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Is It Time to Write a Prescription for Coffee? Coffee and Liver Disease
Commentaries, continued Is It Time to Write a Prescription for Coffee? Coffee and Liver Disease
O
besity, diabetes, the metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD) are on the rise in the United States, with upwards of 40% of the adult population currently meeting criteria for NAFLD. Approximately 10%–20% of patients with NAFLD meet criteria for nonalcoholic steatohepatitis, with a markedly increased risk of developing cirrhosis and/or hepatocellular carcinoma (HCC).1 Therapeutic interventions to mitigate disease on a population level have been limited and lifestyle modification, although effective, is difficult to sustain over time. Coffee is ubiquitous in our society and has recently been shown to be inversely associated with total and cause-specific mortality.2 Specific to the study of liver disease, coffee has been demonstrated to have beneficial effects on weight gain, development of diabetes, the prevention of hepatic fibrosis in NAFLD, and other chronic liver diseases, including chronic hepatitis C, as well as reduction of HCC (Table 1). One large, retrospective survey of patients who participated in a NAFLD prevalence study found caffeinated coffee intake was associated with a significant reduction in fibrosis among biopsy-proven nonalcoholic steatohepatitis patients.3 Similarly, a meta-analysis with pooled data from 457,922 participants demonstrated an inverse association between coffee and risk of incident diabetes.4 Reduced hepatic fibrosis seems to be specific to caffeinated coffee and does not seem to be shared by other caffeinated beverages.5 There are approximately 1000 substances in coffee, including caffeine, diterphenoic alcohols, potassium, niacin, magnesium, and GASTROENTEROLOGY 2013;144:670 – 672
the anti-oxidants chlorogenic acid (CGA) and tocopherols.6 Diterphenoic alcohols, CGA, and caffeine are the most studied and are the focus of this discussion. The exact mechanisms by which coffee exerts its beneficial effects on the liver are still under investigation. The antifibrotic properties of coffee have been demonstrated in Wistar rats, where coffee was shown to protect against liver injury induced by thioacetamide, leading to reduced hepatic necroinflammation and fibrosis.7 Further study has suggested this is mediated by decreased expression of transforming growth factor- and connective tissue growth factor.8 Another potential mechanism by which coffee exerts hepatoprotective effects was suggested by a Japanese study where coffee consumption was positively associated with adiponectin levels and inversely associated with leptin, high-sensitivity C-reactive protein, and liver enzymes.9 Coffee has also been shown to activate a family of enzymes involved in the hepatic detoxification process including uridine 5’-diphospho-glucuronosyltransferases (UGT), with initial studies demonstrating that the diterpines were responsible for the activation of UGT.10 Kalthoff et al11 further showed UGT activation by coffee to be independent of caffeine content as well as the major diterpines found in coffee, cafestol, and kahweol. In the accompanying editorial to this study, Gressner proposes both coffee and caffeine activate multiple hepatoprotective molecular signaling mechanisms and that a full understanding of the beneficial “blend” of coffee remains to be determined.12 The exact ingredients in coffee responsible for its beneficial effects on the liver are uncertain, although several substances as well as the method of preparation are thought to be of importance. Filtered coffee may provide the most benefit because it
