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Association of caffeine intake and histological features of chronic hepatitis C
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Journal of Hepatology June 2011
Charlotte E. Costentin1, Francoise Roudot-Thoraval234, Elie-Serge Zafrani235, Fatiha Medkour1, Jean-Michel Pawlotsky236, Ariane Mallat123, Christophe Hezode123
1AP-HP, Service d'Hepatologie et de Gastroenterologie, Groupe Hospitalier Henri Mondor-Albert Chenevier, Creteil 94000, France; 2INSERM, U955, Creteil 94000, France; 3Universite Paris-Est, Faculte de Medecine, UMR-S955, Creteil 94000, France; 4AP-HP, Service de Sante publique, Groupe Hospitalier Henri Mondor-Albert Chenevier, Creteil 94000, France; 5AP-HP, Service d'Anatomo-pathologie, Groupe Hospitalier Henri Mondor-Albert Chenevier, Creteil 94000, France; 6AP-HP, Service de Virologie, Groupe Hospitalier Henri Mondor-Albert Chenevier, Creteil 94000, France
"In summary, our study uncovers an inverse relationship between caffeine consumption and Metavir activity grade in patients with chronic hepatitis C, suggesting that caffeine intake may lower necroinflammatory injury by an as yet undetermined mechanism. Given the strong relationship between activity grade and fibrosis progression, these results support the hypothesis that caffeine intake may also reduce the progression of liver fibrosis. Additional studies are required to assess whether our findings also apply to other inflammatory chronic liver diseases.......by multivariate analysis, daily caffeine consumption greater than 408mg (3 cups of coffee or more) stood out as an independent predictor of a lesser risk of moderate to marked activity grade....These findings are in keeping with previous studies suggesting a hepatoprotective effect of caffeine in patients with liver disease of various causes [1], [3], [5], [7], [20], [21]. However, conflicting data are present in the literature.....In our homogeneous population of patients with chronic hepatitis C, caffeine intake was shown to be independently associated with low-grade activity, but not with fibrosis or ALT levels.....we found a cut-off of three or more cups of coffee (more than 407mg of caffeine per day) while other studies report a lower cut-off of 2 cups per day.....These discrepancies suggest that a higher caffeine intake may be a surrogate marker for a confounding factor yet to be determined. Socio-economic status, quality of life, and comorbidities, which may be significantly associated with coffee intake, have not been examined in our cohort. The lack of such information limits the scope of our study, as any factor associated with coffee drinking could explain our results.....The mechanisms underlying potential hepatoprotective effects of caffeine in patients with chronic hepatitis C remain to be determined. Several reports suggest caffeine and other constituents of coffee, like kahweol and cafesterol, possess antioxidant properties.....Epidemiological studies support the hypothesis that regular coffee consumption is associated with a substantially lower risk of type 2 diabetes, therefore suggesting that coffee intake may reduce the development of insulin resistance"
ABSTRACT
Background & Aims: The severity of chronic hepatitis C (CHC) is modulated by host and environmental factors. Several reports suggest that caffeine intake exerts hepatoprotective effects in patients with chronic liver disease. The aim of this study was to evaluate the impact of caffeine consumption on activity grade and fibrosis stage in patients with CHC.
Methods: A total of 238 treatment-naïve patients with histologically-proven CHC were included in the study. Demographic, epidemiological, environmental, virological, and metabolic data were collected, including daily consumption of alcohol, cannabis, tobacco, and caffeine during the six months preceding liver biopsy. Daily caffeine consumption was estimated as the sum of mean intakes of caffeinated coffee, tea, and caffeine-containing sodas. Histological activity grade and fibrosis stage were scored according to Metavir. Patients (154 men, 84 women, mean age: 45±11years) were categorized according to caffeine consumption quartiles: group 1 (<225mg/day, n=59), group 2 (225-407mg/day, n=57), group 3 (408-678mg/day, n=62), and group 4 (>678mg/day, n=60).
