Dysuricemia

Abstract

Gout results from elevated serum urate (SU) levels, or hyperuricemia, and is a globally widespread and increasingly burdensome disease. Recent studies have illuminated the pathophysiology of gout/hyperuricemia and its epidemiology, diagnosis, treatment, and complications. The genetic involvement of urate transporters and enzymes is also proven. URAT1, a molecular therapeutic target for gout/hyperuricemia, was initially derived from research into hereditary renal hypouricemia (RHUC). RHUC is often accompanied by complications such as exercise-induced acute kidney injury, which indicates the key physiological role of uric acid. Several studies have also revealed its physiological role as both an anti-oxidant and a pro-oxidant, acting as both a scavenger and a generator of reactive oxygen species (ROSs). These discoveries have prompted research interest in SU and xanthine oxidoreductase (XOR), an enzyme that produces both urate and ROSs, as status or progression biomarkers of chronic kidney disease and cardiovascular disease. The notion of "the lower, the better" is therefore incorrect; a better understanding of uric acid handling and metabolism/transport comes from an awareness that excessively high and low levels both cause problems. We summarize here the current body of evidence, demonstrate that uric acid is much more than a metabolic waste product, and finally propose the novel disease concept of "dysuricemia" on the path toward "normouricemia", or optimal SU level, to take advantage of the dual roles of uric acid. Our proposal should help to interpret the spectrum from hypouricemia to hyperuricemia/gout as a single disease category.

Keywords: Alzheimer’s disease (AD); Parkinson’s disease (PD); anti-oxidative effects; bucket-and-balls theory; cardiovascular disease (CVD); chronic kidney disease (CKD); crystal formation; monosodium urate (MSU); neurodegenerative diseases (NDs); pro-oxidative effects.

Figure 1

Disease concept of dysuricemia. The horizontal axis indicates serum urate (SU) level. The vertical axes on the left side and right side, respectively, indicate the disease risks and harmful/protective effect sizes of uric acid (ionized as urate in serum). Because uric acid has a dual role (providing an anti-oxidative protective effect and a pro-oxidative and/or crystal-forming harmful effect), both of these effect sizes increase as a function of rising SU level. The harmful effects increase more steeply with increasing SU level than the increase in protective effect due to the formation of monosodium urate crystals, which are deposited due to the low solubility (6.8 mg/dL, or approximately 400 μmol/L) of urate in human serum. There are three typical patterns of disease risk associated with SU level. In the “gout pattern”, increasing SU results in a higher disease risk of gout due to crystal formation, while neurodegenerative diseases (NDs) such as Parkinson’s disease show the “ND pattern”, indicating a lowered disease risk with rising SU level due to its neuroprotective effects. The risks for chronic kidney disease (CKD) and cardiovascular disease (CVD) generate a J-curve due to the combination of gout and ND patterns, the “CKD & CVD pattern”. As shown here, “dysuricemia” includes both hyperuricemia and hypouricemia. To reduce the burdens of several common diseases, the dual nature of uric acid should be exploited by maintaining normouricemia, with the optimal SU level being 4 < SU ≤ 7 mg/dL (240 < SU ≤ 420 μmol/L) for males and 3 < SU ≤ 6 mg/dL (180 < SU ≤ 360 μmol/L) for females.

Figure 2

Production of uric acid. At the end of the purine metabolic pathway, uric acid is produced from hypoxanthine and xanthine by xanthine oxidoreductase (XOR). Uric acid is an end product in humans due to a defect in urate oxidase (UOX) and is excreted from the kidney and intestine. Along this pathway, XOR produces reactive oxygen species (ROSs) as a pro-oxidative effect. Uric acid has both anti-oxidative and pro-oxidative effects against ROS. Slightly soluble uric acid, which has low solubility in human serum, occasionally forms crystals before being excreted from the body.

Figure 3

Urate transporters. Serum urate (SU) level is regulated by maintaining a balance between uric acid production and urate transport (excretion and reabsorption) in the kidney and intestine. The urate transporters shown here were identified by both genetic and functional studies: URAT1/SLC22A12, GLUT9/SLC2A9, and OAT10/SLC22A13 genes encode transporters for urate reabsorption, while ABCG2/BCRP and NPT1/SLC17A1 encode urate excretion transporters on the renal proximal tubular cells. ABCG2 is also expressed in the intestinal epithelial cells as the main urate exporter.

Figure 4

“Bucket-and-balls” theory. Genetic factors from ABCG2 variants reportedly had a stronger effect on the progression of hyperuricemia in the Japanese population than common environmental factors. We propose here a “bucket-and-balls theory” to explain this apparent contradiction in the progression of hyperuricemia. The serum urate (SU) level in the human urate pool is regulated by the balance among uric acid production, extra-renal, and renal urate excretion. This can be compared to the water level (SU level) in a bucket (urate pool) and faucets (uric acid production and excretion). Genetic factors due to urate transporter genes that favor hyperuricemia correspond to changing faucet sizes, typically becoming smaller, which is equivalent to putting balls in a bucket, resulting in an elevated water (SU) level ((A), left). The water (SU) level will also be raised by environmental factors such as the overproduction of uric acid due to a purine-rich diet ((A), right). Since Japanese and indigenous Asia-Pacific populations carry strong genetic factors, equivalent to having more balls in the bucket, their SU levels will be higher than those with fewer genetic factors ((B), left); relatively small environmental factors are therefore enough to elevate the SU level to >7 mg/dL (>420 μmol/L), that is, to cause hyperuricemia (HUA; (B), right). This theory is useful not only for explaining why genetic factors show a stronger effect size than environmental factors but also for patient education on gout and hyperuricemia, which stresses the importance of controlling environmental factors.

Figure 5

Strong and frequent genetic factors that favor dysuricemia in the Japanese population. As the allele frequency increases, its effect size generally decreases (adopted from [74,76]). Genetic studies of gout and hyperuricemia (HUA) in the Japanese population have revealed a “common disease-common variant” model with a higher effect size than other common diseases. Furthermore, the founder effect in the Japanese population causes relatively frequent hereditary renal hypouricemia (RHUC) with a higher effect size. Taken together, strong and frequent genetic effects on serum urate levels result in unique distributions of dysuricemia (gout/HUA and RHUC) in the Japanese population.