is thought to reduce cafestol and kahweol, which can raise serum cholesterol while maintaining CGA and caffeine content. Nonfiltered, boiled coffee includes Turkish coffee and coffee brewed in a French press and has been associated with an increase in low-density lipoprotein cholesterol as well as cardiovascular disease.13 Alternatively, these oily diterpenes may have anticarcinogenic properties as shown in cell culture study,14 possibly via anti-angiogenic processes,15 which may explain the reduced rates of HCC seen in a recent meta-analysis of 6 case-controlled studies.16 The polyphenols are another component of coffee that may explain some of coffee’s metabolic benefits. The major polyphenol in coffee is CGA, which has shown potent anti-oxidant activity in vitro and cell culture as well as animal models and human epidemiologic studies.5 A recent study in obese rats fed a high-carbohydrate, highfat diet demonstrated that filtered Columbian coffee extract with a high concentration of CGA can attenuate the development of glucose intolerance and NAFLD as well as hypertension and cardiovascular remodeling.17 These are compelling data, although they do not confirm that CGAs are the specific beneficial agent and validation in prospective, clinical trials is required. Caffeine is another potential candidate that may be responsible for the beneficial effects of coffee on hepatic fibrosis. A large survey study with patients from the National Health and Nutrition Examination Surveys (2001–2008) demonstrated that caffeine intake specifically was associated with a lower risk of NAFLD in multivariate analysis (P ⬍ .001), although this observational study is limited because coffee intake and caffeine are so highly correlated in most individuals.18 The mechanism of action by which caffeine may
Commentaries, continued Table 1. Summary of the Major Human Studies Evaluating Coffee Intake and Chronic Liver Disease First author and year Klatsky 199221
No. of patients 128,934
Ruhl 200522
5994
Ruhl 200523
9849
Bravi 20078
1551
Larsson 200724 Freedman 200925
177 234 63,257 238
Yamashita 20128
2554 males, 763 females 3284
Molloy 20123
73 subjects ⫹ 57 controls 229,119 males; 173,141 females 306
Anty 201212
195
Gutierrez-Grobe 201230 Freedman 20122
Findings
Coffee drinking ⬎4 cups per day had 1/5 the risk of alcoholic cirrhosis as non-coffee drinkers NHANES III 1ALT declined with 1 intake of coffee and caffeine; ⬎2 cups per day vs no coffee; OR 0.56 for 1ALT NHANES I: Epidemiologic Follow-up ⬎2 cups coffee daily vs ⬍1 cup/d had ⬍½ risk (OR, 0.43) of Study chronic liver disease Meta-analysis of case-controlled 41% 2 risk of HCC among coffee vs never coffee drinkers studies of HCC in Europe/Japan Meta-analysis of 9 studies of HCC 2 cups/d associated with 43% 2 risk of liver cancer Californians undergoing physicals
2260 cases 239,146 non-cases 766 HCV patients in the HALT-C trial
Modi 20104 Leung WW 201126 Johnson 201127 Costentin 201128
Matsuura 201229
Diagnoses
121 HCV patients HBV chronic carriers Adult, otherwise healthy Chinese HCV treatment-naïve patients Healthy Japanese workers Healthy Japanese civil servants NAFLD and controls NIH AARP Diet and Health Study NAFLD patients Severely obese patients
RR for disease progression was 1.1 for ⬍1 cup/d; 0.73 for 1–3 cups/d; and 0.47 for ⬎3 cups/d vs no coffee 2.25 cups/d associated with 2 liver fibrosis (OR, 0.33) Moderate coffee associated with 2 HCC (OR, 0.54) ⱖ3 cups/d associated with 2 HCC (OR, 0.56) Caffeine ⬎408 mg/d inversely associated with histologic activity (OR, 0.32) Coffee consumption associated with 1 adiponectin and 2 leptin ⱖ4 cups/d associated with 2 metabolic syndrome (OR, 0.79 vs 0.61) Dose-dependent reduction in consumption of caffeine with increasing severity of steatosis Coffee consumption inversely associated with total and cause-specific mortality Caffeinated coffee associated with 2 hepatic fibrosis in nonalcoholic steatohepatitis patients Regular coffee but not espresso associated with 2 hepatic fibrosis in severely obese patients
AARP, American Association of Retired Persons; ALT, alanine aminotransferase; HALT, Hepatitis C Antiviral Long-term Treatment against Cirrhosis; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; NAFLD, nonalcoholic fatty liver disease; NHANES, National Health and Nutrition Examination Survey; OR, odds ratio; RR, relative risk.
