- Email: [email protected]
Coffee and the Liver
C H A P T E R
62
Coffee and the Liver: An Overview of Epidemiologic Studies Rodolphe Anty1, 2, 3, Alexandre Pariente4 1Institut
National de la Santé et de la Recherche Médicale (INSERM), Nice, France; 2Centre Hospitalier Universitaire of Nice, Digestive Center, Nice, France; 3Faculty of Medecine, University of Nice-Sophia-Antipolis, Nice, France; 4Centre Hospitalier of Pau, Hepatogastroenterology Unit, Pau, France
List of Abbreviations
observed, in an Italian study on cardiovascular risk in the elderly, that the serum activity of liver enzymes and bilirubin were lower in coffee drinkers.1 A few years later, Klatsky et al.2 reported in the United States that coffee drinkers had a reduced risk of cirrhosis, particularly of alcoholic cirrhosis. Finally Kuper et al. were the first, in Greece, to report a negative association between coffee consumption and hepatocellular carcinoma.3 In this chapter, we will review the main epidemiological data linking coffee and liver diseases.
CI Confidence interval NAFLD Nonalcoholic liver disease NASH Nonalcoholic steatohepatitis OR Odds ratio RR Relative risk
62.1 SUMMARY POINTS Coffee consumption is associated with
• • • •
ecrease in serum liver enzymes, d decreased risk of cirrhosis and death from cirrhosis, decreased fibrosis stage in various liver diseases, decrease rate of progression of liver disease in chronic, fibrous, hepatitis C unresponsive to antiviral treatment, • decreased risk of hepatocellular carcinoma.
There is usually a dose–effect relationship between the coffee ingested and the risks reduction. The order of magnitude of these reductions of risk is around 40% for drinkers of three cups or more by day compared with nondrinkers. Numerous coffee components are candidates for these beneficial effects. Coffee consumption could alternatively be an indirect marker of genetic polymorphisms having favorable effects on liver disease progression. Coffee consumption should not be reduced in patients with liver disease but without severe liver failure. That coffee could favorably influence liver function was first reported by Casiglia et al. in 1993, who
Coffee in Health and Disease Prevention http://dx.doi.org/10.1016/B978-0-12-409517-5.00062-0
62.2 THE LIMITS OF EPIDEMIOLOGICAL STUDIES Available epidemiological studies are based on transversal, case–control, and, more rarely, cohort studies, which all have intrinsic bias. Interventional studies are exceptional and have limited fields. The measurement of coffee consumption has been sometimes simply obtained from an self-administered simple questionnaires, or by more complex questionnaires, which must be previously validated, ideally administered by adequately trained investigators, allowing evaluation of the consumption of various types of coffee (regular, espresso, decaffeinated, etc.) and of other caffeine-containing drinks (tea, sodas, etc.)4; coffee consumption is, however, the better reported item in food-frequency questionnaires.5 Tables permit calculating total caffeine consumption (from coffee and other beverages), which can be treated as a continuous variable, or as a categorical variable, classes being defined a priori, or, at best, as quantiles in the studied population. There are, however, large variations
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© 2015 Elsevier Inc. All rights reserved.
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62. COFFEE AND THE LIVER
in the composition of coffee according to its origin, the methods of torrefaction, and particularly the technique of preparation used. So, an ideal questionnaire should at least include questions about the type of coffee and the coffee-making process type. There is a theoretical risk of reduction of coffee consumption when a severe disease is present, because of the decrease in caffeine clearance by the liver, but this observation is of importance only in patients with cirrhosis and moderate-to-severe hepatocellular failure. Coffee consumption seems to be stable all life long, even if it decreases slightly with advanced age. Above all there are interaction and confusion factors, linked to coffee consumption. There is a strong correlation between coffee and tobacco consumption, which can modify the liver enzyme activities,6 hepatic fibrosis, and hepatocellular carcinoma risks. Alcohol and coffee consumptions are more weakly linked, except for the higher levels of coffee consumption.5 Other known risk factors for liver disease should be considered. Confusion factors have to be taken into account by appropriate statistical methods; odds ratios (ORs) and risk ratios must be adjusted (in the absence of interaction) at least on age, sex, alcohol and tobacco consumption, body mass index (BMI; or other markers linked with obesity or insulin resistance), and the other causes of liver disease (if they have not been explicitly excluded in case and controls). Finally we must remember that association is not causation, even when a dose–response relationship is observed, and that only randomized, controlled intervention studies can prove the causal link between coffee consumption and liver health.
