Coffee Consumption and the Risk of Gallstone Disease
This meta-analysis attempted to address the relationship between coffee consumption and gallstone disease using the pooled observational evidence. To the best of our knowledge, this is the first meta-analysis of observational studies to investigate the relationship and dose–response of coffee exposure with gallstone disease.
In a pooled analysis of prospective studies, coffee consumption was associated with a 17% decrease in gallstone disease risk compared with the lowest coffee consumption level. Conversely, the included case–control study did not reveal any association between coffee consumption and gallstone disease (OR, 0.99; 95% CI, 0.64–1.53). However, the included case–control study was a hospital-based design, in which case ascertainment was restricted to subjects requiring hospital admission and surgery for gallstones, and the exposure assessment of the study was based on self-report. Thus, the included case–control study might be subject to recall bias and selection bias and has limited generalisability. Moreover, the restricted number of included case–control studies (n = 1) might also limit the interpretation. Therefore, we concluded that coffee consumption is associated with decreased risk of gallstone disease based on prospective studies.
In the dose–response analysis, we found that an increment of 1 cup of coffee per day was related to a statistically significant decrease (5%) in risk for gallstone disease. In addition, a significant nonlinear dose–response relationship (P for nonlinearity = 0.0106) was also found, and the dose–response analysis demonstrated that the risk for gallstone disease decreased by 11%, 15%, 19%, 22% and 25% according to daily coffee consumption of 2 cups, 3 cups, 4 cups, 5 cups and 6 cups respectively.
We noted that a statistically significant inverse association between coffee consumption and gallstone disease was observed in the overall cohort and in females, but not in males, based on a stratified analysis. Of note and in agreement with our findings, a large, population-based cross-sectional study from the Third National Health and Nutrition Examination Survey revealed that coffee consumption reduced the risk of symptomatic gallstone disease in women (Ptrend = 0.027) but not in men (Ptrend = 0.47). However, in contrast to cohort studies, cross-sectional studies demonstrated a lower level of evidence and might provide spurious results because of selection and recall biases. A prospective cohort study that based on male and female populations with only 1962 subjects revealed an inverse relationship between coffee and gallstone disease, which supported our overall findings, whereas, our study may provide high statistical power to detect the relationship with a larger sample size. One prospective study based on a female cohort did not demonstrate any association between coffee consumption and gallstones. However, in contrast, our study revealed an inverse association for females with a larger cohort size and no heterogeneity; thus, the results could be more reliable. A well-designed prospective study based on a male cohort found that coffee consumption could reduce the risk of gallstone disease; however, we did not find any significant association when we pooled the male cohorts, but the high heterogeneity might limit the interpretation. In addition, with respect to the endpoint measures and exposure assessment of the included studies, the significant inverse associations were observed among almost all of the stratums of the stratified analyses. However, restricted by the limited number of included studies in the stratums, the findings of our subgroup analyses should be interpreted with caution.
The observed inverse association between coffee consumption and risk of gallstone disease is supported by many experimental studies. Coffee stimulates cholecystokinin release, enhances gall-bladder contractility, improves gall-bladder mucosal function, decreases cholesterol crystallisation in the bile and may increase intestinal motility. All these factors are related to decreased cholesterol lithogenesis. Moreover, non-alcoholic fatty liver disease (NAFLD) is regarded as one of the mechanisms that contribute to the risk of cholelithiasis, and coffee consumption can reduce the risk of NAFLD. These mechanisms do not explain the sex differences in our subgroup analysis. Notably, Nordenvall et al. found that an inverse association between coffee consumption and gallstone disease in women was restricted to women who had presumably the highest levels of female sex hormones. In women without these high levels, the association was not significant and was similar to that in men. This finding might indicate that the relationship between coffee consumption and gallstone disease depends on the presence of female sex hormones.
