Coffee, Tea, and Caffeine Consumption and Serum Uric Acid Level: The Third National Health and Nutrition Examination Survey

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1 Arthritis & Rheumatism (Arthritis Care & Research) Vol. 57, No. 5, June 15, 2007, pp DOI /art , American College of Rheumatology ORIGINAL ARTICLE Coffee, Tea, and Caffeine Consumption and Serum Uric Acid Level: The Third National Health and Nutrition Examination Survey HYON K. CHOI 1 AND GARY CURHAN 2 Objective. Coffee is one of the most widely consumed beverages in the world and may affect serum uric acid levels and risk of gout via various mechanisms. Our objective was to evaluate the relationship between coffee, tea, and caffeine intake and serum uric acid level in a nationally representative sample of men and women. Methods. Using data from 14,758 participants ages >20 years in the Third National Health and Nutrition Examination Survey ( ), we examined the relationship between coffee, tea, and caffeine intake and serum uric acid level using linear regression. Additionally, we examined the relationship with hyperuricemia (serum uric acid >7.0 mg/dl among men and >5.7 mg/dl among women) using logistic regression. Intake was assessed by a food frequency questionnaire. Results. Serum uric acid level decreased with increasing coffee intake. After adjusting for age and sex, serum uric acid level associated with coffee intake of 4 to 5 and >6 cups daily was lower than that associated with no intake by 0.26 mg/dl (95% confidence interval [95% CI] 0.11, 0.41) and 0.43 mg/dl (95% CI 0.23, 0.65; P for trend < 0.001), respectively. After adjusting for other covariates, the differences remained significant (P for trend < 0.001). Similarly, there was a modest inverse association between decaffeinated coffee intake and serum uric acid levels (multivariate P for trend 0.035). Total caffeine from coffee and other beverages and tea intake were not associated with serum uric acid levels (multivariate P for trend 0.15). The multivariate odds ratio for hyperuricemia in individuals with coffee intake >6 cups daily compared with those with no coffee use was 0.57 (95% CI 0.35, 0.94; P for trend 0.001). Conclusion. These findings from a nationally representative sample of US adults suggest that coffee consumption is associated with lower serum uric acid level and hyperuricemia frequency, but tea consumption is not. The inverse association with coffee appears to be via components of coffee other than caffeine. KEY WORDS. Uric acid; Gout; Coffee; Tea; Caffeine; NHANES-III. INTRODUCTION Hyperuricemiais considered the precursor of gout, which is the most common inflammatory arthritis in adult men 1 Hyon K. Choi, MD, DrPH: Arthritis Research Centre of Canada, Vancouver General Hospital, University of British Columbia, Vancouver, Canada, and Brigham and Women s Hospital, Boston, Massachusetts; 2 Gary Curhan, MD, ScD: Channing Laboratory, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts. Dr. Choi has served on the advisory board for and received honoraria (less than $10,000 each) from TAP Pharmaceuticals and Savient Pharmaceuticals, and has received grant support from TAP Pharmaceuticals. Address correspondence to Hyon K. Choi, MD, DrPH, Division of Rheumatology, Department of Medicine, University of British Columbia, Arthritis Research Centre of Canada, 895 West 10th Avenue, Vancouver, BC V5Z 1L7, Canada. hchoi@partners.org. Submitted for publication June 26, 2006; accepted in revised form October 31, (1). Coffee and tea consumption may affect serum uric acid levels via various mechanisms including influence on insulin resistance (2 9), but few data are available. Only 1 cross-sectional study investigated the link between these beverages and serum uric acid level based on 2,240 Japanese men and found a significant inverse association between coffee consumption and serum uric acid levels but no association with tea consumption (10). We are not aware of any study that has investigated the relationship with total caffeine or decaffeinated coffee intake. Coffee is one of the most widely consumed beverages in the world; more than 50% of Americans drink coffee, and average per capita intake is 2 cups per day (9,11). Given this widespread use, the potential health effects of coffee are important for public health as well as for helping an individual make an informed choice regarding coffee consumption. To examine these issues, we conducted a cross-sectional study based on the US Third National Health and Nutrition Examination Survey (NHANES-III) (12,13). 816

