Earlier meta-analyses have reported an inverse association between coffee consumption and liver cancer.[10,30,31] Studies have also reported protective effects of coffee in animals with liver disease and in humans where the outcomes were less severe CLD including abnormal LFTs.[9,32,33] However, this is the first meta-analysis to show a protective effect of coffee against cirrhosis. The analysis of five cohort and four case–control studies has shown that increasing daily coffee consumption by two cups is associated with a near halving of the risk of cirrhosis. While statistically significant heterogeneity existed across the studies, this was explained by the effect of one study, and the association was consistent through the sensitivity analysis. Sensitivity analyses showed that increasing daily coffee consumption by two cups is also associated with reduced RRs of alcoholic cirrhosis and death from cirrhosis.
One of the strengths of this meta-analysis was the inclusion of studies that reported a summary dose RR or RRs for three or more categories of coffee consumption only. This allowed the estimation of a clinically relevant dose–response between coffee and cirrhosis. We excluded four studies, including one conference abstract, which reported RRs for less than three categories of coffee consumption.[34–37] Those studies reported inverse associations between coffee and cirrhosis, which were statistically significant in three studies, and thus support the findings of this meta-analysis. There are also limitations. First, the studies included were observational which, by design, do not infer causation and are generally more susceptible to bias and confounding than randomised studies. In the risk of bias assessment, the case–control studies were at high risk of selection bias in choosing cases and controls and to recall bias in the estimation of coffee and alcohol consumption years previously. Despite the risk of bias, the case–control studies agreed broadly with the cohort studies. We found that overall adjustment (including for body mass index, diabetes, alcohol and viral hepatitis) increased the effect size away from null, which suggests that coffee drinkers had greater overall exposure to the known risk factors of cirrhosis compared to noncoffee drinkers. However, residual confounding may have existed in all studies due to confounding variables that were not measured accurately or not adjusted for. While all the studies adjusted for alcohol consumption (we were unclear as to what adjustments were made in the conference abstract), which is the most critical confounder, only six studies adjusted for age, six for body mass index and gender, and four for diabetes. The cohort studies did not adjust for viral hepatitis status but prevalence was likely to be low in the populations studied. One particular concern is the potential for confounding from hidden nutritional and lifestyle factors not measured and adjusted for in the studies. If such factors were associated with coffee consumption and influenced the risk of cirrhosis, this would introduce bias into our findings. Another potential confounder is that people with pre-existing liver disease metabolise caffeine more slowly[38,39] and, as a result, may drink less coffee. This may have been important in the case–control studies, in which participants estimated previous coffee consumption over a time when they probably already had reduced liver function. The corresponding effect would be diluted in the cohort studies due to the long follow-up (all were longer than 14 years) and the exclusion of pre-existing liver disease at baseline in two of the studies.[9,13] Some of the cohort studies investigated confounding by pre-existing liver disease in sensitivity analyses. In one such analysis, Setiawan et al. found that the RR of CLD death for ≥ two cups of coffee daily compared to none remained comparable in magnitude and statistically significant (RR 0.54; 95% CI 0.42–0.69) when deaths in the first 2 years were excluded. Lai et al. found that the RR of CLD death for an extra cup of coffee per day was 0.53 (95% CI 0.44–0.64) in the first 10 years of the trial and 0.57 (95% CI 0.48–0.69) in the last 10 years. As such, drinking coffee appeared to protect against cirrhosis in participants who would have had varying levels of undiagnosed liver disease at baseline.
We investigated the overall effect of confounding by comparing the adjusted and unadjusted RRs across all trials. We found that adjustment for confounding increased the pooled RR away from null. In accordance with the GRADE system, this added to the overall quality of evidence for the protective effect of coffee against cirrhosis.
We found statistically significant heterogeneity between the studies, which may indicate important differences in the populations studied and in the study methods. The ages, countries and regions of origin, and proportions of men and women varied. In addition, and as noted above, participants with evidence of CLD at baseline were excluded from two cohort studies, while in the other cohort studies CLD was not looked for systematically at baseline and, thus, was not excluded. Between the cohort studies, the most significant difference in the populations was that in Lai et al. the participants were all Finnish male smokers recruited from an earlier study into lung cancer, while in the others participants were men and women recruited from databases more representative of the general population (see Table 1). When the study of Lai et al. was excluded during the sensitivity analysis, heterogeneity became statistically insignificant, whereas the pooled RR varied by 5% only.
