Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Rheumatic manifestations of hereditary hemochromatosis

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


Hereditary hemochromatosis (HH), also called genetic hemochromatosis, 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 [1-4]. Details of the interaction between the transferrin receptor and HFE gene product and of the role of the TFR2 gene are still uncertain [5-7]. (See "Genetics of hereditary hemochromatosis".)

The clinical manifestations of this disorder (and of other forms of iron overload) are related to iron deposition in tissues, such as the liver, pancreas, and heart. Approximately one-half of patients with HH, if untreated, eventually develop arthritis [8,9]. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

This topic review will focus on the major rheumatic manifestations of hemochromatosis: arthropathy and osteoporosis (OP). 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".)


The underlying cause of arthritis among patients with hereditary hemochromatosis (HH) is unknown. Iron deposition and defects in cartilage and in immunologic function have been implicated.

Iron deposition — Iron deposition within joints may trigger a number of pathologic events, such as free radical generation and crystal deposition. In some cases, the generation of free radicals may cause changes in immunoglobulin carbohydrate composition that promote immune complex formation and inflammation [10-14]. These alterations are superimposed upon the joint changes resulting from calcium pyrophosphate deposition.


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: Sep 2016. | This topic last updated: Jan 4, 2016.
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 ©2016 UpToDate, Inc.
  1. Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996; 13:399.
  2. Jouanolle AM, Gandon G, Jézéquel P, et al. Haemochromatosis and HLA-H. Nat Genet 1996; 14:251.
  3. Bodmer JG, Parham P, Albert ED, Marsh SG. Putting a hold on "HLA-H'. The WHO Nomenclature Committee for Factors of the HLA System. Nat Genet 1997; 15:234.
  4. Camaschella C, Roetto A, Calì A, et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 2000; 25:14.
  5. Feder JN, Penny DM, Irrinki A, et al. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci U S A 1998; 95:1472.
  6. Roy CN, Penny DM, Feder JN, Enns CA. The hereditary hemochromatosis protein, HFE, specifically regulates transferrin-mediated iron uptake in HeLa cells. J Biol Chem 1999; 274:9022.
  7. Salter-Cid L, Brunmark A, Li Y, et al. Transferrin receptor is negatively modulated by the hemochromatosis protein HFE: implications for cellular iron homeostasis. Proc Natl Acad Sci U S A 1999; 96:5434.
  8. 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.
  9. 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.
  10. Schumacher HR Jr. Ultrastructural characteristics of the synovial membrane in idiopathic haemochromatosis. Ann Rheum Dis 1972; 31:465.
  11. Schumacher HR. Articular cartilage in the degenerative arthropathy of hemochromatosis. Arthritis Rheum 1982; 25:1460.
  12. Muirden KD, Senator GB. Iron in the synovial membrane in rheumatoid arthritis and other joint diseases. Ann Rheum Dis 1968; 27:38.
  13. Lunec J, Blake DR, McCleary SJ, et al. Self-perpetuating mechanisms of immunoglobulin G aggregation in rheumatoid inflammation. J Clin Invest 1985; 76:2084.
  14. Axford JS, Hay FC. Oligosaccharides, just the icing on the protein or are they of functional relevance? Br J Rheumatol 1991; 30:196.
  15. 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.
  16. 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.
  17. McCarty DJ, Palmer DW, Garancis JC. Clearance of calcium pyrophosphate dihydrate crystals in vivo. III. Effects of synovial hemosiderosis. Arthritis Rheum 1981; 24:706.
  18. 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.
  19. COLLINS DH. Haemosiderosis and haemochromatosis of synovial tissues. J Bone Joint Surg Br 1951; 33-B:436.
  20. Wyllie JC. The stromal cell reaction of pigmented villonodular synovitis: an electron microscopic study. Arthritis Rheum 1969; 12:205.
  21. Key JA. Hemophilic Arthritis: Bleeder's Joints. Ann Surg 1932; 95:198.
  22. Roy S, Ghadially FN. Pathology of experimental haemarthrosis. Ann Rheum Dis 1966; 25:402.
  23. Axford JS, Bomford A, Revell P, et al. Hip arthropathy in genetic hemochromatosis. Radiographic and histologic features. Arthritis Rheum 1991; 34:357.
  24. 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.
  25. Berry EM, Miller JP. Hereditary spherocytosis, haemochromatosis, diabetes mellitus and chondrocalcinosis. Proc R Soc Med 1973; 66:9.
  26. Resnick D, Utsinger PD. The wrist arthropathy of "pseudogout" occurring with and without chondrocalcinosis. Radiology 1974; 113:633.
