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Arthritis and bone disease associated with hereditary hemochromatosis

John S Axford, DSc, MD, FRCP, FRCPCH
Section Editor
Michael A Becker, MD
Deputy Editor
Paul L Romain, MD


Arthritis is a common manifestation of hereditary hemochromatosis (HH), also called genetic hemochromatosis. HH is a genetically determined disorder in which mutations in the HFE gene, or less frequently the transferrin receptor 2 (TFR2) gene or other genes, cause increased intestinal iron absorption. (See "Genetics of hereditary hemochromatosis".)

The resulting clinical manifestations of this disorder (and of other forms of iron overload) are related to the iron deposition in organs, such as the liver, pancreas, heart, and pituitary, and in the cartilage and synovial tissues of the joints. Other major clinical manifestations of iron accumulation include liver disease, skin pigmentation, diabetes mellitus, impotence in males, and cardiac enlargement with or without heart failure or conduction defects (table 1). (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

The major rheumatic manifestations of hemochromatosis, including arthropathy and osteoporosis, and their pathogenesis, diagnosis, and management, will be reviewed here. Screening for HH and the major genetic, clinical, diagnostic, and therapeutic features of hereditary hemochromatosis are discussed separately. (See "Genetics of hereditary hemochromatosis" and "Clinical manifestations and diagnosis of hereditary hemochromatosis" and "Screening for hereditary hemochromatosis" and "Management of patients with hereditary hemochromatosis".)


Iron deposition and defects in cartilage and in immunologic function have been implicated as factors that contribute to the development of arthritis in hereditary hemochromatosis (HH). HFE gene analysis is useful in understanding the clinical manifestations of HH and patient management. However, the precise mechanisms underlying the arthritis among patients with HH are unknown. (See 'Iron deposition' below and 'Cartilage defect' below and 'Immunologic defects' below.)

HFE mutations were assessed in 31,192 persons of northern European ancestry who were followed for an average of 12 years [1]. C282Y is the HFE allele most commonly associated with HH. The proportion of HFE C282Y homozygotes with documented iron overload-related disease was 28.4 percent in men and 1.2 percent in women. Male C282Y homozygotes with a serum ferritin level of 1000 mg/L or more were more likely to report fatigue, use of arthritis medicines, and a history of liver disease.

