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Coffee Consumption and Risk of Liver Cancer: A Meta-Analysis

  • Susanna C. Larsson
    Correspondence
    Address requests for reprints to: Susanna C. Larsson, PhD, Division of Nutritional Epidemiology, The National Institute of Environmental Medicine, Karolinska Institutet, P.O. Box 210, SE-171 77 Stockholm, Sweden. fax: (46) 8-304571.
    Affiliations
    Division of Nutritional Epidemiology, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
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  • Alicja Wolk
    Affiliations
    Division of Nutritional Epidemiology, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
    Search for articles by this author
      Background & Aims: Mounting evidence indicates that coffee drinking may protect against liver injury and lower the risk of liver cancer. We quantitatively assessed the relation between coffee consumption and the risk of liver cancer in a meta-analysis of epidemiologic studies. Methods: Relevant studies were identified by searching MEDLINE (from 1966 to February 2007) and the reference lists of retrieved articles. We included cohort and case–control studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) of primary liver cancer or hepatocellular carcinoma by quantitative categories of coffee consumption. Study-specific RRs were pooled using a random-effects model. Results: Four cohort and 5 case–control studies, involving 2260 cases and 239,146 noncases, met the inclusion criteria. All studies observed an inverse relation between coffee consumption and risk of liver cancer, and in 6 studies the association was statistically significant. Overall, an increase in consumption of 2 cups of coffee per day was associated with a 43% reduced risk of liver cancer (RR, 0.57; 95% CI, 0.49–0.67). There was no statistically significant heterogeneity among studies (P = .17). In stratified analysis, the summary RRs of liver cancer for an increase in consumption of 2 cups of coffee per day were 0.69 (95% CI, 0.55–0.87) for persons without a history of liver disease and 0.56 (95% CI, 0.35–0.91) for those with a history of liver disease. Conclusions: Findings from this meta-analysis suggest that an increased consumption of coffee may reduce the risk of liver cancer.

      Abbreviations used in this paper:

      CI (confidence interval), HCC (hepatocellular carcinoma), RR (relative risk)
      Data on potential beneficial effects of coffee on liver function and liver diseases have accrued over the last 2 decades. Several epidemiologic studies have reported inverse associations of coffee drinking with levels of liver enzymes, including γ-glutamyltransferase (an indicator of cirrhosis risk)
      • 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.
      • Pintus F.
      • Mascia P.
      “ATS-SARDEGNA” Research Group
      Distribution and population determinants of gamma-glutamyltransferase in a random sample of Sardinian inhabitants.
      • 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.
      • Zakouji H.
      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.
      • Umeda T.
      • Wakabayashi K.
      • Imanishi K.
      • Nishikawa H.
      • Ogawa S.
      • Katsurada M.
      • Nakagawa K.
      • Yoshizawa N.
      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.
      and alanine aminotransferase (a marker of liver injury),
      • Casiglia E.
      • Spolaore P.
      • Ginocchio G.
      • Ambrosio G.B.
      Unexpected effects of coffee consumption on liver enzymes.
      • Tanaka K.
      • Tokunaga S.
      • Kono S.
      • Tokudome S.
      • Akamatsu T.
      • Moriyama T.
      • Zakouji H.
      Coffee consumption and decreased serum gamma-glutamyltransferase and aminotransferase activities among male alcohol drinkers.
      • 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.
      • Umeda T.
      • Wakabayashi K.
      • Imanishi K.
      • Nishikawa H.
      • Ogawa S.
      • Katsurada M.
      • Nakagawa K.
      • Yoshizawa N.
      Coffee consumption and serum aminotransferases in middle-aged Japanese men.
      as well as with risk of chronic liver disease
      • Ruhl C.E.
      • Everhart J.E.
      Coffee and tea consumption are associated with a lower incidence of chronic liver disease in the United States.
      and liver cirrhosis.
      • Corrao G.
      • Zambon A.
      • Bagnardi V.
      • D’Amicis A.
      • Klatsky A.
      Coffee, caffeine, and the risk of liver cirrhosis.
      • Corrao G.
      • Lepore A.R.
      • Torchio P.
      • Valenti M.
      • Galatola G.
      • D’Amicis A.
      • Arico S.
      • di Orio F.
      Provincial Group for the Study of Chronic Liver Disease
      The effect of drinking coffee and smoking cigarettes on the risk of cirrhosis associated with alcohol consumption A case–control study.
      • Gallus S.
      • Tavani A.
      • Negri E.
      • La Vecchia C.
      Does coffee protect against liver cirrhosis?.
      • Klatsky A.L.
      • Armstrong M.A.
      Alcohol, smoking, coffee, and cirrhosis.
      • Tverdal A.
      • Skurtveit S.
      Coffee intake and mortality from liver cirrhosis.
      Moreover, studies in animals have shown an inhibitory effect of coffee on liver carcinogenesis.
      • Tanaka T.
      • Nishikawa A.
      • Shima H.
      • Sugie S.
      • Shinoda T.
      • Yoshimi N.
      • Iwata H.
      • Mori H.
      Inhibitory effects of chlorogenic acid, reserpine, polyprenoic acid (E-5166), or coffee on hepatocarcinogenesis in rats and hamsters.
      Emerging epidemiologic evidence also indicates that coffee drinking may reduce the risk of primary liver cancer and hepatocellular carcinoma (HCC), the dominant form of primary liver cancer.
      Because the epidemiologic evidence on the association between coffee consumption and liver cancer risk has not yet been summarized, we conducted a meta-analysis to quantitatively summarize the results from cohort and case–control studies on this issue. We also investigated whether the association between coffee drinking and liver cancer differed by history of liver disease.

