REVIEW ARTICLE Impact of coffee on liver diseases: a systematic review Sammy Saab1,2 , Divya Mallam3 , Gerald A. Cox II2 and Myron J. Tong1,2,4 1 Department of Medicine, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA, USA 2 Department of Surgery, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA, USA 3 The Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA 4 The Huntington Medical Research Institutes, Pasadena, CA, USA Keywords coffee – liver disease Correspondence Sammy Saab, MD, MPH, AGAF Pfleger Liver Institute UCLA Medical Center 200 Medical Plaza, Suite 214 Los Angeles, CA 90095 Tel: +310-206-6705 Fax: +310-206-4197 e-mail: ssaab@mednet.ucla.edu Received 3 June 2013 Accepted 5 August 2013 DOI:10.1111/liv.12304 Liver Int. 2014: 34: 495–504 Abstract Coffee is one of the most commonly consumed beverages in the world. Its health benefits including improved overall survival have been demonstrated in a variety of disease states. To examine the association of coffee consumption with liver disease, a systematic review of studies on the effects of coffee on liver associated laboratory tests, viral hepatitis, nonalcoholic fatty liver disease (NAFLD), cirrhosis and hepatocellular carcinoma (HCC) was performed. Coffee consumption was associated with improved serum gamma glutamyltransferase, aspartate aminotransferase and alanine aminotransferase values in a dose dependent manner in individuals at risk for liver disease. In chronic liver disease patients who consume coffee, a decreased risk of progression to cirrhosis, a lowered mortality rate in cirrhosis patients, and a lowered rate of HCC development were observed. In chronic hepatitis C patients, coffee was associated with improved virologic responses to antiviral therapy. Moreover, coffee consumption was inversely related to the severity of steatohepatitis in patients with non-alcoholic fatty liver disease. Therefore, in patients with chronic liver disease, daily coffee consumption should be encouraged. Coffee is a commonly consumed beverage worldwide. In the United States, over 50% of Americans consume coffee on a daily basis (1).The commonly cited reasons for coffee consumption are its stimulatory effects, taste and aroma (2, 3). Recent data suggests that coffee consumption may have health benefits in a number of medical ailments. Long-term coffee drinkers may be at a decrease risk for type II diabetes, symptomatic gallstone disease, Parkinson’s disease, heart disease and stroke (2, 4–7). Moreover, coffee consumption is associated with decreased all-cause mortality (8, 9). In a recent analysis of the NIH-AARP Diet and Health Study data, a dose-dependent inverse association between coffee consumption and total mortality was described (9). Men and women who drank 6 or more cups daily had a 10% and 15% decreased risk of death, respectively. Chronic liver disease is major health burden in the United States, ranking 12th amongst the leading causes of death and accounting for over 30 000 deaths in 2009 alone (10). Chronic liver disease affects approximately 15% of the US population and is a major economic strain through direct healthcare expenditures as well by indirect costs related to lost income due to premature death or disability (11, 12). Treatments for liver disease is often viewed with suspicion, and many patients often seek alternative therapies for their liver disorders (13–15). Given the potential health benefits in a variety of medical conditions and its impact on survival, we explored the impact of coffee consumption on patients with liver ailments. A systematic, comprehensive review on the interaction between coffee consumption and liver associated tests, viral hepatitis, nonalcoholic Fatty Liver Disease (NAFLD), cirrhosis and hepatocellular carcinoma (HCC) was performed and is presented herein. Methods We searched MEDLINE and PubMed for all studies published on coffee and liver diseases from 1986 to September 2012. We used a combination of the keywords ‘coffee’, ‘caffeine’, ‘liver disease’, ‘cirrhosis’, ‘fibrosis’, ‘hepatitis B’, ‘hepatitis C’, ‘non-alcoholic fatty liver disease’, ‘fatty liver’, ‘hepatocellular carcinoma’, ‘liver cancer’, ‘alcoholic liver disease’, and ‘alcoholic hepatitis’. We analyzed all studies published in scientific journals including observational studies and case-controlled studies. Bibliographies of identified studies were searched for relevant articles. Liver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 495 Liver International ISSN 1478-3223 Liver-associated laboratory tests A number of studies noted a beneficial effect of increased coffee consumption on liver-associated laboratory tests. This benefit was reported in a variety of populations at risk for liver disease, including those with excessive alcohol intake, obesity, smokers, and those with chronic viral hepatitis. These studies demonstrated that increased coffee consumption was associated with aspartate-aminotransferase (AST), alanine-aminotransferase (ALT), and Gamma-glutamyltransferase (GGT) levels in a dose-dependent manner. The first studies to demonstrate a relationship between coffee intake and liver-associated test values were two Norwegian reports which revealed an inverse association between coffee consumption and serum GGT values (16, 17). The results were further illustrated in a 7 year longitudinal study of a subset of the Tromsø Study by Nilssen et al. (18). Their findings have since been confirmed in multiple population studies in Japan (19–22), Italy (24, 25), and Finland (26) (Table 1). Another study from Norway also found coffee consumption inversely related to serum GGT (26). The results of a randomized study, however, showed that cafetiere increased liver enzymes (28). In one of the largest studies including over 12 000 health examinees in Japan, Tanaka et al. described that increased coffee consumption had a strong and independent association with decreased GGT activity in male alcohol drinkers (P < 0.0001) (19). However, consumption of coffee was only weakly associated with lowered GGT levels among women. Using the data from the Self-Defense Forces Fukuo Hospital, Honjo et al. further confirmed earlier observations which demonstrated that coffee consumption was associated with lowered serum GGT levels (20–22). Population studies in Italy, Japan, and the United States also have reported an inverse relation of coffee consumption with serum aminotransferase levels. In a cohort study of over 2000 Italian patients