Our objective was to evaluate prospectively the suspected protective effect of vitamin C intake against the risk of gout in a large cohort of men. Using the American College of Rheumatology criteria for gout,15
we found that the risk of gout decreased with increasing vitamin C intake, up to a 45% lower risk at the top vitamin C intake category of 1500 mg or more. These associations were independent of dietary and other risk factors for gout such as body mass index, age, hypertension, diuretic use, alcohol, and chronic renal failure. The decreasing risk persisted across subgroups stratified by body mass index, alcohol use, and dairy intake. The current study provides the first prospective evidence about the inverse association between vitamin C intake and the risk of gout.
The suspicion for a potential protective effect of vitamin C intake against gout originally stemmed from metabolic experiments that examined the impact of short-term loading of high-dose vitamin C on the serum uric acid levels. For example, ingestion of a single dose of 4 g vitamin C doubled the fractional excretion of uric acid and a daily ingestion of 8 g of vitamin C for 3 to 7 days reduced serum uric acid by 2.0 to 3.1 mg/dL as a result of uricosuria.9
Recently, a double-blinded placebo-controlled randomized trial (n=184) showed that supplementation with vitamin C as low as 500 mg daily for two months reduced serum uric acid by 0.5mg/dl, compared to no change in the placebo group.10
Furthermore, a retrospective Taiwanese case-control study (91 gout cases and 91 controls) reported an inverse association between vitamin C intake and the presence of gout (unadjusted odds ratios between the extreme tertiles, 0.31; 95% CI, 0.15 to 0.35), although no multivariate adjustment for the link was reported.22
The uricosuric effect of vitamin C is likely due to a competition for renal reabsorption of uric acid via an anion-exchange transport system at the proximal tubule.7, 9
Recent advances in molecular mechanisms of renal urate transport suggest that the uricosuric effect may be through cis-inhibition of URAT1 (urate transporter 1, the key target of typical uricosurics),23
-dependent anion cotransporter (e.g. SLC5A8/A12), or both in the proximal tubules.2
Furthermore, the recent randomized trial showed vitamin C supplements (500 mg/day) significantly increased glomerular filtration rate, providing another potential mechanism for the uricosuric effect of vitamin C intake.10
It remains speculative whether the antioxidant action of vitamin C may have a protective effect against gouty inflammation, as was suggested for reducing the risk of inflammatory polyarthritis according to a recent prospective study.24
While our data suggest that total vitamin C intake of 500 mg/day or more is associated with a reduced risk, the potential benefit of lower intake is not clear. According to a recent analysis of nine prospective studies, compared with subjects who did not take supplemental vitamin C, those who took > 700 mg supplemental vitamin C/day had a 25% lower risk of coronary heart disease (95% CI, 7%, 40%; P for trend < 0.001).25
The same study found that supplemental vitamin E intake was not significantly related to reduced CHD risk.25
This potential cardiovascular benefit of vitamin C may be particularly relevant among gout patients given their increased risk of cardiovascular morbidity and mortality.26, 27
Given the general safety profile associated with Vitamin C intake, particularly, within the generally consumed ranges as in our study (e.g. tolerable upper intake level of vitamin C < 2000 mg in adults according to the Food and Nutrition Board, Institute of Medicine),28
vitamin C may provide a useful option in the prevention of gout.
Several strengths and potential limitations of our study deserve comment. Our study was substantially larger than previous studies concerning gout1, 29–34
and dietary data including vitamin C information were prospectively collected and validated. Potential biased recall of diet was avoided in this study because the intake data were collected before the diagnosis of gout. Because dietary consumption was self-reported by questionnaire, some misclassification of exposure is inevitable. However, the food frequency questionnaire has been extensively validated in a sub-sample of this cohort, and any remaining misclassification would have likely biased the results toward the null. The use of repeated dietary assessments in the analyses not only accounts for changes in dietary consumption over time but also decreases measurement error.11, 13
However, our study was observational; thus, we cannot rule out the possibility that unmeasured factors might contribute to the observed associations. As in other epidemiologic studies of gout,1, 29–32
our primary definition of gout did not require observation of urate crystals in joint fluid examination. While presence of a tophus or urate crystal in joint fluid would be diagnostic of gout,15
the sensitivity of these findings is too low especially in a population study such as ours because arthrocentesis is performed infrequently. Thus, its application would likely miss the vast majority of genuine gout cases. The reliable information provided by health professionals in our cohort, the obvious nature of clinical presentation of gout, and the ready access to medical care for these men would have helped ensure a high level of sensitivity in our detection of gout. In our study, fulfillment of six of the 11 American College of Rheumatology survey criteria15
showed a high-degree of concordance with medical record review and the incidence rate of gout fulfilling the criteria in our cohort closely agreed with that estimated among male physicians in the Johns Hopkins Precursor Study1
(1.5 vs. 1.7 per 1000 person-years, respectively).
The restriction to health professionals in our cohort is both a strength and a limitation. The cohort of well-educated men minimizes potential for confounding associated with socioeconomic status and we were able to obtain high quality data with minimal loss to follow-up. Although the absolute rates of gout and distribution of vitamin C intake may not be representative of a random sample of US men, the biological effects of vitamin C on gout should be similar. Of note, other dietary and life style risk factors of gout observed in this cohort3, 4, 35, 36
have all been found significant in the studies based on the NHANES III.37–40
Our findings are most directly generalizable to men 40 years old and older (the most gout-prevalent population29
) with no history of gout. Given the potential influence of female hormones on the risk of gout in women41
and an increased role of dietary impact on uric acid levels among patients with existing gout,42
prospective studies of these populations would be valuable.
In conclusion, these prospective data indicate that vitamin C intake is strongly associated with a lower risk of gout. Increasing vitamin C intake may be beneficial in the prevention of gout.