Pathophysiology of hereditary hemochromatosis

Seminars in Liver Disease

Volumn 25, Issue 4, 2005, Pages 411-419

  Fleming, Robert E ^a,b   Britton, Robert S ^b   Waheed, Abdul ^b   Sly, William S ^b   Bacon, Bruce R ^b  

^a SAINT LOUIS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b Saint Louis University   (United States)

Author keywords

Ferroportin; Hemochromatosis; Hepcidin; HFE; Iron

Indexed keywords

HEPCIDIN; HFE PROTEIN; IRON; IRON REGULATORY FACTOR;

BIOACCUMULATION; CELL TYPE; CLINICAL FEATURE; ENVIRONMENTAL FACTOR; GENE MUTATION; GENETIC RISK; HEMOCHROMATOSIS; HOMEOSTASIS; HOMOZYGOSITY; HORMONE ACTION; HUMAN; INTESTINE CELL; IRON ABSORPTION; IRON BLOOD LEVEL; IRON KINETICS; IRON METABOLISM; IRON OVERLOAD; IRON STORAGE; IRON TRANSPORT; NONHUMAN; PATHOPHYSIOLOGY; PHENOTYPE; PHENOTYPIC VARIATION; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; RETICULOENDOTHELIAL CELL; RETICULOENDOTHELIAL SYSTEM; REVIEW; SIGNAL TRANSDUCTION;

ABSORPTION; ANTIMICROBIAL CATIONIC PEPTIDES; GENE EXPRESSION; HEMOCHROMATOSIS; HISTOCOMPATIBILITY ANTIGENS CLASS I; HUMANS; INTESTINES; IRON; MEMBRANE PROTEINS; MUTATION;

EID: 28444445559     PISSN: 02728087     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-2005-923313     Document Type: Review

References (95)

