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  • Author: Yasir Qazi, MD; Chief Editor: Vecihi Batuman, MD, FACP, FASN  more...
Updated: Feb 22, 2016


Despite the fact that uric acid was first identified approximately 2 centuries ago, certain pathophysiologic aspects of hyperuricemia are still not clearly understood. For years, hyperuricemia has been identified with or thought to be the same as gout, but uric acid has now been identified as a marker for a number of metabolic and hemodynamic abnormalities.[1, 2]

Unlike allantoin, the more soluble end product of purine metabolism in lower animals, uric acid is a poorly soluble end product of purine metabolism in humans. Human beings have higher levels of uric acid, in part, because of a deficiency of the hepatic enzyme uricase, and a lower fractional excretion of uric acid. Approximately two thirds of total body urate is produced endogenously, while the remaining one third is accounted for by dietary purines.

Approximately 70% of the urate produced daily is excreted by the kidneys, while the rest is eliminated by the intestines. However, during renal failure, the intestinal contribution of urate excretion increases to compensate for the decreased elimination by the kidneys.

The blood levels of uric acid are a function of the balance between the breakdown of purines and the rate of uric acid excretion. Theoretically, alterations in this balance may account for hyperuricemia, although clinically defective elimination accounts for most cases of hyperuricemia.



Uric acid in the blood is saturated at 6.4-6.8 mg/dL at ambient conditions, with the upper limit of solubility placed at 7 mg/dL. Urate is freely filtered at the glomerulus, reabsorbed, secreted, and then again reabsorbed in the proximal tubule. The recent cloning of certain urate transporters will facilitate the understanding of specific mechanisms by which urate is handled in the kidney and small intestines.

A urate/anion exchanger (URAT1) has been identified in the brush-border membrane of the kidneys and is inhibited by an angiotensin II receptor blocker, losartan.[3] A human organic anion transporter (hOAT1) has been found to be inhibited by both uricosuric drugs and antiuricosuric drugs,[4] while another urate transporter (UAT) has been found to facilitate urate efflux out of the cells.[5] These transporters may account for the reabsorption, secretion, and reabsorption pattern of renal handling of urate.

Urate secretion does appear to correlate with the serum urate concentration because a small increase in the serum concentration results in a marked increase in urate excretion.

Hyperuricemia may occur because of decreased excretion (underexcretors), increased production (overproducers), or a combination of these two mechanisms.

Underexcretion accounts for most causes of hyperuricemia. Urate handling by the kidneys involves filtration at the glomerulus, reabsorption, secretion, and, finally, postsecretory reabsorption. Consequently, altered uric acid excretion can result from decreased glomerular filtration, decreased tubular secretion, or enhanced tubular reabsorption.

While decreased urate filtration may not cause primary hyperuricemia, it can contribute to the hyperuricemia of renal insufficiency. Decreased tubular secretion of urate occurs in patients with acidosis (eg, diabetic ketoacidosis, ethanol or salicylate intoxication, starvation ketosis). The organic acids that accumulate in these conditions compete with urate for tubular secretion. Finally, enhanced reabsorption of uric acid distal to the site of secretion is the mechanism thought to be responsible for the hyperuricemia observed with diuretic therapy and diabetes insipidus.

Overproduction accounts for only a minority of patients presenting with hyperuricemia. The causes for hyperuricemia in overproducers may be either exogenous (diet rich in purines) or endogenous (increased purine nucleotide breakdown). A small percentage of overproducers have enzymatic defects that account for their hyperuricemia. These include a complete deficiency of hypoxanthine guanine phosphoribosyltransferase (HGPRT) as in Lesch-Nyhan syndrome, partial deficiency of HGPRT (Kelley-Seegmiller syndrome), and increased production of 5-phospho-alpha-d-ribosyl pyrophosphate (PRPP) activity. Accelerated purine degradation can result from rapid cell proliferation and turnover (blast crisis of leukemias) or from cell death (rhabdomyolysis, cytotoxic therapy). Glycogenoses types III, IV, and VII can result in hyperuricemia from excessive degradation of skeletal muscle ATP.

Combined mechanisms (underexcretion and overproduction) can also cause hyperuricemia. The most common cause under this group is alcohol consumption,[6] which results in accelerated hepatic breakdown of ATP and the generation of organic acids that compete with urate for tubular secretion. Enzymatic defects such as glycogenoses type I and aldolase-B deficiency are other causes of hyperuricemia that result from a combination of overproduction and underexcretion.