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Literature review current through: Nov 2017. | This topic last updated: Apr 17, 2017.
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  1. Allen KJ, Gurrin LC, Constantine CC, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med 2008; 358:221.
  2. Camacho A, Funck-Brentano T, Simão M, et al. Effect of C282Y genotype on self-reported musculoskeletal complications in hereditary hemochromatosis. PLoS One 2015; 10:e0122817.
  3. Sahinbegovic E, Dallos T, Aigner E, et al. Hereditary hemochromatosis as a risk factor for joint replacement surgery. Am J Med 2010; 123:659.
  4. Wang Y, Gurrin LC, Wluka AE, et al. HFE C282Y homozygosity is associated with an increased risk of total hip replacement for osteoarthritis. Semin Arthritis Rheum 2012; 41:872.
  5. Elmberg M, Hultcrantz R, Simard JF, et al. Increased risk of arthropathies and joint replacement surgery in patients with genetic hemochromatosis: a study of 3,531 patients and their 11,794 first-degree relatives. Arthritis Care Res (Hoboken) 2013; 65:678.
  6. Sherrington CA, Knuiman MW, Divitini ML, et al. Population-based study of the relationship between mutations in the hemochromatosis (HFE) gene and arthritis. J Gastroenterol Hepatol 2006; 21:595.
  7. Sinigaglia L, Fargion S, Fracanzani AL, et al. Bone and joint involvement in genetic hemochromatosis: role of cirrhosis and iron overload. J Rheumatol 1997; 24:1809.
  8. Mathews JL, Williams HJ. Arthritis in hereditary hemochromatosis. Arthritis Rheum 1987; 30:1137.
  9. Schumacher HR Jr. Ultrastructural characteristics of the synovial membrane in idiopathic haemochromatosis. Ann Rheum Dis 1972; 31:465.
  10. Schumacher HR. Articular cartilage in the degenerative arthropathy of hemochromatosis. Arthritis Rheum 1982; 25:1460.
  11. Muirden KD, Senator GB. Iron in the synovial membrane in rheumatoid arthritis and other joint diseases. Ann Rheum Dis 1968; 27:38.
  12. Lunec J, Blake DR, McCleary SJ, et al. Self-perpetuating mechanisms of immunoglobulin G aggregation in rheumatoid inflammation. J Clin Invest 1985; 76:2084.
  13. Axford JS, Hay FC. Oligosaccharides, just the icing on the protein or are they of functional relevance? Br J Rheumatol 1991; 30:196.
  14. Hearn PR, Russell RG, Elliott JC. Formation product of calcium pyrophosphate crystals in vitro and the effect of iron salts. Clin Sci Mol Med 1978; 54:29.
  15. Hearn PR, Russell RG. Formation of calcium pyrophosphate crystals in vitro: implications for calcium pyrophosphate crystal deposition disease (pseudogout). Ann Rheum Dis 1980; 39:222.
  16. McCarty DJ, Palmer DW, Garancis JC. Clearance of calcium pyrophosphate dihydrate crystals in vivo. III. Effects of synovial hemosiderosis. Arthritis Rheum 1981; 24:706.
  17. Carroll GJ, Breidahl WH, Bulsara MK, Olynyk JK. Hereditary hemochromatosis is characterized by a clinically definable arthropathy that correlates with iron load. Arthritis Rheum 2011; 63:286.
  18. Carroll GJ, Sharma G, Upadhyay A, Jazayeri JA. Ferritin concentrations in synovial fluid are higher in osteoarthritis patients with HFE gene mutations (C282Y or H63D). Scand J Rheumatol 2010; 39:413.
  19. Dymock IW, Hamilton EB, Laws JW, Williams R. Arthropathy of haemochromatosis. Clinical and radiological analysis of 63 patients with iron overload. Ann Rheum Dis 1970; 29:469.
  20. COLLINS DH. Haemosiderosis and haemochromatosis of synovial tissues. J Bone Joint Surg Br 1951; 33-B:436.
  21. Wyllie JC. The stromal cell reaction of pigmented villonodular synovitis: an electron microscopic study. Arthritis Rheum 1969; 12:205.
  22. Key JA. Hemophilic Arthritis: Bleeder's Joints. Ann Surg 1932; 95:198.
  23. Roy S, Ghadially FN. Pathology of experimental haemarthrosis. Ann Rheum Dis 1966; 25:402.
  24. Axford JS, Bomford A, Revell P, et al. Hip arthropathy in genetic hemochromatosis. Radiographic and histologic features. Arthritis Rheum 1991; 34:357.
  25. Martel W, Champion CK, Thompson GR, Carter TL. A roentgenologically distinctive arthropathy in some patients with the pseudogout syndrome. Am J Roentgenol Radium Ther Nucl Med 1970; 109:587.
