Coffee And Liver-2

GASTROENTEROLOGY 2007;132:1740 –1745

CLINICAL–LIVER, PANCREAS, AND BILIARY TRACT Coffee Consumption and Risk of Liver Cancer: A Meta-Analysis SUSANNA C. LARSSON and ALICJA WOLK Division of Nutritional Epidemiology, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden CLINICAL–LIVER, PANCREAS, AND BILIARY TRACT

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 ⴝ .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.

D

ata 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 ␥-glutamyltransferase (an indicator of cirrhosis risk)1– 8 and alanine aminotransferase (a marker of liver injury),2,6,9,10 as well as with risk of chronic liver disease11 and liver cirrhosis.12–16 Moreover, studies in animals have shown an inhibitory effect of

coffee on liver carcinogenesis.17 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 articles18 –28 concerning coffee consumption and liver cancer risk. Three publications18 –20 were excluded because of duplicate reports from the same study population. The remaining publications, consisting of 4 cohort studies21–23 (1 article presented results from 2 separate cohorts) and 5 case– control studies,24 –28 were included in the meta-analysis. Abbreviations used in this paper: CI, confidence interval; HCC, hepatocellular carcinoma; RR, relative risk. © 2007 by the AGA Institute 0016-5085/07/$32.00 doi:10.1053/j.gastro.2007.03.044

May 2007

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 study27 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 Longnecker29,30 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.31 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.29 We found that the bestfitting model was a linear model. Statistical heterogeneity among studies was evaluated using the Q and I2 statistics.32 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

1741

test.33 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 studies21–23 and 5 case– control studies 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,22 incidence of HCC in 6 studies,21,24 –28 and mortality from HCC in 1 study.23 Among case– control studies, 4 used hospital-based controls24 –26,28 and 1 used population-based controls.27 In the cohort studies, participants were asked about their coffee consumption during the past month21 or year23 before baseline, or about their recent or usual coffee consumption at baseline.22 In the case– control studies, participants were inquired about their coffee consumption 1 year,24 2 years,28 or 10 years before.25,27 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 disease26; we used the results based on coffee consumption before identification of liver disease. 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 studies21,23–25,27,28 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 al24) to 0.63 (when excluding the study by Tanaka et al27). Excluding the study that consisted of persons chronically infected with hepatitis C virus26 did not alter the results essentially (RR, 0.58; 95% CI, 0.49 – 0.68). One case– control study employed different control groups.27 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 incidence21,24 –28 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 con24 –28

CLINICAL–LIVER, PANCREAS, AND BILIARY TRACT

Data Extraction

COFFEE AND LIVER CANCER

1742

LARSSON AND WOLK

GASTROENTEROLOGY Vol. 132, No. 5

Table 1. Characteristics of Cohort and Case–Control Studies of Coffee Consumption and Liver Cancer Age, years

Outcome

Japan; 1990–2001

40–69

HCC incidence

Shimazu et al, 200522; Cohort 1

Japan; 1984–1992

ⱖ40

Shimazu et al, 200522; Cohort 2

Japan; 1990–1997

Kurozawa et al, 200523

Study Cohort studies Inoue et al, 200521

CLINICAL–LIVER, PANCREAS, AND BILIARY TRACT

Case–control studies Gallus et al, 200224

Country; study period

No. of cases

No. in cohort or controls

Coffee consumption

Relative risk (95% CI)

Almost never 1–2 days/week 3– 4 days/week 1–2 cups/day 3– 4 cups/day ⱖ5 cups/day Nondrinkers Occasionally ⱖ1 cup/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) 1.00 (reference) 0.56 (0.33– 0.97) 0.53 (0.28 –1.00)

38,703 (cohort)

Nondrinkers Occasionally ⱖ1 cup/day

1.00 (reference) 1.05 (0.52–2.16) 0.68 (0.31–1.51)

83,966 (cohort)

Nondrinkers ⬍1 cup/day ⱖ1 cup/day

1.00 (reference) 0.83 (0.54 –1.25) 0.50 (0.31– 0.79)

Nondrinkers 1 cup/day 2 cups/day ⱖ3 cups/day

1.0 (reference) 1.2 (0.9 –1.6) 1.0 (0.7–1.3) 0.7 (0.5–1.0)

Nondrinkers 1–2 cups/day 3– 4 cups/day ⱖ5 cups/day Nondrinkers ⬍1 cup/day ⱖ1 cup/day

1.0 (reference) 0.8 (0.4 –1.3) 0.4 (0.2– 0.8) 0.3 (0.1– 0.7) 1.00 (reference)b 0.61 (0.18 –2.03)b 0.38 (0.13–1.12)b

Nondrinkers Occasionally 1–2 cups/day ⱖ3 cups/day Nondrinkers ⬍14 cups/week 14 –20 cups/week 21–27 cups/week ⱖ28 cups/week

1.00 (reference) 0.33 (0.22– 0.48)c 0.27 (0.15– 0.48)c 0.22 (0.11– 0.43)c 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)

