Clinical Gastroenterology & Hepatology
August 2015 Volume 13, Issue 8, Pages 1521–1531.e3
2015 Aug;13(8):1521-1531.e3. doi: 10.1016/j.cgh.2015.01.030
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Coffee reduces the risk of hepatic fibrosis in Hep C
Coffee and caffeine are associated with decreased risk of advanced hepatic fibrosis among patients with Hepatitis C, reports the latest issue of the Clinical Gastroenterology & Hepatology.
Dr Hashem El-Serag and colleagues from Texas, USA conducted a cross-sectional study of veterans with chronic HCV infection to evaluate the association between daily intake of caffeinated and decaffeinated coffee, tea, and soda, and level of hepatic fibrosis, based on the FibroSURE test.
Models were adjusted for multiple potential confounders including age, alcohol abuse, and obesity.
The hepatoprotective effects were with an average daily intake of 100 mg or more of caffeine
Clinical Gastroenterology & Hepatology
Among 910 patients with chronic HCV infection, 98% were male and 38% had advanced hepatic fibrosis.
The research team found that daily intake of caffeinated coffee was higher among controls than patients with advanced fibrosis.
In contrast, the team noted that daily intake of caffeinated tea or soda did not differ between the groups.
The researchers found that a higher percentage of controls than patients with advanced fibrosis consumed 100 mg or more of caffeine daily from all sources.
Controls also received a larger proportion of their caffeine from coffee.
The team observed that the hepatoprotective effects of an average daily intake of 100 mg or more of caffeine, and 1 cup or more of caffeinated tea by non–coffee drinkers persisted after adjustment for confounders, including insulin resistance.
Dr El-Serag's team concludes, "A modest daily caffeine intake may protect against advanced hepatic fibrosis in men with chronic HCV infection."
"Additional research is needed to confirm these findings in women and in people with other chronic liver diseases."
Coffee and Caffeine Are Associated With Decreased Risk of Advanced Hepatic Fibrosis Among Patients With Hepatitis C
Published Online: March 14, 2015
Discussion Only
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We found that self-reported coffee drinking and caffeine consumption from beverages were associated with a lower risk of advanced hepatic fibrosis in patients with chronic HCV but had no association with degree of hepatic inflammation. An average daily intake of an estimated 100 mg of caffeine from coffee, tea, or soda was associated with an approximately one-third reduction in odds of advanced fibrosis, although higher intake did not seem to confer any additional benefit. Interestingly, tea intake in those who did not consume coffee also was found to be associated with a decreased risk of advanced fibrosis. The inverse association between 100 mg or more of caffeine intake daily and advanced hepatic fibrosis remained significant after adjustment for potential confounders (eg, age, alcohol use, BMI, MELD score, and metabolic syndrome), and was attenuated when adjusted for HOMA-IR status. The inverse association between caffeine consumption and degree of fibrosis was found using caffeine intake data from the year preceding study recruitment, however, lifetime caffeine intake did not seem to influence this relationship.
Our finding that caffeine intake is associated with a decreased risk of advanced HCV-related fibrosis is in line with several other studies that have suggested a beneficial effect of caffeine on hepatic function in various liver diseases, including nonalcoholic steatohepatitis, alcoholic liver disease, and primary sclerosing cholangitis.4, 6, 10, 33, 34, 35, 36, 37, 38 It also is consistent with an analysis of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial, which found that daily coffee consumption was associated with slower disease progression in patients with chronic HCV-related bridging fibrosis and cirrhosis who had failed to respond to treatment with pegylated interferon and ribavirin. However, in contrast to our findings, which suggest no substantial additional benefit of caffeine intake of 100 mg/day or more, they found a dose-dependent response with coffee drinkers who reported 3 or more cups daily experiencing the greatest (∼53%) reduced risk of disease progression (ie, to decompensation or HCC) compared with non–coffee drinkers.1616 We hypothesize that the primary explanation for this discrepancy is the difference in the spectrum of HCV-related liver disease among studies because the HALT-C trial was restricted to cirrhotic patients, whereas our study population included the full spectrum of HCV-related liver disease. However, other differences in study design and among populations also may have contributed to this discrepancy. Our results suggesting that a modest dose of caffeine intake (∼100 mg/d) was associated with a significantly reduced risk of advanced fibrosis in veterans with chronic HCV are similar to an earlier comparable pilot study in 91 HCV-positive veterans.3939 The consistency in these results over time further supports the internal validity of our findings.
