Iron metabolism and disease

Cellular and Molecular Biology of Metals

Volumn , Issue , 2010, Pages 351-378

  Sebastiani, Giada ^a,b   Pantopoulos, Kostas ^c,d  

^a OSPEDALE DELL'ANGELO   (Italy)

^b VENETIAN INSTITUTE OF MOLECULAR MEDICINE   (Italy)

^c MCGILL UNIVERSITY   (Canada)

^d MCGILL UNIVERSITY   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 84939153603     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1201/9781420059984     Document Type: Chapter

References (243)

1. Aisen, P., Enns, C., and Wessling-Resnick, M., 2001. Chemistry and biology of eukaryotic iron metabolism. Int. J. Biochem. Cell Biol. 33, 940-959.
2. Papanikolaou, G. and Pantopoulos, K., 2005. Iron metabolism and toxicity. Toxicol. Appl. Pharmacol. 202, 199-211.
3. Hentze, M.W., Muckenthaler, M.U., and Andrews, N.C., 2004. Balancing acts; molecular control of mammalian iron metabolism. Cell 117, 285-297.
4. Andrews, N.C. and Schmidt, P.J., 2007. Iron homeostasis. Annu. Rev. Physiol. 69, 69-85.
5. De Domenico, I., McVey Ward, D., and Kaplan, J., 2008. Regulation of iron acquisition and storage: Consequences for iron-linked disorders. Nat. Rev. Mol. Cell Biol. 9, 72-81.
6. Shayeghi, M., Latunde-Dada, G.O., Oakhill, J.S., Laftah, A.H., Takeuchi, K., Halliday, N., Khan, Y., Warley, A., McCann, F.E., Hider, R.C., Frazer, D.M., Anderson, G.J., Vulpe, C.D., Simpson, R.J., and McKie, A.T., 2005. Identification of an intestinal heme transporter. Cell 122, 789-801.
7. Qiu, A., Jansen, M., Sakaris, A., Min, S.H., Chattopadhyay, S., Tsai, E., Sandoval, C., Zhao, R., Akabas, M.H., and Goldman, I.D., 2006. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127, 917-928.
8. Nemeth, E., Tuttle, M.S., Powelson, J., Vaughn, M.B., Donovan, A., Ward, D.M., Ganz, T., and Kaplan, J., 2004. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306, 2090-2093.
9. Nemeth, E. and Ganz, T., 2006. Regulation of iron metabolism by hepcidin. Annu. Rev. Nutr. 26, 323-342.
10. Pigeon, C., Ilyin, G., Courselaud, B., Leroyer, P., Turlin, B., Brissot, P., and Loreal, O., 2001. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J. Biol. Chem. 276, 7811-7819.
11. Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf, S., Pedersen, B.K., and Ganz, T., 2004. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Invest. 113, 1271-1276.
12. Nicolas, G., Chauvet, C., Viatte, L., Danan, J.L., Bigard, X., Devaux, I., Beaumont, C., Kahn, A., and Vaulont, S., 2002. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J. Clin. Invest. 110, 1037-1044.
13. Shah, Y.M., Matsubara, T., Ito, S., Yim, S.H., and Gonzalez, F.J., 2009. Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab. 9, 152-164.
14. Mastrogiannaki, M., Matak, P., Keith, B., Simon, M.C., Vaulont, S., and Peyssonnaux, C., 2009. HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J. Clin. Invest. 119, 1159-1166.
15. Wrighting, D.M. and Andrews, N.C., 2006. Interleukin-6 induces hepcidin expression through STAT3. Blood 108, 3204-3209.
16. Pietrangelo, A., Dierssen, U., Valli, L., Garuti, C., Rump, A., Corradini, E., Ernst, M., Klein, C., and Trautwein, C., 2007. STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology 132, 294-300.
17. Verga Falzacappa, M.V., Vujic Spasic, M., Kessler, R., Stolte, J., Hentze, M.W., and Muckenthaler, M.U., 2007. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood 109, 353-358.
18. Truksa, J., Peng, H., Lee, P., and Beutler, E., 2007. Different regulatory elements are required for response of hepcidin to interleukin-6 and bone morphogenetic proteins 4 and 9. Brit. J. Haematol. 139, 138-147.
19. Truksa, J., Lee, P., Peng, H., Flanagan, J., and Beutler, E., 2007. The distal location of the iron responsive region of the hepcidin promoter. Blood 110, 3436-3437.
20. Truksa, J., Lee, P., and Beutler, E., 2009. Two BMP responsive elements, STAT, and bZIP/HNF4/COUP motifs of the hepcidin promoter are critical for BMP, SMAD1, and HJV responsiveness. Blood 113, 688-695.
21. Wang, R.H., Li, C., Xu, X., Zheng, Y., Xiao, C., Zerfas, P., Cooperman, S., et al., 2005. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2, 399-409.
22. Babitt, J.L., Huang, F.W., Wrighting, D.M., Xia, Y., Sidis, Y., Samad, T.A., Campagna, J.A., et al., 2006. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat. Genet. 38, 531-539.
23. Truksa, J., Peng, H., Lee, P., and Beutler, E., 2006. 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 103, 10289-10293.
24. Babitt, J.L., Huang, F.W., Xia, Y., Sidis, Y., Andrews, N.C., and Lin, H.Y., 2007. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J. Clin. Invest. 117, 1933-1939.
25. Xia, Y., Babitt, J.L., Sidis, Y., Chung, R.T., and Lin, H.Y., 2008. Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin. Blood 111, 5195-5204.
26. Pantopoulos, K., 2008. Function of the hemochromatosis protein HFE: Lessons from animal models. World J. Gastroenterol. 14, 6893-6901.
27. Courselaud, B., Pigeon, C., Inoue, Y., Inoue, J., Gonzalez, F.J., Leroyer, P., Gilot, D., et al., 2002. 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. 277, 41163-41170.
28. Andrews, N.C., 1999. Disorders of iron metabolism. N. Engl. J. Med. 341, 1986-1995.
29. Clark, S.F., 2008. Iron deficiency anemia. Nutr. Clin. Pract. 23, 128-141.
30. Zimmermann, M.B. and Hurrell, R.F., 2007. Nutritional iron deficiency. Lancet 370, 511-520.
31. Weiss, G. and Goodnough, L.T., 2005. Anemia of chronic disease. N. Engl. J. Med. 352, 1011-1023.
32. Finberg, K.E., Heeney, M.M., Campagna, D.R., Aydinok, Y., Pearson, H.A., Hartman, K.R., Mayo, M.M., et al., 2008. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat. Genet. 40, 569-571.
