Current Pain and Headache Reports

, Volume 11, Issue 6, pp 440–446

Update on gout: Pathophysiology and potential treatments

  • Aryeh M. Abeles
  • Jean Y. Park
  • Michael H. Pillinger
  • Bruce N. Cronstein


After several decades of senescence, the twin fields of hyperuricemia and gout have again regained attention in both the scientific and clinical spheres, and this review highlights several recent advancements. Specifically, we review newly discovered mechanisms of uric acid-induced inflammation, uric acid’s putative role as a “danger signal” in innate immunity, the possible link between hyperuricemia and cardiovascular disease, and evolutionary evidence suggesting that hyperuricemia conferred a survival advantage in primates (when the gene for uricase was lost) several million years ago. Finally, we provide an overview of the current approach to gout, as well as what treatments are on the horizon.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Nuki G, Simkin PA: A concise history of gout and hyperuricemia and their treatment. Arthritis Res Ther 2006, 8(Suppl 1):S1.PubMedCrossRefGoogle Scholar
  2. 2.
    Terkeltaub RA, Ginsberg MH: The inflammatory reaction to crystals. Rheum Dis Clin North Am 1988, 14:353–364.PubMedGoogle Scholar
  3. 3.
    Terkeltaub R: Gout in 2006: the perfect storm. Bull NYU Hosp Jt Dis 2006, 64:82–86.PubMedGoogle Scholar
  4. 4.
    Schumacher HR Jr: Pathology of crystal deposition diseases. Rheum Dis Clin North Am 1988, 14:269–288.PubMedGoogle Scholar
  5. 5.
    Schumacher HR Jr: Crystal deposition disease. Curr Opin Rheumatol 1997, 9:251–252.PubMedCrossRefGoogle Scholar
  6. 6.
    Ogura Y, Sutterwala FS, Flavell RA: The inflammasome: first line of the immune response to cell stress. Cell 2006, 126:659–662.PubMedCrossRefGoogle Scholar
  7. 7.
    Martinon F, Burns K, Tschopp J: The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2002, 10:417–426.PubMedCrossRefGoogle Scholar
  8. 8.
    Jin Y, Mailloux CM, Gowan K, et al.: NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med 2007, 356:1216–1225.PubMedCrossRefGoogle Scholar
  9. 9.
    Martinon F, Petrilli V, Mayor A, et al.: Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006, 440:237–241.PubMedCrossRefGoogle Scholar
  10. 10.
    Liu-Bryan R, Scott P, Sydlaske A, et al.: Innate immunity conferred by Toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum 2005, 52:2936–2946.PubMedCrossRefGoogle Scholar
  11. 11.
    Chen CJ, Shi Y, Hearn A, et al.: MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals. J Clin Invest 2006, 116:2262–2271.PubMedCrossRefGoogle Scholar
  12. 12.
    Liu R, O’Connell M, Johnson K, et al.: Extracellular signal-regulated kinase 1/extracellular signal-regulated kinase 2 mitogen-activated protein kinase signaling and activation of activator protein 1 and nuclear factor kappaB transcription factors play central roles in interleukin-8 expression stimulated by monosodium urate monohydrate and calcium pyrophosphate crystals in monocytic cells. Arthritis Rheum 2000, 43:1145–1155.PubMedCrossRefGoogle Scholar
  13. 13.
    Shi Y, Evans JE, Rock KL: Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 2003, 425:516–521.PubMedCrossRefGoogle Scholar
  14. 14.
    Janeway CA Jr, Medzhitov R: Innate immune recognition. Annu Rev Immunol 2002, 20:197–216.PubMedCrossRefGoogle Scholar
  15. 15.
    Gallucci S, Matzinger P: Danger signals: SOS to the immune system. Curr Opin Immunol 2001, 13:114–119.PubMedCrossRefGoogle Scholar
  16. 16.
    Skoberne M, Beignon AS, Bhardwaj N: Danger signals: a time and space continuum. Trends Mol Med 2004, 10:251–257.PubMedCrossRefGoogle Scholar
  17. 17.
    Andrews NW: Membrane repair and immunological danger. EMBO Rep 2005, 6:826–830.PubMedCrossRefGoogle Scholar
  18. 18.
    Hu DE, Moore AM, Thomsen LL, Brindle KM: Uric acid promotes tumor immune rejection. Cancer Res 2004, 64:5059–5062.PubMedCrossRefGoogle Scholar
  19. 19.