  26. Berry EM, Miller JP. Hereditary spherocytosis, haemochromatosis, diabetes mellitus and chondrocalcinosis. Proc R Soc Med 1973; 66:9.
  27. Resnick D, Utsinger PD. The wrist arthropathy of "pseudogout" occurring with and without chondrocalcinosis. Radiology 1974; 113:633.
  29. de Sèze S, Solnica J, Mitrovic D, et al. Joint and bone disorders and hypoparathyroidism in hemochromatosis. Semin Arthritis Rheum 1972; 2:71.
  30. Hamilton EB. Diseases associated with CPPD deposition disease. Arthritis Rheum 1976; 19 Suppl 3:353.
  31. Pawlotsky Y, Le Dantec P, Moirand R, et al. Elevated parathyroid hormone 44-68 and osteoarticular changes in patients with genetic hemochromatosis. Arthritis Rheum 1999; 42:799.
  32. von Kempis J. Arthropathy in hereditary hemochromatosis. Curr Opin Rheumatol 2001; 13:80.
  33. de Sousa M. Immune cell functions in iron overload. Clin Exp Immunol 1989; 75:1.
  34. de Martino M, Rossi ME, Resti M, et al. Changes in superoxide anion production in neutrophils from multitransfused beta-thalassemia patients: correlation with ferritin levels and liver damage. Acta Haematol 1984; 71:289.
  35. Kapadia A, de Sousa M, Markenson AL, et al. Lymphoid cell sets and serum immunoglobulins in patients with thalassaemia intermedia: relationship to serum iron and splenectomy. Br J Haematol 1980; 45:405.
  36. Dwyer J, Wood C, McNamara J, et al. Abnormalities in the immune system of children with beta-thalassaemia major. Clin Exp Immunol 1987; 68:621.
  37. Porto G, Reimão R, Gonçalves C, et al. Haemochromatosis as a window into the study of the immunological system: a novel correlation between CD8+ lymphocytes and iron overload. Eur J Haematol 1994; 52:283.
  38. Arosa FA, da Silva AJ, Godinho IM, et al. Decreased CD8-p56lck activity in peripheral blood T-lymphocytes from patients with hereditary haemochromatosis. Scand J Immunol 1994; 39:426.
  39. Arosa FA, Oliveira L, Porto G, et al. Anomalies of the CD8+ T cell pool in haemochromatosis: HLA-A3-linked expansions of CD8+CD28- T cells. Clin Exp Immunol 1997; 107:548.
  40. Cabeda JM, Porto G, da Silval BM, et al. Anomalies of the expression of T-cell receptor variable genes in haemochromatosis: an MHC-class I linked genetic disease of iron overload. Abstract, European Iron Club 1994, Gargano del Garda, Italy, September 24-27,1994.
  41. Heiland GR, Aigner E, Dallos T, et al. Synovial immunopathology in haemochromatosis arthropathy. Ann Rheum Dis 2010; 69:1214.
  42. Walker RJ, Dymock IW, Ansell ID, et al. Synovial biopsy in haemochromatosis arthropathy. Histological findings and iron deposition in relation to total body iron overload. Ann Rheum Dis 1972; 31:98.
  43. Bywaters EG, Hamilton EB, Williams R. The spine in idiopathic haemochromatosis. Ann Rheum Dis 1971; 30:453.
  44. Dorfmann H, Solnica J, Di Menza C, de Sèze S. [The arthropathies of hemochromatosis. Results of a prospective study of 54 patients]. Sem Hop 1969; 45:516.
  45. Hamilton E, Williams R, Barlow KA, Smith PM. The arthropathy of idiopathic haemochromatosis. Q J Med 1968; 37:171.
  46. Charlton RW, Abrahams C, Bothwell TH. Idiopathic hemochromatosis in young subjects. Clinical, pathological, and chemical findings in four patients. Arch Pathol 1967; 83:132.
  47. Cazzola M, Ascari E, Barosi G, et al. Juvenile idiopathic haemochromatosis: a life-threatening disorder presenting as hypogonadotropic hypogonadism. Hum Genet 1983; 65:149.
  48. Idiopathic hemochromatosis in the young (editorial). Lancet 1984; 11:1145.
  49. Sahinbegovic E, Dallos T, Aigner E, et al. Musculoskeletal disease burden of hereditary hemochromatosis. Arthritis Rheum 2010; 62:3792.
  50. de Jonge-Bok JM, Macfarlane JD. The articular diversity of early haemochromatosis. J Bone Joint Surg Br 1987; 69:41.
  51. Hamilton EB, Bomford AB, Laws JW, Williams R. The natural history of arthritis in idiopathic haemochromatosis: progression of the clinical and radiological features over ten years. Q J Med 1981; 50:321.
  52. Budiman-Mak E, Weitzner R, Lertratanakul Y. Arthropathy of hemochromatosis. Arthritis Rheum 1977; 20:1430.
  53. Faraawi R, Harth M, Kertesz A, Bell D. Arthritis in hemochromatosis. J Rheumatol 1993; 20:448.