62.3 COFFEE AND LIVER ENZYMES Coffee consumption is associated with decreased activities of γ-GT and aminotransferases. In Japan, in subjects with normal aminotransferases levels, γ-GT levels decrease with increased coffee consumption, especially when there is an associated consumption of alcohol and tobacco7 or of alcohol in obese persons.8 Mean absolute differences can reach about 30 units; similar results have been observed in Italy.1 In a transversal study carried out in a large North American population, the odds of being in the 5th upper percentile of aminotransferase (AST or ALT) levels decreased with increasing coffee consumption2; similar results were obtained in Japan. In the best study, carried out in persons from general population in the United States, with various risk factors for liver disease (such as alcohol consumption, serum viral markers, or iron overload), there was a dose–effect relationship between coffee and caffeine consumption and a decrease in ALT levels, reducing the prevalence of above-normal ALT value by 50% for two cups a day, and by 66% for three cups a day.9
The increase in serum aminotransferase, in the absence of hepatitis virus infection, increased transferrin saturation and daily alcohol consumption ≥10 g/d in women and 20 g/d in men has been used as a marker for nonalcoholic liver disease (NAFLD) in a representative sample of the US population10; the logistic regression analysis identified five independent factors predictive of NAFLD: Afro-American origin, male gender, obesity, water and caffeine intake, with a decrease in OR of 7% by coffee cup per day. Finally, in the only, to our knowledge, published interventional study, 53 healthy volunteers were randomized to receive either 0.9 l/d of cafetière or filtered coffee during 6 months11 ALT increased (but not in AST or GGT) in subjects who drank cafetière coffee but not in those who drank filtered coffee; there was also an increase in low density lipoprotein (LDL) cholesterol. The authors attributed these adverse effects to the cafestol and kahweol retained by the filter.11
62.4 COFFEE, CIRRHOSIS, AND LIVER FIBROSIS (TABLE 62.1) 62.4.1 Coffee Consumption and Risk of Cirrhosis Four cohorts and two case–control studies concerning cirrhosis risk are available. Klatsky et al. were the first to report the association between coffee consumption and a decrease in liver cirrhosis risk.2 In their cohort of more than 250,000 initially healthy persons, followed for a mean duration of 14 years, the cirrhosis relative risk (RR) (adjusted on gender, race, alcohol and tobacco consumption, BMI, and educational level) decreased progressively with coffee consumption; the analysis of the 330 patients with cirrhosis showed that the effect was only significant in patients with alcoholic cirrhosis.2 In a Norwegian cohort of more than 50,000 persons, followed for a mean duration of 17 years, there were 53 deaths with liver cirrhosis (liver disease being judged responsible for death in 33, alcoholic cirrhosis in 25). The RR of death with or by cirrhosis, adjusted on alcohol and tobacco consumption, blood cholesterol and triglycerides, and blood pressure, decreased to a value of 0.6 (95% confidence interval (CI): 0.5–0.8) per cup of coffee per day, whether cirrhosis was alcoholic or not.12 In the previously quoted US cohort9 of 9650 persons initially free of liver disease and followed for a mean duration of 19 years, 53 cases of cirrhosis were observed. Cirrhosis RR decreased with coffee consumption to 0.43 (95% CI: 0.24–0.78) for more than two cups per day. Subgroup analysis indicated that this decrease was significant only for the subjects initially at high risk for liver disease (consumption of more than 20 g of alcohol per day, transferrin saturation over 50%, diabetes, BMI > 30 kg/m2).
II. EFFECTS OF COFFEE CONSUMPTION
TABLE 62.1 Coffee and Liver Diseases, Liver Cancer Excepted. Epidemiological Studies Country
Year
Study Type
Endpoint
Patients
n
Cohort (n, Duration) or Controls
Association
Dose–Response
Lopez-Garcia
USA
2008
Cohort
Death by cirrhosis
Death by cirrhosis
135
127,950/18–24 years
Yes
Yes
Corrao
Italy
2001
Case–control
Decompensated cirrhosis
Decompensated cirrhosis
274
Matched/age, gender, residence
Yes
Yes
Gallus
Italy
2002
Case–control
Cirrhosis (biopsy)
Cirrhosis (biopsy)
101
1538 acute diseases not linked with coffee
Yes
Yes
Tverdal
Norway
2003
Cohort
Death by cirrhosis
Death by cirrhosis
53
51,306/17 years
Yes
Yes
Klatsky
USA
2006
Cohort
Cirrhosis
Cirrhosis
330
125,580/22 years
Yes
Yes
Freedman
USA
2009
Cohort
Fibrosis
Hepatitis C (biopsy)
766
766/3.8 years
Yes, threshold 3c/d
Yes
Modi
USA
2010
Transversal
Ishak fibrosis stage ≥3
Liver disease (biopsy)
177
Yes, threshold 2.5c/d
Yes
Ong
Hong Kong
2011
Transversal
Fibroscan F > 2
Hepatitis B
1045
No
Carrieri
France
2012
Transversal
Fibrose F > 2
Co-infection HIV–HCV (biopsy)
601
Yes, threshold 3c/d
Yes
Molloy
USA
2012
Case–control
Brunt nash fibrosis stage
NAFLD (biopsy)
180
Yes
No
Anty
France
2012
Transversal
Brunt nash fibrosis stage ≥2
Bariatric surgery
195
Yes
Yes
Bhamba
USA
2012
Transversal
Brunt nash fibrosis stage ≥2
NAFLD (biopsy)
782
Yes if HOMA-IR <4
No
Birerdinc
USA
2012
Case–control
Aminotransferases
Suspected NAFLD
1782
Yes
Yes
Costentin
France
2012
Transversal
METAVIR fibrosis ≥2
Hepatitis C (biopsy)
238
No
No
Catalano
Italy
2012
Transversal
Steatosis by ultrasound
Steatosis by ultrasound
245
Yes
No
126 with normal ultrasonography
16,768 with normal aminotransferases
137 with normal ultrasonography
62.4 Coffee, Cirrhosis, and Liver Fibrosis (Table 62.1)
II. EFFECTS OF COFFEE CONSUMPTION
First Author
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62. COFFEE AND THE LIVER
Finally, in an US cohort of almost 128,000 health professionals, the RR of death by liver disease significantly decreased with coffee consumption and a dose–effect relationship, adjusted RR being 0.35 for more than five cups a day. The first Italian case–control, hospital-based study included 274 patients with decompensated cirrhosis and 458 matched controls. ORs for cirrhosis adjusted on alcohol and tobacco consumption, viral markers, educational level, and nutritional intakes were significantly reduced, with a dose–response relationship; the OR was 0.16 (95% CI: 0.05–0.50) for three or more cups a day.13 Caffeine from other drinks was not associated with a reduced risk. The second case–control study, Italian too, hospitalbased, included 101 patients with biopsy-proven cirrhosis and 1538 controls.14 OR for cirrhosis, adjusted on gender, age, educational level, alcohol and tobacco consumptions, viral hepatitis, diabetes and BMI, decreased with filtered coffee consumption, reaching 0.3 (95% CI: 0.1–0.7) for three or more cups per day. There was a similar relationship with coffee consumption duration. There was no association with decaffeinated coffee or with other sources of caffeine.
