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Coffee, liver enzymes, cirrhosis and liver cancer

  • Carlo La Vecchia
    Correspondence
    Tel.: +39 02 390 14527; fax: +39 02 3320 0231.
    Affiliations
    Istituto di Ricerche Farmacologiche ‘Mario Negri’, via Eritrea 62, Milano, and Istituto di Statistica Medica e Biometria, University of Milan, Milan, Italy
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Published:January 25, 2005DOI:https://doi.org/10.1016/j.jhep.2005.01.004
      Several data on a potentially favourable effect of coffee on liver function and liver diseases have accumulated over the last two decades. These span from liver enzymes, to cirrhosis and to hepatocellular carcinoma, and therefore constitute a continuation not only of epidemiological data, but also of biological and clinical evidences.
      Coffee consumption, in fact, has been inversely related to gamma-glutamyltransferase (GGT) activity in studies from Norway, Italy, Finland, France, Japan and the United States [
      • Arnesen E.
      • Huseby N.E.
      • Brenn T.
      • Try K.
      The Tromso Heart Study: distribution of, and determinants for, gamma-glutamyltransferase in a free-living population.
      ,
      • Nilssen O.
      • Forde O.H.
      • Brenn T.
      • The Tromso Study
      Distribution and population determinants of gamma-glutamyltransferase.
      ,
      • Casiglia E.
      • Spolaore P.
      • Ginocchio G.
      • Ambrosio G.B.
      Unexpected effects of coffee consumption on liver enzymes.
      ,
      • Kono S.
      • Shinchi K.
      • Imanishi K.
      • Todoroki I.
      • Hatsuse K.
      Coffee and serum gamma-glutamyltransferase: a study of self-defense officials in Japan.
      ,
      • Nilssen O.
      • Forde O.H.
      Seven-year longitudinal population study of change in gamma-glutamyltransferase: the Tromso Study.
      ,
      • Sharp D.S.
      • Benowitz N.L.
      Re: ‘alcohol, smoking, coffee, and cirrhosis’ and coffee and serum gamma-glutamyltransferase: a study of self-defense officials in Japan.
      ,
      • Pintus F.
      • Mascia P.
      Distribution and population determinants of gamma-glutamyltransferase in a random sample of Sardinian inhabitants. ‘ATS-SARDEGNA’ Research Group.
      ,
      • Poikolainen K.
      • Vartiainen E.
      Determinants of gamma-glutamyltransferase: positive interaction with alcohol and body mass index, negative association with coffee.
      ,
      • Tanaka K.
      • Tokunaga S.
      • Kono S.
      • Tokudome S.
      • Akamatsu T.
      • Moriyama T.
      • et al.
      Coffee consumption and decreased serum gamma-glutamyltransferase and aminotransferase activities among male alcohol drinkers.
      ,
      • Honjo S.
      • Kono S.
      • Coleman M.P.
      • Shinchi K.
      • Sakurai Y.
      • Todoroki I.
      • et al.
      Coffee drinking and serum gamma-glutamyltransferase: an extended study of Self-Defense Officials of Japan.
      ,
      • Nakanishi N.
      • Nakamura K.
      • Nakajima K.
      • Suzuki K.
      • Tatara K.
      Coffee consumption and decreased serum gamma-glutamyltransferase: a study of middle-aged Japanese men.
      ,
      • Nakanishi N.
      • Nakamura K.
      • Suzuki K.
      • Tatara K.
      Lifestyle and the development of increased serum gamma-glutamyltransferase in middle-aged Japanese men.
      ,
      • Nakanishi N.
      • Nakamura K.
      • Suzuki K.
      • Tatara K.
      Lifestyle and serum gamma-glutamyltransferase: a study of middle-aged Japanese men.
      ,
      • Nakanishi N.
      • Nakamura K.
      • Suzuki K.
      • Tatara K.
      Effects of coffee consumption against the development of liver dysfunction: a 4-year follow-up study of middle-aged Japanese male office workers.
      ,
      • Honjo S.
      • Kono S.
