In this prospective analysis of a large-scale, population-based cohort study of Chinese in Singapore, a statistically significant inverse association between consumption of coffee and the risk of developing HCC was observed. Compared with coffee non-drinkers, drinkers of coffee with three or more cups per day experienced a statistically significant 44% decreased risk of HCC. Findings of the present study in a high-risk population for HCC are consistent with previous epidemiological studies conducted in low- to intermediate-risk populations and further support the hypothesis that coffee or specific constituents in the coffee may protect against the development of HCC in humans.
The inverse association between coffee consumption and HCC risk may arise from the fact that subjects with a broad spectrum of liver disorders and cirrhosis choose to reduce their coffee consumption. However, previous studies found that the inverse association between coffee consumption and risk of HCC was present in subjects with or without chronic liver disease [19
]. One cohort study in Japan reported a statistically significant inverse association between coffee consumption and risk of HCC among the entire cohort. When HCC cases were stratified by HBV and/or HCV serology, the inverse coffee-HCC risk association was present for HCC cases that tested negative for both HBV and HCV [13
]. In the present study, we determined HBV and HCV serology in a subset of HCC cases and matched control subjects. Although the overall association between coffee/caffeine consumption and HCC risk among this subset of individuals with known HBV/HCV serologic status was no longer statistically significant, primarily due to the small number of HCC patients who donated pre-diagnosed blood samples for the test of hepatitis serology, further adjustment for HBV and HCV serology did not alter the inverse association between coffee/caffeine consumption and HCC risk, suggesting that infection with HBV and/or HCV or preexisting chronic liver disease would be less likely to confound the observed inverse coffee-HCC risk association.
Tea contains not only caffeine but also polyphenols, both of which show antioxidative properties. Coffee drinkers of the present study population consumed less green or black tea. Our detailed analysis revealed that the reduced risk of HCC was mainly associated with consumption of coffee, but not with tea, suggesting that unique constituents in coffee may exert a protective effect.
Besides HCC, coffee consumption has been inversely related to serum ALT activity (a specific marker of liver injury), GGT activity (a marker of liver cirrhosis risk), cirrhosis, and other chronic liver disease [7
]. Given that cirrhosis is a hallmark of the liver disease progression towards HCC, these data have lent biological plausibility to the observed coffee-HCC risk association.
The biologic mechanism behind coffee consumption and HCC risk reduction is unclear. Coffee contains more than one thousand chemical compounds including caffeine, diterpenes (cafestol and kahweol), and chlorogenic acids. In one experimental study, caffeine in drinking water significantly reduced the incidence and multiplicity of chemical-induced liver tumors in rats [5
]. The risk of cirrhosis was not associated with consumption of caffeinated, non-coffee beverages, but with consumption of coffee [28
]. Furthermore, decaffeinated coffee has been shown to possess a similar effect as caffeinated coffee on altering phase I and phase II enzymes that probably participate in metabolic activation and detoxification of potential hepatocarcinogens, respectively (see below) [29
]. These data suggest that compounds other than caffeine in coffee may exert beneficial effects on the liver.
Numerous studies have suggested that cafestol and kahweol may exert anti-hepatocarcinogenesis effects. In animal and cell line models, these diterpenes have been shown to significantly reduce the mRNA and protein levels of cytochrome P450 (CYP) isoenzymes 1A1, 1A2, 3A2, 2B1, 2B2, and 2C11, along with the reduced formation of aflatoxin B1
)-DNA adducts [30
], an established risk factor for HCC in humans[9
]. In addition, cafestol and kahweol can upregulate phase II detoxifying enzymes including glutathione S-transferase (GST). The most striking effect identified is a strong dose-dependent induction of the GST pi subunit Yp and Yc2 in the liver at the mRNA and protein levels following long-term treatment with diet containing cafestol and kahweol [8
]. Moreover, the increased GST expression is dependent on the continuous presence of cafestol and kahweol in the diet; GST returned to the baseline level following removal of cafestol and kahweol from diet [9
]. GST Yc2 is known to efficiently conjugate AFB1
], the most genotoxic metabolite of AFB1
The presence of cafestol and kahweol in coffee is dependent on the method of preparation. Scandinavian boiled, French press (i.e., plunger or cafetière coffee), and Turkish/Greek coffees have the highest amounts of the diterpenes, espressos intermediate amounts, and instant and drip-filtered coffees have negligible amounts (paper filters retain the lipid fraction released during brewing) [7
]. In Singapore, dark roasted coffee is commonly prepared by boiling in a muslin bag, a method presumed to preserve cafestol and kahweol levels. Due to the hypercholesterolemic effect of these diterpenes, the positive association between coffee intake and plasma cholesterol in our cohort supports our assumption that the diterpenes are present in the coffee commonly consumed by cohort subjects [32
Chlorogenic acid present in coffee has shown twice the total antioxidant capacity of ascorbic acid over the same concentration range, indicating that chlorogenic acid can effectively scavenge reactive oxygen species, which have mutagenic and tumor-promoting effects [33
]. Chlorogenic acid also increased enzymatic activities of GST and suppressed the chemical-induced neoplastic transformation of cancer cells [32
]. Rats fed a diet with instant coffee, which has no diterpenes, with or without caffeine showed a dose-dependent increase in mRNA and protein expression of GST enzymes involved in cellular antioxidant defenses, along with a protection against both genotoxicity and cytotoxicity of AFB1
]. These data suggest that ingredients of coffee other than diterpenes and caffeine may also play a role in the protection against the development of HCC.
