Skip to main content

Advertisement

Log in

Beyond Joints: a Review of Ocular Abnormalities in Gout and Hyperuricemia

  • Crystal Arthritis (MH Pillinger and SK Samuels, Section Editors)
  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Gout is a common inflammatory arthritis among middle-aged men and postmenopausal women and can be a debilitating disease. Gout results from an elevated body uric acid pool, which leads to deposition of monosodium urate (MSU) crystals, mainly in and around the joints. The MSU crystals trigger release of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. Ocular manifestations have been uncommonly reported in patients with gout. These include descriptions of tophaceous deposits in different locations of the eye including the eyelids, conjunctiva, cornea, iris, sclera, and orbit. Some depositions were coincidentally diagnosed in asymptomatic patients, while the majority were symptomatic. Other ocular abnormalities include dry eye syndrome, red eye, uveitis, intraocular hypertension, glaucoma, and cataracts. Herein, we review the medical literature pertaining to ocular manifestations in gout and hyperuricemia and propose a possible association between ocular abnormalities, hyperuricemia, and gout, including their common risk factors and comorbidities.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 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;63:3136–41.

    Article  PubMed  Google Scholar 

  2. Landis RC, Haskard DO. Pathogenesis of crystal-induced inflammation. Curr Rheumatol Rep. 2001;3:36–41.

    Article  CAS  PubMed  Google Scholar 

  3. Martinon F. Update on biology: uric acid and the activation of immune and inflammatory cells. Curr Rheumatol Rep. 2010;12:135–41.

    Article  CAS  PubMed  Google Scholar 

  4. Dalbeth N, Haskard DO. Mechanisms of inflammation in gout. Rheumatology (Oxford). 2005;44:1090–6.

    Article  CAS  Google Scholar 

  5. Feig DI, Kang D-H, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008;359:1811–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Neogi T. Clinical practice. Gout. N Engl J Med. 2011;364:443–52.

    Article  CAS  PubMed  Google Scholar 

  7. Choi HK. Pathogenesis of gout. Ann Intern Med. 2005;143. American College of Physicians.

  8. Saag KG, Choi H. Epidemiology, risk factors, and lifestyle modifications for gout. Arthritis Res Ther. 2006;8 Suppl 1:S2.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Grahame R, Scott JT. Clinical survey of 354 patients with gout. Ann Rheum Dis. 1970;29:461–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Schlesinger N. Management of acute and chronic gouty arthritis: present state-of-the-art. Drugs. 2004;64:2399–416.

    Article  CAS  PubMed  Google Scholar 

  11. Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, Cavallerano JD, et al. Retinopathy in diabetes. Diabetes Care. 2003;27:S84–7.

    Article  Google Scholar 

  12. Klein R, Klein BEK, Moss SE, Linton KLP. The Beaver Dam Eye Study. Ophthalmology. 1992;99:58–62.

    Article  CAS  PubMed  Google Scholar 

  13. Hutchinson J. The Bowman lecture on the relation of certain diseases of the eye to gout. Br Med J. 1884;2:995–1000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yang CCL, Vagefi MR, Davis D, Mamalis N, Anderson RL, McCann J. Gouty tophus of the upper eyelid. Ophthal Plast Reconstr Surg. 2008;24:404–6.

    Article  PubMed  Google Scholar 

  15. Morris WR, Fleming JC. Gouty tophus at the lateral canthus. Arch Ophthalmo (Chicago, Ill 1960). 2003;121:1195–7.

    Article  Google Scholar 

  16. Chu YC, Hsieh YY, Ma L. Medial canthal tophus associated with gout. Am J Ophthalmol. 2005;140:542–4.

    Article  PubMed  Google Scholar 

  17. De Monteynard MS, Jacquier J, Adotti F, Bodard-Rickelman E. Gouty tophus of the eyelid. Bull Soc Ophtalmol Fr. 1986;86:53–4.