      • Coleman M.P.
      • Shinchi K.
      • Sakurai Y.
      • Todoroki I.
      • et al.
      Coffee consumption and serum aminotransferases in middle-aged Japanese men.
      ,
      • Aubin H.J.
      • Lauteaux C.
      • Zerah F.
      • Tilikere S.
      • Vernier F.
      • Vallat B.
      • et al.
      Joint influence of alcohol, tobacco, and coffee on biological markers of heavy drinking in alcoholics.
      ]. The inverse relation was particularly strong in high risk subjects, including heavy alcohol drinkers [
      • Casiglia E.
      • Spolaore P.
      • Ginocchio G.
      • Ambrosio G.B.
      Unexpected effects of coffee consumption on liver enzymes.
      ,
      • Kono S.
      • Shinchi K.
      • Imanishi K.
      • Todoroki I.
      • Hatsuse K.
      Coffee and serum gamma-glutamyltransferase: a study of self-defense officials in Japan.
      ,
      • Sharp D.S.
      • Benowitz N.L.
      Re: ‘alcohol, smoking, coffee, and cirrhosis’ and coffee and serum gamma-glutamyltransferase: a study of self-defense officials in Japan.
      ,
      • Poikolainen K.
      • Vartiainen E.
      Determinants of gamma-glutamyltransferase: positive interaction with alcohol and body mass index, negative association with coffee.
      ,
      • Tanaka K.
      • Tokunaga S.
      • Kono S.
      • Tokudome S.
      • Akamatsu T.
      • Moriyama T.
      • et al.
      Coffee consumption and decreased serum gamma-glutamyltransferase and aminotransferase activities among male alcohol drinkers.
      ,
      • Honjo S.
      • Kono S.
      • Coleman M.P.
      • Shinchi K.
      • Sakurai Y.
      • Todoroki I.
      • et al.
      Coffee drinking and serum gamma-glutamyltransferase: an extended study of Self-Defense Officials of Japan.
      ]. Thus, in a study of 2494 male self-defence officials from Japan [
      • Kono S.
      • Shinchi K.
      • Imanishi K.
      • Todoroki I.
      • Hatsuse K.
      Coffee and serum gamma-glutamyltransferase: a study of self-defense officials in Japan.
      ], the geometric mean GGT was about 30% lower in subjects who drank five or more cups of coffee per day compared to nondrinkers. In another Japanese dataset [
      • Honjo S.
      • Kono S.
      • Coleman M.P.
      • Shinchi K.
      • Sakurai Y.
      • Todoroki I.
      • et al.
      Coffee drinking and serum gamma-glutamyltransferase: an extended study of Self-Defense Officials of Japan.
      ], the inverse relation between coffee and GGT was restricted, or stronger, in alcohol drinkers.
      Although GGT is a relevant indicator of cirrhosis risk, serum alanine aminotransferase (ALT) activity is a more specific marker of liver injury than GGT, and a few population-based surveys from Italy and Japan [
      • Kono S.
      • Shinchi K.
      • Imanishi K.
      • Todoroki I.
      • Hatsuse K.
      Coffee and serum gamma-glutamyltransferase: a study of self-defense officials in Japan.
      ,
      • Honjo S.
      • Kono S.
      • Coleman M.P.
      • Shinchi K.
      • Sakurai Y.
      • Todoroki I.
      • et al.
      Coffee drinking and serum gamma-glutamyltransferase: an extended study of Self-Defense Officials of Japan.
      ,
      • Honjo S.
      • Kono S.
      • Coleman M.P.
      • Shinchi K.
      • Sakurai Y.
      • Todoroki I.
      • et al.
      Coffee consumption and serum aminotransferases in middle-aged Japanese men.
      ,
      • Aubin H.J.
      • Lauteaux C.
      • Zerah F.
      • Tilikere S.
      • Vernier F.
      • Vallat B.
      • et al.
      Joint influence of alcohol, tobacco, and coffee on biological markers of heavy drinking in alcoholics.