62.4.2 Coffee Consumption and Liver Fibrosis Three transversal studies concerning NAFLD4,15,16 and four transversal studies on liver diseases of various causes (mainly hepatitis C),17 hepatitis C only,18,19 hepatitis B,20 co-infection HIV–HCV,21 are available. All but one (based on elastometry20) rely on liver biopsy, the threshold for significant fibrosis being Ishak 3 or METAVIR F2 stages. Except for the Chinese study of 1045 patients with chronic hepatitis B, where there was no relationship between coffee consumption and liver stiffness measured with Fibroscan®,20 all other studies have shown a reduction of the risk of significant fibrosis with coffee consumption,4,15–19,21 observed with total caffeine consumption and caffeine from coffee, but not with decaffeinated coffee. However, the dose–response relationship was not always linear, sometimes with a slight increase in risk for low consumption followed by a strong reduction for high consumption levels.15 Studies dealing with hepatitis C are the subject of another chapter of this book. In the study from the American network on nonalcoholic steatohepatitis (NASH), there was a significant interaction between coffee consumption and insulin resistance evaluated by the HOMA-IR index, the favorable effect of coffee drinking existing only in patients having an HOMA-IR index lower than the median value (4.3).16 In patients receiving bariatric surgery, there was a significant association between caffeine consumption from filtered but not espresso coffee and a decreased risk
of ≥F2 fibrosis stage, after adjustment on AST level, the presence of NASH, metabolic syndrome and HOMA-IR.4 The PNPLA3 genotype, which is associated with fibrosis stage and progression in various liver diseases, has not been determined in any of these studies.22
62.5 COFFEE, NAFLD, AND NASH Data on the association between coffee consumption NAFLD and NASH are not uniform. In the study carried out in general US population, coffee consumption decreased the risk of an elevated ALT level not due to alcohol, virus, or iron overload, a surrogate marker for NAFLD.10 In an Italian transversal study, coffee consumption was independently associated with a reduced risk of ultrasound-measured steatosis severity.23 In the transversal study of Molloy et al.15 there were significant differences in coffee consumption between four groups of patients: controls with normal ultrasonography, patients with pure steatosis, patients with grade 0–1 NASH, and patients with grade 2–4 NASH. However, patients with pure steatosis drank less coffee than controls and patients with low-grade NASH; in logistic regression analysis, only age, gender, and BMI, but not coffee consumption, were independent predictors of NASH.15 We have not found any association between caffeine or coffee consumption and the presence of NASH, or any correlation with NAS score.4 Finally, in a Californian study, coffee consumption was associated neither with the presence of NASH nor with the components of NAS histological score.16
62.6 COFFEE AND HEPATOCELLULAR CARCINOMA Since the first study carried out in Greece,3 the association between coffee consumption and hepatocellular carcinoma has been regularly observed in 15 cohort and 9 case–control studies, which has been subjected to two meta-analyses, with one actualization in 2009.24,25 All studies show reduced RR or OR with increasing coffee consumption, after adjustment for age, gender, viral markers, cirrhosis, and alcohol and tobacco consumption in various ways. The pooled RR of hepatocellular carcinoma, compared with coffee abstainers, was 0.57 (95% CI: 0.49–0.67) for all coffee drinkers, 0.69 (95% CI: 0.59–0.81) for low drinkers (less than one or three cups of coffee per day, depending on the studies), and 0.44 (95% CI: 0.38–0.50) for heavy coffee drinkers.25 This relationship was independent of the cause, alcoholic or viral, of liver cirrhosis. In the case–control studies, the reduction of OR was of similar magnitude, using as controls patients with or without liver disease.