    PubMed  Google Scholar 

  18. Jordan DR, Belliveau MJ, Brownstein S, McEachren T, Kyrollos M. Medial canthal tophus. Ophthal Plast Reconstr Surg. 2008;24:403–4.

    Article  PubMed  Google Scholar 

  19. Lo WR, Broocker G, Grossniklaus HE. Histopathologic examination of conjunctival tophi in gouty arthritis. Am J Ophthalmol. 2005;140:1152–4.

    Article  PubMed  Google Scholar 

  20. MCWILLIAMS JR. Ocular findings in gout; report of a case of conjunctival tophi. Am J Ophthalmol. 1952;35:1778–83.

    Article  CAS  PubMed  Google Scholar 

  21. Yourish N. Conjunctival tophi associated with gout. AMA Arch Ophthalmol. 1953;50:370–1.

    Article  CAS  PubMed  Google Scholar 

  22. Sarma P, Das D, Deka P, Deka AC. Subconjunctival urate crystals: a case report. Cornea. 2010;29:830–2.

    PubMed  Google Scholar 

  23. Lin J, Zhao G-Q, Che C-Y, Yang S-S, Wang Q, Li C-G. Characteristics of ocular abnormalities in gout patients. Int J Ophthalmol. 2013;6:307–11. This paper describes clinical features of ocular abnormalities found in a cohort of gout patients and is the largest cohort study of ocular manifestations in gout patients.

    PubMed  PubMed Central  Google Scholar 

  24. Fishman RS, Sunderman FW. Band keratopathy in gout. Arch Ophthalmol (Chicago, Ill 1960). 1966;75:367–9.

    Article  CAS  Google Scholar 

  25. Slansky HH, Kubara T. Intranuclear urate crystals in corneal epithelium. Arch Ophthalmol (Chicago, Ill 1960). 1968;80:338–44.

    Article  CAS  Google Scholar 

  26. Bernad B, Narvaez J, Diaz-Torné C, Diez-Garcia M, Valverde J. Clinical image: corneal tophus deposition in gout. Arthritis Rheum. 2006;54:1025.

    Article  PubMed  Google Scholar 

  27. Ferry AP, Safir A, Melikian HE. Ocular abnormalities in patients with gout. Ann Ophthalmol. 1985;17:632–5.

    CAS  PubMed  Google Scholar 

  28. Wood DJ. Inflammatory disease in the eye caused by gout. Br J Ophthalmol. 1936;20:510–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Coassin M, Piovanetti O, Stark WJ, Green WR. Urate deposition in the iris and anterior chamber. Ophthalmology. 2006;113:462–5.

    Article  PubMed  Google Scholar 

  30. Martínez-Cordero E, Barreira-Mercado E, Katona G. Eye tophi deposition in gout. J Rheumatol. 1986;13:471–3.

    PubMed  Google Scholar 

  31. Topping NC, Cassels-Brown A, Chakrabarty A, Cronin P, Ross S, Russell J, et al. Uric acid crystals presenting as an orbital mass. Eye (Lond). 2003;17:427–9.

    Article  CAS  Google Scholar 

  32. Arffa RC, Eve FR. Systemic associations of corneal deposits. Int Ophthalmol Clin. 1991;31:89–110.

    Article  CAS  PubMed  Google Scholar 

  33. Chia E-M, Mitchell P, Rochtchina E, Lee AJ, Maroun R, Wang JJ. Prevalence and associations of dry eye syndrome in an older population: the Blue Mountains Eye Study. Clin Exp Ophthalmol. 2003;31:229–32.

    Article  Google Scholar 

  34. Moss SE. Prevalence of and risk factors for dry eye syndrome. AMA Arch Ophthalmol. 2000;118:1264.

    Article  CAS  Google Scholar 

  35. Serpell G. Ophthalmic gout. Aust N Z J Ophthalmol. 1978;6:77–9.

    Article  Google Scholar 

  36. Killen BU. Gout and uveitis. Report of a case. Br J Ophthalmol. 1968;52:710–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yülek F, Cağil N, Orhan N, Midillioğlu IK, Erten S, Simşek S. Gout attack with unusual ocular complications. Rheumatol Int. 2009;29:557–9.