Results: There was a significant inverse relationship between activity grade and daily caffeine consumption: activity grade>A2 was present in 78%, 61%, 52%, and 48% of patients in group 1, 2, 3, and 4, respectively (p<0.001). By multivariate analysis, daily caffeine consumption greater than 408mg/day was associated with a lesser risk of activity grade>A2 (OR=0.32 (0.12-0.85). Caffeine intake showed no relation with fibrosis stage.
Conclusions: Caffeine consumption greater than 408mg/day (3 cups or more) is associated with reduced histological activity in patients with CHC. These findings support potential hepatoprotective properties of caffeine in chronic liver diseases.
By multivariate analysis, caffeine consumption >408mg/day was associated with a lesser risk of clinically significant activity (>A2) for intakes ranging between 408 and 678mg/day (group 3) (OR=0.32 [0.12-0.85]) or >678mg/day (group 4) (0.28 [0.10-0.75]). In addition, a Metavir activity grade >A2 was also independently related to fibrosis stage F2-F4 (OR=13.3 [5.4-32.7]), moderate-severe steatosis (OR=2.43 [1.01-5.88]), and serum ALT level (OR=1.01 [1.00-1.02]) (Table 4).
Introduction
The natural history of chronic hepatitis C infection is profoundly influenced by a variety of co-factors and co-morbidities that affect both the progression rate and the long-term outcome of infection. These include host parameters such as gender, age at infection, genetic factors, immunosuppression, or the presence of the metabolic syndrome, as well as environmental factors, including excessive alcohol intake or regular cannabis use.
A growing body of evidence suggests that caffeine may have hepatoprotective properties. A large population-based study in the United States has shown that caffeine consumption is associated with a lower risk of elevated serum alanine aminotransferase (ALT) activity in patients at high risk of liver disease [1]. Epidemiological surveys conducted in Europe and Japan also found inverse correlations between coffee drinking and aminotransferases [2], [3], [4], [5] or γ-glutamyltransferase [2], [3], [6], [7], [8], [9], [10], [11], [12], [13] serum levels. Coffee and caffeine consumption has been shown to be associated with a reduced risk of fibrosis or cirrhosis in several prospective studies [14], [15], [16], [17], [18], [19], [20]. Regular coffee consumption was associated with lower rates of fibrosis progression or clinical outcomes in a large cohort of patients with advanced HCV-related liver disease who failed to respond to peginterferon and ribavirin treatment [21]. A Norwegian population-based study also showed an inverse relationship between coffee intake and rate of death in cirrhotic patients [22]. Finally, several cohort and case-control studies, as well as two recent meta-analyses, suggested an inverse relationship between coffee drinking and the risk of hepatocellular carcinoma in cirrhotic patients [23], [24], [25], [26], [27], [28], [29], [30], [31]. Altogether, these data suggest that coffee consumption may reduce liver injury in patients with chronic liver disease. The aim of this study was to evaluate the association of caffeine consumption and severity of histological liver lesions in the specific group of treatment-naive patients with chronic hepatitis C.
Results
Study population
Table 1 shows baseline characteristics of the study population (n=238). There were 154 men, and 84 women with a mean age at liver biopsy of 45±11years. Intravenous drug use represented the main source of HCV infection (41%). HCV Genotype 1 (62%) was predominant, followed by HCV genotype 3 (17%). Caffeine consumption (median: 408mg/day, IQR: 224-680) was mainly related to coffee intake (median: 2 cups per day, IQR: 1-4), whereas tea, colas, or sodas accounted for 0 (0-1) cup per day and 0 (0-0.2) can per day, respectively. Ongoing alcohol abuse, tobacco consumption >15 cigarettes/day [35] and daily cannabis use [37], [38] were reported by 17%, 34%, and 25% of patients, respectively. Metavir activity grades A2 and fibrosis stage >F2 were present in 60% and 39% of patients, respectively. Table 2 depicts the characteristics of patients, ranked by caffeine consumption quartiles. Caffeine consumption was inversely related to age (p<0.001), and correlated with tobacco or cannabis use (p=0.005 and p=0.001, respectively). In contrast, there were no significant differences in rates of alcohol abuse, levels of serum ALT or metabolic features when compared to the caffeine intake level.