334

90,452 (cohort)

Primary liver cancer incidence

70

22,404 (cohort)

40–64

Primary liver cancer incidence

47

Japan; 1988–1999

40–79

HCC mortality

258

Greece; 1995–1998 and Italy; 1984– 1997

18–79

HCC incidence

834

1912

⬍80

HCC incidence

250

500

Gelatti et al, 200525

Italy; 1994–2003

Ohfuji et al, 200626

Japan; 2001–2002

NA

HCC incidence

73a

253a

Tanaka et al, 200727

Japan; 2001–2004

40–79

HCC incidence

209

1253

Montella et al, 200728

Italy; 1999–2002

43–84

HCC incidence

185

412

Adjustments

Age, sex, study area, smoking, and intakes of alcohol, green tea, and green vegetables Age, sex, history of liver disease, smoking, and alcohol intake Age, sex, history of liver disease, smoking, and alcohol intake Age, sex, education, history of diabetes or liver disease, smoking, and alcohol intake Age, sex, education, history of diabetes or hepatitis, body mass index, smoking, and alcohol intake Age, sex, HBV and/or HCV infection, and alcohol intake Age, sex, time since first identification of liver disease, BMI, disease severity, family history of liver disease, interferon therapy, smoking, and alcohol intake Age, sex, smoking, and alcohol intake

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. chronically infected with hepatitis C virus. 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). cOdds 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). aPatients bOdds

ducted in Europe. We found no evidence of publication bias for cohort studies (P ⫽ .24) or case– control studies (P ⫽ .22). Four studies presented results stratified by history of liver disease.21–24 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).

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

Figure 1. Relative 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%.

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 disease22,23,26 or hepatitis,24 and only 3 case– control studies adjusted for hepatitis virus infection.25,26,28 Caffeine metabolism is impaired in persons with chronic liver disease.34,35 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.22,23 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.36 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

COFFEE AND LIVER CANCER

1743

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.17 Caffeine is another major component of coffee. In one animal study, caffeine levels of coffee extracts were inversely related to liver injury.37 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).36 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.36 Several studies in Europe and Japan have also observed inverse relations between coffee consumption and serum levels of aminotransferases2,6,9,10 and ␥-glutamyltransferase1– 8 (a sensitive indicator of several liver diseases). In addition, prospective cohort studies in the United States15 and Norway16 and case– control studies in Italy12–14 have reported an inverse association between coffee consumption and risk of liver cirrhosis, which is strongly related to HCC.38 Therefore, the observed association of coffee consumption with liver cancer could potentially represent an association with liver disease.

Figure 2. Relative 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%.

CLINICAL–LIVER, PANCREAS, AND BILIARY TRACT

May 2007

1744

LARSSON AND WOLK

CLINICAL–LIVER, PANCREAS, AND BILIARY TRACT

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,39 and another meta-analysis showed a strong positive association between type 2 diabetes and risk of HCC.40 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 metaanalysis employed 3 different control groups.27 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).27 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.

GASTROENTEROLOGY Vol. 132, No. 5

8.

9.

10.

11.

12.

13.

14. 15. 16. 17.

18.

19.

References 1. Nilssen O, Forde OH, Brenn T. The Tromso Study. Distribution and population determinants of gamma-glutamyltransferase. Am J Epidemiol 1990;132:318 –326. 2. Casiglia E, Spolaore P, Ginocchio G, Ambrosio GB. Unexpected effects of coffee consumption on liver enzymes. Eur J Epidemiol 1993;9:293–297. 3. Kono S, Shinchi K, Imanishi K, Todoroki I, Hatsuse K. Coffee and serum gamma-glutamyltransferase: a study of self-defense officials in Japan. Am J Epidemiol 1994;139:723–727. 4. Pintus F, Mascia P. Distribution and population determinants of gamma-glutamyltransferase in a random sample of Sardinian inhabitants. “ATS-SARDEGNA” Research Group. Eur J Epidemiol 1996;12:71–76. 5. Poikolainen K, Vartiainen E. Determinants of gamma-glutamyltransferase: positive interaction with alcohol and body mass index, negative association with coffee. Am J Epidemiol 1997;146:1019 – 1024. 6. 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. Int J Epidemiol 1998;27:438 – 443. 7. Honjo S, Kono S, Coleman MP, Shinchi K, Sakurai Y, Todoroki I, Umeda T, Wakabayashi K, Imanishi K, Nishikawa H, Ogawa S,

20.

21.

22.

23.

24.

25.