    Article  PubMed  Google Scholar 

  38. Kimura SJ. Uveitis and joint diseases. AMA Arch Ophthalmol. 1967;77:309.

    Article  CAS  Google Scholar 

  39. DAVENPORT RC. Uveitis. Proc Roy Soc Med. 1956;49:19–23.

  40. SCHWELNITZ O DE. Concerning the symptomatology and etiology of certain types of uveitis. Sect. Ophthalmol. 1902;

  41. McCarty CA, Nanjan MB, Taylor HR. Attributable risk estimates for cataract to prioritize medical and public health action. Invest Ophthalmol Vis Sci. 2000;41:3720–5. The Association for Research in Vision and Ophthalmology.

    CAS  PubMed  Google Scholar 

  42. Safir A, Dunn SN, Martin RG, Tate GW, Mincey GJ. Is asteroid hyalosis ocular gout? Ann Ophthalmol. 1990;22:70–7.

    CAS  PubMed  Google Scholar 

  43. Klein R, Klein BEK, Knudtson MD, Wong TY, Tsai MY. Are inflammatory factors related to retinal vessel caliber? The Beaver Dam Eye Study. Arch Ophthalmol (Chicago, Ill 1960). 2006;124:87–94. American Medical Association.

    Article  Google Scholar 

  44. de la Sainz Maza M, Tauber J, Foster CS. The sclera. Boston: Springer; 2012.

    Book  Google Scholar 

  45. Albini TA, Rao NA, Smith RE. The diagnosis and management of anterior scleritis. Int Ophthalmol Clin. 2005;45:191–204.

    Article  PubMed  Google Scholar 

  46. Mitchell P, Wang MY, Wang JJ. Asteroid hyalosis in an older population: the Blue Mountains Eye Study. Ophthalmic Epidemiol. 2003;10:331–5.

    Article  PubMed  Google Scholar 

  47. Lerman S, Megaw J, Fraunfelder FT. Further studies on allopurinol therapy and human cataractogenesis. Am J Ophthalmol. 1984;97:205–9.

    Article  CAS  PubMed  Google Scholar 

  48. Fraunfelder FT, Hanna C, Dreis MW, Cosgrove KW. Cataracts associated with allopurinol therapy. Am J Ophthalmol. 1982;94:137–40.

    Article  CAS  PubMed  Google Scholar 

  49. Khanna D, Khanna PP, Fitzgerald JD, Singh MK, Bae S, Neogi T, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arth Care Res. 2012;64:1447–61.

    Article  CAS  Google Scholar 

  50. Urban RC, Cotlier E. Corticosteroid-induced cataracts. Surv Ophthalmol. 1986;31:102–10.

    Article  CAS  PubMed  Google Scholar 

  51. Moss SE, Klein R, Klein BEK. Long-term incidence of dry eye in an older population. Optom Vis Sci. 2008;85:668–74.

    Article  PubMed  Google Scholar 

  52. McNearney T, Baethge BA, Cao S, Alam R, Lisse JR, Westlund KN. Excitatory amino acids, TNF-alpha, and chemokine levels in synovial fluids of patients with active arthropathies. Clin Exp Immunol. 2004;137:621–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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;87:1375–81.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Di Giovine FS, Malawista SE, Nuki G, Duff GW. Interleukin 1 (IL 1) as a mediator of crystal arthritis. Stimulation of T cell and synovial fibroblast mitogenesis by urate crystal-induced IL 1. J Immunol. 1987;138:3213–8.

    PubMed  Google Scholar 

  55. Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood Am Soc Hematol. 2011;117:3720–32.

    CAS  Google Scholar 

  56. Guerne PA, Terkeltaub R, Zuraw B, Lotz M. Inflammatory microcrystals stimulate interleukin-6 production and secretion by human monocytes and synoviocytes. Arthritis Rheum. 1989;32:1443–52.