Coffee is a major source of caffeine, and the protective influence of coffee on gallstone formation might be specifically due to the effect of caffeine. In animal models, gall-bladder fluid absorption increases in the early stages of cholesterol gallstone formation, and caffeine prevents cholesterol crystallisation by possibly inhibiting gall-bladder absorption. In addition, caffeine and other methylxanthines may decrease bile cholesterol saturation by stimulating ileal bile acid absorption, increasing hepatic bile acid uptake, and increasing concentrations of sex hormone-binding globulin. On the other hand, caffeine possesses significant thermogenic properties and could prevent the gallstone formation by increasing energy expenditure as well as decreasing body fat stores. Furthermore, decaffeinated coffee was not associated with gallstone disease according to prospective cohorts conducted by Leitzmann et al.. No association was observed with tea consumption in their prospective cohorts, possibly due to the low amount of caffeine in this beverage. Notably, we did not find that caffeinated soft drinks had any potential for reducing the risk of gallstones, which may suggest that other ingredients in coffee may contribute to the preventative effect. The variety of raw coffee and the method of preparation could influence caffeine concentrations. We could not examine the relationship between caffeine and the risk of gallstone disease because most of the included studies reported only the number of cups of coffee consumed and only one study provided information on caffeine intake. Although caffeine is also present in tea, cola and energy drinks, coffee consumption is strongly correlated with total caffeine intake in North America and Europe.
Alternatively, other ingredients in coffee could possibly contribute to the preventive effect. Coffee contains an insoluble hemicellulose fibre that may inhibit the colonic deoxycholic acid absorption. Coffee may also act through the effects of magnesium, a constituent of coffees, which is inversely associated with gallstone disease. In addition, anti-oxidative compounds such as caffeic acid and tocopherols, are capable of inhibiting reactive oxygen metabolites, which appear to promote cholesterol crystal formation.
Strengths of the present meta-analysis included the dose–response analysis, which provides a comprehensive description of the relationship between coffee consumption and gallstone disease. Another strength is the prospective design of the included studies in our analysis, which should minimise the likelihood of recall, interviewer and selection biases that can be a concern in other epidemiological study designs. Furthermore, every study was matched or adjusted for a wide range of potential confounders that may influence gallstone formation, such as age, body mass index, smoking status, alcohol or tea drinking, drug use, physical activities and history of diabetes. The relatively large number of participants and cases provided high statistical power. The overall effect estimates did not altered materially in sensitivity analyses, which contributed to the stable results.
However, several limitations should be acknowledged. First, the exposure assessment of the original studies was based on self-report, and measurement error is inevitable in this circumstances. However, with regard to coffee intake, the FFQ had good validity compared with dietary recall interviews. In addition, we conducted a stratified analysis based on exposure assessment, and the significant inverse association between coffee intake and gallstone disease was observed in both FFQ and dietary recall interview groups.
Second, although the included studies adjusted for multiple known confounding variables, we cannot exclude the possibility that the observed association was in part attributed to unmeasured confounders, such as dietary, behavioural, or genetic factors, in our analysis.
Third, we could not obtain information on the type of coffee consumed or the method of coffee preparation, which might affect the final estimates by influencing caffeine concentrations in the coffee. Moreover, we could not assess whether the effect of coffee intake depended on the duration of exposure because the majority of the included studies did not provide information on long-term coffee use.
Another limitation could be the limited generalisability of our study. All of the included studies in our meta-analysis were from Western Europe/America; thus, we were unable to generalise our findings to general populations. Studies conducted in Asia did not show any associations between coffee intake and gallstone disease; however, the findings from Asian area should be interpreted with caution due to the weakness of their study design.
Finally, different criteria for outcome measurements were used among the studies, which may lead to some heterogeneity. The majority of the included cohorts used cholecystectomy as the outcome; thus, we were unable to generalise our results to gallstone disease per se, but instead more likely to symptomatic gallstones that require surgery. However, using the outcome definition of cholecystectomy represents gallstone disease that is of clinical importance. In addition, it is likely that there was considerable underestimation of gallstone cases in the included studies because most gallstones are asymptomatic. Therefore, we were unable to estimate the incidence of gallstone formation.
In conclusion, our data suggest that coffee consumption is inversely associated with a risk of gallstone disease based on the findings of prospective cohort studies. Specifically, we observed an inverse relation in women but not in men. However, this result should be interpreted with caution because of the high heterogeneity in male cohort studies. This study may provide insight and a better understanding of the coffee-gallstone disease relationship. Further studies should investigate the sex factor in this association and assess the potential therapeutic effects of coffee and individual coffee constituents on gallstone disease, as well as the duration-response of coffee consumption on gallstone disease.