have metabolic or hepatic benefits remains an area of investigation: Early data that showed anti-oxidant effects in vitro with high doses of caffeine19 have not been replicated in animal or human models and caffeine does not affect lipid or other metabolic panels. One study of 195 severely obese patients undergoing bariatric surgery evaluation even suggested that caffeine may not provide benefit; patients who consumed regular coffee had lower rates of hepatic fibrosis compared with those who consumed espresso beverages.20 A notable limitation of this study was that extra fructose consumption among those who drink espresso beverages could negate any potential benefit of the caffeine. In addition, espresso is made using highpressure, boiling water through a column, is not filtered, and has a
highly variable concentration of both caffeine and CGA, although generally with more caffeine than regular filtered coffee. Based on the available data from predominantly observational trials, there seems to be a clinical benefit of coffee consumption for those patients at risk of developing hepatic fibrosis either from NAFLD or viral hepatitis. Rates of liver cancer and the development of metabolic syndrome may also be improved with daily moderate filtered coffee intake. CGA and caffeine are the best candidates for beneficial effects on hepatic fibrosis, and cafestol and kahweol may reduce rates of HCC. It is unclear whether any of these benefits are significant enough to “treat” patients with chronic liver disease and further study is required with standard doses of each
of these purported therapies in appropriately powered, multicenter, randomized, controlled trials with both biochemical and hepatic histology as endpoints. In the interim, moderate daily unsweetened coffee ingestion is a reasonable adjunct to therapy for NAFLD patients that often includes lifestyle modification with diet and exercise. DAWN M. TORRES Division of Gastroenterology Department of Medicine Walter Reed National Military Medical Center Washington, DC STEPHEN A. HARRISON Division of Gastroenterology Department of Medicine San Antonio Military Medical Center Fort Sam Houston, Texas 671
Commentaries, continued References 1. Torres DM, Williams CD, Harrison SA. Features, diagnosis, and treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2012;10:837– 858. 2. 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. 3. 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. 4. Huxley R, Ying Lee CM, Barzi F, et al. Coffee, decaffeinated coffee, and tea consumption in relation to incident type 2 diabetes mellitus. Arch Intern Med 2009;169:2053–2063. 5. Modi AA, Feld JJ, Park Y, et al. Increased caffeine consumption is associated with reduced hepatic fibrosis. Hepatology 2010;51:201–209. 6. Bonita JS, Mandarano M, Shuta D, et al. Coffee and cardiovascular disease: in vitro, cellular, animal, and human studies. Pharmacol Res 2007;55:187–198. 7. Furtado KS, Prado MG, Aguiar E, et al. Coffee and caffeine protect against liver injury induced by thioacetamide in male Wistar rats. Basic Clin Pharmacol Toxicol 2012;111:339 –347. 8. Arauz J, Moreno MG, Cortes-Reynosa P, et al. Coffee attenuates fibrosis by decreasing the expression of TGF- and CTGF in a murine model of liver damage. J Appl Toxicol 2012 Aug 17 [Epub ahead of print]. 9. Yamashita K, Yatsuya H, Toyoshima H, et al. Association of coffee consumption with serum adiponectin, lepin, inflammation, and metabolic markers in Japanese workers: a cross-sectional study. Nutrition and Diabetes 2012;2:e33. 10. Huber WW, Prustomersky S, Delbanco E, et al. Enhancement of the chemoprotective enzymes glucuronyosyl transferase and glutathione transferase in specific organs of the rat by coffee components kahweol and cafestol. Arch Toxicol 2002;76:209 –217.
672
11. Kalthoff S, Ehmer U, Freiberg N, et al. Coffee induces expression of glucoronosyltransferase by the aryl hydrocarbon receptor and Nrf2 in liver and stomach. Gastroenterology 2010;139: 1699 –1710. 12. Gressner OA. In the search of the magic bullet. Gastroenterology 2010;139: 1453–1457. 13. Ranheim T Halvorsen B. Coffee consumption and human health: beneficial or detrimental? Mechanisms for effects of coffee consumption on different risk factors for cardiovascular disease and type 2 diabetes mellitus. Mol Nutr Food Res 2005;49:274 –284. 14. 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. 15. Cardenas C, Quesada AR, Medina MA, et al. Anti-angiogenic and anti-inflammatory properties of kahweol, a coffee diterpene. PLoS One 2011;6:e23407. 16. Bravi F, Bosetti C, Tavani V, et al. Coffee drinking and hepatocellular carcinoma risk: a meta-analysis. Hepatology 2007; 46:430 – 435. 17. Panchal SK, Poudyal H, Waanders J, et al. Coffee extract attenuates changes in cardiovascular function and hepatic structure and function without decreasing obesity in high-carbohydrate, high-fat diet-fed male rats. J Nutrition 2012;142: 690 – 697. 18. Birerdinc A, Stepanova M, Pawloski L, et al. Caffeine is protective in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2012;35:76 – 82. 19. Shi X, Dalal NS, Jain AC. Antioxidant behavior of caffeine: efficient scavenging of hydroxyl radicals. Food Chem Toxicol 1991;29:1– 6. 20. Anty R, Marjoux S, Iannelli A, 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. 21. Klatsky AL, Armstrong MA. Alcohol, smoking, coffee, and cirrhosis. Am J Epidemiol 1992;136:1248 –1257.