Heterogeneity may also exist in the measurement of coffee consumption. In all studies, participants estimated the usual daily intake of coffee or the daily average over a specified preceding period (e.g. 1 year). Participants' responses may have been influenced if they knew they were in a study investigating nutrition, leading to overestimation or underestimation of consumption. This may be more significant for the case–control studies because participants recalled coffee consumption over longer periods and because cases may recall their diet differently to controls leading to differential misclassification of exposure. CLD in cases may have reduced consumption and hence overestimated the apparent protective effect. Differences in cup sizes, the methods of preparation (e.g. filtered vs. boiled) and the types of coffee (e.g. decaffeinated vs. caffeinated) might also be important. For example, one study found that the RR of cirrhosis for an additional cup per day was 0.50 (95% CI 0.40–0.63) for filtered coffee and 0.62 (95% 0.43–0.88) for boiled coffee. Another study found that the RR of CLD death for ≥ two daily cups of decaffeinated coffee was 0.54 (95% CI 0.35–0.85), although this was broadly similar to that for caffeinated coffee.
Heterogeneity might have arisen due to the different outcome measures. First, four studies identified outcomes using death records only, four studies used hospital records only, and one study used both. The importance of these differences is unclear as the pooled RR of death, calculated from studies using death records only, was similar to the RR pooled from the case–control studies, which used hospital records only. Secondly, studies identified cases differently, for example, by histology, a compelling clinical picture or by searching death and hospital records for Classification of Diseases (ICD) codes, for example, 9th edition code 571: 'Chronic liver disease and cirrhosis'. Histology is the reference standard, and ideally would have been used to confirm all cases, but the clinical picture of cirrhosis is specific (e.g. oesophageal varices or spontaneous bacterial peritonitis) and patients who die from CLD (i.e. ICD 571) but do not have HCC are highly likely to have cirrhosis. However, there was one study which appeared to include ICD codes relating to acute liver disease in the total count of CLD deaths. We were uncertain how differences in outcome measurements affected our pooled RR, which did not vary substantially during the sensitivity analysis and remained statistically significant.
The use of biopsy in some studies[9,27,29] may have introduced ascertainment bias if there were differential biopsy use according to baseline coffee consumption or to other correlated risk factors. Bias may also have been introduced if there were undetected cases of compensated cirrhosis on account of the included studies using hospital and/or death records only to identify cases. Some compensated cases might have been detected if biopsies were performed on asymptomatic participants in hospital (e.g. for a reason other than cirrhosis), but undiagnosed compensated cases in the community would have been missed. The risk of bias from these undetected cases is uncertain because the pathological pro-fibrotic mechanism which causes the initial establishment of cirrhosis is the same irrespective of aetiology or subsequent clinical sequelae (i.e. whether the individual remains asymptomatic, is hospitalised or dies). Thus, it is logical to expect that the alleged protective effect of coffee, which likely begins long before cirrhosis is established, would apply equally to cases detected by the included studies and those that were not. However, the uncertainty highlights the need for randomised trials.
We could only partially examine the influence of aetiology on the inverse association between coffee consumption and cirrhosis. We found that the pooled RR for alcoholic cirrhosis was similar to the overall estimate. However, there was insufficient data to calculate estimates for other important aetiologies of cirrhosis, such as viral hepatitis and NAFLD. While the potential influence of aetiology is unclear since the underlying pathological process leading to cirrhosis is the same, this issue should be considered further in new studies.
There also exists the possibility of language bias since we included English language studies only. However, most studies are published in English, and studies investigating the effect of language bias in meta-analyses generally report limited evidence of an effect. There is also some evidence that non-English language trials tend to be of lower quality and report larger effect sizes, and so the inclusion of English language studies only is unlikely to lead to significant bias in our findings. Finally, there also exists the potential of publication bias. While Egger's regression test detected no statistically significant publication bias, we were unable to rule out publication bias completely. First, the relatively small number of studies provided limited statistical power and, secondly, studies with statistically significant results are more likely to be published compared to those with null results. As such, the pooled RR reported in this study may be exaggerated compared to the true value.
It is biologically plausible that coffee protects the liver against the inflammatory and fibrotic process leading to cirrhosis. Caffeine is thought to be important, and animal studies show that caffeine not from coffee protects against toxin-induced liver fibrosis.[33,43] Caffeine's protective mechanism of action may be through antagonism of the adenosine receptor A2aAR. Hepatic stellate cells (HSCs) are the primary effector cells mediating fibrogenesis in the liver and express A2aAR. Activation of A2aAR markedly up-regulates collagen synthesis in HSCs,[45,46] whereas mice lacking expression of A2aAR are protected from toxin-induced fibrosis. Caffeine might also attenuate fibrosis by suppression of inflammation and oxidative stress. Caffeine inhibits tumour necrosis factor-α, a pro-inflammatory cytokine and reactive oxygen species production by Kupffer cells. While caffeine might be important, there is evidence that other noncaffeine-mediated mechanisms also contribute to the protective effect seen. First, adjusting for coffee consumption pushes the association between caffeine and cirrhosis towards null, and some studies report no association between cirrhosis and noncoffee sources of caffeine.[7,8] Secondly, and as is mentioned above, there is some epidemiological evidence that decaffeinated coffee protects against cirrhosis and abnormal liver function tests.[8,49] Decaffeinated coffee also protects against toxin-induced fibrosis in animal studies. The evidence for decaffeinated coffee protecting against cirrhosis is weaker overall than for regular coffee, but there is still biological plausibility. Coffee contains a range of biologically active ingredients beyond caffeine, including anti-oxidative and anti-inflammatory agents, such as chlorogenic acid, kahweol and cafestol, and there is evidence that these may confer protection against liver fibrosis.
