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Coffee Reduces Risk for Hepatocellular Carcinoma: An Updated Meta-analysis

  • Francesca Bravi
    Affiliations
    Department of Epidemiology, IRCCS – Istituto di Ricerche Farmacologiche “Mario Negri,” Milan, Italy

    Department of Clinical Sciences and Community Health, Università degli Studi di Milan, Milan, Italy
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  • Cristina Bosetti
    Affiliations
    Department of Epidemiology, IRCCS – Istituto di Ricerche Farmacologiche “Mario Negri,” Milan, Italy
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  • Alessandra Tavani
    Affiliations
    Department of Epidemiology, IRCCS – Istituto di Ricerche Farmacologiche “Mario Negri,” Milan, Italy
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  • Silvano Gallus
    Affiliations
    Department of Epidemiology, IRCCS – Istituto di Ricerche Farmacologiche “Mario Negri,” Milan, Italy
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  • Carlo La Vecchia
    Correspondence
    Reprint requests Address requests for reprints to: Carlo La Vecchia, MD, Department of Epidemiology, IRCCS – Istituto di Ricerche Farmacologiche “Mario Negri,” Via G. La Masa 19, 20156 Milan, Italy. fax: (39) 0233200231.
    Affiliations
    Department of Epidemiology, IRCCS – Istituto di Ricerche Farmacologiche “Mario Negri,” Milan, Italy

    Department of Clinical Sciences and Community Health, Università degli Studi di Milan, Milan, Italy
    Search for articles by this author

      Background & Aims

      Coffee consumption has been suggested to reduce the risk for hepatocellular carcinoma (HCC). We performed a meta-analysis of epidemiological studies to provide updated information on how coffee drinking affects HCC risk.

      Methods

      We performed a PubMed/MEDLINE search of the original articles published in English from 1966 through September 2012, on case-control or cohort studies that associated coffee consumption with liver cancer or HCC. We calculated the summary relative risk (RR) for any, low, and high consumption of coffee vs no consumption. The cut-off point for low vs high consumption was set to 3 cups per day in 9 studies and 1 cup per day in 5 studies.

      Results

      The summary RR for any coffee consumption vs no consumption was 0.60 from 16 studies, comprising a total of 3153 HCC cases (95% confidence interval [CI], 0.50–0.71); the RRs were 0.56 from 8 case-control studies (95% CI, 0.42–0.75) and 0.64 from 8 cohort studies (95% CI, 0.52–0.78). Compared with no coffee consumption, the summary RR was 0.72 (95% CI, 0.61–0.84) for low consumption and 0.44 (95% CI, 0.39–0.50) for high consumption. The summary RR was 0.80 (95% CI, 0.77–0.84) for an increment of 1 cup of coffee per day. The inverse relationship between coffee and HCC risk was consistent regardless of the subjects’ sex, alcohol drinking, or history of hepatitis or liver disease.

      Conclusions

      From this meta-analysis, the risk of HCC is reduced by 40% for any coffee consumption vs no consumption. The inverse association might partly or largely exist because patients with liver and digestive diseases reduce their coffee intake. However, coffee has been shown to affect liver enzymes and development of cirrhosis, and therefore could protect against liver carcinogenesis.

      Keywords

      Abbreviations used in this paper:

