Abstract
Hereditary hemochromatosis, a very common genetic defect in the Caucasian population, is characterized by progressive tissue iron overload which leads to irreversible organ damage if it is not treated in a timely manner. Recent developments in the field of molecular medicine have radically improved the understanding of the physiopathology and diagnosis of this disease. However, transferrin saturation and serum ferritin are still the most reliable tests for identifying subjects with hereditary hemochromatosis. Therapeutic phlebotomy is the mainstay of the treatment of this disease and the life expectancy of these patients is similar to that of the normal population if phlebotomy is started before the onset of irreversible organ damage. In this review we discuss the genetics, pathophysiology, diagnosis, clinical features, and management of hereditary hemochromatosis.
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References
Barton JC, McDonnell S, Adams P (1998) Management of hemochromatosis. Ann Intern Med 129:932–939
Beutler E, Gelbart T, West C, Lee P, Adams M, Blackstone R, Pockros P, Kosty M, Venditti CP, Phatak PD, Seese NK, Chorney KA, Ten Elshof AE, Gerhard GS, Chorney M (1996) Mutation analysis in hereditary hemochromatosis. Blood Cells Mol Dis 22:187–194
Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T (2002) Penetrance of 845G→A (C282Y) HFE hereditary hemochromatosis mutation in the USA. Lancet 359:211–218
Bomford A (2002) Genetics of haemochromatosis. Lancet 360:1673–1681
Brissot P, Moirand R, Jouanolle AM, Guyader D, Le Gall JY, Deugnier Y, David V (1999) A genotypic study of 217 unrelated probands diagnosed as “genetic hemochromatosis” on “classical” phenotypic criteria. J Hepatol 30:588–593
Camaschella C, De Gobbi M, Roetto A (2000) Hereditary hemochromatosis: progress and perspectives. Rev Clin Exp Hematol 4:302–321
Camaschella C, Roetto A, Cali A, De Gobbi M, Garozzo G, Carella M, Majorano N, Totano A, Gasparini P (2000) The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 25:14–15
Camaschella C, Roetto A, De Gobbi M (2002) Genetic haemochromatosis: genes and mutations associated with iron loading. Best Pract Res Clin Haematol 15:261–276
Carella M, D’Ambrosio L, Totaro A, Grifa A, Valentino MA, Piperno A, Girelli D, Roetto A, Franco B, Gasparini P, Camaschella C (1997) Mutation analysis of HLA-H gene in Italian hemochromatosis patients. Am J Hum Genet 60:828–832
Cazzola M (2002) Novel genes, proteins, and inherited disorders of iron overload: iron metabolism is less boring than thought. Haematologica 87:115–116
Cazzola M (2002) Hereditary hyperferritinaemia/cataract syndrome. Best Pract Res Clin Haematol 15:385–398
Cazzola M (2003) Genetic disorders of iron overload and the novel “ferroportin disease.” Haematologica 88:721–724
De Gobbi M, Roetto A, Piperno A, Mariani R, Alberti F, Papanikolaou G, Politou M, Lockitch G, Girelli D, Fargion S, Cox TM, Gasparini P, Cazzola M, Camaschella C (2002) Natural history of juvenile haemochromatosis. Br J Haematol 117:973–979
Devalia V, Carter K, Walker AP, Perkins SJ, Worwood M, May A, Dooley JS (2002) Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3). Blood 100:695–697
Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R Jr, Ellis MC, Fullan A, Hinton LM, Jones NL, Kimmel BE, Kronmal GS, Lauer P, Lee VK, Loeb DB, Mapa FA, McClelland E, Meyer NC, Mintier GA, Moeller N, Moore T, Morikang E, Wolff RK (1996) A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13:399–408
Franchini M, Gandini G, Aprili G (2000) Advances in iron chelating therapy. Haematologica 85:1122–1125
Franchini M, Veneri D (2004) Iron-chelation therapy: an update. Hematol J 5:287–292
Franchini M, Gandini G, de Gironcoli M, Vassanelli A, Borgna-Pignatti C, Aprili G (2000) Safety and efficacy of subcutaneous bolus injection of deferoxamine in adult patients with iron overload. Blood 95:2776–2779
Girelli D, Piccoli P, Corrocher R (1997) La sindrome iperferritinemia-cataratta. Minerva Med 88:405–410
Hanson EH, Imperatore G, Burke W (2001) HFE gene and hemochromatosis: a HuGE review. Am J Epidemiol 154:193–206
Hemochromatosis. In: Online Mendelian Inheritance in Man, OMIM. Baltimore: McKusick-Nathans Institute for Genetic Medicine, 2000 (http://www.ncbi.nlm.nih.gov/omim/)
Imperatore G, Pinsky LE, Motulsky A, Reyes M, Bradley LA, Burke W (2003) Hereditary hemochromatosis: perspectives of public health, medical genetics, and primary care. Genet Med 5:1–8
Kelly AL, Rhodes DA, Roland JM, Schofield P, Cox TM (1998) Hereditary juvenile haemochromatosis: a genetically heterogeneous life-threatening iron storage disease. QJM 91:607–618
McDonnel SM, Preston BL, Jewell SA, Barton JC, Edwards CQ, Adams PC, Yip R (1999) A survey of 2851 patients with hemochromatosis: symptoms and response to treatment. Am J Med 106:619–624