      ] found a similar inverse relation between coffee drinking and ALT. Furthermore, among 5944 adults in the Third US National Health and Nutrition Examination Survey conducted in 1988–94, the multivariate relative risk (RR) for elevated ALT activity (>43 U/L) was 0.56 in subjects who drank more than two cups of coffee per day compared to non-coffee drinkers [
      • Ruhl C.E.
      • Everhart J.E.
      Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States.
      ]. The inverse relation was consistent across strata of major covariates, including indicators of liver injury and alcohol drinking. This is of specific interest, since coffee may be a substitute for alcoholic beverages on an individual and on a population level, and indicates therefore that the favourable effect of coffee cannot be accounted for only by lower alcohol drinking in (heavy) coffee consumers.
      Coffee drinking has also been inversely related to the risk of cirrhosis [
      • Sharp D.S.
      • Everhart J.E.
      • Benowitz N.L.
      Coffee, alcohol, and the liver.
      ]. In a cohort study, including 59 cases from the Kaiser Permanente Medical Care Program, subjects who drank four or more cups of coffee per day had about five fold lower the risk of non coffee drinkers [
      • Klatsky A.L.
      • Armstrong M.A.
      Alcohol, smoking, coffee, and cirrhosis.
      ]. In the same dataset, coffee was inversely related to the risk of cirrhosis death (multivariate RR=0.77 for coffee drinkers versus nondrinkers [
      • Klatsky A.L.
      • Armstrong M.A.
      • Friedman G.D.
      Coffee, tea, and mortality.
      ]).
      A case-control study from Italy, including 115 cases, showed an inverse relation between coffee and the risk of cirrhosis, and a favorable effect of coffee on alcohol-related cirrhosis risk [
      • Corrao G.
      • Lepore A.R.
      • Torchio P.
      • Valenti M.
      • Galatola G.
      • D'Amicis A.
      • et al.
      The effect of drinking coffee and smoking cigarettes on the risk of cirrhosis associated with alcohol consumption. A case-control study. Provincial Group for the Study of Chronic Liver Disease.
      ]. Another larger Italian study, which included 274 cases and 458 controls, also showed a strong inverse relation between coffee drinking and cirrhosis, with a RR of 0.16 for drinkers of four or more cups per day compared to non-coffee drinkers. The apparent protection was consistent across strata of alcohol drinking, as well as of serum markers of hepatitis B and C [
      • Corrao G.
      • Zambon A.
      • Bagnardi V.
      • D'Amicis A.
      • Klatsky A.
      Coffee, caffeine, and the risk of liver cirrhosis.
      ].
      In a hospital-based case-control study of digestive tract and liver diseases from Milan, Italy, including 101 cases with cirrhosis and 1538 controls, the RR was 0.77 for subjects drinking one cup of coffee per day, 0.57 for two, and 0.29 for three or more cups compared to non coffee drinkers. The RR for 40 years of coffee consumption or more was 0.45. The inverse trend in risk between cancer risk and the number of cups drunk and between cancer risk and duration of coffee drinking were both significant. [
      • Gallus S.
      • Tavani A.
      • Negri E.
      • La Vecchia C.
      Does coffee protect against liver cirrhosis?.
      ].
      Cirrhosis is a major correlate of hepatocellular carcinoma [
      • Adami H.O.
      • Haing A.W.
      • McLaughlin J.K.
      • Trichopoulous D.
      • Hacker D.
      • Ekbom A.
      • et al.
      Alcoholism and liver cirrhosis in the etiology of primary liver cancer.
      ,
      • La Vecchia C.
      • Negri E.
      • Cavalieri D'Oro L.
      • Franceschi S.
      Liver cirrhosis and the risk of primary liver cancer.
      ,
      • Kuper H.
      • Tzonou A.
      • Kaklamani E.
      • Hsieh C.C.
      • Lagiou P.
      • Adami H.O.
      • et al.
      Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma.
      ,
      • Colombo M.
      • de Franchis R.
      • Del Ninno E.
      • Sangiovanni A.
      • De Fazio C.
      • Tommasini M.
      • et al.
