June 28, 2007

Elevated Uric Acid: Could It Be Part of the Metabolic Syndrome?

By Deborah Levenson

Among U.S. children, incidence of the metabolic syndrome—generally defined as central adiposity, elevated blood pressure, dyslipidemia, and hypoglycemia—has been rising steadily in recent years, from 4.2% during 1988–1994 to 6.4% during 1999–2000. Several studies have shown that elevated concentrations of uric acid are strongly associated with these factors in adults, but until recently, researchers had not examined the relationship in young people. This issue of Strategies examines a large study of uric acid and the metabolic syndrome in adolescents, and what clinical laboratorians should know about that research.

Uric acid is not part of any definition of the metabolic syndrome, but a growing number of studies show a strong association between the two in adults. Yet a dearth of data regarding the association in young people has left researchers wondering if the association could be secondary to conditions that arise in adulthood. A recent analysis (Circulation 2007; 115: 2526–2532) of a large cohort of adolescents with metabolic syndrome found that as in adults, a strong association exists between serum concentrations of uric acid, the metabolic syndrome, and several of its components, elevating uric acid’s potential as part of the definition of the metabolic syndrome or even a factor in cardiovascular disease.

Studying Uric Acid in Children

To identify the uric acid-metabolic syndrome link in young people, investigators from the Centers for Disease Control and Prevention (CDC) and five other centers in the U.S. and Canada performed a cross-sectional analysis using data from 1,370 male and female adolescent participants in the National Health and Nutrition Examination Survey (NHANES) 1999–2002. Researchers defined metabolic syndrome for participants ages 12–17 as having three of five criteria: triglyceride levels ≥110 mg/dL, HDL cholesterol ≤40 mg/dL, waist circumference ≥ 9th percentile for sex, glucose concentration ≥ 100 mg/dL, and systolic or diastolic blood pressure ≥ 90th percentile, specific to age, height, and sex.

To examine the association between the metabolic syndrome and uric acid concentration, researchers conducted logistic regression analysis adjusting for age, sex, race or ethnicity, and concentrations of CRP. “We found a graded positive association between concentrations of serum uric acid and the prevalence of the metabolic syndrome,” wrote researchers. Prevalence of the metabolic syndrome among youths in the lowest quartile of concentrations of uric acid was almost negligible, while about 21% of youths in the highest quartile had the metabolic syndrome. The association was independent of age, sex, race or ethnicity, and concentrations of CRP. Prevalence of the metabolic syndrome was <1% among participants in the lowest quartile of serum concentration of uric acid, 3.7% in the second quartile, 103% in the third quartile, and 21.1% in the highest quartile. Compared with the lowest 2 quartiles of uric acid combined, with concentrations of ≤291.5 μmol/L, the odds ratios were 5.80 (95% CI, 322–10.46) for those in the third quartile (>291.5 to ≤339 μmol/L or >4.9 to ≤5.7 mg/dL) and 14.79 (95% CI, 7.78–28.11) for those in the top quartile (>339 μmol/L). Serum concentrations of insulin also increased as concentration of uric acid increased. Starting with the lowest quartile of concentration of uric acid, mean concentrations of serum insulin were 66.2, 66.6, 79.0, and 90.9 μmol/L, respectively.

Researchers noted several mechanisms that could account for elevated uric acid levels among subjects with the metabolic syndrome. One might be reduced renal excretion due to increased insulin concentrations that are known to reduce the renal excretion of urate. Another could be that increased fructose consumption among youth is leading to greater incidence of impaired endothelial function, which has been shown to elevate uric acid concentrations, and is associated with childhood obesity. A third factor could be increased levels of adenosine—resulting in retention or urate as well as sodium and water—due to impaired oxidative phosphorylation and intracellular concentrations of coenzyme A esters of long-chain fatty esters occurring with the metabolic syndrome, according to researchers.

A Brighter Future for Uric Acid?

Clinically, uric acid levels are most commonly used to determine a diagnosis of gout. But according to Sridevi Devaraj, PhD, Associate Professor of Medical Pathology at University of California, Davis School of Medicine in Sacramento, Calif., uric acid has been associated with insulin resistance since the 1920s and is associated with the different features of the metabolic syndrome. However, uric acid is not included in any official definition because it hasn’t been proven to be an independent marker of risk, she pointed out, adding that high levels of uric acid can be reduced through strategies that induce weight loss and decrease hypertension.

Mounting evidence linking uric acid and the metabolic syndrome have led some to suggest that uric acid should be included in the definition of the metabolic syndrome or that it could play a significant role in cardiovascular disease, according to study co-author Chaoyang Li, Medical Epidemiologist in CDC's Division of Adult and Community Health in Atlanta, Ga, “But whether uric acid is an innocent bystander or plays a causal role in cardiovascular disease is still very much under debate,” he noted. While he emphasized that his study looked only at whether uric acid was strongly associated with the metabolic syndrome in young people, Li said any future evidence that uric acid can actually predict or cause cardiovascular disease would be promising for clinicians looking for new diagnostic tools

From the lab perspective, uric acid would be an ideal test for diabetes or cardiovascular disease—if future research proves that it causes or predicts these conditions, noted Devaraj. “As a biomarker, uric acid is easily collected in the same specimen with lipids and glucose, it’s easy to measure, it’s standardized, and may prove to be a cost-effective adjunctive measure to define the metabolic syndrome. Also, high uric acid levels can easily be treated,” she explained.

The metabolic syndrome is a risk factor for cardiovascular disease, but the association between uric acid and cardiovascular disease hasn’t been consistent in studies. It’s difficult to conduct a trial of uric acid as a risk factor, Li noted. “We can only look at whether removal of uric acid can improve the metabolic syndrome in human beings.” Several ongoing studies are looking at whether allopurinol, a medication that reduces uric acid levels, can improve other features of the metabolic syndrome and cardiovascular outcomes. Several prospective studies are also examining whether uric acid can predict mortality.

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