PRESENTATION
Coffee and Liver Health Filomena Morisco, MD, Vincenzo Lembo, PhD, Giovanna Mazzone, PhD, Silvia Camera, MD, and Nicola Caporaso, MD
Abstract: Coffee is one of the most widely used beverages in the world. It includes a wide array of components that can have potential implications for health. Several epidemiological studies associate coffee consumption with a reduced incidence of various chronic diseases such as diabetes, cardiovascular diseases, and neurodegenerative diseases. Over the past 20 years, an increasing number of epidemiological and experimental studies have demonstrated the positive effects of coffee on chronic liver diseases. Coffee consumption has been inversely associated with the activity of liver enzymes in subjects at risk, including heavy drinkers. Coffee favours an improvement in hepatic steatosis and fibrosis, and a reduction in cirrhosis and the risk of hepatocellular carcinoma. The mechanisms of action through which it exerts its beneficial effects are not fully understood. Experimental studies show that coffee consumption reduces fat accumulation and collagen deposition in the liver and promotes antioxidant capacity through an increase in glutathione as well as modulation of the gene and protein expression of several inflammatory mediators. Animal and in vitro studies indicate that cafestol and kahweol, 2 diterpens, can operate by modulating multiple enzymes involved in the detoxification process of carcinogens causing hepatocellular carcinoma. It is unclear whether the benefits are significant enough to “treat” patients with chronic liver disease. While we await clarification, moderate daily unsweetened coffee use is a reasonable adjuvant to therapy for these patients. Key Words: coffee, NAFLD, cirrhosis, hepatocellular carcinoma
(J Clin Gastroenterol 2014;48:S87–S90)
C
offee, 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
From the Department of Clinical Medicine and Surgery, University of Naples “Federico II,” Naples, Italy. The authors declare that they have nothing to disclose. Reprints: Filomena Morisco, MD, Department of Clinical Medicine and Surgery, University of Naples “Federico II,” Via S. Pansini, 5-80131, Naples, Italy (e-mail: fi[email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
J Clin Gastroenterol
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 gglutamyltransferase.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 g-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 Z3 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
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Volume 48, Supp. 1, November/December 2014
TABLE 1. List of Some Studies Evaluating the Effect of Coffee on Liver Diseases
References
Design
Coffee and Viral Hepatitis Cross-sectional Costentin et al15 Retrospective cohort Freedman et al16 17 Retrospective cohort Freedman et al
Country
Patients (n)
France USA USA
238 766 885
USA
177
Prospective cohort
France
106
Ong et al20 Coffee and NAFLD Anty et al21
Cross-sectional
China
1045
Cross-sectional
France
195
Birerdinc et al22 Catalano et al23 Gutie`rrez-Grobe et al24 Molloy et al25 Coffee and Cirrhosis Corrao et al26 Corrao et al27
Cross-sectional Case-control Case-control Cross-sectional
USA Italy Mexico USA
1782 310 130 306
Italy Italy
282 732
Modi et al18 Carrieri et
al19
Retrospective cohort
Case-control Case-control
Case-control Gallus et al28 Tverdal and Skurtveit29 Retrospective cohort Retrospective cohort Klatsky et al30 Coffee and hepatocellular carcinoma Case-control La Vecchia et al31 Case-control Ohishi et al32 Gallus et al28 Hu et al33 Leung et al34
Case-control Prospective cohort Case-control
Italy Norway USA
1639 51,306 125,580
Italy Japan Italy Finland Hong Kong
2095 868 2053 60,323 234
Comments Coffee and caffeine consumption improve histologic activity Coffee reduces the progression of HCV-related liver disease Coffee induces a better virological response to peginterferon plus ribavirin in HCV patients Coffee consumption is associated with less severe fibrosis in HCV patients Coffee intake reduces the side effects of pegylated interferon and ribavirin Lack of association between fibrosis in HBV patients Regular but not espresso coffee is protective against liver fibrosis in patients with NAFLD Caffeine reduces the risk of NAFLD Coffee is inversely related to severity of NAFLD Coffee intake has protective effect in NAFLD patients Coffee reduces the risk of fibrosis in NASH patients Coffee is protective against alcoholic cirrhosis Alcoholic cirrhosis can be prevented by coffee and not other caffeinated beverages Inverse association between coffee and cirrhosis Inverse association between coffee and cirrhosis Coffee consumption protects against cirrhosis, especially alcoholic cirrhosis There is no association between coffee and liver cancer Daily coffee consumption is associated with decreased risk for HCC Inverse association between coffee and HCC incidence Dose-dependent inverse association with risk of HCC Moderate coffee consumption reduces risk of HCC in HBV chronic carriers
HBV indicates hepatitis B viral infection; HCC, hepatocellular carcinoma; HCV, hepatitis C viral infection; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.
