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Association between elevated coffee consumption and daily chocolate intake with normal liver enzymes in HIV-HCV infected individuals: Results from the ANRS CO13 HEPAVIH cohort study. Association of Coffee Consumption With All-Cause and Cardiovascular Disease Mortality - 2 new studies
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from Jules: there are 2 studies below, the first reporting coffee & chocolate appear to reduce liver enzymes in HCV/HIV coinfected, both coffee & chocolate contain similar class of polyphenols which research finds may have anti-inflammatory activity, and the 2nd study from Mayo Clinic Proceedings concluding: "In this large cohort, a positive association between coffee consumption and all-cause mortality was observed in men and in men and women younger than 55 years. On the basis of these findings, it seems appropriate to suggest that younger people avoid heavy coffee consumption (ie, averaging >4 cups per day). However, this finding should be assessed in future studies of other populations."
Association between elevated coffee consumption and daily chocolate intake with normal liver enzymes in HIV-HCV infected individuals: Results from the ANRS CO13 HEPAVIH cohort study
Journal of Hepatology January 2014
"Elevated coffee consumption and daily chocolate intake appear to be associated with reduced levels of liver enzymes in HIV-HCV co-infected patients. Further experimental and observational research is needed to better understand the role that polyphenol intake or supplementation can play on liver disease and liver injury.
This study, conducted on a population of HIV-HCV infected patients, is the first to highlight the potential benefits of regular intake of cocoa-containing products on markers of inflammation (ALT). Consistent with international literature, this study confirms the positive association of elevated coffee consumption on liver enzymes in HIV-HCV infected individuals.
Both coffee and chocolate contain a similar class of polyphenols, which have a significant anti-inflammatory activity [19] and have an indirect effect on occurrence and evolution of those diseases, whose pathogenesis may be related to an inflammatory process. Previous experiments conducted on rats have shown that polyphenol compounds present in cocoa liquor have the potential to decrease the severity of hepatocarcinogenesis [20]. It is probably not by chance that abnormal ALT values, which are more indicative of the presence of inflammation, are most inversely correlated with daily cocoa intake. This association indirectly confirms previous results obtained in vitro, suggesting that the mechanism, through which cocoa may be beneficial to liver cells, is more related to its anti-inflammatory effect and to cell cycle arrest than to apoptosis or autophagy [10].
In conclusion, our results provide the first evidence that daily chocolate intake and, more generally, polyphenol rich food intake, may contribute to decrease AST and ALT levels and potentially improve liver function in HIV-HCV co-infected patients. They also suggest that polyphenols contained in coffee, but also in cocoa, can be involved in the causal process, which leads to reduced inflammation.
The association we found between excessive alcohol consumption and higher levels of liver enzymes is consistent with overwhelming evidence highlighting the detrimental impact of excessive alcohol consumption on liver enzymes in HCV and HIV-HCV co-infected patients [26]. It is important to remember that one of the results of our analysis is that clearing the HCV virus or indeed simply receiving HCV treatment is positively associated with lower levels of liver enzymes. Prompt access to HCV treatment, for patients who present with hazardous or harmful alcohol consumption, can even result in greater benefits than for patients who are abstinent or with moderate consumption, given that excessive alcohol consumption can accelerate the course of HCV disease [27].
During the study period, AST and ALT >2.5 times UNL were documented for 157 (15.86%) and 192 (19.39%) individuals over 201 (11.94%) and 252 (14.96%) visits, respectively......Table 2 shows the distribution of factors potentially associated with AST or ALT >2.5 times UNL in the univariate analysis. Common risk factors for both outcomes included excessive alcohol consumption, smoking, obesity, and HCV genotype 3. Individuals who recovered from HCV or who were receiving HCV treatment were more likely to have values lower than 2.5 times UNL for both AST and ALT. These two categories (recovery and ongoing treatment) were collapsed together in subsequent analyses as they had comparable OR estimates. HIV-related characteristics and duration of HIV infection or ART seemed to have a negative impact mainly on AST values as individuals with CD4 <200 cells/mm3 had twice the risk of having AST >2.5 times UNL. Individuals reporting elevated coffee consumption or daily intake of chocolate had approximately 40% reduced risk of presenting elevated AST or ALT. The combined indicator based on elevated coffee and daily chocolate consumption, was even more significantly associated with both outcomes in univariate analysis....The multivariate analysis (Table 3, left columns) using AST >2.5 times UNL as the outcome showed that after adjustment for excessive alcohol consumption, HCV clearance and CD4 <200 cells/mm3, elevated coffee consumption remained associated with the outcome (p = 0.05) and the association with daily chocolate consumption was close to statistical significance (p = 0.08) (Model 1). When replacing daily chocolate consumption and elevated coffee consumption with the combined indicator, the latter showed similar OR values but increased significance (p = 0.003) (Model 2). The association with the outcome was not increased if the indicator also included moderate red wine consumption (OR = 0.52; 95% CI = 0.36-0.76)......The multivariate model for ALT (Table 3, right columns) highlighted that age, daily chocolate intake (p = 0.04) and elevated coffee consumption (p = 0.04) remained independently inversely correlated with ALT >2.5 times UNL after adjustment for recovery from HCV or ongoing HCV treatment. Individuals with genotype 3 exhibited a higher risk of abnormal ALT values. When replacing daily chocolate consumption and elevated coffee consumption with the combined indicator, similar significant ORs were observed in both models (OR = 0.57; p = 0.002) (Table 3). The association with the outcome was not increased if the indicator also included moderate red wine consumption (OR = 0.59; 95% CI = 0.42-0.82). No significant differences were observed between past or current smokers and non-smokers for either abnormal AST or ALT values. Even after multiple adjustments, smoking was not associated with either outcome and was not retained in the model."