II. EFFECTS OF COFFEE CONSUMPTION
References
62.7 PUTATIVE MECHANISMS OF ACTION OF COFFEE ON THE LIVER Numerous studies have tried to evaluate the effects of coffee, of decaffeinated coffee, and/or of its main constituents on different cell lines in vitro or in diverse murine models. Associations between coffee consumption and circulating concentrations of various hormones and cytokines have also been looked for. An increase in insulin sensitivity, an improvement of serum lipids profile, of inflammation and of endothelial function have been observed in murine models using polyphenols, caffeine, and coffee.26 Coffee consumption could stimulate glucuronidation, a cellular protective process. UDP glucuronyltransferases (UGT1A) are responsible for the formation of glucuronides from a large variety of cytotoxic and genotoxic compounds, including carcinogens and reactive oxygen species. The transcription of several genes of the UGT1A family increased with coffee exposure in hepatoma (HepG2) and colonic cancer (CaCO2) cell lines, and in a transgenic mouse model overexpressing UGT1A. This effect is mediated by two transcription factors, the nuclear erythroid-related factor S (Nrf2) and the aryl hydrocarbon receptor (AhR).27 Caffeine has antifibrogenic effects.28 Caffeine could participate in reducing production of the connective tissue growth factor, implicated in the proliferation of liver stellate cells and fibroblasts, via an alteration of the TGF-β signaling pathway. Chlorogenic acid, coffee, and decaffeinated coffee also exert antifibrogenetic effects in murine models.29 Alternatively, coffee consumption could be only an indirect marker of genetic polymorphisms governing numerous molecules metabolism (the faster the metabolism of coffee components, the more coffee is needed to reinforce/maintain its effect). A recent meta-analysis of four large pangenomic studies carried out in populations of European ancestry showed that two variants, rs2472297-T located between CYP1A1 et CYP1A2 (15q24) et rs6968865-T near AhR (7p21) genes, were associated with coffee consumption.30 These cytochromes metabolize numerous compounds, including polycyclic aromatic hydrocarbons.
62.8 CONCLUSIONS Coffee consumption, but usually not caffeine from other beverages, is associated, often with a dose– response relationship (excepting perhaps the low consumption rates), with a decrease in serum, γ-GT, and aminotransferases, a reduction of cirrhosis risk and of death by cirrhosis, at least for alcoholic cirrhosis, a less severe fibrosis in alcoholic liver disease, in chronic hepatitis C, and probably in NAFLD, and finally with
557
a reduction of hepatocellular carcinoma risk, whatever the cause of underlying liver disease. The magnitude of these risks reduction is important, around 40% for the “heavy” consumption (around three cups a day). New prospective epidemiological studies are needed, including large numbers of persons/patients, a detailed study of coffee and caffeine consumption, simultaneous chemical analysis of the content of the different types of coffee used in the study location, and the determination of genetic markers (especially governing coffee metabolism, and liver disease progression such as PNPLA3) and could turn translational research toward mechanisms and components potentially responsible for the beneficial effects of coffee drinking on the liver. Interventional studies with robust endpoints are now clearly needed. From a clinician’s point of view, the consumption of coffee (at least of usual filtered coffee) has to be respected in patients with liver disease, provided that it is not associated with alcohol or tobacco consumption!
Acknowledgment We acknowledge Christel Baigts, who kindly reviewed this text.
References 1. Casiglia E, Spolaore P, Ginocchio G, et al. Unexpected effects of coffee consumption on liver enzymes. Eur J Epidemiol 1993;9:293–7. 2. Klatsky AL, Morton C, Udaltsova N, et al. Coffee, cirrhosis, and transaminase enzymes. Arch Intern Med 2006;166:1190–5. 3. Kuper H, Tzonou A, Kaklamani E, et al. Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma. Int J Cancer 2000;85:498–502. 4. 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;57:1090–6. 5. Lopez-Garcia E, van Dam RM, Ty Li, et al. The relationship of coffee consumption with mortality. Ann Intern Med 2008;148:904–14. 6. Breitling LP, Arndt V, Drath C, et al. Liver enzymes: interaction analysis of smoking with alcohol consumption or BMI, comparing AST and ALT to gamma-GT. PLoS One 2011;6:e27951. 7. Tanaka K, Hara M, Sakamoto T, 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. 8. Honjo S, Kono S, Coleman MP, et al. Coffee drinking and serum gamma-glutamyltransferase: an extended study of self-defense officials of Japan. Ann Epidemiol 1999;9:325–31. 9. 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. 10. Birerdinc A, Stepanova M, Pawloski L, et al. Caffeine is protective in patients with nonalcoholic fatty liver disease. Aliment Pharmacol Ther 2012;35:76–82. 11. 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 randomised controlled trial. BMJ 1996;313:1362–6. 12. Tverdal A, Skurtveit S. Coffee intake and mortality from liver cirrhosis. Ann Epidemiol 2003;13:419–23.
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62. COFFEE AND THE LIVER
13. Corrao G, Zambon A, Bagnardi V, et al. Coffee, caffeine, and the risk of liver cirrhosis. Ann Epidemiol 2001;11:458–65. 14. Gallus S, Tavani A, Negri E, et al. Does coffee protect against liver cirrhosis? Ann Epidemiol 2002;12:202–5. 15. 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 2011;10: 247–31. 16. Bambha K, Wilson L, Unalp A, et al. Coffee consumption in NAFLD patients with lower insulin resistance is associated with mower risk of severe fibrosis. Hepatology 2012;56:242A. 17. Modi AA, Feld JJ, Park Y, et al. Increased caffeine consumption is associated with reduced hepatic fibrosis. Hepatology 2010;51:201–9. 18. 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;50:1360–9. 19. 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. 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: 1047–53. 21. Carrieri MP, Sogni P, Cohen J, et al. Elevated coffee consumption and reduced risk of insulin resistance in HIV–HCV coinfected patients (HEPAVIH ANRS CO-13). Hepatology 2010;2012:56.