In contrast to our results, Costentin et al1717 found no significant protective association in their study of 238 French patients with treatment-naive chronic HCV. However, they did find that daily caffeine consumption of more than 408 mg (equivalent to ≥3 cups of coffee) was an independent predictor of lower histologic activity grade of hepatitis. Several factors may explain this discrepancy, including differences in populations such as higher average caffeine intake but lower rates of obesity and alcohol abuse overall in the French study population, differences in methods of estimating caffeine intake, and known substantial variability in caffeine found in coffee and tea based on methods of production and preparation.
Our findings suggest that a total combined caffeine intake or dose of 100 mg or more daily is associated with a significant decrease in risk of hepatic fibrosis, but without further risk reduction with higher coffee or caffeine doses. However, the optimal hepatoprotective dose of caffeine in HCV-infected patients overall is unclear. Although some studies suggested the strongest benefit from coffee consumption was at 3 or more cups daily, or approximately 400 mg of caffeine,16, 17 other studies reported a significant reduction in the risk in HCV-related hepatic fibrosis associated with an intake of 1 or 2 cups of cups of coffee daily.11, 40 Our results suggest that as little as 100 mg or more of caffeine daily may be beneficial in a general HCV-infected population with a high prevalence of other risk factors for advanced liver disease. However, our power to evaluate the benefit of higher intake likely was limited by the small number of our study participants who reported drinking higher quantities of caffeinated beverages. Nonetheless, if validated in other HCV-infected populations in the United States, our results suggest that a relatively low (and therefore potentially more tolerable dose) of caffeine, particularly from caffeinated coffee and possibly from tea, may convey a substantial reduction in fibrosis progression.
Several mechanisms have been suggested by which caffeine may act to reduce the risk of advanced fibrosis.4141 Caffeine functions as a nonselective adenosine-receptor antagonist and a phosphodiesterase inhibitor with a broad range of attendant effects including inhibition of growth factors that contribute to hepatic fibrosis.42, 43, 44 Caffeine is metabolized in the liver primarily by CYP1A2, with reduced expression of CYP1A2 correlated with fibrosis progression in a study of HCV patients.4545 Caffeine also has been shown in animal and in vitro studies to act as an antioxidant.4646 Other studies have suggested that the primary hepatoprotective benefit of caffeine is associated with caffeinated coffee intake.4, 6, 11, 16, 47 However, this could be the effect of generally higher daily cumulative caffeine intake in coffee drinkers compared with consumers of other caffeinated beverages overall, or with pharmacodynamic differences in effects given the substantial differences in caffeine per unit intake of caffeinated coffee in comparison with tea or soda. Finally, it also has been postulated that other constituents of coffee, such as diterpenes, polyphenols, kahweol, and cafestrerol, which have anti-oxidant activity, also may be responsible for the particular hepatoprotective effect of coffee.48, 49, 50, 51 However, studies, including ours, have not shown that decaffeinated coffee exerts the same effect on liver disease as caffeinated coffee.11, 47
Inflammation is another known risk factor for progression to fibrosis in chronic HCV,5252 and the role of coffee as an anti-inflammatory agent in nonliver diseases has been suggested.22 In our study, we found no significant association between caffeine intake and the severity of hepatic inflammation, in line with findings by Freedman et al1616 that coffee intake was not associated with lower baseline hepatic inflammation. Prior work has shown that insulin resistance worsens hepatic inflammation in HCV patients,1818 and a meta-analysis suggested that part of the hepatoprotective effect of coffee in part may be related to an associated reduction in insulin resistance and type 2 diabetes mellitus.1919 In our study, caffeine intake was associated inversely with insulin resistance via the surrogate marker of the HOMA-IR score in nondiabetic participants.