      Materials and Methods

       Study Selection

      Pertinent studies were identified by a computerized MEDLINE search from 1966 to February 2007 using the search term coffee combined with hepatocellular carcinoma, liver cancer, or liver neoplasm. Furthermore, we reviewed citations from retrieved articles to search for more studies. No language restrictions were imposed.
      Studies were included in the meta-analysis if (1) they had a cohort or case–control design; (2) the exposure of interest was coffee consumption; (3) the outcome of interest was primary liver cancer or HCC; and (4) relative risk (RR) estimates (odds ratios in case–control studies) with their 95% confidence intervals (CIs) (or data to calculate them) were reported. If data were duplicated in more than 1 study, the most recent study was included in the analysis.
      We identified 11 potentially relevant articles
      • La Vecchia C.
      • Ferraroni M.
      • Negri E.
      • D’Avanzo B.
      • Decarli A.
      • Levi F.
      • Franceschi S.
      Coffee consumption and digestive tract cancers.
      • Kuper H.
      • Tzonou A.
      • Kaklamani E.
      • Hsieh C.C.
      • Lagiou P.
      • Adami H.O.
      • Trichopoulos D.
      • Stuver S.O.
      Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma.
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • Nose T.
      • Yoshimura T.
      • Suzuki H.
      • Sakata R.
      • Fujita Y.
      • Ichikawa S.
      • Iwai N.
      • Fukuda K.
      • Tamakoshi A.
      Dietary habits and risk of death due to hepatocellular carcinoma in a large scale cohort study in Japan Univariate analysis of JACC study data.
      • Inoue M.
      • Yoshimi I.
      • Sobue T.
      • Tsugane S.
      Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan.
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • Ohmori K.
      • Koizumi Y.
      • Nishino Y.
      • Shibuya D.
      • Tsuji I.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • Nose T.
      • Yoshimura T.
      • Suzuki H.
      • Sakata R.
      • Fujita Y.
      • Ichikawa S.
      • Iwai N.
      • Tamakoshi A.
      Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • Bosetti C.
      • Negri E.
      • La Vecchia C.
      • Lagiou P.
      • Trichopoulos D.
      Does coffee protect against hepatocellular carcinoma?.
      • Gelatti U.
      • Covolo L.
      • Franceschini M.
      • Pirali F.
      • Tagger A.
      • Ribero M.L.
      • Trevisi P.
      • Martelli C.
      • Nardi G.
      • Donato F.
      Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case–control study.
      • Ohfuji S.
      • Fukushima W.
      • Tanaka T.
      • Habu D.
      • Tamori A.
      • Sakaguchi H.
      • Takeda T.
      • Kawada N.
      • Seki S.
      • Nishiguchi S.
      • Shiomi S.
      • Hirota Y.
      Coffee consumption and reduced risk of hepatocellular carcinoma among patients with chronic type C liver disease: A case–control study.
      • Tanaka K.
      • Hara M.
      • Sakamoto T.
      • Higaki Y.
      • Mizuta T.
      • Eguchi Y.
      • Yasutake T.
      • Ozaki I.
      • Yamamoto K.
      • Onohara S.
      • Kawazoe S.
      • Shigematsu H.
      • Koizumi S.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case–control study in Japan.
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • Maso L.D.
      • Crispo A.
      • Crovatto M.
      • Casarin P.
      • Izzo F.
      • Tommasi L.G.
      • Talamini R.
      • Franceschi S.
      • Franceschi S.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      concerning coffee consumption and liver cancer risk. Three publications
      • La Vecchia C.
      • Ferraroni M.
      • Negri E.
      • D’Avanzo B.
      • Decarli A.
      • Levi F.
      • Franceschi S.
      Coffee consumption and digestive tract cancers.
      • Kuper H.
      • Tzonou A.
      • Kaklamani E.
      • Hsieh C.C.
      • Lagiou P.
      • Adami H.O.
      • Trichopoulos D.
      • Stuver S.O.
      Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma.
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • Nose T.
      • Yoshimura T.
      • Suzuki H.
      • Sakata R.
      • Fujita Y.
      • Ichikawa S.
      • Iwai N.
      • Fukuda K.
      • Tamakoshi A.
      Dietary habits and risk of death due to hepatocellular carcinoma in a large scale cohort study in Japan Univariate analysis of JACC study data.
      were excluded because of duplicate reports from the same study population. The remaining publications, consisting of 4 cohort studies
      • Inoue M.
      • Yoshimi I.
      • Sobue T.
      • Tsugane S.
      Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan.
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • Ohmori K.
      • Koizumi Y.
      • Nishino Y.
      • Shibuya D.
      • Tsuji I.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • Nose T.
      • Yoshimura T.
      • Suzuki H.
      • Sakata R.
      • Fujita Y.
      • Ichikawa S.
      • Iwai N.
      • Tamakoshi A.
      Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.
      (1 article presented results from 2 separate cohorts) and 5 case–control studies,
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • Bosetti C.
      • Negri E.
      • La Vecchia C.
      • Lagiou P.
      • Trichopoulos D.
      Does coffee protect against hepatocellular carcinoma?.
      • Gelatti U.
      • Covolo L.
      • Franceschini M.
      • Pirali F.
      • Tagger A.
      • Ribero M.L.
      • Trevisi P.
      • Martelli C.
      • Nardi G.
      • Donato F.
      Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case–control study.
      • Ohfuji S.
      • Fukushima W.
      • Tanaka T.
      • Habu D.
      • Tamori A.
      • Sakaguchi H.
      • Takeda T.
      • Kawada N.
      • Seki S.
      • Nishiguchi S.
      • Shiomi S.
      • Hirota Y.
      Coffee consumption and reduced risk of hepatocellular carcinoma among patients with chronic type C liver disease: A case–control study.
      • Tanaka K.
      • Hara M.
      • Sakamoto T.
      • Higaki Y.
      • Mizuta T.
      • Eguchi Y.
      • Yasutake T.
      • Ozaki I.
      • Yamamoto K.
      • Onohara S.
      • Kawazoe S.
      • Shigematsu H.
      • Koizumi S.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case–control study in Japan.
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • Maso L.D.
      • Crispo A.
      • Crovatto M.
      • Casarin P.
      • Izzo F.
      • Tommasi L.G.
      • Talamini R.
      • Franceschi S.
      • Franceschi S.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      were included in the meta-analysis.

       Data Extraction

      The following data were extracted from each study: the first author’s last name, publication year, country where the study was performed, study design, type of controls for case–control studies (patients with other diseases or population-based controls), sample size (cases and controls or cohort size), type of outcome (primary liver cancer or HCC), variables adjusted for in the analysis, and the RR estimates with corresponding 95% CIs for each category of coffee consumption. From each study, we extracted the risk estimates that reflected the greatest degree of control for potential confounders. For 1 case–control study
      • Tanaka K.
      • Hara M.
      • Sakamoto T.
      • Higaki Y.
      • Mizuta T.
      • Eguchi Y.
      • Yasutake T.
      • Ozaki I.
      • Yamamoto K.
      • Onohara S.
      • Kawazoe S.
      • Shigematsu H.
      • Koizumi S.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case–control study in Japan.
      that employed 3 different control groups (population-based controls [n = 1253], hospital-based controls [n = 275], and chronic liver disease patients [n = 381]), we used the results based on comparison with population-based controls in the main analysis and chronic liver disease patients in sensitivity analysis.