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 casecontrol 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
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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 r
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J Clin Gastroenterol
Volume 48, Supp. 1, November/December 2014
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 Z4 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
CONCLUSIONS 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. REFERENCES 1. Larsson SC. Coffee, tea, and cocoa and risk of stroke. Stroke. 2014;45:309–314. 2. Spiller MA. The chemical components of coffee. Prog Clin Biol Res. 1984;158:91–147. 3. Go´mez-Ruiz JA, Leake DS, Ames JM. In vitro antioxidant activity of coffee compounds and their metabolites. J Agric Food Chem. 2007;55:6962–6969. 4. Higdon JV, Frei B. Coffee and health: a review of recent human research. Crit Rev Food Sci Nutr. 2006;46:101–123. 5. Freedman ND, Park Y, Abnet CC, et al. Association of coffee drinking with total and cause-specific mortality. N Engl J Med. 2012;366:1891–1904, 17. 6. Cornelis MC, El-Sohemy A. Coffee, caffeine, and coronary heart disease. Curr Opin Lipidol. 2007;18:13–19. r
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7. Qi H, Li S. Dose-response meta-analysis on coffee, tea and caffeine consumption with risk of Parkinson’s disease. Geriatr Gerontol Int. 2014;14:430–439. 8. Greenland S. A meta-analysis of coffee, myocardial infarction, and coronary death. Epidemiology. 1993;4:366–374. 9. Wu JN, Ho SC, Zhou C, et al. Coffee consumption and risk of coronary heart diseases: a meta-analysis of 21 prospective cohort studies. Int J Cardiol. 2009;137:216–225. 10. Sugiyama K, Kuriyama S, Akhter M, et al. Coffee consumption and mortality due to all causes, cardiovascular disease, and cancer in Japanese women. J Nutr. 2010;140:1007–1013. 11. Lopez-Garcia E, Van Dam RM, Li TY, et al. The relationship of coffee consumption with mortality. Ann Intern Med. 2008; 148:904–914. 12. Tamakoshi A, Lin Y, Kawado M, et al. Effect of coffee consumption on all-cause and total cancer mortality: findings from the JACC study. Eur J Epidemiol. 2011;26:285–293. 13. Andersen LF, Jacobs DR Jr, Carlsen MH, et al. Consumption of coffee is associated with reduced risk of death attributed to inflammatory and cardiovascular diseases in the Iowa Women’s Health Study. Am J Clin Nutr. 2006;83:1039–1046. 14. La Vecchia CL. Coffee, liver enzymes, cirrhosis and liver cancer. J Hepatol. 2005;42:444–446. 15. Costentin CE, Roudot-Thoraval F, Zafrani ES, et al. Association of caffeine intake and histological features of chronic hepatitis C. J Hepatol. 2011;54:1123–1129. 16. 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;50:1360–1369. 17. 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;140:1961–1969. 18. Modi AA, Feld JJ, Park Y, et al. Increased caffeine consumption is associated with reduced hepatic fibrosis. J Hepatol. 2010;51:201–209. 19. Carrieri MP, Cohen J, Salmon-Ceron D, et al. Coffee consumption and reduced self-reported side effects in HIVHCV co-infected patients during PEG-IFN and ribavirin treatment: results from ANRS CO13 HEPAVIH. J Hepatol. 