  28. de Sèze S, Solnica J, Mitrovic D, et al. Joint and bone disorders and hypoparathyroidism in hemochromatosis. Semin Arthritis Rheum 1972; 2:71.
  29. Hamilton EB. Diseases associated with CPPD deposition disease. Arthritis Rheum 1976; 19 Suppl 3:353.
  30. 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.
  31. von Kempis J. Arthropathy in hereditary hemochromatosis. Curr Opin Rheumatol 2001; 13:80.
  32. de Sousa M. Immune cell functions in iron overload. Clin Exp Immunol 1989; 75:1.
  33. 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.
  34. 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.
  35. 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.
  36. 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.
  37. 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.
  38. 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.
  39. 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.
  40. Heiland GR, Aigner E, Dallos T, et al. Synovial immunopathology in haemochromatosis arthropathy. Ann Rheum Dis 2010; 69:1214.
  41. 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.
  42. Bywaters EG, Hamilton EB, Williams R. The spine in idiopathic haemochromatosis. Ann Rheum Dis 1971; 30:453.
  43. 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.
  44. Mathews JL, Williams HJ. Arthritis in hereditary hemochromatosis. Arthritis Rheum 1987; 30:1137.
  45. Charlton RW, Abrahams C, Bothwell TH. Idiopathic hemochromatosis in young subjects. Clinical, pathological, and chemical findings in four patients. Arch Pathol 1967; 83:132.
  46. Cazzola M, Ascari E, Barosi G, et al. Juvenile idiopathic haemochromatosis: a life-threatening disorder presenting as hypogonadotropic hypogonadism. Hum Genet 1983; 65:149.
  47. Idiopathic hemochromatosis in the young (editorial). Lancet 1984; 11:1145.
  48. Gordon DA, Little HA. The arthropathy of hemochromatosis without hemochromatosis. Arthritis Rheum 1973; 16:305.
  49. M'Seffar A, Fornasier VL, Fox IH. Arthropathy as the major clinical indicator of occult iron storage disease. JAMA 1977; 238:1825.
  50. Hamilton E, Williams R, Barlow KA, Smith PM. The arthropathy of idiopathic haemochromatosis. Q J Med 1968; 37:171.
  51. Adams PC, Speechley M. The effect of arthritis on the quality of life in hereditary hemochromatosis. J Rheumatol 1996; 23:707.
  52. de Jonge-Bok JM, Macfarlane JD. The articular diversity of early haemochromatosis. J Bone Joint Surg Br 1987; 69:41.
  53. Sahinbegovic E, Dallos T, Aigner E, et al. Musculoskeletal disease burden of hereditary hemochromatosis. Arthritis Rheum 2010; 62:3792.
  54. 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.
  55. Budiman-Mak E, Weitzner R, Lertratanakul Y. Arthropathy of hemochromatosis. Arthritis Rheum 1977; 20:1430.
  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. Faraawi R, Harth M, Kertesz A, Bell D. Arthritis in hemochromatosis. J Rheumatol 1993; 20:448.
  59. Richette P, Ottaviani S, Vicaut E, Bardin T. Musculoskeletal complications of hereditary hemochromatosis: a case-control study. J Rheumatol 2010; 37:2145.
  60. Sahinbegovic E, Dallos T, Aigner E, et al. Hereditary hemochromatosis as a risk factor for joint replacement surgery. Am J Med 2010; 123:659.
  61. 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.
  62. 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.
  63. Dallos T, Sahinbegovic E, Aigner E, et al. Validation of a radiographic scoring system for haemochromatosis arthropathy. Ann Rheum Dis 2010; 69:2145.
  64. 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.
  65. 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.
  66. Carroll GJ. HFE gene mutations are associated with osteoarthritis in the index or middle finger metacarpophalangeal joints. J Rheumatol 2006; 33:741.
  67. 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.
  68. Smith LH Jr. Overview of hemochromatosis. West J Med 1990; 153:296.
  69. Nielsen P, Fischer R, Buggisch P, Janka-Schaub G. Effective treatment of hereditary haemochromatosis with desferrioxamine in selected cases. Br J Haematol 2003; 123:952.
  70. Milward EA, Baines SK, Knuiman MW, et al. Noncitrus fruits as novel dietary environmental modifiers of iron stores in people with or without HFE gene mutations. Mayo Clin Proc 2008; 83:543.
  71. Announ N, Guerne PA. Treating difficult crystal pyrophosphate dihydrate deposition disease. Curr Rheumatol Rep 2008; 10:228.
  72. Diamond T, Stiel D, Posen S. Osteoporosis in hemochromatosis: iron excess, gonadal deficiency, or other factors? Ann Intern Med 1989; 110:430.
  73. Delbarre F. Haemosiderosis and haemochromatosis of synovial tissues. J Bone Joint Surg 1960; 33:436.
  74. Wardle EN, Patton JT. Bone and joint changes in haemochromatosis. Ann Rheum Dis 1969; 28:15.
  75. 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.
  76. 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.
  77. 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.