Therefore, one potential mechanism linking caffeine intake or the associated lifestyle with decreased risk of advanced fibrosis is the amelioration of insulin resistance. Further studies are needed to better elucidate the underlying pathophysiological mechanisms by which caffeine or its metabolites and other constituents of coffee account for the positive health benefits seen particularly with caffeinated coffee consumption in liver disease patients.
We found that an average of 100 mg or more of caffeine daily from sodas and teas does not have the same protective effect as 100 mg or more of caffeine daily from combined sources (coffee, tea, soda) or from coffee alone, suggesting that caffeine alone may not entirely explain the effect of coffee on liver disease. Although several prior studies have not shown a lower risk of liver disease progression in those who consume caffeine from noncoffee sources such as tea4, 11, 16, 47 or soda,4747 this could be related to differing caffeine content, other ingredients in addition to caffeine that may be partly responsible for the proposed hepatoprotective effects of coffee, or to substantial differences in study design or populations. Among the 413 noncoffee drinkers in our current study, intake of at least 1 cup of caffeinated tea daily was more common in the mild fibrosis control group, and after controlling for potential confounders, this significance was even more pronounced. This finding provides further evidence for the protective role of caffeine from any source against the progression of liver disease.
In regards to soda, an understudied source of caffeine, we found consumption of more than 1 can of caffeinated soda daily to be associated with a decreased risk of hepatic fibrosis, supporting that caffeine likely plays a major role in coffee’s hepatoprotective effects. On multivariate nonstratified analysis, more than 1 can of caffeinated soda daily remained significantly associated with a decreased risk of hepatic fibrosis, with some attenuation after controlling for possible confounders (age, alcohol, BMI, MELD score, and the presence of the metabolic syndrome). When adjusted for self-reported diabetes and HOMA-IR scores, there was a nonsignificant trend toward a decreased risk of fibrosis (adjusted OR, 0.75; 95% CI, 0.55–1.02; P = .063). However, in analyzing soda intake in the subgroup of non–coffee drinkers (n = 413), there was no notable difference in the risk of hepatic fibrosis (P = .41). The findings may indicate that caffeine from soda has hepatoprotective effects, but we cannot exclude the possibility that increased soda consumption reflects an increased intake of caffeinated beverages overall, including coffee. As with coffee, decaffeinated tea and soda were not found to be associated with a decreased risk of liver disease.
Our study had several strengths, including being a large study that examined the association between caffeinated coffee intake and HCV-related liver disease, and adds to the limited research in US populations. It also adds to the sparse literature on the effects of caffeinated tea and soda intake. In addition, we obtained and analyzed information on the consumption of decaffeinated coffee, tea, and soda to better elucidate the mechanisms underlying the potential hepatoprotective effects of caffeine and coffee on liver disease. Finally, our novel use of a validated noninvasive marker for liver fibrosis, the validated FibroSURE test,26, 27, 28, 29, 30, 31, 32 allowed evaluation of a large and diverse HCV patient group, many of whom would have been precluded from biopsy based on highly prevalent comorbid conditions in this population.