22. 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. 23. Ruhl CE, Everhart JE. Coffee and tea consumption are associated with a lower incidence of chronic liver disease in the United States. Gastroenterology 2005; 129:1928 –1936. 24. Larsson SC, Wolk A. Coffee consumption and risk of liver cancer: a metaanalysis. Gastroenterology 2007;132: 1740 –1745. 25. Freedman ND, Everhart JE, Lindsay KL, et al. Coffee intake is associated with lower rates of liver disease progression in chronic hepatitis C. Hepatology 2009; 50:1360 –1369. 26. Leung WW, Ho SC, Chan HL, 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. 27. 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– 510. 28. Costentin CE, Roudot-Thoraval F, Zafrani E, et al. Association of caffeine intake and histological features of chronic hepatitis C. J Hepatol 2011;54:1123– 1129. 29. Matsuura H, Mure K, Nishio N, et al. Relationship between coffee consumption and prevalence of metabolic syndrome among Japanese civil servants. J Epidemiol 2012;22:160 –166. 30. Gutierrez-Grobe Y, Chavez-Tapia N, Sanchez-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.
Conflicts of interest The authors disclose no conflicts. http://dx.doi.org/10.1053/j.gastro.2013.02.015
O
besity, diabetes, the metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD) are on the rise in the United States, with upwards of 40% of the adult population currently meeting criteria for NAFLD. Approximately 10%–20% of patients with NAFLD meet criteria for nonalcoholic steatohepatitis, with a markedly increased risk of developing cirrhosis and/or hepatocellular carcinoma (HCC).1 Therapeutic interventions to mitigate disease on a population level have been limited and lifestyle modification, although effective, is difficult to sustain over time. Coffee is ubiquitous in our society and has recently been shown to be inversely associated with total and cause-specific mortality.2 Specific to the study of liver disease, coffee has been demonstrated to have beneficial effects on weight gain, development of diabetes, the prevention of hepatic fibrosis in NAFLD, and other chronic liver diseases, including chronic hepatitis C, as well as reduction of HCC (Table 1). One large, retrospective survey of patients who participated in a NAFLD prevalence study found caffeinated coffee intake was associated with a significant reduction in fibrosis among biopsy-proven nonalcoholic steatohepatitis patients.3 Similarly, a meta-analysis with pooled data from 457,922 participants demonstrated an inverse association between coffee and risk of incident diabetes.4 Reduced hepatic fibrosis seems to be specific to caffeinated coffee and does not seem to be shared by other caffeinated beverages.5 There are approximately 1000 substances in coffee, including caffeine, diterphenoic alcohols, potassium, niacin, magnesium, and GASTROENTEROLOGY 2013;144:670 – 672
the anti-oxidants chlorogenic acid (CGA) and tocopherols.6 Diterphenoic alcohols, CGA, and caffeine are the most studied and are the focus of this discussion. The exact mechanisms by which coffee exerts its beneficial effects on the liver are still under investigation. The antifibrotic properties of coffee have been demonstrated in Wistar rats, where coffee was shown to protect against liver injury induced by thioacetamide, leading to reduced hepatic necroinflammation and fibrosis.7 Further study has suggested this is mediated by decreased expression of transforming growth factor- and connective tissue growth factor.8 Another potential mechanism by which coffee exerts hepatoprotective effects was suggested by a Japanese study where coffee consumption was positively associated with adiponectin levels and inversely associated with leptin, high-sensitivity C-reactive protein, and liver enzymes.9 Coffee has also been shown to activate a family of enzymes involved in the hepatic detoxification process including uridine 5’-diphospho-glucuronosyltransferases (UGT), with initial studies demonstrating that the diterpines were responsible for the activation of UGT.10 Kalthoff et al11 further showed UGT activation by coffee to be independent of caffeine content as well as the major diterpines found in coffee, cafestol, and kahweol. In the accompanying editorial to this study, Gressner proposes both coffee and caffeine activate multiple hepatoprotective molecular signaling mechanisms and that a full understanding of the beneficial “blend” of coffee remains to be determined.12 The exact ingredients in coffee responsible for its beneficial effects on the liver are uncertain, although several substances as well as the method of preparation are thought to be of importance. Filtered coffee may provide the most benefit because it
