Pathophysiology of Hereditary Hemochromatosis

ABSTRACT

Hereditary hemochromatosis (HH) encompasses several inherited disorders of iron homeostasis characterized by increased gastrointestinal iron absorption and tissue iron deposition. The most common form of this disorder is HFE-related HH, nearly always caused by homozygosity for the C282Y mutation. A substantial proportion of C282Y homozygotes do not develop clinically significant iron overload, suggesting roles for environmental factors and modifier genes in determining the phenotype. Recent studies have demonstrated that the pathogenesis of nearly all forms of HH involves inappropriately decreased expression of the iron-regulatory hormone hepcidin. Hepcidin serves to decrease the export of iron from reticuloendothelial cells and absorptive enterocytes. Thus, HH patients demonstrate increased iron release from these cell types, elevated circulating iron, and iron deposition in vulnerable tissues. The mechanism by which HFE influences hepcidin expression is an area of current investigation and may offer insights into the phenotypic variability observed in persons with mutations in HFE.

Hemochromatosis - iron - HFE - hepcidin - ferroportin

REFERENCES

• 1 Pietrangelo A. Hereditary hemochromatosis-a new look at an old disease.  N Engl J Med. 2004;  350 2383-2397
• 2 Feder J N, 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 X Y, Tomatsu S, Fleming R E 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 L C 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 J E, Montross L K, Cohen D E et al.. The C282Y mutation causing hereditary hemochromatosis does not produce a null allele.  Blood. 1999;  94 9-11
• 7 Feder J N, 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 X Y 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 A K, 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 M W, Rademakers L H 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 J H, Zhou X Y 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 A S, Fleming W H 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 A M, Bjorkman P J. 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 A S, 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 J M, Jones M, O'Callaghan C A 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 R S 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 L W, Subramaniam V N, Yapp T R. Haemochromatosis in the new millennium.  J Hepatol. 2000;  32 48-62
• 20 Rochette J, Pointon J J, Fisher C A et al.. Multicentric origin of hemochromatosis gene (HFE) mutations.  Am J Hum Genet. 1999;  64 1056-1062
• 21 Beckman L E, 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 V J, Koziol J A et al.. Penetrance of 845G→ A (C282Y) HFE hereditary haemochromatosis mutation in the USA.  Lancet. 2002;  359 211-218
• 23 Adams P C, Reboussin D M, Barton J C et al.. Hemochromatosis and iron-overload screening in a racially diverse population.  N Engl J Med. 2005;  352 1769-1778
• 24 Olynyk J K, Cullen D J, 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 M J, George P M, Upton J D et al.. The significance of haemochromatosis gene mutations in the general population: implications for screening.  Gut. 1998;  43 830-836
• 26 McDonnell S M, 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 K K, Cogswell M E, Chang J C et al.. Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States.  JAMA. 2001;  285 2216-2222
• 28 Gochee P A, Powell L W, Cullen D J et al.. A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation.  Gastroenterology. 2002;  122 646-651
• 29 Bacon B R. 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 J J, Wallace D, Merryweather-Clarke A T et al.. Uncommon mutations and polymorphisms in the hemochromatosis gene.  Genet Test. 2000;  4 151-161
• 32 Britton R S, Fleming R E, Parkkila S et al.. Pathogenesis of hereditary hemochromatosis: genetics and beyond.  Semin Gastrointest Dis. 2002;  13 68-79
• 33 Andrews N C. Disorders of iron metabolism.  N Engl J Med. 1999;  341 1986-1995
• 34 McKie A T, Barrow D, Latunde-Dada G O et al.. An iron-regulated ferric reductase associated with the absorption of dietary iron.  Science. 2001;  291 1755-1759
• 35 Fleming M D, Trenor III C C, Su M A 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 U V 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 A T, 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 D J. A novel mammalian iron-regulated protein involved in intracellular iron metabolism.  J Biol Chem. 2000;  275 19906-19912
• 40 Vulpe C D, Kuo Y M, Murphy T L 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 G D, Nathanson M H, 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 R O, 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 H L, Kohlroser J G et al.. Intestinal expression of genes involved in iron absorption in humans.  Am J Physiol Gastrointest Liver Physiol. 2002;  282 G598-G607
• 45 Fleming R E, Migas M C, 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 R E, Migas M C, Holden C C 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 H L. Iron and the liver.  Am J Med Sci. 1991;  301 32-43
• 50 Brissot P, Wright T L, Ma W L 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 R G, 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 A C, Olynyk J K, Leedman P J 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 G D. Reticuloendothelial iron stores and hereditary hemochromatosis: a paradox [editorial].  J Lab Clin Med. 1989;  113 137-138
• 55 Moura E, Noordermeer M A, 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 M E, Ludwig E H 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 P L, Beutler E, Rao S V 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 E V, 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 E H, 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 J I et al.. Hepcidin in iron overload disorders.  Blood. 2005;  105 4103-4105
• 72 Frazer D M, Wilkins S J, Becker E M 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 D M, Inglis H R, Wilkins S J 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 M S, Powelson J et al.. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.  Science. 2004;  306 2090-2093
• 75 Fleming R E, Sly W S. Mechanisms of iron accumulation in hereditary hemochromatosis.  Annu Rev Physiol. 2002;  64 663-680
• 76 Fleming R E, Ahmann J R, Migas M C 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 R E, 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 K R, Frazer D M, Wilkins S J 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 K A, Ahmann J R, Migas M C et al.. Decreased liver hepcidin expression in the Hfe knockout mouse.  Blood Cells Mol Dis. 2002;  29 361-366
• 81 Muckenthaler M, Roy C N, Custodio A O et al.. Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 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 R J, Jiang W, Constante M, Santo M M. 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 R S et al.. Molecular aspects of iron absorption and HFE expression.  Gastroenterology. 2001;  121 1489-1496
• 85 Trinder D, Olynyk J K, Sly W S, Morgan E H. 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 D M, Anderson G J. 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 D Q 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 D M, Nemeth E et al.. The molecular basis of ferroportin-linked hemochromatosis.  Proc Natl Acad Sci USA. 2005;  102 8955-8960
• 91 Drakesmith H, Schimanski L M, Ormerod E et al.. Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin.  Blood. 2005;  106 1092-1097
• 92 Gordeuk V R. African iron overload.  Semin Hematol. 2002;  39 263-269
• 93 Gordeuk V R, 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 J C, Acton R T, Rivers C A 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 J C, Felitti V J et al.. Ferroportin 1 (SCL40A1) variant associated with iron overload in African-Americans.  Blood Cells Mol Dis. 2003;  31 305-309