Smarter Decisions,
Better Care

UpToDate synthesizes the most recent medical information into evidence-based practical recommendations clinicians trust to make the right point-of-care decisions.

  • Rigorous editorial process: Evidence-based treatment recommendations
  • World-Renowned physician authors: over 5,100 physician authors and editors around the globe
  • Innovative technology: integrates into the workflow; access from EMRs

Choose from the list below to learn more about subscriptions for a:


Subscribers log in here


Related Searches

Pathophysiology of gouty arthritis

INTRODUCTION

Gout refers to disease that occurs in response to the presence of crystals of monosodium urate (MSU) in joints, bones, and soft tissues. Both acute arthritis and chronic arthropathy (tophaceous gout) are considered under the rubric of gout.

The mechanisms of crystal deposition, crystal-induced inflammation, and destructive lesions of joints and bones associated with macroscopic collections of MSU (tophi) will be reviewed here. The clinical features, diagnosis, and treatment of acute gout; the prevention of recurrent gout; asymptomatic hyperuricemia; and associated renal diseases are discussed elsewhere. (See "Clinical manifestations and diagnosis of gout" and "Treatment of acute gout" and "Prevention of recurrent gout" and "Asymptomatic hyperuricemia" and "Uric acid nephrolithiasis" and "Uric acid renal diseases".)

HYPERURICEMIA AND GOUT

Hyperuricemia can be caused by impaired renal excretion, overproduction of uric acid, and/or by overconsumption of purine-rich foods that are metabolized to urate. Detailed discussions of the causes of hyperuricemia and of the normal mechanisms of urate handling are presented separately. (See "Asymptomatic hyperuricemia" and "Uric acid balance".)

A causative relationship among hyperuricemia, deposition of urate crystals, and gout was proposed by Garrod in 1859 and later [1]. However, injection of solutions of uric acid into blood or joints failed to reproduce the clinical features of the disease, casting doubt on the association. Freudweiler noted in 1899 that injection of tophaceous material caused inflammation [2,3].

The identification of monosodium urate (MSU) crystals within phagocytes when synovial fluid was examined using compensated polarized microscopy was an important advance in understanding the pathogenesis of gout [4]. This was followed by the observation that injection of MSU crystals into normal joints produced acute gout attacks, reestablishing the connection between urate crystals and gout [5,6]. The outline of the pathophysiology of gout is as follows: a period of hyperuricemia leads to MSU crystal deposition, reaction to which can result in acute and/or chronic inflammation.

       