    Wu XW, Muzny DM, Lee CC, Caskey CT: Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol 1992, 34:78–84.PubMedCrossRefGoogle Scholar
  20. 20.
    Watanabe S, Kang DH, Feng L, et al.: Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity. Hypertension 2002, 40:355–360.PubMedCrossRefGoogle Scholar
  21. 21.
    Mazzali M, Hughes J, Kim YG, et al.: Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 2001, 38:1101–1106.PubMedCrossRefGoogle Scholar
  22. 22.
    Feig DI, Nakagawa T, Karumanchi SA, et al.: Hypothesis: uric acid, nephron number, and the pathogenesis of essential hypertension. Kidney Int 2004, 66:281–287.PubMedCrossRefGoogle Scholar
  23. 23.
    Feig DI, Rodriguez-Iturbe B, Nakagawa T, Johnson RJ: Nephron number, uric acid, and renal microvascular disease in the pathogenesis of essential hypertension. Hypertension 2006, 48:25–26.PubMedCrossRefGoogle Scholar
  24. 24.
    Kanellis J, Watanabe S, Li JH, et al.: Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension 2003, 41:1287–1293.PubMedCrossRefGoogle Scholar
  25. 25.
    Sanchez-Lozada LG, Tapia E, Avila-Casado C, et al.: Mild hyperuricemia induces glomerular hypertension in normal rats. Am J Physiol Renal Physiol 2002, 283:F1105–F1110.PubMedGoogle Scholar
  26. 26.
    Feig DI, Johnson RJ: The role of uric acid in pediatric hypertension. J Ren Nutr 2007, 17:79–83.PubMedCrossRefGoogle Scholar
  27. 27.
    Puig JG, Ruilope LM: Uric acid as a cardiovascular risk factor in arterial hypertension. J Hypertens 1999, 17:869–872.PubMedCrossRefGoogle Scholar
  28. 28.
    Lee J, Sparrow D, Vokonas PS, et al.: Uric acid and coronary heart disease risk: evidence for a role of uric acid in the obesity-insulin resistance syndrome. The Normative Aging Study. Am J Epidemiol 1995, 142:288–294.PubMedGoogle Scholar
  29. 29.
    Culleton BF, Larson MG, Kannel WB, Levy D: Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med 1999, 131:7–13.PubMedGoogle Scholar
  30. 30.
    Fang J, Alderman MH: Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971–1992. National Health and Nutrition Examination Survey. JAMA 2000, 283:2404–2410.PubMedCrossRefGoogle Scholar
  31. 31.
    Niskanen LK, Laaksonen DE, Nyyssonen K, et al.: Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study. Arch Intern Med 2004, 164:1546–1551.PubMedCrossRefGoogle Scholar
  32. 32.
    Krishnan E, Baker JF, Furst DE, Schumacher HR: Gout and the risk of acute myocardial infarction. Arthritis Rheum 2006, 54:2688–2696.PubMedCrossRefGoogle Scholar
  33. 33.
    Alderman M, Aiyer KJ: Uric acid: role in cardiovascular disease and effects of losartan. Curr Med Res Opin 2004, 20:369–379.PubMedCrossRefGoogle Scholar
  34. 34.
    Bengtsson C, Lapidus L, Stendahl C, Waldenstrom J: Hyperuricaemia and risk of cardiovascular disease and overall death. A 12-year follow-up of participants in the population study of women in Gothenburg, Sweden. Acta Med Scand 1988, 224:549–555.PubMedCrossRefGoogle Scholar
  35. 35.
    Levine W, Dyer AR, Shekelle RB, et al.: Serum uric acid and 11.5-year mortality of middle-aged women: findings of the Chicago Heart Association Detection Project in Industry. J Clin Epidemiol 1989, 42:257–267.PubMedCrossRefGoogle Scholar
  36. 36.
    Wang JG, Staessen JA, Fagard RH, et al.: Prognostic significance of serum creatinine and uric acid in older Chinese patients with isolated systolic hypertension. Hypertension 2001, 37:1069–1074.PubMedGoogle Scholar
  37. 37.
    Freedman DS, Williamson DF, Gunter EW, Byers T: Relation of serum uric acid to mortality and ischemic heart disease. The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol 1995, 141:637–644.PubMedGoogle Scholar
  38. 38.
    Franse LV, Pahor M, Di Bari M, et al.: Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program (SHEP). J Hypertens 2000, 18:1149–1154.PubMedCrossRefGoogle Scholar
  39. 39.