is thought to reduce cafestol and kahweol, which can raise serum cholesterol while maintaining CGA and caffeine content. Nonfiltered, boiled coffee includes Turkish coffee and coffee brewed in a French press and has been associated with an increase in low-density lipoprotein cholesterol as well as cardiovascular disease.13 Alternatively, these oily diterpenes may have anticarcinogenic properties as shown in cell culture study,14 possibly via anti-angiogenic processes,15 which may explain the reduced rates of HCC seen in a recent meta-analysis of 6 case-controlled studies.16 The polyphenols are another component of coffee that may explain some of coffee’s metabolic benefits. The major polyphenol in coffee is CGA, which has shown potent anti-oxidant activity in vitro and cell culture as well as animal models and human epidemiologic studies.5 A recent study in obese rats fed a high-carbohydrate, highfat diet demonstrated that filtered Columbian coffee extract with a high concentration of CGA can attenuate the development of glucose intolerance and NAFLD as well as hypertension and cardiovascular remodeling.17 These are compelling data, although they do not confirm that CGAs are the specific beneficial agent and validation in prospective, clinical trials is required. Caffeine is another potential candidate that may be responsible for the beneficial effects of coffee on hepatic fibrosis. A large survey study with patients from the National Health and Nutrition Examination Surveys (2001–2008) demonstrated that caffeine intake specifically was associated with a lower risk of NAFLD in multivariate analysis (P ⬍ .001), although this observational study is limited because coffee intake and caffeine are so highly correlated in most individuals.18 The mechanism of action by which caffeine may
Commentaries, continued Table 1. Summary of the Major Human Studies Evaluating Coffee Intake and Chronic Liver Disease First author and year Klatsky 199221
No. of patients 128,934
Ruhl 200522
5994
Ruhl 200523
9849
Bravi 20078
1551
Larsson 200724 Freedman 200925
177 234 63,257 238
Yamashita 20128
2554 males, 763 females 3284
Molloy 20123
73 subjects ⫹ 57 controls 229,119 males; 173,141 females 306
Anty 201212
195
Gutierrez-Grobe 201230 Freedman 20122
Findings
Coffee drinking ⬎4 cups per day had 1/5 the risk of alcoholic cirrhosis as non-coffee drinkers NHANES III 1ALT declined with 1 intake of coffee and caffeine; ⬎2 cups per day vs no coffee; OR 0.56 for 1ALT NHANES I: Epidemiologic Follow-up ⬎2 cups coffee daily vs ⬍1 cup/d had ⬍½ risk (OR, 0.43) of Study chronic liver disease Meta-analysis of case-controlled 41% 2 risk of HCC among coffee vs never coffee drinkers studies of HCC in Europe/Japan Meta-analysis of 9 studies of HCC 2 cups/d associated with 43% 2 risk of liver cancer Californians undergoing physicals
2260 cases 239,146 non-cases 766 HCV patients in the HALT-C trial
Modi 20104 Leung WW 201126 Johnson 201127 Costentin 201128
Matsuura 201229
Diagnoses
121 HCV patients HBV chronic carriers Adult, otherwise healthy Chinese HCV treatment-naïve patients Healthy Japanese workers Healthy Japanese civil servants NAFLD and controls NIH AARP Diet and Health Study NAFLD patients Severely obese patients
RR for disease progression was 1.1 for ⬍1 cup/d; 0.73 for 1–3 cups/d; and 0.47 for ⬎3 cups/d vs no coffee 2.25 cups/d associated with 2 liver fibrosis (OR, 0.33) Moderate coffee associated with 2 HCC (OR, 0.54) ⱖ3 cups/d associated with 2 HCC (OR, 0.56) Caffeine ⬎408 mg/d inversely associated with histologic activity (OR, 0.32) Coffee consumption associated with 1 adiponectin and 2 leptin ⱖ4 cups/d associated with 2 metabolic syndrome (OR, 0.79 vs 0.61) Dose-dependent reduction in consumption of caffeine with increasing severity of steatosis Coffee consumption inversely associated with total and cause-specific mortality Caffeinated coffee associated with 2 hepatic fibrosis in nonalcoholic steatohepatitis patients Regular coffee but not espresso associated with 2 hepatic fibrosis in severely obese patients