Urate crystals can engage an intracellular pattern recognition receptor, the macromolecular NALP3 (cryopyrin) inflammasome complex.[7, 8] NALP3 inflammasome may result in interleukin 1 (IL-1) beta production, which, in turn, incites an inflammatory response. Inhibition of this pathway has been targeted as a treatment for hyperuricemia-induced crystal arthritis, with recent reports documenting the efficacy of the IL-1 inhibitors canakinumab and rilonacept for preventing gout flares during the initiation of allopurinol therapy.[9]

Zinc and magnesium are important nutrients with anti-inflammatory properties. Chinese studies have linked low dietary levels to hyperuricemia in men. A study by Xie et al in 2697 men and 2471 women indicated that dietary zinc intake was inversely associated with hyperuricemia in middle-aged and older males, but not in females.[10] Wang et al reported that in 5168 subjects, dietary magnesium intake was inversely associated with hyperuricemia, independent of some major confounding factors, but only in males.[11]




United States

The prevalence rate of asymptomatic hyperuricemia in the general population is estimated at 2-13%.


Worldwide, the prevalence of hyperuricemia has increased substantially in recent decades. The progressive increase in serum levels of uric acid levels may be linked to the rising prevalence of overweight and obesity, as well as the increase in consumption of sugar-sweetened beverages, foods rich in purines, and alcohol.[12, 13]

A Japanese study that used an administrative claims database to ascertain 10-year trends in the prevalence of hyperuricemia concluded that the prevalence of hyperuricemia in the overall study population increased during the 10-year follow-up. When stratified by age, the prevalence increased among groups older than 65 years in both sexes. In those younger than 65 years, men had a prevalence 4 times higher than that in women, but in those older than 65 years, the gender gap narrowed to 1:3 (female-to-male ratio) with gout and/or hyperuricemia.


Hyperuricemia has been associated with increased morbidity[14] in patients with hypertension and is associated with increased mortality in women and elderly persons. In a study of 837 elderly patients with hypertension followed up over 3.5 years, Lin et al found that increases in uric acid levels were independently associated with decline in renal function.[15] Ding et al reported that serum uric acid concentration and prevalence of hyperuricemia were positively associated with osteoarthritis of the knee in a cohort of Chinese women.[16]

The cause for these associations is unknown, but hyperuricemia is probably a marker for comorbid risk factors rather than a causative factor, per se. Results of a cross-sectional study by Yang et al suggested that levels of high-sensitivity C-reactive protein (a nonspecific marker for inflammation) are positively associated with the prevalence of hyperuricemia.[17]

Although observational studies on hyperuricemia and stroke have yielded conflicting results, a meta-analysis by Kim et al suggested that hyperuricemia may modestly increase the risk of stroke incidence and mortality.[18] The authors reviewed 16 studies that together included 238,449 adults. Investigating risk ratios (RRs) for the incidence of stroke and mortality in relation to serum uric acid levels in adults, the authors found that in studies that adjusted for known risk factors, the RR for stroke in patients with hyperuricemia was 1.47 (4 studies; 95% confidence interval [CI] 1.19, 1.76) and the RR for mortality was 1.26 (6 studies; 95% CI 1.12, 1.39). Kim et al concluded that further research is needed to determine whether reducing patients' uric acid levels will have beneficial effects relating to stroke.

Race-, Sex-, and Age-related Demographics

A high prevalence of hyperuricemia exists in indigenous races of the Pacific, which appears to be associated with a low fractional excretion of uric acid.[19] In the United States, African Americans develop hyperuricemia more commonly than whites.

Hyperuricemia, and particularly gouty arthritis, are far more common in men than in women. Only 5% of patients with gout are female, but uric acid levels increase in women after menopause.[20]

The normal serum uric acid level is lower in children than in adults. The upper limit of the reference range for children is 5 mg/dL (0.30 mmol/L). The upper limit of the reference range for men is 7 mg/dL (0.42 mmol/L) and for women is 6 mg/dL (0.36 mmol/L). The tendency to develop hyperuricemia increases with age.

Contributor Information and Disclosures

Yasir Qazi, MD Assistant Professor of Medicine, Division of Nephrology, University of Southern California at Keck School of Medicine

Yasir Qazi, MD is a member of the following medical societies: American Society of Nephrology

Disclosure: Nothing to disclose.


