The Hazardous Highs and Lows of Uric Acid Save

Both high and low levels of uric acid were linked with increased risks of death, showing a U-shaped association between serum uric acid levels and all-cause, cardiovascular, and cancer mortality, Korean researchers reported.

In men, for example, the hazard ratio for all-cause mortality among those with the highest level of uric acid was 2.39 (95% CI 1.57-3.66) when compared with the reference category (the uric acid category with the lowest mortality), while the hazard ratio for those with the lowest levels was 1.58 (95% CI 1.18-2.10), according to Seungho Ryu, MD, PhD, of Sungkyunkwan University School of Medicine in Seoul, and colleagues.

Similarly, in women, the hazard ratios for all-cause mortality were 3.77 (95% CI 1.17-12.17) in the highest uric acid category and 1.80 (95% CI 1.10-2.93) in the lowest category, the researchers reported in Arthritis & Rheumatology.

Elevated uric acid has been clearly linked with gout and kidney stones, and epidemiologic studies have suggested that it also may contribute to hypertension, cardiovascular disease, metabolic syndrome, and kidney ailments.

However, uric acid is also an antioxidant and low levels can result in oxidative stress and endothelial dysfunction, which can predispose to illnesses such as hypertension and diabetes.

Previous studies looking for associations between uric acid levels and various causes of death have had conflicting results, and have primarily focused on the effects of high levels.

Therefore, to assess potential relationships between the full range of uric acid levels and all-cause, cardiovascular, and cancer mortality, Ryu's group analyzed outcomes for the Kangbuk Samsung Health Study that included 375,163 individuals enrolled between 2002 and 2012.

Complete health histories were obtained from all participants, including medication use, smoking and alcohol use, exercise, blood pressure, body mass index, and serum levels of cholesterol and glucose. Death certificates were obtained from Statistics Korea.

Because uric acid levels differ in men and women, they were categorized separately into eight groups each. For men, the lowest uric acid category was 3.5 to 4.4 mg/dL and the highest was 9.5 mg/dL or greater. For women, the lowest was 2.5 to 3.4 mg/dL and the highest was 8.5 or more. The reference categories were 6.5 to 7.4 mg/dL for men and 3.5 to 4.4 mg/dL for women.

Among men with the highest levels, the hazard ratios for cardiovascular and cancer mortality were 3.76 (95% CI 1.54-9.20) and 2.67 (95% CI 1.47-4.87), respectively, while among women with the highest levels, the hazard ratio for cardiovascular mortality was 11.44 (95% CI 2.74-47.68).

Among men with the lowest levels, the hazard ratios for cardiovascular and cancer mortality were 1.50 (95% CI 0.62-3.64) and 1.38 (95% CI 0.91-2.11) neither of which was significant. For women with the lowest levels, the hazard ratios for cardiovascular and cancer mortality were 3.96 (95% CI 1.37-11.47) and 1.58 (95% CI 0.76-3.29), with the latter not being significant.

In multivariable models, the U-shaped association between uric acid levels and all-cause mortality had inflection points at approximately 7 mg/dL for men and 4 mg/dL for women.

In subgroup analyses, associations between uric acid levels and mortality showed no interactions with alcohol or smoking, exercise, body mass index, or comorbidities including diabetes and chronic kidney disease.

The study found an increased risk for all-cause mortality with low uric acid for both men and women, as well as an increased risk for cancer mortality in men and cardiovascular mortality in women. "Individuals with hypouricemia are hypothesized to develop increased risk of atherosclerotic diseases due to decreased antioxidant potential," the researchers noted. In addition, "the induction of cancer cell proliferation was observed in low uric acid conditions through reactive oxygen species production in a mouse model."

As to the mechanisms behind hyperuricemia and mortality, oxidative stress and the inflammasome have been implicated. "Hyperuricemia can activate the NLRP3 inflammasome and induce the production of interleukin-1Β," which in turn leads to an inflammatory cascade.

"Intracellular hyperuricemia also generates inflammatory stress from reactive oxygen species/reactive nitrogen species generation and cyclooxygenase 2 activation," they explained.

Limitations of the study included a lack of information on diet and urate-lowering medications and reliance on a single measurement of uric acid levels, as well as its inclusion of only a relatively young Asian population.