AARP, American Association of Retired Persons; ALT, alanine aminotransferase; HALT, Hepatitis C Antiviral Long-term Treatment against Cirrhosis; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; NAFLD, nonalcoholic fatty liver disease; NHANES, National Health and Nutrition Examination Survey; OR, odds ratio; RR, relative risk.
have metabolic or hepatic benefits remains an area of investigation: Early data that showed anti-oxidant effects in vitro with high doses of caffeine19 have not been replicated in animal or human models and caffeine does not affect lipid or other metabolic panels. One study of 195 severely obese patients undergoing bariatric surgery evaluation even suggested that caffeine may not provide benefit; patients who consumed regular coffee had lower rates of hepatic fibrosis compared with those who consumed espresso beverages.20 A notable limitation of this study was that extra fructose consumption among those who drink espresso beverages could negate any potential benefit of the caffeine. In addition, espresso is made using highpressure, boiling water through a column, is not filtered, and has a
highly variable concentration of both caffeine and CGA, although generally with more caffeine than regular filtered coffee. Based on the available data from predominantly observational trials, there seems to be a clinical benefit of coffee consumption for those patients at risk of developing hepatic fibrosis either from NAFLD or viral hepatitis. Rates of liver cancer and the development of metabolic syndrome may also be improved with daily moderate filtered coffee intake. CGA and caffeine are the best candidates for beneficial effects on hepatic fibrosis, and cafestol and kahweol may reduce rates of HCC. It is unclear whether any of these benefits are significant enough to “treat” patients with chronic liver disease and further study is required with standard doses of each
of these purported therapies in appropriately powered, multicenter, randomized, controlled trials with both biochemical and hepatic histology as endpoints. In the interim, moderate daily unsweetened coffee ingestion is a reasonable adjunct to therapy for NAFLD patients that often includes lifestyle modification with diet and exercise. DAWN M. TORRES Division of Gastroenterology Department of Medicine Walter Reed National Military Medical Center Washington, DC STEPHEN A. HARRISON Division of Gastroenterology Department of Medicine San Antonio Military Medical Center Fort Sam Houston, Texas 671
Commentaries, continued References 1. Torres DM, Williams CD, Harrison SA. Features, diagnosis, and treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2012;10:837– 858. 2. 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. 3. 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. 4. Huxley R, Ying Lee CM, Barzi F, et al. Coffee, decaffeinated coffee, and tea consumption in relation to incident type 2 diabetes mellitus. Arch Intern Med 2009;169:2053–2063. 5. Modi AA, Feld JJ, Park Y, et al. Increased caffeine consumption is associated with reduced hepatic fibrosis. Hepatology 2010;51:201–209. 6. Bonita JS, Mandarano M, Shuta D, et al. Coffee and cardiovascular disease: in vitro, cellular, animal, and human studies. Pharmacol Res 2007;55:187–198. 7. Furtado KS, Prado MG, Aguiar E, et al. Coffee and caffeine protect against liver injury induced by thioacetamide in male Wistar rats. Basic Clin Pharmacol Toxicol 2012;111:339 –347. 8. Arauz J, Moreno MG, Cortes-Reynosa P, et al. Coffee attenuates fibrosis by decreasing the expression of TGF- and CTGF in a murine model of liver damage. J Appl Toxicol 2012 Aug 17 [Epub ahead of print]. 9. Yamashita K, Yatsuya H, Toyoshima H, et al. Association of coffee consumption with serum adiponectin, lepin, inflammation, and metabolic markers in Japanese workers: a cross-sectional study. Nutrition and Diabetes 2012;2:e33. 10. Huber WW, Prustomersky S, Delbanco E, et al. Enhancement of the chemoprotective enzymes glucuronyosyl transferase and glutathione transferase in specific organs of the rat by coffee components kahweol and cafestol. Arch Toxicol 2002;76:209 –217.