2 Coffee and Uric Acid 817 SUBJECTS AND METHODS Study population. Conducted between 1988 and 1994, the NHANES-III included a representative sample of the noninstitutionalized civilian US population, which was selected by using a multistage, stratified sampling design (12). After a home interview, participants were invited to attend examination sessions where blood and urine specimens were obtained. For participants unable to attend the examination for health reasons, a blood sample was obtained during the home interview. We limited our analysis to participants ages 20 years who attended the medical examination, and we included the 14,758 participants (6,906 men and 7,852 women) with complete information in our analyses. We repeated our analyses among 14,314 participants after excluding participants who self-reported gout or were taking allopurinol or uricosuric agents (n 444). Uric acid measurement. Serum uric acid level was measured by oxidization with the specific enzyme uricase to form allantoin and H 2 O 2 (Hitachi Model 737 Multichannel Analyzer; Boehringer Mannheim Diagnostics, Indianapolis, IN). Details about quality-control procedures have been published elsewhere (13). Values are reported in milligrams per deciliter; to convert to micromoles per liter, multiply by Assessment of coffee and tea intake. During the home interview, coffee and tea intake were determined from responses to the food frequency questionnaire administered to participants to assess their usual consumption over the past month. Using the US Department of Agriculture food composition sources, we estimated that the caffeine content of the individual beverages was 137 mg per cup of coffee, 47 mg per cup of tea, and 46 mg per bottle or can of cola beverage (9). Assessment of covariates. The average daily intakes of total meat, seafood, and dairy foods were derived from responses to the food frequency questionnaire. Food frequency questionnaire assessment of dietary intake has been shown to be a valid and reliable method for assessing average dietary consumption (14,15). Total energy intake was calculated from a single 24-hour dietary recall. The NHANES-III collected information on body measurements (including height and weight), medication use (including diuretics, antihypertensives, allopurinol, and uricosuric agents), medical conditions (including self-reported hypertension and gout), and serum creatinine. Glomerular filtration rate (GFR) was estimated using the simplified Modification of Diet in Renal Disease study equation: GFR (ml/minute per 1.73 m 2 ) 186 (serum creatinine level [mg/dl]) (age) (0.742, if female) (1.212, if black) (16 18). Body mass index (BMI) was calculated by dividing the weight in kilograms by the square of the height in meters. Statistical analysis. All statistical analyses were computed using survey commands of STATA version 8.2 (e.g., SVYMEAN and SVYREG) to incorporate sample weights and adjust for clusters and strata of the complex sample design (StataCorp, College Station, TX). We used linear regression modeling to evaluate the relationship between beverage and caffeine intake and serum uric acid level. For these analyses, coffee consumption was categorized into 5 groups: never, 1 cup per day, 1 3 cups per day, 4 5 cups per day, and 6 cups per day. Caffeine intake was categorized into quintiles. Multivariate models were adjusted for age; sex; smoking status; total energy intake; BMI; use of diuretics, beta-blockers, allopurinol, and uricosuric agents; self-reported hypertension; GFR; and intake of total meats, seafood, dairy foods, decaffeinated coffee, and tea. Trends in serum uric acid levels across categories of intake were assessed in linear regression models using the median values of each category to minimize the influence of outliers. We also performed logistic regression with a dichotomous variable of hyperuricemia (i.e., serum uric acid level 7.0 mg/dl among men and 5.7 mg/dl among women [13]) adjusting for the same