aged 65 or older, Casiglia et al. observed that ALT values were 10.3% lower in those who drank three or more cups of coffee daily (P = 0.0160) (24). In a Japanese study of 12 020 middle-aged and elderly male participants, a strong inverse association between coffee consumption and elevated ALT values also were noted (29). The results of the third National Health and Nutrition Examination Survey (NHANES) found that coffee consumption and caffeine were associated with a decreased risk of elevated ALT levels amongst persons at high risk for liver injury in the United States, such as persons who were overweight, had viral hepatitis, impaired glucose metabolism, iron overload or excessive alcohol intake (30). In an unadjusted analysis, a lowered ALT activity was associated with an increasing consumption of coffee (P = 0.001) and caffeine (P = 0.001). Chronic liver disease and cirrhosis Chronic liver disease Coffee intake has also been associated with a decreased incidence of chronic liver disease (Table 2). The histologic benefit of coffee was first demonstrated by Modi et al. who examined the association between daily caffeine intake and severity of hepatic fibrosis amongst persons with chronic liver diseases (31). The authors described that daily caffeine intake above two cups of Table 1. Studies assessing impact on coffee on liver related health outcomes - Liver Enzymes Reference Year Design Population Country Findings Pintus et al25 1996 Cross-Sectional 4803 Italy Coffee consumption is inversely related to serum GGT in men Nilssen et al17 1990 Cross-Sectional 21 782 Norway Coffee consumption is inversely related to serum GGT Nilssen et al*19 1994 Prospective Cohort 2438 Norway Coffee consumption is inversely related to serum GGT in women Skurtveit et al27 2002 Cross-Sectional 16 805 Norway Coffee consumption is inversely related to serum GGT Honjo et al†22 2001 Cross-Sectional 7313 Japan Coffee decreases AST/ALT values Nakanishi et al†23 2000 Cross-Sectional 1353 Japan Coffee consumption is inversely related to serum GGT Poikolainen et al27 1997 Cross-Sectional 6010 Finland Boiled coffee elevated GGT values more often that filtered or instant coffee Urgert et al28 1996 Randomized Controlled Trial 46 Netherlands Cafetiere coffee increases serum ALT level Casiglia et al24 1993 Prospective Cohort 2240 Italy Liver enzymes consistently lower in coffee drinkers Ikeda et al29 2010 Cross-Sectional 12 020 Japan Inverse association between coffee and ALT values, particularly among men Ruhl et al30 2005 Cross-Sectional 5944 USA Coffee associated with lower ALT values Tanaka et al19 1998 Cross-Sectional 12 687 Japan Coffee associated with lower GGT, particularly among alcohol drinkers ALT, Alanine-aminotransferase; AST, Aspartate-aminotransferase; GGT, Gamma-glutamyltransferase. *Longitudinal subset of previously published study (17). †The most recent study was included in Table if data was duplicated in more than one study. Liver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd496 Impact of coffee on liver diseases Saab et al. coffee was associated with lower rates of hepatic fibrosis (OR 0.33, 95% CI .14–0.8, P = 0.015). The observed protective relationship persisted after controlling for age, sex, race, liver disease, BMI, alcohol intake, and hepatitis C viral infection (HCV) infection. Of note was the fact that caffeine intake from non-coffee sources was not associated with decreased hepatic fibrosis. In a large cross sectional US study, intake of regular ground coffee and caffeine intake was associated with a decreased risk of chronic liver disease (32). Persons included in the report were those with hepatitis B, hepatitis C, iron overload, impaired glucose metabolism, and excessive alcohol intake (>2 alcoholic beverages per day). In the study, participants were followed for a median of 19 years, and those who drank greater than two cups of coffee daily had less than half the rate of chronic liver disease than those who drank less than one cup daily. Cirrhosis and mortality In addition to the decreased risk of chronic liver disease, coffee consumption has been associated with a decreased risk of cirrhosis (Table 2). Two Italian hospital-based case-control studies found that coffee may delay the development of cirrhosis. The first study by Corrao et al. found a dose-dependent inverse relationship between caffeine intake and risk of cirrhosis (33). The odds ratios of cirrhosis development decreased from 1.0 (lifetime non-coffee drinkers) to 0.47 (95% CI 0.2–1.10), 0.23 (0.10–0.53), 0.21 (0.06–0.74), and 0.16 (0.05–0.50) in those ingesting 1, 2, 3, and 4 or more cups of coffee daily respectively. A longer term follow up in the same cohort confirmed earlier observations (35). The second study by Gallus et al. found an inverse relationship between coffee consumption and cirrhosis [odds ratio (OR) 0.54 for coffee drinkers compared to non-coffee drinkers; OR 0.29 for 3 or more cups daily]. An inverse relationship with duration of coffee consumption and cirrhosis also was observed (OR 0.45 for 40 years or more of coffee consumption) (34). The results of a large 10-year cohort follow-up study in the US revealed that coffee may be protective against both hospitalization and death from alcoholic cirrhosis (36). Subsequently, Klatsky et al. reported that coffee consumption may lead to a decreased mortality risk from nonalcoholic and alcoholic cirrhosis; the relative risk per cup of coffee daily was 0.77 (95% CI 0.67, 0.89) (37). Further expanding upon their original cohort study from 1992, Klatsky et al. presented a 22-year follow-up report in which they provided further evidence that increased coffee intake led to a decreased risk of alcoholic cirrhosis; with greater coffee intake associated with a lower relative risk of cirrhosis [1–3 cups, 0.6 (95% CI, 0.4–0.8; P < 0.001; 4 or more cups, 0.2 (95% CI, 0.1–0.4, P < 0.001)] (38). There was no relationship between tea intake and the development of alcohol-related cirrhosis. The inverse association between coffee intake and mortality from cirrhosis also was supported by a Norwegian cohort study by Tverdal et al. (39). In the study, mortality rates were lower for persons drinking 3 or more cups of coffee daily compared to those drinking 2 or less cups. After adjusting for age, sex, alcohol use and other cardiovascular risk factors, similar benefits of coffee were also observed among patients with alcoholic cirrhosis. The relative risk of cirrhosis associated with an increase of two cups of coffee was 0.6 (95% CI, 0.5– 0.8) (39). Chronic hepatitis B and hepatitis C There are limited published data on the association between caffeine consumption and chronic viral hepatitis (Table 3). Only one report assessed the association in chronic hepatitis B, and found no benefit from coffee consumption on severity of hepatitis B as measured by transient elastography (40). Since most participants who consumed alcohol were also mostly coffee drinkers, the benefit of caffeine intake may have been confounded by the deleterious effects of alcohol consumption. FurtherTable 2. Studies assessing impact on coffee on liver related health outcomes – Cirrhosis Reference Year Design Cohort* Country Findings Corrao et al.