Merryweather-Clarke AT, Pointon JJ, Sherman JD, Robson KJH (1997) Global prevalence of putative haemochromatosis mutations. J Med Genet 34:275–278
Merryweather-Clarke AT, Pointon JJ, Jouanolle AM, Rochette J, Robson KIH (2000) Geography of HFE C282Y and H63D mutations. Genet Test 4:183–198
Montosi G, Donovan A, Totano A, Garuti C, Pignatti E, Cassanelli S, Trenor CC, Gasparini P, Andrews NC, Pietrangelo A (2001) Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest 108:619–623
Mura C, Raguenes O, Férec C (1999) HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis. Blood 93:2502–2505
Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G (1985) Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med 313:1256–1262
Njajou OT, Vaessen N, Joosse M, Berghuis B, van Dongen JW, Breuning MH, Snijders PJ, Rutten WP, Sandkuijl LA, Oostra BA, van Duijn CM, Heutink P (2001) A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet 28:213–214
Njajou O, Alizadeh BZ, van Duijn CM (2004) Is genetic screening for hemochromatosis worthwhile? Eur J Epidemiol 19:101–108
Olynyk JK, Cullen DJ, Aquila S, Rossi E, Summerville L, Powell LW (1999) A population-based study of the clinical expression of the hemochromatosis gene. N Engl J Med 341:718–724
Papanikolaou G, Politou M, Terpos E, Fourlemadis S, Sakellaropoulos N, Loukopoulos D (2000) Hereditary hemochromatosis: HFE mutation analysis in Greeks reveals genetic heterogeneity. Blood Cells Mol Dis 26:163–168
Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dube MP, Andres L, MacFarlane J, Sakellaropoulos N, Politou M, Nemeth E, Thompson J, Risler JK, Zaborowska C, Babakaiff R, Radomski CC, Pape TD, Davidas O, Christakis J, Brissot P, Lockitch G, Ganz T, Hayden MR, Goldberg YP (2004) Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 36:77–82
Pietrangelo A, Camaschella C (1998) Molecular genetics and control of iron metabolism in hemochromatosis. Haematologica 83:456–461
Pietrangelo A (2003) Haemochromatosis. Gut 52:23–30
Pietrangelo A (2004) Non-HFE hemochromatosis. Hepatology 39:21–29
Pietrangelo A (2004) Hereditary hemochromatosis—a new look at an old disease. N Engl J Med 350:2383–2397
Piperno A, Sampietro M, Pietrangelo A, Arosio C, Lupica L, Montosi G, Vergani A, Fraquelli M, Girelli D, Pasquero P, Roetto A, Gasparini P, Fargion S, Conte D, Camaschella C (1998) Heterogeneity of hemochromatosis in Italy. Gastroenterology 114:996–1002
Piperno A (1998) Classification and diagnosis of iron overload. Haematologica 83:447–455
Piperno A, Arosio C, Fossati L, Vigano M, Trombini P, Vergani A, Mancia G (2000) Two novel mutations of HFE gene in five unrelated Italian patients with hemochromatosis. Gastroenterology 119:441–445
Powell LW, George DK, McDonnel SM, Kowdley KV (1998) Diagnosis of hemochromatosis. Ann Intern Med 129:925–931
Restagno G, Gomez AM, Sbaiz L, De Gobbi M, Roetto A, Bertino E, Fabris C, Fiorucci GC, Fortina P, Camaschella C (2000) A pilot C282Y hemochromatosis screening in Italian newborns by TaqMan technology. Genet Test 4:177–181
Robson KJH, Merryweather-Clarke AT, Cadet E, Viprakasit V, Zaahl MG, Pointon JJ, Weatherall DJ, Rochette J (2004) Recent advances in understanding hemochromatosis: a transition state. J Med Genet 41:721–730
Rochette J, Pointon JJ, Fisher CA, Perera G, Arambepola M, Arichchi DS, De Silva S, Vandwalle JL, Monti JP, Old JM, Merryweather-Clarke AT, Weatherall DJ, Robson KJ (1999) Multicentric origin of hemochromatosis gene (HFE) mutations. Am J Hum Genet 64:1054–1062
Roetto A, Totaro A, Cazzola M, Cicilano M, Bosio S, D’Ascola G, Carella M, Zelante L, Kelly AL, Cox TM, Gasparini P, Camaschella C (1999) Juvenile hemochromatosis locus maps to chromosome 1q. Am J Hum Genet 64:1388–1393
Roetto A, Merryweather-Clarke AT, Daraio F, Livesey K, Pointon JJ, Barbabietola G, Piga A, Mackie PH, Robson KJ, Camaschella C (2002) A valine deletion of ferroportin 1: a common mutation in hemochromatosis type 4. Blood 100:733–734
Roetto A, Papanikolaou G, Politou M (2003) Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet 33:21–22
Salvioni A, Mariani R, Oberkanins C, Moritz A, Mauri V, Pelucchi S, Riva A, Arosio C, Cerutti P, Piperno A (2003) Prevalence of C282Y and E168X HFE mutations in an Italian population of Northern European ancestry. Haematologica 88:250–255
Simon M, Bourel M, Genetet B, Fauchet R (1977) Idiopathic hemochromatosis: demonstration of recessive transmission and early detection by family HLA typing. N Engl J Med 297:1017–1021
Wallace DF, Pedersen P, Dixon JL, Stephenson P, Searle JW, Powell LW, Subramaniam VN (2002) Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis. Blood 100:692–694
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Franchini, M., Veneri, D. Recent advances in hereditary hemochromatosis. Ann Hematol 84, 347–352 (2005). https://doi.org/10.1007/s00277-005-1006-8
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DOI: https://doi.org/10.1007/s00277-005-1006-8