22. Trépo E, Pradat P, Potthoff A, et al. Impact of patatin-like phospholipase-3 (rs738409 C > G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C. Hepatology 2011;54:60–9. 23. Catalano D, Martines GF, Tonzuso A, et al. Protective role of coffee in non-alcoholic fatty liver disease (NAFLD). Dig Dis Sci 2010;55:3200–6. 24. Bravi F, Bosetti C, Tavani A, et al. Coffee drinking and hepatocellular carcinoma risk: a meta-analysis. Hepatology 2007;46:430–5. 25. Bravi F, Bosetti C, Tavani A, et al. Coffee drinking and hepatocellular carcinoma: an update. Hepatology 2009;50:1317–8. 26. Murase T, Misawa K, Minegishi Y, et al. Coffee polyphenols suppress diet-induced body fat accumulation by downregulating SREBP-1c and related molecules in C57BL/6J mice. Am J Physiol Endocrinol Metab 2011;300:E122–33. 27. 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. 28. Gressner OA, Lahme B, Rehbein K, et al. Pharmacological application of caffeine inhibits TGF-beta-stimulated connective tissue growth factor expression in hepatocytes via PPARgamma and SMAD2/3-dependent pathways. J Hepatol 2008;49:758–67. 29. Muriel P, Arauz J. Coffee and liver diseases. Fitoterapia 2010;81: 297–305. 30. Sulem P, Gudbjartsson DF, Geller F, et al. Sequence variants at CYP1A1-CYP1A2 and AHR associate with coffee consumption. Hum Mol Genet 2011;20:2071–7.
II. EFFECTS OF COFFEE CONSUMPTION
62
Coffee and the Liver: An Overview of Epidemiologic Studies Rodolphe Anty1, 2, 3, Alexandre Pariente4 1Institut
National de la Santé et de la Recherche Médicale (INSERM), Nice, France; 2Centre Hospitalier Universitaire of Nice, Digestive Center, Nice, France; 3Faculty of Medecine, University of Nice-Sophia-Antipolis, Nice, France; 4Centre Hospitalier of Pau, Hepatogastroenterology Unit, Pau, France
List of Abbreviations
observed, in an Italian study on cardiovascular risk in the elderly, that the serum activity of liver enzymes and bilirubin were lower in coffee drinkers.1 A few years later, Klatsky et al.2 reported in the United States that coffee drinkers had a reduced risk of cirrhosis, particularly of alcoholic cirrhosis. Finally Kuper et al. were the first, in Greece, to report a negative association between coffee consumption and hepatocellular carcinoma.3 In this chapter, we will review the main epidemiological data linking coffee and liver diseases.
CI Confidence interval NAFLD Nonalcoholic liver disease NASH Nonalcoholic steatohepatitis OR Odds ratio RR Relative risk
62.1 SUMMARY POINTS Coffee consumption is associated with
• • • •
ecrease in serum liver enzymes, d decreased risk of cirrhosis and death from cirrhosis, decreased fibrosis stage in various liver diseases, decrease rate of progression of liver disease in chronic, fibrous, hepatitis C unresponsive to antiviral treatment, • decreased risk of hepatocellular carcinoma.
There is usually a dose–effect relationship between the coffee ingested and the risks reduction. The order of magnitude of these reductions of risk is around 40% for drinkers of three cups or more by day compared with nondrinkers. Numerous coffee components are candidates for these beneficial effects. Coffee consumption could alternatively be an indirect marker of genetic polymorphisms having favorable effects on liver disease progression. Coffee consumption should not be reduced in patients with liver disease but without severe liver failure. That coffee could favorably influence liver function was first reported by Casiglia et al. in 1993, who
Coffee in Health and Disease Prevention http://dx.doi.org/10.1016/B978-0-12-409517-5.00062-0
62.2 THE LIMITS OF EPIDEMIOLOGICAL STUDIES Available epidemiological studies are based on transversal, case–control, and, more rarely, cohort studies, which all have intrinsic bias. Interventional studies are exceptional and have limited fields. The measurement of coffee consumption has been sometimes simply obtained from an self-administered simple questionnaires, or by more complex questionnaires, which must be previously validated, ideally administered by adequately trained investigators, allowing evaluation of the consumption of various types of coffee (regular, espresso, decaffeinated, etc.) and of other caffeine-containing drinks (tea, sodas, etc.)4; coffee consumption is, however, the better reported item in food-frequency questionnaires.5 Tables permit calculating total caffeine consumption (from coffee and other beverages), which can be treated as a continuous variable, or as a categorical variable, classes being defined a priori, or, at best, as quantiles in the studied population. There are, however, large variations
553
© 2015 Elsevier Inc. All rights reserved.
554
62. COFFEE AND THE LIVER
in the composition of coffee according to its origin, the methods of torrefaction, and particularly the technique of preparation used. So, an ideal questionnaire should at least include questions about the type of coffee and the coffee-making process type. There is a theoretical risk of reduction of coffee consumption when a severe disease is present, because of the decrease in caffeine clearance by the liver, but this observation is of importance only in patients with cirrhosis and moderate-to-severe hepatocellular failure. Coffee consumption seems to be stable all life long, even if it decreases slightly with advanced age. Above all there are interaction and confusion factors, linked to coffee consumption. There is a strong correlation between coffee and tobacco consumption, which can modify the liver enzyme activities,6 hepatic fibrosis, and hepatocellular carcinoma risks. Alcohol and coffee consumptions are more weakly linked, except for the higher levels of coffee consumption.5 Other known risk factors for liver disease should be considered. Confusion factors have to be taken into account by appropriate statistical methods; odds ratios (ORs) and risk ratios must be adjusted (in the absence of interaction) at least on age, sex, alcohol and tobacco consumption, body mass index (BMI; or other markers linked with obesity or insulin resistance), and the other causes of liver disease (if they have not been explicitly excluded in case and controls). Finally we must remember that association is not causation, even when a dose–response relationship is observed, and that only randomized, controlled intervention studies can prove the causal link between coffee consumption and liver health.