covariates. We examined the potential impact of an alternative definition of hyperuricemia (serum uric acid level 6.0 mg/dl regardless of sex) in these regression models. We explored potential interactions by sex, BMI ( 25 kg/m 2 versus 25 kg/m 2 ), and alcohol use (abstainer versus drinker) by testing the significance of interaction terms added to our final multivariate models. For all difference estimates, we calculated 95% confidence intervals (95% CIs). All P values were 2-sided. RESULTS The mean age of the population was 45 years. The mean serum uric acid level was 5.32 mg/dl (6.07 mg/dl in men and 4.65 mg/dl in women) and 18% of participants were hyperuricemic (19% of men and 17% of women). The relevant characteristics according to coffee and tea intake are shown in Table 1. With increasing coffee intake, the proportion of men increased. Individuals in the highest category of coffee intake reported hypertension more often and had slightly higher total meat intake, but used diuretics less often. With increasing tea intake, the proportion of men tended to decrease. Individuals in the highest category of tea intake tended to report hypertension and diuretic use less often. Serum uric acid level tended to decrease with increasing coffee intake (Figure 1). After adjusting for age and sex, serum uric acid level in individuals with coffee intake 6 cups daily was lower than in those with no use by 0.43 mg/dl (95% CI 0.22, 0.65; P for trend 0.001). After adjusting for other covariates, the differences were attenuated but remained significant (P for trend 0.001) (Table 2). Similarly, there was a modest inverse association between decaffeinated coffee intake and serum uric acid levels (multivariate P for trend 0.035) (Table 2). However, there was no association between tea consumption and serum uric acid levels (multivariate P for trend 0.96)

3 818 Choi and Curhan Table 1. Characteristics according to categories of coffee and tea intake in the Third National Health and Nutrition Examination Survey (NHANES-III)* All participants Coffee, cups/day Tea, cups/day 0 < >6 0 <1 1 3 >4 Number 14,758 5,417 6,668 1, ,986 6, Age, years Men, % Body mass index, kg/m Diuretic use, % History of hypertension, % Alcohol, servings/day Total meat, servings/day Seafood, servings/day Dairy foods, servings/day Use of uric acid drugs, % Creatinine, mg/dl * Values are the mean unless otherwise indicated. Data are presented incorporating sample weights and adjusted for clusters and strata of the complex sample design of NHANES-III. Allopurinol and uricosuric agents. (Figure 1, Table 2). Similarly, total caffeine intake from beverages was not associated with serum uric acid levels (multivariate P for trend 0.14) (Figure 1, Table 3). When we repeated our analyses after excluding participants who self-reported gout or were taking allopurinol or uricosuric agents (n 444), the results did not materially change. The results of logistic regression with hyperuricemia as a dichotomous outcome were similar. For example, the multivariate odds ratio (OR) for hyperuricemia in individuals with coffee intake of 6 cups per day as compared with those with no coffee use was 0.57 (95% CI 0.35, 0.94; P for trend 0.001). In contrast, the corresponding OR for tea intake of 4 cups was 1.00 (95% CI 0.65, 1.53; P for trend 0.72). An alternative definition of hyperuricemia (serum uric acid level 6.0 mg/dl regardless of sex) did not alter these results materially. Figure 1. Age- and sex-adjusted serum uric acid levels according to categories of coffee, tea, and caffeine intake. Error bars indicate standard errors. Data are presented incorporating sample weights and adjusted for clusters and strata of the complex sample design of the Third National Health and Nutrition Examination Survey. When we additionally adjusted for caffeine intake in our multivariate models (linear or logistic), there was no material change in the inverse association with coffee (all multivariate P values for trend 0.01) and the association with tea was null (all multivariate P values 0.5). There was no significant interaction for any of the individual beverages or total caffeine by sex, BMI ( 25 kg/m 2 versus 25 kg/m 2 ), or alcohol intake (yes or no; all P values for interaction 0.1). DISCUSSION In this