Coffee Intake and Mortality from Liver Cirrhosis

Coffee Intake and Mortality from Liver Cirrhosis AAGE TVERDAL, PHD, AND SVETLANA SKURTVEIT, PHD PURPOSE: The aim of the study was to evaluate the association between coffee consumption and mortality from liver cirrhosis. METHODS: We conducted a mortality follow-up of 51,306 adults who underwent screening for cardiovascular disease from 1977 to 1983. During the subsequent 17 years, the total number of from all causes in the studied cohort was 4207. Fifty-three had the diagnosis of cirrhosis mentioned on the death certificate; of these, 36 had alcoholic cirrhosis. RESULTS: The relative risk of liver cirrhosis mentioned on the death certificate associated with an increase of two cups of coffee, adjusted for sex, age, alcohol use and other major cardiovascular risk factors was 0.6 (95% confidence interval, 0.5 0.8). For alcoholic cirrhosis the results were identical. When studying cirrhosis as the underlying cause of death, the inverse relationship becomes somewhat stronger. CONCLUSIONS: The present study confirms the existence of an inverse association between coffee consumption and liver cirrhosis. Ann Epidemiol 2003;13:419 423. 2003 Elsevier Inc. All rights reserved. KEY WORDS: Liver cirrhosis, Alcohol, Coffee consumption. INTRODUCTION Alcoholic beverages and coffee have been part of the human diet for centuries. Norway is well known for a restrictive alcohol policy and the total alcohol consumption is relatively low and liver cirrhosis mortality is not predominant. On the other hand Norwegians are among the highest consumers of coffee in the world (1). Alcohol has a well-established toxic and graded effect on liver, including cirrhosis. Since most heavy drinkers do not develop alcoholic cirrhosis, it is widely believed that alcoholic cirrhosis has multiple causes and that both start and progression of the process may be dependent upon predisposing factors and other causes. It has the well known effect of raising blood concentration of the liver enzyme glutamyltransferase (GGT) which is widely used as a marker of alcohol intake, although it is documented that other factors also are associated with serum levels of GGT (2 4). An inverse association between serum GGT and intake of coffee has been documented in the study of Arnesen et al. (2) in population studies in Norway. This finding has been consistently observed in population studies from other countries (3 6). Attention has recently been drawn to possible beneficial effects of coffee drinking on liver diseases. A prospective study of Klatsky et al. (7 8) reported a lower risk of hospitalization, From the Norwegian Institute of Public Health, Oslo, Norway (A.T., S.S.). Address correspondences to: Svetlana Skurtveit, Ph.D., Norwegian Institute of Public Health, P.O. Box 4404, Nydalen, 0403 Oslo, Norway. Tel.: ( 47) 234-081-72; Fax: ( 47) 234-082-60. E-mail:svetlana.skurtveit @fhi.no Received May 28, 2002; accepted October 4, 2002. and death from alcoholic cirrhosis in association with coffee drinking. Similar results were also observed in three casecontrol studies published later (9 11). To provide further information on the issue, we utilized a cardiovascular survey in a population characterized by high coffee consumption and low risk of liver cirrhosis and did mortality follow-up with liver cirrhosis mentioned on the death certificate as endpoint. MATERIALS AND METHODS Between 1977 and 1983, men and women living in three counties in different parts of Norway (Finmark 1977 78, Sogn og Fjordane 1980, Oppland 1981 83) were invited to participate in a cardiovascular screening program organized by the National Health Screening Service. The screening procedures have been described in detail elsewhere (1, 12). The survey included all residents aged 40 55, and an approximately 20% random sample of men and women aged 20 39 years. Response rate was high (87% for men and 93% for women) and it was much the same in the three counties. On the reverse side of the invitation letter was a questionnaire including questions on smoking habits, physical activity, and history of cardiovascular diseases. The information about coffee and alcohol consumption was obtained from a self-administered food-frequency questionnaire (13). This was handed out to the person who attended the screening, and was to be returned by mail. All participants, except in 5 municipalities in Sogn Fjordane, got this additional questionnaire and about 94% returned it. A small percentage, 4%, of those who responded, did not answer the question on coffee habits. 2003 Elsevier Inc. All rights reserved. 1047-2797/03/$ see front matter 360 Park Avenue South, New York, NY 10010 doi:10.1016/s1047-2797(02)00462-3