62.3 COFFEE AND LIVER ENZYMES Coffee consumption is associated with decreased activities of γ-GT and aminotransferases. In Japan, in subjects with normal aminotransferases levels, γ-GT levels decrease with increased coffee consumption, especially when there is an associated consumption of alcohol and tobacco7 or of alcohol in obese persons.8 Mean absolute differences can reach about 30 units; similar results have been observed in Italy.1 In a transversal study carried out in a large North American population, the odds of being in the 5th upper percentile of aminotransferase (AST or ALT) levels decreased with increasing coffee consumption2; similar results were obtained in Japan. In the best study, carried out in persons from general population in the United States, with various risk factors for liver disease (such as alcohol consumption, serum viral markers, or iron overload), there was a dose–effect relationship between coffee and caffeine consumption and a decrease in ALT levels, reducing the prevalence of above-normal ALT value by 50% for two cups a day, and by 66% for three cups a day.9
The increase in serum aminotransferase, in the absence of hepatitis virus infection, increased transferrin saturation and daily alcohol consumption ≥10 g/d in women and 20 g/d in men has been used as a marker for nonalcoholic liver disease (NAFLD) in a representative sample of the US population10; the logistic regression analysis identified five independent factors predictive of NAFLD: Afro-American origin, male gender, obesity, water and caffeine intake, with a decrease in OR of 7% by coffee cup per day. Finally, in the only, to our knowledge, published interventional study, 53 healthy volunteers were randomized to receive either 0.9 l/d of cafetière or filtered coffee during 6 months11 ALT increased (but not in AST or GGT) in subjects who drank cafetière coffee but not in those who drank filtered coffee; there was also an increase in low density lipoprotein (LDL) cholesterol. The authors attributed these adverse effects to the cafestol and kahweol retained by the filter.11
62.4 COFFEE, CIRRHOSIS, AND LIVER FIBROSIS (TABLE 62.1) 62.4.1 Coffee Consumption and Risk of Cirrhosis Four cohorts and two case–control studies concerning cirrhosis risk are available. Klatsky et al. were the first to report the association between coffee consumption and a decrease in liver cirrhosis risk.2 In their cohort of more than 250,000 initially healthy persons, followed for a mean duration of 14 years, the cirrhosis relative risk (RR) (adjusted on gender, race, alcohol and tobacco consumption, BMI, and educational level) decreased progressively with coffee consumption; the analysis of the 330 patients with cirrhosis showed that the effect was only significant in patients with alcoholic cirrhosis.2 In a Norwegian cohort of more than 50,000 persons, followed for a mean duration of 17 years, there were 53 deaths with liver cirrhosis (liver disease being judged responsible for death in 33, alcoholic cirrhosis in 25). The RR of death with or by cirrhosis, adjusted on alcohol and tobacco consumption, blood cholesterol and triglycerides, and blood pressure, decreased to a value of 0.6 (95% confidence interval (CI): 0.5–0.8) per cup of coffee per day, whether cirrhosis was alcoholic or not.12 In the previously quoted US cohort9 of 9650 persons initially free of liver disease and followed for a mean duration of 19 years, 53 cases of cirrhosis were observed. Cirrhosis RR decreased with coffee consumption to 0.43 (95% CI: 0.24–0.78) for more than two cups per day. Subgroup analysis indicated that this decrease was significant only for the subjects initially at high risk for liver disease (consumption of more than 20 g of alcohol per day, transferrin saturation over 50%, diabetes, BMI > 30 kg/m2).
