday to Sunday). These were added up to give the weekly intake to be harmonized with data from the Copenhagen City Heart Study and the Copenhagen County Centre of Preventive Medicine. The overall intake differed in the different cohorts included in the study, but within relevant age- and gender-strata there was consistency between the cohorts. A Danish standard drink contains 12 g of alcohol, corresponding to 1 beer, 1 glass of table wine, or 3 cl of 40% proof spirit. Individuals abstaining because of drug treatment for an alcohol-related problem (n 17) were excluded. Total alcohol intake was classified into 5 categories: less than 1 drink per week (nondrinkers); 1 to 7; 8 to 21; 22 to 35; and more than 35 drinks per week. The statistical models do not allow simultaneous inclusion of all 3 types of alcohol (classified in drinks/wk) and total alcohol intake (classified in drinks/wk). Therefore, variables describing the percentages of wine, beer, and spirits, respectively, classified into 3 levels (less than 1%; 1% to 30%; 31% to 100%), were used in all analyses that also total alcohol intake (classified in drinks/wk). In the final analyses, the wine percentage of total alcohol intake was classified into 5 levels (less than 1%; 1% to 15%; 16% to 30%; 31% to 50%; and 51% to 100%) to obtain a more detailed dose-response function. Other Covariates. Smokers gave information on daily consumption of cigarettes (1 g), cheroots (3 g), cigars (5 g), and pipe tobacco (50 g). Smoking habits were then classified as never-smokers, ex-smokers, current smokers 1 to 14 g/d, current smokers 15 to 24 g/d, and current smokers more than 24 g/d. All participants reported the number of years of school education (classified as less than 8 years; 8-11 years; 12 years or more). Data included measurement of height and weight. Body mass index was calculated as the weight divided by the squared height (classified as 20 kg/m 2 or less; more than kg/m 2 ; more than kg/m 2 ; and more than 30 kg/m 2 [obesity]). Follow-up. The subjects were followed-up from date of entry into the study to date of diagnosis of alcoholinduced cirrhosis, death, disappearance, emigration, or end of follow up, whichever came first. The population was followed up by using the unique person identification number in the national Central Person Register until January 1, Vital status of the population was obtained from the Central Person Register, and the cause of death was determined from the death certificate. Less than 1% of the subjects (n 10) were lost to follow-up. End point of interest was death or discharge with alcohol-induced cirrhosis defined according to the International Classification of Diseases (ICD-8 code ). Register-based information indicating alcohol-induced liver disease has previously been validated, and more than 85% of cirrhosis cases fulfill accepted diagnostic criteria. 5,10 From the Danish National Hospital Discharge Register, information on all hospital discharges from somatic hospitals was obtained. The total study sample included 30,630 individuals (14,335 women and 16,295 men) with a complete set of data and with a total observation time of 417,325 personyears. The mean age at first examination was 52 years (range, years). The distribution of the study sample on covariates is shown in Tables 2 and 3.

3 870 BECKER ET AL. HEPATOLOGY, April 2002 Table 2. Distribution of Determinants and Covariates in Study Sample and Cases Covariate Total Sample 30,630 (100%) Alcoholic Cirrhosis 292 (100%) Sex Women, n (%) 14,335 (46.8%) 80 (27.4%) Median age (yrs) at first examination (range) 52.4 ( ) 51.4 ( ) Total alcohol intake (drinks/wk) n (%) 1 6,119 (20.0%) 26 (8.9%) ,460 (37.4) 35 (12.0%) ,918 (29.1%) 75 (25.7%) ,481 (8.1%) 58 (19.9%) 35 1,652 (5.4%) 98 (33.6%) Percent wine of total alcohol intake n 1% 5,675 (18.5%) 119 (40.8%) 1%-15% 3,303 (10.8%) 58 (19.9%) 16%-30% 3,463 (11.3%) 29 (9.9%) 31%-50% 5,929 (19.4%) 32 (11.0%) 50% 6,141 (20.0%) 28 (9.6%) Total alcohol 0 6,119 (20.0%) 26 (8.9%) Current smokers n (%) 17,897 (58.7%) 225 (77.3%) Body mass index 25 kg/m 2 (%) 13,642 (45.0%) 185 (64.2%) Education 8 years n (%) 12,821 (42.8%) 126 (43.9%) Statistical Analysis. Data were analyzed by means of multiplicative Poisson regression models, assuming constant intensity within each 10-year age interval. The alcohol variables could not be included in the analyses as continuous variables because the risk functions, as seen in Fig. 1, are not linear. Alcohol variables as well as other covariates in the models were classified as described earlier. Whenever information was available on more than 1 occasion, the variables in the model, including alcohol intake and type of alcohol, were updated. An individual with changing covariates within the observation period, and observed in more than 1 age