Coffee, appreciated for its aroma and flavor, is the most popular and common worldwide drink,1 and its frequent use derives principally from its invigorating characteristics and exciting properties. Coffee is a complex mixture of approximately 1000 compounds and caffeine does not represent the main component. There are carbohydrates, lipids, proteins, minerals, potassium, and magnesium. Furthermore, coffee is a rich source of antioxidants and other bioactive compounds such as chlorogenic acid, melanoidins, and diterpenes, and has a wide array of physiological effects.2,3 Coffee is sold as 2 types of mixtures, Arabica and Robusta, which differ because of their content of caffeine and chlorogenic acid. Because of its widespread use, coffee is considered a major contributor of redox-active phytochemicals in the diet.
Coffee consumption has been associated with various health benefits and a reduced incidence of various chronic diseases such as diabetes, cardiovascular diseases, and neurodegenerative diseases.4–7 More recently, coffee has been demonstrated to be inversely associated with total and cause-specific mortality. Drinking coffee, about 4 to 6 cups per day, lowers the risk of death by 10% in men and 15% in women.5,8–13
Over the past 20 years, an increasing number of epidemiological and experimental studies have demonstrated the positive effects of coffee on chronic liver diseases. The beneficial effects span positive effects on liver enzymes to improvements in liver steatosis and fibrosis, and a reduction in the risk of cirrhosis and hepatocellular carcinoma (HCC).14 Several case-control, cross-sectional, and randomized studies have assessed the association between coffee consumption and liver disease (Table 1).
COFFEE AND LIVER ENZYMES
Drinking coffee has been associated with a decrease in serum concentrations of liver enzymes: alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltransferase.30,35–38
It should be noted that this inverse relationship is particularly strong in heavy drinkers of alcohol,14,39 HCV patients,40 and HIV-HCV coinfected patients.41 Ruhl and Everhart38 in a cross-sectional study, conducted in about 6000 adult Americans at high risk of liver damage, found that coffee and caffeine consumption reduces the risk of elevated aminotranferase levels, and the reduction is related to the amount of caffeine consumed. In one of the largest studies, including over 12,000 Japanese subjects, Tanaka et al39 reported that coffee consumption had an independent/inverse association with decreased γ-glutamyltransferase activity in male alcohol drinkers. In a cohort study of >2000 Italian patients aged 65 years or over, Casiglia et al36 observed that alanine aminotransferase values were lower in those who drank ≥3 cups of coffee per day.
COFFEE AND VIRAL HEPATITIS
Few studies have examined the effects of coffee consumption in patients with chronic hepatitis C (HCV).15,17 Freedman et al16 reported that regular coffee intake was associated with decreased rates of liver disease progression among HCV patients. Modi et al18 documented that coffee consumption has a beneficial impact on the severity of liver fibrosis in patients with HCV infection. Cardin and colleagues demonstrated that coffee consumption, in patients with HCV, reduces oxidative DNA damage, increases apoptosis, leads to telomere elongation and DNA stabilization, and finally reduces procollagen III deposition.19,42 No association was found between coffee consumption and severity of chronic hepatitis B.20
COFFEE AND NONALCOHOLIC FATTY LIVER DISEASES (NAFLD)
The beneficial effects of coffee on the liver seem to be independent of the etiology and have been observed also in patients with NAFLD.21,22,24 Catalano et al,23 in a case-control study on patients with NAFLD, found that less fatty liver involvement is present in coffee versus noncoffee drinkers, concluding that coffee use is inversely associated with the degree of bright liver, along with insulin resistance and obesity. Molloy provides the first demonstration of a histopathologic correlation between fatty liver disease and estimated coffee intake. The results suggest that, in patients with nonalcoholic steatohepatitis (NASH), increased intake of coffee confers a significantly decreased risk of advanced fibrosis: an inverse relationship was found between coffee consumption and hepatic fibrosis (r=−9.215, P=0.035). Furthermore, there was a significant difference between the amount of coffee consumption in patients with bland