Katsurada M, Nakagawa K, Yoshizawa N. Coffee drinking and serum gamma-glutamyltransferase: an extended study of Self-Defense Officials of Japan. Ann Epidemiol 1999;9:325–331. Nakanishi N, Nakamura K, Nakajima K, Suzuki K, Tatara K. Coffee consumption and decreased serum gamma-glutamyltransferase: a study of middle-aged Japanese men. Eur J Epidemiol 2000;16:419 – 423. 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. Ind Health 2000;38:99 –102. Honjo S, Kono S, Coleman MP, 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. J Clin Epidemiol 2001;54:823– 829. Ruhl CE, Everhart JE. Coffee and tea consumption are associated with a lower incidence of chronic liver disease in the United States. Gastroenterology 2005;129:1928 –1936. Corrao G, Zambon A, Bagnardi V, D’Amicis A, Klatsky A. Coffee, caffeine, and the risk of liver cirrhosis. Ann Epidemiol 2001;11: 458 – 465. Corrao G, Lepore AR, Torchio P, Valenti M, Galatola G, D’Amicis A, Arico S, di Orio F. 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. Eur J Epidemiol 1994;10:657– 664. Gallus S, Tavani A, Negri E, La Vecchia C. Does coffee protect against liver cirrhosis? Ann Epidemiol 2002;12:202–205. Klatsky AL, Armstrong MA. Alcohol, smoking, coffee, and cirrhosis. Am J Epidemiol 1992;136:1248 –1257. Tverdal A, Skurtveit S. Coffee intake and mortality from liver cirrhosis. Ann Epidemiol 2003;13:419 – 423. 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. Basic Life Sci 1990;52:429 – 440. La Vecchia C, Ferraroni M, Negri E, D’Avanzo B, Decarli A, Levi F, Franceschi S. Coffee consumption and digestive tract cancers. Cancer Res 1989;49:1049 –1051. Kuper H, Tzonou A, Kaklamani E, Hsieh CC, Lagiou P, Adami HO, Trichopoulos D, Stuver SO. Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma. Int J Cancer 2000;85:498 –502. 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. Kurume Med J 2004;51:141–149. Inoue M, Yoshimi I, Sobue T, Tsugane S. Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan. J Natl Cancer Inst 2005;97:293–300. 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. Int J Cancer 2005;116:150 –154. 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. Br J Cancer 2005;93:607– 610. Gallus S, Bertuzzi M, Tavani A, Bosetti C, Negri E, La Vecchia C, Lagiou P, Trichopoulos D. Does coffee protect against hepatocellular carcinoma? Br J Cancer 2002;87:956 –959. Gelatti U, Covolo L, Franceschini M, Pirali F, Tagger A, Ribero ML, Trevisi P, Martelli C, Nardi G, Donato F. Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case– control study. J Hepatol 2005;42:528 –534.

26. 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. Hepatol Res 2006;36:201–208. 27. 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. Cancer Sci 2007;98:214 –218. 28. Montella M, Polesel J, La Vecchia C, Maso LD, Crispo A, Crovatto M, Casarin P, Izzo F, Tommasi LG, Talamini R, Franceschi S. Coffee and tea consumption and risk of hepatocellular carcinoma in Italy. Int J Cancer [published online Jan 4, 2006, ahead of print] 2007. 29. Greenland S, Longnecker MP. Methods for trend estimation from summarized dose–response data, with applications to meta-analysis. Am J Epidemiol 1992;135:1301–1309. 30. Orsini N, Bellocco R, Greenland S. Generalized least squares for trend estimation of summarized dose–response data. Stata J 2006;6:40 –57. 31. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–188. 32. Higgins JP, Thompson SG. Quantifying heterogeneity in a metaanalysis. Stat Med 2002;21:1539 –1558. 33. Egger M, Davey Smith G, Schneider M, Minder C. Bias in metaanalysis detected by a simple, graphical test. BMJ 1997;315: 629 – 634. 34. Hasegawa M, Yamada S, Hirayama C. Fasting plasma caffeine level in cirrhotic patients: relation to plasma levels of catecholamines and renin activity. Hepatology 1989;10:973–977.

COFFEE AND LIVER CANCER

1745

35. Wahllander A, Renner E, Preisig R. Fasting plasma caffeine concentration. A guide to the severity of chronic liver disease. Scand J Gastroenterol 1985;20:1133–1141. 36. Ruhl CE, Everhart JE. Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States. Gastroenterology 2005;128:24 –32. 37. He P, Noda Y, Sugiyama K. Suppressive effect of coffee on lipopolysaccharide-induced hepatitis in D-galactosamine-sensitized rats. Biosci Biotechnol Biochem 2001;65:1924 –1927. 38. La Vecchia C, Negri E, Cavalieri d’Oro L, Franceschi S. Liver cirrhosis and the risk of primary liver cancer. Eur J Cancer Prev 1998;7:315–320. 39. van Dam RM, Hu FB. Coffee consumption and risk of type 2 diabetes: a systematic review. JAMA 2005;294:97–104. 40. El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 2006;4: 369 –380.

Received January 26, 2007. Accepted March 8, 2007. 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. e-mail: [email protected]; fax: (46) 8-304571. The sponsor had no role in the study design or in the collection, analysis, and interpretation of the data. No conflicts of interest exist. Supported by research grants from the Swedish Cancer Society.

CLINICAL–LIVER, PANCREAS, AND BILIARY TRACT

May 2007