      BMI (body mass index), CI (confidence interval), d (day), HbsAg (hepatitis B surface antigen), HBV (hepatitis B virus), HCC (hepatocellular carcinoma), HCV (hepatitis C virus), OR (odds ratio), RR (relative risk), w (week)
      See editorial on page 1422; see related article, Bhoo-Pathy N et al, on page 1486 in this issue of CGH.
      Liver cancer is the sixth most common cancer in the world and the third most common cause of cancer mortality.
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      • Bray F.
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      • et al.
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      In 2008, approximately 750,000 liver cancers were reported worldwide, with approximately 700,000 deaths. Of these, more than 80% were from low- and middle-income countries, and about 50% were from China alone. Hepatocellular carcinoma (HCC) is the main type of liver cancer, accounting for more than 90% of cases worldwide. HCC rates have been increasing moderately over the past few decades in North America and Northern Europe.
      • Bosetti C.
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      Trends in mortality from hepatocellular carcinoma in Europe, 1980-2004.
      • Chuang S.C.
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      • Boffetta P.
      Liver cancer: descriptive epidemiology and risk factors other than HBV and HCV infection.
      Chronic infections with hepatitis B and C viruses are the main causes of HCC worldwide. Other relevant risk factors are alcohol and alcohol-related cirrhosis, tobacco, being overweight, and diabetes, and, in selected low-income countries, foodstuff contamination with aflatoxin. Oral contraceptives and selected other drugs also have been related to HCC risk.
      • Chuang S.C.
      • La Vecchia C.
      • Boffetta P.
      Liver cancer: descriptive epidemiology and risk factors other than HBV and HCV infection.
      • Franceschi S.
      • Montella M.
      • Polesel J.
      • et al.
      Hepatitis viruses, alcohol, and tobacco in the etiology of hepatocellular carcinoma in Italy.
      • La Vecchia C.
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      Oral contraceptives and neoplasms other than breast and female genital tract.
      • Trichopoulos D.
      • Bamia C.
      • Lagiou P.
      • et al.
      Hepatocellular carcinoma risk factors and disease burden in a European cohort: a nested case-control study.
      In contrast, coffee drinking has been related inversely to the risk of liver cancer—and specifically HCC—in various studies. A meta-analysis of case-control and cohort studies published up to February 2007,
      • Bravi F.
      • Bosetti C.
      • Tavani A.
      • et al.
      Coffee drinking and hepatocellular carcinoma risk: a meta-analysis.
      based on 10 studies and a total of 2260 HCC cases, showed a summary relative risk (RR) of 0.59 (95% confidence interval [CI], 0.49–0.72) for coffee drinkers compared with nondrinkers. Moreover, there was a trend in risk with dose: the summary RR was 0.70 (95% CI, 0.57–0.85) for low/moderate coffee drinkers, and 0.45 (95% CI, 0.38–0.53) for high coffee drinkers vs nondrinkers, and the summary RR was 0.77 (95% CI, 0.72–0.82) for an increment of 1 cup of coffee per day.
      Since then, 4 prospective
      • Hu G.
      • Tuomilehto J.
      • Pukkala E.
      • et al.
      Joint effects of coffee consumption and serum gamma-glutamyltransferase on the risk of liver cancer.
      • Inoue M.
      • Kurahashi N.
      • Iwasaki M.
      • et al.
      Effect of coffee and green tea consumption on the risk of liver cancer: cohort analysis by hepatitis virus infection status.
      • Johnson S.
      • Koh W.P.
      • Wang R.
      • et al.
      Coffee consumption and reduced risk of hepatocellular carcinoma: findings from the Singapore Chinese Health Study.
      • Ohishi W.
      • Fujiwara S.
      • Cologne J.B.
      • et al.
      Risk factors for hepatocellular carcinoma in a Japanese population: a nested case-control study.
      and 2 case-control studies
      • Kanazir M.
      • Boricic I.
      • Delic D.
      • et al.
      Risk factors for hepatocellular carcinoma: a case-control study in Belgrade (Serbia).
      • Leung W.W.
      • Ho S.C.
      • Chan H.L.
      • et al.
      Moderate coffee consumption reduces the risk of hepatocellular carcinoma in hepatitis B chronic carriers: a case-control study.
      have been published on an additional 900 cases of HCC. A Finnish prospective study of 60,323 subjects followed-up for 19 years, including 128 liver cancer cases, showed an RR of 0.32 for drinkers of at least 8 cups of coffee per day as compared with 1 cup or less.
      • Hu G.
      • Tuomilehto J.
      • Pukkala E.
      • et al.
      Joint effects of coffee consumption and serum gamma-glutamyltransferase on the risk of liver cancer.
      In the Japan Public Health Center–based Prospective Study Cohort II, which included 18,815 participants followed up for 13 years and 110 liver cancers among subjects affected by hepatitis C virus (HCV) or hepatitis B virus (HBV), an RR of 0.54 was found for drinkers of 3 or more cups of coffee per day compared with never/almost never drinkers.
      • Inoue M.
      • Kurahashi N.
      • Iwasaki M.
      • et al.
      Effect of coffee and green tea consumption on the risk of liver cancer: cohort analysis by hepatitis virus infection status.
      In the Singapore Chinese Health Study, a prospective cohort of 63,257 subjects followed up for 13 years and including 362 HCC incident cases, an RR of 0.56 was observed for drinkers of at least 3 cups per day vs noncoffee drinkers.
      • Johnson S.
      • Koh W.P.
      • Wang R.
      • et al.
      Coffee consumption and reduced risk of hepatocellular carcinoma: findings from the Singapore Chinese Health Study.
      In a Japanese case-control study of 224 HCC cases, nested within the cohort of atomic bomb survivors, an RR of 0.40 was found for daily coffee drinkers vs nondrinkers.
      • Ohishi W.
      • Fujiwara S.
      • Cologne J.B.
      • et al.
      Risk factors for hepatocellular carcinoma in a Japanese population: a nested case-control study.
      A Serbian case-control study including 45 HCC cases showed an odds ratio (OR) of 1.0 for coffee drinkers vs nondrinkers.
      • Kanazir M.
      • Boricic I.
      • Delic D.
      • et al.
      Risk factors for hepatocellular carcinoma: a case-control study in Belgrade (Serbia).
      In a Chinese case-control study including 109 HBV-positive HCC cases, an OR of 0.41 was found for drinkers of at least 4 cups of coffee per week compared with non–coffee drinkers.
      • Leung W.W.
      • Ho S.C.
      • Chan H.L.
      • et al.
      Moderate coffee consumption reduces the risk of hepatocellular carcinoma in hepatitis B chronic carriers: a case-control study.
      To obtain an updated quantification of the association between coffee drinking and HCC risk, we updated the previous meta-analysis, including the results from studies published between 2007 and 2012.

      Materials and Methods

       Search Strategy

      We performed a PubMed/MEDLINE search of the articles published between 1966 and September 2012, using the terms “coffee” or “caffeine” or “beverage,” “risk,” and combinations of “liver” or “hepatocellular” and “carcinoma” or “cancer” or “neoplasm,” following the Meta-analysis of Observational Studies in Epidemiology.
      • Stroup D.F.
      • Berlin J.A.
      • Morton S.C.
      • et al.
      Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
      • Kanwal F.
      • White D.
      "Systematic reviews and meta-analyses" in Clinical Gastroenterology and Hepatology.
      We limited the search to studies performed in human beings. Moreover, we checked the reference lists of the identified studies to find any other relevant publication. Studies were included in the meta-analysis if they met the following criteria: (1) provided information on the association between coffee consumption and liver cancer, including estimates of the RR (for cohort studies) or the OR (for case-control studies), with the corresponding 95% CI, or frequency distribution to calculate them; (2) were focused on primary liver cancer or HCC; (3) were original case-control or cohort studies; and (4) were published as full-length articles in English. When we found multiple articles based on the same study population, we included only the most recent and informative one. We used the Newcastle-Ottawa Scale

      Ottawa Hospital Research Institute. The Newcastel-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available at: www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed: March 13, 2013.

      to assess the quality of individual studies and performed a sensitivity analysis according to the quality of each study.
      From each publication, we extracted details on study design, country, number of subjects (cases, controls, or cohort size), duration of follow-up period (for cohort studies), frequency of coffee consumption and/or measure of association (RR or OR) and the corresponding 95% CI, and confounding variables allowed for in the analyses, if any. Whenever possible, estimates adjusted for multiple potential confounding variables were used. When the RR—or the corresponding 95% CI—was not provided, this was derived from tabular data.

