This study is the first quantitative review of published randomized, clinical trials examining the effect of oral vitamin C supplementation on SUA. Overall, vitamin C supplementation reduced SUA with a mean aggregate effect of -0.35 mg/dL (P = 0.032; SI: -20.8 μmol/L). Although only 6 of the 13 trials reported significant reductions in SUA, pooling these small trials made it possible to estimate an overall effect, a key advantage of the meta-analysis method. These findings support the observed inverse associations between intake of dietary and supplemental vitamin C and SUA levels.
Vitamin C is an essential micronutrient in a number of physiologic processes. When plasma ascorbate levels fall below 11 μmol/L, clinical features of scurvy may develop (47
). The median dose of vitamin C used in trials was 500 mg/d, which is well above the recommended dietary allowance for vitamin C, 90 mg/d in men and 75 mg/d in women. Surpassing the tolerable upper intake level of 2 g/d (48
) may cause osmotic diarrhea, gastrointestinal disturbance (49
), and calcium oxalate nephrolithiasis (50
). Most studies report few side effects, however, when doses are below the tolerable upper intake level (49
). None of the trials included in this meta-analysis reported adverse effects from vitamin C supplementation.
Several studies have described biological mechanisms by which vitamin C reduces SUA. In vivo
studies suggest that vitamin C has uricosuric properties, increasing renal fractional clearance of uric acid, thereby reducing SUA (14
). This is likely due to competitive inhibition of an anion exchange transport system at the proximal tubule in the nephron (16
). Vitamin C may act specifically at uric acid reabsorption sites in the apical brush border of the proximal tubule, such as urate transporter 1 (URAT1), and a sodium-dependent anion cotransporter, SLC5A8/A12 (22
). It is also possible that vitamin C increases the glomerular filtration rate by reducing glomerular microvascular ischemia and increasing dilatation of afferent arterioles (10
). Furthermore, as an effective antioxidant vitamin C decreases free radical-induced damage to body cells (57
), thereby reducing production and ultimately serum concentration of uric acid (22
There are a number of limitations to this meta-analysis that warrant consideration. Heterogeneity between trials was found to be significant (I2
= 77%; P
< 0.01). An attempt to address heterogeneity by performing subgroup analyses based on trial characteristics did not fully explain differences in effect as demonstrated by elevated I2
values within strata. Significance observed among some subgroup strata may indicate that baseline SUA, dose of vitamin C, use of vitamin C alone without any other supplement(s), and placebo use play a greater role in heterogeneity than other subject and trial characteristics. However, strata based on the comparison of patient characteristics across trials, specifically mean age, percent male gender, baseline serum ascorbate, and baseline serum uric acid, are prone to ecological bias and should be interpreted with additional caution (58
Another important consideration is publication bias. Although our funnel plot () and other analyses did not support the presence of publication bias (Egger's test: P
= 0.70), during the search we identified one trial whose authors decided not to report SUA findings because of non-significant results (41
). It is possible that other trials lacking significant results were never published, skewing the overall results toward an effect. Another interpretation of the asymmetrical funnel plot is “small study effects.” Smaller studies often lack methodological rigor in design and analysis, contributing to inflated treatment effects (44
). This is particularly evidenced by trials’ rare mention of design quality features in this meta-analysis (). Further, even when optimally designed, small trials suffer from the inherent limitation of low statistical power. Indeed, small trial size and the paucity of reported assurances regarding trial quality constitute an important limitation of this meta-analysis.
