Uric Acid,Parathyroid Hormone,and Vitamin D: New Players in an Old Game

Childhood obesity has become a worldwide epidemic. The number of children affected with obesity-related comorbidities continues to rise; however, our understanding of the underlying mechanisms that make some obese individuals more susceptible to metabolic disease than others is lagging behind. Chronic low-grade systemic inflammation is associated with many pathologic features of obesity, most notably the cardiovascular risk factors that comprise metabolic syndrome. ^1,2 Targeting this inflammatory response is a reasonable therapeutic strategy, but the pathophysiologic sequence of events and major contributors to inflammation are not well understood.

Uric acid is most well known for its pathogenic role in the development of gout, ^3,4 but it has recently attracted interest for its role in other medical conditions, including metabolic dysfunction. ^5,6 Historically, uric acid, the end product of purine metabolism, was thought to be an inert compound with no cellular function. Evidence from recent studies proposes a variety of actions for uric acid that are dependent on its location within the tissue. In extracellular fluid, uric acid can act as an antioxidant in concert with ascorbic acid. ⁷ Conversely, it behaves in a proinflammatory manner when inside the cell. ⁸ Evidence from epidemiologic studies demonstrates hyperuricemia in patients with obesity and several obesity-related comorbidities, including dysglycemia, insulin resistance, dyslipidemia, and hypertension. ^5,6,9 As such, uric acid is rapidly gaining attention as a potential inflammatory mediator in obesity.

Children and adolescents demonstrate the same strong association between uric acid levels and prevalence of metabolic syndrome as previously reported in adults. ¹⁰ In a cross-sectional analysis, children in the top quartile of uric acid serum concentrations were 14.8 times more likely to have metabolic syndrome than those in the lower two quartiles. ¹¹ Allopurinol, a pharmacologic treatment that lowers uric acid levels by blocking its synthesis, was shown to reduce blood pressure in adolescents with newly diagnosed hypertension, ¹² validating the pathologic role of uric acid in hypertension.

Hyperparathyroidism is another condition associated with elevated uric acid levels. ¹³ This is thought to be a consequence of reduced renal uric acid excretion because of elevated parathyroid hormone (PTH) levels. ¹⁴ In their recent article, ¹⁵ Alemzadeh et al. explore the relationships between hyperparathyroidism, vitamin D status, uric acid levels, and C-reactive protein in obese adolescents. To address this question, the authors collected fasting blood samples from 152 obese adolescents with varying degrees of metabolic dysfunction and vitamin D levels. Their findings confirmed previous associations between elevated uric acid levels, components of metabolic syndrome, and low-grade inflammation. In addition, the authors identified PTH:25(OH)D ratio as the stable link between uric acid levels and inflammation after controlling for other factors.

Although the potential relationship between calcium homeostasis, low-grade inflammation, and uric acid is appealing, one must use caution in interpreting the results. One of the biggest limitations to this article is the authors' reliance on correlation analyses, which makes it difficult to determine causality. In addition, establishing temporality is problematic because of the cross-sectional nature of the study design. However, one must recognize the importance of this article in raising awareness of an interesting pathophysiologic web than can be confirmed and fleshed out with subsequent longitudinal studies as well as mechanistic investigations involving in vitro and in vivo experiments.

Alemzadeh et al. have identified hormones related to calcium homeostasis as potentially mediating the proinflammatory effects of elevated uric acid levels. ¹⁵ Their work corroborates other literature linking elevated uric acid levels with obesity and systemic inflammation and sets the stage for further investigation. The therapeutic potential of vitamin D is unclear in this vulnerable population. The participants with elevated uric acid levels had lower serum 25(OH)D than their peers with normal uric acid levels. Yet, the PTH:25(OH)D ratio and uric acid levels were predictors of systemic inflammation independent of vitamin D status. Further investigations will reveal whether uric acid, PTH, and vitamin D are major players in the inflammation game, or just sitting on the sidelines.