Coffee is consumed by 50 percent of Americans every day. After oil, coffee is the second most valuable commodity in the world. In recent years a number of studies have suggested potential health risks associated with coffee consumption; however, the results are controversial. Whilst coffee has been reported to increase cardiovascular risk factors, other investigators have demonstrated its protective effects on diseases ranging from type 2 diabetes to Parkinson's disease. A number of investigators have focused their attention on the relationship between the consumption of coffee and liver disease.
Aim To examine the published literature to date in an attempt to establish the presence of an hepatoprotective effect of coffee.
Methods Using PubMed, we identified published studies and review articles relating to the effect of coffee consumption on diseases of the liver.
Conclusion A number of studies have reported the beneficial effects of coffee on abnormal liver biochemistry, cirrhosis and hepatocellular carcinoma. At the present time the mechanism of this effect remains unclear as does the ‘‘dose’’ required to achieve these benefits.
After oil, coffee is the second most valuable commodity in the world.1 More than 50% of Americans drink coffee everyday,1 on average consuming 3.1 cups daily.2 In 1999, consumers in the US spent an estimated $17.9 billion in the retail and foodservice sectors on coffee products.3 Coffee’s aroma permeates everywhere; you can even study ‘Starbucks’ at Syracuse University.1 However, is our addiction to the humble coffee bean damaging our health?
A number of studies have suggested potential health risks associated with coffee consumption; however, the results are controversial. Whilst coffee has been reported to increase cardiovascular risk factors, such as blood pressure,4 cholesterol5 and plasma homocysteine,6 prospective studies have not reported increased cardiovascular risk 7, 8. Other research has demonstrated protective effects of coffee intake on diseases ranging from type 2 diabetes9 to Parkinson’s disease.10 A number of investigators have focused their attention on the relationship between the consumption of coffee and liver disease. In this review, we attempt to assess the impact of coffee consumption on a spectrum of liver abnormalities ranging from alteration of biochemical tests to its potential effect on the development of hepatocellular carcinoma (HCC).
We used PubMed (http://www.ncbi.nlm.nih.gov/entrez) to identify published studies and review articles, using the searching expressions ‘Coffee and liver disease’, ‘Coffee and hepatic disease’, ‘Coffee and cirrhosis’, ‘Coffee and liver cancer’ and ‘Coffee and hepatocellular carcinoma’. The search process was then repeated substituting the term ‘Coffee’ with ‘Caffeine’. Subsequently, the reference lists provided by the identified papers was hand-searched for any additional articles not identified by the PubMed search.
Coffee and serum liver biochemistry
First reports of a relationship between coffee and liver biochemistry dates back 20 years.11 Since then, numerous studies have reported the association of coffee consumption with reduced levels of liver enzymes in diverse geographical regions extending from North America, through Europe and into Asia.
In 1980, Arnesen et al.11 was the first to report an inverse relationship between coffee drinking and serum gamma-glutamyltransferase (GGT) in the Tromso Heart Study. Subsequently, a series of cross-sectional and longitudinal studies have reported similar findings. Tanaka et al.12 conducted a cross-sectional study of 12 687 healthy Japanese subjects, excluding those with pre-existing liver disease or abnormal liver enzymes. This group demonstrated an inverse association between coffee consumption and serum GGT levels. Multivariate analysis showed a highly significant inverse relationship between coffee and GGT in men (P < 0.0001) with a much less, however still significant, relationship for females (P < 0.002). Moreover, the association was more evident amongst heavy alcohol drinkers, being absent amongst abstainers. The investigators postulated that the weaker association observed for females could be explained by lower alcohol consumption by this sex. In this study, current drinkers represented only 24% of female subjects compared with 78% of males. Additionally, even within alcohol consumption categories, the mean intake levels for females were lower than males. Taking into account the observation that the inverse relationship between coffee and GGT was maximal for high alcohol drinkers, the lower alcohol consumption amongst females in the study may account for the less significant results for this gender.
The study by Tanaka et al. also investigated the potential relationship between coffee consumption and alanine (ALT) and aspartate (AST) aminotransferase. As with GGT, coffee intake was significantly related to decreased serum concentrations of both enzymes among males, whereas the corresponding relationship amongst females did not achieve statistical significance.12
A second group of Japanese investigators also addressed the potential relationship between coffee consumption and AST/ALT levels. In this study, 7313 males attending for health examination were recruited; as before, individuals with previous history of liver disease and former consumption of alcohol were excluded.13 415 (58%) of subjects had elevated AST/ALT. Following categorization of subjects according to coffee intake, analysis demonstrated a stepwise reduction in odds ratio (OR) of having liver inflammation (i.e. raised AST/ALT) with increasing levels of coffee use. Compared with subjects not drinking coffee, those men consuming ≥5 cups of coffee per day had a 40% decrease in OR. This relationship was independent of possible confounders including alcohol, smoking and body mass index.
