In this large prospective study of women, we found that the risk of incident gout increased with increasing intake of sugar sweetened soda. In contrast, diet soda intake was not associated with the risk of incident gout. Women who consumed one serving of sugar-sweetened soda had a 74% higher risk of incident gout and women who consumed two servings or more had 2.4 times increased risk. Similarly, women who consumed two servings or more of orange juice showed a 2.4 times increased risk of incident gout. Furthermore, the risk of gout was significantly increased with increasing intake of fructose, the main suspected ingredient behind the increased risk. These associations were independent of risk factors for gout such as body mass index, age, hypertension, menopause, diuretic use, alcohol, and intake of dairy, meat, seafood, coffee, and vitamin C. These findings confirm the associations observed in the recent prospective study of men13
and provide the first prospective evidence among women that fructose and fructose-rich beverages are important risk factors to be considered in the primary prevention of gout.
While the relative risks of gout associated with fructose-rich beverages among women were substantial, the corresponding absolute risk differences were modest given the low incidence rate of gout among women. For example, the magnitudes of relative risks associated with sugar-sweetened sodas or orange juice were comparable to those associated with alcoholic beverages (RR for ≥ 2 servings per day, 1.60 for liquor vs 2.5 for beer) among men.18
However, the corresponding absolute risk differences were less than one case per 1,000 person years. While the relative risk data suggest a substantial biologic link, the risk difference data suggest that their contribution to the risk of gout in the population is likely modest given the low incidence rate among women. Because the urate-raising effect of fructose is greatest in patients with gout and hyperuricemia,8-10, 28
our findings may be even more relevant in those patients.
Previous animal experiments14, 29, 30
and NHANES studies15, 31
suggest that the magnitude of urate-raising effect of fructose or sugar-sweetened sodas may be weaker among females than among males. For example, an analysis based on NHANES III found that the increase in serum uric acid level associated with sugar-sweetened soda intake was significantly larger among men than women, although the association among women was still statistically significant.15
This potential gender difference has been thought be due to sex hormones because studies in rats have shown that female sex hormones protect against the development of hyperinsulinemia associated with high fructose intake.14, 29, 30
Because hyperinsulinemia decreases renal excretion of urate and correlates with higher serum uric acid levels,32
the protective effect of estrogen may lead to an attenuated impact of fructose on serum uric acid levels. Nevertheless, as gout among women occurs predominantly after menopause, when the female hormonal influence substantially declines, the gender difference of the fructose effect on the risk of gout may be less apparent than that on serum uric acid levels observed in the general population that included premenopausal women.
Fructose induces uric acid production by increasing ATP degradation to AMP, a uric acid precursor ().12, 28, 33
Fructose phosphorylation in the liver uses ATP, and the accompanying phosphate depletion limits regeneration of ATP from ADP, which in turn serves as substrate for the catabolic pathway to uric acid formation.34
Thus, within minutes after fructose infusion, plasma (and later urinary) uric acid concentrations are increased.28
In conjunction with purine nucleotide depletion, rates of purine synthesis de novo
are accelerated, thus potentiating uric acid production.11
In contrast, glucose and other simple sugars do not have the same effect.35
Furthermore, fructose could indirectly increase serum uric acid level and the risk of gout by increasing insulin resistance and circulating insulin levels.36
Experimental studies in animal models and from short-term feeding trials among humans suggest that higher fructose intake contributes to insulin resistance, impaired glucose tolerance, and hyperinsulinemia.23, 37, 38
In contrast, glucose intake had no similar adverse effects.38
Mechanism of Fructose-Induced Hyperuricemia
Our findings have practical implications for the prevention of gout in women. As conventional dietary recommendations for gout have focused on restriction of purine intake, lowpurine diets are often high in carbohydrates including fructose-rich foods.39
Our data provide prospective evidence that fructose poses an increased risk for gout among women, thus supporting the importance of reducing fructose intake. Interestingly, this recommendation is consistent with Osler's diets prescription as a means to prevent gout over 100 years ago, as reflected in his 1893 text40
- “The sugar should be reduced to a minimum.”35
Furthermore, because fructose intake is associated with increased serum insulin levels, insulin resistance, and increased adiposity,23, 37, 38
the overall negative health impact from fructose is expected to be larger in women with a history of gout, 70% of whom suffer from the metabolic syndrome.32
Several strengths and potential limitations of our study deserve comment. Our study had a large number of cases of confirmed female incident gout and dietary data including beverage and fructose intake information were prospectively collected and validated. While there were a relatively large number of cases in the highest fructose quintile groups, the numbers in the top intake categories of fructose-rich beverage items were small. Nevertheless, it was reassuring that the next top categories also showed significant positive associations with a dose-response relationship. 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, self-reported dietary consumption has been extensively validated in sub-samples of this cohort,16, 22
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. The validity of gout ascertainment in this cohort and our companion male cohort4, 18, 19
has been documented by the high-degree of concordance with medical record review.
The restriction to registered nurses in our cohort is both a strength and a limitation. The cohort of well-educated women 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 related measures as well as distribution of fructose intake may not be representative of a random sample of US women, the biological effects of fructose intake on gout (as reflected in relative risks) should be similar. Our findings are most directly generalizable to middle-age and elderly white women with no history of gout. Since the prevalence of risk factors for gout and its incidence tend to be higher in the general population and among African Americans, the magnitude of the absolute risk increase associated with these beverages might be greater than the increase we observed.
In conclusion, our findings provide prospective evidence that consumption of sugar-sweetened sodas, orange juice, and fructose is associated with an increased risk of incident gout among women, although their contribution to the risk of gout in the population is likely modest given the low incidence rate among women. In contrast, diet soda intake is not associated with the risk of gout. Physicians should be aware of the impact of these beverages on the risk of gout, a common and excruciatingly painful arthritis.