1. Pietrangelo A. Hereditary hemochromatosis-a new look at an old disease. N Engl J Med 2004;350:2383-2397
2. 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;13:399-408
3. Simon M, Bourel M, Fauchet R, et al. Association of HLA-A3 and HLA-B14 antigens with idiopathic haemochromatosis. Gut 1976;17:332-334
4. Zhou XY, Tomatsu S, Fleming RE, et al. HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc Natl Acad Sci USA 1998;95:2492-2497
5. Bahram S, Gilfillan S, Kuhn LC, et al. Experimental hemochromatosis due to MHC class I HFE deficiency: immune status and iron metabolism. Proc Natl Acad Sci USA 1999;96:13312-13317
6. Levy JE, Montross LK, Cohen DE, et al. The C282Y mutation causing hereditary hemochromatosis does not produce a null allele. Blood 1999;94:9-11
7. Feder JN, Tsuchihashi Z, Irrinki A, et al. The hemochromatosis founder mutation in HLA-H disrupts beta2-microglobulin interaction and cell surface expression. J Biol Chem 1997;272:14025-14028
8. Waheed A, Parkkila S, Zhou XY, et al. Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with beta2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proc Natl Acad Sci USA 1997;94:12384-12389
9. Parkkila S, Parkkila AK, Waheed A, et al. Cell surface expression of HFE protein in epithelial cells, macrophages, and monocytes. Haematologica 2000;85:340-345
10. de Sousa M, Reimao R, Lacerda R, et al. Iron overload in beta 2-microglobulin-deficient mice. Immunol Lett 1994;39:105-111
11. Santos M, Schilham MW, Rademakers LH, et al. Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man. J Exp Med 1996;184:1975-1985
12. Waheed A, Grubb JH, Zhou XY, et al. Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis. Proc Natl Acad Sci USA 2002;99:3117-3122
13. Carlson H, Zhang AS, Fleming WH, et al. The hereditary hemochromatosis protein, HFE, lowers intracellular iron levels independently of transferrin receptor 1 in TRVb cells. Blood 2005;105:2564-2570
14. Giannetti AM, Bjorkman PJ. HFE and transferrin directly compete for transferrin receptor in solution and at the cell surface. J Biol Chem 2004;279:25866-25875
15. Holmstrom P, Dzikaite V, Hultcrantz R, et al. Structure and liver cell expression pattern of the HFE gene in the rat. J Hepatol 2003;39:308-314
16. Zhang AS, Xiong S, Tsukamoto H, et al. Localization of iron metabolism-related mRNAs in rat liver indicate that HFE is predominantly expressed in hepatocytes. Blood 2004;103:1509-1514
17. Bastin JM, Jones M, O'Callaghan CA, et al. Kupffer cell staining by an HFE-specific monoclonal antibody: implications for hereditary haemochromatosis. Br J Haematol 1998;103:931-941
18. Parkkila S, Waheed A, Britton RS, et al. Immunohistochemistry of HLA-H, the protein defective in patients with hereditary hemochromatosis, reveals unique pattern of expression in gastrointestinal tract. Proc Natl Acad Sci USA 1997;94:2534-2539
19. Powell LW, Subramaniam VN, Yapp TR. Haemochromatosis in the new millennium. J Hepatol 2000;32:48-62
20. Rochette J, Pointon JJ, Fisher CA, et al. Multicentric origin of hemochromatosis gene (HFE) mutations. Am J Hum Genet 1999;64:1056-1062
21. Beckman LE, Saha N, Spitsyn V, et al. Ethnic differences in the HFE codon 282 (Cys/Tyr) polymorphism. Hum Hered 1997;47:263-267
22. Beutler E, Felitti VJ, Koziol JA, et al. Penetrance of 845G → A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002;359:211-218
23. Adams PC, Reboussin DM, Barton JC, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 2005;352:1769-1778
24. Olynyk JK, Cullen DJ, Aquilia S, et al. A population-based study of the clinical expression of the hemochromatosis gene. N Engl J Med 1999;341:718-724
25. Burt MJ, George PM, Upton JD, et al. The significance of haemochromatosis gene mutations in the general population: implications for screening. Gut 1998;43:830-836
26. McDonnell SM, Hover A, Gloe D, et al. Population-based screening for hemochromatosis using phenotypic and DNA testing among employees of health maintenance organizations in Springfield, Missouri. Am J Med 1999;107:30-37
27. Steinberg KK, Cogswell ME, Chang JC, et al. Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States. JAMA 2001;285:2216-2222
28. Gochee PA, Powell LW, Cullen DJ, et al. A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation. Gastroenterology 2002;122:646-651
29. Bacon BR. Hemochromatosis: diagnosis and management. Gastroenterology 2001;120:718-725