In 2005, Ruhl and Everhart14 published the results of a large population-based study examining whether elevated serum ALT activity was less common with increasing coffee intake. These investigators examined those at high risk of liver injury, namely those who were overweight, consuming excess quantities of alcohol, with iron overload, impaired glucose tolerance or suffering from viral hepatitis. ALT activity decreased significantly with higher coffee and caffeine intake. Moreover, unadjusted logistic regression and multivariate analyses revealed a lower risk of ALT elevation with increasing coffee (P = 0.001) and caffeine (P = 0.001) consumption, although the relationship was stronger with caffeine in the multivariate analysis (coffee: P = 0.034; caffeine: P < 0.001). Those with the highest caffeine intake had one-third the risk of an elevated ALT compared with individuals with the lowest consumption [OR 0.31, 95% confidence interval (CI) 0.16–0.61]. This relationship held true across all the liver disease risk factors examined.
More recently, a group from California published results of a 22-year follow-up of 125 580 individuals, again without known liver disease at recruitment.15 In addition to a cohort study examining a potential role played by coffee consumption on the development of alcoholic cirrhosis, a cross-sectional analysis of coffee’s effect on transaminase levels was also investigated. In keeping with the previously discussed findings of Tanaka et al.12 and Honjo et al.,13 coffee drinking was related to a lower prevalence of high AST and ALT levels. Following stratification of levels of alcohol intake, logistic models demonstrated an inverse relationship between coffee drinking and enzyme levels within these alcohol consumption categories. Whilst the lower prevalence of elevated enzyme levels was not limited to the heavy alcohol drinkers, coffee’s inverse relationship was strongest amongst the heaviest consumers of alcohol.
Coffee and the development of liver cirrhosis
As discussed above, coffee consumption appears to be associated with lower levels of hepatic enzymes. However, does the inferred protective effect of coffee against hepatocellular damage translate into a reduction in chronic liver disease, such as cirrhosis?
Coffee consumption has been shown to be inversely associated with the risk of cirrhosis in several case–control studies. In the early 1990s, Klatsky et al.16 published results of a 10-year follow-up of 132 patients hospitalized for or dying because of cirrhosis. This group reported an inverse relationship between coffee drinking and risk of liver cirrhosis, the effect being strongest for alcohol-related cirrhosis. In the same dataset, coffee was inversely related to the risk of death attributed to cirrhosis. More recently, these investigators reported the findings of their 22-year follow-up study, during which 330 subjects developed cirrhosis.15 As before, this study demonstrated a robust negative relationship between coffee and cirrhosis independent of confounders (P < 0.001); however, the relationship between coffee intake and non-alcoholic cirrhosis did not achieve statistical significance. Relative risks of alcoholic cirrhosis for coffee drinking were 0.7 (95% CI 0.4–1.1) for 1 cup, 0.6 (0.4–0.8; P < 0.001) for 1–3 cups and 0.2 (0.1–0.4; P < 0.001) for ≥4 cups/day. For the 131 individuals with non-alcoholic cirrhosis, the corresponding values were 1.2 (0.4–2.2), 1.3 (0.8–2.1) and 0.7 (0.4–1.3) for 1, 1–3 and ≥4 cups/day respectively.
Several Italian studies have also examined this relationship.17, 18 Corrao et al.17 demonstrated that coffee consumption was associated with a reduced risk of cirrhosis in both prospective epidemiological and case–control studies. In a recent study of over 700 subjects (274 cases and 458 controls), these investigators attempted to address several unresolved issues. As in earlier studies, Corrao et al. reported a dose–response relationship between coffee intake and risk of liver cirrhosis with the OR for liver cirrhosis decreasing from 1.0 for abstainers to 0.47, 0.23, 0.21 and 0.16 for 1, 2, 3 or 4 cups of coffee respectively. The influence of caffeine was also assessed by examining the effect of other caffeine-containing beverages on the risk of liver cirrhosis. Unlike coffee, the intake of caffeine in other beverages did not show a significant relationship with reduction of cirrhosis risk.17
A second Italian study of 101 cirrhotic patients and >1500 controls showed that, compared with the individuals who had never consumed coffee, there was a significant reduction in multivariate OR for cirrhosis amongst coffee drinkers (OR 0.54).18 Moreover, there was a significant trend in risk reduction with increasing numbers of cups/day, reaching 0.29 (CI 0.13–0.67) for those drinking ≥3 cups/day. In addition, these investigators also demonstrated that not only was the quantity of coffee consumed important, but also the duration of coffee consumption [OR declining to 0.45 (95% CI 0.21–0.97) for 40 years or more]. Once again, doubt was cast upon the potential of beneficial effect of caffeine given that the consumption of other caffeine-containing beverages was not associated with reduced cirrhosis risk.