2012;56:745–747. 20. Ong A, Wong VW, Wong GL, et al. The effect of caffeine and alcohol consumption on liver fibrosis—a study of 1045 Asian hepatitis B patients using transient elastography. Liver Int. 2011;31:1047–1053. 21. 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;57:1090–1096. 22. Birerdinc A, Stepanova M, Younossi ZM. Caffeine is protective in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2011;35:76–82. 23. Catalano D, Martines GF, Tonzuso A, et al. Protective role of coffee in non-alcoholic fatty liver disease (NAFLD). Dig Dis Sci. 2010;55:3200–3206. 24. Gutie`rrez-Grobe Y, Cha`vez-Tapia N, Sa`nchez-Valle V, et al. High coffee intake is associated with lower grade nonalcoholic fatty liver disease: the role of peripheral antioxidant activity. Ann Hepatol. 2012;11:350–355. 25. 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. Hepatology. 2012;55:429–436. 26. 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: 657–664. 27. Corrao G, Zambon A, Bagnardi V, et al. Coffee, caffeine, and the risk of liver cirrhosis. Ann Epidemiol. 2001;11:458–465. 28. Gallus S, Tavani A, Negri E, et al. Does coffee protect against liver cirrhosis? Ann Epidemiol. 2002;12:202–205.
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29. Tverdal A, Skurtveit S. Coffee intake and mortality from liver cirrhosis. Ann Epidemiol. 2003;13:419–423. 30. Klatsky AL, Morton C, Udaltsova N, et al. Coffee, cirrhosis, and transaminase enzymes. Arch Intern Med. 2006;166:1190–1195. 31. La Vecchia C, Ferraroni M, Negri E, et al. Coffee consumption and digestive tract cancers. Cancer Res. 1989;49:1049–1051. 32. 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: 849–854. 33. 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;48:129–136. 34. 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;65:556–558. 35. Arnesen E, Huseby NE, Brenn T, et al. The Tromso Heart Study: distribution of, and determinants for, gamma-glutamyltransferase in a free-living population. Scand J Clin Lab Invest. 1986;46:63–70. 36. Casiglia E, Spolaore P, Ginocchio G, et al. Unexpected effects of coffee consumption on liver enzymes. Eur J Epidemiol. 1993;9:293–297. 37. Honjo S, Kono S, Coleman MP, et al. Coffee consumption and serum aminotransferases in middle-aged Japanese men. J Clin Epidemiol. 2001;54:823–829. 38. 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. 39. 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;27:438–443. 40. Macaluso FS, Maida M, Minissale MG, et al. Metabolic factors and chronic hepatitis C: a complex interplay. Biomed Res Int. 2013;2013:564645. 41. Carrieri MP, Lions C, Sogni P, et al. Association between elevated coffee consumption and daily chocolate intake with normal liver enzymes in HIV-HCV infected individuals: results from the ANRS CO13 HEPAVIH cohort study. J Hepatol. 2014;60:46–53. 42. Cardin R, Piciocchi M, Martines D, et al. Effects of coffee consumption in chronic hepatitis C: a randomized controlled trial. Dig Liver Dis. 2013;45:499–504.