       Statistical Analysis

      The measure of effect of interest is the relative risk for cohort studies, approximated by the odds ratio in case–control studies, and the corresponding statistical significance (95% CI). We attempted to place the studies on a common scale by estimating the RR per 2 cups per day increase of coffee consumption (eg, from no coffee consumption to 2 cups per day). For each study, we estimated the median coffee consumption for each category by assigning the midpoint of the upper and lower boundary in each category as the average consumption. The highest, open-ended category was assumed to have the same amplitude of consumption as the preceding category. We used the covariance-corrected method of Greenland and Longnecker
      • Greenland S.
      • Longnecker M.P.
      Methods for trend estimation from summarized dose–response data, with applications to meta-analysis.
      • Orsini N.
      • Bellocco R.
      • Greenland S.
      Generalized least squares for trend estimation of summarized dose–response data.
      to model the log RRs for liver cancer as a linear function of coffee consumption. This provided an estimate of the regression coefficient and its standard error for each study. Study-specific RR estimates were combined using a random-effects model, which incorporates both within- and between-study variability.
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      We checked for nonlinearity of the dose–response relationship between coffee consumption and liver cancer by estimating polynomial models. This was done using the “pool-first” method described by Greenland and Longnecker.
      • Greenland S.
      • Longnecker M.P.
      Methods for trend estimation from summarized dose–response data, with applications to meta-analysis.
      We found that the best-fitting model was a linear model.
      Statistical heterogeneity among studies was evaluated using the Q and I2 statistics.
      • Higgins J.P.
      • Thompson S.G.
      Quantifying heterogeneity in a meta-analysis.
      We did a sensitivity analysis in which 1 study at a time was removed and the rest analyzed to evaluate whether the results could have been affected markedly by a single study. We also conducted analyses stratified by study design, geographic area (Japan vs. Europe), and history of liver disease. To assess the potential for publication bias, we used Egger’s regression test.
      • Egger M.
      • Davey Smith G.
      • Schneider M.
      • Minder C.
      Bias in meta-analysis detected by a simple, graphical test.
      All statistical analyses were performed with Stata (version 9.0; StataCorp, College Station, TX). P values < .1 were considered statistically significant.

