- Michael A Becker, MD
Michael A Becker, MD
- Section Editor — Crystal Diseases
- Professor Emeritus of Medicine
- University of Chicago Pritzker School of Medicine
Asymptomatic hyperuricemia is a term traditionally applied to settings in which the serum urate concentration is elevated but in which neither symptoms nor signs of monosodium urate (MSU) crystal deposition disease, such as gout, or uric acid renal disease, have occurred. Although these clinical manifestations may develop in a hyperuricemic individual at any point, about two-thirds or more of such individuals remain asymptomatic, never developing gouty arthritis, tophaceous gout, acute or chronic hyperuricemic nephropathy, or uric acid nephrolithiasis [1-5]. (See "Clinical manifestations and diagnosis of gout" and "Uric acid renal diseases" and "Uric acid nephrolithiasis".)
In addition to its relationship with urate or uric acid crystal deposition, asymptomatic hyperuricemia has also been associated with other disorders that appear to be largely unrelated to crystal deposition, including hypertension, chronic kidney disease, cardiovascular disease, and the insulin resistance syndrome. (See "Overview of the possible risk factors for cardiovascular disease", section on 'Uric acid' and "Secondary factors and progression of chronic kidney disease", section on 'Hyperuricemia' and "The metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Other associations'.)
The definition, etiology and management of asymptomatic hyperuricemia will be reviewed here. Gout, uric acid renal diseases, and uric acid nephrolithiasis are discussed separately. (See "Clinical manifestations and diagnosis of gout" and "Treatment of acute gout" and "Prevention of recurrent gout: Pharmacologic urate-lowering therapy and treatment of tophi" and "Uric acid renal diseases" and "Uric acid nephrolithiasis".)
There is no universally accepted definition of hyperuricemia. For purposes relating to urate crystal deposition, a physiochemical definition of hyperuricemia, based upon the solubility limit of urate in body fluids (ie, the concentration above which a state of supersaturation for urate is reached in the serum) is widely preferred over a statistical definition because of the non-normal distribution of serum urate concentrations in most populations [6-11]. This physicochemical definition corresponds to urate concentrations exceeding about 7 mg/dL (416 micromol/L), as measured by automated enzymatic (uricase) methods in routine clinical laboratory use. These values are approximately 1 mg/dL (60 micromol/L) lower than those obtained with colorimetric methods.
A definition of hyperuricemia appropriate to the non-crystal deposition associations with hyperuricemia (eg, cardiovascular disease) is more problematic for two reasons. One is the high prevalence of urate values exceeding saturation but within two standard deviations of the population mean (eg, an estimated 5 to 8 percent in adult white males in the US and 25 percent in Taiwan Chinese males) . The other is that associations of serum urate levels with cardiovascular and other disorders are detected at concentrations that are clearly subsaturating [13,14].
- Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. Am J Med 1987; 82:421.
- Langford HG, Blaufox MD, Borhani NO, et al. Is thiazide-produced uric acid elevation harmful? Analysis of data from the Hypertension Detection and Follow-up Program. Arch Intern Med 1987; 147:645.
- Hall AP, Barry PE, Dawber TR, McNamara PM. Epidemiology of gout and hyperuricemia. A long-term population study. Am J Med 1967; 42:27.
- Fessel WJ. Renal outcomes of gout and hyperuricemia. Am J Med 1979; 67:74.
- Johnson RJ, Feig DI, Herrera-Acosta J, Kang DH. Resurrection of uric acid as a causal risk factor in essential hypertension. Hypertension 2005; 45:18.
- Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2006; 65:1312.
- Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken) 2012; 64:1431.
- Neogi T. Clinical practice. Gout. N Engl J Med 2011; 364:443.
- Terkeltaub R. Update on gout: new therapeutic strategies and options. Nat Rev Rheumatol 2010; 6:30.
- Yamanaka H, Japanese Society of Gout and Nucleic Acid Metabolism. Japanese guideline for the management of hyperuricemia and gout: second edition. Nucleosides Nucleotides Nucleic Acids 2011; 30:1018.
- Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis 2017; 76:29.
- Lin KC, Lin HY, Chou P. Community based epidemiological study on hyperuricemia and gout in Kin-Hu, Kinmen. J Rheumatol 2000; 27:1045.
- Sánchez-Lozada LG, Tapia E, Rodríguez-Iturbe B, et al. Hemodynamics of hyperuricemia. Semin Nephrol 2005; 25:19.
- Neogi T. Asymptomatic hyperuricemia: cardiovascular and renal complications. In: Gout and Other Crystal Arthropathies, Terkeltaub R. (Ed), Elsevier, Philadelphia 2012. p.226.
- Bardin T, Richette P. Definition of hyperuricemia and gouty conditions. Curr Opin Rheumatol 2014; 26:186.
- Desideri G, Castaldo G, Lombardi A, et al. Is it time to revise the normal range of serum uric acid levels? Eur Rev Med Pharmacol Sci 2014; 18:1295.
- Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, et al. Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic gout. Ann Rheum Dis 1998; 57:545.
- Shoji A, Yamanaka H, Kamatani N. A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Rheum 2004; 51:321.
- Qaseem A, Harris RP, Forciea MA, Clinical Guidelines Committee of the American College of Physicians. Management of Acute and Recurrent Gout: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med 2017; 166:58.
- Wyngaarden JB, Kelley WN. Gout and Hyperuricemia, Grune and Stratton, New York 1976.
- 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.
- Ljubojevic M, Herak-Kramberger CM, Hagos Y, et al. Rat renal cortical OAT1 and OAT3 exhibit gender differences determined by both androgen stimulation and estrogen inhibition. Am J Physiol Renal Physiol 2004; 287:F124.
- Arromdee E, Michet CJ, Crowson CS, et al. Epidemiology of gout: is the incidence rising? J Rheumatol 2002; 29:2403.
- Mikuls TR, Farrar JT, Bilker WB, et al. Gout epidemiology: results from the UK General Practice Research Database, 1990-1999. Ann Rheum Dis 2005; 64:267.
- Kjellstrand CM, Cambell DC 2nd, von Hartitzsch B, Buselmeier TJ. Hyperuricemic acute renal failure. Arch Intern Med 1974; 133:349.
- Choi HK, Atkinson K, Karlson EW, et al. Alcohol intake and risk of incident gout in men: a prospective study. Lancet 2004; 363:1277.
- Choi HK, Atkinson K, Karlson EW, et al. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med 2004; 350:1093.
- Choi HK, Soriano LC, Zhang Y, Rodríguez LA. Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study. BMJ 2012; 344:d8190.
- Lin KC, Lin HY, Chou P. The interaction between uric acid level and other risk factors on the development of gout among asymptomatic hyperuricemic men in a prospective study. J Rheumatol 2000; 27:1501.
- Choi HK, Atkinson K, Karlson EW, Curhan G. Obesity, weight change, hypertension, diuretic use, and risk of gout in men: the health professionals follow-up study. Arch Intern Med 2005; 165:742.
- De Miguel E, Puig JG, Castillo C, et al. Diagnosis of gout in patients with asymptomatic hyperuricaemia: a pilot ultrasound study. Ann Rheum Dis 2012; 71:157.
- Pineda C, Amezcua-Guerra LM, Solano C, et al. Joint and tendon subclinical involvement suggestive of gouty arthritis in asymptomatic hyperuricemia: an ultrasound controlled study. Arthritis Res Ther 2011; 13:R4.
- Chowalloor PV, Keen HI. A systematic review of ultrasonography in gout and asymptomatic hyperuricaemia. Ann Rheum Dis 2013; 72:638.
- Ottaviani S, Allard A, Bardin T, Richette P. An exploratory ultrasound study of early gout. Clin Exp Rheumatol 2011; 29:816.
- Puig JG, de Miguel E, Castillo MC, et al. Asymptomatic hyperuricemia: impact of ultrasonography. Nucleosides Nucleotides Nucleic Acids 2008; 27:592.