James W Lohr, MD Professor, Department of Internal Medicine, Division of Nephrology, Fellowship Program Director, University of Buffalo State University of New York School of Medicine and Biomedical Sciences

James W Lohr, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Nephrology, Central Society for Clinical and Translational Research

Disclosure: Partner received salary from Alexion for employment.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

George R Aronoff, MD Director, Professor, Departments of Internal Medicine and Pharmacology, Section of Nephrology, Kidney Disease Program, University of Louisville School of Medicine

George R Aronoff, MD is a member of the following medical societies: American Federation for Medical Research, American Society of Nephrology, Kentucky Medical Association, National Kidney Foundation

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FACP, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System

Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, International Society of Nephrology

Disclosure: Nothing to disclose.

Additional Contributors

James H Sondheimer, MD, FACP, FASN Associate Professor of Medicine, Wayne State University School of Medicine; Medical Director of Hemodialysis, Harper University Hospital at Detroit Medical Center; Medical Director, DaVita Greenview Dialysis (Southfield)

James H Sondheimer, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Nephrology

Disclosure: Receive dialysis unit medical director fee (as independ ent contractor) for: DaVita .

  1. Stack A, Manolis AJ, Ritz E. Detrimental role of hyperuricemia on the cardio-reno-vascular system. Curr Med Res Opin. 2015 Sep. 31 Suppl 2:21-6. [Medline].

  2. Johnson RJ, Kivlighn SD, Kim YG, Suga S, Fogo AB. Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal disease. Am J Kidney Dis. 1999 Feb. 33(2):225-34. [Medline].

  3. Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature. 2002 May 23. 417(6887):447-52. [Medline].

  4. Ichida K, Hosoyamada M, Kimura H, Takeda M, Utsunomiya Y, Hosoya T, et al. Urate transport via human PAH transporter hOAT1 and its gene structure. Kidney Int. 2003 Jan. 63(1):143-55. [Medline].

  5. Leal-Pinto E, Cohen BE, Lipkowitz MS, Abramson RG. Functional analysis and molecular model of the human urate transporter/channel, hUAT. Am J Physiol Renal Physiol. 2002 Jul. 283 (1):F150-63. [Medline].

  6. Shiraishi H, Une H. The effect of the interaction between obesity and drinking on hyperuricemia in Japanese male office workers. J Epidemiol. 2009. 19(1):12-6. [Medline]. [Full Text].

  7. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006 Mar 9. 440(7081):237-41. [Medline].

  8. Dalbeth N, Merriman T. Crystal ball gazing: new therapeutic targets for hyperuricaemia and gout. Rheumatology (Oxford). 2009 Mar. 48(3):222-6. [Medline].

  9. Latourte A, Bardin T, Richette P. Prophylaxis for acute gout flares after initiation of urate-lowering therapy. Rheumatology (Oxford). 2014 Nov. 53 (11):1920-6. [Medline].

  10. Xie DX, Xiong YL, Zeng C, Wei J, Yang T, Li H, et al. Association between low dietary zinc and hyperuricaemia in middle-aged and older males in China: a cross-sectional study. BMJ Open. 2015 Oct 13. 5 (10):e008637. [Medline].

  11. Wang YL, Zeng C, Wei J, Yang T, Li H, Deng ZH, et al. Association between Dietary Magnesium Intake and Hyperuricemia. PLoS One. 2015. 10 (11):e0141079. [Medline].

  12. Desideri G, Puig JG, Richette P. The management of hyperuricemia with urate deposition. Curr Med Res Opin. 2015 Sep. 31 Suppl 2:27-32. [Medline].

  13. Meneses-Leon J, Denova-Gutiérrez E, Castañón-Robles S, Granados-García V, Talavera JO, Rivera-Paredez B, et al. Sweetened beverage consumption and the risk of hyperuricemia in Mexican adults: a cross-sectional study. BMC Public Health. 2014 May 12. 14:445. [Medline].

  14. Kim SY, De Vera MA, Choi HK. Gout and mortality. Clin Exp Rheumatol. 2008 Sep-Oct. 26(5 Suppl 51):S115-9. [Medline].

  15. Lin F, Zhang H, Huang F, Chen H, Lin C, Zhu P. Influence of changes in serum uric acid levels on renal function in elderly patients with hypertension: a retrospective cohort study with 3.5-year follow-up. BMC Geriatr. 2016 Feb 3. 16 (1):35. [Medline].

  16. Ding X, Zeng C, Wei J, Li H, Yang T, Zhang Y, et al. The associations of serum uric acid level and hyperuricemia with knee osteoarthritis. Rheumatol Int. 2016 Jan 7. [Medline].

  17. Yang T, Ding X, Wang YL, Zeng C, Wei J, Li H, et al. Association between high-sensitivity C-reactive protein and hyperuricemia. Rheumatol Int. 2016 Feb 10. [Medline].