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43. Vitaglione P, Morisco F, Mazzone G, et al. Coffee reduces liver damage in a rat model of steatohepatitis: the underlying mechanisms and the role of polyphenols and melanoidins. Hepatology. 2010;52:1652–1661. 44. Esposito F, Morisco F, Verde V, et al. Moderate coffee consumption increases plasma glutathione but not homocysteine in healthy subjects. Aliment Pharmacol Ther. 2003;17: 595–601. 45. Salomone F, Li Volti G, Vitaglione P, et al. Coffee enhances the expression of chaperones and antioxidant proteins in rats with nonalcoholic fatty liver disease. Transl Res. 2013;13: 431–433. 46. Klatsky AL, Armstrong MA, Friedman GD. Coffee, tea, and mortality. Ann Epidemiol. 1993;3:375–381. 47. Ruhl CE, Everhart JE. Coffee and teas consumption are associated with a lower incidence of chronic liver disease in the United States. Gastroenterology. 2005;129:1928–1936. 48. Bravi F, Bosetti C, Tavani A, et al. Coffee reduces risk for hepatocellular carcinoma: an updated meta-analysis. Clin Gastroenterol Hepatol. 2013;11:1413–1421. 49. Muriel P, Arauz J. Coffee and liver diseases. Fitoterapia. 2010;81:297–305. 50. Cavin C, Holzhaeuser D, Scharf G, et al. Cafestol and kahweol, two coffee specific diterpenes with anticarcinogenic activity. Food Chem Toxicol. 2002;40:1155–1163. 51. Huber WW, Rossmanith W, Grusch M, et al. Effects of coffee and its chemopreventive components kahweol and cafestol on cytochrome P450 and sulfotransferase in rat liver. Food Chem Toxicol. 2008;46:1230–1238. 52. Huber WW, Teitel CH, Coles BF, et al. Potential chemoprotective effects of the coffee components kahweol and cafestol palmitates via modification of hepatic N-acetyltransferase and glutathione S-transferase activities. Environ Mol Mutagen. 2004;44:265–276. 53. Lam LKT, Sparnins 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: 1193–1198. 54. Forrester LM, Neal GE, Judath DJ, et al. Evidence for involvement of multiple forms of cytochrome P-450 in aflatoxin B1 metabolism in human liver. Proc Natl Acad Sci U S A. 1990;87:8306–8310.
r
2014 Lippincott Williams & Wilkins
Coffee and Liver Health Filomena Morisco, MD, Vincenzo Lembo, PhD, Giovanna Mazzone, PhD, Silvia Camera, MD, and Nicola Caporaso, MD
Abstract: Coffee is one of the most widely used beverages in the world. It includes a wide array of components that can have potential implications for health. Several epidemiological studies associate coffee consumption with a reduced incidence of various chronic diseases such as diabetes, cardiovascular diseases, and neurodegenerative diseases. Over the past 20 years, an increasing number of epidemiological and experimental studies have demonstrated the positive effects of coffee on chronic liver diseases. Coffee consumption has been inversely associated with the activity of liver enzymes in subjects at risk, including heavy drinkers. Coffee favours an improvement in hepatic steatosis and fibrosis, and a reduction in cirrhosis and the risk of hepatocellular carcinoma. The mechanisms of action through which it exerts its beneficial effects are not fully understood. Experimental studies show that coffee consumption reduces fat accumulation and collagen deposition in the liver and promotes antioxidant capacity through an increase in glutathione as well as modulation of the gene and protein expression of several inflammatory mediators. Animal and in vitro studies indicate that cafestol and kahweol, 2 diterpens, can operate by modulating multiple enzymes involved in the detoxification process of carcinogens causing hepatocellular carcinoma. It is unclear whether the benefits are significant enough to “treat” patients with chronic liver disease. While we await clarification, moderate daily unsweetened coffee use is a reasonable adjuvant to therapy for these patients. Key Words: coffee, NAFLD, cirrhosis, hepatocellular carcinoma