      Results

      The 4 cohort studies
      • Inoue M.
      • Yoshimi I.
      • Sobue T.
      • Tsugane S.
      Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan.
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • Ohmori K.
      • Koizumi Y.
      • Nishino Y.
      • Shibuya D.
      • Tsuji I.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • Nose T.
      • Yoshimura T.
      • Suzuki H.
      • Sakata R.
      • Fujita Y.
      • Ichikawa S.
      • Iwai N.
      • Tamakoshi A.
      Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.
      and 5 case–control studies
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • Bosetti C.
      • Negri E.
      • La Vecchia C.
      • Lagiou P.
      • Trichopoulos D.
      Does coffee protect against hepatocellular carcinoma?.
      • Gelatti U.
      • Covolo L.
      • Franceschini M.
      • Pirali F.
      • Tagger A.
      • Ribero M.L.
      • Trevisi P.
      • Martelli C.
      • Nardi G.
      • Donato F.
      Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case–control study.
      • Ohfuji S.
      • Fukushima W.
      • Tanaka T.
      • Habu D.
      • Tamori A.
      • Sakaguchi H.
      • Takeda T.
      • Kawada N.
      • Seki S.
      • Nishiguchi S.
      • Shiomi S.
      • Hirota Y.
      Coffee consumption and reduced risk of hepatocellular carcinoma among patients with chronic type C liver disease: A case–control study.
      • Tanaka K.
      • Hara M.
      • Sakamoto T.
      • Higaki Y.
      • Mizuta T.
      • Eguchi Y.
      • Yasutake T.
      • Ozaki I.
      • Yamamoto K.
      • Onohara S.
      • Kawazoe S.
      • Shigematsu H.
      • Koizumi S.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case–control study in Japan.
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • Maso L.D.
      • Crispo A.
      • Crovatto M.
      • Casarin P.
      • Izzo F.
      • Tommasi L.G.
      • Talamini R.
      • Franceschi S.
      • Franceschi S.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      that were included in this meta-analysis were published between 2002 and 2007 (Table 1) and involved a total of 2260 cases and 239,146 noncases. Of these studies, 6 were conducted in Japan and 3 in southern Europe (Italy and Greece). All studies consisted of both men and women. The outcome was incidence of primary liver cancer in 2 studies,
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • Ohmori K.
      • Koizumi Y.
      • Nishino Y.
      • Shibuya D.
      • Tsuji I.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      incidence of HCC in 6 studies,
      • Inoue M.
      • Yoshimi I.
      • Sobue T.
      • Tsugane S.
      Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan.
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • Bosetti C.
      • Negri E.
      • La Vecchia C.
      • Lagiou P.
      • Trichopoulos D.
      Does coffee protect against hepatocellular carcinoma?.
      • Gelatti U.
      • Covolo L.
      • Franceschini M.
      • Pirali F.
      • Tagger A.
      • Ribero M.L.
      • Trevisi P.
      • Martelli C.
      • Nardi G.
      • Donato F.
      Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case–control study.
      • Ohfuji S.
      • Fukushima W.
      • Tanaka T.
      • Habu D.
      • Tamori A.
      • Sakaguchi H.
      • Takeda T.
      • Kawada N.
      • Seki S.
      • Nishiguchi S.
      • Shiomi S.
      • Hirota Y.
      Coffee consumption and reduced risk of hepatocellular carcinoma among patients with chronic type C liver disease: A case–control study.
      • Tanaka K.
      • Hara M.
      • Sakamoto T.
      • Higaki Y.
      • Mizuta T.
      • Eguchi Y.
      • Yasutake T.
      • Ozaki I.
      • Yamamoto K.
      • Onohara S.
      • Kawazoe S.
      • Shigematsu H.
      • Koizumi S.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case–control study in Japan.
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • Maso L.D.
      • Crispo A.
      • Crovatto M.
      • Casarin P.
      • Izzo F.
      • Tommasi L.G.
      • Talamini R.
      • Franceschi S.
      • Franceschi S.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      and mortality from HCC in 1 study.
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • Nose T.
      • Yoshimura T.
      • Suzuki H.
      • Sakata R.
      • Fujita Y.
      • Ichikawa S.
      • Iwai N.
      • Tamakoshi A.
      Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.
      Among case–control studies, 4 used hospital-based controls
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • Bosetti C.
      • Negri E.
      • La Vecchia C.
      • Lagiou P.
      • Trichopoulos D.
      Does coffee protect against hepatocellular carcinoma?.
      • Gelatti U.
      • Covolo L.
      • Franceschini M.
      • Pirali F.
      • Tagger A.
      • Ribero M.L.
      • Trevisi P.
      • Martelli C.
      • Nardi G.
      • Donato F.
      Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case–control study.
      • Ohfuji S.
      • Fukushima W.
      • Tanaka T.
      • Habu D.
      • Tamori A.
      • Sakaguchi H.
      • Takeda T.
      • Kawada N.
      • Seki S.
      • Nishiguchi S.
      • Shiomi S.
      • Hirota Y.
      Coffee consumption and reduced risk of hepatocellular carcinoma among patients with chronic type C liver disease: A case–control study.
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • Maso L.D.
      • Crispo A.
      • Crovatto M.
      • Casarin P.
      • Izzo F.
      • Tommasi L.G.
      • Talamini R.
      • Franceschi S.
      • Franceschi S.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      and 1 used population-based controls.
      • Tanaka K.
      • Hara M.
      • Sakamoto T.
      • Higaki Y.
      • Mizuta T.
      • Eguchi Y.
      • Yasutake T.
      • Ozaki I.
      • Yamamoto K.
      • Onohara S.
      • Kawazoe S.
      • Shigematsu H.
      • Koizumi S.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case–control study in Japan.
      In the cohort studies, participants were asked about their coffee consumption during the past month
      • Inoue M.
      • Yoshimi I.
      • Sobue T.
      • Tsugane S.
      Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan.
      or year
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • Nose T.
