Date Published: August 7, 2017
Publisher: Public Library of Science
Author(s): Toshiko Tanaka, Yuri Milaneschi, Yongqing Zhang, Kevin G. Becker, Linda Zukley, Luigi Ferrucci, Yoshihiro Fukumoto.
Uric acid has been linked with increased risk of chronic disease such as cardiovascular disease and this association has been attributed to a pro-inflammatory effect. Indeed, observational studies have shown that high uric acid is associated with high level of pro-inflammatory cytokines in the blood. However, whether high uric acid directly affects inflammation or rather represents a parallel defensive antioxidant mechanism in response to pathology that causes inflammation is unknown. To determine whether acute increase or decrease uric acid levels affects inflammation in healthy individuals, a randomized, placebo-controlled, double blind clinical study of uric acid or rasburicase with 20 healthy volunteers in each treatment-placebo group was conducted at the National Institute on Aging (NIA) Clinical Research Unit (CRU) at Harbor Hospital in Baltimore, MD. Change in inflammatory response was assessed by administering an oral lipid tolerance before and after the treatment of uric acid, rasburicase and placebo. Following uric acid administration, there was an accentuated increase in IL-6 during the oral lipid tolerance test (P<0.001). No significant differences were observed after lowering of uric acid with rasburicase. No side effects were reported throughout the trial. In health individuals, acute increase in uric acid results in an increased IL-6 response when challenged with lipid load. Such effect of amplification of inflammatory response may explain the higher risk of chronic diseases observed in subclinical hyperuricemia in observational studies.
There is growing interest in understanding the role of uric acid (UA) in inflammation, and chronic diseases [1, 2]. Uric acid is a product of purine metabolism with strong antioxidant properties found in high levels in humans due to the silencing of the uricase gene in the course of evolution [3, 4]. It has been proposed that the high level of UA was selected in humans because UA has powerful antioxidant properties . However, contrary to this view, there is ample evidence that even moderately elevated levels of uric acid have detrimental effects on health. In observational studies, hyperuricemia is an independent risk factor for diabetes , impaired fasting glucose , insulin resistance , and hypertension in the general population [7, 9]. In addition to a causative role in gout, high UA concentrations have been associated with recurrence of stroke, high risk of cardiovascular events, congestive heart failure, hypertension and chronic kidney disease [10, 11]. Moreover, UA is a strong negative prognostic factor in patients affected by chronic heart failure , and an independent predictor of cardiovascular , and all-causes mortality . Interestingly, the mechanism of these associations and whether uric acid plays a causal role in the pathogenesis of those diseases remain unclear.
The study protocol was approved by the Institutional ethics committee at Medstar Research Institute and each participant gave written informed consent before enrollment. This study was a placebo-controlled double blind randomized trial carried out at the National Institute on Aging (NIA) Clinical Research Unit (CRU) at Harbor Hospital in Baltimore, MD.
In this study we examined the changes in serum inflammatory markers following an acute change in uric acid levels. In addition, we examined whether acute changes in uric acid level affect the inflammatory response induced by a lipid tolerance test, operationalized as rising levels of pro-inflammatory biomarkers. Out of all the inflammatory markers measured in this study, IL-6 was most informative in measuring the postprandial increase in inflammation as indicated in the study rise in serum IL-6 levels following consumption of a fatty meal. This change in IL-6 levels following a various fat load has been previously described . In this study, we observed that there is an accentuated postprandial rise in IL-6 in subjects treated with uric acid while this elevation was not observed in the placebo group. For the rasburicase arm of the study, the rasburicase group did not differ in their postprandial responses despite the acute lowering of uric acid levels. However, contrary to expectations, the placebo group had an elevated postprandial IL-6 level the day after the rasburicase placebo.