nationally representative sample of US men and women, we found that the serum uric acid level significantly decreased with increasing coffee intake, but not with tea intake. Furthermore, there was no association with total caffeine intake from beverages. These associations were independent of both the other beverages we studied and other risk factors for hyperuricemia such as age, sex, BMI, dietary risk factors, alcohol use, renal function, hypertension, and diuretic use. These findings did not appear to differ across different subgroups stratified by sex, BMI, and alcohol use. Our results are closely in line with the only previous study on the topic (10). That cross-sectional study of 2,240 Japanese middle-aged men found that coffee consumption, not tea consumption, was inversely associated with serum uric acid levels, despite more common use of tea than coffee in that study population (10). The mean serum acid level in individuals consuming 5 cups of coffee daily was lower than that in individuals consuming 1 cup by 0.4 mg/dl (P 0.001), which is very similar to our results. This level of population mean difference of serum uric acid levels (19,20) can be translated into a clinically relevant difference in the risk for incident gout as demonstrated in our previous studies (21,22). For example, one daily serving increase in beer intake was associated with a

4 Coffee and Uric Acid 819 Table 2. Differences in serum uric acid levels (mg/dl) according to categories of coffee and tea intake in the Third National Health and Nutrition Examination Survey (NHANES-III)* Participants, no. Age- and sex-adjusted difference (95% CI) Multivariate difference (95% CI) Multivariate difference (95% CI) Coffee (cups/day) 0 5,417 0 (referent) 0 (referent) 0 (referent) 1 6, ( 0.16, 0.01) 0.01 ( 0.08, 0.05) 0.02 ( 0.09, 0.05) 1 3 1, ( 0.14, 0.07) 0.01 ( 0.08, 0.11) 0.00 ( 0.10, 0.09) ( 0.41, 0.11) 0.18 ( 0.30, 0.05) 0.22 ( 0.35, 0.09) ( 0.65, 0.22) 0.35 ( 0.56, 0.14) 0.36 ( 0.57, 0.14) P value for trend Decaffeinated coffee (cups/day) 0 14,270 0 (referent) 0 (referent) 0 (referent) ( 0.18, 0.22) 0.02 ( 0.21, 0.16) 0.05 ( 0.24, 0.15) ( 0.43, 0.12) 0.20 ( 0.50, 0.10) 0.24 ( 0.54, 0.06) ( 0.96, 0.17) 0.41 ( 1.04, 0.22) 0.42 ( 1.01, 0.17) P value for trend Tea (cups/day) 0 7,986 0 (referent) 0 (referent) 0 (referent) 1 6, ( 0.10, 0.04) 0.03 ( 0.09, 0.04) 0.02 ( 0.09, 0.04) ( 0.12, 0.20) 0.00 ( 0.17, 0.16) 0.01 ( 0.15, 0.18) ( 0.21, 0.22) 0.01 ( 0.19, 0.17) 0.02 ( 0.19, 0.15) P value for trend * Uric acid levels are reported in milligrams per deciliter; to convert to micromoles per liter, multiply by Data are presented incorporating sample weights and adjusted for clusters and strata of the complex sample design of NHANES-III. 95% CI 95% confidence interval. Adjusted for age; sex; smoking status; body mass index; smoking; use of diuretics, beta-blockers, allopurinol, and uricosuric agents; hypertension; and glomerular filtration rate. Additionally adjusted for intake of alcohol; total meats, seafood, and dairy foods; and the other 2 beverages in this table. mean serum uric acid level increase of 0.4 mg/dl in the cross-sectional analysis of NHANES-III (21) and with a 50% increased risk of incident gout in our prospective analysis of Health Professionals Follow-up Study (19). This potentially significant impact on the eventual risk of gout is also supported by our results using hyperuricemia as a dichotomous outcome and when using various definitions for hyperuricemia. We found no association between total caffeine intake and hyperuricemia. However, we did find a modest inverse association with decaffeinated coffee consumption. These findings suggest that components of coffee other than caffeine contribute to the observed inverse association between coffee intake and uric acid levels. These findings closely agree with a recent study that found that both caffeinated and decaffeinated coffee were inversely associated with C peptide levels (a marker of endogenous insulin levels), but tea intake and total caffeine intake after adjusting for coffee intake were not (7). Because there is a strong positive relationship between serum insulin resistance and hyperuricemia (23 27) and insulin reduces the renal excretion of urate (25,28,29), decreased insulin