       Statistical Analysis

      We derived summary estimates of the RR using both fixed-effects models (ie, as weighted averages on the sum of the inverse of the variance of the log RR/OR) and random-effects models (ie, as weighted averages on the sum of the inverse of the variance of the log RR/OR and the moment estimator of the variance between studies).
      • Greenland S.
      Quantitative methods in the review of epidemiologic literature.
      However, only the results from the latter models were presented to take into account the heterogeneity of risk estimates and thus be more conservative. We carefully evaluated heterogeneity among studies through the chi-square test,
      • Greenland S.
      • Longnecker M.P.
      Methods for trend estimation from summarized dose-response data, with applications to meta-analysis.
      and we quantified heterogeneity using the I2 statistic, which represents the percentage of the total variation across studies that is attributable to heterogeneity rather than chance.
      • Higgins J.P.
      • Thompson S.G.
      Quantifying heterogeneity in a meta-analysis.
      Furthermore, a sensitivity analysis was performed to identify which studies influenced the most heterogeneity.
      We computed summary RR for any coffee consumption, and for low and high consumption vs no consumption (including occasional consumption). Given the differences in the intake of coffee, different cut-off points were chosen for various study populations: thus, the cut-off point between low and high consumption was 3 cups per day in 9 studies
      • Hu G.
      • Tuomilehto J.
      • Pukkala E.
      • et al.
      Joint effects of coffee consumption and serum gamma-glutamyltransferase on the risk of liver cancer.
      • Inoue M.
      • Kurahashi N.
      • Iwasaki M.
      • et al.
      Effect of coffee and green tea consumption on the risk of liver cancer: cohort analysis by hepatitis virus infection status.
      • Johnson S.
      • Koh W.P.
      • Wang R.
      • et al.
      Coffee consumption and reduced risk of hepatocellular carcinoma: findings from the Singapore Chinese Health Study.
      • Leung W.W.
      • Ho S.C.
      • Chan H.L.
      • et al.
      Moderate coffee consumption reduces the risk of hepatocellular carcinoma in hepatitis B chronic carriers: a case-control study.
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • et al.
      Does coffee protect against hepatocellular carcinoma?.
      • Gelatti U.
      • Covolo L.
      • Franceschini M.
      • et al.
      Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case-control study.
      • Inoue M.
      • Yoshimi I.
      • Sobue T.
      • et al.
      Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan.
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • et al.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      and 1 cup per day in 5 studies.
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • et al.
      Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • et al.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      • Ohfuji S.
      • Fukushima W.
      • Tanaka T.
      • et al.
      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.
      • et al.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case-control study in Japan.
      In addition, we provided a continuous summary RR for an increment of 1 cup of coffee per day, using the method proposed by Greenland and Longnecker.
      • Greenland S.
      • Longnecker M.P.
      Methods for trend estimation from summarized dose-response data, with applications to meta-analysis.
      We also performed a cumulative meta-analysis to determine whether the association between coffee and HCC changed over time, and we performed separate analyses by strata of sex, alcohol drinking, and history of hepatitis/liver diseases, including those studies for which such information was available.
      We showed study-specific and summary RRs for any, low, and high coffee consumption vs no consumption, using forest plots. Publication bias was evaluated using a funnel plot
      • Thornton A.
      • Lee P.
      Publication bias in meta-analysis: its causes and consequences.
      and was quantified by the Egger's test.
      • Egger M.
      • Davey Smith G.
      • Schneider M.
      • et al.
      Bias in meta-analysis detected by a simple, graphical test.

      Results

      From the literature search we identified 76 publications; 2 other publications were retrieved from the references of the identified articles (Supplementary Figure 1). After exclusions of publications not pertinent or not satisfying the inclusion criteria, and further excluding 2 studies
      • Kuper H.
      • Tzonou A.
      • Kaklamani E.
      • et al.
      Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma.
      • Wakai K.
      • Kurozawa Y.
      • Shibata A.
      • et al.
      Liver cancer risk, coffee, and hepatitis C virus infection: a nested case-control study in Japan.
      whose data were included in 2 subsequent publications
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • et al.
      Does coffee protect against hepatocellular carcinoma?.
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • et al.
      Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.
      and 1 study that had no sufficient information to obtain estimates of the RR,
      • Yu S.Z.
      • Huang X.E.
      • Koide T.
      • et al.
      Hepatitis B and C viruses infection, lifestyle and genetic polymorphisms as risk factors for hepatocellular carcinoma in Haimen, China.
      we considered 14 articles. Of these, 1 article reported data from 2 case-control studies performed in Greece and Italy,
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • et al.
      Does coffee protect against hepatocellular carcinoma?.
      which were considered separately (afterwards referred to as Kuper et al, 2000 and Gallus et al, 2002), and 1 article reported results from 2 prospective cohorts (afterwards referred to as Shimazu et al, 2005, cohort 1; and Shimazu et al, 2005, cohort 2),
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • et al.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      again considered as 2 separate studies. Thus, in the present meta-analysis we combined data from 16 studies (8 cohort and 8 control studies), including a total of 3153 HCC cases (Table 1).
      Table 1Case-Control and Cohort Studies on Coffee Consumption and HCC
      StudyCountryCases, nControls/cohort size, nFollow-up period, y (cohort studies)AdjustmentQuality score
      Based on the Newcastle-Ottawa Scale.16
      Case-control studies
       Kuper et al,
      • Kuper H.
      • Tzonou A.
      • Kaklamani E.
      • et al.
      Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma.
      2000
      Hospital-based case-control study.
      Greece333360-Age, sex5
       Gallus et al,
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • et al.
      Does coffee protect against hepatocellular carcinoma?.
      2002
      Hospital-based case-control study.
      Italy5011552-Age, sex4
       Gelatti et al,
      • Gelatti U.
      • Covolo L.
      • Franceschini M.
      • et al.
      Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case-control study.
      2005
      Hospital-based case-control study.
      Italy250500-Age, sex, alcohol drinking, HCV, HBV7
       Ohfuji et al,
      • Ohfuji S.
      • Fukushima W.
      • Tanaka T.
      • et al.
      Coffee consumption and reduced risk of hepatocellular carcinoma among patients with chronic type C liver disease: a case-control study.
      2006
      Hospital-based case-control study.
      ,
      All cases and controls had HCV.
      Japan73253-Age, sex, date of first visit, duration of liver disease, BMI, disease severity, family history of liver disease, interferon therapy, tobacco smoking, alcohol drinking, other caffeine-containing beverages5
       Montella et al,
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • et al.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      2007
      Hospital-based case-control study.
      Italy185412-Age, sex, education, tobacco smoking, alcohol drinking, serologic evidence of HCV and/or HBV infection6
       Tanaka, et al,
      • Tanaka K.
      • Hara M.
      • Sakamoto T.
      • et al.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case-control study in Japan.
      2007
      Population-based case-control study.
      Japan2091253-Age, sex, alcohol drinking, tobacco smoking4
       Kanazir et al,
      • Kanazir M.
      • Boricic I.
      • Delic D.
      • et al.
      Risk factors for hepatocellular carcinoma: a case-control study in Belgrade (Serbia).
      2010
      Population-based case-control study.
      Serbia4590--5
       Leung et al,
      • Leung W.W.
      • Ho S.C.
      • Chan H.L.
      • et al.
      Moderate coffee consumption reduces the risk of hepatocellular carcinoma in hepatitis B chronic carriers: a case-control study.
      2011
      All cases and controls had HCV.
      ,
      Population-based case-control study.
      China109125-Age, sex, tobacco smoking, alcohol drinking, tea drinking, physical activity5
      Cohort studies
       Inoue et al,
      • Inoue M.
      • Yoshimi I.
      • Sobue T.
      • et al.
      Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan.
      2005
      Japan33490,45210Age, sex, study center, tobacco smoking, alcohol drinking, vegetable consumption, tea drinking7
       Kurozawa et al,
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • et al.
      Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.
      2005
      Japan25883,96611Age, sex, education, history of diabetes and liver disease, tobacco smoking, alcohol drinking7
       Shimazu et al,
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • et al.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      2005:

