Journal of Hepatology
Volume 48 , Pages S113-S123 , 2008

Iron and the liver: Update 2008

  • Yves Deugnier

      Affiliations

    • Service des maladies du Foie, INSERM CIC 0203, Université de Rennes 1 and IFR 140, CHU Pontchaillou, 35033 Rennes, France
    • Corresponding Author InformationCorresponding author.
    • ,
  • Pierre Brissot

      Affiliations

    • Service des maladies du Foie, INSERM U 522, Université de Rennes 1 and IFR 140, CHU Pontchaillou, 35033 Rennes, France
    • ,
  • Olivier Loréal

      Affiliations

    • INSERM U 522, Université de Rennes 1 and IFR 140, CHU Pontchaillou, 35033 Rennes, France

References 

  1. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996;13:399–408
  2. Krause A, Neitz S, Magert HJ, Schulz A, Forssmann WG, Schulz-Knappe P, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 2000;480:147–150
  3. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276:7806–7810
  4. Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, 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
  5. Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood. 2003;101:2461–2463
  6. Ganz T. Molecular control of iron transport. J Am Soc Nephrol. 2007;18:394–400
  7. Loreal O, Haziza-Pigeon C, Troadec MB, Detivaud L, Turlin B, Courselaud B, et al. Hepcidin in iron metabolism. Curr Protein Pept Sci. 2005;6:279–291
  8. Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A, 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
  9. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090–2093
  10. Bekri S, Gual P, Anty R, Luciani N, Dahman M, Ramesh B, et al. Increased adipose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH. Gastroenterology. 2006;131:788–796
  11. Peyssonnaux C, Zinkernagel AS, Datta V, Lauth X, Johnson RS, Nizet V. TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens. Blood. 2006;107:3727–3732
  12. Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002;110:1037–1044
  13. Anderson GJ, Darshan D, Wilkins SJ, Frazer DM. Regulation of systemic iron homeostasis: how the body responds to changes in iron demand. Biometals. 2007;20:665–674
  14. Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38:531–539
  15. Wang RH, Li C, Xu X, Zheng Y, Xiao C, Zerfas P, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2005;2:399–409
  16. Truksa J, Peng H, Lee P, Beutler E. Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6. Proc Natl Acad Sci USA. 2006;103:10289–10293
  17. Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dube MP, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile haemochromatosis. Nat Genet. 2004;36:77–82
  18. Goswami T, Andrews NC. Hereditary haemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem. 2006;281:28494–28498
  19. Calzolari A, Raggi C, Deaglio S, Sposi NM, Stafsnes M, Fecchi K, et al. TfR2 localizes in lipid raft domains and is released in exosomes to activate signal transduction along the MAPK pathway. J Cell Sci. 2006;119:4486–4498
  20. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J. 2003;374:1–20
  21. Verga Falzacappa MV, Vujic Spasic M, Kessler R, Stolte J, Hentze MW, Muckenthaler MU. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood. 2007;109:353–358
  22. Courselaud B, Pigeon C, Inoue Y, Inoue J, Gonzalez FJ, Leroyer P, et al. C/EBPalpha regulates hepatic transcription of hepcidin, an antimicrobial peptide and regulator of iron metabolism. Cross-talk between C/EBP pathway and iron metabolism. J Biol Chem. 2002;277:41163–41170
  23. Lin L, Valore EV, Nemeth E, Goodnough JB, Gabayan V, Ganz T. Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4. Blood. 2007;110:2182–2189