(J Clin Gastroenterol 2014;48:S87–S90)
C
offee, 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
From the Department of Clinical Medicine and Surgery, University of Naples “Federico II,” Naples, Italy. The authors declare that they have nothing to disclose. Reprints: Filomena Morisco, MD, Department of Clinical Medicine and Surgery, University of Naples “Federico II,” Via S. Pansini, 5-80131, Naples, Italy (e-mail: fi[email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
J Clin Gastroenterol
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 gglutamyltransferase.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 g-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 Z3 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
Volume 48, Supp. 1, November/December 2014
www.jcge.com |
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J Clin Gastroenterol
Morisco et al
Volume 48, Supp. 1, November/December 2014
TABLE 1. List of Some Studies Evaluating the Effect of Coffee on Liver Diseases
References
Design
Coffee and Viral Hepatitis Cross-sectional Costentin et al15 Retrospective cohort Freedman et al16 17 Retrospective cohort Freedman et al
Country
Patients (n)
France USA USA
238 766 885
USA
177
Prospective cohort
France
106
Ong et al20 Coffee and NAFLD Anty et al21
Cross-sectional
China
1045
Cross-sectional
France
195
Birerdinc et al22 Catalano et al23 Gutie`rrez-Grobe et al24 Molloy et al25 Coffee and Cirrhosis Corrao et al26 Corrao et al27
Cross-sectional Case-control Case-control Cross-sectional
USA Italy Mexico USA
1782 310 130 306
Italy Italy
282 732
Modi et al18 Carrieri et
al19
Retrospective cohort
Case-control Case-control
Case-control Gallus et al28 Tverdal and Skurtveit29 Retrospective cohort Retrospective cohort Klatsky et al30 Coffee and hepatocellular carcinoma Case-control La Vecchia et al31 Case-control Ohishi et al32 Gallus et al28 Hu et al33 Leung et al34
Case-control Prospective cohort Case-control
Italy Norway USA
1639 51,306 125,580
Italy Japan Italy Finland Hong Kong
2095 868 2053 60,323 234
Comments Coffee and caffeine consumption improve histologic activity Coffee reduces the progression of HCV-related liver disease Coffee induces a better virological response to peginterferon plus ribavirin in HCV patients Coffee consumption is associated with less severe fibrosis in HCV patients Coffee intake reduces the side effects of pegylated interferon and ribavirin Lack of association between fibrosis in HBV patients Regular but not espresso coffee is protective against liver fibrosis in patients with NAFLD Caffeine reduces the risk of NAFLD Coffee is inversely related to severity of NAFLD Coffee intake has protective effect in NAFLD patients Coffee reduces the risk of fibrosis in NASH patients Coffee is protective against alcoholic cirrhosis Alcoholic cirrhosis can be prevented by coffee and not other caffeinated beverages Inverse association between coffee and cirrhosis Inverse association between coffee and cirrhosis Coffee consumption protects against cirrhosis, especially alcoholic cirrhosis There is no association between coffee and liver cancer Daily coffee consumption is associated with decreased risk for HCC Inverse association between coffee and HCC incidence Dose-dependent inverse association with risk of HCC Moderate coffee consumption reduces risk of HCC in HBV chronic carriers
HBV indicates hepatitis B viral infection; HCC, hepatocellular carcinoma; HCV, hepatitis C viral infection; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.