       cohort 1
      Japan7022,4049Age, sex, history of liver disease, tobacco smoking, alcohol drinking7
       Shimazu et al,
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • et al.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      2005:

       cohort 2
      Japan4738,7036Age, sex, history of liver disease, tobacco smoking, alcohol drinking6
       Hu et al,
      • Hu G.
      • Tuomilehto J.
      • Pukkala E.
      • et al.
      Joint effects of coffee consumption and serum gamma-glutamyltransferase on the risk of liver cancer.
      2008
      Finland12860,32330Age, sex, study year, alcohol drinking, tobacco smoking, education, diabetes, chronic liver disease, BMI8
       Ohishi et al,
      • Ohishi W.
      • Fujiwara S.
      • Cologne J.B.
      • et al.
      Risk factors for hepatocellular carcinoma in a Japanese population: a nested case-control study.
      2008
      Nested case-control study.
      Japan13947244-6
       Inoue et al,
      • Inoue M.
      • Kurahashi N.
      • Iwasaki M.
      • et al.
      Effect of coffee and green tea consumption on the risk of liver cancer: cohort analysis by hepatitis virus infection status.
      2009
      Japan11018,81513Age, sex, study center, tobacco smoking, alcohol drinking, BMI, history of diabetes mellitus, tea drinking, serum ALT level, HCV infection, HBV infection8
       Johnson et al,
      • Johnson S.
      • Koh W.P.
      • Wang R.
      • et al.
      Coffee consumption and reduced risk of hepatocellular carcinoma: findings from the Singapore Chinese Health Study.
      2011
      China36263,25713Age, sex, dialect group, study year, BMI, education, alcohol drinking, tobacco smoking, tea drinking, history of diabetes8
      a Based on the Newcastle-Ottawa Scale.

      Ottawa Hospital Research Institute. The Newcastel-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available at: www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed: March 13, 2013.