steatosis/not-NASH (P=0.005), NASH stage 0 to 1, and NASH stage 2 to 4 (P=0.005). Moderate coffee consumption may be a benign adjuvant to the comprehensive management of patients with NASH.25 Regarding the mechanism by which coffee exerts its effects on steatosis and fibrosis, there is a quantity of convincing evidence that it is able to reduce the rate of fat and collagen deposition in the liver. In a rat model of fatty liver disease, we showed that animals fed with high-fat diet and decaffeinated coffee showed lower levels of hepatic fat and collagen, reduced liver oxidative stress, and improved liver inflammation and fibrosis.43,44 In a recent study, our group demonstrated that decaffeinated coffee consumption is able to modulate the expression of endoplasmic reticulum and mitochondrial chaperones both under standard diet and high-fat diet conditions. Among proteins upregulated by coffee consumption, there seems to be a particularly significant induction of the chaperone glucose-related protein 78 (GRP78), a master regulator of endoplasmic reticulum homeostasis, belonging to the heat shock protein 70 (HSP70) family. Consistent with GRP78 induction, coffee increases the expression of mitochondrial HSP70, which plays a pivotal role in endogenous antitumour defense against different cancers through activation of both innate and adaptive immune systems. In addition, coffee induces the expression of another chaperone called DJ-1, which plays a role in autophagy, and is also a redox-sensitive protein that scavenges reactive oxygen species by increasing glutathione synthesis. Finally, coffee induces the expression of antioxidant and stress sensor proteins, in particular peroxiredoxin 1 (PRDX1), which is able to catalyze the peroxide reduction of H2O2, organic hydroperoxides, and peroxynitrite. The PRDX1 induction leads to inhibition of JNK activation, which has been involved in NASH pathogenesis.45
COFFEE AND CIRRHOSIS
Several case-control studies have shown an inverse association between coffee consumption and cirrhosis.26,29 In particular, Corrao and colleagues identified a dose-dependent inverse relationship between caffeine intake and risk of cirrhosis. The odds ratios of cirrhosis development decreased from 1.0 (lifetime noncoffee drinkers) to 0.16 (0.05 to 0.50) in those with an intake of ≥4 cups of coffee daily. In addition, the authors demonstrated that this effect was not due to caffeine but rather to other factors, which probably include different ingredients of coffee and lifestyle factors correlated with coffee consumption.27 In a further case-control study, Gallus et al28 found an inverse relationship between duration of coffee consumption and cirrhosis. Further large cohort studies conducted in the United States indicate that coffee consumption reduces the risk of mortality from alcoholic cirrhosis, increased coffee consumption leads to a decrease in the relative risk of alcoholic cirrhosis,30,46 and that coffee decreases the risk of chronic liver disease among patients at increased risk of liver disease.47
COFFEE AND HCC
Coffee has been associated with a reduced risk of HCC.31–34 In a recent meta-analysis of epidemiological studies to provide updated information on how coffee drinking affects HCC risk, Bravi and colleagues found that the risk of HCC is reduced by 40% for any coffee consumption versus no consumption. Coffee has been shown to affect liver enzymes and development of cirrhosis, and therefore could protect against liver carcinogenesis.48 The coffee constituents, namely cafestol and kahweol, may play an important protective role in hepatocarcinogenesis.49,50 In animal and cell culture models, these diterpenes reduce the toxicity of a variety of carcinogens. Furthermore, cafestol and kahweol induce phase II enzyme activity,51 enhance hepatic glutathione levels,52,53 and decrease liver DNA adducts.54
On the basis of the available data, coffee consumption seems to exert a beneficial effect on patients with liver diseases or at risk of developing liver diseases.
It is unclear whether any of these benefits are significant enough to “treat” patients with chronic liver disease and further cross-sectional, cohort, case-control, animal, and cell culture studies are warranted to further elucidate the biochemical basis for the potential beneficial effects of coffee on liver disease patients. In the interim, moderate daily unsweetened coffee use is a reasonable adjuvant to therapy for these patients.
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