      Hepatocellular carcinoma in Italian patients with cirrhosis.
      ], and the relation between coffee drinking and the risk of primary liver cancer has been examined in at least two studies. An Italian case-control study [
      • La Vecchia C.
      • Ferraroni M.
      • Negri E.
      • D'Avanzo B.
      • Decarli A.
      • Levi F.
      • et al.
      Coffee consumption and digestive tract cancers.
      ] based on 151 cases with hepatocellular carcinoma, reported a multivariate RR of 0.78 for drinkers of ≥3 cups of coffee per day, compared to non coffee drinkers. In a Greek case-control study [
      • Kuper H.
      • Tzonou A.
      • Kaklamani E.
      • Hsieh C.C.
      • Lagiou P.
      • Adami H.O.
      • et al.
      Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma.
      ], including 333 cases, the age- and sex-adjusted RR was 0.7 for drinkers of ≥20 cups of coffee per week compared to non drinkers.
      In an updated and combined analysis of the above mentioned Greek and Italian datasets, which included a total of 844 cases and 1912 controls, the multivariate RR was 0.7 for drinkers of three or more cups of coffee per day compared to non-coffee drinkers [
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • Bosetti C.
      • Negri E.
      • La Vecchia C.
      • et al.
      Does coffee protect against hepatocellular carcinoma?.
      ]. The apparent favourable effect of coffee consumption on hepatocellular carcinoma may be due to its inverse relation with cirrhosis, but allowance for clinical history of cirrhosis did not totally account for the inverse association in the combined analysis [
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • Bosetti C.
      • Negri E.
      • La Vecchia C.
      • et al.
      Does coffee protect against hepatocellular carcinoma?.
      ]. However, allowance for clinical history of cirrhosis may well be subject to underdiagnosis, and hence residual confounding may be present. More important, the RR for the highest level of coffee drinking was only of borderline statistical significance, and even modest residual bias or confounding could well explain the apparent inverse association.
      The study by Gelatti et al. in this issue of the Journal [
      • Gelatti U.
      • Covolo L.
      • Franceschini M.
      • Pirali F.
      • Tagger A.
      • Ribero M.L.
      • et al.
      Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case-control study.
      ], a hospital-based case-control study of 250 cases and 500 controls from northern Italy, provided additional relevant quantification of the inverse relation between coffee and hepatocellular carcinoma. Compared with non coffee drinkers, the RRs were 0.8 for drinkers of 1–2 cups per day, 0.4 for those of 3–4 cups, and 0.3 for drinkers of five or more cups per day. The inverse relation between coffee and primary liver cancer is therefore apparently stronger than in previous studies, indicating that the relation is probably real, and not due to chance alone. The combined, pooled RR from three published studies of coffee and hepatocellular carcinoma for drinkers of three or more cups of coffee per day as compared to non coffee drinkers is therefore around 0.6 (Table 1). More important, the study by Gelatti et al. provides original information on the independent effect of coffee from the major recognized risk factors for primary liver cancer. The inverse relation with coffee, in fact, was of similar magnitude in subjects negative or positive for HBV or HCV serum markers, as well as in non- or moderate drinkers and in heavy drinkers. The data were inadequate to investigate tobacco, another known liver carcinogen [
      • Kuper H.
      • Tzonou A.
      • Kaklamani E.
      • Hsieh C.C.
      • Lagiou P.
      • Adami H.O.
      • et al.
      Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma.
      ,
      • Chen Z.M.
      • Liu B.Q.
      • Boreham J.
      • Wu Y.P.
      • Chen J.S.
      • Peto R.
      Smoking and liver cancer in China; case-control comparison of 36,000 liver cancer deaths vs. 17,000 cirrhosis deaths.
      ,
      • Jee S.H.
      • Ohrr H.
      • Sull J.W.
      • Samet J.M.
      Cigarette smoking, alcohol drinking, hepatitis B, and risk for hepatocellular carcinoma in Korea.
      ], and its potential interaction with coffee.
