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People with low serum urate concentrations were more likely to die than those with normal levels, but it's probably a marker for other pathologies rather than direct cause-and-effect, a new study indicated.

The hazard ratio for death during 10 to 15 years of follow-up was 1.61 (95% CI 1.14-2.28) among participants in the National Health and Nutrition Examination Survey (NHANES) with low versus normal urate levels, according to Joshua F. Baker, MD, MSCE, of the University of Pennsylvania in Philadelphia, and colleagues.

But when the data were adjusted for body composition parameters and previous weight loss, the association was weaker and lost statistical significance (HR 1.30, 95% CI 0.92-1.85), the researchers .

Meanwhile, high serum urate -- the precursor to gout, and far more common in the 14,000-plus cohort -- was also associated with increased mortality, both in the raw data and following adjustment (adjusted HR 1.29, 95% CI 1.14-1.46).

Overall, the long-standing question of whether low serum urate portends an early death remains incompletely settled, given the trend toward higher mortality in the adjusted data. Nevertheless, the authors suggested that low urate is likely an epiphenomenon related to the real culprits: unhealthy body composition and frailty.

"Investigators should take care to consider confounding related to weight loss, sarcopenia, cachexia, frailty, and related conditions when interpreting associations between low [serum urate] levels and long-term outcomes in population-based studies," Baker and colleagues wrote.

A number of earlier studies had identified increased death rates and other adverse outcomes associated with low urate levels. It's an important issue insofar as urate-lowering drugs are given to patients with high levels, as a means of preventing or treating gout, which may end up overshooting the target. At the same time, however, low urate levels could also "occur in the setting of pathologic weight loss and sarcopenia which themselves may be the underlying cause of adverse outcomes and mortality," Baker and colleagues observed, and some studies have supported this notion.

To explore the matter further, the researchers drew on data from the 1999-2006 iterations of NHANES, during which participants provided blood samples; some were then tested for urate. Participants' later deaths were also recorded in NHANES, and these data were examined through 2015.

Out of some 14,000 adult NHANES participants with urate tests, 208 had low levels (<2.5 mg/dL for women, <3.5 mg/dL for men), 11,308 had levels in the normal range, and 2,463 had high levels (>6 mg/dL for women, >7 mg/dL for men). Mean age at baseline was about 47, and half overall were women (high urate was more common in men, however, comprising 60% of that subgroup).

Sarcopenia (as established via DXA body scans) was dramatically more common at baseline among those with low urate levels: 29% of the group, compared with 16% of those with normal urate and 8% of those in the high range. Similarly, 6.8% of the low-urate group were underweight (body mass index <18.5), versus 1.8% of participants with normal urate and 0.4% of those with high levels.

Previous weight loss was also substantial with low urate. Across the entire subgroup, participants had lost BMI points at an average 16.6% relative to their maximum earlier in life, far higher than in the other urate categories.

One defect of the analysis was that hardly any NHANES participants were using urate-lowering drugs (just 1% of the high-urate group), such that the potential role of these agents could not be examined. Also, Baker and colleagues acknowledged, mortality was the only adverse outcome analyzed, although others such as dementia would be worthwhile to study, too. Another limitation was that data on previous weight loss were self-reported.

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