The present pooled analyses of 21 controlled feeding trials in 425 prediabetic/diabetic and nondiabetic participants demonstrate that the uric acid response to fructose feeding differs between isocaloric and hypercaloric feeding conditions. Isocaloric fructose intake did not raise uric acid, whereas hypercaloric fructose intake did. The mean increase in the hypercaloric trials was 31.0 μmol/L.
The clinical and practical importance of the increase in uric acid in the hypercaloric trials is unclear. The 3 hypercaloric trials in this meta-analysis fed fructose at 35% excess E (852–876 kcal/d or 213–219 g/d) in fluid form in nondiabetic males for 1 wk, a level of exposure that is more than double the 95th percentile (87 g/d) of fructose intake in the US (46
). At these tremendous doses, the resulting 31.0-μ
mol/L increase in uric acid has the potential to place many individuals at risk of hyperuricemia (>416 μ
mol/L in men or >339 μ
mol/L in women), where the mean serum urate concentrations in U.S. adults are 365 μ
mol/L in men and 290 μ
mol/L in women (4
). Extreme fructose doses inducing hyperuricemia have also been studied in the past. Perez-Pozo et al. (10
) conducted a randomized, 2-wk crossover trial in which participants were randomized to either allopurinol, a xanthine oxidase inhibitor which inhibits the production of uric acid, or placebo while consuming 200 g/d of fructose for 2 wk. Allopurinol was shown to decrease the fructose-induced rise in uric acid by 65 μ
mol/L. Although this increase was reported under weight-maintaining conditions, the evidence from observational studies suggests that an excess of energy may be a prerequisite for a sustainable uric acid-increasing effect of fructose. In models not adjusted for total energy or carbohydrate intake, high fructose intake increased uric acid in the NHANES III (32
); however, in energy- and nonfructose carbohydrate-adjusted models, no effect of total fructose was found on either uric acid concentrations or risk of gout in NHANES 1999–2004 (32
). Although these data taken together with our findings highlight possible confounding from excess energy at high doses, the small number of trials in our hypercaloric analysis limits the confidence in our estimates.
In the isocaloric setting, there was no effect of fructose substitution for other carbohydrate on uric acid concentrations. This lack of effect contradicts data from the Health Professionals Follow-up study that found that sweetened soft drink intake (equivalent to ~ ≥100 g/d of fructose as high fructose corn syrup) was associated with a 29.1-μ
mol/L increase in uric acid concentrations (29). Similarly, an analysis of NHANES III found that isocaloric substitution of sugar-sweetened beverages (equivalent to ~≥16% E as fructose) for other energy was associated with a 25.0-μ
mol/L increase in uric acid and a multivariate OR of 1.82 for hyperuricemia (29
). The reason for the discordance between these observational data and our meta-analysis of controlled feeding trials is unclear. It is possible that there may be a threshold for fructose-mediated ATP depletion/AMP production, which is thought to lead to increased uric acid concentrations. The mean fructose dose in the isocaloric trials (93.4 g/d) was below the level of exposure associated with higher uric acid concentrations in the observational studies, which may also have incompletely adjusted for energy compensation. It was also well below the mean dose used in our included hypercaloric trials (215 g/d) used to induce higher uric acid concentrations and the animal models (60% E as fructose, which is equivalent to 300 g/d on a 2000-kcal diet) used to elucidate the mechanism of fructose-induced uric acid production (9
). A fructose dose threshold has been observed in clinical trials, below which the effects on other metabolic biomarkers are lost, e.g., ≤60 g/d in type 2 diabetes (36
) and <100 g/d across all subject types (47
) for TG. Additionally, there is evidence of fructose intolerance and incomplete absorption at higher doses and concentrations, further confounding results from trials at high doses (48
). Population-level intakes of fructose, where the 50th percentile of fructose intake in the US is 49 g/d (46
), may be unlikely to elicit this mechanism in a clinically significant way. Both dose alone and dose in relation to excess energy, therefore, are important considerations in assessing adverse effects of fructose on uric acid.
The strength of the present analyses is the lack of both statistical heterogeneity and clinical heterogeneity. Neither stratification of the data nor a priori subgroup analyses altered the significance of the effect estimates or heterogeneity. The lack of an effect of fructose in isocaloric exchange for carbohydrate on uric acid was robust to stratification by diabetes status. It was also not modified by dose at a lower threshold (≤ or >60 g/d), comparator (starch, sucrose, and glucose), follow-up (< or ≥4 wk), design (crossover, parallel), study quality (MQS ≥ or <8), randomization (yes, no), or fructose form (solid, liquid, mixed). Although not tested formally in subgroup analyses, composition of the background diet in the trials also did not appear to have an effect. One of the included isocaloric trials, Forster et al. (17
), had a background diet devoid of fat. This study was included, because it met all eligibility criteria. Removal of this trial during sensitivity analyses did not alter the conclusions, although this trial should be interpreted cautiously. The consistency across these different trial conditions helps to strengthen the generalizability of our conclusions.
Our analyses, nevertheless, have several limitations. First, our literature search would not have identified trials that measured uric acid and displayed uric acid data but was only discussed within a table or figure. Second, the hypercaloric studies recruited only men; previous studies have shown both sex and hormone effects on uric acid concentrations. Men generally have higher concentrations of uric acid than women and hormones play a role. Estrogen can reduce uric acid concentrations, mitigating many of the metabolic effects of uric acid (49
), whereas testosterone has been associated with increased uric acid (50
). Although the data support increased uric acid concentrations in men, we could not determine from the existing data the effects of hypercaloric fructose on women. Third, only 5 of the included isocaloric trials and none of the hypercaloric trials were longer than 12 wk. Although we found no evidence of effect according to follow-up, it is unclear whether the lack of effect of isocaloric fructose exchange for other carbohydrates on uric acid would be sustainable over the long term. It is also unclear whether isocaloric exchange conditions can be maintained over the long term. Longer-term trials would be helpful in separating out the short-term from the longer-term effects of fructose. Fourth, study quality was poor (MQS <8) in 50% of the included trials. Complicating this issue was the incomplete reporting in many publications requiring a fair degree of imputations (7/18 trials required imputations). There was, however, no effect (P
= 0.97) of MQS (<8 vs. ≥8) in subgroup analyses. Although the use of a quality scoring method, such as the MQS, may have been inadequate (51
), the consistent lack of effect of all a priori subgroups () supports the lack of a uric acid–raising effect (P
> 0.2 for all comparisons) of isocaloric fructose exchange for other carbohydrates. Fifth, only two-thirds of the isocaloric trials used crossover designs. However, Lathyris et al. (52
) performed a systematic review of Cochrane Reviews and found generally good agreement between parallel and crossover trials. Finally, publication bias was a possibility in both the isocaloric and hypercaloric trials. Visual inspection of funnel plots for both sets of trials along with Egger or Begg tests found limited evidence of funnel plot asymmetry and publication bias.
In conclusion, our work suggests that contrary to concerns, isocaloric fructose exchange for other sources of carbohydrate does not raise uric acid concentrations and this lack of effect holds across different experimental conditions. These conclusions, however, are limited by the short follow-up of the majority of trials and poor quality of one-half of the trials included in the meta-analysis. On the other hand, high fructose intake (213–219 g/d) under hypercaloric feeding conditions (+35% E) does raise serum uric acid concentrations, although confounding from excess energy cannot be ruled out in these trials. These data highlight the need for larger and longer fructose feeding trials conducted under free-living conditions to assess whether fructose consumption leads to excess energy intake and whether in turn the effects on uric acid are dependent on excess energy.