Further support for the reduction in cirrhosis risk with coffee drinking comes from a Norwegian study. Tverdal and Skurtveit19 followed up >50 000 adults undergoing screening for cardiovascular disease. During 17 years of follow-up, 4207 deaths were recorded, 53 from cirrhosis. This report provides evidence of a favourable role of coffee intake on the risk of death from liver cirrhosis. The mortality rates were distinctively lower amongst persons drinking ≥3 cups of coffee compared with those drinking ≤2. In contrast to the work from Klatsky et al.,15 the observed relationship was present for both those with alcoholic cirrhosis and individuals developing cirrhosis secondary to other factors.
Coffee consumption and the development of hepatocellular carcinoma
We have previously discussed the reports suggesting that coffee inhibits elevation of liver transaminases11–15 and that this possible hepato-protective effect translates into reduced risk of and mortality from liver cirrhosis.15, 17–19 Cirrhosis is a major risk factor for the development of HCC.20 In developed countries, the major risk factors for HCC include alcohol21 and infection with the hepatitis B (HBV) and C (HCV) viruses.22 Given the inverse relationship between coffee and liver cirrhosis, a number of groups have addressed the effect of consumption of this beverage on risk of or mortality from HCC.
Gelatti et al.23 recruited 250 HCC cases and 500 control subjects. As expected, infection with HCV and HBV together with alcohol was all strongly positively associated with HCC. Coffee consumption, conversely, was associated with a decreasing risk of HCC. Despite the result for low levels of coffee consumption failing to achieve significance, at higher levels there was a significant decrease in hepatoma risk (1–2 cups OR 0.8; 3–4 cups OR 0.4; ≥5 cups OR 0.3). The effect of coffee on the risk of HCC development related to each of the three HCC risk factors was considered separately. With respect to alcohol, individuals were categorized according to their levels of consumption. For each category, increasing coffee intake was associated with a decrease in HCC risk, with the largest differences demonstrated in those consuming the highest quantities of alcohol. Considering HBV and HCV status, a substantial reduction of HCC risk was demonstrated amongst those drinking >2 cups compared with those whose coffee intake was lower.23
The results from this Italian group are mirrored by those of Inoue et al.24 who carried out a prospective analysis of a large-scale (>9000 subjects) population-based cohort study in Japan. Over an average follow-up approaching 10 years, 334 subjects were newly diagnosed with HCC. Compared with non-coffee drinkers, individuals consuming coffee daily had half the hepatoma risk (hazard ratio 0.49, 95% CI 0.36–0.66). Furthermore, as has been observed by other studies, there was an incremental protective effect with increasing coffee consumption (non-drinkers 547/100 000 patients, daily coffee 215/100 000 patients, ≥5 cups/days 121/100 000 patients). Amongst the Japanese population, chronic infection with HBV or HCV has been established as a major risk factor for HCC.25 When patients were analysed according to hepatitis virus infective status, an inverse association was evident between coffee drinking and HCV-associated HCC. In the case of HBV-related HCC, a trend was also evident; however, this failed to achieve statistical significance.
A second large Japanese cohort study has also addressed the proposed relationship between coffee and HCC. Results from this group support those reported by Gelatti et al.23 and Inoue et al.24 in demonstrating coffee consumption’s inverse relationship with HCC.26 Amongst those drinking ≥1 cup of coffee/day, the risk of death from HCC was 0.5 (95% CI 0.31–0.79) compared with individuals abstaining from coffee. Interestingly, further analysis revealed that the protective effect of coffee was only present for those with a previous history of liver disease. The investigators proposed that this may be explained by the well-documented inhibitory effect of coffee consumption on the development of liver cirrhosis, with subsequent reduction in the number of cirrhotic cases progressing to hepatoma.