Discussion
This meta-analysis attempted to address the relationship between coffee consumption and gallstone disease using the pooled observational evidence. To the best of our knowledge, this is the first meta-analysis of observational studies to investigate the relationship and dose–response of coffee exposure with gallstone disease.
In a pooled analysis of prospective studies, coffee consumption was associated with a 17% decrease in gallstone disease risk compared with the lowest coffee consumption level. Conversely, the included case–control study did not reveal any association between coffee consumption and gallstone disease (OR, 0.99; 95% CI, 0.64–1.53). However, the included case–control study was a hospital-based design, in which case ascertainment was restricted to subjects requiring hospital admission and surgery for gallstones, and the exposure assessment of the study was based on self-report. Thus, the included case–control study might be subject to recall bias and selection bias and has limited generalisability. Moreover, the restricted number of included case–control studies (n = 1) might also limit the interpretation. Therefore, we concluded that coffee consumption is associated with decreased risk of gallstone disease based on prospective studies.
In the dose–response analysis, we found that an increment of 1 cup of coffee per day was related to a statistically significant decrease (5%) in risk for gallstone disease. In addition, a significant nonlinear dose–response relationship (P for nonlinearity = 0.0106) was also found, and the dose–response analysis demonstrated that the risk for gallstone disease decreased by 11%, 15%, 19%, 22% and 25% according to daily coffee consumption of 2 cups, 3 cups, 4 cups, 5 cups and 6 cups respectively.
We noted that a statistically significant inverse association between coffee consumption and gallstone disease was observed in the overall cohort and in females, but not in males, based on a stratified analysis. Of note and in agreement with our findings, a large, population-based cross-sectional study from the Third National Health and Nutrition Examination Survey revealed that coffee consumption reduced the risk of symptomatic gallstone disease in women (Ptrend = 0.027) but not in men (Ptrend = 0.47). However, in contrast to cohort studies, cross-sectional studies demonstrated a lower level of evidence and might provide spurious results because of selection and recall biases. A prospective cohort study that based on male and female populations with only 1962 subjects revealed an inverse relationship between coffee and gallstone disease, which supported our overall findings, whereas, our study may provide high statistical power to detect the relationship with a larger sample size. One prospective study based on a female cohort did not demonstrate any association between coffee consumption and gallstones. However, in contrast, our study revealed an inverse association for females with a larger cohort size and no heterogeneity; thus, the results could be more reliable. A well-designed prospective study based on a male cohort found that coffee consumption could reduce the risk of gallstone disease; however, we did not find any significant association when we pooled the male cohorts, but the high heterogeneity might limit the interpretation. In addition, with respect to the endpoint measures and exposure assessment of the included studies, the significant inverse associations were observed among almost all of the stratums of the stratified analyses. However, restricted by the limited number of included studies in the stratums, the findings of our subgroup analyses should be interpreted with caution.
The observed inverse association between coffee consumption and risk of gallstone disease is supported by many experimental studies. Coffee stimulates cholecystokinin release, enhances gall-bladder contractility, improves gall-bladder mucosal function, decreases cholesterol crystallisation in the bile and may increase intestinal motility. All these factors are related to decreased cholesterol lithogenesis. Moreover, non-alcoholic fatty liver disease (NAFLD) is regarded as one of the mechanisms that contribute to the risk of cholelithiasis, and coffee consumption can reduce the risk of NAFLD. These mechanisms do not explain the sex differences in our subgroup analysis. Notably, Nordenvall et al. found that an inverse association between coffee consumption and gallstone disease in women was restricted to women who had presumably the highest levels of female sex hormones. In women without these high levels, the association was not significant and was similar to that in men. This finding might indicate that the relationship between coffee consumption and gallstone disease depends on the presence of female sex hormones.