      • Yoshimura T.
      • Suzuki H.
      • Sakata R.
      • Fujita Y.
      • Ichikawa S.
      • Iwai N.
      • Tamakoshi A.
      Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.
      before baseline, or about their recent or usual coffee consumption at baseline.
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • Ohmori K.
      • Koizumi Y.
      • Nishino Y.
      • Shibuya D.
      • Tsuji I.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      In the case–control studies, participants were inquired about their coffee consumption 1 year,
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • Bosetti C.
      • Negri E.
      • La Vecchia C.
      • Lagiou P.
      • Trichopoulos D.
      Does coffee protect against hepatocellular carcinoma?.
      2 years,
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • Maso L.D.
      • Crispo A.
      • Crovatto M.
      • Casarin P.
      • Izzo F.
      • Tommasi L.G.
      • Talamini R.
      • Franceschi S.
      • Franceschi S.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      or 10 years before.
      • Gelatti U.
      • Covolo L.
      • Franceschini M.
      • Pirali F.
      • Tagger A.
      • Ribero M.L.
      • Trevisi P.
      • Martelli C.
      • Nardi G.
      • Donato F.
      Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case–control study.
      • Tanaka K.
      • Hara M.
      • Sakamoto T.
      • Higaki Y.
      • Mizuta T.
      • Eguchi Y.
      • Yasutake T.
      • Ozaki I.
      • Yamamoto K.
      • Onohara S.
      • Kawazoe S.
      • Shigematsu H.
      • Koizumi S.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case–control study in Japan.
      In 1 case–control study that consisted of persons chronically infected with hepatitis C virus, participants were asked about their coffee consumption both before and after first identification of liver disease
      • Ohfuji S.
      • Fukushima W.
      • Tanaka T.
      • Habu D.
      • Tamori A.
      • Sakaguchi H.
      • Takeda T.
      • Kawada N.
      • Seki S.
      • Nishiguchi S.
      • Shiomi S.
      • Hirota Y.
      Coffee consumption and reduced risk of hepatocellular carcinoma among patients with chronic type C liver disease: A case–control study.
      ; we used the results based on coffee consumption before identification of liver disease.
      Table 1Characteristics of Cohort and Case–Control Studies of Coffee Consumption and Liver Cancer
      StudyCountry; study periodAge, yearsOutcomeNo. of casesNo. in cohort or controlsCoffee consumptionRelative risk (95% CI)Adjustments
      Cohort studies
       Inoue et al, 2005
      • Inoue M.
      • Yoshimi I.
      • Sobue T.
      • Tsugane S.
      Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan.
      Japan; 1990–200140–69HCC incidence33490,452 (cohort)
      • Almost never
      • 1–2 days/week
      • 3–4 days/week
      • 1–2 cups/day
      • 3–4 cups/day
      • ≥5 cups/day
      • 1.00 (reference)
      • 0.75 (0.56–1.01)
      • 0.79 (0.55–1.14)
      • 0.52 (0.38–0.73)
      • 0.48 (0.28–0.83)
      • 0.24 (0.08–0.77)
      Age, sex, study area, smoking, and intakes of alcohol, green tea, and green vegetables
       Shimazu et al, 2005
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • Ohmori K.
      • Koizumi Y.
      • Nishino Y.
      • Shibuya D.
      • Tsuji I.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      ; Cohort 1
      Japan; 1984–1992≥40Primary liver cancer incidence7022,404 (cohort)
      • Nondrinkers
      • Occasionally
      • ≥1 cup/day
      • 1.00 (reference)
      • 0.56 (0.33–0.97)
      • 0.53 (0.28–1.00)
      Age, sex, history of liver disease, smoking, and alcohol intake
       Shimazu et al, 2005
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • Ohmori K.
      • Koizumi Y.
      • Nishino Y.
      • Shibuya D.
      • Tsuji I.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      ; Cohort 2
      Japan; 1990–199740–64Primary liver cancer incidence4738,703 (cohort)
      • Nondrinkers
      • Occasionally
      • ≥1 cup/day
      • 1.00 (reference)
      • 1.05 (0.52–2.16)
      • 0.68 (0.31–1.51)
      Age, sex, history of liver disease, smoking, and alcohol intake
       Kurozawa et al, 2005
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • Nose T.
      • Yoshimura T.
      • Suzuki H.
      • Sakata R.
      • Fujita Y.
      • Ichikawa S.
      • Iwai N.
      • Tamakoshi A.
      Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.
      Japan; 1988–199940–79HCC mortality25883,966 (cohort)
      • Nondrinkers
      • <1 cup/day
      • ≥1 cup/day
      • 1.00 (reference)
      • 0.83 (0.54–1.25)
      • 0.50 (0.31–0.79)
      Age, sex, education, history of diabetes or liver disease, smoking, and alcohol intake
      Case–control studies
       Gallus et al, 2002
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • Bosetti C.
      • Negri E.
      • La Vecchia C.
      • Lagiou P.
      • Trichopoulos D.
      Does coffee protect against hepatocellular carcinoma?.
      Greece; 1995–1998 and Italy; 1984–199718–79HCC incidence8341912
      • Nondrinkers
      • 1 cup/day
      • 2 cups/day
      • ≥3 cups/day
      • 1.0 (reference)
      • 1.2 (0.9–1.6)
      • 1.0 (0.7–1.3)
      • 0.7 (0.5–1.0)
      Age, sex, education, history of diabetes or hepatitis, body mass index, smoking, and alcohol intake
       Gelatti et al, 2005
      • Gelatti U.
      • Covolo L.
      • Franceschini M.
      • Pirali F.
      • Tagger A.
      • Ribero M.L.
      • Trevisi P.
      • Martelli C.
      • Nardi G.
      • Donato F.
      Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case–control study.
      Italy; 1994–2003<80HCC incidence250500
      • Nondrinkers
      • 1–2 cups/day
      • 3–4 cups/day
      • ≥5 cups/day
      • 1.0 (reference)
      • 0.8 (0.4–1.3)
      • 0.4 (0.2–0.8)
      • 0.3 (0.1–0.7)
      Age, sex, HBV and/or HCV infection, and alcohol intake
       Ohfuji et al, 2006
      • Ohfuji S.
      • Fukushima W.
      • Tanaka T.
      • Habu D.
      • Tamori A.
      • Sakaguchi H.
      • Takeda T.
      • Kawada N.
      • Seki S.
      • Nishiguchi S.
      • Shiomi S.
      • Hirota Y.