Table 3. Factors independently associated with AST >2.5 ULN or ALT >2.5 ULN in the HEPAVIH ANRS CO13 cohort (N = 990 patients, 1684 visits); multivariate analyses with OR estimates based on GEE logistic regression analyses.
Table 2. Factors associated with AST >2.5 UNL or ALT >2.5 UNL in the HEPAVIH ANRS CO13 cohort (N = 990 patients, 1684 visits); univariate analysis with OR estimates based on GEE logistic regression analyses.
Background & Aims
We used longitudinal data from the ANRS CO13 HEPAVIH cohort study of HIV-HCV co-infected individuals to investigate whether polyphenol rich food intake through coffee and/or daily chocolate consumption could play a role in reducing liver enzymes levels.
Methods
Longitudinal data collection included self-administered questionnaires and medical data (aspartate aminotransferase (AST) and alanine aminotransferase (ALT) liver enzymes). Two analyses were performed to assess the association between coffee ( 3 cups a day) and daily chocolate intake and abnormal values of AST and ALT (AST or ALT >2.5 x upper normal limit (UNL)) (N = 990) over time, after adjustment for known correlates. Logistic regression models based on generalized estimating equations were used to take into account the correlations between repeated measures and estimate adjusted odds ratio.
Results
After adjustment, patients reporting elevated coffee consumption and daily chocolate intake were less likely to present abnormal ALT (OR = 0.65; p = 0.04 and OR = 0.57; p = 0.04, for coffee and chocolate respectively), while only patients reporting elevated coffee consumption were less likely to have abnormal AST values (p = 0.05). Nevertheless, the combined indicator of coffee and chocolate intake was most significantly associated with approximately 40% reduced risk of abnormal liver enzymes (p = 0.003 for AST; p = 0.002 for ALT).
Conclusions
Elevated coffee consumption and daily chocolate intake appear to be associated with reduced levels of liver enzymes in HIV-HCV co-infected patients. Further experimental and observational research is needed to better understand the role that polyphenol intake or supplementation can play on liver disease and liver injury.
Introduction
It is estimated that 170 million people are living with chronic hepatitis C (HCV) in western Europe and the United States [1], [2]. The burden of HCV disease is undeniable in many countries all over the world, particularly where drug use is highly prevalent and where the implementation of HCV preventive measures is either inadequate or not prompt enough [3].
HIV-HCV co-infected individuals constitute per se a population at higher risk of abnormal liver enzymes due to liver injury often determined by previous exposure to specific antiretroviral agents [4] but also to specific behaviors. While the role that caffeine, coffee or other caffeinated beverages can play in liver function [5], fibrosis [6], cirrhosis [7] and liver cancer [8] is widely recognized, the extent to which elevated coffee consumption may be particularly beneficial for patients with HIV-HCV co-infection is less evident.
Cocoa and its derivatives contain a specific class of polyphenols, named flavonols, which are recognized as having important anti-inflammatory properties, and which reduce the risk of coronary heart disease, cancer and other inflammatory-related diseases [9]. A recent study [10] has shown that catechin (a polyphenol contained in cocoa) can have an antifibrotic effect as it decreases the production of TGF-beta by GRX liver cells. Indeed, one randomized study conducted in pregnant women [11] receiving either a placebo or 30mg of dark chocolate per day, showed significantly lower levels of liver enzymes in the latter group.
We used the longitudinal data of the ANRS CO13 HEPAVIH cohort to investigate, whether polyphenol intake through coffee and daily chocolate consumption could play a protective role on serum ALT AST activity.
Materials and methods
Study design
The French ANRS CO13 HEPAVIH cohort was designed to study the clinical, immunological, virological and socio-behavioral course of HIV-HCV co-infected individuals.
From October 2006 to June 2008, this prospective cohort study recruited 1175 HIV-HCV co-infected individuals in 17 outpatient hospital clinics delivering care to HIV and HCV infected individuals in France [12]. Enrolled individuals had to meet the following inclusion criteria: aged 18 years or more, HIV-1/HCV chronically co-infected as confirmed by a positive HIV antibody test and an HCV RNA assay (regardless of clinical stage, gender or transmission group). In addition to these chronically co-infected patients, HIV/HCV co-infected patients who had cleared their HCV after successful anti-HCV therapy, as evaluated by a negative HCV RNA six months after the end of anti-HCV treatment (HCV-sustained responders [12]) could also be enrolled.
Patients on HCV treatment at enrolment, with undetectable HCV-RNA but not yet classified as sustained responders were included in the cohort at the end of their treatment phase.
Medical follow-up visits were scheduled according to both clinical practice and recommendations from the European consensus conferences on hepatitis C [13], [14], i.e., every six months for cirrhotic patients and every year for non-cirrhotic ones. Clinical and histological/biological data were collected from medical records and updated during the follow-up by medical staff in outpatient hospital services. A self-administered questionnaire was filled-in at the enrolment visit and at any annual medical visit scheduled for the whole cohort follow-up period. All patients who agreed to participate in the cohort provided written informed consent. The study was approved by the institutional review board of the Cochin Hospital (Paris, France).
Data collection and analysis
Clinical variables
Clinical variables considered in the analyses included HIV plasma viral load, CD4 cell count, CDC clinical HIV stage, HCV genotype and time since antiretroviral therapy (ART) initiation at each follow-up visit. A detectable HIV viral load was defined as having an HIV RNA level higher than the assay's threshold. Information on current ART and of past history of nevirapine treatment was also available at each follow-up visit.
Liver biochemistry including serum alanine aminotransferase (ALT, normal range 27-65 IU/L) and aspartate aminotransferase level (AST, normal range 19-65 IU/L) were collected at each follow-up visit.