      b Hospital-based case-control study.
      c All cases and controls had HCV.
      d Population-based case-control study.
      e Nested case-control study.
      Figure 1 shows the study-specific and summary RRs of HCC for coffee consumption vs no consumption. The summary RR from all the 16 studies
      • Hu G.
      • Tuomilehto J.
      • Pukkala E.
      • et al.
      Joint effects of coffee consumption and serum gamma-glutamyltransferase on the risk of liver cancer.
      • Inoue M.
      • Kurahashi N.
      • Iwasaki M.
      • et al.
      Effect of coffee and green tea consumption on the risk of liver cancer: cohort analysis by hepatitis virus infection status.
      • Johnson S.
      • Koh W.P.
      • Wang R.
      • et al.
      Coffee consumption and reduced risk of hepatocellular carcinoma: findings from the Singapore Chinese Health Study.
      • Ohishi W.
      • Fujiwara S.
      • Cologne J.B.
      • et al.
      Risk factors for hepatocellular carcinoma in a Japanese population: a nested case-control study.
      • Kanazir M.
      • Boricic I.
      • Delic D.
      • et al.
      Risk factors for hepatocellular carcinoma: a case-control study in Belgrade (Serbia).
      • Leung W.W.
      • Ho S.C.
      • Chan H.L.
      • et al.
      Moderate coffee consumption reduces the risk of hepatocellular carcinoma in hepatitis B chronic carriers: a case-control study.
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • et al.
      Does coffee protect against hepatocellular carcinoma?.
      • Gelatti U.
      • Covolo L.
      • Franceschini M.
      • et al.
      Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case-control study.
      • Inoue M.
      • Yoshimi I.
      • Sobue T.
      • et al.
      Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan.
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • et al.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • et al.
      Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • et al.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      • Ohfuji S.
      • Fukushima W.
      • Tanaka T.
      • et al.
      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.
      • et al.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case-control study in Japan.
      was 0.60 (95% CI, 0.50–0.71) overall, 0.56 (95% CI, 0.42–0.75) from 8 case-control studies, and 0.64 (95% CI, 0.52–0.78) from 8 cohort studies. Significant heterogeneity was found between studies, both among case-control and cohort studies, although all studies provided risk estimates below 1. Sensitivity analyses showed that heterogeneity was mainly owing to a case-control study from Japan reporting a strong inverse association
      • Tanaka K.
      • Hara M.
      • Sakamoto T.
      • et al.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case-control study in Japan.
      and a large cohort study from China showing no significant association.
      • Johnson S.
      • Koh W.P.
      • Wang R.
      • et al.
      Coffee consumption and reduced risk of hepatocellular carcinoma: findings from the Singapore Chinese Health Study.
      The summary RR of HCC for coffee consumption vs no consumption from the 6 studies published after 2007 was 0.62 (95% CI, 0.44–0.87, data not shown). The summary RR was 0.61 (95% CI, 0.50–0.74) from 6 European studies
      • Hu G.
      • Tuomilehto J.
      • Pukkala E.
      • et al.
      Joint effects of coffee consumption and serum gamma-glutamyltransferase on the risk of liver cancer.
      • Kanazir M.
      • Boricic I.
      • Delic D.
      • et al.
      Risk factors for hepatocellular carcinoma: a case-control study in Belgrade (Serbia).
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • et al.
      Does coffee protect against hepatocellular carcinoma?.
      • Gelatti U.
      • Covolo L.
      • Franceschini M.
      • et al.
      Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case-control study.
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • et al.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      and 0.58 (95% CI, 0.45–0.75) from 10 Asian studies.
      • Inoue M.
      • Kurahashi N.
      • Iwasaki M.
      • et al.
      Effect of coffee and green tea consumption on the risk of liver cancer: cohort analysis by hepatitis virus infection status.
      • Johnson S.
      • Koh W.P.
      • Wang R.
      • et al.
      Coffee consumption and reduced risk of hepatocellular carcinoma: findings from the Singapore Chinese Health Study.
      • Ohishi W.
      • Fujiwara S.
      • Cologne J.B.
      • et al.
      Risk factors for hepatocellular carcinoma in a Japanese population: a nested case-control study.
      • Leung W.W.
      • Ho S.C.
      • Chan H.L.
      • et al.
      Moderate coffee consumption reduces the risk of hepatocellular carcinoma in hepatitis B chronic carriers: a case-control study.
      • Inoue M.
      • Yoshimi I.
      • Sobue T.
      • et al.
      Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan.
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • et al.
      Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • et al.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      • Ohfuji S.
      • Fukushima W.
      • Tanaka T.
      • et al.
      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.
      • et al.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case-control study in Japan.
      Figure thumbnail gr1
      Figure 1Study-specific and summary RRs of HCC for coffee consumption vs no consumption.
      Study-specific and overall estimates of HCC for low coffee consumption vs no consumption are shown in Figure 2. The summary RR was 0.72 (95% CI, 0.61–0.84) based on 14 studies,
      • Hu G.
      • Tuomilehto J.
      • Pukkala E.
      • et al.
      Joint effects of coffee consumption and serum gamma-glutamyltransferase on the risk of liver cancer.
      • Inoue M.
      • Kurahashi N.
      • Iwasaki M.
      • et al.
      Effect of coffee and green tea consumption on the risk of liver cancer: cohort analysis by hepatitis virus infection status.
      • Johnson S.
      • Koh W.P.
      • Wang R.
