- Michael A Becker, MD
Michael A Becker, MD
- Section Editor — Crystal Diseases
- Professor Emeritus of Medicine
- University of Chicago Pritzker School of Medicine
Uric acid is the end product of the metabolism of purine compounds in humans and some primate species. With a (functional) pKa of about 5.75 in blood (5.35 in urine), the reaction
Uric acid <—> Urate- + H+
is shifted far to the right at the normal arterial pH of 7.40. As a result, most uric acid circulates as the urate anion.
The vast majority of other mammalian species have extremely low serum urate levels (about 1 mg/dL; 60 micromol/L) because uric acid is converted to allantoin, a highly soluble excretory product. By contrast, uric acid is the end product of purine metabolism in humans, because the human homolog of the mammalian uricase (urate oxidase) gene is structurally modified to an unexpressed (pseudogene) state. Thus, normal humans have serum urate concentrations approaching the theoretical limit of solubility of urate in serum (6.8 mg/dL) and regularly excrete urine that is supersaturated with respect to uric acid. As an example, the mean serum urate concentration was formerly reported to be between 5 and 6 mg/dL among healthy adult white men in the United States, and the prevalence of hyperuricemia in this group was estimated to be at least 5 to 8 percent. However, subsequent epidemiologic data from the National Health and Nutrition Examination Survey 2007 to 2008 indicate that hyperuricemia (as defined in that study by a single urate determination exceeding 7 mg/dL) is much more prevalent, occurring in up to 21.4 percent of adults in the surveyed US adult population . (See "Asymptomatic hyperuricemia".)
The normal adult male has a total body urate pool of approximately 1200 mg, about twice that of the normal adult female. This gender difference may be explained by an enhancement of renal urate excretion in women of childbearing age due to the effects of estrogenic compounds , which likely reduce the number of active renal urate transporters, resulting in lesser renal tubular uric acid reabsorption and thus increased urate clearance . Normally, all urate measured in the body pool is believed to be soluble urate. When insoluble urate crystal deposition occurs (in gout), body pool measurements underestimate the body urate pool. Under normal steady state conditions, daily turnover of about 60 percent of the urate pool is achieved by balanced production and elimination of uric acid.
- Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum 2011; 63:3136.
- Antón FM, García Puig J, Ramos T, et al. Sex differences in uric acid metabolism in adults: evidence for a lack of influence of estradiol-17 beta (E2) on the renal handling of urate. Metabolism 1986; 35:343.
- Döring A, Gieger C, Mehta D, et al. SLC2A9 influences uric acid concentrations with pronounced sex-specific effects. Nat Genet 2008; 40:430.
- Griebsch A, Zöllner N. Effect of ribomononucleotides given orally on uric acid production in man. Adv Exp Med Biol 1974; 41:443.
- Matsuo H, Takada T, Ichida K, et al. Common defects of ABCG2, a high-capacity urate exporter, cause gout: a function-based genetic analysis in a Japanese population. Sci Transl Med 2009; 1:5ra11.
- Ichida K, Matsuo H, Takada T, et al. Decreased extra-renal urate excretion is a common cause of hyperuricemia. Nat Commun 2012; 3:764.
- Mandal AK, Mount DB. The molecular physiology of uric acid homeostasis. Annu Rev Physiol 2015; 77:323.
- Huls M, Brown CD, Windass AS, et al. The breast cancer resistance protein transporter ABCG2 is expressed in the human kidney proximal tubule apical membrane. Kidney Int 2008; 73:220.
- Sorensen LB. The elimination of uric acid in man. Scand J Clin Lab Invest 1960; 12 (supplement 54):1.
- Roch-Ramel F, Diezi J. Renal transport of organic ions and uric acid. In: Diseases of the Kidney, 6th, Schrier RW, Gottschalk CE (Eds), Little, Brown, Boston 1996. p.231.
- Woodward OM, Köttgen A, Coresh J, et al. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc Natl Acad Sci U S A 2009; 106:10338.
- Enomoto A, Kimura H, Chairoungdua A, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002; 417:447.
- Caulfield MJ, Munroe PB, O'Neill D, et al. SLC2A9 is a high-capacity urate transporter in humans. PLoS Med 2008; 5:e197.