The protective effect of coffee against cirrhosis may also involve indirect mechanisms that modify risk factors. Laboratory studies have shown that various constituents of coffee inhibit the activities of hepatitis B and C viruses.[50–52] In addition, and of even greater significance to public health, is the inverse association between coffee (both caffeinated and decaffeinated) and type 2 diabetes mellitus (T2DM). A recent meta-analysis calculated that the RR of T2DM for an increase in consumption of one cup per day was 0.91 (95% CI 0.89–0.94) for regular coffee and 0.94 (95% CI 0.91–0.98) for decaffeinated coffee. The mechanism of action of coffee on T2DM is unclear, but caffeine is unlikely to be the sole mediator. Caffeine causes a short-term reduction in insulin sensitivity and generally studies do not show a protective effect of caffeine against T2DM after adjustment for coffee and tea intake.[55,56] Chlorogenic acid in coffee is likely important; it has been shown to inhibit glucose absorption in the gut. It also inhibits hydrolysis of glucose-6-phosphate, which is the final step of glucose production by gluconeogenesis and glycogenolysis. Other constituents in coffee that may improve glucose metabolism and partly explain the relationship between coffee and T2DM include magnesium, trigonelle, lignans and quindes.[58–61] The favourable metabolic effects of coffee would be expected to protect against NAFLD and the related inflammation (NASH) which can lead to fibrosis and cirrhosis.
Cirrhosis is by far the most important risk factor for HCC. Accordingly, the findings of this meta-analysis may in part explain observational studies showing an inverse association between coffee and HCC. However, while it is logical to suggest that preventing cirrhosis would reduce HCC, other mechanisms involving a direct anti-carcinogenic effect of coffee may exist. Caffeine is thought to directly inhibit the proliferation of HCC cells. In addition, cafestol and kahweol upregulate phase II enzymes in the liver, which may increase clearance of potentially carcinogenic toxic insults,[63,64] and the anti-oxidative effects of coffee may reduce DNA damage from reactive oxygen species. Observational studies do not show a consistent association between HCC and decaffeinated coffee,[8,65] which indicates that caffeine may be the primary agent. This is supported by a recent meta-analysis which showed an inverse association between HCC and green tea, a noncoffee source of caffeine.
Before recommending an increase in coffee consumption to those at risk of cirrhosis, consideration is required of the wider effects of coffee. There is evidence of an association of coffee with lung and bladder cancer and with bone fractures.[19,67,68] However, there are also benefits of coffee beyond those on the liver. Coffee has been inversely associated with all-cause mortality, neurological diseases and a number of different cancers. Coffee may also protect against stroke, although there is a need for further work to understand fully the effects of coffee on the cardiovascular system. This is especially important at higher levels of consumption, where there is less evidence concerning the beneficial effects of coffee as well as the potential harms.
In conclusion, this meta-analysis shows that an increase in daily coffee consumption of two cups is associated with a near halving of the risk of cirrhosis. This is a large effect compared to many medications used for the prevention of disease. For example, statin therapy reduces the risk of cardiovascular disease by 25%. Furthermore, unlike many medications, coffee is generally well tolerated and has an excellent safety profile. The findings of this meta-analysis are important given the high incidence of severe liver disease, the positive interaction between alcohol and obesity for liver disease risk and the lack of specific treatments to prevent liver disease due to these factors. The next steps should be to develop interventions that support patients at risk of or with mild–moderate CLD, to increase their coffee consumption, even in existing coffee drinkers given the dose–response relationship, and then to evaluate the effect of increasing consumption on robust markers of CLD in well-designed randomised studies. However, such studies would be challenging (e.g. blinding would not be possible) and would require careful consideration of patient selection/stratification, trial methodology and the availability of suitable surrogate endpoints, given that hard clinical endpoints would take years to occur.
Aliment Pharmacol Ther. 2016;43(5):562-574. © 2016 Blackwell Publishing