(35) 1994 Case-Control Cases 115 Italy Protective effect of coffee on alcohol cirrhosis Controls 167 Corrao et al.(33) 2001 Case-Control Cases 274 Italy Coffee, but not othercaffeine containing beverages, may prevent Alcohol cirrhosisControls 458 Gallus et al.(34) 2002 Case-Control Cases 101 Italy Inverse association between coffee and cirrhosis Controls 1538 Tverdal & Skurtveit (39) 2003 Retrospective Cohort 51 306 Norway Inverseassociationbetween coffee and cirrhosis Klatsky et al.† (38) 2006 Retrospective Cohort 125 580 USA Coffee protects against cirrhosis, particularly alcoholic cirrhosis Ruhl et al.(32) 2005 Retrospective Cohort 9849 USA Coffee and tea decrease risk of chronic liver disease among patients at increased risk of liver disease *Cases were patients with cirrhosis. †The most recent study was included in Table if data was duplicated in more than one study. Liver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 497 Saab et al. Impact of coffee on liver diseases more, the use of transient elastography, while proven to be accurate in diagnosing histological advanced fibrosis in chronic Hepatitis B viral infection (HBV)-infected patients, may be of limited utility in patients with elevated serum transaminase levels (41). Several studies have examined the impact of coffee consumption on fibrosis severity in patients with chronic hepatitis C (Table 3). Modi et al. demonstrated the beneficial impact of coffee consumption on fibrosis severity in patients with hepatitis C (OR 0.19, 95% CI 0.05–0.66, P = 0.009) (31). The patients in this study completed detailed caffeine questionnaires on three occasions over a six-month period of time. Freedman et al. also found that regular coffee intake was associated with decreased rates of liver disease progression amongst chronic hepatitis C patients enrolled in the HALT-C Trial (42). The rates of liver disease progression declined with increasing coffee intake (P = 0.0 011). Compared to non-coffee drinkers, the relative risks for reaching pre-defined endpoints indicating disease progression were 1.11 for less than 1 cup daily (CI 0.76–1.61), 0.7 for 1 to <3 cups daily (CI 0.48–1.02), and 0.47 for 3 or more cups daily (CI 0.27–0.85, P = 0.0003). Utilizing data from the HALT-C trial, Freedman et al. also explored the relationship between coffee consumption and response to antiviral therapy (43). The authors demonstrated that greater than 3 cups of coffee daily was an independent predictor of improved virologic response to retreatment with peginterferon plus ribavirin in patients with hepatitis C who failed initial treatment. Consumption of 3 or more cups daily was associated with a higher tolerance for the full dose of peg-IFN (60.6% compared to 50.4% of noncoffee drinkers). A prospective cohort study done in France by Costentin et al. evaluated the effect of coffee consumption on treatment-na€ıve chronic hepatitis C patients (44). In the report, multivariate analysis showed that daily caffeine consumption equivalent to 3 cups of coffee was associated with a decreased necroinflammatory activity [OR 0.32, Confidence Interval (CI) 0.12–0.85]. Of note, caffeine intake in this study was not limited to coffee alone, but included caffeinated coffee, tea, and caffeinecontaining sodas. Carrieri et al. evaluated whether coffee intake improved the tolerability of peginterferon alfa-2a and ribavirin in HIV-HCV co-infected patients (45). The authors found that those patients drinking 3 or more cups of coffee daily were less likely to report adverse effects compared to coffee nondrinkers (OR 0.19, CI .05–0.78, P = 0.02). These findings remained Table 3. Studies assessing impact on coffee on liver related health outcomes – Hepatitis B and C Reference Year Design Cohort Country Findings Ong et al.(40) 2011 Cross-Sectional 1045 China Caffeine not associated with decreased fibrosis HBV-infectedpatients Costentin et al.(44) 2011 Cross-Sectional 238 France Caffeine consumption greater than 3 cups or more a day is associated with reduced histological activity Freedman et al.† (42) 2009 Retrospective Cohort 766 USA Coffee decreases rate of HCV disease progression in HCV Freedman et al.† (43) 2011 Retrospective Cohort 885 USA Coffee predictor of improved virologic response to peginterferon plus ribavirin for HCV Modi et al.(31) 2010 Retrospective Cohort 177 USA Caffeinated coffee consumption associated with lowerodds of liver fibrosis in HCV patients Carrieri et al.(45) 2012 Prospective Cohort 106 France Coffee consumption alleviated pegylated interferon and ribavirin adverse effects HBV, hepatitis B viral infection; HCV, hepatitis C viral infection. †Studies from similar database. Table 4. Studies assessing impact on coffee on liver related health outcomes – Non-alcoholic fatty liver disease Reference Year Design Cohort* Country Findings Anty et al.(50) 2012 Cross-Sectional 195 France Regular but not espresso coffee protective against liver fibrosis in patients with NAFLD Birerdinc et al.(46) 2011 Cross-Sectional 1782 USA Caffeine associated with a lower risk of NAFLD Catalano et al.(47) 2010 Case- Control Cases 157 Italy Coffee inversely related to severity of NAFLD Controls 153 Gutierrez-Grobe et al.(48) 2012 Case-Control Cases 57 Mexico Coffee protectiveagainstNAFLD Controls 73 Molloy et al.