Relationship between caffeine consumption and activity grade of biopsies
The relationship between caffeine intake and histological activity grade is shown in Table 3. Prevalence of a Metavir activity grade >A2 declined gradually, with increasing levels of daily caffeine consumption, from 78% in patients consuming less than 225mg/day (group 1) to 48% in those with a daily intake greater than 678mg/day (group 4) (p<0.001, test for linear trend). Other factors related to activity grades higher than A2 included age (at liver biopsy) >40years (64%, p=0.025), BMI>25kg/m2 (69%, p=0.011), moderate or marked steatosis (80%, p<0.001), fibrosis stage >F2 (92%, p<0.001), and median serum ALT level (91IU/ml (55-129), p<0.001) (Table 3). There was no significant relationship between activity grade and either gender, route of transmission, hyperglycemia, or diabetes, daily alcohol intake, tobacco smoking, cannabis use, or HCV genotype.
Relationship between caffeine consumption and fibrosis
By univariate analysis, advanced fibrosis (>F2) significantly correlated with male gender (47% versus 24%, p<0.001), age>40years (45% versus 27%, p=0.006), alcohol abuse (60% versus 35%, p=0.003), tobacco smoking>15 cigarettes/day (49% versus 34%, p=0.03), daily cannabis use (54% versus 29% in occasional users and 35% in non-users, p=0.019), HCV genotype 3 (57% versus 35%, p=0.011), BMI>25kg/m2 (48% versus 32%, p=0.009), moderate-severe steatosis (60% versus 33%, p<0.001), and median serum ALT level (99IU/ml (67-136) versus 56IU/ml (37-86), p<0.001). However, there was no significant relationship between the severity of fibrosis and caffeine consumption, (p=0.08, test for linear trend): severe fibrosis (F2-F4) was found in 52% (31/59), 30% (17/57), 37% (23/62), and 37% (22/60) of patients in group 1, 2, 3, and 4, respectively.
By logistic regression analysis, predictors of fibrosis (F2) were: age at liver biopsy>40years (OR=5.8 [2.3-14.5]), male gender (OR=4.2 [1.9-9.6]), activity gradeA2 (OR=22.1 [8.5-56.9]), moderate-severe steatosis (OR=2.4 [1.1-5.3]), and daily cannabis use (OR=3.7 [1.4-9.8]).
Interactions between caffeine consumption and tobacco use
The relationship between caffeine intake and tobacco smoking is shown in Table 2. The proportion of heavy smokers raised gradually with increasing levels of daily caffeine consumption, from 25% in patients consuming less than 225mg/day (group 1) to 52% when daily intake was greater than 678mg/day (group 4) (p=0.005). There was an association between Metavir activity grade >A2 and tobacco smoking in individuals with low caffeine consumption (<408mg/day), but not in those with a higher caffeine intake (p=0.007 and p=0.58, respectively). However, by multivariate analysis, tobacco use did not reach significant levels and was not independently associated with Metavir activity grade 2 (Table 4).
Discussion
Our data show that caffeine consumption is inversely associated with the severity of necroinflammatory lesions in patients with untreated chronic hepatitis C. Indeed, the prevalence of patients with an activity grade >A2 was inversely related to the amount of caffeine taken on a daily basis, (p<0.001, test for linear trend). Moreover, by multivariate analysis, daily caffeine consumption greater than 408mg (3 cups of coffee or more) stood out as an independent predictor of a lesser risk of moderate to marked activity grade, together with age and steatosis grade, two parameters previously described as independent risk factors of activity [36], [38]. These findings are in keeping with previous studies suggesting a hepatoprotective effect of caffeine in patients with liver disease of various causes [1], [3], [5], [7], [20], [21]. However, conflicting data are present in the literature.
In our homogeneous population of patients with chronic hepatitis C, caffeine intake was shown to be independently associated with low-grade activity, but not with fibrosis or ALT levels. Ruhl et al. [1] demonstrated that higher caffeine intake was associated with lower ALT levels, and Modi et al. [20] reported the impact of caffeine intake on fibrosis but not on activity or ALT levels. Furthermore, we found a cut-off of three or more cups of coffee (more than 407mg of caffeine per day) while other studies report a lower cut-off of 2 cups per day [1], [20]. These conflicting results might be explained by the fact that these are, not very large, cross-sectional studies (except for the Ruhl et al. study) and different methods are used for the estimation of caffeine intake or histological analysis (Ishak versus Metavir). These discrepancies suggest that a higher caffeine intake may be a surrogate marker for a confounding factor yet to be determined. Socio-economic status, quality of life, and comorbidities, which may be significantly associated with coffee intake, have not been examined in our cohort. The lack of such information limits the scope of our study, as any factor associated with coffee drinking could explain our results.