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Mar 2014. | This topic last updated: Jan 22, 2013.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2014 UpToDate, Inc.
References
Top
  1. Garrod AB. The Nature and Treatment of Gout and Rheumatic Gout, 2nd Edition, 1863.
  2. BRILL JM, MCCARTY DJ. "STUDIES ON THE NATURE OF GOUTY TOPHI" BY MAX FREUDWEILER, 1899. (AN INFLAMMATORY RESPONSE TO INJECTED SODIUM URATE, 1899). AN ABRIDGED TRANSLATION, WITH COMMENTS. Ann Intern Med 1964; 60:486.
  3. FREUDWEILER M. EXPERIMENTAL INVESTIGATIONS INTO THE ORIGIN OF GOUTY TOPHI. Arthritis Rheum 1965; 8:267.
  4. MCCARTY DJ, HOLLANDER JL. Identification of urate crystals in gouty synovial fluid. Ann Intern Med 1961; 54:452.
  5. Seegmiller JE, Howell RR, Malawista SE. The inflammatory reaction to sodium urate: its possible relationship to the genesis of acute gouty arthritis. JAMA 1962; 180:469.
  6. Faires JS, McCarty DJ. Acute arthritis in man and dog after intrasynovial injection of sodium urate crystals. Lancet 1962; 2:682.
  7. Reynolds PP, Knapp MJ, Baraf HS, Holmes EW. Moonshine and lead. Relationship to the pathogenesis of hyperuricemia in gout. Arthritis Rheum 1983; 26:1057.
  8. Krishnan E, Lingala B, Bhalla V. Low-level lead exposure and the prevalence of gout: an observational study. Ann Intern Med 2012; 157:233.
  9. Riches PL, Wright AF, Ralston SH. Recent insights into the pathogenesis of hyperuricaemia and gout. Hum Mol Genet 2009; 18:R177.
  10. Hall AP, Barry PE, Dawber TR, McNamara PM. Epidemiology of gout and hyperuricemia. A long-term population study. Am J Med 1967; 42:27.
  11. Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. Am J Med 1987; 82:421.
  12. Zalokar J, Lellouch J, Claude JR, Kuntz D. Epidemiology of serum uric acid and gout in Frenchmen. J Chronic Dis 1974; 27:59.
  13. Agudelo CA, Weinberger A, Schumacher HR, et al. Definitive diagnosis of gout by identification of urate crystals in asymptomatic metatarsophalangeal joints. Arthritis Rheum 1979; 22:559.
  14. Rouault T, Caldwell DS, Holmes EW. Aspiration of the asymptomatic metatarsophalangeal joint in gout patients and hyperuricemic controls. Arthritis Rheum 1982; 25:209.
  15. Lin KC, Lin HY, Chou P. Community based epidemiological study on hyperuricemia and gout in Kin-Hu, Kinmen. J Rheumatol 2000; 27:1045.
  16. Zhang Y, Woods R, Chaisson CE, et al. Alcohol consumption as a trigger of recurrent gout attacks. Am J Med 2006; 119:800.e13.
  17. Hunter DJ, York M, Chaisson CE, et al. Recent diuretic use and the risk of recurrent gout attacks: the online case-crossover gout study. J Rheumatol 2006; 33:1341.
  18. Craig MH, Poole GV, Hauser CJ. Postsurgical gout. Am Surg 1995; 61:56.
  19. Chakravarty K, Durkin CJ, al-Hillawi AH, et al. The incidence of acute arthritis in stroke patients, and its impact on rehabilitation. Q J Med 1993; 86:819.
  20. Borstad GC, Bryant LR, Abel MP, et al. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol 2004; 31:2429.
  21. 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.
  22. Terkeltaub R. Gout. A. Epidemiology, pathology, and pathogenesis. In: Primer on the Rheumatic Diseases, 12th Edition, Klippel JH (Ed), Arthritis Foundation, Atlanta 2001. p.307.
  23. Simkin PA. The pathogenesis of podagra. Ann Intern Med 1977; 86:230.
  24. Loeb JN. The influence of temperature on the solubility of monosodium urate. Arthritis Rheum 1972; 15:189.
  25. Horvath SM, Hollander JL. INTRA-ARTICULAR TEMPERATURE AS A MEASURE OF JOINT REACTION. J Clin Invest 1949; 28:469.
  26. Tak HK, Cooper SM, Wilcox WR. Studies on the nucleation of monosodium urate at 37 degrees c. Arthritis Rheum 1980; 23:574.
  27. McGill NW, Dieppe PA. The role of serum and synovial fluid components in the promotion of urate crystal formation. J Rheumatol 1991; 18:1042.
  28. Hasselbacher P. Binding of IgG and complement protein by monosodium urate monohydrate and other crystals. J Lab Clin Med 1979; 94:532.
  29. Kam M, Perl-Treves D, Caspi D, Addadi L. Antibodies against crystals. FASEB J 1992; 6:2608.
  30. Hasselbacher P, Schumacher HR. Immunoglobulin in tophi and on the surface of monosodium urate crystals. Arthritis Rheum 1978; 21:353.
  31. Cherian PV, Schumacher HR Jr. Immunochemical and ultrastructural characterization of serum proteins associated with monosodium urate crystals (MSU) in synovial fluid cells from patients with gout. Ultrastruct Pathol 1986; 10:209.
  32. Fiddis RW, Vlachos N, Calvert PD. Studies of urate crystallisation in relation to gout. Ann Rheum Dis 1983; 42 Suppl 1:12.
  33. Phelps P, McCarty DJ Jr. Crystal-induced inflammation in canine joints. II. Importance of polymorphonuclear leukocytes. J Exp Med 1966; 124:115.
  34. Wigley FM, Fine IT, Newcombe DS. The role of the human synovial fibroblast in monosodium urate crystal-induced synovitis. J Rheumatol 1983; 10:602.