    Article  CAS  PubMed  Google Scholar 

  57. Schiltz C, Lioté F, Prudhommeaux F, Meunier A, Champy R, Callebert J, et al. Monosodium urate monohydrate crystal-induced inflammation in vivo: quantitative histomorphometric analysis of cellular events. Arthritis Rheum. 2002;46:1643–50.

    Article  CAS  PubMed  Google Scholar 

  58. Landis RC, Yagnik DR, Florey O, Philippidis P, Emons V, Mason JC, et al. Safe disposal of inflammatory monosodium urate monohydrate crystals by differentiated macrophages. Arthritis Rheum. 2002;46:3026–33.

    Article  CAS  PubMed  Google Scholar 

  59. Scanu A, Oliviero F, Ramonda R, Frallonardo P, Dayer J-M, Punzi L. Cytokine levels in human synovial fluid during the different stages of acute gout: role of transforming growth factor β1 in the resolution phase. Ann Rheum Dis. 2012;71:621–4.

    Article  CAS  PubMed  Google Scholar 

  60. Schweyer S, Hemmerlein B, Radzun HJ, Fayyazi A. Continuous recruitment, co-expression of tumour necrosis factor-α and matrix metalloproteinases, and apoptosis of macrophages in gout tophi. Virchows Arch. 2000;437:534–9.

    Article  CAS  PubMed  Google Scholar 

  61. Planck S, Huang X. Cytokine mRNA levels in rat ocular tissues after systemic endotoxin treatment. Investig. 1994;

  62. Yoshida M, Yoshimura N, Hangai M, Tanihara H, Honda Y. Interleukin-1 alpha, interleukin-1 beta, and tumor necrosis factor gene expression in endotoxin-induced uveitis. Invest Ophthalmol Vis Sci. 1994;35:1107–13. The Association for Research in Vision and Ophthalmology.

    CAS  PubMed  Google Scholar 

  63. Hoekzema R, Verhagen C, van Haren M, Kijlstra A. Endotoxin-induced uveitis in the rat. The significance of intraocular interleukin-6. Invest Ophthalmol Vis Sci. 1992;33:532–9. The Association for Research in Vision and Ophthalmology.

    CAS  PubMed  Google Scholar 

  64. Huhtinen M. Systemic inflammation and innate immune response in patients with previous anterior uveitis. Br J Ophthalmol. 2002;86:412–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Perez V, Papaliodis G, Chu D, Anzaar F, Christen W, Foster C. Elevated levels of interleukin 6 in the vitreous fluid of patients with pars planitis and posterior uveitis: the Massachusetts eye & ear experience and review of previous studies. Ocul Immunol Inflamm 2004;12:193–201.

  66. Murray PI, Hoekzema R, van Haren MA, de Hon FD, Kijlstra A. Aqueous humor interleukin-6 levels in uveitis. Invest Ophthalmol Vis Sci. 1990;31:917–20.

    CAS  PubMed  Google Scholar 

  67. Ongkosuwito JV, Feron EJ, van Doornik CE, Van der Lelij A, Hoyng CB, La Heij EC, et al. Analysis of immunoregulatory cytokines in ocular fluid samples from patients with uveitis. Invest Ophthalmol Vis Sci. 1998;39:2659–65.

    CAS  PubMed  Google Scholar 

  68. Rosenbaum JT, Howes EL, Rubin RM, Samples JR. Ocular inflammatory effects of intravitreally-injected tumor necrosis factor. Am J Pathol. 1988;133:47–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Bhattacherjee P, Henderson B. Inflammatory responses to intraocularly injected interleukin 1. Curr Eye Res. 1987;6(7):929-34

  70. Rosenbaum JT, Samples JR, Hefeneider SH, Howes EL. Ocular inflammatory effects of intravitreal interleukin 1. Arch Ophthalmol. 1987;105:1117–20.