  54. Gordon DA, Little HA. The arthropathy of hemochromatosis without hemochromatosis. Arthritis Rheum 1973; 16:305.
  55. M'Seffar A, Fornasier VL, Fox IH. Arthropathy as the major clinical indicator of occult iron storage disease. JAMA 1977; 238:1825.
  56. Schumacher HR Jr. Arthropathy in hemochromatosis. Hosp Pract (1995) 1998; 33:81.
  57. Dallos T, Sahinbegovic E, Stamm T, et al. Idiopathic hand osteoarthritis vs haemochromatosis arthropathy--a clinical, functional and radiographic study. Rheumatology (Oxford) 2013; 52:910.
  58. Richette P, Ottaviani S, Vicaut E, Bardin T. Musculoskeletal complications of hereditary hemochromatosis: a case-control study. J Rheumatol 2010; 37:2145.
  59. Adamson TC 3rd, Resnik CS, Guerra J Jr, et al. Hand and wrist arthropathies of hemochromatosis and calcium pyrophosphate deposition disease: distinct radiographic features. Radiology 1983; 147:377.
  60. Farpour F, Phan SJ, Burns J, Tehranzadeh J. Enhanced MR imaging of the shoulder, and sternoclavicular and acromioclavicular joint arthritis in primary hemochromatosis. Rheumatol Int 2011; 31:395.
  61. Papakonstantinou O, Mohana-Borges AV, Campell L, et al. Hip arthropathy in a patient with primary hemochromatosis: MR imaging findings with pathologic correlation. Skeletal Radiol 2005; 34:180.
  62. Dallos T, Sahinbegovic E, Aigner E, et al. Validation of a radiographic scoring system for haemochromatosis arthropathy. Ann Rheum Dis 2010; 69:2145.
  63. Diamond T, Stiel D, Posen S. Osteoporosis in hemochromatosis: iron excess, gonadal deficiency, or other factors? Ann Intern Med 1989; 110:430.
  64. Delbarre F. Haemosiderosis and haemochromatosis of synovial tissues. J Bone Joint Surg 1960; 33:436.
  65. Wardle EN, Patton JT. Bone and joint changes in haemochromatosis. Ann Rheum Dis 1969; 28:15.
  66. Guggenbuhl P, Deugnier Y, Boisdet JF, et al. Bone mineral density in men with genetic hemochromatosis and HFE gene mutation. Osteoporos Int 2005; 16:1809.
  67. Cauza E, Hanusch-Enserer U, Etemad M, et al. HFE genotyping demonstrates a significant incidence of hemochromatosis in undifferentiated arthritis. Clin Exp Rheumatol 2005; 23:7.
  68. Scotet V, Le Gac G, Mérour MC, et al. Impact of HFE genetic testing on clinical presentation of hereditary hemochromatosis: new epidemiological data. BMC Med Genet 2005; 6:24.
  69. Aigner E, Schmid I, Osterreicher CH, et al. Contribution of anti-cyclic citrullinated peptide antibody and rheumatoid factor to the diagnosis of arthropathy in haemochromatosis. Ann Rheum Dis 2007; 66:1249.
  70. Carroll GJ. HFE gene mutations are associated with osteoarthritis in the index or middle finger metacarpophalangeal joints. J Rheumatol 2006; 33:741.
  71. Carroll GJ. Primary osteoarthritis in the ankle joint is associated with finger metacarpophalangeal osteoarthritis and the H63D mutation in the HFE gene: evidence for a hemochromatosis-like polyarticular osteoarthritis phenotype. J Clin Rheumatol 2006; 12:109.
  72. Axford JS. Rheumatic manifestations of haemochromatosis. Baillieres Clin Rheumatol 1991; 5:351.
  73. Guggenbuhl P, Brissot P, Loréal O. Miscellaneous non-inflammatory musculoskeletal conditions. Haemochromatosis: the bone and the joint. Best Pract Res Clin Rheumatol 2011; 25:649.
  74. Carroll GJ, Breidahl WH, Olynyk JK. Characteristics of the arthropathy described in hereditary hemochromatosis. Arthritis Care Res (Hoboken) 2012; 64:9.
  75. Smith LH Jr. Overview of hemochromatosis. West J Med 1990; 153:296.
  76. Adams PC, Speechley M. The effect of arthritis on the quality of life in hereditary hemochromatosis. J Rheumatol 1996; 23:707.
  77. Lunn JV, Gallagher PM, Hegarty S, et al. The role of hereditary hemochromatosis in aseptic loosening following primary total hip arthroplasty. J Orthop Res 2005; 23:542.
  78. Adams PC, Reboussin DM, Barton JC, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 2005; 352:1769.
  79. Ong SY, Dolling L, Dixon JL, et al. Should HFE p.C282Y homozygotes with moderately elevated serum ferritin be treated? A randomised controlled trial comparing iron reduction with sham treatment (Mi-iron). BMJ Open 2015; 5:e008938.