We used the body mass index (BMI = weight divided by height squared) to classify patients as overweight or obese (BMI >25 kg/m2). We also recorded information about exposure to HCV treatment before enrollment and during follow-up and whether individuals cleared the virus after HCV treatment.
Data concerning patients' tobacco use were recorded during face-to-face medical interviews with physicians. Patients were asked about their experience of smoking (non-smoker, former smoker, current smoker).
Variables from the self-administered questionnaire
Data on patients' socio-demographic characteristics, food and drug consumption habits (including coffee, chocolate and red wine intake) were collected using a self-administered questionnaire, which, as previously indicated, was scheduled at enrolment and yearly thereafter.
Alcohol consumption habits focused on consumption in the six months prior to the visit. The AUDIT-C questionnaire was used to calculate the number of alcohol units (AU) per day [a standard drink, defined as one AU contains 11-14 g of alcohol and corresponds to one small bottle of beer, one medium glass of wine, or a shot of distilled spirits] for those who reported being current consumers. Excessive alcohol consumption was defined as reporting to drink at least 3 AU (for men) or 2 AU (for women) per day.
Coffee intake was investigated using a question referring to the 6 months prior to the visit. Five answers were possible: never, occasionally, one cup/day, 2 cups/day, more than two cups/day (a cup corresponding to 150-200 ml). The chocolate intake question also referred to the 6 months prior to the visit. The possible answers were: never, once a week, more than once a week, once a day, more than once a day.
Patients were classified as having elevated coffee consumption if they drank three cups of coffee or more per day at a given visit [15]. Patients were classified as daily chocolate consumers or not. Moderate red wine consumption was defined as 1-2 AU for women and 1-3 alcohol units per day for men. In order to obtain a more "sensitive" variable to capture polyphenol rich food intake, an indicator combining daily chocolate consumers and/or individuals drinking 3 or more cups of coffee per day was also created. Among individuals exposed to polyphenol rich food, a second variable to describe polyphenol rich food intake adding a moderate consumption of red wine (1-2 AU for women and 1-3 alcohol units/day for men) was built.
The self-administered questionnaire also collected information about drug consumption (cocaine, heroin, crack, ecstasy, street buprenorphine, amphetamines and other drugs) in the months prior to the interview, as well as any history of drug use and access to opioid substitution treatment for those with a history of intravenous drug use (IDU). Patients were asked about their presumed mode and date of HCV infection. HIV-HCV individuals infected via injecting drug use were compared with the rest of the cohort. For those who reported a history of drug injection, the presumed year of HCV acquisition was taken to be the year of first injection. For the rest of the study population, it was the self-reported year of HCV infection.
Study population
From the 1175 patients included in the HEPAVIH cohort, 1173 had at least one medical visit with both AST and ALT measurements. Among these, 990 had completed at least one self-administrated questionnaire during a medical visit at follow-up.
These 990 patients became our study group and only follow-up visits, where both AST and ALT measurements as well as the self-administered questionnaire were all available, were considered in the statistical analysis (N = 1684 visits).
Outcomes
The AST and ALT cut-offs were chosen according to the WHO grading system for the monitoring of laboratory toxicities adopted in the French National HIV treatment guidelines, as follows: Grade I (Mild) 1.23-2.5 times UNL, Grade II (Moderate) 2.5-5.0 times UNL, Grade III (Severe) 5.0-10.0 times UNL and Grade IV (Potentially life threatening) 10.0 times (UNL) [16].
In order to explore the association between coffee and chocolate intake on abnormal liver enzymes two different outcomes were considered:
(1)WHO grade II or higher liver injury, defined as AST liver enzymes (>2.5 times the upper normal limit (UNL)) (N = 990, 1694 visits)
(2)WHO grade II or higher liver injury, defined as ALT Liver enzymes (>2.5 times the UNL) (N = 990, 1694 visits)
We did not combine AST with ALT as we wished to better understand the role that intake of specific polyphenol-containing food could play on each liver enzyme.
Statistical methods
As we used complete data for both AST and ALT measurements and for the self-administered questionnaire, we compared characteristics of the included and excluded individuals using a Mann Whitney U test for continuous variables or a Chi-square test for dichotomous variables.
Logit models based on generalized estimating equations (GEE) were used to identify correlates of each outcome (AST and ALT >2.5 times UNL) and estimate ORs and their 95% confidence intervals.
The GEE model permits the presence of missing data in the repeated measure design (i.e., missing data in the self-administered questionnaire) under the hypothesis that missing data occur completely at random. Moreover, using the GEE approach means that the correlation existing between repeated observations for the same individual can be taken into account [17]. Because of their robustness, these methods are typically used to estimate the degree of association between potential explanatory variables and outcomes in repeated measure designs (i.e., repeated observations of the same individual during follow-up [18]).
The following potential correlates and confounders were considered in the analyses: (1) age and sex; (2) clinical variables: CD4 cell count <200 mm3, detectable HIV viral load, CDC clinical stage >1, HCV genotype, recovery after HCV treatment, BMI >25 kg/m2; (3) treatment variables: exposure to HCV treatment (PegIFN + ribavirin), time since ART initiation and past history of nevirapine; (4) consumption variables: smoking, current excessive alcohol consumption, elevated coffee consumption (at least 3 cups a day), daily chocolate intake, the combined indicator of polyphenol rich food intake (at least 3 cups of coffee per day or daily chocolate consumption); (5) history of drug use: history of injection, history of substitution treatment; (6) HCV transmission group (injecting drug user vs. other) and time since HCV infection.