  35. Malawista SE, Duff GW, Atkins E, et al. Crystal-induced endogenous pyrogen production. A further look at gouty inflammation. Arthritis Rheum 1985; 28:1039.
  36. Falasca GF, Ramachandrula A, Kelley KA, et al. Superoxide anion production and phagocytosis of crystals by cultured endothelial cells. Arthritis Rheum 1993; 36:105.
  37. Schumacher HR, Phelps P, Agudelo CA. Urate crystal induced inflammation in dog joints: sequence of synovial changes. J Rheumatol 1974; 1:102.
  38. Gordon TP, Kowanko IC, James M, Roberts-Thomson PJ. Monosodium urate crystal-induced prostaglandin synthesis in the rat subcutaneous air pouch. Clin Exp Rheumatol 1985; 3:291.
  39. 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.
  40. Scott P, Ma H, Viriyakosol S, et al. Engagement of CD14 mediates the inflammatory potential of monosodium urate crystals. J Immunol 2006; 177:6370.
  41. 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.
  42. Guerne PA, Terkeltaub R, Zuraw B, Lotz M. Inflammatory microcrystals stimulate interleukin-6 production and secretion by human monocytes and synoviocytes. Arthritis Rheum 1989; 32:1443.
  43. Terkeltaub R, Zachariae C, Santoro D, et al. Monocyte-derived neutrophil chemotactic factor/interleukin-8 is a potential mediator of crystal-induced inflammation. Arthritis Rheum 1991; 34:894.
  44. di Giovine FS, Malawista SE, Thornton E, Duff GW. Urate crystals stimulate production of tumor necrosis factor alpha from human blood monocytes and synovial cells. Cytokine mRNA and protein kinetics, and cellular distribution. J Clin Invest 1991; 87:1375.
  45. Terkeltaub R, Baird S, Sears P, et al. The murine homolog of the interleukin-8 receptor CXCR-2 is essential for the occurrence of neutrophilic inflammation in the air pouch model of acute urate crystal-induced gouty synovitis. Arthritis Rheum 1998; 41:900.
  46. Chapman PT, Yarwood H, Harrison AA, et al. Endothelial activation in monosodium urate monohydrate crystal-induced inflammation: in vitro and in vivo studies on the roles of tumor necrosis factor alpha and interleukin-1. Arthritis Rheum 1997; 40:955.
  47. Jaramillo M, Godbout M, Naccache PH, Olivier M. Signaling events involved in macrophage chemokine expression in response to monosodium urate crystals. J Biol Chem 2004; 279:52797.
  48. Schreiner O, Wandel E, Himmelsbach F, et al. Reduced secretion of proinflammatory cytokines of monosodium urate crystal-stimulated monocytes in chronic renal failure: an explanation for infrequent gout episodes in chronic renal failure patients? Nephrol Dial Transplant 2000; 15:644.
  49. Roberge CJ, de Médicis R, Dayer JM, et al. Crystal-induced neutrophil activation. V. Differential production of biologically active IL-1 and IL-1 receptor antagonist. J Immunol 1994; 152:5485.
  50. Burt HM, Jackson JK. The priming action of tumour necrosis factor-alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on neutrophils activated by inflammatory microcrystals. Clin Exp Immunol 1997; 108:432.
  51. Torres R, Macdonald L, Croll SD, et al. Hyperalgesia, synovitis and multiple biomarkers of inflammation are suppressed by interleukin 1 inhibition in a novel animal model of gouty arthritis. Ann Rheum Dis 2009; 68:1602.
  52. 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.
  53. Terkeltaub R, Sundy JS, Schumacher HR, et al. The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis: results of a placebo-controlled, monosequence crossover, non-randomised, single-blind pilot study. Ann Rheum Dis 2009; 68:1613.
  54. Martinon F, Pétrilli V, Mayor A, et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440:237.
  55. Simchowitz L, Atkinson JP, Spilberg I. Stimulation of the respiratory burst in human neutrophils by crystal phagocytosis. Arthritis Rheum 1982; 25:181.
  56. Hoffstein S, Weissmann G. Mechanisms of lysosomal enzyme release from leukocytes. IV. Interaction of monosodium urate crystals with dogfish and human leukocytes. Arthritis Rheum 1975; 18:153.
  57. Lin HY, Rocher LL, McQuillan MA, et al. Cyclosporine-induced hyperuricemia and gout. N Engl J Med 1989; 321:287.
  58. Abramson S, Hoffstein ST, Weissmann G. Superoxide anion generation by human neutrophils exposed to monosodium urate. Arthritis Rheum 1982; 25:174.
  59. Rae SA, Davidson EM, Smith MJ. Leukotriene B4, an inflammatory mediator in gout. Lancet 1982; 2:1122.
  60. Terkeltaub R. Pathogenesis of inflammatory manifestations caused by crystals. In: Gout, Hyperuricemia, and Other Crystal-associated Arthropathies, Smyth CJ, Holers VM (Eds), Marcel Dekker, New York 1999. p.1.
  61. Liu-Bryan R, Lioté F. Monosodium urate and calcium pyrophosphate dihydrate (CPPD) crystals, inflammation, and cellular signaling. Joint Bone Spine 2005; 72:295.