420 Tverdal and Skurtveit AEP Vol. 13, No. 6 COFFEE AND MORTALITY FROM CIRRHOSIS July 2003: 419 423 Our study population included persons, aged 20 55 years (median 43.6 years), who answered all questions on life style habits used in the present study a total of 25,763 men and 25,543 women. The examination comprised measurements of weight, height, systolic and diastolic blood pressure, and collection of venous non-fasting blood samples. Serum cholesterol and triglycerides were determined at the same laboratory Central Laboratory, Ullevål Hospital, Oslo (1, 12). The question about coffee read, How many cups of coffee do you usually drink per day? with preset categories: Do not drink coffee or less than one cup, 1 2 cups, 3 4 cups, 5 6 cups, 7 8 cups, and 9 or more cups. These categories were coded as 1, 2, 3, 4, 5 and 6 when estimating linear trend and relative risk. No question about the method of coffee preparation was asked. Alcohol consumption was recorded using two questions: Do you usually drink wine/spirits during one week? and Do you usually drink beer during one week? Drinkers of alcohol were defined as people who answered yes on one or both alcohol questions. Information on smoking habits was collected by the questions: Do you smoke daily at present? and How many cigarettes do you or did you usually smoke daily? The number of observation years was calculated for each person from the time of examination at screening to the time of death, time of emigration, or at the end of the follow-up (end of 1997). Mean follow-up was 16.9 years. The total number of from all causes in the studied cohort was 4207, and 173 persons emigrated from Norway during follow-up period. The follow-up period covered three versions of the International Classification of Diseases (ICD). Liver cirrhosis was defined as ICD-8, 9: 571 and ICD10: K70 or K73 or K74. Alcoholic liver cirrhosis was defined as ICD-8, 9: 571.0 571.3 and ICD 10: K70. Up to four causes of death were recorded on the death certificate in ICD-8 and ICD-9 and up to seven causes of in ICD-10. The first cause is the underlying; the others are contributory causes of death. Altogether, 33 were recorded with cirrhosis as the underlying cause and 20 with cirrhosis as the contributing cause; i.e. cirrhosis was mentioned on the death certificate for 53, 38 of the in men and 15 in women. The corresponding figures for alcoholic cirrhosis were 25 as the underlying cause and 11 as the contributing cause; i.e. alcoholic cirrhosis was mentioned on the death certificate for 36, 32 of the in men and 4 in women. The mean age at death was 46.3 years for cirrhosis and 45.1 years for alcoholic cirrhosis. Relative risks were estimated by using the Cox proportional hazards regression model in SPSS (14). Interaction was tested by comparing 2 *(log likelihood) in models with and without the interaction term. Direct standardization was used to obtain rates/100000 personyears with the study population in five-year age-groups as the standard. Linear trend across various variables of the coffee categories was estimated by linear regression, with coffee as the dependent variable. RESULTS Table 1 shows biologic variables and other lifestyle factors according to different levels of coffee intake. Cholesterol levels and prevalence of the current daily smoking and alcohol use increased steadily with increasing level of coffee intake. The mortality rates were distinctly lower among persons drinking three or more cups of coffee than in those drinking two or less (Table 2). This applies to both cirrhosis and alcoholic cirrhosis as mentioned and underlying causes. For above three cups of coffee there was no clear relationship with liver cirrhosis mortality. When coffee intake was entered as a continuous variable in the Cox regression analysis, a distinct inverse relationship with death from liver-, total- and alcoholic cirrhosis appeared. (Table 3). The relationship persisted or became even stronger after adjustment for smoking and alcohol use. Additional adjustment for triglycerides, systolic blood pressure, BMI, and cholesterol did not change the relationship. Smoking and alcohol use were positively related