Fructose-Rich Fructose-Rich Beverages and Beverages and Risk of GoutRisk of Gout in in

WomenWomenJAMA, November 24, 2010—Vol 304, No. 20JAMA, November 24, 2010—Vol 304, No. 20

張秋密 張秋密 02240224

Gouts is a common and Gouts is a common and excruciatingly painful inflammatory excruciatingly painful inflammatory arthritis.arthritis.

Emerging evidence suggests that Emerging evidence suggests that gout is strongly associated gout is strongly associated with with metabolic syndrome metabolic syndrome and may lead to and may lead to myocardial infarction,diabetesmyocardial infarction,diabetes, and , and premature.premature.

The increasing disease burden of gout in the The increasing disease burden of gout in the United States over the last few decades (eg, United States over the last few decades (eg, an annual incidence of 16/ 100 000 in 1977 vs an annual incidence of 16/ 100 000 in 1977 vs 42/100 000 in 19966) coincided with a 42/100 000 in 19966) coincided with a substantial increase substantial increase in soft drink in soft drink and and fructose fructose consumptionconsumption

A recent prospective study of A recent prospective study of menmen found that found that sugar-sweetened sodas, fruit juices, and sugar-sweetened sodas, fruit juices, and fructose were associated with a substantially fructose were associated with a substantially increased risk of gout among men.increased risk of gout among men.

ObjectiveObjective

To examine the relationship To examine the relationship between intake of fructose-rich between intake of fructose-rich beverages beverages and fructose and the risk and fructose and the risk of incident gout among women.of incident gout among women.

METHODSMETHODSStudy PopulationStudy Population

The The Nurses’ Health StudyNurses’ Health Study was was established in 1976 when 121 700 established in 1976 when 121 700 female registered nurses who were female registered nurses who were predominantly white (95%), aged 30 to predominantly white (95%), aged 30 to 55 years, and living in 11 states 55 years, and living in 11 states completed acompleted a

mailed mailed questionnairequestionnaire providing providing detailed information about their detailed information about their medical medical history, lifestylehistory, lifestyle, and other risk factors, and other risk factors

The information is updated The information is updated every 2 yearsevery 2 years to to identify newly diagnosed diseases and the follow-identify newly diagnosed diseases and the follow-up rate exceeds 90%. up rate exceeds 90%.

In 1980, a In 1980, a food frequency questionnairefood frequency questionnaire was was added and in added and in 19841984, participants were asked about , participants were asked about intake of sodasintake of sodas in detail. in detail.

For our analysis, we excluded women with a For our analysis, we excluded women with a previous diagnosis of gout before 1984 or previous diagnosis of gout before 1984 or participants who did not complete more than 10 participants who did not complete more than 10 items on the 1984 dietary questionnaire, leaving items on the 1984 dietary questionnaire, leaving 78 90678 906 eligible women who were followed up eligible women who were followed up from from 1984 to 2006.1984 to 2006.

Assessment of Beverage, Assessment of Beverage, Fructose,and Other Fructose,and Other

Dietary IntakeDietary Intake The dietary questionnaires were completed in The dietary questionnaires were completed in 1980, 1984, 1986, 1990, 1994, 1998, and 1980, 1984, 1986, 1990, 1994, 1998, and 2002. 2002.

Starting in 1984, participants were asked howStarting in 1984, participants were asked how

often on average during the previous year often on average during the previous year they had consumed they had consumed sugar sweetened sodasugar sweetened soda (“Coke, Pepsi, or other cola with sugar,” (“Coke, Pepsi, or other cola with sugar,” “caffeine-free Coke, Pepsi, or other cola with “caffeine-free Coke, Pepsi, or other cola with sugar,” and “sugar,” and “other carbonated beverages with other carbonated beverages with sugarsugar”) and ”) and diet sodasdiet sodas (“low-calorie cola with (“low-calorie cola with caffeine,” “low-calorie caffeine-free cola,” caffeine,” “low-calorie caffeine-free cola,” and“other low-calorie beverages”).and“other low-calorie beverages”).

Half of the disaccharide sucrose is Half of the disaccharide sucrose is fructosefructose, which is split from sucrose , which is split from sucrose in the small intestine.in the small intestine.

Therefore, Therefore, total fructose intaketotal fructose intake is is equal to theequal to the

intake of intake of free fructosefree fructose plus plus half the half the intake of sucrose.intake of sucrose.

雙醣的形式：以蔗糖為例，蔗糖由一分子的葡萄糖及一分子的果 糖脫去一分子的水而形成

Assessment of Nondietary Assessment of Nondietary FactorsFactors

At baseline and every 2 years At baseline and every 2 years thereafter, participants provided thereafter, participants provided information on information on weight,weight, regular use of regular use of medicationsmedications (including diuretics), and (including diuretics), and medical conditionsmedical conditions (including (including hypertension).hypertension).

Body massBody mass index was calculated index was calculated

Ascertainment of Incident Cases

of Gout We ascertained incident cases of gout using the American College of

Rheumatology gout survey criteria.

Statistical AnalysisStatistical Analysis We used Cox proportional hazards modeling (PROC We used Cox proportional hazards modeling (PROC

PHREG) to estimate the relative risk PHREG) to estimate the relative risk (RR)(RR) of incident of incident gout in all multivariate analyses (SAS software, gout in all multivariate analyses (SAS software, version 9.1, SAS Institute Inc, Cary North Carolina).version 9.1, SAS Institute Inc, Cary North Carolina).