    Reunanen A, Takkunen H, Knekt P, Aromaa A: Hyperuricemia as a risk factor for cardiovascular mortality. Acta Med Scand Suppl 1982, 668:49–59.PubMedGoogle Scholar
  40. 40.
    Arromdee E, Michet CJ, Crowson CS, et al.: Epidemiology of gout: is the incidence rising? J Rheumatol 2002, 29:2403–2406.PubMedGoogle Scholar
  41. 41.
    Wallace KL, Riedel AA, Joseph-Ridge N, Wortmann R: Increasing prevalence of gout and hyperuricemia over 10 years among older adults in a managed care population. J Rheumatol 2004, 31:1582–1587.PubMedGoogle Scholar
  42. 42.
    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, 350:1093–1103.PubMedCrossRefGoogle Scholar
  43. 43.
    Choi HK, Liu S, Curhan G: Intake of purine-rich foods, protein, and dairy products and relationship to serum levels of uric acid: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 2005, 52:283–289.PubMedCrossRefGoogle Scholar
  44. 44.
    Choi HK, Atkinson K, Karlson EW, et al.: Alcohol intake and risk of incident gout in men: a prospective study. Lancet 2004, 363:1277–1281.PubMedCrossRefGoogle Scholar
  45. 45.
    Terkeltaub R, Bushinsky DA, Becker MA: Recent developments in our understanding of the renal basis of hyperuricemia and the development of novel antihyperuricemic therapeutics. Arthritis Res Ther 2006, 8(Suppl 1):S4.PubMedCrossRefGoogle Scholar
  46. 46.
    Enomoto A, Kimura H, Chairoungdua A, et al.: Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002, 417:447–452.PubMedGoogle Scholar
  47. 47.
    Hatch M, Freel RW, Shahinfar S, Vaziri ND: Effects of the specific angiotensin II receptor antagonist losartan on urate homeostasis and intestinal urate transport. J Pharmacol Exp Ther 1996, 276:187–193.PubMedGoogle Scholar
  48. 48.
    Lipkowitz MS, Leal-Pinto E, Rappoport JZ, et al.: Functional reconstitution, membrane targeting, genomic structure, and chromosomal localization of a human urate transporter. J Clin Invest 2001, 107:1103–1115.PubMedGoogle Scholar
  49. 49.
    Malawista SE, Bensch KG: Human polymorphonuclear leukocytes: demonstration of microtubules and effect of colchicine. Science 1967, 156:521–522.PubMedCrossRefGoogle Scholar
  50. 50.
    Cronstein BN, Molad Y, Reibman J, et al.: Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils. J Clin Invest 1995, 96:994–1002.PubMedCrossRefGoogle Scholar
  51. 51.
    Abramson SB: Treatment of gout and crystal arthropathies and uses and mechanisms of action of nonsteroidal anti-inflammatory drugs. Curr Opin Rheumatol 1992, 4:295–300.PubMedCrossRefGoogle Scholar
  52. 52.
    Terkeltaub RA: Clinical practice. Gout. N Engl J Med 2003, 349:1647–1655.PubMedCrossRefGoogle Scholar
  53. 53.
    Becker MA, Schumacher HR Jr, Wortmann RL, et al.: Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005, 353:2450–2461.PubMedCrossRefGoogle Scholar
  54. 54.
    Schumacher HR Jr: Febuxostat: a non-purine, selective inhibitor of xanthine oxidase for the management of hyperuricaemia in patients with gout. Expert Opin Investig Drugs 2005, 14:893–903.PubMedCrossRefGoogle Scholar
  55. 55.
    Rampello E, Fricia T, Malaguarnera M: The management of tumor lysis syndrome. Nat Clin Pract Oncol 2006, 3:438–447.PubMedCrossRefGoogle Scholar
  56. 56.
    Richette P, Bardin T: Successful treatment with rasburicase of a tophaceous gout in a patient allergic to allopurinol. Nat Clin Pract Rheumatol 2006, 2:338–342; quiz 343.PubMedCrossRefGoogle Scholar
  57. 57.
    Sundy JS, Ganson NJ, Kelly SJ, et al.: Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout. Arthritis Rheum 2007, 56:1021–1028.PubMedCrossRefGoogle Scholar
  58. 58.
    So A, De Smedt T, Revaz S, Tschopp J: A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther 2007, 9:R28.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group LLC 2007

Authors and Affiliations

  • Aryeh M. Abeles
    • 1
  • Jean Y. Park
  • Michael H. Pillinger
  • Bruce N. Cronstein
  1. 1.Division of RheumatologyMedical Arts and Research BuildingFarmingtonUSA

Personalised recommendations