      Table 1Coffee consumption and primary liver cancer: findings from 3 studies
      Study, CountryNo. of cases: no. of controlRelative risk for coffee consumption. Cups per day:
      Nondrinkers1–2≥3
      Gallus et al., 2002, Greece and Italy
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • Bosetti C.
      • Negri E.
      • La Vecchia C.
      • et al.
      Does coffee protect against hepatocellular carcinoma?.
      834: 19121+1.10.7
      Gelatti et al., 2005, Italy
      • Gelatti U.
      • Covolo L.
      • Franceschini M.
      • Pirali F.
      • Tagger A.
      • Ribero M.L.
      • et al.
      Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case-control study.
      250:5001+0.80.4
      Overall, pooled estimate1084:24121+1.00.6
      +, Reference category.
      It is conceivable that the results on cirrhosis are influenced by possible physicians' recommendation about restrictions of coffee drinking in cirrhotic patients. It is, however, unlikely that any such bias has materially influenced the findings on liver enzymes as well as on hepatocellular carcinoma, since the inverse associations for liver cancer were consistent across strata of cirrhosis and/or cirrhosis severity.
      Given its effects on liver enzymes and cirrhosis, and the weight of epidemiological evidence, coffee appears therefore to have a real—though moderate—effect in reducing the risk of hepatocellular carcinoma, as suggested also by limited available data on rodents [
      • Tanaka T.
      • Nishikawa A.
      • Shima H.
      • Sugie S.
      • Shinoda T.
      • Yoshimi N.
      • et al.
      Inhibitory effects of chlorogenic acid, reserpine, polyprenoic acid (E-5166), or coffee on hepatocarcinogenesis in rats and hamsters.
      ]. Various components of coffee have been related to such a favourable effect, including caffeine, coffee oils kahweol of cafestol, and antioxidant substances from coffee beans [
      • He P.
      • Noda Y.
      • Sugiyama K.
      Suppression of lipopolysaccaride-induced liver injury by various types of tea and coffee in d-galactosamine-sensitized rats.
      ,
      • Huber W.W.
      • Scharf G.
      • Rossmanith W.
      • Prustomerksy S.
      • Grasl-Kraupp B.
      • Peter B.
      • et al.
      The coffee components kahweol and cafestol induce gamma-glutamylcysteine synthetase, the rate limiting enzyme of chemoprotective glutathione synhesis, in several organs of the rat.
      ,
      • Scharf G.
      • Prustomerksy S.
      • Huber W.W.
      Elevation of glutathione levels by coffee components and its potential mechanisms.
      ,
      • Lee K.G.
      • Mitchell A.
      • Shibamoto T.
      Antioxidative activities of aroma extracts isolated from natural plants.
      ], but no definite evidence is available for any of these components.
      Despite these uncertainties, HCC should be added to other digestive tract cancers on which a favourable role of coffee drinking has been suggested, including oral and pharyngeal, oesophageal [
      • La Vecchia C.
      • Ferraroni M.
      • Negri E.
      • D'Avanzo B.
      • Decarli A.
      • Levi F.
      • et al.
      Coffee consumption and digestive tract cancers.
      ,
      • La Vecchia C.
      Epidemiological evidence on coffee and digestive tract cancers: a review.
      ,
      • Tavani A.
      • Bertuzzi M.
      • Talamini R.
      • Gallus S.
      • Parpinel M.
      • Franceschi S.
      • et al.
      Coffee and tea intake and risk of oral, pharyngeal and esophageal cancer.
      ] and colorectal cancers [
      • Tavani A.
      • La Vecchia C.
      Coffee, decaffeinated coffee, tea and cancer of the colon and rectum: a review of epidemiological studies, 1990–2003.
      ,
      IARC
      Coffee, tea, mate, methylxanthines and methylglyoxal.
      ].

      Acknowledgements

      This work was supported by the Italian Association for Cancer Research (AIRC), Milan, Italy, the Italian League against Cancer, and the Italian Ministry of Education (MIUR/COFIN 2003). The author thanks Ms I. Garimoldi for Editorial assistance.

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