Our study also had some limitations. Given the observational retrospective nature of the study, a causal association cannot be made. We studied a select patient population of HCV-monoinfected, largely male veterans, and therefore the findings may not be applicable to women with HCV or co-infected patients. Beverage consumption was self-reported, and caffeine intake was estimated based on the average reported intake, and therefore may not accurately reflect the actual intake given the known variability in caffeine levels in coffee and tea of the same type owing to differences in production and preparation. However, any misclassification should be nondifferential (ie, similar among cases and controls) and therefore any possible bias should be toward the null or finding of no association. A potential for reverse causality may be present if patients with more advanced liver disease are averse to drinking caffeine-containing beverages including coffee; however, we did not enroll patients with decompensated liver disease. We also found that the decreased risk of advanced fibrosis with an average daily intake of 100 mg or more of caffeine or 1 or more cups of tea in non–coffee drinkers remained significant or nearly significant after adjusting for MELD scores and insulin resistance. In total, 40% of our participants were classified as marijuana users, and we found no significant association with the degree of hepatic fibrosis or inflammation and marijuana use. However, we did not have information on the duration or frequency of marijuana use, a limitation of our study.5353 Prior studies also have suggested women who consume alcohol may have a less pronounced response to the hepatoprotective effects of caffeine as measured by γ-glutamyltransferase levels,5454 and in animal models, females may recover more slowly from hepatic injury than males.5555 Our study participants were largely male (n = 888), with only 22 females represented. As such, our study lacked the statistical power to find a notable gender-specific difference in the hepatoprotective effects of caffeine or coffee.
In conclusion, we found that an average daily intake of 100 mg or more of caffeine was associated with a lower risk of hepatic fibrosis in a general clinical population with chronic HCV infection. We further showed that in non–coffee drinkers, daily caffeinated tea intake also may protect against progressive liver disease in this population. Our study further suggests that caffeinated coffee overall and caffeinated tea in non–coffee drinkers likely provide the most benefit in liver disease compared with other caffeinated beverages or decaffeinated coffee. Future prospective studies are warranted to determine the optimal dose and preparation of caffeinated beverage intake that could be safely and tolerably recommended for prevention of progressive liver disease in HCV patients in routine clinical practice.
Our finding that caffeine intake is associated with a decreased risk of advanced HCV-related fibrosis is in line with several other studies that have suggested a beneficial effect of caffeine on hepatic function in various liver diseases, including nonalcoholic steatohepatitis, alcoholic liver disease, and primary sclerosing cholangitis.4, 6, 10, 33, 34, 35, 36, 37, 38 It also is consistent with an analysis of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial, which found that daily coffee consumption was associated with slower disease progression in patients with chronic HCV-related bridging fibrosis and cirrhosis who had failed to respond to treatment with pegylated interferon and ribavirin. However, in contrast to our findings, which suggest no substantial additional benefit of caffeine intake of 100 mg/day or more, they found a dose-dependent response with coffee drinkers who reported 3 or more cups daily experiencing the greatest (∼53%) reduced risk of disease progression (ie, to decompensation or HCC) compared with non–coffee drinkers.1616 We hypothesize that the primary explanation for this discrepancy is the difference in the spectrum of HCV-related liver disease among studies because the HALT-C trial was restricted to cirrhotic patients, whereas our study population included the full spectrum of HCV-related liver disease. However, other differences in study design and among populations also may have contributed to this discrepancy. Our results suggesting that a modest dose of caffeine intake (∼100 mg/d) was associated with a significantly reduced risk of advanced fibrosis in veterans with chronic HCV are similar to an earlier comparable pilot study in 91 HCV-positive veterans.3939 The consistency in these results over time further supports the internal validity of our findings.
In contrast to our results, Costentin et al1717 found no significant protective association in their study of 238 French patients with treatment-naive chronic HCV. However, they did find that daily caffeine consumption of more than 408 mg (equivalent to ≥3 cups of coffee) was an independent predictor of lower histologic activity grade of hepatitis. Several factors may explain this discrepancy, including differences in populations such as higher average caffeine intake but lower rates of obesity and alcohol abuse overall in the French study population, differences in methods of estimating caffeine intake, and known substantial variability in caffeine found in coffee and tea based on methods of production and preparation.