      • et al.
      Coffee consumption and reduced risk of hepatocellular carcinoma: findings from the Singapore Chinese Health Study.
      • Leung W.W.
      • Ho S.C.
      • Chan H.L.
      • et al.
      Moderate coffee consumption reduces the risk of hepatocellular carcinoma in hepatitis B chronic carriers: a case-control study.
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • et al.
      Does coffee protect against hepatocellular carcinoma?.
      • Gelatti U.
      • Covolo L.
      • Franceschini M.
      • et al.
      Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case-control study.
      • Inoue M.
      • Yoshimi I.
      • Sobue T.
      • et al.
      Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan.
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • et al.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • et al.
      Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • et al.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      • Ohfuji S.
      • Fukushima W.
      • Tanaka T.
      • et al.
      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.
      • et al.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case-control study in Japan.
      0.67 (95% CI, 0.49–0.92) from 7 case-control studies, and 0.75 (95% CI, 0.62–0.90) from 7 cohort studies.
      Figure thumbnail gr2
      Figure 2Study-specific summary RRs of HCC for low coffee consumption vs no consumption.
      The corresponding estimates for high coffee consumption vs no consumption are shown in Figure 3. The summary RR was 0.44 (95% CI, 0.39–0.50) overall, 0.41 (95% CI, 0.33–0.52) from case-control studies, and 0.46 (95% CI, 0.38–0.57) from cohort studies. The RR estimate for an increment of 1 cup of coffee per day was 0.80 (95% CI, 0.77–0.84) from all the studies, 0.77 (95% CI, 0.71–0.83) from case-control studies, and 0.83 (95% CI, 0.78–0.88) from cohort studies (data not shown).
      Figure thumbnail gr3
      Figure 3Study-specific summary RRs of HCC for high coffee consumption vs no consumption.
      Table 2 shows the study-specific RR of HCC and the corresponding CI for coffee consumption vs no consumption, according to strata of alcohol drinking and history of hepatitis or liver disease. Seven studies
      • Hu G.
      • Tuomilehto J.
      • Pukkala E.
      • et al.
      Joint effects of coffee consumption and serum gamma-glutamyltransferase on the risk of liver cancer.
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • et al.
      Does coffee protect against hepatocellular carcinoma?.
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • et al.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • et al.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      • Tanaka K.
      • Hara M.
      • Sakamoto T.
      • et al.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case-control study in Japan.
      provided information on coffee drinking according to strata of alcohol consumption and gave a summary RR of 0.61 (95% CI, 0.51–0.72) among never/low alcohol drinkers and of 0.60 (95% CI, 0.49–0.73) among moderate/high alcohol drinkers. The summary RR was 0.59 (95% CI, 0.45–0.78) among subjects with a self-reported history of hepatitis B and/or C or liver disease, and 0.52 (95% CI, 0.39–0.69) among subjects with serologic evidence of HBV and/or HCV from 9 studies.
      • Inoue M.
      • Kurahashi N.
      • Iwasaki M.
      • et al.
      Effect of coffee and green tea consumption on the risk of liver cancer: cohort analysis by hepatitis virus infection status.
      • Leung W.W.
      • Ho S.C.
      • Chan H.L.
      • et al.
      Moderate coffee consumption reduces the risk of hepatocellular carcinoma in hepatitis B chronic carriers: a case-control study.
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • et al.
      Does coffee protect against hepatocellular carcinoma?.
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • et al.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • et al.
      Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • et al.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      • Ohfuji S.
      • Fukushima W.
      • Tanaka T.
      • et al.
      Coffee consumption and reduced risk of hepatocellular carcinoma among patients with chronic type C liver disease: a case-control study.
      The summary RR in subjects with no evidence of hepatitis/liver disease from 7 studies was 0.70 (0.56–0.88).
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • et al.
      Does coffee protect against hepatocellular carcinoma?.
      • Inoue M.
      • Yoshimi I.
      • Sobue T.
      • et al.
      Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan.
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • et al.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • et al.
      Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • et al.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      The summary RR for coffee consumption was 0.58 (95% CI, 0.46–0.74) among men, and 0.70 (95% CI, 0.55–0.89) among women (data not shown).
      Table 2Study-Specific RRs and Summary RRs, With Corresponding 95% CIs, for Coffee Consumption and HCC, According to Strata of Alcohol Drinking and History of Hepatitis/Liver Disease
      StudyStrata of covariateCoffee consumptionRR (95% CI)
      Gallus et al, 2002; Kuper et al, 2000
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • et al.
      Does coffee protect against hepatocellular carcinoma?.
      <4 drinks/d2 vs ≤1 cups/d0.9 (0.7–1.2)
      ≥3 vs ≤1 cups/d0.6 (0.4–0.9)
      ≥4 drinks/d2 vs ≤1 cups/d0.8 (0.5–1.2)
      ≥3 vs ≤1 cups/d0.7 (0.5–1.2)
      Montella et al,
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • et al.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      2007
      Maximum lifetime alcohol intake <14 drinks/week<14 cups/week vs no coffee0.82 (0.31–2.20)
      14–20 cups/wk vs no coffee0.50 (0.17–1.48)
      ≥21 cups/wk vs no coffee0.56 (0.21–1.53)
      Maximum lifetime alcohol intake ≥14 drinks/week<14 cups/wk vs no coffee0.86 (0.42–1.77)
      14–20 cups/wk vs no coffee0.77 (0.37–1.61)
      ≥21 cups/wk vs no coffee0.34 (0.16–0.72)