A univariate analysis (one explanatory variable at a time) enabled us to identify major correlates, which were considered candidates to enter the multivariate model if p <0.25. These models were built using an approach, which was based on the log-likelihood ratio test (p <0.05), and which tested whether the relationship between polyphenol-containing food intake and the study outcomes were confirmed after adjustment for possible correlates or confounders selected in the univariate analysis. Plausible interactions were also tested. The relationships between daily chocolate intake and elevated coffee consumption and AST or ALT were first tested together (Model 1) and then as a combined indicator of both (Model 2).
We also used the linear models based on GEE to evaluate the linear relationship between AST and ALT based on four categories reflecting the WHO's grading of liver injury and the five-level variable of chocolate and coffee consumption.
A sensitivity analysis was performed to study whether including the red wine consumption in the combined indicator changes the association with abnormal AST and ALT.
Results
The 990 included individuals did not significantly differ from the others at enrolment; except that the latter group's HIV plasma viral load was more often undetectable and the percentage of HIV transmission by non-IDU means was lower (Table 1).
Median interquartile range [IQR] age was 45 [42-48] years, 70% were males, 49% were employed and 37% had a high school certificate. The majority (80%) were HIV-HCV infected through IDU. At baseline, 13% and 17% had AST and ALT counts >2.5 times UNL, respectively. At enrolment, median [IQR] CD4 cell count was 448 [307-646] cells/mm3, 689 (71%) had an undetectable HIV viral load, 898 (91%) were receiving ART.
During the study period, AST and ALT >2.5 times UNL were documented for 157 (15.86%) and 192 (19.39%) individuals over 201 (11.94%) and 252 (14.96%) visits, respectively.
Median (IQR) duration of follow-up was 40 [34-49] months.
Table 2 shows the distribution of factors potentially associated with AST or ALT >2.5 times UNL in the univariate analysis. Common risk factors for both outcomes included excessive alcohol consumption, smoking, obesity, and HCV genotype 3. Individuals who recovered from HCV or who were receiving HCV treatment were more likely to have values lower than 2.5 times UNL for both AST and ALT. These two categories (recovery and ongoing treatment) were collapsed together in subsequent analyses as they had comparable OR estimates. HIV-related characteristics and duration of HIV infection or ART seemed to have a negative impact mainly on AST values as individuals with CD4 <200 cells/mm3 had twice the risk of having AST >2.5 times UNL. Individuals reporting elevated coffee consumption or daily intake of chocolate had approximately 40% reduced risk of presenting elevated AST or ALT. The combined indicator based on elevated coffee and daily chocolate consumption, was even more significantly associated with both outcomes in univariate analysis.
The relationships between coffee and chocolate consumption, both as categorial and dichotomous variables and abnormal values of AST and ALT, are reported in Table 2. However, for the ALT measure, only the dichotomous ones remained statistically significant after multiple adjustments.
It is worth noting that when categorizing ALT and AST according to the WHO classification of liver injury (grades I, II, III+IV) and considering all categories of coffee and chocolate intake as explanatory variables, a significant linear trend was found between coffee and chocolate consumption and the severity of liver injury, measured using AST (p <10-3, p = 0.01 for coffee and chocolate, respectively). Although no linear relationship was found for ALT, a threshold effect was observed when using a cut-off daily intake of three cups or more of coffee (p = 0.04).
Exposure to nevirapine was not found to be associated with abnormal AST and ALT values in the univariate analysis OR = 0.51; 95% CI = 0.20-1.29; for AST >2.5 x UNL; OR = 0.67; 95% CI = 0.32-1.42; for ALT >2.5 x UNL).
The multivariate analysis (Table 3, left columns) using AST >2.5 times UNL as the outcome showed that after adjustment for excessive alcohol consumption, HCV clearance and CD4 <200 cells/mm3, elevated coffee consumption remained associated with the outcome (p = 0.05) and the association with daily chocolate consumption was close to statistical significance (p = 0.08) (Model 1). When replacing daily chocolate consumption and elevated coffee consumption with the combined indicator, the latter showed similar OR values but increased significance (p = 0.003) (Model 2). The association with the outcome was not increased if the indicator also included moderate red wine consumption (OR = 0.52; 95% CI = 0.36-0.76).
Discussion
This study, conducted on a population of HIV-HCV infected patients, is the first to highlight the potential benefits of regular intake of cocoa-containing products on markers of inflammation (ALT). Consistent with international literature, this study confirms the positive association of elevated coffee consumption on liver enzymes in HIV-HCV infected individuals.
It is interesting to note that, when individuals with elevated coffee consumption or daily chocolate intake were aggregated to better classify those exposed to regular polyphenol rich food intake, the association with liver enzymes was reinforced. We combined elevated coffee consumption and daily chocolate intake together in order to better identify any possible association with liver enzymes, if any, by using a more sensitive indicator of intake of food containing similar types of polyphenols.
Both coffee and chocolate contain a similar class of polyphenols, which have a significant anti-inflammatory activity [19] and have an indirect effect on occurrence and evolution of those diseases, whose pathogenesis may be related to an inflammatory process. Previous experiments conducted on rats have shown that polyphenol compounds present in cocoa liquor have the potential to decrease the severity of hepatocarcinogenesis [20]. It is probably not by chance that abnormal ALT values, which are more indicative of the presence of inflammation, are most inversely correlated with daily cocoa intake. This association indirectly confirms previous results obtained in vitro, suggesting that the mechanism, through which cocoa may be beneficial to liver cells, is more related to its anti-inflammatory effect and to cell cycle arrest than to apoptosis or autophagy [10].