      Coffee consumption and reduced risk of hepatocellular carcinoma among patients with chronic type C liver disease: A case–control study.
      Japan; 2001–2002NAHCC incidence73
      Patients chronically infected with hepatitis C virus.
      253
      Patients chronically infected with hepatitis C virus.
      • Nondrinkers
      • <1 cup/day
      • ≥1 cup/day
      • 1.00 (reference)
        Odds ratios for hepatocellular carcinoma calculated before first identification of liver disease; the corresponding odds ratios calculated after first identification of liver disease were 1.00 (reference), 0.57 (95% CI, 0.20–1.67), and 0.19 (95% CI, 0.05–0.71).
      • 0.61 (0.18–2.03)
        Odds ratios for hepatocellular carcinoma calculated before first identification of liver disease; the corresponding odds ratios calculated after first identification of liver disease were 1.00 (reference), 0.57 (95% CI, 0.20–1.67), and 0.19 (95% CI, 0.05–0.71).
      • 0.38 (0.13–1.12)
        Odds ratios for hepatocellular carcinoma calculated before first identification of liver disease; the corresponding odds ratios calculated after first identification of liver disease were 1.00 (reference), 0.57 (95% CI, 0.20–1.67), and 0.19 (95% CI, 0.05–0.71).
      Age, sex, time since first identification of liver disease, BMI, disease severity, family history of liver disease, interferon therapy, smoking, and alcohol intake
       Tanaka et al, 2007
      • Tanaka K.
      • Hara M.
      • Sakamoto T.
      • Higaki Y.
      • Mizuta T.
      • Eguchi Y.
      • Yasutake T.
      • Ozaki I.
      • Yamamoto K.
      • Onohara S.
      • Kawazoe S.
      • Shigematsu H.
      • Koizumi S.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case–control study in Japan.
      Japan; 2001–200440–79HCC incidence2091253
      • Nondrinkers
      • Occasionally
      • 1–2 cups/day
      • ≥3 cups/day
      • 1.00 (reference)
      • 0.33 (0.22–0.48)
        Odds ratios for hepatocellular carcinoma for coffee consumption 10 years before by comparing cases with population-based controls; the corresponding odds ratios for coffee consumption during the last 1–2 years were 1.00 (reference), 0.31 (95% CI, 0.21–0.46), 0.11 (95% CI, 0.06–0.21), and 0.10 (95% CI, 0.04–0.24).
      • 0.27 (0.15–0.48)
        Odds ratios for hepatocellular carcinoma for coffee consumption 10 years before by comparing cases with population-based controls; the corresponding odds ratios for coffee consumption during the last 1–2 years were 1.00 (reference), 0.31 (95% CI, 0.21–0.46), 0.11 (95% CI, 0.06–0.21), and 0.10 (95% CI, 0.04–0.24).
      • 0.22 (0.11–0.43)
        Odds ratios for hepatocellular carcinoma for coffee consumption 10 years before by comparing cases with population-based controls; the corresponding odds ratios for coffee consumption during the last 1–2 years were 1.00 (reference), 0.31 (95% CI, 0.21–0.46), 0.11 (95% CI, 0.06–0.21), and 0.10 (95% CI, 0.04–0.24).
      Age, sex, smoking, and alcohol intake
       Montella et al, 2007
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • Maso L.D.
      • Crispo A.
      • Crovatto M.
      • Casarin P.
      • Izzo F.
      • Tommasi L.G.
      • Talamini R.
      • Franceschi S.
      • Franceschi S.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      Italy; 1999–200243–84HCC incidence185412
      • Nondrinkers
      • <14 cups/week
      • 14–20 cups/week
      • 21–27 cups/week
      • ≥28 cups/week
      • 2.28 (0.99–5.24)
      • 1.00 (reference)
      • 0.54 (0.27–1.07)
      • 0.57 (0.25–1.32)
      • 0.43 (0.16–1.13)
      Age, sex, center, HBV and/or HCV infection, education, smoking, and alcohol intake
      BMI, body mass index; CI, confidence interval; HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus; NA, not available.
      a Patients chronically infected with hepatitis C virus.
      b Odds ratios for hepatocellular carcinoma calculated before first identification of liver disease; the corresponding odds ratios calculated after first identification of liver disease were 1.00 (reference), 0.57 (95% CI, 0.20–1.67), and 0.19 (95% CI, 0.05–0.71).
      c Odds ratios for hepatocellular carcinoma for coffee consumption 10 years before by comparing cases with population-based controls; the corresponding odds ratios for coffee consumption during the last 1–2 years were 1.00 (reference), 0.31 (95% CI, 0.21–0.46), 0.11 (95% CI, 0.06–0.21), and 0.10 (95% CI, 0.04–0.24).
      The estimated RRs for each study and all studies combined for an increase of 2 cups of coffee per day are presented in Figure 1. All studies reported an inverse association between coffee consumption and risk of liver cancer, and in 6 studies
      • Inoue M.
      • Yoshimi I.
      • Sobue T.
      • Tsugane S.
      Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan.
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • Nose T.
      • Yoshimura T.
      • Suzuki H.
      • Sakata R.
      • Fujita Y.
      • Ichikawa S.
      • Iwai N.
      • Tamakoshi A.
      Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • Bosetti C.
      • Negri E.
      • La Vecchia C.
      • Lagiou P.
      • Trichopoulos D.
      Does coffee protect against hepatocellular carcinoma?.
      • Gelatti U.
      • Covolo L.
      • Franceschini M.
      • Pirali F.
      • Tagger A.
      • Ribero M.L.
      • Trevisi P.
      • Martelli C.
      • Nardi G.
      • Donato F.
      Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case–control study.
      • Tanaka K.
      • Hara M.
      • Sakamoto T.
      • Higaki Y.
      • Mizuta T.
      • Eguchi Y.
      • Yasutake T.
      • Ozaki I.
      • Yamamoto K.
      • Onohara S.
      • Kawazoe S.
      • Shigematsu H.
      • Koizumi S.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case–control study in Japan.
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • Maso L.D.
      • Crispo A.
      • Crovatto M.
      • Casarin P.
      • Izzo F.
      • Tommasi L.G.
      • Talamini R.
      • Franceschi S.
      • Franceschi S.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      the association was statistically significant. Meta-analysis of all studies found a 43% reduced risk of liver cancer (RR, 0.57; 95% CI, 0.49–0.67) for an increment of 2 cups of coffee per day. There was no statistically significant heterogeneity among the results of individual studies (Q = 11.56; P = .17; I2 = 30.8%). In a sensitivity analysis in which 1 study at a time was removed and the rest analyzed, the summary RR ranged from 0.54 (when excluding the study by Gallus et al