33. Guillem, F., Lawson, S., Kannengiesser, C., Westerman, M., Beaumont, C., and Grandchamp, B., 2008. Two nonsense mutations in the TMPRSS6 gene in a patient with microcytic anemia and iron deficiency. Blood 112, 2089-2091.
34. Folgueras, A.R., Martin de Lara, F., Pendas, A.M., Garabaya, C., Rodriguez, F., Astudillo, A., Bernal, T., Cabanillas, R., Lopez-Otin, C., and Velasco, G., 2008. The membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis. Blood 112, 2539-2545.
35. Du, X., She, E., Gelbart, T., Truksa, J., Lee, P., Xia, Y., Khovananth, K., Mudd, S., Mann, N., Moresco, E.M., Beutler, E., and Beutler, B., 2008. The serine protease TMPRSS6 is required to sense iron defi-ciency. Science 320, 1088-1092.
36. Adams, P.C. and Barton, J.C., 2007. Haemochromatosis. Lancet 370, 1855-1860.
37. Ramm, G.A. and Ruddell, R.G., 2005. Hepatotoxicity of iron overload: Mechanisms of iron-induced hepatic fibrogenesis. Semin. Liver Dis. 25, 433-449.
38. Kowdley, K.V., 2004. Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology 127, S79-S86.
39. Pietrangelo, A., 2003. Iron-induced oxidant stress in alcoholic liver fibrogenesis. Alcohol 30, 121-129.
40. Sebastiani, G. and Walker, A.P., 2007. HFE gene in primary and secondary hepatic iron overload. World J. Gastroenterol. 13, 4673-4689.
41. Pietrangelo, A., 2004. Hereditary hemochromatosis-a new look at an old disease. N. Engl. J. Med. 350, 2383-2397.
42. Beutler, E., 2006. Hemochromatosis: Genetics and pathophysiology. Annu. Rev. Med. 57, 331-347.
43. Feder, J.N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy, D.A., Basava, A., Dormishian, F., et al., 1996. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat. Genet. 13, 399-408.
44. Simon, M., Bourel, M., Fauchet, R., and Genetet, B., 1976. Association of HLA-A3 and HLA-B14 antigens with idiopathic haemochromatosis. Gut 17, 332-334.
45. Jazwinska, E.C., Lee, S.C., Webb, S.I., Halliday, J.W., and Powell, L.W., 1993. Localization of the hemochromatosis gene close to D6S105. Am. J. Hum. Genet. 53, 347-352.
46. Lebrón, J.A., Bennet, M.J., Vaughn, D.E., Chirino, A.J., Snow, P.M., Mintier, G.A., Feder, J.N., and Bjorkman, P.J., 1998. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell 93, 111-123.
47. 2-microglobulin interaction and cell surface expression. J. Biol. Chem. 272, 14025-14028.
48. 2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proc. Natl. Acad. Sci. USA 94, 12384-12389.
49. de Almeida, S.F., Fleming, J.V., Azevedo, J.E., Carmo-Fonseca, M., and de Sousa, M., 2007. Stimulation of an unfolded protein response impairs MHC class I expression. J. Immunol. 178, 3612-3619.
50. Allen, K.J., Gurrin, L.C., Constantine, C.C., Osborne, N.J., Delatycki, M.B., Nicoll, A.J., McLaren, C.E., et al., 2008. Iron-overload-related disease in HFE hereditary hemochromatosis. N. Engl. J. Med. 358, 221-230.
51. Waalen, J. and Beutler, E., 2008. Iron-overload-related disease in HFE hereditary hemochromatosis. N. Engl. J. Med. 358, 2293-2294 (author reply 2294-2295).
52. Beutler, E., 2007. Iron storage disease: Facts, fiction and progress. Blood Cells Mol. Dis. 39, 140-147.
53. Zhou, X.Y., Tomatsu, S., Fleming, R.E., Parkkila, S., Waheed, A., Jiang, J., Fei, Y., et al., 1998. HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc. Natl. Acad. Sci. USA 95, 2492-2497.
54. Bahram, S., Gilfillan, S., Kühn, L.C., Moret, R., Schulze, J.B., Lebeau, A., and Schümann, K., 1999. Experimental hemochromatosis due to MHC class I HFE deficiency: Immune status and iron metabolism. Proc. Natl. Acad. Sci. USA 96, 13312-13317.
55. 2-microglobulin-deficient mice. Immunol. Lett. 39, 105-111.
56. 2 Knockout mice develop parenchymal iron overload: A putative role for class I genes of the major histocompatibility complex in iron metabolism. Proc. Natl. Acad. Sci. USA 93, 1529-1534.
57. Levy, J.E., Montross, L.K., Cohen, D.E., Fleming, M.D., and Andrews, N.C., 1999. The C282Y mutation causing hereditary hemochromatosis does not produce a null allele. Blood 94, 9-11.
58. Tomatsu, S., Orii, K.O., Fleming, R.E., Holden, C.C., Waheed, A., Britton, R.S., Gutierrez, M.A., et al., 2003. Contribution of the H63D mutation in HFE to murine hereditary hemochromatosis. Proc. Natl. Acad. Sci. USA 100, 15788-15793.
59. Fleming, R.E., Holden, C.C., Tomatsu, S., Waheed, A., Brunt, E.M., Britton, R.S., Bacon, B.R., Roopenian, D.C., and Sly, W.S., 2001. Mouse strain differences determine severity of iron accumulation in Hfe knockout model of hereditary hemochromatosis. Proc. Natl. Acad. Sci. USA 98, 2707-2711.
60. Levy, J.E., Montross, L.K., and Andrews, N.C., 2000. Genes that modify the hemochromatosis phenotype in mice. J. Clin. Invest. 105, 1209-1216.
61. Sproule, T.J., Jazwinska, E.C., Britton, R.S., Bacon, B.R., Fleming, R.E., Sly, W.S., and Roopenian, D.C., 2001. Naturally variant autosomal and sex-linked loci determine the severity of iron overload in beta 2-microglobulin-deficient mice. Proc. Natl. Acad. Sci. USA 98, 5170-5174.
62. Wang, F., Paradkar, P.N., Custodio, A.O., McVey Ward, D., Fleming, M.D., Campagna, D., Roberts, K.A., et al., 2007. Genetic variation in Mon1a affects protein trafficking and modifies macrophage iron loading in mice. Nat. Genet. 39, 1025-1032.