group, contributed with observation time in several strata. Because age-adjusted morbidity may differ among cohorts, a covariate identifying the cohort of origin was included in every model. A close relationship exists between total alcohol intake and intake of wine, beer, and spirits. Therefore, models analyzing the significance of wine, beer, or spirits always included total alcohol intake as a covariate. First, total alcohol intake from any source was analyzed as a risk factor for cirrhosis. Next, analyses assessing the effects of each separate source of alcohol were performed. Finally, models including total alcohol intake as 1 variable, and either percentage of wine, beer, or spirits of total alcohol intake, were estimated. The main effects of available variables were first identified, and significant variables were included in the statistical model. By using backward elimination, insignificant variables were removed by likelihood ratio test (5% level). Estimated rate ratios called relative risks are given with 95% confidence intervals. First-order interactions between total alcohol intake and percentage of wine and between these 2 variables and gender on the risk for developing alcohol-induced cirrhosis were analyzed by inclusion of the interaction components one at a time in the statistical model and checked for significance. Table 3. Baseline Characteristics of Participants by Wine Drinking Group Level of Wine Intake (Percent Wine of Total Alcohol Intake) Covariate Nondrinkers < >50 Number of individuals (N) (row %) 6,119 (20.0%) 3,329 (12.1%) 5,147 (18.7%) 4,991 (18.1%) 5,304 (19.2%) 6,291 (22.8%) Alcohol-induced cirrhosis N (%) 26 (8.9%) 119 (40.8%) 58 (19.9%) 28 (9.6%) 33 (11.3%) 28 (9.6%) Sex % women Age (yrs) Median (range) 57 (21-91) 58 (21-93) 52 (21-93) 51 (21-86) 50 (21-88) 50 (21-89) Smoking % Current smokers Body mass index % Body mass index 25 kg/m Education % 8 years Total alcohol intake Mean drinks per week in each alcohol group drinks/wk 1-7 drinks/wk drinks/wk drinks/wk drinks/wk

4 HEPATOLOGY, Vol. 35, No. 4, 2002 BECKER ET AL. 871 Fig. 1. Relative risks for men developing alcohol-induced cirrhosis. Relative risks were adjusted for age, smoking habits, body mass index, and educational level. Individuals drinking less than 1 drink per week were used as a reference group (relative risk 1.00). Individual lines connect point estimates for groups with the same level of wine intake. For those drinking more than 50% wine, it was not possible to estimate relative risks below a total alcohol intake of 22 drinks per week because of too few participants in these categories., 1% wine;, 1%-15% wine; Œ, 16%-30% wine;, 31%-50% wine;, 50% wine. Results A total of 292 individuals (80 women and 212 men) developed alcohol-induced cirrhosis during the observation period (Table 2) corresponding to an incidence rate of 0.070% per year (0.035% per year for women and 0.100% per year for men). Among the individuals developing alcohol-induced cirrhosis, 10% drank more than 50% of their total alcohol intake as wine whereas 20% of the total sample drank more then 50% of their total alcohol intake as wine. Furthermore, it is seen in Table 2 that 26 individuals developing alcohol-induced cirrhosis were nondrinkers. The number of current smokers was higher among those who later developed alcohol-induced cirrhosis (77.3%) than in the total sample (58.6%), whereas no differences in school education were observed. Obesity, defined as body mass index greater than 32 kg/m 2,was more prevalent among those who developed cirrhosis (19.4%) than in the total sample (10.6%). Total Alcohol Intake. A dose-dependent increase in relative risk for developing alcohol-induced cirrhosis with increasing alcohol intake was observed among women, and a J-shaped relation among men, as shown in Table 4. Because of the number of cases of alcohol-induced cirrhosis among nondrinkers, reference was defined as lightdrinking men (1-6 drinks/wk). Compared with these, heavy-drinking men (more than 35 drinks/wk) had a relative risk for alcohol-induced cirrhosis of 20.4 (95% confidence limits ) and heavy-drinking women had a relative risk of 14.1 ( ). However, the risk function was somewhat steeper for women than for men. This interaction was the only significant interaction observed and it was included in all subsequent analyses. Type of Alcohol. Compared with subjects with a low percentage of their total alcohol intake as wine, wine drinkers were more often women, they were younger, smoked less, and had a higher level of education (Table 3). Table 3 also shows that there was a clear inverse relationship between total alcohol intake and wine percent, attesting to the importance of keeping total alcohol intake as a covariate in the analysis of the wine effects. When total alcohol intake