  24. Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P, Lee YT, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007;13:1096–1101
  25. Pietrangelo A. Haemochromatosis: an endocrine liver disease. Hepatology. 2007;46:1291–1301
  26. Camaschella C, Roetto A, Cali A, De Gobbi M, Garozzo G, Carella M, et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet. 2000;25:14–15
  27. Pietrangelo A. Non-HFE haemochromatosis. Hepatology. 2004;39:21–29
  28. Kono S, Suzuki H, Takahashi K, Takahashi Y, Shirakawa K, Murakawa Y, et al. Hepatic iron overload associated with a decreased serum ceruloplasmin level in a novel clinical type of aceruloplasminemia. Gastroenterology. 2006;131:240–245
  29. Miyajima H, Takahashi Y, Kono S. Aceruloplasminemia, an inherited disorder of iron metabolism. Biometals. 2003;16:205–213
  30. Beutler E, Gelbart T, Lee P, Trevino R, Fernandez MA, Fairbanks VF. Molecular characterization of a case of atransferrinemia. Blood. 2000;96:4071–4074
  31. Beaumont C, Delaunay J, Hetet G, Grandchamp B, de Montalembert M, Tchernia G. Two new human DMT1 gene mutations in a patient with microcytic anemia, low ferritinemia, and liver iron overload. Blood. 2006;107:4168–4170
  32. Iolascon A, d’Apolito M, Servedio V, Cimmino F, Piga A, Camaschella C. Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2). Blood. 2006;107:349–354
  33. Mims MP, Guan Y, Pospisilova D, Priwitzerova M, Indrak K, Ponka P, et al. Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload. Blood. 2005;105:1337–1342
  34. Deugnier Y, Loreal O, Carre F, Duvallet A, Zoulim F, Vinel JP, et al. Increased body iron stores in elite road cyclists. Med Sci Sports Exerc. 2002;34:876–880
  35. Nemeth E, Ganz T. Hepcidin and iron-loading anemias. Haematologica. 2006;91:727–732
  36. Deugnier Y, Turlin B, le Quilleuc D, Moirand R, Loreal O, Messner M, et al. A reappraisal of hepatic siderosis in patients with end-stage cirrhosis: practical implications for the diagnosis of haemochromatosis. Am J Surg Pathol. 1997;21:669–675
  37. Ludwig J, Hashimoto E, Porayko MK, Moyer TP, Baldus WP. Hemosiderosis in cirrhosis: a study of 447 native livers. Gastroenterology. 1997;112:882–888
  38. Detivaud L, Nemeth E, Boudjema K, Turlin B, Troadec MB, Leroyer P, et al. Hepcidin levels in humans are correlated with hepatic iron stores, hemoglobin levels, and hepatic function. Blood. 2005;106:746–748
  39. Gandon Y, Olivie D, Guyader D, Aube C, Oberti F, Sebille V, et al. Non-invasive assessment of hepatic iron stores by MRI. Lancet. 2004;363:357–362
  40. Pietrangelo A. Haemochromatosis gene modifies course of hepatitis C viral infection. Gastroenterology. 2003;124:1509–1523
  41. Harrison-Findik DD. Role of alcohol in the regulation of iron metabolism. World J Gastroenterol. 2007;13:4925–4930
  42. Mendler MH, Turlin B, Moirand R, Jouanolle AM, Sapey T, Guyader D, et al. Insulin resistance-associated hepatic iron overload. Gastroenterology. 1999;117:1155–1163
  43. Moirand R, Mortaji AM, Loreal O, Paillard F, Brissot P, Deugnier Y. A new syndrome of liver iron overload with normal transferrin saturation. Lancet. 1997;349:95–97
  44. Laine F, Deugnier Y. Increased expression of hepcidin in obese patients: impact on phenotypic expression of haemochromatosis and pathophysiology of dysmetabolic iron overload syndrome. Gastroenterology. 2006;131:2028
  45. Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, et al. Haemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med. 2005;352:1769–1778
  46. Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845G–> A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet. 2002;359:211–218