63. Pietrangelo, A., Montosi, G., Totaro, A., Garuti, C., Conte, D., Cassanelli, S., Fraquelli, M., Sardini, C., Vasta, F., and Gasparini, P., 1999. Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene. N. Engl. J. Med. 341, 725-732.
64. Pietrangelo, A., 2004. Non-HFE hemochromatosis. Hepatology 39, 21-29.
65. Wallace, D.F. and Subramaniam, V.N., 2007. Non-HFE haemochromatosis. World J. Gastroenterol. 13, 4690-4698.
66. Trinder, D. and Baker, E., 2003. Transferrin receptor 2: A new molecule in iron metabolism. Int. J. Biochem. Cell Biol. 35, 292-296.
67. Camaschella, C., Roetto, A., Cali, A., De Gobbi, M., Garozzo, G., Carella, M., Majorano, N., Totaro, A., and Gasparini, P., 2000. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat. Genet. 25, 14-15.
68. Fleming, R.E., Ahmann, J.R., Migas, M.C., Waheed, A., Koeffler, H.P., Kawabata, H., Britton, R.S., Bacon, B.R., and Sly, W.S., 2002. Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis. Proc. Natl. Acad. Sci. USA 99, 10653-10658.
69. Wallace, D.F., Summerville, L., and Subramaniam, V.N., 2007. Targeted disruption of the hepatic transferrin receptor 2 gene in mice leads to iron overload. Gastroenterology 132, 301-310.
70. Camaschella, C., Roetto, A., and De Gobbi, M., 2002. Juvenile hemochromatosis. Semin. Hematol. 39, 242-248.
71. Pietrangelo, A., 2006. Juvenile hemochromatosis. J. Hepatol. 45, 892-894.
72. Roetto, A., Totaro, A., Cazzola, M., Cicilano, M., Bosio, S., D’Ascola, G., Carella, M., et al., 1999. Juvenile hemochromatosis locus maps to chromosome 1q. Am. J. Hum. Genet. 64, 1388-1393.
73. Rivard, S.R., Lanzara, C., Grimard, D., Carella, M., Simard, H., Ficarella, R., Simard, R., et al., 2003. Juvenile hemochromatosis locus maps to chromosome 1q in a French Canadian population. Eur. J. Hum. Genet. 11, 585-589.
74. Papanikolaou, G., Politou, M., Roetto, A., Bosio, S., Sakelaropoulos, N., Camaschella, C., and Loukopoulos, D., 2001. Linkage to chromosome 1q in Greek families with juvenile hemochromatosis. Blood Cells Mol. Dis. 27, 744-749.
75. Papanikolaou, G., Papaioannou, M., Politou, M., Vavatsi, N., Kioumi, A., Tsiatsiou, P., Marinaki, P., Loukopoulos, D., and Christakis, J.I., 2002. Genetic heterogeneity underlies juvenile hemochro matosis phenotype: Analysis of three families of northern Greek origin. Blood Cells Mol. Dis. 29, 168-173.
76. Roetto, A., Papanikolaou, G., Politou, M., Alberti, F., Girelli, D., Christakis, J., Loukopoulos, D., and Camaschella, C., 2003. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat. Genet. 33, 21-22.
77. Nicolas, G., Bennoun, M., Devaux, I., Beaumont, C., Grandchamp, B., Kahn, A., and Vaulont, S., 2001. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc. Natl. Acad. Sci. USA 98, 8780-8785.
78. Lesbordes-Brion, J.C., Viatte, L., Bennoun, M., Lou, D.Q., Ramey, G., Houbron, C., Hamard, G., Kahn, A., and Vaulont, S., 2006. Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis. Blood 108, 1402-1405.
79. Papanikolaou, G., Samuels, M.E., Ludwig, E.H., MacDonald, M.L., Franchini, P.L., Dube, M.P., Andres, L., et al., 2004. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat. Genet. 36, 77-82.
80. Lanzara, C., Roetto, A., Daraio, F., Rivard, S., Ficarella, R., Simard, H., Cox, T., et al., 2004. The spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood 11, 4317-4321.
81. Monnier, P.P., Sierra, A., Macchi, P., Deitinghoff, L., Andersen, J.S., Mann, M., Flad, M., et al., 2002. RGM is a repulsive guidance molecule for retinal axons. Nature 419, 392-395.
82. Niederkofler, V., Salie, R., and Arber, S., 2005. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J. Clin. Invest. 115, 2180-2186.
83. Huang, F.W., Pinkus, J.L., Pinkus, G.S., Fleming, M.D., and Andrews, N.C., 2005. A mouse model of juvenile hemochromatosis. J. Clin. Invest. 115, 2187-2191.
84. Andriopoulos Jr, B., Corradini, E., Xia, Y., Faasse, S.A., Chen, S., Grgurevic, L., Knutson, M.D., et al., 2009. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat. Genet. 41, 482-487.
85. Meynard, D., Kautz, L., Darnaud, V., Canonne-Hergaux, F., Coppin, H., and Roth, M.P., 2009. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat. Genet. 41, 478-481.
86. Zhang, A.S., West, A.P., Jr., Wyman, A.E., Bjorkman, P.J., and Enns, C.A., 2005. Interaction of HJV with neogenin results in iron accumulation in HEK293 cells. J. Biol. Chem. 280, 33885-33894.
87. Kuninger, D., Kuns-Hashimoto, R., Kuzmickas, R., and Rotwein, P., 2006. Complex biosynthesis of the muscle-enriched iron regulator RGMc. J. Cell Sci. 119, 3273-3283.
88. Lin, L., Goldberg, Y.P., and Ganz, T., 2005. Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin. Blood 106, 2884-2889.
89. Silvestri, L., Pagani, A., and Camaschella, C., 2008. Furin-mediated release of soluble hemojuvelin: A new link between hypoxia and iron homeostasis. Blood 111, 924-931.
90. Lin, L., Nemeth, E., Goodnough, J.B., Thapa, D.R., Gabayan, V., and Ganz, T., 2008. Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site. Blood Cells Mol. Dis. 40, 122-131.
91. Silvestri, L., Pagani, A., Nai, A., De Domenico, I., Kaplan, J., and Camaschella, C., 2008. The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab. 8, 502-511.
92. Bridle, K.R., Frazer, D.M., Wilkins, S.J., Dixon, J.L., Purdie, D.M., Crawford, D. H., Subramaniam, V.N., Powell, L.W., Anderson, G.J., and Ram, G.A., 2003. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet 361, 669-673.