The association we found between elevated coffee consumption and abnormal levels of liver enzymes is consistent with the literature in the field of liver disease regarding HCV and HIV-HCV co-infected patients. Indeed, an increasing body of evidence exists, highlighting the hepatoprotective role of caffeine/coffee intake in patients with liver disease. It has already been shown that caffeine and coffee consumption are associated with a reduced risk of high serum ALT activity in populations at risk of liver disease [5], with a reduced risk of fibrosis and cirrhosis [7], [21], and with death in cirrhotic patients [22]. Two meta-analyses have also suggested an inverse relationship between coffee drinking and the risk of hepatocellular carcinoma in cirrhotic patients [8]. Furthermore, it has been shown that elevated coffee consumption is associated with better patient response to HCV therapy in individuals with chronic HCV infection [23]. More recently, it has also been hypothesized that polyphenols contained in coffee [24] and chocolate [25] may also play a protective role in liver injury through a reduced risk of insulin resistance.
The association we found between excessive alcohol consumption and higher levels of liver enzymes is consistent with overwhelming evidence highlighting the detrimental impact of excessive alcohol consumption on liver enzymes in HCV and HIV-HCV co-infected patients [26]. It is important to remember that one of the results of our analysis is that clearing the HCV virus or indeed simply receiving HCV treatment is positively associated with lower levels of liver enzymes. Prompt access to HCV treatment, for patients who present with hazardous or harmful alcohol consumption, can even result in greater benefits than for patients who are abstinent or with moderate consumption, given that excessive alcohol consumption can accelerate the course of HCV disease [27].
Immunosuppression, defined as CD4 <200 cells/mm3, seems to be associated with higher values of liver enzymes. Previous research has widely documented that HIV infection can accelerate the course of liver disease in HIV-HCV co-infected patients [28]. The lack of association between nevirapine and abnormal levels of liver enzymes may be explained by the fact that this antiretroviral drug is now under-prescribed in patients at risk of hepatotoxicity.
The study population may be considered representative of the general HIV/HCV co-infected population in France, because the French health insurance system provides even marginalized populations, including individuals with co-infection and drug dependence, with free access to care [29].
One limitation of the study is that alcohol consumption, coffee and chocolate intake are based on self-reports, which may be affected by social desirability bias. For alcohol use, data collection was based on a self-administered questionnaire instead of face-to-face interviews and in the same cohort it was shown that alcohol under-reporting was affected by the characteristics of the physician [30]. However, the validity of using self-reports of alcohol consumption has already been demonstrated in previous studies [31]. Furthermore, in the present study, this validity is also indirectly confirmed by the fact that excessive alcohol consumption remained a significant independent predictor of higher levels of both AST and ALT.
It is also possible that chocolate consumption may have been under-reported, especially by overweight individuals. Moreover, we were unable to assess the type of chocolate intake, i.e., milk or dark chocolate bars or chocolate cakes. As cocoa is the main source of polyphenols in chocolate, the lack of this information may result in an overestimation of cocoa intake and this may affect the ORs towards unity. On the other side, it is possible that this association is more readily observed in France because the proportion of dark chocolate consumers among chocolate consumers is higher than in other countries (30% in France vs. 5% in the other European countries [http://www.vfc.fr/syndicat-du-chocolat/]). Accordingly, the average cocoa intake in French daily consumers of chocolate is likely to be higher than in daily users in other countries. Under-reporting alcohol or chocolate consumption may have tended to misclassify consumers as non-consumers and thus was more likely to produce an underestimation of the true effect.
Because this cohort study was not designed to investigate the role of nutrients in HCV disease, the questionnaire detailed only few dietary habits, which are common in the French population. Therefore we only focused on intake of coffee and chocolate, which are sources of a similar class of polyphenols. So, one further limitation is that the study could not investigate the association with other caffeine or cocoa-containing beverages or other sources of similar polyphenols like green tea, which has been found to be associated with inhibition of HCV cell entry [32] and protection against development of primary hepatocellular carcinoma [33]. For this reason, it is possible that unidirectional misclassification may have occurred and individuals with a high consumption of caffeine or cocoa-containing beverages were misclassified as non-consumers. This may have reduced the association found between coffee/chocolate intake and the outcomes, which in turn may have underestimated the OR expressing the association between polyphenol intake and higher level of AST and ALT.
In conclusion, our results provide the first evidence that daily chocolate intake and, more generally, polyphenol rich food intake, may contribute to decrease AST and ALT levels and potentially improve liver function in HIV-HCV co-infected patients. They also suggest that polyphenols contained in coffee, but also in cocoa, can be involved in the causal process, which leads to reduced inflammation.
Further experimental and observational research is needed to better understand the role that polyphenol intake or supplementation can play on liver disease and liver injury.
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Association of Coffee Consumption With All-Cause and Cardiovascular Disease Mortality
"The results of the stratified analysis showed that younger men and women who consumed more than 28 cups of coffee per week had a higher risk of all-cause mortality than those who did not drink coffee, after adjusting for the potential confounders and CRF level......In the age-adjusted analyses, compared with men who did not drink coffee, men who drank coffee at a rate of 8 to 14, 15 to 21, and more than 28 cups per week had a higher risk of all-cause mortality (see table below). In the multivariable-adjusted model, men who consumed more than 28 cups of coffee per week had the highest risk of all-cause mortality......The associations between coffee consumption and all-cause mortality for younger and older age groups are depicted in Figure 2. Figure 2, A shows that younger men who consumed coffee at a rate of 8 to 14, 15 to 21, and more than 28 cups per week had higher risks of all-cause mortality than did those who did not drink coffee, after adjusting for the potential confounders and CRF level. The hazard ratio of all-cause mortality for younger men (<55 years old) who drank more than 28 cups per week is 1.56 (95% CI, 1.30-1.87). The final model indicated that younger women who consumed more than 28 cups of coffee per week also had a higher risk of all-cause mortality than did those who did not drink coffee (hazard ratio, 2.13; 95% CI, 1.26-3.59). However, coffee consumption was not associated with all-cause mortality in older men and women"
Association of Coffee Consumption With All-Cause and Cardiovascular Disease Mortality
Mayo Clinic Proceedings
October 2013
Abstract
Objective
To evaluate the association between coffee consumption and mortality from all causes and from cardiovascular disease.
