Evolutionary mutations have made the uricase gene become non-functional, and human beings are currently unable to metabolize uric acid to allantoin.¹ Stored in our body, uric acid contributes to 55% of plasma antioxidant activity.¹ It has a very high affinity to superoxide dismutase, free oxygen radicals and anti-inflammatory benefits, which are usually seen in the extracellular compartments and will lead to cellular injury.¹ In the 24^th Asia-Pacific League of Associations for Rheumatology (APLAR) Congress, Dr. Binit Vaidya from the National Center for Rheumatic Diseases, Nepal, shared his views on the management of gout beyond pain and urate-lowering therapy.

Recent studies highlighted a U-shaped association of uric acid, with higher overall mortality relating to a significantly low or high uric acid level, demonstrating the need for maintenance of a specific level of uric acid in the body to achieve an oxidant-antioxidant balance.¹ A systematic review and meta-analysis showed the risk of metabolic syndrome (MetS), which was 2 times higher among hyperuricemia patients in most of the studies, and a 1.5 times risk of non-alcoholic fatty liver disease in hyperuricemia patients which is commonly associated with MetS and increased cardiovascular (CV) outcomes, along with increased urine microalbumin (UMA).¹

According to Dr. Vaidya’s study from Nepal targeting gout patients, 30.6% and 60.6% of patients met 3 and 2 out of 5 criteria of MetS, respectively.¹ The UMA levels were also higher (>20mg/dL) in 15.5% of patients.¹ This showed that in South Asia, the prevalence of metabolic variants is common in patients with hyperuricemia.¹ A separate systematic review and meta-analysis on a pediatric MetS population showed that the parameters associated with MetS, such as low glucose, high low-density lipoprotein (LDL), abdominal obesity, insulin resistance, and hypertension, had a greater relative risk in pediatric patients with hyperuricemia.¹

Currently, it is still uncertain as to whether uric acid is the cause of MetS.¹ A recent review on the definitive role of uric acid found out that possible mechanisms were mostly within the intracellular pathway, including activation of cytosolic enzyme, calpain, increasing endoplasmic stress; activation of phosphatidylinositol (PI), activating the mammalian target of rapamycin (mTORC) pathway leading to mitochondrial stress; activation of p53 mitogen-activated protein kinase (MAPK) pathway, increasing inflammasome response; inhibition of endothelial nitric oxide synthetase (eNOS), decreasing nitric oxide availability; cytotoxicity from the reaction of the increased reactive oxygen species (ROS) with peroxin, nitrile and hydroxyl molecules; lipogenesis and increased triglyceride (TG) levels causing cellular injury.¹

A study on a Chinese cohort showed that there was a greater incidence of MetS with a high interval increase in the uric acid level, regardless of a high or low uric acid baseline.¹ Another study investigated the response to treatment in a non-corrected manifestation increase in the UMA levels among hyperuricemia patients.¹ The study included 2 groups of gout patients: one with hypertension and concurrently on angiotensin II receptor blocker (ARB); and the other with no hypertension (non-ARB).¹ Urate lowering therapy decreased the UMA levels in both ARB (127.9 ± 111.6 to 44.9 ± 61.6; p=0.07) and non-ARB (69.6 ± 14.6 to 15.7 ± 4.9; p=0.04) groups at 6 months, indicating the possible role of urate-lowering therapy in improving one of the metabolic parameters.¹  Moreover, sodium-glucose cotransporter-2 (SGLT2) inhibitors, which are usually used in diabetes, also significantly decreased the uric acid levels in both diabetic and non-diabetic patients, without causing hyperglycemia, thus showing potential in the hyperuricemia treatment.¹

A Mendelian Randomization Analysis of the solute carrier family 2 member 9 (SLC2A9) gene encoding urate 9, a common factor of hyperuricemia and uric acid excretion, observed that uric acid might not be a causal factor for metabolic syndrome when adjusted for genetic factors.¹ It means that there are possibilities of other unidentified confounders, which may not be independent, but also interlinked.¹

An overarching principle of the clinical practice guideline for gout treatment by APLAR is the “treatment of comorbidities, such as CV diseases, hypertension, diabetes mellitus, MetS”.¹ However, a study on the management of gout by clinicians in Nepal showed that most clinicians referred to gout as an inflammatory but curable disease (n=210; 55.3%), and focused on alcohol (n=345; 90.8%) and excess red meat intake (n=365; 96.1%), instead of other metabolic parameters.¹ Ironically, while recognizing the need for metabolic factors screening, most clinicians only screen for renal functions before gout treatment, and >50% of them do not screen for any metabolic parameters.¹

In conclusion, Dr. Vaidya suggested that comorbidities should be actively screened in gout and hyperuricemia patients, especially when considering genetic factors, such that individual metabolic parameters are addressed, possibly independently due to the uncertain guidelines for urate-lowering therapy.¹ The bidirectional relationship between MetS and uric acid should also be considered when it comes to hyperuricemia screening in metabolic patients.¹ In the future, large-scale randomized controlled trials on urate-lowering therapies in comorbidity patients should adhere to guidelines and subsequently add screening protocols to clinical practice.¹