Our findings suggest that a total combined caffeine intake or dose of 100 mg or more daily is associated with a significant decrease in risk of hepatic fibrosis, but without further risk reduction with higher coffee or caffeine doses. However, the optimal hepatoprotective dose of caffeine in HCV-infected patients overall is unclear. Although some studies suggested the strongest benefit from coffee consumption was at 3 or more cups daily, or approximately 400 mg of caffeine,16, 17 other studies reported a significant reduction in the risk in HCV-related hepatic fibrosis associated with an intake of 1 or 2 cups of cups of coffee daily.11, 40 Our results suggest that as little as 100 mg or more of caffeine daily may be beneficial in a general HCV-infected population with a high prevalence of other risk factors for advanced liver disease. However, our power to evaluate the benefit of higher intake likely was limited by the small number of our study participants who reported drinking higher quantities of caffeinated beverages. Nonetheless, if validated in other HCV-infected populations in the United States, our results suggest that a relatively low (and therefore potentially more tolerable dose) of caffeine, particularly from caffeinated coffee and possibly from tea, may convey a substantial reduction in fibrosis progression.
Several mechanisms have been suggested by which caffeine may act to reduce the risk of advanced fibrosis.4141 Caffeine functions as a nonselective adenosine-receptor antagonist and a phosphodiesterase inhibitor with a broad range of attendant effects including inhibition of growth factors that contribute to hepatic fibrosis.42, 43, 44 Caffeine is metabolized in the liver primarily by CYP1A2, with reduced expression of CYP1A2 correlated with fibrosis progression in a study of HCV patients.4545 Caffeine also has been shown in animal and in vitro studies to act as an antioxidant.4646 Other studies have suggested that the primary hepatoprotective benefit of caffeine is associated with caffeinated coffee intake.4, 6, 11, 16, 47 However, this could be the effect of generally higher daily cumulative caffeine intake in coffee drinkers compared with consumers of other caffeinated beverages overall, or with pharmacodynamic differences in effects given the substantial differences in caffeine per unit intake of caffeinated coffee in comparison with tea or soda. Finally, it also has been postulated that other constituents of coffee, such as diterpenes, polyphenols, kahweol, and cafestrerol, which have anti-oxidant activity, also may be responsible for the particular hepatoprotective effect of coffee.48, 49, 50, 51 However, studies, including ours, have not shown that decaffeinated coffee exerts the same effect on liver disease as caffeinated coffee.11, 47
Inflammation is another known risk factor for progression to fibrosis in chronic HCV,5252 and the role of coffee as an anti-inflammatory agent in nonliver diseases has been suggested.22 In our study, we found no significant association between caffeine intake and the severity of hepatic inflammation, in line with findings by Freedman et al1616 that coffee intake was not associated with lower baseline hepatic inflammation. Prior work has shown that insulin resistance worsens hepatic inflammation in HCV patients,1818 and a meta-analysis suggested that part of the hepatoprotective effect of coffee in part may be related to an associated reduction in insulin resistance and type 2 diabetes mellitus.1919 In our study, caffeine intake was associated inversely with insulin resistance via the surrogate marker of the HOMA-IR score in nondiabetic participants.
Therefore, one potential mechanism linking caffeine intake or the associated lifestyle with decreased risk of advanced fibrosis is the amelioration of insulin resistance. Further studies are needed to better elucidate the underlying pathophysiological mechanisms by which caffeine or its metabolites and other constituents of coffee account for the positive health benefits seen particularly with caffeinated coffee consumption in liver disease patients.
We found that an average of 100 mg or more of caffeine daily from sodas and teas does not have the same protective effect as 100 mg or more of caffeine daily from combined sources (coffee, tea, soda) or from coffee alone, suggesting that caffeine alone may not entirely explain the effect of coffee on liver disease. Although several prior studies have not shown a lower risk of liver disease progression in those who consume caffeine from noncoffee sources such as tea4, 11, 16, 47 or soda,4747 this could be related to differing caffeine content, other ingredients in addition to caffeine that may be partly responsible for the proposed hepatoprotective effects of coffee, or to substantial differences in study design or populations. Among the 413 noncoffee drinkers in our current study, intake of at least 1 cup of caffeinated tea daily was more common in the mild fibrosis control group, and after controlling for potential confounders, this significance was even more pronounced. This finding provides further evidence for the protective role of caffeine from any source against the progression of liver disease.