Patients and Methods
Data from the Aerobics Center Longitudinal Study representing 43,727 participants with 699,632 person-years of follow-up were included. Baseline data were collected by an in-person interview on the basis of standardized questionnaires and a medical examination, including fasting blood chemistry analysis, anthropometry, blood pressure, electrocardiography, and a maximal graded exercise test, between February 3, 1971, and December 30, 2002. Cox regression analysis was used to quantify the association between coffee consumption and all-cause and cause-specific mortality.
Results
During the 17-year median follow-up, 2512 deaths occurred (804 [32%] due to cardiovascular disease). In multivariate analyses, coffee intake was positively associated with all-cause mortality in men. Men who drank more than 28 cups of coffee per week had higher all-cause mortality (hazard ratio [HR], 1.21; 95% CI, 1.04-1.40). However, after stratification based on age, younger (<55 years old) men and women showed a significant association between high coffee consumption (>28 cups per week) and all-cause mortality after adjusting for potential confounders and fitness level (HR, 1.56; 95% CI, 1.30-1.87 for men; and HR, 2.13; 95% CI, 1.26-3.59 for women).
Conclusion
In this large cohort, a positive association between coffee consumption and all-cause mortality was observed in men and in men and women younger than 55 years. On the basis of these findings, it seems appropriate to suggest that younger people avoid heavy coffee consumption (ie, averaging >4 cups per day). However, this finding should be assessed in future studies of other populations.
Drinking coffee has become a normal daily routine for more than half of Americans and large numbers of people worldwide. According to the latest National Coffee Drinking Study from the National Coffee Association, approximately 64% of American adults drink coffee each day, and among coffee drinkers, the average coffee consumption in the United States is 3.1 cups per day.1 Nevertheless, coffee has long been suspected to contribute to a variety of chronic health conditions. During the past 4 decades, the association between coffee consumption and chronic health outcomes has been investigated in relation to conditions such as obesity,2, 3, 4, 5, 6 hypertension,7, 8 and coronary heart disease.9, 10 However, studies on coffee consumption in relation to all-cause and cause-specific mortality are limited, and the results are often controversial. Several studies have found a positive association between higher levels of coffee consumption and all-cause and cardiovascular disease (CVD) mortality,11, 12, 13 whereas others have found an inverse association with all-cause mortality in men and women,14, 15, 16 in women only,17, 18 or in men only,19, 20, 21 with some evidence suggesting that there may be a U- or J-shaped relationship between coffee drinking and health outcomes. Still, other researchers suggest that the association may not exist at all.22, 23, 24 The objective of the present study was to investigate the effect of coffee consumption on all-cause and CVD mortality in the Aerobics Center Longitudinal Study (ACLS) cohort, with average follow-up of 16 years and a relatively large sample of men and women.
Discussion
Key Findings
We found that coffee intake was positively associated with higher all-cause mortality in men, but only a suggestion of an effect was found in women. In men, those who drank more than 28 cups of coffee weekly had a 21% higher risk of dying compared with their non-coffee-consuming peers. Neither men nor women had significant associations between CVD mortality and coffee consumption. The results of the stratified analysis showed that younger men and women who consumed more than 28 cups of coffee per week had a higher risk of all-cause mortality than those who did not drink coffee, after adjusting for the potential confounders and CRF level. For people, particularly men, who were overweight or obese, coffee consumption trended positively, although not significantly, on all-cause mortality. We did not conduct stratified analyses on the basis of CVD mortality because of the null findings between coffee consumption and CVD death.
Comparison With Other Studies
The present findings for all-cause mortality are consistent with those of earlier studies,11, 13, 20, 21 but the results of recent studies have been highly variable.15, 16, 17, 23, 27 Most inverse associations between coffee consumption and mortality were observed from studies on the basis of middle-aged or older populations. Freedman et al16 found an inverse association between coffee consumption and all-cause mortality after adjusting for potential confounders. Lopez-Garcia et al23 also found an inverse association in men.
However, Kleemola et al18 found this inverse association only in women. One possible explanation for this inverse association between coffee consumption and all-cause mortality might be survival selection because the results of most of the previous studies are based on older or middle-aged populations. The present study, however, had a very wide age range, from 20 to 87 years, so the survival selection might be smaller. Our stratified analyses also support this explanation. Figure 2 shows that younger men and women had an increased risk of mortality for heavy coffee drinking (>28 cups per week) compared with non-coffee drinkers. In addition, the non-coffee-drinking group may have had a higher mortality risk not related to the consumption of coffee; however, those unknown factors may exert an inverse effect on the association between coffee consumption and mortality. No statistically significant association was found between coffee consumption and CVD mortality in this study. Some cohort studies also have examined the effect of coffee consumption on CVD mortality, and the results have been variable, somewhat similar to the situation with all-cause mortality in our study.
Possible Mechanism
Coffee is a complex mixture of chemicals consisting of thousands of components.28 Recent research has found that coffee is one of the major sources of antioxidants in the diet29, 30 and has potential beneficial effects on inflammation.31, 32 However, it is also well known that coffee has potential adverse effects because of caffeine's potential to stimulate the release of epinephrine,33 inhibit insulin activity,34 and increase blood pressure and homocysteine levels.35 Thus, all of these mechanisms could counterbalance one another. Research also suggests that heavy coffee drinkers may experience additional risk through potential genetic mechanisms36 or because of confounding through the deleterious effects of other risk factors with which coffee drinking is associated. Genetic factors may partly explain why moderate coffee consumption is not as likely to be associated with increased mortality, whereas heavy coffee consumption could lead to increased mortality, as was especially noted in the men in this study. Therefore, we hypothesize that the positive association between coffee and mortality may be due to the interaction of age and coffee consumption, combined with a component of genetic coffee addiction.