672
11. Kalthoff S, Ehmer U, Freiberg N, et al. Coffee induces expression of glucoronosyltransferase by the aryl hydrocarbon receptor and Nrf2 in liver and stomach. Gastroenterology 2010;139: 1699 –1710. 12. Gressner OA. In the search of the magic bullet. Gastroenterology 2010;139: 1453–1457. 13. Ranheim T Halvorsen B. Coffee consumption and human health: beneficial or detrimental? Mechanisms for effects of coffee consumption on different risk factors for cardiovascular disease and type 2 diabetes mellitus. Mol Nutr Food Res 2005;49:274 –284. 14. 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. 15. Cardenas C, Quesada AR, Medina MA, et al. Anti-angiogenic and anti-inflammatory properties of kahweol, a coffee diterpene. PLoS One 2011;6:e23407. 16. Bravi F, Bosetti C, Tavani V, et al. Coffee drinking and hepatocellular carcinoma risk: a meta-analysis. Hepatology 2007; 46:430 – 435. 17. Panchal SK, Poudyal H, Waanders J, et al. Coffee extract attenuates changes in cardiovascular function and hepatic structure and function without decreasing obesity in high-carbohydrate, high-fat diet-fed male rats. J Nutrition 2012;142: 690 – 697. 18. Birerdinc A, Stepanova M, Pawloski L, et al. Caffeine is protective in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2012;35:76 – 82. 19. Shi X, Dalal NS, Jain AC. Antioxidant behavior of caffeine: efficient scavenging of hydroxyl radicals. Food Chem Toxicol 1991;29:1– 6. 20. Anty R, Marjoux S, Iannelli A, 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. 21. Klatsky AL, Armstrong MA. Alcohol, smoking, coffee, and cirrhosis. Am J Epidemiol 1992;136:1248 –1257.
22. 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. 23. Ruhl CE, Everhart JE. Coffee and tea consumption are associated with a lower incidence of chronic liver disease in the United States. Gastroenterology 2005; 129:1928 –1936. 24. Larsson SC, Wolk A. Coffee consumption and risk of liver cancer: a metaanalysis. Gastroenterology 2007;132: 1740 –1745. 25. Freedman ND, Everhart JE, Lindsay KL, et al. Coffee intake is associated with lower rates of liver disease progression in chronic hepatitis C. Hepatology 2009; 50:1360 –1369. 26. Leung WW, Ho SC, Chan HL, 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. 27. 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– 510. 28. Costentin CE, Roudot-Thoraval F, Zafrani E, et al. Association of caffeine intake and histological features of chronic hepatitis C. J Hepatol 2011;54:1123– 1129. 29. Matsuura H, Mure K, Nishio N, et al. Relationship between coffee consumption and prevalence of metabolic syndrome among Japanese civil servants. J Epidemiol 2012;22:160 –166. 30. Gutierrez-Grobe Y, Chavez-Tapia N, Sanchez-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.
Conflicts of interest The authors disclose no conflicts. http://dx.doi.org/10.1053/j.gastro.2013.02.015