  47. Deugnier Y, Jouanolle AM, Chaperon J, Moirand R, Pithois C, Meyer JF, et al. Gender-specific phenotypic expression and screening strategies in C282Y-linked haemochromatosis: a study of 9396 French people. Br J Haematol. 2002;118:1170–1178
  48. Olynyk JK, Cullen DJ, Aquilia S, Rossi E, Summerville L, Powell LW. A population-based study of the clinical expression of the haemochromatosis gene. N Engl J Med. 1999;341:718–724
  49. Beutler E. Iron storage disease: facts, fiction and progress. Blood Cells Mol Dis. 2007;39:140–147
  50. Pietrangelo A. The penetrance of haemochromatosis: mice to the rescue. Gastroenterology. 2007;132:805–808
  51. van der AD, Peeters PH, Grobbee DE, Roest M, Voorbij HA, van der Schouw YT. HFE genotypes and dietary heme iron: no evidence of strong gene-nutrient interaction on serum ferritin concentrations in middle-aged women. Nutr Metab Cardiovasc Dis. 2006;16:60–68
  52. Cade JE, Moreton JA, O’Hara B, Greenwood DC, Moor J, Burley VJ, et al. Diet and genetic factors associated with iron status in middle-aged women. Am J Clin Nutr. 2005;82:813–820
  53. Kaltwasser JP, Werner E, Schalk K, Hansen C, Gottschalk R, Seidl C. Clinical trial on the effect of regular tea drinking on iron accumulation in genetic haemochromatosis. Gut. 1998;43:699–704
  54. Bridle K, Cheung TK, Murphy T, Walters M, Anderson G, Crawford DG, et al. Hepcidin is down-regulated in alcoholic liver injury: implications for the pathogenesis of alcoholic liver disease. Alcohol Clin Exp Res. 2006;30:106–112
  55. Harrison-Findik DD, Klein E, Crist C, Evans J, Timchenko N, Gollan J. Iron-mediated regulation of liver hepcidin expression in rats and mice is abolished by alcohol. Hepatology. 2007;46:1879–1885
  56. Harrison-Findik DD, Schafer D, Klein E, Timchenko NA, Kulaksiz H, Clemens D, et al. Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. J Biol Chem. 2006;281:22974–22982
  57. Barton JC, Preston BL, McDonnell SM, Rothenberg BE. Severity of iron overload in haemochromatosis: effect of volunteer blood donation before diagnosis. Transfusion. 2001;41:123–129
  58. Laine F, Jouannolle AM, Morcet J, Brigand A, Pouchard M, Lafraise B, et al. Phenotypic expression in detected C282Y homozygous women depends on body mass index. J Hepatol. 2005;43:1055–1059
  59. Beutler E, Waalen J, Gelbart T. Chronic inflammation does not appear to modify the homozygous hereditary haemochromatosis phenotype. Blood Cells Mol Dis. 2005;35:326–327
  60. Hutchinson C, Geissler CA, Powell JJ, Bomford A. Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary haemochromatosis. Gut. 2007;56:1291–1295
  61. Ludwiczek S, Theurl I, Muckenthaler MU, Jakab M, Mair SM, Theurl M, et al. Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1. Nat Med. 2007;13:448–454
  62. Beutler E, Gelbart T. Helicobacter pylori infection and HFE haemochromatosis. Blood Cells Mol Dis. 2006;37:188–191
  63. Moirand R, Adams PC, Bicheler V, Brissot P, Deugnier Y. Clinical features of genetic haemochromatosis in women compared with men. Ann Intern Med. 1997;127:105–110
  64. Jacolot S, Le Gac G, Scotet V, Quere I, Mura C, Ferec C. HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype. Blood. 2004;103:2835–2840
  65. Merryweather-Clarke AT, Cadet E, Bomford A, Capron D, Viprakasit V, Miller A, et al. Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis. Hum Mol Genet. 2003;12:2241–2247
  66. Le Gac G, Scotet V, Ka C, Gourlaouen I, Bryckaert L, Jacolot S, et al. The recently identified type 2A juvenile haemochromatosis gene (HJV), a second candidate modifier of the C282Y homozygous phenotype. Hum Mol Genet. 2004;13:1913–1918