More recently, three large, hospital-based, case–control studies add further weight to the hypothesis of a hepato-protective effect of coffee. Ohfuji et al.27 examined the relationship between HCV-related HCC and coffee consumption demonstrating that drinking at least one cup per day was associated with a significantly lower risk of HCC compared with non-drinkers (P = 0.0032). As discussed earlier, this putative protective effect may reflect a reduction in coffee consumption related to impaired caffeine clearance in those with liver disease. To account for this, Ohfuji et al. excluded those individuals admitting to a reduction in coffee intake following identification of liver disease. Following exclusion of these subjects, a reduced OR for HCC amongst higher coffee drinkers was still evident, albeit just failing to achieve statistical significance. In a second Japanese study, Tanaka et al.28 examined over 200 HCC cases and 2000 controls. Not only did this group assess the effect of current levels of coffee consumption, they also focused on prior intake. In both cases, coffee use was associated with a decreased HCC risk compared with controls. In recent months, Montella et al.29 have also reported the results of a hospital-based, case–control study exploring the relationship between coffee and HCC risk. This group also reported a beneficial effect of coffee with those consuming in excess of 28 cups per week having a significantly reduced risk compared with those whose intake is under 14 cups (OR 0.4, 95% CI 0.2–1.1, P = 0.02). This relationship held true across a number of HCC risk factors, including HBV/HCV infection or alcohol consumption. Interestingly, no significant association was demonstrated between consumption of decaffeinated coffee or tea and the development of HCC.
Mechanism of coffee’s protective effect
Despite the body of evidence supporting a hepato-protective effect of coffee, the mechanism underlying this effect is yet to be elucidated. Coffee is a complex ‘blend’ of a vast number of different chemicals, any of which may be responsible for its reported effects on the liver.
Several investigators have suggested that the inverse relationship which has been described between coffee and liver disease may not be attributable to a coffee effect at all. Given the well-documented impairment of caffeine metabolism in those with cirrhosis,30 the association may reflect a reduction in coffee intake in those with liver disease in order to limit caffeine side effects.12, 18, 23 However, the results reported by these studies do not support this interpretation.12, 18
One hypothesis that has been suggested is a caffeine-related effect mediated through adenosine receptor antagonists or antioxidant actions.31 It is attractive to propose that caffeine, the major constituent of coffee, might play a significant role. Work by Ruhl and Everhart14 reported that, following multivariate analysis, the relationship between caffeine and reduced serum ALT levels was of greater significance than that for coffee. Indeed, work by Sharp and Benowitz32 has demonstrated that caffeine intake and serum caffeine levels were associated with lower levels of GGT and, in animal studies, caffeine has been shown to inhibit chemically induced hepatic carcinogenesis.33, 34 However, a number of other studies, including those by Tanaka et al.,12 Corrao et al.17 and Inoue et al.24 do not support this hypothesis. Using other caffeine containing beverages such as green tea or cola to substitute for coffee, these groups failed to demonstrate a significant association between these beverages and reduction in liver-related endpoints.
Work by Cavin et al.35 has suggested that other coffee constituents, namely cafestol and kahweol, may play an important role. In animal and cell culture models, these diterpenes have been shown to reduce the toxicity of a variety of carcinogens. Furthermore, cafestol and kahweol have been shown to induce phase II enzyme activity, enhance hepatic glutathione levels and decrease liver DNA adducts caused by chemical carcinogens in animal models.35–37 However, these substances are only present in small amounts in filtered coffee; therefore, in populations consuming this variety of coffee, it is unlikely that the entire hepato-protective effect is because of these constituents. Moreover, studies by Urgert et al.38 and Weusten-Van der Wouw et al.39 have shown that these coffee constituents actually increase liver function tests (AST/ALT), which is contrary to the results of Tanaka et al., Honjo et al. and Klatsky et al., all of which have been shown a significant inverse relationship between coffee consumption and transaminase levels.12, 13, 15
There is a wealth of literature supporting the favourable effect of the coffee on liver function. These studies span the breadth of liver disease from an association between coffee and lower levels of transaminases at one end of the spectrum, to a reported reduction in HCC mortality at the other. A number of studies have suggested various potential methods to explain these results; however, no mechanism has consistently been proposed.
Overall, there appears to be some evidence that consumption of a modest amount of coffee may confer some health benefits. However, it is difficult to provide clear guidance as to the ‘coffee dose’ required to obtain these beneficial effects. It has been reported that caffeine concentrations can reportedly vary wildly from shop to shop40 and even on a daily basis at the same coffee house.31
In summary, whilst the results of these studies are interesting, their significance in a clinical setting remains open to discussion. Future prospective clinical trials in this area may be appropriate.
Declaration of personal and funding interests: None.