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • Bosetti C.
      • Negri E.
      • La Vecchia C.
      • Lagiou P.
      • Trichopoulos D.
      Does coffee protect against hepatocellular carcinoma?.
      ) to 0.63 (when excluding the study by Tanaka et al
      • Tanaka K.
      • Hara M.
      • Sakamoto T.
      • Higaki Y.
      • Mizuta T.
      • Eguchi Y.
      • Yasutake T.
      • Ozaki I.
      • Yamamoto K.
      • Onohara S.
      • Kawazoe S.
      • Shigematsu H.
      • Koizumi S.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case–control study in Japan.
      ). Excluding the study that consisted of persons chronically infected with hepatitis C virus
      • Ohfuji S.
      • Fukushima W.
      • Tanaka T.
      • Habu D.
      • Tamori A.
      • Sakaguchi H.
      • Takeda T.
      • Kawada N.
      • Seki S.
      • Nishiguchi S.
      • Shiomi S.
      • Hirota Y.
      Coffee consumption and reduced risk of hepatocellular carcinoma among patients with chronic type C liver disease: A case–control study.
      did not alter the results essentially (RR, 0.58; 95% CI, 0.49–0.68). One case–control study employed different control groups.
      • Tanaka K.
      • Hara M.
      • Sakamoto T.
      • Higaki Y.
      • Mizuta T.
      • Eguchi Y.
      • Yasutake T.
      • Ozaki I.
      • Yamamoto K.
      • Onohara S.
      • Kawazoe S.
      • Shigematsu H.
      • Koizumi S.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case–control study in Japan.
      In a sensitivity analysis, the summary RR did not change materially when we used results based on comparison with chronic liver disease patients (RR, 0.63; 95% CI, 0.56–0.71). Restricting the analysis to 6 studies in which the outcome was HCC incidence
      • Inoue M.
      • Yoshimi I.
      • Sobue T.
      • Tsugane S.
      Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan.
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • Bosetti C.
      • Negri E.
      • La Vecchia C.
      • Lagiou P.
      • Trichopoulos D.
      Does coffee protect against hepatocellular carcinoma?.
      • Gelatti U.
      • Covolo L.
      • Franceschini M.
      • Pirali F.
      • Tagger A.
      • Ribero M.L.
      • Trevisi P.
      • Martelli C.
      • Nardi G.
      • Donato F.
      Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case–control study.
      • Ohfuji S.
      • Fukushima W.
      • Tanaka T.
      • Habu D.
      • Tamori A.
      • Sakaguchi H.
      • Takeda T.
      • Kawada N.
      • Seki S.
      • Nishiguchi S.
      • Shiomi S.
      • Hirota Y.
      Coffee consumption and reduced risk of hepatocellular carcinoma among patients with chronic type C liver disease: A case–control study.
      • Tanaka K.
      • Hara M.
      • Sakamoto T.
      • Higaki Y.
      • Mizuta T.
      • Eguchi Y.
      • Yasutake T.
      • Ozaki I.
      • Yamamoto K.
      • Onohara S.
      • Kawazoe S.
      • Shigematsu H.
      • Koizumi S.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case–control study in Japan.
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • Maso L.D.
      • Crispo A.
      • Crovatto M.
      • Casarin P.
      • Izzo F.
      • Tommasi L.G.
      • Talamini R.
      • Franceschi S.
      • Franceschi S.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      yielded a summary RR of 0.59 (95% CI, 0.49–0.71). Summary relative risks were similar for cohort and case–control studies (Figure 1). Stratifying by geographic region, the summary RRs were 0.52 (95% CI, 0.43–0.61) for studies conducted in Japan and 0.68 (95% CI, 0.58–0.80) for studies conducted in Europe. We found no evidence of publication bias for cohort studies (P = .24) or case–control studies (P = .22).
      Figure thumbnail gr1
      Figure 1Relative risks of liver cancer associated with coffee consumption (per 2 cups/day increment). Squares represent study-specific relative risk estimates (size of the square reflects the study-specific statistical weight, that is, the inverse of the variance); horizontal lines represent 95% CIs; diamonds represent summary relative risk estimates with corresponding 95% CIs. Tests for heterogeneity: all studies, Q = 11.56; P = .17; I2 = 30.8%; cohort studies, Q = 1.74; P = .63; I2 = 0%; case–control studies, Q = 9.28; P = .05; I2 = 36.9%.
      Four studies presented results stratified by history of liver disease.
      • Inoue M.
      • Yoshimi I.
      • Sobue T.
      • Tsugane S.
      Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan.
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • Ohmori K.
      • Koizumi Y.
      • Nishino Y.
      • Shibuya D.
      • Tsuji I.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • Nose T.
      • Yoshimura T.
      • Suzuki H.
      • Sakata R.
      • Fujita Y.
      • Ichikawa S.
      • Iwai N.
      • Tamakoshi A.
      Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • Bosetti C.
      • Negri E.
      • La Vecchia C.
      • Lagiou P.
      • Trichopoulos D.
      Does coffee protect against hepatocellular carcinoma?.
      In meta-analysis of these studies, the summary RRs of liver cancer for a 2 cups per day increase in coffee consumption were 0.69 (95% CI, 0.55–0.87) for persons without a history of liver disease and 0.56 (95% CI, 0.35–0.91) for those with a history of liver disease (Figure 2). The difference in summary RR by strata of history liver disease was not statistically significant (P = .44).
      Figure thumbnail gr2
      Figure 2Relative risks of liver cancer associated with coffee consumption (per 2 cups/day increment), stratified by history of liver disease. Squares represent study-specific relative risk estimates (size of the square reflects the study-specific statistical weight, that is, the inverse of the variance); horizontal lines represent 95% CIs; diamonds represent summary relative risk estimates with corresponding 95% CIs. Tests for heterogeneity: without a history of liver disease, Q = 4.58; P = .21; I2 = 34.6%; with a history of liver disease, Q = 7.00; P = .07; I2 = 57.1%.