Tea consumption, particularly green tea consumption, has been suggested as having protective effects against the development of cancer at a number of sites. Green tea polyphenols show antioxidative properties [34
], which may protect against oxidative damage in humans [35
]. Several epidemiologic studies have examined the association between green tea consumption and HCC risk [13
]. Most of those studies reported a null association [13
]. A recent report from a prospective cohort study in Japan found a dose-dependent inverse association between green tea consumption and liver cancer incidence in women, but not in men. Women consuming ≥5 cups green tea per day experienced only half the risk that for women with <1 cup green tea per day [36
]. We did not find a statistically significant association between consumption of either green tea or black tea at least on a weekly basis and HCC risk in the present study. To control for potential confounding effect of coffee on the tea-HCC risk association, we analyzed data cross-classified by consumption of green/black tea and coffee. The null tea-HCC risk association was present in both low (B2 cups/day) and high coffee drinkers (>2 cups/day), whereas high consumption of coffee was associated with reduced risk of HCC in tea drinkers and non-drinkers. Our null findings on tea and HCC risk, consistent with most of epidemiological studies, could be due to the low consumption of green tea in our study population (12.4% of cohort participants were daily drinkers who, on average, consumed 2.0 cups of green tea per day) compared with the study subjects of the Japanese cohort of which subjects consuming ≥1 and ≥5 cups green tea per day accounted for 73% and 30%, respectively [36
Potential limitations of this study include the lack of HBV and HCV status for all cohort participants, though some effort was made to address this using a nested case-control study. Additionally, participants in the cohort were not measured for the amount of liver damage present at baseline, making it difficult to address what effect this might have on the association between coffee consumption and risk of HCC. Finally, the number of observed cases is still relatively small in this cohort when compared to some others. This is particularly true among those where HBV/HCV serology is available. Given a small proportion of HCC cases with available prediagnostic blood samples, potential selection bias is a concern. However, we examined and found comparable distributions between HCC cases with and those without known HBV and HCV serology in coffee consumption (1.23 vs. 1.30 cups per day, p = .59), body mass index (23.9 vs. 23.7 kg/m2, p = .64), level of education (28.9% vs. 23.6% of secondary school or higher, p = .51), alcohol consumption (9.6% vs. 10.0% of ≥7 drinks per week, p = .17), and history of diabetes (22.9% vs. 18.2%, p = .35). These data indicate that patients with HCC of the nested case-control study were a representative sample of the HCC patients of the entire cohort.
The strengths of this study include its prospective nature. In all participants, exposure factors were measured before the diagnosis of disease, allowing us to analyze the data in a temporal manner. The relatively high consumption of both coffee and tea in Singaporean Chinese provided a unique setting to test whether coffee or tea or both exert protective effect on HCC risk in this high-risk population given that coffee is a less popular drink for Chinese in mainland China or elsewhere. The presence of an inverse association between coffee/caffeine and HCC risk among non-drinkers of any tea confirmed the protective effect of coffee against the development of HCC, whereas tea did not show any significantly protective effect. The completeness of ascertainment of HCC cases among the cohort through the nationwide cancer registry in Singapore minimized the selection bias given that very few cohort participants emigrated from Singapore. Finally, the comprehensive questionnaire that asked for demographic, lifestyle, and other environmental exposures allowed for more thorough adjustment and less residual confounding effect on the observed coffee-HCC risk association.
In summary, high consumption of coffee/caffeine was associated with a statistically significant, reduced risk of HCC among Singaporean Chinese. Further studies are warranted to clarify the protective role of specific constituents in coffee in the development of HCC.