      Tanaka et al,
      • Tanaka K.
      • Hara M.
      • Sakamoto T.
      • et al.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case-control study in Japan.
      2007
      <23 g alcohol/d (community controls)≥1 vs <1 cups/d0.19 (0.11–0.35)
      ≥23 g alcohol/d (community controls)≥1 vs <1 cups/d0.18 (0.07–0.44)
      Shimazu et al,
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • et al.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      2005: cohort 1 Shimazu et al,
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • et al.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      2005: cohort 2
      Never alcohol drinker<1 cup/d vs never0.69 (0.29–1.65)
      ≥1 cup/d vs never0.46 (0.14–1.52)
      Former alcohol drinker<1 cup/d vs never0.60 (0.20–1.78)
      ≥1 cup/d vs never0.74 (0.23–2.39)
      Current alcohol drinker<1 cup/d vs never0.90 (0.47–1.71)
      ≥1 cup/d vs never0.56 (0.24–1.29)
      Hu et al,
      • Hu G.
      • Tuomilehto J.
      • Pukkala E.
      • et al.
      Joint effects of coffee consumption and serum gamma-glutamyltransferase on the risk of liver cancer.
      2008
      Never alcohol drinker2–3 vs 0–1 cups/d0.59 (0.26–1.33)
      4–5 vs 0–1 cups/d0.46 (0.22–0.97)
      6–7 vs 0–1 cups/d0.36 (0.16–0.79)
      ≥8 vs 0–1 cups/d0.35 (0.14–0.85)
      Alcohol drinker2–3 vs 0–1 cups/d0.62 (0.27–1.39)
      4–5 vs 0–1 cups/d0.32 (0.13–0.77)
      6–7 vs 0–1 cups/d0.36 (0.15–0.88)
      ≥8 vs 0–1 cups/d0.29 (0.11–0.79)
      Summary estimatesNever/low alcohol drinkersModerate/high vs no/low0.61 (0.51–0.72)
      Moderate/high alcohol drinkers0.60 (0.49–0.73)
      Gallus et al,
      • Gallus S.
      • Bertuzzi M.
      • Tavani A.
      • et al.
      Does coffee protect against hepatocellular carcinoma?.
      2002; Kuper et al,
      • Kuper H.
      • Tzonou A.
      • Kaklamani E.
      • et al.
      Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma.
      2000
      Self-reported hepatitis2 vs ≤1 cups/d0.6 (0.3–1.1)
      3+ vs ≤1 cups/d0.5 (0.2–1.3)
      No self-reported hepatitis2 vs ≤1 cups/d0.9 (0.7–1.2)
      3+ vs ≤1 cups/d0.7 (0.5–0.9)
      Inoue et al,
      • Inoue M.
      • Yoshimi I.
      • Sobue T.
      • et al.
      Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan.
      2005
      HCV and HBV negative1–-2 cups/wk vs almost never0.87 (0.41–1.87)
      3–4 cups/wk vs almost never0.57 (0.19–1.70)
      1–2 cups/d vs almost never0.50 (0.20–1.20)
      Inoue et al,
      • Inoue M.
      • Kurahashi N.
      • Iwasaki M.
      • et al.
      Effect of coffee and green tea consumption on the risk of liver cancer: cohort analysis by hepatitis virus infection status.
      2009
      HCV and/or HBsAg positive<1 cup vs almost never0.55 (0.33–0.93)
      1–2 cups vs almost never0.47 (0.24–0.93)
      ≥3 cups vs almost never0.61 (0.23–1.62)
      Kurozawa et al,
      • Kurozawa Y.
      • Ogimoto I.
      • Shibata A.
      • et al.
      Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.
      2005
      Self-reported history of liver disease<1 cup/d vs nondrinker0.94 (0.53–1.66)
      ≥1 cup/d vs nondrinker0.44 (0.22–0.88)
      No self-reported history of liver disease<1 cup/d vs nondrinker0.79 (0.44–1.41)
      ≥1 cup/d vs nondrinker0.61 (0.32–1.16)
      Leung et al,
      • Leung W.W.
      • Ho S.C.
      • Chan H.L.
      • et al.
      Moderate coffee consumption reduces the risk of hepatocellular carcinoma in hepatitis B chronic carriers: a case-control study.
      2011
      HBV positiveDrinkers vs nondrinkers0.54 (0.30–0.97)
      Montella et al,
      • Montella M.
      • Polesel J.
      • La Vecchia C.
      • et al.
      Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.
      2007
      HCV and/or HBsAg positive<14 cups/wk vs nondrinkers0.56 (0.15–2.15)
      14–20 cups/wk vs nondrinkers0.36 (0.09–1.36)
      ≥21 cups/wk vs nondrinkers0.67 (0.16–2.85)
      HCV and/or HBsAg negative<14 cups/wk vs nondrinkers0.55 (0.22–1.39)
      14–20 cups/wk vs nondrinkers0.35 (0.12–1.01)
      ≥21 cups/wk vs nondrinkers0.27 (0.10–0.73)
      Ohfuji et al,
      • Ohfuji S.
      • Fukushima W.
      • Tanaka T.
      • et al.
      Coffee consumption and reduced risk of hepatocellular carcinoma among patients with chronic type C liver disease: a case-control study.
      2006
      HCV positiveDrinkers vs nondrinkers0.47 (0.21–1.05)
      Shimazu et al,
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • et al.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      2005: cohort 1 Shimazu et al,
      • Shimazu T.
      • Tsubono Y.
      • Kuriyama S.
      • et al.
      Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan.
      2005: cohort 2
      Self-reported history of liver diseaseOccasional vs never0.51 (0.27–0.97)
      ≥1 vs never0.52 (0.25–1.07)
      No self-reported history of liver diseaseOccasional vs never0.98 (0.53–1.80)
      ≥1 vs never0.75 (0.37–1.50)
      Summary estimatesSelf-reported hepatitis/liver diseaseModerate/high vs no/low0.59 (0.45–0.78)
      Serologic evidence of HBV or HCV0.52 (0.39–0.69)
      No evidence of hepatitis/liver disease0.70 (0.56–0.88)
      Figure 4 shows the cumulative meta-analysis of HCC risk for coffee consumption vs no consumption over time, from 2000 to 2011. The estimate was 0.80 (95% CI, 0.50–1.29) in 2000 and decreased to 0.59 (95% CI, 0.48–0.72) in 2007 and was almost stable over the past few years (RR, 0.60; 95% CI, 0.50–0.71).
      Figure thumbnail gr4
      Figure 4Cumulative meta-analysis of studies on coffee consumption and HCC. RR for coffee consumption vs no consumption.
      No evidence of publication bias was found either from visual inspection of the funnel plot (Supplementary Figure 2) or from the Egger's test (P = .379).
      Quality score ranged between 4 and 7 for case-control studies and between 6 and 8 for cohort studies (median scores: case-control studies, 5; cohort studies, 7). The pooled RR was 0.63 (95% CI, 0.53–0.74) from 10 high-quality studies (ie, studies with quality score ≥6), 0.58 (95% CI, 0.45–0.74) from 2 case-control studies, and 0.64 (95% CI, 0.52–0.78) from 8 cohort studies (data not shown).