(49) 2012 Cross-Sectional 306 USA Coffee caffeine associated with a significant reduction in risk of fibrosis among NASH patients NAFLD, Non-alcoholic fatty liver disease; NASH, Non-alcoholic steatohepatitis. *Case were patients with non-alcoholic fatty liver disease Liver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd498 Impact of coffee on liver diseases Saab et al. significant after adjustments for gender, age, cirrhosis, and history of opioid use. Nonalcoholic fatty liver disease Several studies have assessed the association between coffee consumption and NAFLD (Table 4). In an analysis of four continuous cycles (2001–2008) of the Nat-ional Health and Nutrition Examination Survey (NHANES), a dietary intake questionnaire collected by the National Center for Health Statistics of the Centers for Disease Control and Prevention revealed that caffeine intake was independently associated with a decreased risk of development of NAFLD (OR 0.931, CI 0.900–0.964) (46). Two case–control studies have suggested the beneficial effect of coffee on the risk of NAFLD as defined by abdominal imaging (47, 48). Catalano et al. found that a decrease in fatty liver severity in coffee drinkers as compared to non-coffee drinkers (b = À2.585, P = 0.0 11, CI À0.133 to 0.018). Also, coffee drinking was inversely associated with obesity and insulin resistance (47). A case control study performed in Mexico showed similar results with a dose-dependent reduction in coffee intake with increasing severity of hepatic steatosis (48). In addition, a cross-sectional study demonstrated that coffee consumption was associated with a significant decrease in the risk of hepatic fibrosis among patients with nonalcoholic steatohepatitis (NASH) (49). In the study, an inverse relationship was found between coffee consumption and hepatic fibrosis (r = À9.215, P = 0.035). There was a significant difference between coffee consumption in patients with bland steatosis/not-NASH (P = 0.005), NASH Stage 0–1, and between NASH stage 0–1 and NASH stage 2– 4 (P = 0.005). Table 5. Studies assessing impact on coffee on liver related health outcomes – Hepatocellular carcinoma Reference Year Design Cohort† Country Findings La Vecchia et al.‡ (51) 1989 Case Control Cases 151 Italy No association between coffee and liver cancerControls 1944 Ohfuji et al.(67) 2006 Case-Control Cases 73 Japan Inverse association between coffee drinking and HCC incidenceControls 253 Ohishi et al.(57) 2008 Case-Control Cases 224 Japan Daily consumption associated with decreased risk for HCCControls 644 Gelatti et al.(54) 2005 Case Control Cases 250 Italy Inverse association between coffee and HCC incidenceControls 500 Gallus et al.(53) 2002 Case-Control Cases 501 Italy Inverse association between coffee and HCC incidenceControls 1552 Johnson et al.(62) 2011 Retrospective Cohort 61 321 China Coffee may reduce risk of HCC Kuper et al.‡ (52) 2000 Case-Control Cases 333 Greece Coffee not positively associated with HCC incidenceControls 360 Shimazu et al.(58) 2005 Prospective Cohort 1 Prospective Cohort 2 22 404 Japan Dose-dependent inverse association between coffee and HCCincidence38 703 Montella et al.(56) 2007 Case-Control Cases 185 Italy Inverse association between caffeinated coffee and HCCControls 412 Tanaka et al.(55) 2007 Case-Control Cases 209 Japan Dose-dependent inverse association between coffee use particularly among community and CLD controls Controls 1308 Community 275 Hospital 381 CLD Hu et al.(61) 2008 Prospective Cohort 60 323 Finland Dose-dependent inverse association with risk of HCC Inoue et al.† (59) 2009 Prospective Cohort 18 815 Japan Coffee consumption mayreducethe risk of liver cancer regardless of HCV and HBV Leung et al.(63) 2011 Case-Control Cases 109 Hong Kong Moderate coffee consumption in HBV carriers reduce risk of HCCControls 125 Wakai et al.(66) 2007 Case-Control Cases 96 Japan Coffee associatedwithdecreased risk of death from HCC in patients with hepatitis C 420 3024 Control (HCV+) Control (HCVÀ) HBV, Hepatitis B viral infection; HCV, Hepatitis C viral infection; HCC, hepatocellular carcinoma; CLD, Chronic liver disease. Case were patients with hepatocellular carcinoma. †The most recent study was included in Table if data was duplicated in more than one study. ‡Data reanalyzed by Gallus et al. (53) above. Liver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 499 Saab et al. Impact of coffee on liver diseases The results of a recent European study provided further evidence regarding the protective effects of coffee in morbidly obese persons with NAFLD (50). Regular coffee consumption was associated with decreased liver fibrosis in morbidly obese women with NAFLD undergoing bariatric surgery (OR 0.752, CI 0.578–0.98, P = 0.035) (50). However, regular filtered coffee, but not espresso coffee, was found to be associated with the decreased likelihood of fibrosis. Hepatocellular carcinoma Decreased risk of hepatocellular carcinoma The relationship between coffee and the development of HCC was initially unsettled (Table 5). Two early case-control studies found no association between coffee consumption and the risk of HCC (51, 52). However, the results of a follow up study combining both data sets indicated that coffee was indeed protective against HCC (51–53). Additional more recent reports indicate a potential benefit of coffee on the incidence of hepatocellular carcinoma. Several case-control studies also demonstrated that coffee drinking was associated with decreasing HCC risk with a dose-effect relationship. Gelatti et al. found that compared to non-coffee drinkers, the odds ratio for HCC development was 0.4 (95% CI 0.2–0.8) for those consuming 3– 4 cups daily regardless of the underlying liver disease cause (54). Tanaka et al. reported on coffee use either during the last 1–2 years or 10 years using three different control groups (hospital, community, and patients with chronic liver disease) (55). Coffee use during the last 1–2 years was associated with decreased risk of HCC against all three control groups. Coffee use over the last 10 years was associated with decreased risk of HCC in reference to community controls or patients with chronic liver disease. The results of another casecontrol study by Montella et al. also found a doseeffect relationship between coffee intake and risk for HCC for persons who consumed 4 or more cups daily (OR = 0.4, 95% CI 0.2–1.1); the inverse relationship was maintained amongst both HBV and HCV-infected individuals (56). Several studies support the hypothesis that coffee consumption leads to decreased risk of liver cancer (57). In a Japanese pooled analysis of two prospective cohort studies, a significant inverse relationship was found between coffee consumption and risk of liver cancer in patients with liver disease (58). Compared to nondrinkers, those with coffee intake of 1 or more cups daily had a relative risk 0.58 (CI 0.36–0.96) (58). Another