30. Risch N. Haemochromatosis, HFE and genetic complexity [letter]. Nat Genet 1997;17:375-376
31. Pointon JJ, Wallace D, Merryweather-Clarke AT, et al. Uncommon mutations and polymorphisms in the hemochromatosis gene. Genet Test 2000;4:151-161
32. Britton RS, Fleming RE, Parkkila S, et al. Pathogenesis of hereditary hemochromatosis: genetics and beyond. Semin Gastrointest Dis 2002;13:68-79
33. Andrews NC. Disorders of iron metabolism. N Engl J Med 1999;341:1986-1995
34. McKie AT, Barrow D, Latunde-Dada GO, et al. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 2001;291:1755-1759
35. Fleming MD, Trenor CC III, Su MA, et al. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet 1997;16:383-386
36. Gunshin H, Mackenzie B, Berger UV, et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 1997;388:482-488
37. Donovan A, Brownlie A, Zhou Y, et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 2000;403:776-781
38. McKie AT, Marciani P, Rolfs A, et al. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 2000;5:299-309
39. Abboud S, Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 2000;275:19906-19912
40. Vulpe CD, Kuo YM, Murphy TL, et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet 1999;21:195-199
41. McLaren GD, Nathanson MH, Jacobs A, et al. Regulation of intestinal iron absorption and mucosal iron kinetics in hereditary hemochromatosis. J Lab Clin Med 1991;117:390-401
42. Zoller H, Pietrangelo A, Vogel W, et al. Duodenal metal-transporter (DMT-1, NRAMP-2) expression in patients with hereditary haemochromatosis. Lancet 1999;353:2120-2123
43. Zoller H, Koch RO, Theurl I, et al. Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload. Gastroenterology 2001;120:1412-1419
44. Rolfs A, Bonkovsky HL, Kohlroser JG, et al. Intestinal expression of genes involved in iron absorption in humans. Am J Physiol Gastrointest Liver Physiol 2002;282:G598-G607
45. Fleming RE, Migas MC, Zhou X, et al. Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: increased duodenal expression of the iron transporter DMT1. Proc Natl Acad Sci USA 1999;96:3143-3148
46. Dupic F, Fruchon S, Bensaid M, et al. Inactivation of the hemochromatosis gene differentially regulates duodenal expression of iron-related mRNAs between mouse strains. Gastroenterology 2002;122:745-751
47. Kawabata H, Yang R, Hirama T, et al. Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J Biol Chem 1999;274:20826-20832
48. Fleming RE, Migas MC, Holden CC, et al. Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis. Proc Natl Acad Sci USA 2000;97:2214-2219
49. Bonkovsky HL. Iron and the liver. Am J Med Sci 1991;301:32-43
50. Brissot P, Wright TL, Ma WL, et al. Efficient clearance of non-transferrin-bound iron by rat liver. Implications for hepatic iron loading in iron overload states. J Clin Invest 1985;76:1463-1470
51. Batey RG, Lai Chung Fong P, Shamir S, et al. A non-transferrin-bound serum iron in idiopathic hemochromatosis. Dig Dis Sci 1980;25:340-346
52. Chua AC, Olynyk JK, Leedman PJ, et al. Nontransferrin-bound iron uptake by hepatocytes is increased in the Hfe knockout mouse model of hereditary hemochromatosis. Blood 2004;104:1519-1525
53. Deiss A. Iron metabolism in reticuloendothelial cells. Semin Hematol 1983;20:81-90
54. McLaren GD. Reticuloendothelial iron stores and hereditary hemochromatosis: a paradox [editorial]. J Lab Clin Med 1989;113:137-138
55. Moura E, Noordermeer MA, Verhoeven N, et al. Iron release from human monocytes after erythrophagocytosis in vitro: an investigation in normal subjects and hereditary hemochromatosis patients. Blood 1998;92:2511-2519
56. Roetto A, Papanikolaou G, Politou M, et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet 2003;33:21-22
57. Roetto A, Totaro A, Piperno A, et al. New mutations inactivating transferrin receptor 2 in hemochromatosis type 3. Blood 2001;97:2555-2560
58. Papanikolaou G, Samuels ME, Ludwig EH, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 2004;36:77-82
59. Lanzara C, Roetto A, Daraio F, et al. Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood 2004;103:4317-4321
60. Lee PL, Beutler E, Rao SV, et al. Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin. Blood 2004;103:4669-4671
61. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003;102:783-788
62. Nicolas G, Viatte L, Bennoun M, et al. Hepcidin, a new iron regulatory peptide. Blood Cells Mol Dis 2002;29:327-335