      Discussion

      Since the publication of previous meta-analyses on coffee and HCC,
      • Bravi F.
      • Bosetti C.
      • Tavani A.
      • et al.
      Coffee drinking and hepatocellular carcinoma risk: a meta-analysis.
      • Larsson S.C.
      • Wolk A.
      Coffee consumption and risk of liver cancer: a meta-analysis.
      4 cohort
      • Hu G.
      • Tuomilehto J.
      • Pukkala E.
      • et al.
      Joint effects of coffee consumption and serum gamma-glutamyltransferase on the risk of liver cancer.
      • Inoue M.
      • Kurahashi N.
      • Iwasaki M.
      • et al.
      Effect of coffee and green tea consumption on the risk of liver cancer: cohort analysis by hepatitis virus infection status.
      • Johnson S.
      • Koh W.P.
      • Wang R.
      • et al.
      Coffee consumption and reduced risk of hepatocellular carcinoma: findings from the Singapore Chinese Health Study.
      • Ohishi W.
      • Fujiwara S.
      • Cologne J.B.
      • et al.
      Risk factors for hepatocellular carcinoma in a Japanese population: a nested case-control study.
      and 2 case-control
      • Kanazir M.
      • Boricic I.
      • Delic D.
      • et al.
      Risk factors for hepatocellular carcinoma: a case-control study in Belgrade (Serbia).
      • Leung W.W.
      • Ho S.C.
      • Chan H.L.
      • et al.
      Moderate coffee consumption reduces the risk of hepatocellular carcinoma in hepatitis B chronic carriers: a case-control study.
      studies have been published. The pooled estimate from the 6 studies published after 2007 was comparable with that of previous ones. Thus, recent studies add up to the evidence that coffee drinkers have a 40% reduced risk of HCC compared with nondrinkers, and high drinkers have a more than 50% risk reduction.
      Coffee contains several bioactive compounds with potential favorable effects on health,
      • Ferruzzi M.G.
      The influence of beverage composition on delivery of phenolic compounds from coffee and tea.
      including minerals and antioxidants, mainly phenolic compounds (eg, chlorogenic, caffeic, ferulic, and cumaric acids), melanoidins and diterpenes (eg, cafestol and kahweol). In particular, chlorogenic acid and other antioxidant substances from coffee beans have been indicated to have an inhibitory effect on liver carcinogenesis.
      • Tanaka T.
      • Nishikawa A.
      • Shima H.
      • et al.
      Inhibitory effects of chlorogenic acid, reserpine, polyprenoic acid (E-5166), or coffee on hepatocarcinogenesis in rats and hamsters.
      Studies in animal models and cell culture systems have suggested potential anticarcinogenic effects of cafestol and kahweol against aflatoxin B1–induced genotoxicity in both rats and human beings,
      • Cavin C.
      • Holzhauser D.
      • Constable A.
      • et al.
      The coffee-specific diterpenes cafestol and kahweol protect against aflatoxin B1-induced genotoxicity through a dual mechanism.
      • Cavin C.
      • Holzhaeuser D.
      • Scharf G.
      • et al.
      Cafestol and kahweol, two coffee specific diterpenes with anticarcinogenic activity.
      • Majer B.J.
      • Hofer E.
      • Cavin C.
      • et al.
      Coffee diterpenes prevent the genotoxic effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and N-nitrosodimethylamine in a human derived liver cell line (HepG2).
      although it is not clear if these compounds reach sufficient levels for such actions in human beings after coffee intake. Coffee consumption has been related inversely to the activity of some hepatic enzymes, including glutamyltransferase, an indicator of several liver diseases,
      • Tanaka K.
      • Tokunaga S.
      • Kono S.
      • et al.
      Coffee consumption and decreased serum gamma-glutamyltransferase and aminotransferase activities among male alcohol drinkers.
      and serum alanine aminotransferase.
      • Ruhl C.E.
      • Everhart J.E.
      Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States.
      Coffee components were found to modify the xenobiotic metabolism, inducing glutathione-S-transferase and inhibiting N-acetyltransferase.
      • Huber W.W.
      • Parzefall W.
      Modification of N-acetyltransferases and glutathione S-transferases by coffee components: possible relevance for cancer risk.
      Moreover, coffee consumption has been associated inversely with cirrhosis,
      • Corrao G.
      • Lepore A.R.
      • Torchio P.
      • 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.
      • Corrao G.
      • Zambon A.
      • Bagnardi V.
      • et al.
      Coffee, caffeine, and the risk of liver cirrhosis.
      • Gallus S.
      • Tavani A.
      • Negri E.
      • et al.
      Does coffee protect against liver cirrhosis?.
      • Klatsky A.L.
      • Armstrong M.A.
      Alcohol, smoking, coffee, and cirrhosis.
      and thus it is possible that the favorable effect of coffee on HCC is mediated by its beneficial effects on cirrhosis, suggesting the existence of a continuum of clinical and epidemiologic evidence in the favorable effect of coffee, which spans from liver enzymes to cirrhosis to HCC. Moreover, part of the favorable effect of coffee on HCC might be mediated by its prevention of diabetes, a known risk factor for HCC.
      • Huxley R.
      • Lee C.M.
      • Barzi F.
      • et al.
      Coffee, decaffeinated coffee, and tea consumption in relation to incident type 2 diabetes mellitus: a systematic review with meta-analysis.
      • El-Serag H.B.
      • Hampel H.
      • Javadi F.
      The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence.
      • Polesel J.
      • Zucchetto A.
      • Montella M.
      • et al.
      The impact of obesity and diabetes mellitus on the risk of hepatocellular carcinoma.
      The present results may be affected by bias and confounding inherent to the observational studies included in the meta-analysis. Coffee consumption is based on patients’ self-reported information. However, information on coffee consumption has been shown to be satisfactorily reproducible and valid.
      • D'Avanzo B.
      • La Vecchia C.
      • Katsouyanni K.
      • et al.
      Reliability of information on cigarette smoking and beverage consumption provided by hospital controls.
      • Ferraroni M.
      • Tavani A.
      • Decarli A.
      • et al.
      Reproducibility and validity of coffee and tea consumption in Italy.
      • Jacobsen B.K.
      • Bonaa K.H.
      The reproducibility of dietary data from a self-administered questionnaire. The Tromso Study.
      Moreover, the inverse relation between coffee and HCC was observed in both retrospective (case-control) and prospective (cohort) studies, in populations from Europe and Asia, thus reassuring against a major role of bias. Allowance for confounding factors varied among different studies, but the fact that the inverse relation persisted after allowance for major risk factors for HCC, including evidence of hepatitis B and C infection, cirrhosis and other liver diseases, social class indicators, alcohol drinking, and tobacco smoking, reassures against a major role of confounding. Moreover, the inverse relation between coffee and HCC were consistent across different categories at increased risk of HCC, particularly subjects with a history of HBV/HCV, liver disease, and alcohol drinkers. The inverse association also was consistent over time, pointing against the hypothesis of a false-positive result.
      • Boffetta P.
      • McLaughlin J.K.
      • La Vecchia C.
      • et al.
      False-positive results in cancer epidemiology: a plea for epistemological modesty.
      Significant heterogeneity between studies was found, which mainly was owing to a case-control study from Japan
      • Tanaka K.
      • Hara M.
      • Sakamoto T.
      • et al.
      Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case-control study in Japan.
      and a cohort study from China.
      • Johnson S.
      • Koh W.P.
      • Wang R.
      • et al.
      Coffee consumption and reduced risk of hepatocellular carcinoma: findings from the Singapore Chinese Health Study.
      However, because results from these studies diverged from the pooled estimate in opposite directions, their exclusion did not modify the results substantially. Further, the association was of similar magnitude when only high-quality studies were considered.
      Still, despite the consistency of results across studies, time periods, and populations, it is difficult to establish whether the inverse relation between coffee drinking and HCC is causal on the basis of evidence from observational studies only.
      • La Vecchia C.
      Cancer and liver cancer prevention: is it a fact or just a potential?.
      This inverse relation indeed may be partly attributable to the fact that patients with a broad spectrum of digestive tract conditions, including liver disease and cirrhosis, may reduce their coffee intake. Thus, a reduction of coffee consumption in unhealthy subjects cannot be ruled out, although the inverse relation between coffee and liver cancer also was present in subjects with no history of hepatitis/liver disease. Publication bias also is possible in meta-analyses, with selective publication of favorable results, particularly when a relatively small number of studies is available. However, we did not find any relevant asymmetry in the funnel plot, and the Egger's test was not statistically significant. Thus, publication bias does not seem to have influenced the relation between coffee and HCC appreciably.
      Further, it remains difficult to translate the apparent inverse relation between coffee drinking and liver cancer risk observed in epidemiologic studies into potential implications on a public health level. Primary liver cancers are the most largely avoidable neoplasms, through HBV vaccination, control of HCV transmission, and reduction of alcohol drinking. These three measures can, in principle, avoid more than 90% of primary liver cancers worldwide. It remains unclear whether coffee drinking has an additional role in liver cancer prevention, but in any case such a role would be limited compared with that achievable through control of HBV, HCV, and reduction of alcohol intake.
      • La Vecchia C.
      Cancer and liver cancer prevention: is it a fact or just a potential?.
      In summary, the present meta-analysis confirmed that coffee consumption is associated with a reduction in HCC risk of approximately 40%. The protective effect of coffee was consistent across different populations and subgroups at increased HCC risk. However, the issue of causality and the role of specific coffee components remain open to discussion.

      Acknowledgments

      The authors thank Mrs Ivana Garimoldi for editorial assistance.

      Supplementary Material

      Figure thumbnail fx1
      Supplementary Figure 1Flow-chart of the selection of studies on coffee consumption and HCC included in the meta-analysis.
      Figure thumbnail fx2
      Supplementary Figure 2Funnel plot of studies on coffee consumption and HCC. RR, relative risk for coffee consumption vs no consumption.

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