Japanese prospective cohort of 18 815 subjects with 110 incident cases of liver cancer found increased coffee consumption to be associated with reduced liver cancer risk (hazard ratio for <1, 1–2, 3 or more cups daily 0.67, 0.49, 0.54, p trend 0.025) (59, 60). A similar risk tendency was observed in patients with HBV and/or HCV infections. The results of a large population-based cohort study by Hu et al. performed in Finland supported the finding that coffee drinking led to a decreased liver cancer risk in a dose-response manner (61). Multivariable-adjusted hazards ratios of liver cancer in participants who drank 0–1, 2–3, 4–5, 6–7, and 8 or more cups of coffee daily were 1.00, 0.66, 0.44, 0.38, and 0.32 (P = 0.003), respectively. The operational definition of ‘liver cancer’ in the study included a diagnosis of HCC, cholangiocarcinoma, adenocarcinoma, and primary liver cancer of unspecified etiology. A Japanese cohort study also showed that those who drank coffee on a daily or almost daily basis had a lower HCC risk than those who almost never drank coffee with a dose-response effect [HR for 3–4 cups daily: 0.48 (95% CI 0.28–0.83)] (60). The risk of HCC in subjects who never or occasionally drank coffee was 547.2 cases per 100 000 over 10 years, but was 214.6 cases per 100 000 in those who drank coffee regularly. Findings from a Singapore prospective cohort study found that compared with coffee non-drinkers, persons who drank 3 or more cups of coffee daily had a 44% risk reduction of HCC (HR 0.56, 95% CI 0.31–1.00, P = 0.049), after adjustment for confounding variables and tea intake (62). A Hong Kong case-control study found that moderate coffee intake led to a reduction in HCC risk by almost half in daily coffee drinkers with chronic HBV infection compared to non-drinkers (OR 0.54, 95% CI 0.3–0.97), with a dose-response effect (P = 0.02) (63). The results of several studies analyzing data from the Japan Collaborative Cohort Study indicated the beneficial effects of coffee consumption on the incidence of HCC deaths (64–66). All three studies found a statistically significant decrease in risk of death from HCC in persons consuming one or more cups of coffee daily. Kurozawa et al. found that in persons aged 60–79 with a history of liver disease, drinking one or more cups of coffee daily had a significant inverse relationship with mortality due to HCC (men: HR 0.44, CI 0.19–0.90, women: 0.30, 0.10–0.89). No significant relationship was found for men and women aged 40–59 (64). In another case-control study by Kurozawa et al., coffee was again found to be protective against HCC mortality (65). Hazard ratio for one or more cups per day compared to non-coffee drinkers was 0.5 (95% CI 0.31– 0.79). The HCC mortality Hazard Ratio was significantly reduced in men who drank one or more cups of coffee daily, but not in women. The authors did not control for HBV or HCV infection. In a nested case-control study, the multivariateadjusted OR(with 95% CI) for HCC mortality in daily coffee drinkers (1 or more cups daily) in contrast to nondrinkers was 0.49(0.25–0.96) in all participants, 0.31 (0.11–0.85) in HCV-positive patients, and 0.75 (0.29– 1.92) in HCV-negative patients (66). This study supports previous findings in case-control studies by Gelatti et al. and Ohfuji et al. that coffee has a protective effect amongst HCV-infected persons (54, 67). However, Liver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd500 Impact of coffee on liver diseases Saab et al. another report did not find a protective effect of coffee consumption among HCV-infected individuals (56). Discussion Coffee is one of the most commonly consumed beverages in the world (2). There is increasing evidence that daily consumption of 2–3 cups of coffee has significant health benefits. Not only has coffee been associated with a decrease in a number of liver diseases, but its consumption may also decrease mortality (9). Thus, coffee appears to have ‘hepatoprotective’ health benefits (68). Coffee is composed of over one hundred compounds, any of which could be responsible for its beneficial effects (50). It is possible not one compound in particular, but the synergistic effect of multiple compounds, which provides the health benefits described. Not all types of coffee may be beneficial in liver disease. Numerous studies have shown a hepatoprotective role for filtered coffee, and a potentially deleterious effect for unfiltered coffee (26, 28). It was postulated that this difference is due to the presence of kahweol and cafestol, which are caffeine diterpenes that are released from ground coffee beans but removed by paper filters (28, 69). Moreover, another study found that espresso coffee had no beneficial effect on liver disease, particularly in NAFLD (50). In the US, filtered coffee is one of the main types of coffee consumed, whereas in Europe, espresso coffee is more commonly consumed (50). Anty et al. postulated that perhaps espresso coffee was not found to be beneficial in NAFLD because of the sucrose added to the coffee (50). Sucrose is composed of glucose and fructose, and fructose has been associated with increased severity of hepatic fibrosis in NASH (79). There are a number of proposed mechanisms for the hepatoprotective effects of caffeine (Table 6). In rat studies, methylxanthine caffeine has been implicated in the hepatic fibrinogenesis pathway by (i) downregulating transforming growth factor beta-1 (TGFB-1)induced connective tissue growth factor (CTGF) production in hepatocytes via promotion of breakdown of SMAD2 (a TGF-B effector protein), (ii) inhibition of SMAD3 phosphorylation, and (iii), by upregulation of the PPAR-gamma receptor (70). The antioxidant hepatoprotective effects of coffee may also be induced by UDP glucoronosyltransferases (UGT1A) (71). Caffeine has also been implicated to have antifibrotic effects via its influence on hepatic stellate cells (HSC) through inhibition of focal adhesion kinase (FAK) and actin synthesis, stimulation of HSC apoptosis, induction of intracellular F-actin and cAMP expression, and via inhibition of procollagen type 1C and alpha-smooth muscle actin expression (72). Caffeine as well as cafestol and kahweol may have anticarcinogenic effects by upregulation of antioxidantresponsive element (ARE)-regulating signaling (Table 6) (73, 74). The ARE sequence plays a key role in carcinogenesis as it has been found on the promoter of numerous genes involved in detoxification