- Ichida K, Hosoyamada M, Hisatome I, et al. Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol 2004; 15:164.
- Taniguchi A, Urano W, Yamanaka M, et al. A common mutation in an organic anion transporter gene, SLC22A12, is a suppressing factor for the development of gout. Arthritis Rheum 2005; 52:2576.
- Shima Y, Teruya K, Ohta H. Association between intronic SNP in urate-anion exchanger gene, SLC22A12, and serum uric acid levels in Japanese. Life Sci 2006; 79:2234.
- Vitart V, Rudan I, Hayward C, et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 2008; 40:437.
- Dehghan A, Köttgen A, Yang Q, et al. Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. Lancet 2008; 372:1953.
- Urano W, Taniguchi A, Anzai N, et al. Sodium-dependent phosphate cotransporter type 1 sequence polymorphisms in male patients with gout. Ann Rheum Dis 2010; 69:1232.
- Kolz M, Johnson T, Sanna S, et al. Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations. PLoS Genet 2009; 5:e1000504.
- Endou H, Anzai N. Urate transport across the apical membrane of renal proximal tubules. Nucleosides Nucleotides Nucleic Acids 2008; 27:578.
- Eraly SA, Vallon V, Rieg T, et al. Multiple organic anion transporters contribute to net renal excretion of uric acid. Physiol Genomics 2008; 33:180.
- Matsuo H, Chiba T, Nagamori S, et al. Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia. Am J Hum Genet 2008; 83:744.
- Anzai N, Ichida K, Jutabha P, et al. Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans. J Biol Chem 2008; 283:26834.
- Nakagawa T, Tuttle KR, Short RA, Johnson RJ. Hypothesis: fructose-induced hyperuricemia as a causal mechanism for the epidemic of the metabolic syndrome. Nat Clin Pract Nephrol 2005; 1:80.
- Gao X, Qi L, Qiao N, et al. Intake of added sugar and sugar-sweetened drink and serum uric acid concentration in US men and women. Hypertension 2007; 50:306.
- Choi JW, Ford ES, Gao X, Choi HK. Sugar-sweetened soft drinks, diet soft drinks, and serum uric acid level: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 2008; 59:109.
- Choi HK, Curhan G. Soft drinks, fructose consumption, and the risk of gout in men: prospective cohort study. BMJ 2008; 336:309.
- Matsuo H, Nakayama A, Sakiyama M, et al. ABCG2 dysfunction causes hyperuricemia due to both renal urate underexcretion and renal urate overload. Sci Rep 2014; 4:3755.
- Togawa N, Miyaji T, Izawa S, et al. A Na+-phosphate cotransporter homologue (SLC17A4 protein) is an intestinal organic anion exporter. Am J Physiol Cell Physiol 2012; 302:C1652.
- Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A 1981; 78:6858.
- Sautin YY, Johnson RJ. Uric acid: the oxidant-antioxidant paradox. Nucleosides Nucleotides Nucleic Acids 2008; 27:608.
- Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008; 359:1811.
- Neogi T, George J, Rekhraj S, et al. Are either or both hyperuricemia and xanthine oxidase directly toxic to the vasculature? A critical appraisal. Arthritis Rheum 2012; 64:327.
- Meotti FC, Jameson GN, Turner R, et al. Urate as a physiological substrate for myeloperoxidase: implications for hyperuricemia and inflammation. J Biol Chem 2011; 286:12901.
- Shao B, Oda MN, Oram JF, Heinecke JW. Myeloperoxidase: an oxidative pathway for generating dysfunctional high-density lipoprotein. Chem Res Toxicol 2010; 23:447.
- Imaram W, Gersch C, Kim KM, et al. Radicals in the reaction between peroxynitrite and uric acid identified by electron spin resonance spectroscopy and liquid chromatography mass spectrometry. Free Radic Biol Med 2010; 49:275.
- Wyngaarden JB, Kelley WN. Gout and Hyperuricemia, Grune and Stratton, New York 1976.
- Perez-Ruiz F, Calabozo M, Erauskin GG, et al. Renal underexcretion of uric acid is present in patients with apparent high urinary uric acid output. Arthritis Rheum 2002; 47:610.