II. EFFECTS OF COFFEE CONSUMPTION
TABLE 62.1 Coffee and Liver Diseases, Liver Cancer Excepted. Epidemiological Studies Country
Year
Study Type
Endpoint
Patients
n
Cohort (n, Duration) or Controls
Association
Dose–Response
Lopez-Garcia
USA
2008
Cohort
Death by cirrhosis
Death by cirrhosis
135
127,950/18–24 years
Yes
Yes
Corrao
Italy
2001
Case–control
Decompensated cirrhosis
Decompensated cirrhosis
274
Matched/age, gender, residence
Yes
Yes
Gallus
Italy
2002
Case–control
Cirrhosis (biopsy)
Cirrhosis (biopsy)
101
1538 acute diseases not linked with coffee
Yes
Yes
Tverdal
Norway
2003
Cohort
Death by cirrhosis
Death by cirrhosis
53
51,306/17 years
Yes
Yes
Klatsky
USA
2006
Cohort
Cirrhosis
Cirrhosis
330
125,580/22 years
Yes
Yes
Freedman
USA
2009
Cohort
Fibrosis
Hepatitis C (biopsy)
766
766/3.8 years
Yes, threshold 3c/d
Yes
Modi
USA
2010
Transversal
Ishak fibrosis stage ≥3
Liver disease (biopsy)
177
Yes, threshold 2.5c/d
Yes
Ong
Hong Kong
2011
Transversal
Fibroscan F > 2
Hepatitis B
1045
No
Carrieri
France
2012
Transversal
Fibrose F > 2
Co-infection HIV–HCV (biopsy)
601
Yes, threshold 3c/d
Yes
Molloy
USA
2012
Case–control
Brunt nash fibrosis stage
NAFLD (biopsy)
180
Yes
No
Anty
France
2012
Transversal
Brunt nash fibrosis stage ≥2
Bariatric surgery
195
Yes
Yes
Bhamba
USA
2012
Transversal
Brunt nash fibrosis stage ≥2
NAFLD (biopsy)
782
Yes if HOMA-IR <4
No
Birerdinc
USA
2012
Case–control
Aminotransferases
Suspected NAFLD
1782
Yes
Yes
Costentin
France
2012
Transversal
METAVIR fibrosis ≥2
Hepatitis C (biopsy)
238
No
No
Catalano
Italy
2012
Transversal
Steatosis by ultrasound
Steatosis by ultrasound
245
Yes
No
126 with normal ultrasonography
16,768 with normal aminotransferases
137 with normal ultrasonography
62.4 Coffee, Cirrhosis, and Liver Fibrosis (Table 62.1)
II. EFFECTS OF COFFEE CONSUMPTION
First Author
555
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62. COFFEE AND THE LIVER
Finally, in an US cohort of almost 128,000 health professionals, the RR of death by liver disease significantly decreased with coffee consumption and a dose–effect relationship, adjusted RR being 0.35 for more than five cups a day. The first Italian case–control, hospital-based study included 274 patients with decompensated cirrhosis and 458 matched controls. ORs for cirrhosis adjusted on alcohol and tobacco consumption, viral markers, educational level, and nutritional intakes were significantly reduced, with a dose–response relationship; the OR was 0.16 (95% CI: 0.05–0.50) for three or more cups a day.13 Caffeine from other drinks was not associated with a reduced risk. The second case–control study, Italian too, hospitalbased, included 101 patients with biopsy-proven cirrhosis and 1538 controls.14 OR for cirrhosis, adjusted on gender, age, educational level, alcohol and tobacco consumptions, viral hepatitis, diabetes and BMI, decreased with filtered coffee consumption, reaching 0.3 (95% CI: 0.1–0.7) for three or more cups per day. There was a similar relationship with coffee consumption duration. There was no association with decaffeinated coffee or with other sources of caffeine.
62.4.2 Coffee Consumption and Liver Fibrosis Three transversal studies concerning NAFLD4,15,16 and four transversal studies on liver diseases of various causes (mainly hepatitis C),17 hepatitis C only,18,19 hepatitis B,20 co-infection HIV–HCV,21 are available. All but one (based on elastometry20) rely on liver biopsy, the threshold for significant fibrosis being Ishak 3 or METAVIR F2 stages. Except for the Chinese study of 1045 patients with chronic hepatitis B, where there was no relationship between coffee consumption and liver stiffness measured with Fibroscan®,20 all other studies have shown a reduction of the risk of significant fibrosis with coffee consumption,4,15–19,21 observed with total caffeine consumption and caffeine from coffee, but not with decaffeinated coffee. However, the dose–response relationship was not always linear, sometimes with a slight increase in risk for low consumption followed by a strong reduction for high consumption levels.15 Studies dealing with hepatitis C are the subject of another chapter of this book. In the study from the American network on nonalcoholic steatohepatitis (NASH), there was a significant interaction between coffee consumption and insulin resistance evaluated by the HOMA-IR index, the favorable effect of coffee drinking existing only in patients having an HOMA-IR index lower than the median value (4.3).16 In patients receiving bariatric surgery, there was a significant association between caffeine consumption from filtered but not espresso coffee and a decreased risk
of ≥F2 fibrosis stage, after adjustment on AST level, the presence of NASH, metabolic syndrome and HOMA-IR.4 The PNPLA3 genotype, which is associated with fibrosis stage and progression in various liver diseases, has not been determined in any of these studies.22
62.5 COFFEE, NAFLD, AND NASH Data on the association between coffee consumption NAFLD and NASH are not uniform. In the study carried out in general US population, coffee consumption decreased the risk of an elevated ALT level not due to alcohol, virus, or iron overload, a surrogate marker for NAFLD.10 In an Italian transversal study, coffee consumption was independently associated with a reduced risk of ultrasound-measured steatosis severity.23 In the transversal study of Molloy et al.15 there were significant differences in coffee consumption between four groups of patients: controls with normal ultrasonography, patients with pure steatosis, patients with grade 0–1 NASH, and patients with grade 2–4 NASH. However, patients with pure steatosis drank less coffee than controls and patients with low-grade NASH; in logistic regression analysis, only age, gender, and BMI, but not coffee consumption, were independent predictors of NASH.15 We have not found any association between caffeine or coffee consumption and the presence of NASH, or any correlation with NAS score.4 Finally, in a Californian study, coffee consumption was associated neither with the presence of NASH nor with the components of NAS histological score.16
62.6 COFFEE AND HEPATOCELLULAR CARCINOMA Since the first study carried out in Greece,3 the association between coffee consumption and hepatocellular carcinoma has been regularly observed in 15 cohort and 9 case–control studies, which has been subjected to two meta-analyses, with one actualization in 2009.24,25 All studies show reduced RR or OR with increasing coffee consumption, after adjustment for age, gender, viral markers, cirrhosis, and alcohol and tobacco consumption in various ways. The pooled RR of hepatocellular carcinoma, compared with coffee abstainers, was 0.57 (95% CI: 0.49–0.67) for all coffee drinkers, 0.69 (95% CI: 0.59–0.81) for low drinkers (less than one or three cups of coffee per day, depending on the studies), and 0.44 (95% CI: 0.38–0.50) for heavy coffee drinkers.25 This relationship was independent of the cause, alcoholic or viral, of liver cirrhosis. In the case–control studies, the reduction of OR was of similar magnitude, using as controls patients with or without liver disease.