to mortality from cirrhosis and alcoholic cirrhosis. When the analyses were done with cirrhosis as the underlying cause of death as endpoint, similar relative risks emerged. When number of cigarettes was used as covariate, similar relative risk of coffee consumption on death from cirrhosis was observed. Testing for interaction between coffee and smoking, and smoking and alcohol in relation to death of liver cirrhosis produced no significance. However, our study had less than 20% power to reveal the interactions of the magnitudes that we actually found, with 5% significance level. This is based on the sample size consideration given by Schmoor et al. (15) for binary prognostic factors in survival analysis. In this case, we dichotomized coffee intake into 4 and 4 cups/day. Hence, the existence of interactions cannot be ruled out by this study. It is mentioned that our study had close to 80% power to detect the main effect of coffee. DISCUSSION This study provides evidence of a favorable role of coffee intake on the risk of death from liver cirrhosis. To our knowledge, only the studies of Klatsky et al. (7 8), Corrao et al. (9 10) and Gallus et al. (11) have related the risk of cirrhosis to coffee intake. In the prospective study conducted in Northern California (7), an inverse coffee-cirrhosis relation was reported for the first time. Coffee drinking, but not tea drinking, was inversely related to alcoholic cirrhosis risk, with persons who drank four or more cups per day at onefifth the risk of those who did not drink coffee. These find-

AEP Vol. 13, No. 6 Tverdal and Skurtveit 421 July 2003: 419 423 COFFEE AND MORTALITY FROM CIRRHOSIS TABLE 1. Baseline characteristics according to coffee consumption in Norwegian men and women 20 55 years Baseline characteristics Cups of coffee per day 1 1 2 3 4 5 6 7 8 9 p (trend) No. at risk 2327 4802 15,138 15,598 8059 5382 Median age 40.2 43.2 44.6 44.1 43.1 41.7 0.001 Sex (men %) 57.1 48.0 43.0 48.6 56.6 64.7 0.001 Alcohol use (%) 26.6 28.3 26.4 28.4 32.3 37.0 0.001 Current daily smokers (%) 17.8 23.1 29.0 43.8 58.9 71.0 0.001 BMI (kg/m2) 24.4 24.7 25.0 25.0 25.0 25.0 0.001 Total cholesterol (mmol/l) 5.59 5.91 6.10 6.19 6.27 6.37 0.001 Triglycerides (mmol/l) 1.74 1.80 1.75 1.76 1.79 1.79 ns Systolic blood pressure (mmhg) 132 134 135 134 134 133 0.05 ings were later supported by case-control studies with morbidity of liver cirrhosis as endpoint (9 10). In the study of Gallus et al. (11), an inverse relation was observed across strata of tobacco and alcohol consumption, also after adjustment to age, sex and other major covariates like body mass index, fruit or vegetable consumption, and education. Results from our study are in agreement with these studies. One strength of our study is the prospective design minimizing the chance of exposure recall bias. It is unlikely that our findings are due to selection of people with a favorable life style. In previous studies in almost the same study population, correlation coefficients between coffee consumption and a battery of lifestyle and biological variables were estimated (13). Coffee drinking was largely related to factors that are considered to constitute an unfavorable lifestyle. Furthermore, previously discussed studies (7 11) on coffee and liver cirrhosis and our study are obtained from different patients or populations who have very different cultural and dietary patterns. One weakness of the study is that we only have mortality as the endpoint. People might have liver cirrhosis without dying from it or without having it mentioned on the death certificate. However, it is less likely that a diagnosis of liver cirrhosis is passed over in alcohol users. As there is a positive correlation between coffee intake and alcohol intake, it is reasonable to believe that diagnosis of liver cirrhosis also is less likely to be missed in coffee users. The corollary is that if a differential misclassification is present, it is more likely that the consequence has been a dilution of the relationship between coffee intake and mortality from liver cirrhosis. The questions on alcohol intake did not concern alcohol dose. However, it is hard to believe that those who usually did not consume alcohol during one week should have the highest intake. Another potential confounder is the smoking. Coffee consumers smoke more cigarettes (13). The analysis with number of cigarettes as covariate produced similar results. It is also