processes. Furthermore, animal models and in-vitro studies indicate that kahweol and cafestol may deregulate enzymes involved in detoxification of carcinogens (75, 76). These compounds also induce glutathione-S-transferase and gamma-glutamylcysteine synthetase (GCS), leading to protection against mutagenesis, and inhibit N-acetyltransferase (77, 78). Although caffeine is a major component of coffee, studies evaluating non-coffee caffeinated sources have revealed inconsistent evidence of hepatoprotective effects (30, 33). With regards to tea consumption, studies have found no statistically significant association between tea intake and risk of cirrhosis (33, 34), death from cirrhosis (36), chronic liver disease (32), HCC (58), or death due to HCC (56, 64, 80). Most studies Table 6. Proposed antifibrotic and cancer preventive mechanisms of action of coffee Compound Mechanism† Principal site of action Effect/Properties Caffeine Decrease TGF – B Hepatocyte Antifibrotic Inhibit FAK and actin synthesis Hepatic Stellate Cell Antifibrotic Increase HSC apoptosis and intracellular Hepatic Stellate Cell Antifibrotic F-actin and cAMP expression Inhibit procollagen type 1C and alpha-SMA Hepatic Stellate Cell Antifibrotic Expression Stimulate ARE-regulated signaling Hepatocyte Cancer prevention Cafestol and Kahweol Inhibit phase I activating enzyme expression and activity Hepatocyte Cancer prevention Induce phase II detoxifying enzymes Hepatocyte Cancer prevention (i.e.- glutathione S–transferase) Stimulate ARE-regulated signaling Hepatocyte Cancer prevention Induction of GCS Hepatocyte Cancer prevention TGF-B, Transforming growth factor-beta; FAK, Focal adhesion kinase; HSC, Hepatic stellate cell; Alpha-SMA, alpha-smooth muscle actin; ARE, Antioxidant-responsive element; GCS, Gamma-glutamylcysteine synthetase. †Mechanisms of action may not be exclusive of the compound. References: 70–78. Liver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 501 Saab et al. Impact of coffee on liver diseases did not specify which type of tea participants consumed. However, Inoue et al. studied green tea and Kurozawa et al. studied green, black, and oolong tea (60, 64). Coffee preparation methods include filtered, unfiltered, and espresso, and can also vary in its roast profile (medium vs. dark). Differences in preparation method (filtered, unfiltered, espresso) as well as type of roast play a role in the composition of coffee. Filtered coffee does not contain cafestol and kahweol; however, filtration of coffee better preserves chlorogenic acids than the barista method of espresso preparation (50). The various degrees of roast refer to the internal bean temperatures found during roasting. Darker roasts have had higher roasting temperatures. Caffeine content also varies between types of coffee [generic brewed coffee (95–200 mg per 8 oz), espresso (40–75 mg per 1 oz), generic instant coffee (27–173 per 8 oz)]. There are numerous limitations when interpreting the studies regarding the health benefits of coffee. Many of the larger studies, including those by Freedman et al., Modi et al., Hu et al., and Molloy et al., did not necessarily account for differences in socioeconomic status or other dietary factors (31, 42, 49, 61). Although one would argue that perhaps patients who had greater coffee intake were likely healthier, Freedman et al. found that coffee drinkers tended to have poorer overall health (P = 0.29) and vitality scores (P = 0.018) compared to non-coffee drinkers. In addition, participants who drank coffee may have had higher cigarette use and alcohol consumption (42). Also, many studies collected data on coffee intake at only one time point, thus, the coffee intake noted may not have accurately reflected participants’ intake over time (30, 34, 36–38). If it is assumed that caffeine is indeed responsible for the hepatoprotective effects of coffee, then another potential limitation is the variation of caffeine content of coffee within and among coffee shops (80). Furthermore, many studies failed to define coffee cup size (24, 30, 33, 36). Although it is clear that coffee intake has hepatoprotective effects, the lack of standardization of coffee cup size amongst various studies leads to ambiguity regarding how much coffee intake is necessary for these effects. Our study is limited in that it is based mostly upon observational studies with inherent biases, including recall bias in retrospective studies, as well as selection bias and unmeasurable confounding factors amongst all non-randomized controlled studies (81). Cross-sectional studies, such as NHANES III, are limited in that they cannot establish a temporal association between coffee intake and study findings (30, 81). Numerous epidemiological studies suggest that consumption of approximately 3 or more cups of coffee daily will reduce the risk for and severity of hepatotoxicity due to a variety of underlying pathologic processes. While the aforementioned studies provide compelling evidence to suggest that coffee is useful as an alternative medicine in the treatment of the most common types of liver disease, blinded randomized controlled trials must be performed to provide evidence for causation, and to eliminate confounding variables and various types of bias inherent in cross-sectional, cohort, and case-control studies. Additional animal and cell culture studies are also warranted to further elucidate the biochemical basis for the potential beneficial effects of coffee in liver disease patients. Acknowledgments Conflicts of interest: The authors do not have any disclosures to report. References 1. National Coffee Association USA. http://www.ncausa.org. Accessed February 2, 2013 2. Higdon JV, Frei B. Coffee and health: a review of recent human research. Crit Rev Food Sci Nutr 2006; 46: 101–23. 3. Ponte S. The ‘Latte Revolution’? Regulation, markets and consumption in the global coffee chain. World Dev 2002; 30: 1099–122. 4. Ruhl CE, Everhart JE. Association of coffee consumption with gallbladder disease. Am J Epidemiol 2000; 152: 1034– 8. 5. Ascherio A, Zhang SM, Hernan MA, et al. Prospective study of caffeine consumption and risk of Parkinson’s disease in men and women. Ann Neurol 2001; 50: 56–63. 6. Wu JN, Ho SC, Zhou C, et al. Coffee consumption and risk of coronary heart disease: a meta-analysis of 21 prospective cohort studies. Int J Cardiol 2009; 137: 216–25. 7. Lopez-Garcia E, Rodriguez-Artalejo F, Rexrode KM, et al. Coffee consumption and risk of stroke in women. Circulation 2009; 119: 1116–23. 