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 casecontrol 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
S88 | www.jcge.com
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 r
2014 Lippincott Williams & Wilkins
J Clin Gastroenterol
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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 Z4 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
CONCLUSIONS 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. REFERENCES 1. Larsson SC. Coffee, tea, and cocoa and risk of stroke. Stroke. 2014;45:309–314. 2. Spiller MA. The chemical components of coffee. Prog Clin Biol Res. 1984;158:91–147. 3. Go´mez-Ruiz JA, Leake DS, Ames JM. In vitro antioxidant activity of coffee compounds and their metabolites. J Agric Food Chem. 2007;55:6962–6969. 4. Higdon JV, Frei B. Coffee and health: a review of recent human research. Crit Rev Food Sci Nutr. 2006;46:101–123. 5. Freedman ND, Park Y, Abnet CC, et al. Association of coffee drinking with total and cause-specific mortality. N Engl J Med. 2012;366:1891–1904, 17. 6. Cornelis MC, El-Sohemy A. Coffee, caffeine, and coronary heart disease. Curr Opin Lipidol. 2007;18:13–19. r
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7. Qi H, Li S. Dose-response meta-analysis on coffee, tea and caffeine consumption with risk of Parkinson’s disease. Geriatr Gerontol Int. 2014;14:430–439. 8. Greenland S. A meta-analysis of coffee, myocardial infarction, and coronary death. Epidemiology. 1993;4:366–374. 9. Wu JN, Ho SC, Zhou C, et al. Coffee consumption and risk of coronary heart diseases: a meta-analysis of 21 prospective cohort studies. Int J Cardiol. 2009;137:216–225. 10. Sugiyama K, Kuriyama S, Akhter M, et al. Coffee consumption and mortality due to all causes, cardiovascular disease, and cancer in Japanese women. J Nutr. 2010;140:1007–1013. 11. Lopez-Garcia E, Van Dam RM, Li TY, et al. The relationship of coffee consumption with mortality. Ann Intern Med. 2008; 148:904–914. 12. Tamakoshi A, Lin Y, Kawado M, et al. Effect of coffee consumption on all-cause and total cancer mortality: findings from the JACC study. Eur J Epidemiol. 2011;26:285–293. 13. Andersen LF, Jacobs DR Jr, Carlsen MH, et al. Consumption of coffee is associated with reduced risk of death attributed to inflammatory and cardiovascular diseases in the Iowa Women’s Health Study. Am J Clin Nutr. 2006;83:1039–1046. 14. La Vecchia CL. Coffee, liver enzymes, cirrhosis and liver cancer. J Hepatol. 2005;42:444–446. 15. Costentin CE, Roudot-Thoraval F, Zafrani ES, et al. Association of caffeine intake and histological features of chronic hepatitis C. J Hepatol. 2011;54:1123–1129. 16. 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;50:1360–1369. 17. 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;140:1961–1969. 18. Modi AA, Feld JJ, Park Y, et al. Increased caffeine consumption is associated with reduced hepatic fibrosis. J Hepatol. 2010;51:201–209. 19. Carrieri MP, Cohen J, Salmon-Ceron D, et al. Coffee consumption and reduced self-reported side effects in HIVHCV co-infected patients during PEG-IFN and ribavirin treatment: results from ANRS CO13 HEPAVIH. J Hepatol. 2012;56:745–747. 20. Ong A, Wong VW, Wong GL, et al. The effect of caffeine and alcohol consumption on liver fibrosis—a study of 1045 Asian hepatitis B patients using transient elastography. Liver Int. 2011;31:1047–1053. 21. 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;57:1090–1096. 22. Birerdinc A, Stepanova M, Younossi ZM. Caffeine is protective in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2011;35:76–82. 23. Catalano D, Martines GF, Tonzuso A, et al. Protective role of coffee in non-alcoholic fatty liver disease (NAFLD). Dig Dis Sci. 2010;55:3200–3206. 24. Gutie`rrez-Grobe Y, Cha`vez-Tapia N, Sa`nchez-Valle V, et al. High coffee intake is associated with lower grade nonalcoholic fatty liver disease: the role of peripheral antioxidant activity. Ann Hepatol. 2012;11:350–355. 25. 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. Hepatology. 2012;55:429–436. 26. 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: 657–664. 27. Corrao G, Zambon A, Bagnardi V, et al. Coffee, caffeine, and the risk of liver cirrhosis. Ann Epidemiol. 2001;11:458–465. 28. Gallus S, Tavani A, Negri E, et al. Does coffee protect against liver cirrhosis? Ann Epidemiol. 2002;12:202–205.