93. Gehrke, S.G., Kulaksiz, H., Herrmann, T., Riedel, H.D., Bents, K., Veltkamp, C., and Stremmel, W., 2003. Expression of hepcidin in hereditary hemochromatosis: Evidence for a regulation in response to serum transferrin saturation and non-transferrin-bound iron. Blood 102, 371-376.
94. Nemeth, E., Roetto, A., Garozzo, G., Ganz, T., and Camaschella, C., 2005. Hepcidin is decreased in TFR2 hemochromatosis. Blood 105, 1803-1806.
95. Piperno, A., Girelli, D., Nemeth, E., Trombini, P., Bozzini, C., Poggiali, E., Phung, Y., Ganz, T., and Camaschella, C., 2007. Blunted hepcidin response to oral iron challenge in HFE-related hemochromatosis. Blood 110, 4096-4100.
96. Ahmad, K.A., Ahmann, J.R., Migas, M.C., Waheed, A., Britton, R.S., Bacon, B.R., Sly, W.S., and Fleming, R.E., 2002. Decreased liver hepcidin expression in the Hfe knockout mouse. Blood Cells Mol. Dis. 29, 361-366.
97. Muckenthaler, M., Roy, C.N., Custodio, A.O., Minana, B., DeGraaf, J., Montross, L.K., Andrews, N.C., and Hentze, M.W., 2003. Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nat. Genet. 34, 102-107.
98. Constante, M., Jiang, W., Wang, D., Raymond, V.A., Bilodeau, M., and Santos, M.M., 2006. Distinct requirements for Hfe in basal and induced hepcidin levels in iron overload and inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 291, G229-G237.
99. Ludwiczek, S., Theurl, I., Bahram, S., Schumann, K., and Weiss, G., 2005. Regulatory networks for the control of body iron homeostasis and their dysregulation in HFE mediated hemochromatosis. J. Cell. Physiol. 204, 489-499.
100. Kawabata, H., Fleming, R.E., Gui, D., Moon, S.Y., Saitoh, T., O’Kelly, J., Umehara, Y., Wano, Y., Said, J.W., and Koeffler, H.P., 2005. Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood 105, 376-381.
101. Goswami, T. and Andrews, N.C., 2006. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J. Biol. Chem. 281, 28494-28498.
102. Feder, J.N., Penny, D.M., Irrinki, A., Lee, V.K., Lebron, J.A., Watson, N., Tsuchihashi, Z., Sigal, E., Bjorkman, P.J., and Schatzman, R.C., 1998. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc. Natl. Acad. Sci. USA 95, 1472-1477.
103. Johnson, M.B. and Enns, C.A., 2004. Diferric transferrin regulates transferrin receptor 2 protein stability. Blood 104, 4287-4293.
104. Robb, A. and Wessling-Resnick, M., 2004. Regulation of transferrin receptor 2 protein levels by transferrin. Blood 104, 4294-4299.
105. Vujic Spasic, M., Kiss, J., Herrmann, T., Galy, B., Martinache, S., Stolte, J., Grone, H.J., Stremmel, W., Hentze, M.W., and Muckenthaler, M.U., 2008. Hfe acts in hepatocytes to prevent hemochromatosis. Cell Metab. 7, 173-178.
106. Vujic Spasic, M., Kiss, J., Herrmann, T., Kessler, R., Stolte, J., Galy, B., Rathkolb, B., et al., 2007. Physiologic systemic iron metabolism in mice deficient for duodenal Hfe. Blood 109, 4511-4517.
107. Schmidt, P.J., Toran, P.T., Giannetti, A.M., Bjorkman, P.J., and Andrews, N.C., 2008. The transferrin receptor modulates hfe-dependent regulation of hepcidin expression. Cell Metab. 7, 205-214.
108. Gao, J., Chen, J., Kramer, M., Tsukamoto, H., Zhang, A.S., and Enns, C.A., 2009. Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab. 9, 217-227.
109. Pantopoulos, K., 2004. Iron metabolism and the IRE/IRP regulatory system: An update. Ann. N.Y. Acad. Sci. 1012, 1-13.
110. Pietrangelo, A., 2004. The ferroportin disease. Blood Cells Mol. Dis. 32, 131-138.
111. Njajou, O.T., Vaessen, N., Joosse, M., Berghuis, B., van Dongen, J.W., Breuning, M.H., Snijders, P.J., et al., 2001. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat. Genet. 28, 213-214.
112. Montosi, G., Donovan, A., Totaro, A., Garuti, C., Pignatti, E., Cassanelli, S., Trenor, C.C., Gasparini, P., Andrews, N.C., and Pietrangelo, A., 2001. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J. Clin. Invest. 108, 619-623.
113. De Domenico, I., Ward, D.M., Nemeth, E., Vaughn, M.B., Musci, G., Ganz, T., and Kaplan, J., 2005. The molecular basis of ferroportin-linked hemochromatosis. Proc. Natl. Acad. Sci. USA 102, 8955-8960.
114. Zohn, I.E., De Domenico, I., Pollock, A., Ward, D.M., Goodman, J.F., Liang, X., Sanchez, A.J., Niswander, L., and Kaplan, J., 2007. The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease. Blood 109, 4174-4180.
115. Hayashi, A., Wada, Y., Suzuki, T., and Shimizu, A., 1993. Studies on familial hypotransferrinemia: Unique clinical course and molecular pathology. Am. J. Hum. Genet. 53, 201-213.
116. Beutler, E., Gelbart, T., Lee, P., Trevino, R., Fernandez, M.A., and Fairbanks, V.F., 2000. Molecular characterization of a case of atransferrinemia. Blood 96, 4071-4074.
117. Trenor, C.C., Campagna, D.R., Sellers, V.M., Andrews, N.C., and Fleming, M.D., 2000. The molecular defect in hypotransferrinemic mice. Blood 96, 1113-1118.
118. Levy, J.E., Jin, O., Fujiwara, Y., Kuo, F., and Andrews, N.C., 1999. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat. Genet. 21, 396-399.
119. Yoshida, K., Furihata, K., Takeda, S., Nakamura, A., Yamamoto, K., Morita, H., Hiyamuta, S., Ikeda, S., Shimizu, N., and Yanagisawa, N., 1995. A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nat. Genet. 9, 267-272.
120. Nittis, T. and Gitlin, J.D., 2002. The copper-iron connection: Hereditary aceruloplasminemia. Semin. Hematol. 39, 282-289.