Strengths
There are several strengths of this study. First, it examined a large cohort, including 43,727 participants of both sexes and with a wide age range from 20 to almost 90 years. Although most of the study population was white, highly educated, and from middle to upper social economic status, the homogeneity of the study population enhanced the internal validity. Second, we were able to control for potential confounders, including physical activity and CRF. Third, subclinical disease is unlikely to be a major problem in this study because we excluded people who had baseline CVD, cancer, underweight, and abnormal electrocardiographic findings, and we controlled for major chronic diseases, such as hypertension, diabetes, and hypercholesterolemia in the analysis. Fourth, the possibility that reverse causality may bias the results is small because the current study is prospective cohort.
Limitations
On the other hand, this study does have certain limitations. First, this study did not have repeated measures of coffee consumption over time, which prevents analysis of long-term coffee consumption patterns and changes in coffee consumption over time. However, several studies have examined long-term habitual coffee intake and have found that coffee drinking, besides being easy to measure, tends to be stable in adulthood23, 37 and that a single point measurement of coffee consumption is a valid indicator for long-term coffee consumption.38 Still, future studies with repeated measures of coffee consumption are warranted to elucidate the effect of change in coffee consumption on longevity. Second, we did not have data on coffee preparation methods, and the constituents of coffee may differ, which might also impact its potential association with CVD risk factors on the basis of the different preparation methods. Third, data on marital status and total energy consumption were not included in the present study. Although educational level is not available for the analysis,39 we reported previously that the ACLS population is highly educated and homogeneous, which in fact increases the study's internal validity. Fourth, residual confounding may still exist even though we adjusted for all the potential confounders available in the present study. Smoking is likely to be one of the most important factors to cause residual confounding in this investigation. We therefore stratified the analysis by smoking status and the results are shown in Supplemental Figures 1 and 2, available online at http://www.mayoclinicproceedings.org. We did not observe the significant association between coffee consumption and all-cause mortality both in current smokers and non-current smokers. Finally, a cohort effect might still exist even though we included the baseline examination year as a way to control for it. A recent ACLS report by Willis et al40 examining the secular change across different decades when participants entered the ACLS study, from the 1970s, 1980s, 1990s, and 2000s, revealed that there was little change in participants' characteristics, such as age, BMI, blood profile, and chronic disease over time. However, to remove or control for the possible cohort effect, we included the baseline examination year as a covariate,which is a general approach that we have applied in most of our ACLS analyses.
Conclusion
In this large US cohort study, a positive association between heavy coffee consumption (>28 cups per week) and all-cause mortality was observed in the total population of men and in men and women younger than 55 years. However, for people 55 years and older, this association was not statistically significant for either sex. Hence, it may be appropriate to recommend that younger people, in particular, avoid heavy coffee consumption (>28 cups per week or >4 cups in a typical day). Further studies are needed to assess details regarding the effects of long-term coffee consumption and changes in coffee consumption over time on all-cause and CVD mortality.
Patients and Methods
Study Population
The ACLS is a prospective observational study and has been described in detail previously.24, 25 Between February 3, 1971, and December 30, 2002, 44,963 individuals aged 20 to 87 years participated and returned a medical history questionnaire assessing lifestyle habits (including coffee intake) and personal and family medical history. We examined 43,727 participants (33,900 men and 9827 women; 699,632 person-years of follow-up) in the final analysis after excluding those with a history of myocardial infarction (n=54), stroke (n=11), or cancer (n=141); those with abnormal results of resting or exercise electrocardiography (n=319); those who did not achieve 85% age-predicted maximal heart rate (n=122), those who were underweight (body mass index [BMI] [calculated as weight in kilograms divided by height in meters squared] <18.5) (n=501), and those with less than 1-year mortality follow-up (n=88). All the study participants provided written informed consent. The Cooper Clinic (Dallas, Texas) Institutional Review Board reviewed and approved the study protocol annually.
Measurement of Exposure
Regular coffee consumption, expressed as number of cups per week, was assessed by a standardized questionnaire. Consumption of regular coffee was grouped as 0, 1 to 7, 8 to 14, 15 to 21, 22 to 28, and more than 28 cups per week for primary analysis.
Measurement of Outcome
All the participants were observed for mortality from the baseline examination to the date of death or December 31, 2003. All-cause mortality and CVD mortality were identified through the National Death Index or by accessing the death certificates in the decedents' states of residence. The CVD mortality was determined using International Classification of Diseases, Ninth Revision codes 390 to 449.9 before 1999 and Tenth Revision codes 100 to 178 between 1999 and 2003.
Measurement of Covariates
All the participants underwent a baseline clinical examination at the Cooper Clinic between February 3, 1971, and December 30, 2002. The medical examination was performed after an overnight fast (>12 hours) and included fasting blood chemistry analysis, personal and family health history, anthropometry, blood pressure, electrocardiography, and a maximal graded exercise test. Responses to a standardized questionnaire were used to assess smoking status; alcohol consumption; regular tea, regular and decaffeinated coffee, and decaffeinated or herbal tea drinking (cups per week); physical activity; and parental history of CVD. Medical conditions, including hypertension, hypercholesterolemia, diabetes, cancer, myocardial infarction, and stroke, were evaluated using a standardized questionnaire.