was stratified in interval levels as indicated in Table 3, the mean alcohol intake within each such interval proved to be reasonably stable across the categories of wine intake, which indicated that this stratification of the alcohol intake performed adequately without leaving residual confounding of the wine effects by the total alcohol intake. By using data from cohorts in which re-examinations were available, we observed that the percentage of wine increased from first to second examination (mean 8.0% for women and mean 3.6% for men). These changes in alcohol intake as well as in preference of alcohol type was taken into account by updating the variables in the models whenever possible. In the separate analysis of the effects of wine intake (drinks/wk), adjusting for beer and spirits intake as well as adjusting for the other covariates, we found a relative risk for developing cirrhosis of 0.5 (95% confidence limits ) in the group drinking 1 to 7 drinks of wine per week and a relative risk of 0.6 (95% confidence limits ) and 2.5 (95% confidence limits ), respectively, for the 2 groups drinking 8 to 21 drinks and more than 21 drinks of wine per week. The group drinking less Table 4. Relative Risks for Developing Histologic or Clinical Signs of Alcohol-Induced Cirrhosis in Men and Women Alcohol Intake (drinks/wk) Men Cirrhosis Women ( ) 1.32 ( ) (reference) 1.19 ( ) ( ) 5.33 ( ) ( ) 10.8 ( ) ( ) 14.1 ( ) NOTE. Relative risks were adjusted for age, smoking habits, body mass index, educational level, and percentage wine of total alcohol intake.

5 872 BECKER ET AL. HEPATOLOGY, April 2002 than 1 drink of wine per week was used as reference (relative risk set at 1.0). The results of the final model including total alcohol intake (drinks/wk) and wine percent are shown in Fig. 1. An increase in risk for cirrhosis with increasing total alcohol intake was observed in all categories of wine percent. However, the risk for alcohol-induced cirrhosis was lower for wine drinkers compared with those drinking no or little wine even for heavy drinkers (total alcohol intake more than 35 drinks/wk). For heavy drinkers who drank more than 50% of their alcohol intake as wine, the relative risk was 8.2 (95% confidence limits ) for developing cirrhosis compared with individuals drinking less than 1 drink per week (reference group; relative risk set at 1.0). In contrast, heavy drinkers who drank no wine had a relative risk for developing alcohol-induced cirrhosis of 21.1 (95% confidence limits ). When individuals drinking no wine are used as a reference group in both sexes combined, but with adjustment for gender and total alcohol intake, a dosedependent decrease in relative risk for developing cirrhosis with increasing percentage wine was observed until a wine intake of 16% to 30 % (Fig. 2). Above this level, the risk function leveled off. Compared with individuals who drank no wine (reference, relative risk set at 1.0), 16% to 30% wine had a relative risk of 0.4 (95% confidence limits ) for developing cirrhosis for any Fig. 2. Relative risks for developing alcohol-induced cirrhosis. Relative risks were adjusted for sex, age, smoking habits, body mass index, educational level, and total alcohol intake. Individuals drinking less than 1% wine of total alcohol intake in both sexes combined were used as a reference group (relative risk 1.00). Vertical bars are estimated 95% confidence limits. given level of alcohol intake. Individuals drinking 51% wine or more had a relative risk of 0.3 (95% confidence limits ) for developing cirrhosis. No interactions were observed between wine percent or beer percent and gender, as well as between wine percent and total alcohol intake on the risk for alcohol-induced cirrhosis. Inclusion of percentage beer or percentage of spirits of total alcohol intake in the model was insignificant. Furthermore, no interaction was observed between beer percent and total alcohol intake, as well as no interaction between wine percent and beer percent. This means that for any given level of alcohol intake and wine percent, the relative risk for cirrhosis was independent of level of beer percent (data not shown). In all models, we adjusted for age, sex, cohort, body mass index, smoking, level of education, and total alcohol intake. Other Covariates. Age had a significant influence on the risk for cirrhosis. Individuals aged 20 to 39 years had the lowest risk for developing alcohol-induced cirrhosis. By using this age group as a reference, individuals aged 50 to 59 years had the highest risk for developing cirrhosis (relative risk 6.6; 95% confidence limits ). The duration of education did not significantly influence the risk for developing alcohol-induced cirrhosis. Individuals with a body mass index of 20 to 24 kg/m 2 had the lowest risk for cirrhosis (reference group), whereas individuals with a body mass index less than 20 kg/m 2 had an increased risk (relative risk 2.2; 95% confidence limits ), and individuals with a body mass index greater than 30 kg/m 2 had a relative risk of 2.2 (95% confidence limits ). Finally, smoking was independently and significantly associated with the risk for cirrhosis. Taking all the other variables into account, never-smokers (reference group) had the lowest relative risk for developing cirrhosis. Ex-smokers had a relative risk of 1.4 (95% confidence limits ), smokers of 1 to 14 g/d had a relative risk of 2.0 (95% confidence limits ), smokers of 15 to 24 g/d had a relative risk of 2.1 (95% confidence limits ), and smokers of 25 g/d or greater had a relative risk of 1.4 (95% confidence limits ) for developing alcohol-induced cirrhosis. No significant interactions were observed between total alcohol intake or wine percent and smoking habits. Discussion In this cohort study, the risk for developing alcoholinduced cirrhosis decreased with increasing percentage of wine of total alcohol intake. Furthermore, we confirm findings in earlier studies of the increasing risk for developing alcohol-induced cirrhosis with increasing alcohol intake as well as the steeper risk function in women. 5,11-14

6 HEPATOLOGY, Vol. 35, No. 4, 2002 BECKER ET AL. 873 The validity of self-reported alcohol intake may be questioned, but recent studies have shown that data on alcohol intake, obtained by means of questionnaires, are reasonably accurate. 15,16 The nondrinking group may include individuals who have become nondrinkers because they developed liver disease before inclusion into the study (sick quitters), currently abstaining but formerly heavy-drinking individuals with increased risk for relapse, underreporting, or individuals taking up drinking after the examination. This may have led to a higher relative risk for cirrhosis in nondrinking men compared with those with a moderate intake (J-shaped risk function) as observed earlier and discussed elsewhere. 1,5,12,17-19 Systematic underreporting of alcohol intake may have occurred, leading to overestimation of the relative risks at any given level of alcohol intake. Some light drinkers may previously have had, or later have developed, a heavier alcohol intake. In the analysis we have tried to minimize this problem by updating the alcohol variable when information was available on more than 1 occasion (76.9% of the participants), though excessive alcohol intake of short duration could not be controlled for. A higher degree of underestimation in women than among men may contribute to the observed sex differences as discussed earlier. 5 Concomitant viral hepatitis, especially hepatitis C, may be an additional risk factor for developing alcoholinduced cirrhosis. 20 We have no information on serologic status of the participants, but Denmark is a low-prevalence area for hepatitis B and C (0.1%-0.3%). Variation in prevalence of viral hepatitis with beverage choice to such extent that it may bias results is very unlikely, though it cannot be ruled out. Misclassification of alcohol-induced cirrhosis on death certificates and in hospital discharge records is possible, but, as previously discussed, is probably not a major problem. 5 These cases are probably equally distributed in the different groups of alcohol intake and are not likely to produce the observed associations. The observed incidence rate of 0.035% per year for women and 0.1% per year for men is approximately half of what was observed in a National Register based incidence study from 1981 to 1985 (incidence rates for women and men 0.085% per year and 0.19% per year, respectively). 21 This is probably owing to underestimation in our study because of underrepresentation of heavy drinkers, but it is not likely to bias the estimates of the risk functions within our cohorts. The risk for developing cirrhosis in wine drinkers (more than 30% wine of total alcohol intake) was less than 50% of the risk in nonwine drinkers for any given level of total alcohol intake. However, the risk for developing cirrhosis increased with increasing alcohol intake in all categories of wine percent. Beer and spirits drinking did not modify the relation between total alcohol intake and risk for developing cirrhosis. A recent trend analysis of aggregated data showed a consistent long-term relation between per capita spirits consumption and cirrhosis mortality without establishing a direct link between type of alcohol and cirrhosis mortality. 22 Cross-sectional and cross-national studies have shown a higher prevalence of cirrhosis in wine-drinking countries compared with predominantly beer-drinking countries. 