121. Jeong, S.Y. and David, S., 2003. Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J. Biol. Chem. 278, 27144-27148.
122. De Domenico, I., Ward, D.M., di Patti, M.C., Jeong, S.Y., David, S., Musci, G., and Kaplan, J., 2007. Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPIceruloplasmin. EMBO J. 26, 2823-2831.
123. Harris, Z.L., Durley, A.P., Man, T.K., and Gitlin, J.D., 1999. Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc. Natl. Acad. Sci. USA 96, 10812-10817.
124. Patel, B.N., Dunn, R.J., Jeong, S.Y., Zhu, Q., Julien, J.P., and David, S., 2002. Ceruloplasmin regulates iron levels in the CNS and prevents free radical injury. J. Neurosci. 22, 6578-6586.
125. Ryter, S.W., Alam, J., and Choi, A.M., 2006. Heme oxygenase-1/carbon monoxide: From basic science to therapeutic applications. Physiol. Rev. 86, 583-650.
126. Yachie, A., Niida, Y., Wada, T., Igarashi, N., Kaneda, H., Toma, T., Ohta, K., Kasahara, Y., and Koizumi, S., 1999. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J. Clin. Invest. 103, 129-135.
127. Poss, K.D. and Tonegawa, S., 1997. Heme oxygenase 1 is required for mammalian iron reutilization. Proc. Natl. Acad. Sci. USA 94, 10919-10924.
128. Kato, J., Fujikawa, K., Kanda, M., Fukuda, N., Sasaki, K., Takayama, T., Kobune, M., et al., 2001. A mutation, in the iron-responsive element of H ferritin mRNA, causing autosomal dominant iron overload. Am. J. Hum. Genet. 69, 191-197.
129. Zecca, L., Youdim, M.B., Riederer, P., Connor, J.R., and Crichton, R.R., 2004. Iron, brain ageing and neurodegenerative disorders. Nat. Rev. Neurosci. 5, 863-873.
130. Kaur, D., Yantiri, F., Rajagopalan, S., Kumar, J., Mo, J.Q., Boonplueang, R., Viswanath, V., et al., 2003. Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: A novel therapy for Parkinson’s disease. Neuron 37, 899-909.
131. Curtis, A.R., Fey, C., Morris, C.M., Bindoff, L.A., Ince, P.G., Chinnery, P.F., Coulthard, A., et al., 2001. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat. Genet. 28, 350-354.
132. Vidal, R., Miravalle, L., Gao, X., Barbeito, A.G., Baraibar, M.A., Hekmatyar, S.K., Widel, M., Bansal, N., Delisle, M.B., and Ghetti, B., 2008. Expression of a mutant form of the ferritin light chain gene induces neurodegeneration and iron overload in transgenic mice. J. Neurosci. 28, 60-67.
133. Zhou, B., Westaway, S.K., Levinson, B., Johnson, M.A., Gitschier, J., and Hayflick, S.J., 2001. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat. Genet. 28, 345-349.
134. Ponka, P., Schulman, H.M., and Cox, T.M., 1990. Iron Metabolism in Relation to Heme Synthesis, New York: McGraw-Hill.
135. Lill, R. and Muhlenhoff, U., 2008. Maturation of iron-sulfur proteins in eukaryotes: Mechanisms, connected processes, and diseases. Annu. Rev. Biochem. 77, 669-700.
136. Camaschella, C., 2008. Recent advances in the understanding of inherited sideroblastic anaemia. Brit. J. Haematol. 143, 27-38.
137. Brownlie, A., Donovan, A., Pratt, S.J., Paw, B.H., Oates, A.C., Brugnara, C., Witkowska, H.E., Sassa, S., and Zon, L.I., 1998. Positional cloning of the zebrafish sauternes gene: A model for congenital sideroblastic anaemia. Nat. Genet. 20, 244-250.
138. Campuzano, V., Montermini, L., Molto, M.D., Pianese, L., Cossee, M., Cavalcanti, F., Monros, E., et al., 1996. Friedreich’s ataxia: Autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271, 1423-1427.
139. Pandolfo, M., 1999. Friedreich’s ataxia: Clinical aspects and pathogenesis. Semin. Neurol. 19, 311-321.
140. Babcock, M., de Silva, D., Oaks, R., Davis-Kaplan, S., Jiralerspong, S., Montermini, L., Pandolfo, M., and Kaplan, J., 1997. Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science 276, 1709-1712.
141. Puccio, H., Simon, D., Cossee, M., Criqui-Filipe, P., Tiziano, F., Melki, J., Hindelang, C., Matyas, R., Rustin, P., and Koenig, M., 2001. Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Nat. Genet. 27, 181-186.
142. Whitnall, M., Rahmanto, Y.S., Sutak, R., Xu, X., Becker, E.M., Mikhael, M.R., Ponka, P., and Richardson, D.R., 2008. The MCK mouse heart model of Friedreich’s ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation. Proc. Natl. Acad. Sci. USA 105, 9757-9762.
143. Allikmets, R., Raskind, W.H., Hutchinson, A., Schueck, N.D., Dean, M., and Koeller, D.M., 1999. Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). Hum. Mol. Genet. 8, 743-749.
144. Kispal, G., Csere, P., Prohl, C., and Lill, R., 1999. The mitochondrial proteins Atm1p and Nfs1p are essential for biogenesis of cytosolic Fe/S proteins. EMBO J. 18, 3981-3989.
145. Csere, P., Lill, R., and Kispal, G., 1998. Identification of a human mitochondrial ABC transporter, the functional orthologue of yeast Atm1p. FEBS Lett. 441, 266-270.
146. Pondarre, C., Antiochos, B.B., Campagna, D.R., Clarke, S.L., Greer, E.L., Deck, K.M., McDonald, A., et al., 2006. The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron-sulfur cluster biogenesis. Hum. Mol. Genet. 15, 953-964.
147. Camaschella, C., Campanella, A., De Falco, L., Boschetto, L., Merlini, R., Silvestri, L., Levi, S., and Iolascon, A., 2007. The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload. Blood 110, 1353-1358.
148. Wingert, R.A., Galloway, J.L., Barut, B., Foott, H., Fraenkel, P., Axe, J.L., Weber, G.J., et al., 2005. Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis. Nature 436, 1035-1039.
149. Mochel, F., Knight, M.A., Tong, W.H., Hernandez, D., Ayyad, K., Taivassalo, T., Andersen, P.M., et al., 2008. Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance. Am. J. Hum. Genet. 82, 652-660.