  71. Kang D-H. Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol. 2005;16:3553–62.

    Article  CAS  PubMed  Google Scholar 

  72. Choi HK, Ford ES. Prevalence of the metabolic syndrome in individuals with hyperuricemia. Am J Med. 2007;120:442–7.

    Article  PubMed  Google Scholar 

  73. Kanbay M, Segal M, Afsar B, Kang D-H, Rodriguez-Iturbe B, Johnson RJ. The role of uric acid in the pathogenesis of human cardiovascular disease. Heart. 2013;99:759–66. A comprehensive review of uric acid’s role in cardiovascular disease, chronic kidney disease, the metabolic syndrome and diabetes mellitus, and their association with retinopathy and microvascular changes in the eye.

    Article  CAS  PubMed  Google Scholar 

  74. Bos MJ, Koudstaal PJ, Hofman A, Witteman JCM, Breteler MMB. Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam study. Stroke. 2006;37:1503–7.

    Article  CAS  PubMed  Google Scholar 

  75. Grayson PC, Kim SY, LaValley M, Choi HK. Hyperuricemia and incident hypertension: a systematic review and meta-analysis. Arth Care Res. 2011;63:102–10.

    Article  CAS  Google Scholar 

  76. Lee J-J, Yang I-H, Kuo H-K, Chung M-S, Chen Y-J, Chen C-H, et al. Serum uric acid concentration is associated with worsening in severity of diabetic retinopathy among type 2 diabetic patients in Taiwan—a 3-year prospective study. Diabetes Res Clin Pract. 2014;106:366–72. A prospective study, which found that a higher serum uric acid level is associated with an increase in severity of diabetic retinopathy over a 3-year period in patients with diabetes mellitus.

    Article  CAS  PubMed  Google Scholar 

  77. Munilakshmi U, Prabhavathi K, Shashidhar KN, Madhavi R, Lakshmaiah V. Association of serum uric acid with anthropometric, HbA1c and lipid profile in diabetic retinopathy. Int J Curr Res Rev. 2015;7:20–6.

    Google Scholar 

  78. Xia J, Wang Z, Zhang F. Association between related purine metabolites and diabetic retinopathy in type 2 diabetic patients. Int J Endocrinol. 2014;2014:651050.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Krizova L, Kalousova M, Kubena A, Benakova H, Zima T, Kovarik Z, et al. Increased uric acid and glucose concentrations in vitreous and serum of patients with diabetic macular oedema. Ophthalmic Res. 2011;46:73–9.

    Article  CAS  PubMed  Google Scholar 

  80. Muenzler WS, Gerber M. Uveitis associated with hyperuricemia. Am J Ophthalmol. 1963;55:289–91. Elsevier.

    Article  Google Scholar 

  81. Jain IS, Kaul RL, Jain GC, Munjal VP. Hyperuricemic uveitis. Indian J Ophthalmol. 1977;25:27–8.

    CAS  PubMed  Google Scholar 

  82. Scharf J, Nahir M, Rubilovitsch M. Scleritis associated with hyperuricaemia. Rheumatol Rehabil. 1975;14:251–2.

    Article  CAS  PubMed  Google Scholar 

  83. Roddy E, Doherty M. Gout epidemiology of gout. Arth Res Ther. 2010;12:223.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yael Sharon.

Ethics declarations

Conflicts of Interest

YS declares that she has no conflicts of interest. NS reports advisory board membership with Novartis, Takeda, Astra Zeneca, Alkermes, and Sobi; consultancy (paid to institution) for BMS, SGS, and Sobi; grants/grants pending (paid to institution) from Astra Zeneca; and payment for lectures from Takeda.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Crystal Arthritis

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sharon, Y., Schlesinger, N. Beyond Joints: a Review of Ocular Abnormalities in Gout and Hyperuricemia. Curr Rheumatol Rep 18, 37 (2016). https://doi.org/10.1007/s11926-016-0586-8

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11926-016-0586-8

Keywords

Navigation