In men without hypertension and BMI< 30 kg/m2, we found intakes of vitamin C to be inversely related to serum uric acid concentrations, independent of dietary and other risk factors for gout such as body mass index, age, and alcohol intake. The associations were largely derived by vitamin C supplement use. Furthermore, we observed similar significant associations when we used dietary exposure data, which were assessed 4–8 years before blood collection, as predictors.
Our results showed that total vitamin C intake of 500 mg/d or higher is associated with a ~0.6–0.7 mg/dL lower level of serum uric acid relative to those with intake < 90 mg/d. The magnitude of difference of serum uric acid associated with total vitamin C intake of 500mg/d was closely in line with that from a recent trial (6
). This randomized trial showed that supplementation with vitamin C as low as 500 mg/d for two months reduced serum uric acid by 0.5 mg/dL, compared to no change in the placebo group (6
). This level of population mean difference of serum uric acid levels (17
) can be translated into a clinically relevant difference in the risk for incident gout, as demonstrated in our previous studies (19
). For example, one daily serving increase in beer intake was associated with a mean serum uric acid level increase of 0.4 mg/dL in the cross-sectional analysis of National Health and Nutrition Examination Survey III (17
) and with a 50% increased risk of incident gout in our prospective analysis of the HPFS (19
). This potentially significant impact on the eventual risk of gout is also supported by our results, using hyperuricemia as a dichotomous outcome. Nevertheless, prospective studies with outcome of incident gout would be valuable.
Vitamin C likely modulates serum uric acid concentration via its uricosuric effect. Vitamin C and uric acid are reabsorbed through anion-exchange transport in the proximal tubule (6
). Increased vitamin C concentration in the filtrate may competitively inhibit uric acid reabsorption (5
). Recent advances in our understanding of the molecular mechanisms of renal uric acid transport suggest that the uricosuric effect may be through cis-inhibition of URAT1 (uric acid transporter 1, the key target of typical uricosurics) (21
-dependent anion cotransporter (e.g. SLC5A8/A12) (22
) or both in the proximal tubules(23
). Furthermore, greater vitamin C intake may possibly improve renal function and increase the glomerular filtration rate (6
), providing another potential mechanism for the uricosuric effect of vitamin C intake. Both human and animal studies have demonstrated that administration of vitamin C increases renal plasma flow and glomerular filtration rate and attenuates the increases in arterial pressure (24
). The antioxidant property of Vitamin C could reduce oxidative stress and inflammation, and could, therefore, be related to lower uric acid synthesis (16
Strengths of the current study include use of a validated FFQ to assess dietary intake, and multiple measurements of dietary exposure. Besides use of dietary intake in 1994 as the predictor of serum uric acid, we conducted a sensitivity analysis using average dietary intake collected in 1986 and 1990. In this way we may reduce random errors introduced by a single dietary measurement, and, because of both dietary assessments prior to blood collection, minimize misclassification of exposure (vitamin C intake) due to change of diet related to high serum uric acid. We observed similar results with the main analyses, suggesting robustness of our findings. Our study population consisted of participants without hypertension and with BMI <30 kg/m2
, limiting the generalizability of our findings. Our study is also limited by including only men; thus, the effect of gender could not be studied. Another limitation is that our cohort does not represent random samples of US men; therefore, the dietary patterns cannot be taken to reflect the general population. Nevertheless, the biological effects of diet in this cohort should be the same as those among men in general. Although validation studies suggested a high level of validity in Vitamin C intake measured by the FFQ used in the current study, (9
) measurement of plasma vitamin C concentration could provide a more accurate estimate of vitamin C status. Further, because of the observational design of the current study, we cannot exclude a possibility of residual confounding due to unmeasured confounders. For example, lack of information of use of gout-specific medicines may confound the association between vitamin C and uric acid concentration. However, we obtained similar results after excluding patients with gout.
In conclusion, we found that that intake of vitamin C is inversely associated with serum uric acid concentrations in a population-based study. These findings support a potential role for vitamin C in the prevention of hyperuricemia and gout. Our findings are most directly generalizable to men aged 50 years or older without hypertension and obesity. Corresponding studies of men with these conditions and of women would be valuable.