In regards to soda, an understudied source of caffeine, we found consumption of more than 1 can of caffeinated soda daily to be associated with a decreased risk of hepatic fibrosis, supporting that caffeine likely plays a major role in coffee’s hepatoprotective effects. On multivariate nonstratified analysis, more than 1 can of caffeinated soda daily remained significantly associated with a decreased risk of hepatic fibrosis, with some attenuation after controlling for possible confounders (age, alcohol, BMI, MELD score, and the presence of the metabolic syndrome). When adjusted for self-reported diabetes and HOMA-IR scores, there was a nonsignificant trend toward a decreased risk of fibrosis (adjusted OR, 0.75; 95% CI, 0.55–1.02; P = .063). However, in analyzing soda intake in the subgroup of non–coffee drinkers (n = 413), there was no notable difference in the risk of hepatic fibrosis (P = .41). The findings may indicate that caffeine from soda has hepatoprotective effects, but we cannot exclude the possibility that increased soda consumption reflects an increased intake of caffeinated beverages overall, including coffee. As with coffee, decaffeinated tea and soda were not found to be associated with a decreased risk of liver disease.
Our study had several strengths, including being a large study that examined the association between caffeinated coffee intake and HCV-related liver disease, and adds to the limited research in US populations. It also adds to the sparse literature on the effects of caffeinated tea and soda intake. In addition, we obtained and analyzed information on the consumption of decaffeinated coffee, tea, and soda to better elucidate the mechanisms underlying the potential hepatoprotective effects of caffeine and coffee on liver disease. Finally, our novel use of a validated noninvasive marker for liver fibrosis, the validated FibroSURE test,26, 27, 28, 29, 30, 31, 32 allowed evaluation of a large and diverse HCV patient group, many of whom would have been precluded from biopsy based on highly prevalent comorbid conditions in this population.
Our study also had some limitations. Given the observational retrospective nature of the study, a causal association cannot be made. We studied a select patient population of HCV-monoinfected, largely male veterans, and therefore the findings may not be applicable to women with HCV or co-infected patients. Beverage consumption was self-reported, and caffeine intake was estimated based on the average reported intake, and therefore may not accurately reflect the actual intake given the known variability in caffeine levels in coffee and tea of the same type owing to differences in production and preparation. However, any misclassification should be nondifferential (ie, similar among cases and controls) and therefore any possible bias should be toward the null or finding of no association. A potential for reverse causality may be present if patients with more advanced liver disease are averse to drinking caffeine-containing beverages including coffee; however, we did not enroll patients with decompensated liver disease. We also found that the decreased risk of advanced fibrosis with an average daily intake of 100 mg or more of caffeine or 1 or more cups of tea in non–coffee drinkers remained significant or nearly significant after adjusting for MELD scores and insulin resistance. In total, 40% of our participants were classified as marijuana users, and we found no significant association with the degree of hepatic fibrosis or inflammation and marijuana use. However, we did not have information on the duration or frequency of marijuana use, a limitation of our study.5353 Prior studies also have suggested women who consume alcohol may have a less pronounced response to the hepatoprotective effects of caffeine as measured by γ-glutamyltransferase levels,5454 and in animal models, females may recover more slowly from hepatic injury than males.5555 Our study participants were largely male (n = 888), with only 22 females represented. As such, our study lacked the statistical power to find a notable gender-specific difference in the hepatoprotective effects of caffeine or coffee.
In conclusion, we found that an average daily intake of 100 mg or more of caffeine was associated with a lower risk of hepatic fibrosis in a general clinical population with chronic HCV infection. We further showed that in non–coffee drinkers, daily caffeinated tea intake also may protect against progressive liver disease in this population. Our study further suggests that caffeinated coffee overall and caffeinated tea in non–coffee drinkers likely provide the most benefit in liver disease compared with other caffeinated beverages or decaffeinated coffee. Future prospective studies are warranted to determine the optimal dose and preparation of caffeinated beverage intake that could be safely and tolerably recommended for prevention of progressive liver disease in HCV patients in routine clinical practice.
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