Cardiorespiratory fitness (CRF) was quantified by the total time of the treadmill test using a modified Balke protocol.25 Participants were encouraged to reach their maximal effort, and the test was terminated when the participant requested to stop because of exhaustion or when the physician stopped the test for medical reasons. Maximal metabolic equivalents (1 metabolic equivalent = 3.5 mL of oxygen uptake per kilogram per minute) were estimated from the final treadmill speed and grade.26
Statistical Analyses
Baseline characteristics of the population were estimated by baseline coffee consumption categories and sex status. Hazard ratios and 95% CIs for mortality associated with coffee consumption were estimated using Cox proportional hazards regression models, with person-years as the underlying time metric; models also were stratified by age and BMI using the same underlying time metric. The proportional hazards assumption was tested by Martingale-based residuals, and the observed results satisfied the assumption. Analyses were conducted using SAS software version 9.3 (SAS Institute, Inc). Statistical tests were 2-sided, and significance was set at α=.05. Risk estimates are presented separately for men and women. Multivariate models were adjusted for age, baseline examination year, decaffeinated coffee use, regular tea use, decaffeinated or herbal tea use, physical inactivity, BMI, smoking, alcohol consumption, diabetes, hypertension, hypercholesterolemia, parental history of CVD, and CRF. Hazard ratios for death associated with categories of coffee consumption (1-7, 8-14, 15-21, 22-28, and >28 cups per week) were compared with that for no coffee consumption. In stratified analyses, we categorized age and BMI into 2 groups (age <55 years and age ≥55 years and BMI <25 and BMI ≥25). The covariates were the same as in the main analysis.
Results
During the 17-year median follow-up, 2512 deaths occurred (2198 men [87.5%] and 314 women [12.5%]), and 804 (32%) were caused by CVD. Tables 1 and 2 show the association between coffee consumption and participants' characteristics at baseline. Men and women who consumed higher amounts of coffee were more likely to smoke and had lower levels of CRF.
aCVD = cardiovascular disease; MET = metabolic equivalent.
bSI conversion factors: To convert total cholesterol values to mmol/L, multiply
by 0.0259; to convert fasting blood glucose values to mmol/L, multiply by 0.0555.
cAlcohol heavy drinker is defined as more than 14 alcoholic drinks per week for men and more than 7 per week for women.
dPhysical inactivity is defined as no leisure time physical activity during the past 3 months.
eDiabetes is defined as a fasting glucose level of at least 126 mg/dL, physician-diagnosed diabetes, or insulin use.
fHypercholesterolemia is defined as a total cholesterol level of at least 240 mg/dL or physician-diagnosed hypercholesterolemia.
gHypertension is defined as resting blood pressure of at least 140/90 mm Hg or physician-diagnosed hypertension.
aCVD = cardiovascular disease; MET = metabolic equivalent.
bSI conversion factors: To convert total cholesterol values to mmol/L, multiply by 0.0259; to convert fasting blood glucose values to mmol/L, multiply by 0.0555.
cAlcohol heavy drinker is defined as more than 14 alcoholic drinks per week for men and more than 7 per week for women.
dPhysical inactivity is defined as no leisure time physical activity during the past 3 months.
eDiabetes is defined as a fasting glucose level of at least 126 mg/dL, physician-diagnosed diabetes, or insulin use.
fHypercholesterolemia is defined as a total cholesterol level of at least 240 mg/dL or physician-diagnosed hypercholesterolemia.
gHypertension is defined as resting blood pressure of at least 140/90 mm Hg or physician-diagnosed hypertension.
Coffee Consumption and All-Cause Mortality
The hazard ratios for all-cause mortality in coffee consumption groups are shown in Table 3. In the age-adjusted analyses, compared with men who did not drink coffee, men who drank coffee at a rate of 8 to 14, 15 to 21, and more than 28 cups per week had a higher risk of all-cause mortality. In the multivariable-adjusted model, men who consumed more than 28 cups of coffee per week had the highest risk of all-cause mortality. This association persisted in the final model, which further adjusted for CRF level. However, coffee consumption was not associated with all-cause mortality risk in women. Kaplan-Meier survival curves indicate that women (Figure 1, A) and men (Figure 1, B) with higher coffee consumption had lower mortality-free time compared with those who did not drink coffee.
Coffee Consumption and CVD-Related Mortality
The hazard ratios for CVD-related mortality in coffee consumption groups are shown in Table 3. In the age-adjusted analyses, compared with men who did not drink coffee, men who drank coffee at a rate of more than 28 cups per week had a 36% higher risk of CVD mortality. However, this association disappeared in the final model, which adjusted for potential confounders and CRF level. For women, coffee consumption was not associated with CVD mortality risk in any model.
Coffee Consumption and All-Cause Mortality by Age Group
The associations between coffee consumption and all-cause mortality for younger and older age groups are depicted in Figure 2. Figure 2, A shows that younger men who consumed coffee at a rate of 8 to 14, 15 to 21, and more than 28 cups per week had higher risks of all-cause mortality than did those who did not drink coffee, after adjusting for the potential confounders and CRF level. The hazard ratio of all-cause mortality for younger men (<55 years old) who drank more than 28 cups per week is 1.56 (95% CI, 1.30-1.87). The final model indicated that younger women who consumed more than 28 cups of coffee per week also had a higher risk of all-cause mortality than did those who did not drink coffee (hazard ratio, 2.13; 95% CI, 1.26-3.59). However, coffee consumption was not associated with all-cause mortality in older men and women (Figure 2, B).
Coffee Consumption and All-Cause Mortality by BMI Group
The only marginally significant association of coffee consumption and all-cause mortality was observed in men with a BMI of at least 25 who consumed more than 28 cups of coffee per week, indicating that overweight/obese men who consumed more than 28 cups of coffee per week had slightly higher all-cause mortality risk than those who did not drink coffee. Because of sample size limitations, we could not further investigate this association on the basis of additional age stratification.
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