Association between serum uric acid level and mortality in China

Uric acid is best known as the compound that causes gout, but new research from China reveals it plays a far more complex role in overall health. A large, population-based study finds that both high and low serum uric acid (SUA) levels are linked to higher mortality rates in men—while women show no such association. The findings, published in the Chinese Medical Journal, shed light on a “U-shaped” relationship between SUA and death risk, offering critical insights for public health in a country where hyperuricemia (high SUA) is on the rise.

Key Background: Uric Acid’s Dual Role

Uric acid is a waste product of purine metabolism (found in foods like organ meats, seafood, and alcohol). It’s mostly excreted by the kidneys, but its levels are also influenced by genetics and lifestyle. For years, scientists have debated uric acid’s impact on health: it acts as a potent antioxidant (protecting cells from damage) but can also trigger inflammation and oxidative stress when levels are too high.

Previous studies—including the Framingham Heart Study and EPOCH-JAPAN Study—hinted at a U-shaped link between SUA and mortality, but few have focused on China, where hyperuricemia prevalence has risen to 8.4–9.9% of adults (Liu et al., 2014).

The Study: A Large Cohort from China

Led by researchers from Peking University First Hospital’s Renal Division and affiliated key labs (National Health Commission, Ministry of Education, Chinese Academy of Medical Sciences), the study analyzed data from the China National Survey of Chronic Kidney Disease—a multistage, stratified sample of 33,268 adults (ages 18+) from 13 provinces. Participants were followed for an average of 9 years (2006–2017), with mortality data linked to China’s national death registry.

The team adjusted for factors known to affect mortality: age, education, smoking, alcohol use, BMI, hypertension, diabetes, rural/urban residence, cholesterol levels, and kidney function (estimated glomerular filtration rate, or eGFR). They divided participants into quartiles (four equal groups) based on SUA levels, with the middle quartile serving as the reference (lowest risk).

What They Found: A U-Shaped Link in Men

The most striking result was a U-shaped association between SUA and mortality in men. Both the lowest (≤4.475 mg/dL) and highest (≥6.55 mg/dL) SUA quartiles were linked to higher death rates compared to the middle quartile (5.464–6.550 mg/dL). Here’s the breakdown after adjusting for confounders:

All-Cause Mortality

Men in the lowest SUA quartile: 31% more likely to die than those in the middle (hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.04–1.67).
Men in the highest SUA quartile: 55% more likely to die (HR 1.55, 95% CI 1.24–1.93).

Cardiovascular (CVD) Mortality

Lowest quartile: 47% higher risk (HR 1.47, 95% CI 1.00–2.18).
Highest quartile: 67% higher risk (HR 1.67, 95% CI 1.16–2.43).

Cancer Mortality

Highest quartile: Marginally significant 43% higher risk (HR 1.43, 95% CI 0.99–2.08).

Using restricted cubic spline models (a statistical tool to visualize non-linear relationships), the team confirmed the U-shape: the lowest risk for men was at ~5.5 mg/dL—right in the middle of the reference quartile.

Why Women Are Different

Women showed no significant association between SUA and mortality, even though the highest SUA group had numerically higher death rates. The researchers point to estrogen as a key factor: estrogen increases uric acid excretion, keeping SUA levels lower in premenopausal women. Since the study didn’t track menopausal status, it’s unclear whether postmenopausal women (who lose estrogen’s protective effect) would show a similar U-shape.

Other differences: Men with higher SUA were more likely to smoke and drink—habits far less common in women, which may explain why these factors didn’t correlate with SUA in women.

The Science: Uric Acid as Antioxidant and Inflammatory Trigger

The U-shaped link in men makes sense when you consider uric acid’s dual role:

High SUA: Triggers the NLRP3 inflammasome (a protein complex that drives inflammation) and oxidative stress, leading to endothelial dysfunction (damage to blood vessel linings)—the first step in CVD. High SUA is also linked to gout, hypertension, and chronic kidney disease.
Low SUA: Reduces the body’s antioxidant capacity (uric acid accounts for 50% of plasma antioxidant activity), making cells more vulnerable to damage from free radicals. This may increase risk for chronic diseases like cancer and CVD.

For men, the “sweet spot” at 5.5 mg/dL balances these effects—enough antioxidant protection without the inflammation.

Limitations to Consider

Like all observational studies, this one has limitations:

Baseline only: SUA levels were measured once at the start—changes over time (e.g., from diet or medication) could affect outcomes.
Underreporting: The national death registry had a 16.68% underreporting rate (2006–2008), which may have underestimated mortality.
Missing data: The study didn’t track use of uric acid-lowering drugs (e.g., allopurinol) or menopausal status in women.
Lifestyle changes: Participants’ habits (smoking, alcohol) were recorded at baseline, but changes during follow-up weren’t measured.

What This Means for Public Health

The findings have important implications for China, where hyperuricemia is becoming more common due to rising rates of obesity and Western-style diets. For men, the study suggests that:

High SUA (≥6.55 mg/dL) needs to be managed (e.g., with diet or medication) to reduce CVD and all-cause mortality risk.
Low SUA (<4.475 mg/dL) may also be harmful—avoiding overly aggressive lowering of SUA (e.g., in gout treatment) could be key.
The optimal SUA range for men is ~5.5 mg/dL.

For women, more research is needed—especially on how menopause affects the SUA-mortality link. The study’s authors call for future work to include menopausal status and long-term SUA monitoring.

Conclusion: A “Sweet Spot” for Uric Acid in Men

This large, rigorous study confirms a U-shaped association between serum uric acid and mortality in Chinese men—both high and low levels increase risk, with the lowest risk at ~5.5 mg/dL. Women, meanwhile, show no significant link, likely due to estrogen’s protective effect.

As China grapples with rising hyperuricemia, these findings offer a roadmap for personalized SUA management. For men, keeping uric acid in the “sweet spot” could save lives—while women may need targeted research to understand their unique risk profile.

The study was published in the Chinese Medical Journal in 2021 (Chang et al.). The full paper is available at doi.org/10.1097/CM9.0000000000001631.

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