8. Lopez-Garcia E, Van Dam RM, Li TY, et al. The relationship of coffee consumption with mortality. Ann Intern Med 2008; 148: 904–14. 9. Freedman ND, Park Y, Abnet CC, et al. Association of coffee drinking with total and cause-specific mortality. N Engl J Med 2012; 366: 1891–904. 10. Kochanek KD, Xu J, Murphy SL, et al. Deaths: final data for 2009. Natl Vital Stat Rep 2011; 60: 1–166. 11. Younoussi Z, Stepanova M, Afendy M, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol and Hepatol 2011; 9: 524–30. 12. Kim WR, Brown RS, Terrault NA, El-Serag H. Burden of liver disease in the United States: summary of a workshop. J Hepatol 2002; 36: 227–42. 13. Luk JM, Wang X, Liu P, et al. Traditional Chinese herbal medicines for treatment of liver fibrosis and cancer: from laboratory discovery to clinical evaluation. Liver Int 2007; 27: 879–90. 14. Seeff LB, Lindsay KL, Bacon BR, Kresina TF, Hoofnagle JH. Complementary and alternative medicine in chronic liver disease. Hepatology 2001; 34: 595–603. 15. Richmond JA, Bailey DE, Patel K, et al. The use of complementary and alternative medicine by patients with chronic hepatitis C. Complement Ther Clin Pract 2010; 16: 124–31. Liver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd502 Impact of coffee on liver diseases Saab et al. 16. Arnesen E, Huseby NE, Brenn T, et al. The TromsØ heart study: distribution of, and determinants for, gamma-glutamyltransferase in a free-living population. Scand J Clin Lab Invest 1986; 46: 63–70. 17. Nilssen O, Førde OH, Brenn T. The Tromsø study: distribution and population determinants of gamma-glutamyltransferase. Am J Epidemiol 1990; 132: 318–26. 18. Nilssen O, Førde OH. Seven-year longitudinal population study of change in gamma-glutamyltransferase: the Tromsø Study. Am J Epidemiol 1994; 139: 787–92. 19. Tanaka K, Tokunaga S, Kono S, et al. Coffee consumption and decreased serum gamma-glutamyltransferase and aminotransferase activities among male alcohol drinkers. Int J Epidemiol 1998; 27: 438–43. 20. Kono S, Shinchi K, Imanishi K, et al. Coffee and serum gamma-glutamyltransferase: a study of self-defense officials in Japan. Am J Epidemiol 1994; 139: 723–7. 21. Honjo S, Kono S, Ogawa S, et al. Coffee drinking and serum gamma-glutamyltransferase: an extended study of self-defense officials of Japan. Ann Epidemiol 1999; 9: 325– 31. 22. Honjo S, Kono S, Ogawa S, et al. Coffee consumption and serum aminotransferases in middle-aged Japanese men. J Clin Epidemiol 2001; 54: 823–9. 23. Nakanishi N, Nakamura K, Nakajima K, et al. Coffee consumption and decreased serum gamma-glutamyltransferase: a study of middle-aged Japanese men. Eur J Epidemiol 2000; 16: 419–23. 24. Casiglia E, Spolaore P, Ginocchio G, Ambrosio GB. Unexpected effects of coffee consumption on liver enzymes. Eur J Epidemiol 1993; 9: 293–7. 25. Pintus F, Mascia P. Distribution and population determinants of gamma-glutamyltransferase in a random sample of Sardinian inhabitants. Eur JEpidemiol 1996; 12:71–6. 26. Poikolainen K, Vartiainen E. Determinants of gammaglutamyltransferase: positive interaction with alcohol and body mass index, negative association with coffee. Am J Epidemiol 1997; 146: 1019–24. 27. Skurtveit S, Tverdal A. Sex differences in gamma-glutamyltransferase in people aged 40–42 years in two Norwegian counties. Drug Alcohol Depend 2003; 69: 103–6. 28. Urgert R, Meyboom S, Kuilman M, et al. Comparison of effect of cafetiere and filtered coffee on serum concentrations of liver aminotransferases and lipids: six month randomized controlled trial. BMJ 1996; 313: 1362–6. 29. Ikeda M, Maki T, Yin G, et al. Relation of coffee consumption and serum liver enzymes in Japanese men and women with reference to effect modification of alcohol use and body mass index. Scand J Clin Lab Invest 2010; 70: 171–9. 30. Ruhl CE, Everhart JE. Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States. Gastroenterology 2005; 128: 24–32. 31. Modi AA, Feld JJ, Park Y, et al. Increased caffeine consumption is associated with reduced hepatic fibrosis. J Hepatol 2010; 51: 201–9. 32. Ruhl CE, Everhart JE. Coffee and teas consumption are associated with a lower incidence of chronic liver disease in the United States. Gastroenterology 2005; 129: 1928–36. 33. Corrao G, Zambon A, Bagnardi V, et al. Coffee, caffeine, and the risk of liver cirrhosis. Ann Epidemiol 2001; 11: 458–65. 34. Gallus S, Tavani A, Negri E, La Vecchia C. Does coffee protect against liver cirrhosis? Ann Epidemiol 2002; 12: 202–5. 35. Corrao G, Lepore AR, Torchio P, et al. The effect of drinking coffee and smoking cigarettes on the risk of cirrhosis associated with alcohol consumption. Eur J Epidemiol 1994; 10: 657–64. 36. Klatsky AL, Armstrong MA. Alcohol, smoking, coffee, and cirrhosis. Am J Epidemiol 1992; 136: 1248–57. 37. Klatsky AL, Armstrong MA, Friedman GD. Coffee, tea, and mortality. Ann Epidemiol 1993; 3: 375–81. 38. Klatsky AL, Morton C, Udaltsova N, Friedman GD. Coffee, cirrhosis, and transaminase enzymes. Arch Intern Med 2006; 166: 1190–5. 39. Tverdal A, Skurtveit S. Coffee intake and mortality from liver cirrhosis. Ann Epidemiol 2003; 13: 419–23. 40. Ong A, Wong VW, Wong GL, Chan HL. The effect of caffeine and alcohol consumption on liver fibrosis – a study of 1045 Asian hepatitis B patients using transient elastography. Liver Int 2011; 31: 1047–53. 41. Wong G, Wong V, Choi P, et al. Assessment of fibrosis by transient elastography compared with liver biopsy and morphometry in chronic liver diseases. Clin Gastroenterol Hepatol 2008; 6: 1027–35. 42. Freedman ND, Everhart JE, Hoefs JC, et al. Coffee intake is associated with lower rates of liver disease progression in chronic hepatitis C. J Hepatol 2009; 50: 1360–9. 43. Freedman ND, Curto TM, Lindsay KL, et al. Coffee consumption is associated with response to peginterferon and ribavirin therapy in patients with chronic hepatitis C. Gastroenterology 2011; 140: 1961–9. 44. Costentin CE, Roudot-Thoraval F, Zafrani ES, et al. Association of caffeine intake and histological features of chronic hepatitis C. J Hepatol 2011; 54: 1123–9. 45. Carrieri MP, Cohen J, Salmon-Ceron D, Winnock M. Coffee consumption and reduced self-reported side effects in HIV-HCV co-infected patients during PEG-IFN and ribavirin treatment: results from ANRS CO13 HEPAVIH. J Hepatol 2012; 56: 745–7. 46. Birerdinc A, Stepanova M, Younossi ZM. Caffeine is protective in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2011; 35: 76–82. 