II. EFFECTS OF COFFEE CONSUMPTION
References
62.7 PUTATIVE MECHANISMS OF ACTION OF COFFEE ON THE LIVER Numerous studies have tried to evaluate the effects of coffee, of decaffeinated coffee, and/or of its main constituents on different cell lines in vitro or in diverse murine models. Associations between coffee consumption and circulating concentrations of various hormones and cytokines have also been looked for. An increase in insulin sensitivity, an improvement of serum lipids profile, of inflammation and of endothelial function have been observed in murine models using polyphenols, caffeine, and coffee.26 Coffee consumption could stimulate glucuronidation, a cellular protective process. UDP glucuronyltransferases (UGT1A) are responsible for the formation of glucuronides from a large variety of cytotoxic and genotoxic compounds, including carcinogens and reactive oxygen species. The transcription of several genes of the UGT1A family increased with coffee exposure in hepatoma (HepG2) and colonic cancer (CaCO2) cell lines, and in a transgenic mouse model overexpressing UGT1A. This effect is mediated by two transcription factors, the nuclear erythroid-related factor S (Nrf2) and the aryl hydrocarbon receptor (AhR).27 Caffeine has antifibrogenic effects.28 Caffeine could participate in reducing production of the connective tissue growth factor, implicated in the proliferation of liver stellate cells and fibroblasts, via an alteration of the TGF-β signaling pathway. Chlorogenic acid, coffee, and decaffeinated coffee also exert antifibrogenetic effects in murine models.29 Alternatively, coffee consumption could be only an indirect marker of genetic polymorphisms governing numerous molecules metabolism (the faster the metabolism of coffee components, the more coffee is needed to reinforce/maintain its effect). A recent meta-analysis of four large pangenomic studies carried out in populations of European ancestry showed that two variants, rs2472297-T located between CYP1A1 et CYP1A2 (15q24) et rs6968865-T near AhR (7p21) genes, were associated with coffee consumption.30 These cytochromes metabolize numerous compounds, including polycyclic aromatic hydrocarbons.
62.8 CONCLUSIONS Coffee consumption, but usually not caffeine from other beverages, is associated, often with a dose– response relationship (excepting perhaps the low consumption rates), with a decrease in serum, γ-GT, and aminotransferases, a reduction of cirrhosis risk and of death by cirrhosis, at least for alcoholic cirrhosis, a less severe fibrosis in alcoholic liver disease, in chronic hepatitis C, and probably in NAFLD, and finally with
557
a reduction of hepatocellular carcinoma risk, whatever the cause of underlying liver disease. The magnitude of these risks reduction is important, around 40% for the “heavy” consumption (around three cups a day). New prospective epidemiological studies are needed, including large numbers of persons/patients, a detailed study of coffee and caffeine consumption, simultaneous chemical analysis of the content of the different types of coffee used in the study location, and the determination of genetic markers (especially governing coffee metabolism, and liver disease progression such as PNPLA3) and could turn translational research toward mechanisms and components potentially responsible for the beneficial effects of coffee drinking on the liver. Interventional studies with robust endpoints are now clearly needed. From a clinician’s point of view, the consumption of coffee (at least of usual filtered coffee) has to be respected in patients with liver disease, provided that it is not associated with alcohol or tobacco consumption!
Acknowledgment We acknowledge Christel Baigts, who kindly reviewed this text.
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22. Trépo E, Pradat P, Potthoff A, et al. Impact of patatin-like phospholipase-3 (rs738409 C > G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C. Hepatology 2011;54:60–9. 23. Catalano D, Martines GF, Tonzuso A, et al. Protective role of coffee in non-alcoholic fatty liver disease (NAFLD). Dig Dis Sci 2010;55:3200–6. 24. Bravi F, Bosetti C, Tavani A, et al. Coffee drinking and hepatocellular carcinoma risk: a meta-analysis. Hepatology 2007;46:430–5. 25. Bravi F, Bosetti C, Tavani A, et al. Coffee drinking and hepatocellular carcinoma: an update. Hepatology 2009;50:1317–8. 26. Murase T, Misawa K, Minegishi Y, et al. Coffee polyphenols suppress diet-induced body fat accumulation by downregulating SREBP-1c and related molecules in C57BL/6J mice. Am J Physiol Endocrinol Metab 2011;300:E122–33. 27. 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. 28. Gressner OA, Lahme B, Rehbein K, et al. Pharmacological application of caffeine inhibits TGF-beta-stimulated connective tissue growth factor expression in hepatocytes via PPARgamma and SMAD2/3-dependent pathways. J Hepatol 2008;49:758–67. 29. Muriel P, Arauz J. Coffee and liver diseases. Fitoterapia 2010;81: 297–305. 30. Sulem P, Gudbjartsson DF, Geller F, et al. Sequence variants at CYP1A1-CYP1A2 and AHR associate with coffee consumption. Hum Mol Genet 2011;20:2071–7.
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