Coffee is a major source of caffeine, and the protective influence of coffee on gallstone formation might be specifically due to the effect of caffeine. In animal models, gall-bladder fluid absorption increases in the early stages of cholesterol gallstone formation, and caffeine prevents cholesterol crystallisation by possibly inhibiting gall-bladder absorption. In addition, caffeine and other methylxanthines may decrease bile cholesterol saturation by stimulating ileal bile acid absorption, increasing hepatic bile acid uptake, and increasing concentrations of sex hormone-binding globulin. On the other hand, caffeine possesses significant thermogenic properties and could prevent the gallstone formation by increasing energy expenditure as well as decreasing body fat stores. Furthermore, decaffeinated coffee was not associated with gallstone disease according to prospective cohorts conducted by Leitzmann et al.. No association was observed with tea consumption in their prospective cohorts, possibly due to the low amount of caffeine in this beverage. Notably, we did not find that caffeinated soft drinks had any potential for reducing the risk of gallstones, which may suggest that other ingredients in coffee may contribute to the preventative effect. The variety of raw coffee and the method of preparation could influence caffeine concentrations. We could not examine the relationship between caffeine and the risk of gallstone disease because most of the included studies reported only the number of cups of coffee consumed and only one study provided information on caffeine intake. Although caffeine is also present in tea, cola and energy drinks, coffee consumption is strongly correlated with total caffeine intake in North America and Europe.
Alternatively, other ingredients in coffee could possibly contribute to the preventive effect. Coffee contains an insoluble hemicellulose fibre that may inhibit the colonic deoxycholic acid absorption. Coffee may also act through the effects of magnesium, a constituent of coffees, which is inversely associated with gallstone disease. In addition, anti-oxidative compounds such as caffeic acid and tocopherols, are capable of inhibiting reactive oxygen metabolites, which appear to promote cholesterol crystal formation.
Strengths of the present meta-analysis included the dose–response analysis, which provides a comprehensive description of the relationship between coffee consumption and gallstone disease. Another strength is the prospective design of the included studies in our analysis, which should minimise the likelihood of recall, interviewer and selection biases that can be a concern in other epidemiological study designs. Furthermore, every study was matched or adjusted for a wide range of potential confounders that may influence gallstone formation, such as age, body mass index, smoking status, alcohol or tea drinking, drug use, physical activities and history of diabetes. The relatively large number of participants and cases provided high statistical power. The overall effect estimates did not altered materially in sensitivity analyses, which contributed to the stable results.
However, several limitations should be acknowledged. First, the exposure assessment of the original studies was based on self-report, and measurement error is inevitable in this circumstances. However, with regard to coffee intake, the FFQ had good validity compared with dietary recall interviews. In addition, we conducted a stratified analysis based on exposure assessment, and the significant inverse association between coffee intake and gallstone disease was observed in both FFQ and dietary recall interview groups.
Second, although the included studies adjusted for multiple known confounding variables, we cannot exclude the possibility that the observed association was in part attributed to unmeasured confounders, such as dietary, behavioural, or genetic factors, in our analysis.
Third, we could not obtain information on the type of coffee consumed or the method of coffee preparation, which might affect the final estimates by influencing caffeine concentrations in the coffee. Moreover, we could not assess whether the effect of coffee intake depended on the duration of exposure because the majority of the included studies did not provide information on long-term coffee use.
Another limitation could be the limited generalisability of our study. All of the included studies in our meta-analysis were from Western Europe/America; thus, we were unable to generalise our findings to general populations. Studies conducted in Asia did not show any associations between coffee intake and gallstone disease; however, the findings from Asian area should be interpreted with caution due to the weakness of their study design.
Finally, different criteria for outcome measurements were used among the studies, which may lead to some heterogeneity. The majority of the included cohorts used cholecystectomy as the outcome; thus, we were unable to generalise our results to gallstone disease per se, but instead more likely to symptomatic gallstones that require surgery. However, using the outcome definition of cholecystectomy represents gallstone disease that is of clinical importance. In addition, it is likely that there was considerable underestimation of gallstone cases in the included studies because most gallstones are asymptomatic. Therefore, we were unable to estimate the incidence of gallstone formation.
In conclusion, our data suggest that coffee consumption is inversely associated with a risk of gallstone disease based on the findings of prospective cohort studies. Specifically, we observed an inverse relation in women but not in men. However, this result should be interpreted with caution because of the high heterogeneity in male cohort studies. This study may provide insight and a better understanding of the coffee-gallstone disease relationship. Further studies should investigate the sex factor in this association and assess the potential therapeutic effects of coffee and individual coffee constituents on gallstone disease, as well as the duration-response of coffee consumption on gallstone disease.
SHARE