150. Olsson, A., Lind, L., Thornell, L.E., and Holmberg, M., 2008. Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect. Hum. Mol. Genet. 17, 1666-1672.
151. Clarke, S.L., Vasanthakumar, A., Anderson, S.A., Pondarre, C., Koh, C.M., Deck, K.M., Pitula, J.S., Epstein, C.J., Fleming, M.D., and Eisenstein, R.S., 2006. Iron-responsive degradation of iron-regulatory protein 1 does not require the Fe-S cluster. EMBO J. 25, 544-553.
152. Wang, J., Fillebeen, C., Chen, G., Biederbick, A., Lill, R., and Pantopoulos, K., 2007. Iron-dependent degradation of apo-IRP1 by the ubiquitin-proteasome pathway. Mol. Cell. Biol. 27, 2423-2430.
153. Pippard, M.J., 1994. Secondary Iron Overload, London: W.B. Saunders Company Ltd.
154. Tanno, T., Bhanu, N.V., Oneal, P.A., Goh, S.H., Staker, P., Lee, Y.T., Moroney, J.W., et al., 2007. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat. Med. 13, 1096-1101.
155. Chaston, T.B. and Richardson, D.R., 2003. Iron chelators for the treatment of iron overload disease: Relationship between structure, redox activity, and toxicity. Am. J. Hematol. 73, 200-210.
156. Tam, T.F., Leung-Toung, R., Li, W., Wang, Y., Karimian, K., and Spino, M., 2003. Iron chelator research: Past, present, and future. Curr. Med. Chem. 10, 983-995.
157. Kontoghiorghes, G.J., Pattichis, K., Neocleous, K., and Kolnagou, A., 2004. The design and development of deferiprone (L1) and other iron chelators for clinical use: Targeting methods and application prospects. Curr. Med. Chem. 11, 2161-2183.
158. Liu, Z.D. and Hider, R.C., 2002. Design of clinically useful iron(III)-selective chelators. Med. Res. Rev. 22, 26-64.
159. Doulias, P.T., Christoforidis, S., Brunk, U.T., and Galaris, D., 2003. Endosomal and lysosomal effects of desferrioxamine: Protection of HeLa cells from hydrogen peroxide-induced DNA damage and induction of cell-cycle arrest. Free Radic. Biol. Med. 35, 719-728.
160. Kattamis, A., 2005. Combined therapy with deferoxamine and deferiprone. Ann. NY Acad. Sci. 1054, 175-182.
161. Cappellini, M.D., 2008. Long-term efficacy and safety of deferasirox. Blood Rev. 22(Suppl. 2), S35-S41.
162. Adams, P., Brissot, P., and Powell, L.W., 2000. EASL international consensus conference on haemochromatosis. J. Hepatol. 33, 485-504.
163. Alla, V. and Bonkovsky, H.L., 2005. Iron in nonhemochromatotic liver disorders. Semin. Liver Dis. 25, 461-472.
164. Alberti, A., Chemello, L., and Benvegnu, L., 1999. Natural history of hepatitis C. J. Hepatol. 31(Suppl 1), 17-24.
165. Seeff, L.B., 2002. Natural history of chronic hepatitis C. Hepatology 36, S35-S46.
166. Di Bisceglie, A.M., Axiotis, C.A., Hoofnagle, J.H., and Bacon, B.R., 1992. Measurements of iron status in patients with chronic hepatitis. Gastroenterology 102, 2108-2113.
167. Arber, N., Konikoff, F.M., Moshkowitz, M., Baratz, M., Hallak, A., Santo, M., Halpern, Z., Weiss, H., and Gilat, T., 1994. Increased serum iron and iron saturation without liver iron accumulation distinguish chronic hepatitis C from other chronic liver diseases. Dig. Dis. Sci. 39, 2656-2659.
168. Bonkovsky, H.L., Banner, B.F., and Rothman, A.L., 1997. Iron and chronic viral hepatitis. Hepatology 25, 759-768.
169. Sebastiani, G., Vario, A., Ferrari, A., Pistis, R., Noventa, F., and Alberti, A., 2006. Hepatic iron, liver steatosis and viral genotypes in patients with chronic hepatitis C. J. Viral Hepatitis 13, 199-205.
170. Piperno, A., Vergani, A., Malosio, I., Parma, L., Fossati, L., Ricci, A., Bovo, G., Boari, G., and Mancia, G., 1998. Hepatic iron overload in patients with chronic viral hepatitis: Role of HFE gene mutations. Hepatology 28, 1105-1109.
171. Van Thiel, D.H., Friedlander, L., Fagiuoli, S., Wright, H.I., Irish, W., and Gavaler, J.S., 1994. Response to interferon alpha therapy is influenced by the iron content of the liver. J. Hepatol. 20, 410-415.
172. Sherrington, C.A. and Olynyk, J.K., 2002. Iron as a cofactor in chronic hepatitis C infection. Liver 22, 187-189.
173. Corengia, C., Galimberti, S., Bovo, G., Vergani, A., Arosio, C., Mariani, R., Redaelli, A., et al., 2005. Iron accumulation in chronic hepatitis C: Relation of hepatic iron distribution, HFE genotype, and disease course. Am. J. Clin. Pathol. 124, 846-853.
174. Negro, F., Samii, K., Rubbia-Brandt, L., Quadri, R., Male, P.J., Zarski, J.P., Baud, M., Giostra, E., Beris, P., and Hadengue, A., 2000. Hemochromatosis gene mutations in chronic hepatitis C patients with and without liver siderosis. J. Med. Virol. 60, 21-27.
175. Pirisi, M., Scott, C.A., Avellini, C., Toniutto, P., Fabris, C., Soardo, G., Beltrami, C.A., and Bartoli, E., 2000. Iron deposition and progression of disease in chronic hepatitis C. Role of interface hepatitis, portal inflammation, and HFE missense mutations. Am. J. Clin. Pathol. 113, 546-554.
176. Kaji, K., Nakanuma, Y., Sasaki, M., Unoura, M., Kobayashi, K., and Nonomura, A., 1995. Hemosiderin deposition in portal endothelial cells: A novel hepatic hemosiderosis frequent in chronic viral hepatitis B and C. Hum. Pathol. 26, 1080-1085.
177. Boucher, E., Bourienne, A., Adams, P., Turlin, B., Brissot, P., and Deugnier, Y., 1997. Liver iron concentration and distribution in chronic hepatitis C before and after interferon treatment. Gut 41, 115-120.