  67. Milet J, Dehais V, Bourgain C, Jouanolle AM, Mosser A, Perrin M, et al. Common variants in the BMP2, BMP4, and HJV genes of the hepcidin regulation pathway modulate HFE haemochromatosis penetrance. Am J Hum Genet. 2007;81:799–807
  68. Fletcher LM, Bridle KR, Crawford DH. Effect of alcohol on iron storage diseases of the liver. Best Pract Res Clin Gastroenterol. 2003;17:663–677
  69. Loréal O, Deugnier Y, Moirand R, Lauvin L, Guyader D, Jouanolle H, et al. Liver fibrosis in genetic haemochromatosis. Respective roles of iron and non-iron-related factors in 127 homozygous patients. J Hepatol. 1992;16:122–127
  70. Powell EE, Ali A, Clouston AD, Dixon JL, Lincoln DJ, Purdie DM, et al. Steatosis is a cofactor in liver injury in haemochromatosis. Gastroenterology. 2005;129:1937–1943
  71. Valenti L, Conte D, Piperno A, Dongiovanni P, Fracanzani AL, Fraquelli M, et al. The mitochondrial superoxide dismutase A16V polymorphism in the cardiomyopathy associated with hereditary haemochromatosis. J Med Genet. 2004;41:946–950
  72. Osterreicher CH, Datz C, Stickel F, Hellerbrand C, Penz M, Hofer H, et al. TGF-beta1 codon 25 gene polymorphism is associated with cirrhosis in patients with hereditary haemochromatosis. Cytokine. 2005;31:142–148
  73. Distante S, Berg JP, Lande K, Haug E, Bell H. HFE gene mutation (C282Y) and phenotypic expression among a hospitalised population in a high prevalence area of haemochromatosis. Gut. 2000;47:575–579
  74. Walsh A, Dixon JL, Ramm GA, Hewett DG, Lincoln DJ, Anderson GJ, et al. The clinical relevance of compound heterozygosity for the C282Y and H63D substitutions in haemochromatosis. Clin Gastroenterol Hepatol. 2006;4:1403–1410
  75. Pietrangelo A, Corradini E, Ferrara F, Vegetti A, De Jong G, Luca Abbati G, et al. Magnetic resonance imaging to identify classic and nonclassic forms of ferroportin disease. Blood Cells Mol Dis. 2006;37:192–196
  76. Deugnier Y, Turlin B. Pathology of hepatic iron overload. World J Gastroenterol. 2007;13:4755–4760
  77. Pietrangelo A. The ferroportin disease. Blood Cells Mol Dis. 2004;32:131–138
  78. Guyader D, Jacquelinet C, Moirand R, Turlin B, Mendler MH, Chaperon J, et al. Noninvasive prediction of fibrosis in C282Y homozygous haemochromatosis. Gastroenterology. 1998;115:929–936
  79. Falize L, Guillygomarc’h A, Perrin M, Laine F, Guyader D, Brissot P, et al. Reversibility of hepatic fibrosis in treated genetic haemochromatosis: a study of 36 cases. Hepatology. 2006;44:472–477
  80. Laine F, Bendavid C, Moirand R, Tessier S, Perrin M, Guillygomarc’h A, et al. Prediction of liver fibrosis in patients with features of the metabolic syndrome regardless of alcohol consumption. Hepatology. 2004;39:1639–1646
  81. Loréal O, Turlin B, Pigeon C, Moisan A, Ropert M, Morice P, et al. Aceruloplasminemia: new clinical, pathophysiological and therapeutic insights. J Hepatol. 2000;36:851–856
  82. Miyajima H, Takahashi Y, Kamata T, Shimizu H, Sakai N, Gitlin JD. Use of desferrioxamine in the treatment of aceruloplasminemia. Ann Neurol. 1997;41:404–407
  83. Cappellini MD, Cohen A, Piga A, Bejaoui M, Perrotta S, Agaoglu L, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood. 2006;107:3455–3462
  84. Brissot P, de Bels F. Current approaches to the management of haemochromatosis. Hematology. 2006;36–41

☆ The authors declare that they do not have anything to disclose regarding industry funding or conflict of interest with respect to this manuscript.

PII: S0168-8278(08)00061-5

doi: 10.1016/j.jhep.2008.01.014

Journal of Hepatology
Volume 48 , Pages S113-S123 , 2008

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