63. Pigeon C, Ilyin G, Courselaud B, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 2001;276:7811-7819
64. Nicolas G, Bennoun M, Devaux I, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA 2001;98:8780-8785
65. Nicolas G, Bennoun M, Porteu A, et al. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci USA 2002;99:4596-4601
66. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002;110:1037-1044
67. Pigeon C, Ilyin G, Courselaud B, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 2001;276:7811-7819
68. Nemeth E, Valore EV, Territo M, et al. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 2003;101:2461-2463
69. Kemna EH, Pickkers P, Nemeth E, van der Hoeven H, Swinkels D. Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood 2005;106:1864-1866
70. Detivaud L, Nemeth E, Boudjema K, et al. Hepcidin levels in humans are correlated with hepatic iron stores, hemoglobin levels, and hepatic function. Blood 2005;106:746-748
71. Papanikolaou G, Tzilianos M, Christakis JI, et al. Hepcidin in iron overload disorders. Blood 2005;105:4103-4105
72. Frazer DM, Wilkins SJ, Becker EM, et al. Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats. Gastroenterology 2002;123:835-844
73. Frazer DM, Inglis HR, Wilkins SJ, et al. Delayed hepcidin response explains the lag period in iron absorption following a stimulus to increase erythropoiesis. Gut 2004;53:1509-1515
74. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004;306:2090-2093
75. Fleming RE, Sly WS. Mechanisms of iron accumulation in hereditary hemochromatosis. Annu Rev Physiol 2002;64:663-680
76. Fleming RE, Ahmann JR, Migas MC, et al. Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis. Proc Natl Acad Sci USA 2002;99: 10653-10658
77. Nemeth E, Roetto A, Garozzo G, et al. Hepcidin is decreased in TFR2 hemochromatosis. Blood 2005;105: 1803-1806
78. Kawabata H, Fleming RE, Gui D, et al. Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood 2005;105:376-381
79. Bridle KR, Frazer DM, Wilkins SJ, et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet 2003;361:669-673
80. Ahmad KA, Ahmann JR, Migas MC, et al. Decreased liver hepcidin expression in the Hfe knockout mouse. Blood Cells Mol Dis 2002;29:361-366
81. Muckenthaler M, Roy CN, Custodio AO, et al. Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrdl expression in mouse hemochromatosis. Nat Genet 2003;34:102-107
82. Lee P, Peng H, Gelbart T, et al. The IL-6- and lipopolysaccharide-induced transcription of hepcidin in HFE-, transferrin receptor 2-, and beta 2-microglobulin-deficient hepatocytes. Proc Natl Acad Sci USA 2004;101:9263-9265
83. Makui H, Soares RJ, Jiang W, Constante M, Santo MM. Contribution of Hfe expression in macrophages to the regulation of hepatic hepcidin levels and iron loading. Blood 2005; (in press)
84. Parkkila S, Niemela O, Britton RS, et al. Molecular aspects of iron absorption and HFE expression. Gastroenterology 2001;121:1489-1496
85. Trinder D, Olynyk JK, Sly WS, Morgan EH. Iron uptake from plasma transferrin by the duodenum is impaired in the Hfe knockout mouse. Proc Natl Acad Sci USA 2002;99:5622-5626
86. Frazer DM, Anderson GJ. The orchestration of body iron intake: how and where do enterocytes receive their cues? Blood Cells Mol Dis 2003;30:288-297
87. Nicolas G, Viatte L, Lou DQ, et al. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat Genet 2003;34:97-101
88. Pietrangelo A. Non-HFE hemochromatosis. Hepatology 2004;39:21-29
89. Camaschella C, Roetto A, Cali A, et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 2000;25:14-15
90. De Domenico I, Ward DM, Nemeth E, et al. The molecular basis of ferroportin-linked hemochromatosis. Proc Natl Acad Sci USA 2005;102:8955-8960
91. Drakesmith H, Schimanski LM, Ormerod E, et al. Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Blood 2005;106:1092-1097
92. Gordeuk VR. African iron overload. Semin Hematol 2002;39:263-269
93. Gordeuk VR, Caleffi A, Corradini E, et al. Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene. Blood Cells Mol Dis 2003;31:299-304
94. Barton JC, Acton RT, Rivers CA, et al. Genotypic and phenotypic heterogeneity of African Americans with primary iron overload. Blood Cells Mol Dis 2003;31:310-319
95. Beutler E, Barton JC, Felitti VJ, et al. Ferroportin 1 (SCL40A1) variant associated with iron overload in African-Americans. Blood Cells Mol Dis 2003;31:305-309