178. Brunt, E.M., Olynyk, J.K., Britton, R.S., Janney, C.G., Di Bisceglie, A.M., and Bacon, B.R., 2000. Histological evaluation of iron in liver biopsies: Relationship to HFE mutations. Am. J. Gastroenterol. 95, 1788-1793.
179. Distante, S., Bjoro, K., Hellum, K.B., Myrvang, B., Berg, J.P., Skaug, K., Raknerud, N., and Bell, H., 2002. Raised serum ferritin predicts non-response to interferon and ribavirin treatment in patients with chronic hepatitis C infection. Liver 22, 269-275.
180. Thorburn, D., Curry, G., Spooner, R., Spence, E., Oien, K., Halls, D., Fox, R., McCruden, E.A., MacSween, R.N., and Mills, P.R., 2002. The role of iron and haemochromatosis gene mutations in the progression of liver disease in chronic hepatitis C. Gut 50, 248-252.
181. Hourigan, L.F., Macdonald, G.A., Purdie, D., Whitehall, V.H., Shorthouse, C., Clouston, A., and Powell, E.E., 1999. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology 29, 1215-1219.
182. Hwang, S.J., Luo, J.C., Chu, C.W., Lai, C.R., Lu, C.L., Tsay, S. H., Wu, J.C., Chang, F.Y., and Lee, S.D., 2001. Hepatic steatosis in chronic hepatitis C virus infection: Prevalence and clinical correlation. J. Gastroenterol. Hepatol. 16, 190-195.
183. Fargion, S., Mattioli, M., Fracanzani, A.L., Sampietro, M., Tavazzi, D., Fociani, P., Taioli, E., Valenti, L., and Fiorelli, G., 2001. Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis. Am. J. Gastroenterol. 96, 2448-2455.
184. Bugianesi, E., Manzini, P., D’Antico, S., Vanni, E., Longo, F., Leone, N., Massarenti, P., Piga, A., Marchesini, G., and Rizzetto, M., 2004. Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology 39, 179-187.
185. Lecube, A., Hernandez, C., Genesca, J., Esteban, J.I., Jardi, R., Garcia, L., and Simo, R., 2004. Diabetes is the main factor accounting for the high ferritin levels detected in chronic hepatitis C virus infection. Diabetes Care 27, 2669-2675.
186. Sebastiani, G., Vario, A., and Alberti, A., 2005. Diabetes is the main factor accounting for the high ferritin levels detected in chronic hepatitis C virus infection: Response to Lecube et al. Diabetes Care 28, 1838 (author reply 1838-1839).
187. Bonkovsky, H.L., Naishadham, D., Lambrecht, R.W., Chung, R.T., Hoefs, J.C., Nash, S.R., Rogers, T.E., et al., 2006. Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C. Gastroenterology 131, 1440-1451.
188. Fargion, S., Fracanzani, A.L., Rossini, A., Borzio, M., Riggio, O., Belloni, G., Bissoli, F., et al., 2002. Iron reduction and sustained response to interferon-alpha therapy in patients with chronic hepatitis C: Results of an Italian multicenter randomized study. Am. J. Gastroenterol. 97, 1204-1210.
189. Fillebeen, C., Rivas-Estilla, A.M., Bisaillon, M., Ponka, P., Muckenthaler, M., Hentze, M.W., Koromilas, A.E., and Pantopoulos, K., 2005. Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus. J. Biol. Chem. 280, 9049-9057.
190. Fillebeen, C., Muckenthaler, M., Andriopoulos, B., Bisaillon, M., Mounir, Z., Hentze, M.W., Koromilas, A.E., and Pantopoulos, K., 2007. Expression of the subgenomic hepatitis C virus replicon alters iron homeostasis in Huh7 cells. J. Hepatol. 47, 12-22.
191. Fujita, N., Sugimoto, R., Motonishi, S., Tomosugi, N., Tanaka, H., Takeo, M., Iwasa, M., et al., 2008. Patients with chronic hepatitis C achieving a sustained virological response to peginterferon and ribavirin therapy recover from impaired hepcidin secretion. J. Hepatol. 49, 702-710.
192. Nishina, S., Hino, K., Korenaga, M., Vecchi, C., Pietrangelo, A., Mizukami, Y., Furutani, T., et al., 2008. Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology 134, 226-238.
193. Miura, K., Taura, K., Kodama, Y., Schnabl, B., and Brenner, D.A., 2008. Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity. Hepatology 48, 1420-1429.
194. Bonkovsky, H.L., Lambrecht, R.W., and Shan, Y., 2003. Iron as a co-morbid factor in nonhemochromatotic liver disease. Alcohol 30, 137-144.
195. Day, C.P. and Bassendine, M.F., 1992. Genetic predisposition to alcoholic liver disease. Gut 33, 1444-1447.
196. Ludwig, J., Hashimoto, E., Porayko, M.K., Moyer, T.P., and Baldus, W.P., 1997. Hemosiderosis in cirrhosis: A study of 447 native livers. Gastroenterology 112, 882-888.
197. Milman, N., Ovesen, L., Byg, K., and Graudal, N., 1999. Iron status in Danes updated 1994. I: Prevalence of iron deficiency and iron overload in 1332 men aged 40-70 years. Influence of blood donation, alcohol intake, and iron supplementation. Ann. Hematol. 78, 393-400.
198. Ioannou, G.N., Dominitz, J.A., Weiss, N.S., Heagerty, P.J., and Kowdley, K.V., 2004. The effect of alcohol consumption on the prevalence of iron overload, iron deficiency, and iron deficiency anemia. Gastroenterology 126, 1293-1301.
199. Grove, J., Daly, A.K., Burt, A.D., Guzail, M., James, O.F., Bassendine, M.F., and Day, C.P., 1998. Heterozygotes for HFE mutations have no increased risk of advanced alcoholic liver disease. Gut 43, 262-266.
200. Gleeson, D., Evans, S., Bradley, M., Jones, J., Peck, R.J., Dube, A., Rigby, E., and Dalton, A., 2006. HFE genotypes in decompensated alcoholic liver disease: Phenotypic expression and comparison with heavy drinking and with normal controls. Am. J. Gastroenterol. 101, 304-310.
201. Fargion, S., Fracanzani, A.L., Piperno, A., Braga, M., D’Alba, R., Ronchi, G., and Fiorelli, G., 1994. Prognostic factors for hepatocellular carcinoma in genetic hemochromatosis. Hepatology 20, 1426-1431.