      Discussion

      The findings from the present meta-analysis of observational studies indicate that an increased coffee consumption is associated with a reduced risk of liver cancer, both among individuals with and without a history of liver disease. Overall, the risk of liver cancer decreased by 43% for an increment of 2 cups of coffee per day.
      Our study has several potential limitations. First, as in all observational studies of diet and disease, the possibility of bias and confounding cannot be excluded. However, cohort studies, which are less susceptible to bias because of the prospective design, also showed an inverse association between coffee consumption and risk of liver cancer, suggesting that the finding is not likely attributable to recall and selection bias. Individual studies may have failed to adjust for potential known or unknown confounders. For example, only 5 studies controlled for liver disease
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • Ohmori K.
      • Koizumi Y.
      • Nishino Y.
      • Shibuya D.
      • Tsuji I.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • Nose T.
      • Yoshimura T.
      • Suzuki H.
      • Sakata R.
      • Fujita Y.
      • Ichikawa S.
      • Iwai N.
      • Tamakoshi A.
      Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.
      • Ohfuji S.
      • Fukushima W.
      • Tanaka T.
      • Habu D.
      • Tamori A.
      • Sakaguchi H.
      • Takeda T.
      • Kawada N.
      • Seki S.
      • Nishiguchi S.
      • Shiomi S.
      • Hirota Y.
      Coffee consumption and reduced risk of hepatocellular carcinoma among patients with chronic type C liver disease: A case–control study.
      or hepatitis,
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • Bosetti C.
      • Negri E.
      • La Vecchia C.
      • Lagiou P.
      • Trichopoulos D.
      Does coffee protect against hepatocellular carcinoma?.
      and only 3 case–control studies adjusted for hepatitis virus infection.
      • Gelatti U.
      • Covolo L.
      • Franceschini M.
      • Pirali F.
      • Tagger A.
      • Ribero M.L.
      • Trevisi P.
      • Martelli C.
      • Nardi G.
      • Donato F.
      Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case–control study.
      • Ohfuji S.
      • Fukushima W.
      • Tanaka T.
      • Habu D.
      • Tamori A.
      • Sakaguchi H.
      • Takeda T.
      • Kawada N.
      • Seki S.
      • Nishiguchi S.
      • Shiomi S.
      • Hirota Y.
      Coffee consumption and reduced risk of hepatocellular carcinoma among patients with chronic type C liver disease: A case–control study.
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • Maso L.D.
      • Crispo A.
      • Crovatto M.
      • Casarin P.
      • Izzo F.
      • Tommasi L.G.
      • Talamini R.
      • Franceschi S.
      • Franceschi S.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      Caffeine metabolism is impaired in persons with chronic liver disease.
      • Hasegawa M.
      • Yamada S.
      • Hirayama C.
      Fasting plasma caffeine level in cirrhotic patients: relation to plasma levels of catecholamines and renin activity.
      • Wahllander A.
      • Renner E.
      • Preisig R.
      Fasting plasma caffeine concentration A guide to the severity of chronic liver disease.
      Hence, if persons with liver disease or hepatitis virus infection who are at high risk of liver cancer consume less coffee (eg, to avoid the side effects of caffeine) compared with healthy persons, it could lead to a spurious protective association between coffee consumption and liver cancer. Arguing against this possibility, in 3 cohort studies with data on liver disease, coffee consumption was not significantly related to history of liver disease at baseline.
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • Ohmori K.
      • Koizumi Y.
      • Nishino Y.
      • Shibuya D.
      • Tsuji I.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • Nose T.
      • Yoshimura T.
      • Suzuki H.
      • Sakata R.
      • Fujita Y.
      • Ichikawa S.
      • Iwai N.
      • Tamakoshi A.
      Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.
      In addition, in a U.S. population-based study, intakes of coffee and caffeine were not significantly associated with the prevalence of risk indicators for liver injury, including viral hepatitis and elevated transferrin saturation.
      • Ruhl C.E.
      • Everhart J.E.
      Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States.
      A second limitation is that our results are likely to be affected by some misclassification of coffee consumption. In cohort studies, such misclassification is probably nondifferential, and would most likely lead to an underestimation of the relationship. The influence of misclassification on the results in case–control studies is less predictable. Third, heterogeneity may have been introduced by methodologic differences among studies, such as differences in type of coffee consumed (eg, filtered vs instant coffee) in the studied populations and differences in outcome (primary liver cancer vs HCC). Fourth, all studies in this meta-analysis were conducted in Japan or southern Europe; therefore, the observed finding may not be generalizable to other populations. Finally, in a meta-analysis of published studies, publication bias could be of concern because small studies with null results tend not to be published. Because of the relatively small number of studies, we had limited statistical power to conclusively reject the null hypothesis of no publication bias. The presence of possible publication bias could have led to an overestimation of the relation between coffee consumption and risk of liver cancer.
      A protective effect of coffee consumption on liver cancer is biologically plausible. Coffee contains large amounts of antioxidants, such as chlorogenic acids, and experimental studies in animals have demonstrated an inhibitory effect of coffee and chlorogenic acids on liver carcinogenesis.
      • Tanaka T.
      • Nishikawa A.
      • Shima H.
      • Sugie S.
      • Shinoda T.
      • Yoshimi N.
      • Iwata H.
      • Mori H.
      Inhibitory effects of chlorogenic acid, reserpine, polyprenoic acid (E-5166), or coffee on hepatocarcinogenesis in rats and hamsters.
      Caffeine is another major component of coffee. In one animal study, caffeine levels of coffee extracts were inversely related to liver injury.
      • He P.
      • Noda Y.
      • Sugiyama K.
      Suppressive effect of coffee on lipopolysaccharide-induced hepatitis in D-galactosamine-sensitized rats.
      A population-based study in the United States showed that higher intake of coffee, and especially caffeine, was associated with a lower prevalence of abnormal alanine aminotransferase activity (a marker of liver injury).
      • Ruhl C.E.
      • Everhart J.E.
      Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States.
      The protective relationships of coffee and caffeine were consistent across subgroups at risk for liver injury and remained in analysis limited to persons without impaired liver function.
      • Ruhl C.E.
      • Everhart J.E.
      Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States.
      Several studies in Europe and Japan have also observed inverse relations between coffee consumption and serum levels of aminotransferases
      • Casiglia E.
      • Spolaore P.
      • Ginocchio G.
      • Ambrosio G.B.
      Unexpected effects of coffee consumption on liver enzymes.
      • Tanaka K.
      • Tokunaga S.
      • Kono S.
      • Tokudome S.
      • Akamatsu T.
      • Moriyama T.
      • Zakouji H.
      Coffee consumption and decreased serum gamma-glutamyltransferase and aminotransferase activities among male alcohol drinkers.
      • 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.
      • Umeda T.
      • Wakabayashi K.
      • Imanishi K.
      • Nishikawa H.
      • Ogawa S.
      • Katsurada M.
      • Nakagawa K.
      • Yoshizawa N.
      Coffee consumption and serum aminotransferases in middle-aged Japanese men.
      and γ-glutamyltransferase
      • 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.
      • Pintus F.
      • Mascia P.
      “ATS-SARDEGNA” Research Group
      Distribution and population determinants of gamma-glutamyltransferase in a random sample of Sardinian inhabitants.
      • 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.
      • Zakouji H.
      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.
      • Umeda T.
      • Wakabayashi K.
      • Imanishi K.
      • Nishikawa H.
      • Ogawa S.
      • Katsurada M.
      • Nakagawa K.
      • Yoshizawa N.
      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.
      (a sensitive indicator of several liver diseases). In addition, prospective cohort studies in the United States
      • Klatsky A.L.
      • Armstrong M.A.
      Alcohol, smoking, coffee, and cirrhosis.
      and Norway
      • Tverdal A.
      • Skurtveit S.
      Coffee intake and mortality from liver cirrhosis.
      and case–control studies in Italy
      • Corrao G.
      • Zambon A.
      • Bagnardi V.
      • D’Amicis A.
      • Klatsky A.
      Coffee, caffeine, and the risk of liver cirrhosis.
      • Corrao G.
      • Lepore A.R.
      • Torchio P.
      • Valenti M.
      • Galatola G.
      • D’Amicis A.
      • Arico S.
      • di Orio F.
      Provincial Group for the Study of Chronic Liver Disease
      The effect of drinking coffee and smoking cigarettes on the risk of cirrhosis associated with alcohol consumption A case–control study.
      • Gallus S.
      • Tavani A.
      • Negri E.
      • La Vecchia C.
      Does coffee protect against liver cirrhosis?.
      have reported an inverse association between coffee consumption and risk of liver cirrhosis, which is strongly related to HCC.
      • La Vecchia C.
      • Negri E.
      • Cavalieri d’Oro L.
      • Franceschi S.
      Liver cirrhosis and the risk of primary liver cancer.
      Therefore, the observed association of coffee consumption with liver cancer could potentially represent an association with liver disease. Nevertheless, in a stratified analysis by history of liver disease, coffee consumption was inversely associated with risk of liver cancer both among those with and without a history of liver disease. This finding suggests that coffee drinking may lower the risk of liver cancer even after the acquisition of liver disease. A recent meta-analysis indicated that coffee consumption may reduce the risk of type 2 diabetes,
      • van Dam R.M.
      • Hu F.B.
      Coffee consumption and risk of type 2 diabetes: a systematic review.
      and another meta-analysis showed a strong positive association between type 2 diabetes and risk of HCC.
      • El-Serag H.B.
      • Hampel H.
      • Javadi F.
      The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence.
      Thus, a potential protective effect of coffee consumption against liver cancer may also, in part, be mediated through a reduced risk of type 2 diabetes.
      One of the case–control studies included in this meta-analysis employed 3 different control groups.
      • Tanaka K.
      • Hara M.
      • Sakamoto T.
      • Higaki Y.
      • Mizuta T.
      • Eguchi Y.
      • Yasutake T.
      • Ozaki I.
      • Yamamoto K.
      • Onohara S.
      • Kawazoe S.
      • Shigematsu H.
      • Koizumi S.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case–control study in Japan.
      In that study, results based on community controls and a control group with chronic liver disease (chronic hepatitis or cirrhosis), but not hospital-based controls, showed that coffee drinking during the last 1–2 years and 10 years before was significantly inversely associated with the risk of HCC, even after adjustment for hepatitis virus markers (in analysis with liver disease patients as control group).
      • Tanaka K.
      • Hara M.
      • Sakamoto T.
      • Higaki Y.
      • Mizuta T.
      • Eguchi Y.
      • Yasutake T.
      • Ozaki I.
      • Yamamoto K.
      • Onohara S.
      • Kawazoe S.
      • Shigematsu H.
      • Koizumi S.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case–control study in Japan.
      In summary, findings from this meta-analysis indicate that coffee consumption may reduce the risk of liver cancer. The mechanisms involved and the substances in coffee that may be responsible for the relation remain to be elucidated. Cohort studies with information on coffee consumption throughout life and type of coffee consumed (eg, caffeinated vs decaffeinated) and that take into account potential confounders (such as the presence and severity of liver disease and hepatitis virus infections) and, ideally, intervention studies among persons at high risk for liver cancer are warranted to clarify the potential protective effect of coffee drinking on liver cancer. Such studies may also establish the temporal relationship between coffee use, liver disease, and liver cancer.

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