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Coffee Consumption and Risk of Liver Cancer: A Meta-Analysis. Coffee, 2 Cups Daily, May Reduce Risk for Liver Disease, ALT Elevations

Gastroenterology May 2007

findings from this meta-analysis indicate that coffee consumption may reduce the risk of liver cancer. 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. 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 I3-glutamyltransferase1, 2, 3, 4, 5, 6, 7, 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, 13, 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. 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. 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.

Gastroenterology
Volume 132, Issue 5, Pages 1740-1745 (May 2007)
Susanna C. Larsson, Alicja Wolk

ABSTRACT
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.

Article Outline
Abstract
Materials and Methods
Study Selection
Data Extraction
Statistical Analysis
Results
Discussion
References
Copyright

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 I3-glutamyltransferase (an indicator of cirrhosis risk)1, 2, 3, 4, 5, 6, 7, 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, 13, 14, 15, 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, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 concerning coffee consumption and liver cancer risk. Three publications18, 19, 20 were excluded because of duplicate reports from the same study population. The remaining publications, consisting of 4 cohort studies21, 22, 23 (1 article presented results from 2 separate cohorts) and 5 case-control studies,24, 25, 26, 27, 28 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 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 best-fitting 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 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, 22, 23 and 5 case-control studies24, 25, 26, 27, 28 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, 25, 26, 27, 28 and mortality from HCC in 1 study.23 Among case-control studies, 4 used hospital-based controls24, 25, 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, 24, 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, 25, 26, 27, 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 conducted 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, 22, 23, 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).

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%.

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 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 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
I3-
glutamyltransferase1, 2, 3, 4, 5, 6, 7, 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, 13, 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. 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 replica 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 meta-analysis 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.

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