resistance and insulin levels associated with coffee consumption may lead to lower uric acid levels. Coffee is the major source of the phenol chlorogenic acid, which is a strong antioxidant (8,30). Previous studies have suggested that plasma glucose concentrations are reduced by chlorogenic acid (30,31), which may combine with other antioxidants in coffee to decrease oxidative stress. Antioxidants may improve insulin sensitivity Table 3. Differences in serum uric acid levels (mg/dl) according to quintiles of caffeine intake in the Third National Health and Nutrition Examination Survey (NHANES-III)* Caffeine intake Age- and sex-adjusted difference (95% CI) Multivariate difference (95% CI) Multivariate difference (95% CI) 34 mg/day 0 (referent) 0 (referent) 0 (referent) mg/day 0.08 ( 0.02, 0.18) 0.02 ( 0.07, 0.11) 0.00 ( 0.09, 0.08) mg/day 0.13 (0.02, 0.23) 0.12 (0.03, 0.22) 0.09 (0.01, 0.19) mg/day 0.02 ( 0.07, 0.12) 0.00 ( 0.09, 0.09) 0.03 ( 0.12, 0.06) 274 mg/day 0.00 ( 0.11, 0.10) 0.00 ( 0.09, 0.09) 0.04 ( 0.13, 0.06) P value for trend * Uric acid levels are reported in milligrams per deciliter; to convert to micromoles per liter, multiply by Data are presented incorporating sample weights and adjusted for clusters and strata of the complex sample design of NHANES-III. 95% CI 95% confidence interval. Adjusted for age; sex; smoking status; body mass index; smoking; use of diuretics, beta-blockers, allopurinol, and uricosuric agents; hypertension; and glomerular filtration rate. Additionally adjusted for intake of alcohol, total meats, seafood, and dairy foods.

5 820 Choi and Curhan (32,33) and decrease insulin levels in rats (30,34). Chlorogenic acid also acts as a competitive inhibitor of glucose absorption in the intestine (8,35). Indeed, decaffeinated coffee seemed to delay intestinal absorption of glucose and increased glucagon-like peptide 1 concentrations in an intervention study in humans (8,36). Glucagon-like peptide 1 is well known for its beneficial effects on glucoseinduced insulin secretion and insulin action (8,37). Tea also has many different types of antioxidants; however, antioxidant capacity per serving and total contributions are substantially higher in coffee than in tea (30,38 40). Furthermore, the effect of caffeine may also depend on other components of coffee. It has also been speculated that noncaffeine xanthines contained in coffee may inhibit xanthine oxidase, thus contributing to lowering serum uric acid levels (10). Strengths and limitations of our study deserve comment. This study was performed in a nationally representative sample of US women and men; therefore, the findings are likely to be generalizable to US men and women. A crosssectional study design tends to leave uncertainty regarding the temporal sequence of exposure-outcome relationships and is also vulnerable to a recall bias as opposed to prospective studies. However, given the absence of existing conventional recommendations on coffee or tea consumption for hyperuricemia and gout, it is unlikely that some participants changed their coffee or tea intake based on previously identified hyperuricemia or gout. In the NHANES-III, the health examination component including serum uric acid measurement (outcome) was performed after the household interview that inquired about intake of these beverages during the past month (exposure). Therefore, it appears implausible that serum uric acid levels measured in this study would somehow systematically influence the reporting of intake of these beverages. Furthermore, these potential methodologic limitations would not explain differential effects among these beverages. In conclusion, our results suggest that coffee consumption is associated with a lower level of uric acid and frequency of hyperuricemia, but tea consumption is not. The inverse association with coffee appears to be via components of coffee other than caffeine. AUTHOR CONTRIBUTIONS Dr. Choi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study design. Choi. Acquisition of data. Choi. Analysis and interpretation of data. Choi, Curhan. Manuscript preparation. Choi, Curhan. Statistical analysis. Choi. REFERENCES 1. Roubenoff R, Klag MJ, Mead LA, Liang KY, Seidler AJ, Hochberg MC. 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