  18. Kim SY, Guevara JP, Kim KM, et al. Hyperuricemia and risk of stroke: a systematic review and meta-analysis. Arthritis Rheum. 2009 Jul 15. 61(7):885-92. [Medline]. [Full Text].

  19. Liu L, Lou S, Xu K, Meng Z, Zhang Q, Song K. Relationship between lifestyle choices and hyperuricemia in Chinese men and women. Clin Rheumatol. 2012 Nov 7. [Medline].

  20. Ioannou GN, Boyko EJ. Effects of menopause and hormone replacement therapy on the associations of hyperuricemia with mortality. Atherosclerosis. 2012 Oct 22. [Medline].

  21. Chen SC, Huang YF, Wang JD. Hyperferritinemia and hyperuricemia may be associated with liver function abnormality in obese adolescents. PLoS One. 2012. 7(10):e48645. [Medline]. [Full Text].

  22. Lee YM, Bae SG, Lee SH, Jacobs DR Jr, Lee DH. Persistent organic pollutants and hyperuricemia in the U.S. general population. Atherosclerosis. 2013 Sep. 230(1):1-5. [Medline].

  23. Rho YH, Zhu Y, Choi HK. The epidemiology of uric acid and fructose. Semin Nephrol. 2011 Sep. 31(5):410-9. [Medline]. [Full Text].

  24. Bae J, Chun BY, Park PS, Choi BY, Kim MK, Shin MH, et al. Higher consumption of sugar-sweetened soft drinks increases the risk of hyperuricemia in Korean population: The Korean Multi-Rural Communities Cohort Study. Semin Arthritis Rheum. 2014 Apr. 43(5):654-61. [Medline].

  25. López-Molina R, Parra-Cabrera S, López-Ridaura R, González-Villalpando ME, Ferrannini E, González-Villalpando C. Sweetened beverages intake, hyperuricemia and metabolic syndrome: the Mexico City Diabetes Study. Salud Publica Mex. 2013 Dec. 55(6):557-63. [Medline].

  26. Lecoultre V, Egli L, Theytaz F, Despland C, Schneiter P, Tappy L. Fructose-induced hyperuricemia is associated with a decreased renal uric acid excretion in humans. Diabetes Care. 2013 Sep. 36(9):e149-50. [Medline]. [Full Text].

  27. Becker MA, Schumacher HR, Espinoza LR, Wells AF, MacDonald P, Lloyd E, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010. 12 (2):R63. [Medline]. [Full Text].

  28. Frampton JE. Febuxostat: a review of its use in the treatment of hyperuricaemia in patients with gout. Drugs. 2015 Mar. 75 (4):427-38. [Medline].

  29. Zurampic (lesinurad) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals. December, 2015. Available at [Full Text].

  30. Dinnel J, Moore BL, Skiver BM, Bose P. Rasburicase in the management of tumor lysis: an evidence-based review of its place in therapy. Core Evid. 2015. 10:23-38. [Medline]. [Full Text].

  31. Li L, Yang C, Zhao Y, Zeng X, Liu F, Fu P. Is hyperuricemia an independent risk factor for new-onset chronic kidney disease?: A systematic review and meta-analysis based on observational cohort studies. BMC Nephrol. 2014 Jul 27. 15:122. [Medline]. [Full Text].

  32. Bisht M, Bist SS. Febuxostat: a novel agent for management of hyperuricemia in gout. Indian J Pharm Sci. 2011 Nov. 73(6):597-600. [Medline]. [Full Text].

  33. Schumacher HR Jr, Becker MA, Lloyd E, et al. Febuxostat in the treatment of gout: 5-yr findings of the FOCUS efficacy and safety study. Rheumatology (Oxford). 2009 Feb. 48(2):188-94. [Medline].

  34. Schumacher HR Jr, Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum. 2008 Nov 15. 59(11):1540-8. [Medline].

  35. Becker G. The CARI guidelines. Kidney stones: uric acid stones. Nephrology (Carlton). 2007 Feb. 12 Suppl 1:S21-5. [Medline].

  36. Iseki K, Ikemiya Y, Inoue T, Iseki C, Kinjo K, Takishita S. Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort. Am J Kidney Dis. 2004 Oct. 44(4):642-50. [Medline].

  37. Maesaka JK, Fishbane S. Regulation of renal urate excretion: a critical review. Am J Kidney Dis. 1998 Dec. 32(6):917-33. [Medline].

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