Another important consideration affecting interpretation of our results is the method by which SUA is measured. Of the thirteen trials included in this study, there are considerable differences in the manner by which SUA was determined and in the detail provided to describe this critical aspect of trial methodology (). Prior research describes the ability of vitamin C to interfere with SUA measurements (19
). Moreover, depending on the biochemical assay, vitamin C has been demonstrated to artificially increase (15
) or decrease measured SUA (67
). Artificial reduction in SUA is particularly related to the use of a biochemical assay employing the oxidase-peroxidase system, i.e. the Trinder method (68
). In one study, Martinello et al (2006) administered vitamin C to eighteen volunteers and measured SUA via the Trinder method and ultraviolent light (UV) (67
). The Trinder method found a significant baseline decrease in SUA, while UV showed no change in SUA (67
). Although the exact mechanism of interference is not understood, it is believed that vitamin C as an antioxidant depletes the hydrogen peroxide utilized by the Trinder method to produce chromophore and detect SUA (69
). Contrary to expectations in this meta-analysis, however, the one trial that explicitly describes use of the oxidase-peroxidase system without addressing vitamin C interference (35
) did not observe a reduction in SUA after vitamin C supplementation. A number of researchers note that the addition of ascorbate oxidase, which oxidizes ascorbic acid to dehydroascorbic acid, does not interfere with the chromogen system responsible for SUA detection (69
). Of all the trials included in this meta-analysis, this method was only explicitly mentioned by Huang and colleagues (10
). Despite potential interference in serum measurements, prior small clinical studies have documented concurrent increase in uric acid excretion after introduction of vitamin C (14
). Mitch et al (1980) notes, however, that urine uric acid measures are also susceptible to interference, depending on the measurement assay used (62
). As SUA measurement integrally affects conclusions, future trials should employ methods that minimize vitamin C interference in serum measurements and also quantify urinary excretion of uric acid.
One trial in this meta-analysis that reported null effects of vitamin C on SUA included 300mg/d of aspirin in its combination therapy (27
). Aspirin has a mixed effect on the uric acid excretion with doses >3 grams/day causing uricosuria, while doses between 1-2 grams promote UA retention (72
). Recent studies suggest that even small doses of aspirin, i.e. doses between 75 - 325 mg/day, also decrease uric acid clearance, causing uric acid retention (73
). It is hypothesized that aspirin competes with uric acid at tubular secretion and reabsorption receptors and more globally suppresses glomerular filtration rate (72
). Consistent with this hypothesis, the trial utilizing aspirin in this meta-analysis (27
) contributed the largest weight against vitamin C reduction of SUA. It is possible that aspirin inhibits the uricosuric action of vitamin C, nullifying its effect. Exclusion of this trial increased the magnitude and significance of our pooled effect to -0.40 mg/dL (P
= 0.019; SI: -23.8 μmol/L).
Five of the 13 trials in this study (26
) evaluated SUA in the context of exercise. As acute exercise is known to increase oxidative stress and levels of serum and salivary uric acid (39
), we attempted to avoid inclusion of this variable in our pooled analysis. This was not possible in one of the trials, because the authors did not measure pre-exercise SUA values (30
). Conducting the meta-analysis using the SUA values measured closest to the conclusion of exercise rather than pre-exercise SUA values, revealed an overall SUA reduction of -0.42 (P
= 0.012), which is greater and more significant than the pooled effect reported in our analysis. This may suggest that the role of vitamin C is more pronounced in contexts of oxidative stressors and that greater protection against acute hyperuricemia could be achieved. Additional trials are necessary to evaluate this hypothesis.
Hyperuricemia has been associated with a wide range of diseases, including hypertension, obesity, renal disease, metabolic syndrome, obstructive sleep apnea, stroke, vascular dementia, and preeclampsia (83
). However, large trials of vitamin C on cardiovascular events (84
) as well as a recent meta-analysis on mortality have failed to demonstrate significant protective effects (86
). These studies did not examine gout among their outcomes. Among all of the aforementioned clinical outcomes, the strongest support for a casual relationship exists between elevated SUA and gout (1
). Importantly, none of the trials included in this meta-analysis examined vitamin C in a population of patients with gout, though an exploratory subgroup analysis suggests that greater SUA reduction could be achieved in individuals with SUA above 4.85 mg/dL (). If vitamin C with its low cost and relatively innocuous side effect profile were administered to patients with gout as an adjunctive therapy, it is possible that a greater number would achieve target SUA levels, reducing the likelihood of flares. It has yet to be determined, however, whether vitamin C would enhance or add to the SUA reduction of standard anti-hyperuricemic agents.
In summary, this meta-analysis suggests that oral vitamin C supplementation results in modest SUA reduction. Future trials of adequate size and duration should address issues of vitamin C assay interference and should measure both SUA and renal excretion of uric acid. Furthermore, future trials should be adequately powered to evaluate whether or not the urate-lowering effects of vitamin C are enhanced in patients with elevated SUA as found in our exploratory subgroup analysis and described in a previous trial (10
). Ultimately, whether vitamin C supplementation lowers the risk of gout or hyperuricemia needs to be determined.