23 Likewise, a cross-sectional study of the association between alcohol intake and cirrhosis mortality in 38 countries 24 seems to show increased cirrhosis mortality in wine drinkers. However, wine-drinking countries are also characterized by a high total alcohol intake, and cross-sectional studies at the aggregate level must be interpreted with caution because they do not elucidate the risk function at the individual level. First, the measure of exposure must precede the event (i.e., development of cirrhosis) to be a valid predictor. Second, it is likely that the risk for dying among cirrhotic patients increases with increasing alcohol intake, whereas the risk for development of cirrhosis may well be independent of a dose above a certain threshold. 3,4 In a prospective study of 258 alcohol-abusing men, Sørensen 3 did not find any relationship between preferred alcohol type and subsequent incidence of cirrhosis. However, only preference for beer or spirits but not for wine was available in that study. There is no reason to believe that wine drinkers report their alcohol intake differently from beer or spirits drinkers, and most drinkers do not drink 1 type of alcohol exclusively. 15 If, however, nonwine drinkers do underreport their alcohol intake in comparison with wine drinkers, a correction for this phenomenon would lead to a reduction of the observed differences between wine and nonwine drinkers. Our results must be interpreted in the light of former studies 3,4 showing that the relation between current alcohol intake and risk for development of cirrhosis may be a dose-independent conditioning effect that starts when the alcohol intake exceeds a threshold at about 3 to 5 drinks per day. Thus, the relation between alcohol intake at a given point in time, and later cirrhosis, may reflect the relation between this alcohol intake and the likelihood that the alcohol intake later exceeds the threshold. Therefore, the present result may suggest that wine drinkers run a lower risk for exceeding the threshold for the conditioning effect of alcohol on the development of alcohol-induced cirrhosis. Along this line, we found a lower risk for developing alcohol-induced cirrhosis in individuals with a normal body mass index (20-24 kg/m 2 ) and in individuals

7 874 BECKER ET AL. HEPATOLOGY, April 2002 who had never smoked, possibly also indicating a low risk for developing an excessive alcohol intake. Wine intake was positively correlated with level of education, 25 but educational level was controlled for in all analyses. Dietary deficiencies may contribute to the development of alcohol-induced cirrhosis, though no solid evidence exists for the role in humans of nutritional disturbances in the development of cirrhosis. 29 A high level of wine intake may also be related to a low-fat diet, healthy with regard to cardiovascular disease and cancer, and wine is more often consumed with a meal than the other types of alcohol. Free radical formation after alcohol intake and a reduced level of antioxidants has been implicated in the pathogenesis of alcohol-induced liver disease. 33,34 Nonalcoholic constituents of wine have antioxidant properties 35,36 and intake of red wine has been shown to increase antioxidant activity in serum. 37,38 The flavonoid, quercetin, has been shown to reduce oxidative damage to the liver in rats, 39 and resveratrol as well as quercetin can inhibit activation of rat hepatic stellate cells. 36 However, antioxidants are also abundant in a diet with a high content of vegetables and fruits, 40 and a causal relation between ingestion of these substances and a reduced risk for cirrhosis remains to be shown. The observed effect of wine drinking may merely reflect a lower risk for later excessive drinking or a lower risk for being exposed to the unknown additional risk factors that initiate liver damage in subjects conditioned by heavy drinking. The association between wine intake and other lifestyle factors including current alcohol intake should also be studied in detail. The public health implications of these results remains to be determined because a causal relationship between wine drinking and beneficial health effects have not yet been established. Acknowledgment: The authors thank Birgitte Bredesen, Susanne Dahl, and the staff members of the Copenhagen Centre for Prospective Population Studies for valuable help. Adam Gottschau, Anders Munch Bjerg, and Michael Gamborg are acknowledged for statistical advice and Michael Larsen for data management. References 1. Grønbæk M, Deis A, Sørensen TIA, Becker U, Schnohr P, Jensen G. Mortality associated with moderate intakes of wine, beer, or spirits. Br Med J 1995;310: Grønbæk M, Becker U, Johansen D, Gottschau A, Schnohr P, Hein HO, Jensen G, et al. Type of alcohol consumed and mortality from all causes, coronary heart disease, and cancer. 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