Multivariate models for soda and juice consumption Multivariate models for soda and juice consumption were adjusted for the following variables in a time-were adjusted for the following variables in a time-varying manner: age (continuous), total energy intakevarying manner: age (continuous), total energy intake

For all RRs, we calculated For all RRs, we calculated 95%95% confidence intervals confidence intervals (CIs).(CIs).

All All P values are 2-sided, with P values are 2-sided, with P P ＜＜ .05.05 considered considered statistically significant.statistically significant.

RESULTS

The corresponding absolute risk differences were 36 and 68 cases per 100 000 person-years.

Women who consumed 1 serving per day of sugar sweetened soda had a 74% higher risk of incident gout and women who consumed 2 servings or more per day had a 2.4-fold increased risk.

Orange juice was by far the highest contributor of free fructose intake (17%) among juices in this cohort, followed by apple juice at 2.9% and other juices at 2.6% at the midpoint of follow-up.

The corresponding absolute risk differences were 14 and 47 cases per 100 000 person-years, respectively

women who consumed 2 servings or more of orange juice showed women who consumed 2 servings or more of orange juice showed a 2.4-fold increased risk of incident gout.a 2.4-fold increased risk of incident gout.

Similar trends were observed with intake of total fructose (ie, free fructose plus half the intake of sucrose), although the magnitudes of associations tended to be smaller (Table 4). When we examined fructose intake as a continuous variable, the multivariate RR for a 5% increment in energy from free fructose, compared with equivalent energy intake from other types of carbohydrates, was 1.86 (95% CI,1.44-2.40) and the corresponding RR for total fructose was 1.47 (95% CI, 1.20-1.80)

The corresponding absolute risk difference was 28 cases per 100 000 person-years

•We also conducted stratified analyses to evaluate whether the association between sweetened soda and fructose consumption and risk of gout varied according to body mass index, alcohol use, and dairy intake. •Relative risks from these stratified analyses consistently suggested associations similar to those from main analyses, and there was no significant interaction with these variables (all P.14 for interaction)

COMMENTCOMMENT In this large prospective study of women, In this large prospective study of women,

we found that risk of incident gout we found that risk of incident gout increased with increased with increasing intake of sugar-increasing intake of sugar-sweetened sodasweetened soda..

In contrast, In contrast, diet soda diet soda intake intake was not was not associated with risk of incident gout. associated with risk of incident gout.

Further more,risk of gout was significantly Further more,risk of gout was significantly increased with increased with increasing intake of increasing intake of fructosefructose, the main ingredient thought to , the main ingredient thought to cause the increased riskcause 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 men and provide the first prospective evidence among women

Fructose and fructose-rich beverages are important risk factors to be considered in the primary prevention

of gout.

This potential This potential sex difference sex difference has been has been thought to be due to thought to be due to sex hormones sex hormones because studies in rats have shown that because studies in rats have shown that female sex hormones protect against the female sex hormones protect against the development of development of hyperinsulinemia hyperinsulinemia associated with associated with high fructose intakehigh fructose intake..

Hyperinsulinemia decreases renal Hyperinsulinemia decreases renal excretion of urate and correlates with excretion of urate and correlates with higher serum uric acid levels, higher serum uric acid levels, the the protective effect of protective effect of estrogenestrogen may lead to may lead to an attenuated effect of fructose on serum an attenuated effect of fructose on serum uric acid levels. uric acid levels.

Nevertheless, as Nevertheless, as gout gout among women among women occurs predominantly after occurs predominantly after menopausemenopause, when the female hormonal , when the female hormonal influence substantially declines, the influence substantially declines, the sex difference of the fructose effect on sex difference of the fructose effect on the risk of gout may be less apparent the risk of gout may be less apparent than that on serum uric acid levels than that on serum uric acid levels observed in the general population that observed in the general population that included premenopausal women.included premenopausal women.

Fructose induces uric acid production by increasing adenosine triphosphate (ATP) degradation to adenosinemonophosphate, a uric acid precursorFructose phosphorylation in the liver uses ATP, and the accompanying phosphate depletion limitsregeneration of ATP from adenosine diphosphate, which in turn serves as substrate for the catabolic pathway to uric acid formation.

Our findings have practical implications Our findings have practical implications for the prevention of gout in women. for the prevention of gout in women.

As conventional dietary As conventional dietary recommendations for gout have focused recommendations for gout have focused on restriction of on restriction of purine intakepurine intake, , low low purine diets are often high in purine diets are often high in carbohydrates, including fructose-rich carbohydrates, including fructose-rich foods.foods.

Our data provide prospective evidence that fructose Our data provide prospective evidence that fructose poses an increased risk of gout among women, thus poses an increased risk of gout among women, thus supporting the importance supporting the importance of reducing fructose intakeof reducing fructose intake. . Interestingly, this recommendation is consistent with Interestingly, this recommendation is consistent with Osler’s diet prescription as a means to prevent gout Osler’s diet prescription as a means to prevent gout more than 100 years ago:more than 100 years ago:

“ “The sugar should be reduced to a minimumThe sugar should be reduced to a minimum.”.” Furthermore, because Furthermore, because fructose intake fructose intake is associated with is associated with

increased serum insulin levelsincreased serum insulin levels, , insulininsulin resistance, resistance, and and increased adiposityincreased adiposity, the overall negative health effect of , the overall negative health effect of fructose is expected to be larger in women with a fructose is expected to be larger in women with a history of gout, 70% of whom have metabolic syndrome.history of gout, 70% of whom have metabolic syndrome.

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 potential effect of these beverages on the risk of gout, a common and excruciatingly painful arthritis.

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