47. Catalano D, Martines GF, Tonzuso A, et al. Protective role of coffee in non-alcoholic fatty liver disease (NAFLD). Dig Dis Sci 2010; 55: 3200–6. 48. Gutierrez-Grobe Y, Chavez-Tapia N, Sanchez-Valle V, et al. High coffee intake is assocaited with lower grade nonalcoholic fatty liver disease: the role of peripheral antioxidant activity. Ann Hepatol 2012; 11: 350–5. 49. Molloy JW, Calcagno CJ, Williams CD, et al. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. J Hepatol 2012; 55: 429–36. 50. Anty R, Marjoux S, Marine-Barjoan E, et al. Regular coffee but not espresso drinking is protective against fibrosis in a cohort mainly composed of morbidly obese European women with NAFLD undergoing bariatric surgery. J Hepatol 2012; 57: 1090–6. 51. La Vecchia C, Ferraroni M, Negri E, et al. Coffee consumption and digestive tract cancers. Cancer Res 1989; 49: 1049–51. 52. Kuper H, Tzonou A, Kaklamani E, et al. Tobacco smoking, alcohol consumption and their interaction in the Liver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 503 Saab et al. Impact of coffee on liver diseases causation of hepatocellular carcinoma. Int J Cancer 2000; 85: 498–502. 53. Gallus S, Bertuzzi M, Tavani A, et al. Does coffee protect against hepatocellular carcinoma. Br J Cancer 2002; 87: 956–9. 54. Gelatti U, Covolo L, Franceschini M, et al. Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case-control study. J Hepatol 2005; 42: 528–34. 55. Tanaka K, Hara M, Kawazoe S, et al. Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case-control study in Japan. Cancer Sci 2007; 98: 214–8. 56. Montella M, Polesel J, Franceschi S, et al. Coffee and tea consumption and risk of hepatocellular carcinoma in Italy. Int J Cancer 2007; 120: 1555–9. 57. Ohishi W, Fujwara S, Cologne JB, et al. Risk factors for hepatocellular carcinoma in a Japanese population: a nested case-control study. Cancer Epidemiol Biomarkers Prev 2008; 17: 849–54. 58. Shimazu T, Tsubono Y, Kuryama S, et al. Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan. Int J Cancer 2005; 116: 150–4. 59. Inoue M, Kurahashi N, Iwasaki M, et al. Effect of coffee and green tea consumption on the risk of liver cancer: cohort analysis by hepatitis virus infection status. Cancer Epidemiol Biomark Prev 2009; 18: 1746–53. 60. Inoue M, Yoshimi I, Sobue T, Tsugane S. Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan. J Natl Cancer Inst 2005; 97: 293–300. 61. Hu G, Tuomilehto J, Pukkala E, et al. Joint effects of coffee consumption and serum gamma-glutamyltransferase on the risk of liver cancer. J Hepatol 2008; 48: 129–36. 62. Johnson S, Koh WP, Wang R, et al. Coffee consumption and reduced risk of hepatocellular carcinoma: findings from the Singapore Chinese health study. Cancer Causes Control 2011; 22: 503–10. 63. Leung WW, Ho SC, Chan HLY, et al. Moderate Coffee consumption reduces the risk of hepatocellular carcinoma in hepatitis B chronic carriers: a case-control study. J Epidemiol Community Health 2011; 65: 556–8. 64. Kurozawa Y, Ogimoto I, Fukudo K, et al. Dietary habits and risk of death due to hepatocellular carcinoma in a large scale cohort study in Japan. Kurume Med J 2004; 51: 141–9. 65. Kurozawa Y, Ogimoto I, Tamakoshi A, et al. Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan. Br J Cancer 2005; 93: 607–10. 66. Wakai K, Kurozawa Y, Tamakoshi A, et al. Liver cancer risk, coffee, and hepatitis C virus infection: a nested casecontrol study in Japan. Br J Cancer 2007; 97: 426–8. 67. Ohfuji S. Coffee consumption and reduced risk of hepatocellular carcinoma among patients with chronic type C liver disease: a case-control study. Hepatol Res 2006; 36: 201–8. 68. Torres DM, Harrison SA. Is it time to write a prescription for coffee? Coffee and liver disease. Gastroenterology. 2013; 144: 670–2. 69. Urgert R, Essed N, Van der Weg G, Kosmeijer-Schuil TG, Katan MB. Separate effects of the coffee diterpenescafestol and kahweol on serum lipids and liver aminotransferases. Am J Clin Nutr 1997; 65: 519–24. 70. Gressner OA, Lahme B, Rehbein K, et al. Pharmacological application of caffeine inhibits TGF-Beta-stimulated connective tissue growth factor expression in hepatocytes via PPAR-gamma and SMAD2/3-dependent pathways. J Hepatol 2008; 49: 758–67. 71. Kalthoff S, Ehmer U, Freiberg N, et al. Coffee induces expression of glucuronosyltransferases by the aryl hydrocarbon receptor and Nrf2 in liver and stomach. Gastroenterology 2010; 139: 1699–710. 72. Shim SG, Jun DW, Kim EK, et al. Caffeine attenuates liver fibrosis via defective adhesion of hepatic stellate cells in cirrhotic model. J Gastroenterol Hepatol 2013. Epub ahead of print. 73. Okano J, Nagahara T, Matsumoto K, Murawaki Y. Caffeine inhibits the proliferation of liver cancer cells and activates the MEK/ERK/EGFR signalling pathway. Basic Clin Pharmacol Toxicol 2008; 102: 543–51. 74. McMahon M, Itoh K, Yamamoto M, et al. The cap ‘n’ collar basic leucine zipper transcription factor Nrf2 controls not only the basal expression of intestinal detoxification and glutathione biosynthetic enzymes but also their induction by cancer chemopreventive agents. Cancer Res 2001; 61: 3299–307. 75. Cavin C, Mace K, Offort EA, Schilter B. Protective effects of coffee diterpenes against aflatoxin B1-inuced genotoxicity: mechanisms in rat and human cells. Food Chem Toxicol 2001; 39: 549–56. 76. Lam LKT, Spamins VL, Wattenberg LW. Isolation and identification of kahweol and cafestol palmitate as active constituents of green coffee beans that enhance glutathione S-transferase activity in the mouse. Cancer Res 1982; 42: 1193–8. 77. Huber WW, Scharf G, Rossmanith W, et al. The coffee components kahweol and cafestol induce gammaglutamylcysteine synthetase, the rate limiting enzyme of chemoprotective glutathione synthesis, in several organs of the rat. Arch Toxicol 2002; 75: 685–94. 78. Huber WW, Parzefall W. Modification of N-acetyltransferases and glutathione S-Transferases by coffee components for cancer risk. Methods Enzymol 2005; 401: 307–41. 79. Ouyang X, Cirillo P, Sautin Y, et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol 2008; 48: 993–9. 80. Cadden SH, Partovi N, Yoshida EM. Review article: possible beneficial effects of coffee on liver disease and function. Aliment Pharmacol Ther 2007; 26: 1–7. 81. Mann CJ. Observational research methods. Research design II: cohort, cross sectional, and case-control studies. Emerg Med J 2003; 20: 54–60. Liver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd504 Impact of coffee on liver diseases Saab et al.