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29. Tverdal A, Skurtveit S. Coffee intake and mortality from liver cirrhosis. Ann Epidemiol. 2003;13:419–423. 30. Klatsky AL, Morton C, Udaltsova N, et al. Coffee, cirrhosis, and transaminase enzymes. Arch Intern Med. 2006;166:1190–1195. 31. La Vecchia C, Ferraroni M, Negri E, et al. Coffee consumption and digestive tract cancers. Cancer Res. 1989;49:1049–1051. 32. 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: 849–854. 33. 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;48:129–136. 34. 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;65:556–558. 35. Arnesen E, Huseby NE, Brenn T, et al. The Tromso Heart Study: distribution of, and determinants for, gamma-glutamyltransferase in a free-living population. Scand J Clin Lab Invest. 1986;46:63–70. 36. Casiglia E, Spolaore P, Ginocchio G, et al. Unexpected effects of coffee consumption on liver enzymes. Eur J Epidemiol. 1993;9:293–297. 37. Honjo S, Kono S, Coleman MP, et al. Coffee consumption and serum aminotransferases in middle-aged Japanese men. J Clin Epidemiol. 2001;54:823–829. 38. 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. 39. 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;27:438–443. 40. Macaluso FS, Maida M, Minissale MG, et al. Metabolic factors and chronic hepatitis C: a complex interplay. Biomed Res Int. 2013;2013:564645. 41. Carrieri MP, Lions C, Sogni P, et al. Association between elevated coffee consumption and daily chocolate intake with normal liver enzymes in HIV-HCV infected individuals: results from the ANRS CO13 HEPAVIH cohort study. J Hepatol. 2014;60:46–53. 42. Cardin R, Piciocchi M, Martines D, et al. Effects of coffee consumption in chronic hepatitis C: a randomized controlled trial. Dig Liver Dis. 2013;45:499–504.
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43. Vitaglione P, Morisco F, Mazzone G, et al. Coffee reduces liver damage in a rat model of steatohepatitis: the underlying mechanisms and the role of polyphenols and melanoidins. Hepatology. 2010;52:1652–1661. 44. Esposito F, Morisco F, Verde V, et al. Moderate coffee consumption increases plasma glutathione but not homocysteine in healthy subjects. Aliment Pharmacol Ther. 2003;17: 595–601. 45. Salomone F, Li Volti G, Vitaglione P, et al. Coffee enhances the expression of chaperones and antioxidant proteins in rats with nonalcoholic fatty liver disease. Transl Res. 2013;13: 431–433. 46. Klatsky AL, Armstrong MA, Friedman GD. Coffee, tea, and mortality. Ann Epidemiol. 1993;3:375–381. 47. Ruhl CE, Everhart JE. Coffee and teas consumption are associated with a lower incidence of chronic liver disease in the United States. Gastroenterology. 2005;129:1928–1936. 48. Bravi F, Bosetti C, Tavani A, et al. Coffee reduces risk for hepatocellular carcinoma: an updated meta-analysis. Clin Gastroenterol Hepatol. 2013;11:1413–1421. 49. Muriel P, Arauz J. Coffee and liver diseases. Fitoterapia. 2010;81:297–305. 50. Cavin C, Holzhaeuser D, Scharf G, et al. Cafestol and kahweol, two coffee specific diterpenes with anticarcinogenic activity. Food Chem Toxicol. 2002;40:1155–1163. 51. Huber WW, Rossmanith W, Grusch M, et al. Effects of coffee and its chemopreventive components kahweol and cafestol on cytochrome P450 and sulfotransferase in rat liver. Food Chem Toxicol. 2008;46:1230–1238. 52. Huber WW, Teitel CH, Coles BF, et al. Potential chemoprotective effects of the coffee components kahweol and cafestol palmitates via modification of hepatic N-acetyltransferase and glutathione S-transferase activities. Environ Mol Mutagen. 2004;44:265–276. 53. Lam LKT, Sparnins 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: 1193–1198. 54. Forrester LM, Neal GE, Judath DJ, et al. Evidence for involvement of multiple forms of cytochrome P-450 in aflatoxin B1 metabolism in human liver. Proc Natl Acad Sci U S A. 1990;87:8306–8310.
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