noted that adjustment for smoking did not alter or strengthen the inverse relationship between coffee intake and mortality from liver cirrhosis. Hence, it is not likely that the observed relationship is due to residual confounding of smoking. Coffee drinking was associated with higher levels of cholesterol. To see if the favorable effect of coffee drinking on death from liver cirrhosis was mediated through cholesterol level, we related serum cholesterol to liver cirrhosis mentioned on the death certificate in a Cox analysis. Serum cholesterol was not related to liver cirrhosis. What agent in coffee may explain the protective effect of coffee consumption on liver cirrhosis is not clear today. The possibility that substances contained in coffee may exert a protective effect on the hepatocyte has been underlined by the study of Casiglia et al. (16), which found consistently lower liver enzymes in coffee drinkers than in non-coffee drinkers; the higher the daily number of cups of coffee, the lower the serum levels of all liver enzymes and bilirubin. Coffee intake was significantly related to decreased serum concentrations of liver enzymes also in other previous studies (5, 17). The study of Corrao et al. (10) concluded that the inverse relationship of coffee and cirrhosis is probably not attributable to caffeine because no negative liver cirrhosis relationship was found to the other beverages containing caffeine. Studies of Urgert et al (18) and Weusten-Van der Wouw et al. (19) showed in human experimental studies that coffee oils, brews, and grounds containing cafestol and kahweol increased liver function enzymes such as alanin aminotransferase, asparate aminotransferase but reduced serum level of GGT and creatinin. The acute alteration in liver enzyme levels with intake of cafestol and kahweol as individual agents differ from the results of epidemiological studies that examined the association between coffee intake and liver enzymes other than GGT. Such findings could suggest that cafestol and kahweol are not the only agents in coffee responsible for the epidemiological findings in our study. Other ingredients contained in coffee with various biological actions may well play a role, as there are three to four-hundred pharmaceutically active substances in coffee (20). There seems to be a threshold in the relationship; no further decline in mortality when the intake is more than three to four cups of coffee. The size of the cups varies a lot in Norway, with an average of 1.25 dl (1). If part of the etiology, a sufficient dose seems to be in order of at least 3.7 dl per day.

422 Tverdal and Skurtveit AEP Vol. 13, No. 6 COFFEE AND MORTALITY FROM CIRRHOSIS July 2003: 419 423 TABLE 2. Crude and mortality per 100,000 person-years from liver cirrhosis or alcoholic cirrhosis by coffee intake for men and women 20 55 years Cirrhosis Alcoholic cirrhosis Mentioned Underlying Mentioned Underlying Cups of coffee/day 1 5 12.90 15.50 4 10.31 12.29 3 7.73 9.04 2 5.15 5.88 1 2 12 15.05 15.64 9 11.28 11.60 9 11.28 12.07 8 10.03 10.42 3 4 11 4.35 3.89 7 2.77 2.57 6 2.37 2.19 5 1.98 1.85 5 6 15 5.68 5.59 10 3.78 3.72 10 3.78 3.76 7 2.65 2.63 7 8 6 4.33 4.60 2 1.44 1.66 6 4.33 4.60 2 1.44 1.66 9 4 4.21 4.54 1 1.05 1.09 2 2.10 2.18 1 1.05 1.09 p (trend) 0.01 0.01 0.001 0.001 0.05 0.05 0.01 0.01 TABLE 3. Relative risks (95% confidence intervals) estimated by Cox proportional hazards regression for men and women 20 55 years Mentioned Underlying Model with sex, age and Model with sex, age and Coffee or alcohol or smoking, one at time Coffee, alcohol and smoking Coffee, alcohol, smoking and others a Coffee or alcohol or smoking, one at time Coffee, alcohol and smoking Coffee, alcohol, smoking and others a Cirrhosis Coffee drinking (per unit) 0.7 0.6 (0.5 0.8) 0.6 (0.5 0.8) 0.6 0.5 (0.4 0.7) 0.5 (0.4 0.7) Alcohol use (yes/no) 5.3 4.8 (2.6 8.9) 4.9 (2.6 9.1) 7.6 6.7 (2.9 15.4) 6.9 (2.9 16.1) Smoking (yes/no) 2.4 2.8 (1.6 5.0) 3.0 (1.7 5.4) 2.7 3.4 (1.6 7.3) 3.7 (1.7 7.9) Alcoholic cirrhosis Coffee drinking (per unit) 0.7 0.6 (0.5 0.8) 0.6 (0.5 0.8) 0.6 0.5 (0.4 0.7) 0.5 (0.4 0.7) Alcohol use (yes/no) 11.0 10.1 (3.8 26.6) 10.1 (3.8 27.1) 14.4 12.9 (3.7 44.6) 13.3 (3.8 46.6) Smoking (yes/no) 2.4 2.7 (1.3 5.5) 2.9 (1.4 6.0) 2.6 3.1 (1.3 7.5) 3.4 (1.4 8.2) a BMI, total cholesterol, systolic blood pressure and triglycerides (log transformed); all variables in the model.

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