In contrast with previous reports [32], [36], [38], we found no relationship between histological activity grade and either alcohol abuse or tobacco smoking, raising the question as to a confounding effect of caffeine with respect to these factors. In our cohort, the weak impact of alcohol intake on necroinflammation may be related to the low prevalence of alcohol abuse, as reflected by a median daily consumption below 5g, and by a low (16.8%) rate of ongoing alcohol intake (>30g/day). Such a low prevalence of alcohol abuse may reflect changes of lifestyle in patients following a diagnosis of HCV infection. As for tobacco use, our data show a correlation between heavy smoking and caffeine consumption (p=0.005, Table 2), as previously reported [39], [40]. There was an association between Metavir activity grade >A2 and tobacco smoking in individuals with low caffeine consumption (<408mg/day), but not in those with a higher caffeine intake, suggesting a protective role of caffeine in these heavy smokers.
Multivariate analysis of predictors of fibrosis severity revealed known cofactors, including male gender, Metavir activity grade >A2, steatosis severity, and daily cannabis use [33], [41], [42], [43], [44]. Prior reports have suggested that coffee consumption may reduce the risk of hepatic fibrosis or disease progression [14], [15], [16], [17], [18], [19], [20], [21]. Modi et al. demonstrated that coffee consumption above a 2 cup equivalent per day was associated with less severe hepatic fibrosis [20]. In a sub-analysis of the HALT-C trial, there was no association between coffee intake and baseline cirrhosis status or Ishak inflammation grade. Nevertheless, there was a trend for a reduced rate of cirrhosis in heavy coffee drinkers (>3 cups a day) as compared to the other categories (31.5% versus 40%, p=0.073) [21]. In the present study, although we found no relationship between fibrosis stage and caffeine intake, necroinflammatory grade was positively related to fibrosis stage and negatively associated with caffeine intake. Taken together, these data suggest that caffeine intake might result in limited fibrosis progression by reducing necroinflammatory liver injury. However, further study is required to validate this hypothesis.
The mechanisms underlying potential hepatoprotective effects of caffeine in patients with chronic hepatitis C remain to be determined. Several reports suggest caffeine and other constituents of coffee, like kahweol and cafesterol, possess antioxidant properties [45], [46], [47], [48], [49], [50]. As our study focused on total caffeine intake and not coffee intake, we cannot exclude that other components of coffee may play a role in our findings.
Epidemiological studies support the hypothesis that regular coffee consumption is associated with a substantially lower risk of type 2 diabetes, therefore suggesting that coffee intake may reduce the development of insulin resistance [51]. Interestingly, it has been contended that insulin resistance enhances intrahepatic inflammation in patients with chronic hepatitis C [52]. Freedman et al. [21] reported an inverse association between coffee intake and both serum insulin levels and HOMA 2 scores. In this study, the inclusion of data on both insulin levels or HOMA 2 scores to the statistical models attenuated the observed results for caffeine, suggesting that the beneficial effects of caffeine might be partly explained by a modulation of insulin signaling. Nevertheless, whether the beneficial effects of caffeine/coffee on insulin resistance might also account for the reduction in necroinflammatory lesions, found in HCV patients consuming higher quantities of caffeine, remains to be investigated.
In summary, our study uncovers an inverse relationship between caffeine consumption and Metavir activity grade in patients with chronic hepatitis C, suggesting that caffeine intake may lower necroinflammatory injury by an as yet undetermined mechanism. Given the strong relationship between activity grade and fibrosis progression, these results support the hypothesis that caffeine intake may also reduce the progression of liver fibrosis. Additional studies are required to assess whether our findings also apply to other inflammatory chronic liver diseases.
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