  62. Gaudry M, Roberge CJ, de Médicis R, et al. Crystal-induced neutrophil activation. III. Inflammatory microcrystals induce a distinct pattern of tyrosine phosphorylation in human neutrophils. J Clin Invest 1993; 91:1649.
  63. Jackon JK, Tudan C, Burt HM. The involvement of phospholipase C in crystal induced human neutrophil activation. J Rheumatol 2000; 27:2877.
  64. Ryckman C, McColl SR, Vandal K, et al. Role of S100A8 and S100A9 in neutrophil recruitment in response to monosodium urate monohydrate crystals in the air-pouch model of acute gouty arthritis. Arthritis Rheum 2003; 48:2310.
  65. Chapman PT, Jamar F, Harrison AA, et al. Noninvasive imaging of E-selectin expression by activated endothelium in urate crystal-induced arthritis. Arthritis Rheum 1994; 37:1752.
  66. Zhou X, Li J, Kucik DF. The microtubule cytoskeleton participates in control of beta2 integrin avidity. J Biol Chem 2001; 276:44762.
  67. 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.
  68. Stankovíc A, Front P, Barbara A, Mitrovíc DR. Tophus-derived monosodium urate monohydrate crystals are biologically much more active than synthetic counterpart. Rheumatol Int 1991; 10:221.
  69. Nagase M, Baker DG, Schumacher HR Jr. Immunoglobulin G coating on crystals and ceramics enhances polymorphonuclear cell superoxide production: correlation with immunoglobulin G adsorbed. J Rheumatol 1989; 16:971.
  70. Kozin F, Ginsberg MH, Skosey JL. Polymorphonuclear leukocyte responses to monosodium urate crystals: modification by adsorbed serum proteins. J Rheumatol 1979; 6:519.
  71. Terkeltaub R, Curtiss LK, Tenner AJ, Ginsberg MH. Lipoproteins containing apoprotein B are a major regulator of neutrophil responses to monosodium urate crystals. J Clin Invest 1984; 73:1719.
  72. Phelps P, Prockop DJ, McCarty DJ. Crystal induced inflammation in canine joints. 3. Evidence against bradykinin as a mediator of inflammation. J Lab Clin Med 1966; 68:433.
  73. Spilberg I. Urate crystal arthritis in animals lacking Hageman factor. Arthritis Rheum 1974; 17:143.
  74. Fields TR, Abramson SB, Weissmann G, et al. Activation of the alternative pathway of complement by monosodium urate crystals. Clin Immunol Immunopathol 1983; 26:249.
  75. Russell IJ, Papaioannou C, McDuffie FC, et al. Effect of IgG and C-reactive protein on complement depletion by monosodium urate crystals. J Rheumatol 1983; 10:425.
  76. Webster ME, Maling HM, Zweig MH, et al. Urate crystal induced inflammation in the rat: evidence for the combined actions of kinins, histamine and components of complement. Immunol Commun 1972; 1:185.
  77. Kellermeyer RW, Naff GB. Chemical mediators of inflammation in acute gouty arthritis. Arthritis Rheum 1975; 18:765.
  78. Tramontini N, Huber C, Liu-Bryan R, et al. Central role of complement membrane attack complex in monosodium urate crystal-induced neutrophilic rabbit knee synovitis. Arthritis Rheum 2004; 50:2633.
  79. Townes AS, Sowa JM. Complement in synovial fluid. Johns Hopkins Med J 1970; 127:23.
  80. Yagnik DR, Evans BJ, Florey O, et al. Macrophage release of transforming growth factor beta1 during resolution of monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum 2004; 50:2273.
  81. Akahoshi T, Namai R, Murakami Y, et al. Rapid induction of peroxisome proliferator-activated receptor gamma expression in human monocytes by monosodium urate monohydrate crystals. Arthritis Rheum 2003; 48:231.
  82. Terkeltaub RA. What stops a gouty attack? J Rheumatol 1992; 19:8.
  83. Marcolongo R, Calabria AA, Lalumera M, et al. The "switch-off" mechanism of spontaneous resolution of acute gout attack. J Rheumatol 1988; 15:101.
  84. Rosen MS, Baker DG, Schumacher HR Jr, Cherian PV. Products of polymorphonuclear cell injury inhibit IgG enhancement of monosodium urate-induced superoxide production. Arthritis Rheum 1986; 29:1473.
  85. Ortiz-Bravo E, Sieck MS, Schumacher HR Jr. Changes in the proteins coating monosodium urate crystals during active and subsiding inflammation. Immunogold studies of synovial fluid from patients with gout and of fluid obtained using the rat subcutaneous air pouch model. Arthritis Rheum 1993; 36:1274.
  86. Dalbeth N, Pool B, Gamble G, et al. Cellular characterization of the gouty tophus: A quantitiative analysis. (abstract number 1947). Presented at the American College of Rheumatology Annual Scientific Sessions, October 20, 2009.
  87. Agudelo CA, Schumacher HR. The synovitis of acute gouty arthritis. A light and electron microscopic study. Hum Pathol 1973; 4:265.
  88. Schumacher HR, Jimenez SA, Gibson T, et al. Acute gouty arthritis without urate crystals identified on initial examination of synovial fluid. Arthritis Rheum 1975; 18:603.
  89. Gordon TP, Roberts-Thomson PJ. Preliminary evidence for the presence of an inhibitor on the surface of natural monosodium urate crystals. Arthritis Rheum 1986; 29:1172.