- Ottaviani S, Richette P, Allard A, et al. Ultrasonography in gout: a case-control study. Clin Exp Rheumatol 2012; 30:499.
- Baker JF, Synnott KA. Clinical images: gout revealed on arthroscopy after minor injury. Arthritis Rheum 2010; 62:895.
- Ogdie A, Taylor WJ, Weatherall M, et al. Imaging modalities for the classification of gout: systematic literature review and meta-analysis. Ann Rheum Dis 2015; 74:1868.
- Liang MH, Fries JF. Asymptomatic hyperuricemia: the case for conservative management. Ann Intern Med 1978; 88:666.
- Bose B, Badve SV, Hiremath SS, et al. Effects of uric acid-lowering therapy on renal outcomes: a systematic review and meta-analysis. Nephrol Dial Transplant 2014; 29:406.
- Shadick NA, Kim R, Weiss S, et al. Effect of low level lead exposure on hyperuricemia and gout among middle aged and elderly men: the normative aging study. J Rheumatol 2000; 27:1708.
- Murray T, Goldberg M. Chronic interstitial nephritis: etiologic factors. Ann Intern Med 1975; 82:453.
- Curhan GC, Taylor EN. 24-h uric acid excretion and the risk of kidney stones. Kidney Int 2008; 73:489.
- Yü T, Gutman AB. Uric acid nephrolithiasis in gout. Predisposing factors. Ann Intern Med 1967; 67:1133.
- Lu N, Dubreuil M, Zhang Y, et al. Gout and the risk of Alzheimer's disease: a population-based, BMI-matched cohort study. Ann Rheum Dis 2016; 75:547.
- Roddy E, Choi HK. Epidemiology of gout. Rheum Dis Clin North Am 2014; 40:155.
- Choi HK, Mount DB, Reginato AM, et al. Pathogenesis of gout. Ann Intern Med 2005; 143:499.
- Simkin PA. Urate excretion in normal and gouty men. Adv Exp Med Biol 1977; 76B:41.
- Becker MA. Clinical aspects of monosodium urate monohydrate crystal deposition disease (gout). Rheum Dis Clin North Am 1988; 14:377.
- Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129:S76.
- Elmer PJ, Obarzanek E, Vollmer WM, et al. Effects of comprehensive lifestyle modification on diet, weight, physical fitness, and blood pressure control: 18-month results of a randomized trial. Ann Intern Med 2006; 144:485.
- Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005; 112:2735.
- Feher MD, Hepburn AL, Hogarth MB, et al. Fenofibrate enhances urate reduction in men treated with allopurinol for hyperuricaemia and gout. Rheumatology (Oxford) 2003; 42:321.
- Würzner G, Gerster JC, Chiolero A, et al. Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia and gout. J Hypertens 2001; 19:1855.
- Singer JZ, Wallace SL. The allopurinol hypersensitivity syndrome. Unnecessary morbidity and mortality. Arthritis Rheum 1986; 29:82.
- Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med 1984; 76:47.
- Sampat R, Fu R, Larovere LE, et al. Mechanisms for phenotypic variation in Lesch-Nyhan disease and its variants. Hum Genet 2011; 129:71.
- Yu TF. Urolithiasis in hyperuricemia and gout. J Urol 1981; 126:424.
- Gois PH, Souza ER. Pharmacotherapy for hyperuricemia in hypertensive patients. Cochrane Database Syst Rev 2013; :CD008652.
- Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA 2008; 300:924.
- POTENTIAL CLINICAL CONSEQUENCES
- Urate crystal deposition disorders
- - Gout
- - Chronic kidney disease
- - Nephrolithiasis
- Non-crystal deposition disorders
- Initial evaluation
- Further evaluation
- General measures
- Sustained marked hyperuricemia
- Marked asymptomatic hyperuricosuria
- Recurrent uric acid urolithiasis
- Tumor lysis
- Hyperuricemia and conditions unassociated with crystal deposition
- SUMMARY AND RECOMMENDATIONS