202. Adams, P.C. and Agnew, S., 1996. Alcoholism in hereditary hemochromatosis revisited: Prevalence and clinical consequences among homozygous siblings. Hepatology 23, 724-727.
203. Raynard, B., Balian, A., Fallik, D., Capron, F., Bedossa, P., Chaput, J.C., and Naveau, S., 2002. Risk factors of fibrosis in alcohol-induced liver disease. Hepatology 35, 635-638.
204. Grove, J., Daly, A.K., Bassendine, M.F., and Day, C.P., 1997. Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis. Hepatology 26, 143-146.
205. Grove, J., Brown, A.S., Daly, A.K., Bassendine, M.F., James, O.F., and Day, C. P., 1998. The RsaI polymorphism of CYP2E1 and susceptibility to alcoholic liver disease in Caucasians: Effect on age of presentation and dependence on alcohol dehydrogenase genotype. Pharmacogenetics 8, 335-342.
206. Lauret, E., Rodriguez, M., Gonzalez, S., Linares, A., Lopez-Vazquez, A., Martinez-Borra, J., Rodrigo, L., and Lopez-Larrea, C., 2002. HFE gene mutations in alcoholic and virus-related cirrhotic patients with hepatocellular carcinoma. Am. J. Gastroenterol. 97, 1016-1021.
207. Nahon, P., Sutton, A., Rufat, P., Ziol, M., Thabut, G., Schischmanoff, P.O., Vidaud, D., et al., 2008. Liver iron, HFE gene mutations, and hepatocellular carcinoma occurrence in patients with cirrhosis. Gastroenterology 134, 102-110.
208. Pascoe, A., Kerlin, P., Steadman, C., Clouston, A., Jones, D., Powell, L., Jazwinska, E., Lynch, S., and Strong, R., 1999. Spur cell anaemia and hepatic iron stores in patients with alcoholic liver disease undergoing orthotopic liver transplantation. Gut 45, 301-305.
209. Suzuki, Y., Saito, H., Suzuki, M., Hosoki, Y., Sakurai, S., Fujimoto, Y., and Kohgo, Y., 2002. Up-regulation of transferrin receptor expression in hepatocytes by habitual alcohol drinking is implicated in hepatic iron overload in alcoholic liver disease. Alcohol. Clin. Exp. Res. 26, 26S-31S.
210. Harrison-Findik, D.D., Schafer, D., Klein, E., Timchenko, N.A., Kulaksiz, H., Clemens, D., Fein, E., Andriopoulos, B., Pantopoulos, K., and Gollan, J., 2006. Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. J. Biol. Chem. 281, 22974-22982.
211. Harrison-Findik, D.D., Klein, E., Crist, C., Evans, J., Timchenko, N., and Gollan, J., 2007. Iron-mediated regulation of liver hepcidin expression in rats and mice is abolished by alcohol. Hepatology 46, 1979-1985.
212. Clark, J.M. and Diehl, A.M., 2003. Nonalcoholic fatty liver disease: An underrecognized cause of cryptogenic cirrhosis. JAMA 289, 3000-3004.
213. Matteoni, C.A., Younossi, Z.M., Gramlich, T., Boparai, N., Liu, Y.C., and McCullough, A.J., 1999. Nonalcoholic fatty liver disease: A spectrum of clinical and pathological severity. Gastroenterology 116, 1413-1419.
214. Day, C.P. and James, O.F., 1998. Steatohepatitis: A tale of two “hits”? Gastroenterology 114, 842-845.
215. Tsukamoto, H., Horne, W., Kamimura, S., Niemela, O., Parkkila, S., Yla-Herttuala, S., and Brittenham, G.M., 1995. Experimental liver cirrhosis induced by alcohol and iron. J. Clin. Invest. 96, 620-630.
216. Duvnjak, M., Lerotic, I., Barsic, N., Tomasic, V., Virovic Jukic, L., and Velagic, V., 2007. Pathogenesis and management issues for non-alcoholic fatty liver disease. World J. Gastroenterol. 13, 4539-4550.
217. Bacon, B.R., Farahvash, M.J., Janney, C.G., and Neuschwander-Tetri, B.A., 1994. Nonalcoholic steatohepatitis: An expanded clinical entity. Gastroenterology 107, 1103-1109.
218. George, D.K., Goldwurm, S., MacDonald, G.A., Cowley, L.L., Walker, N.I., Ward, P.J., Jazwinska, E.C., and Powell, L.W., 1998. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 114, 311-318.
219. Angulo, P., Keach, J.C., Batts, K.P., and Lindor, K.D., 1999. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 30, 1356-1362.
220. Younossi, Z.M., Gramlich, T., Bacon, B.R., Matteoni, C.A., Boparai, N., O’Neill, R., and McCullough, A.J., 1999. Hepatic iron and nonalcoholic fatty liver disease. Hepatology 30, 847-850.
221. Facchini, F.S., Hua, N.W., and Stoohs, R.A., 2002. Effect of iron depletion in carbohydrate-intolerant patients with clinical evidence of nonalcoholic fatty liver disease. Gastroenterology 122, 931-939.
222. Valenti, L., Fracanzani, A.L., Dongiovanni, P., Bugianesi, E., Marchesini, G., Manzini, P., Vanni, E., and Fargion, S., 2007. Iron depletion by phlebotomy improves insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia: Evidence from a case-control study. Am. J. Gastroenterol. 102, 1251-1258.
223. Sorrentino, P., D’Angelo, S., Ferbo, U., Micheli, P., Bracigliano, A., and Vecchione, R., 2009. Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis. J. Hepatol. 50, 351-357.
224. Bonkovsky, H.L., Jawaid, Q., Tortorelli, K., LeClair, P., Cobb, J., Lambrecht, R. W., and Banner, B.F., 1999. Non-alcoholic steatohepatitis and iron: Increased prevalence of mutations of the HFE gene in nonalcoholic steatohepatitis. J. Hepatol. 31, 421-429.
225. Chitturi, S., Weltman, M., Farrell, G.C., McDonald, D., Kench, J., Liddle, C., Samarasinghe, D., Lin, R., Abeygunasekera, S., and George, J., 2002. HFE mutations, hepatic iron, and fibrosis: Ethnic-specific association of NASH with C282Y but not with fibrotic severity. Hepatology 36, 142-149.
226. Harrison, P.M. and Arosio, P., 1996. The ferritins: Molecular properties, iron storage function and cellular regulation. Biochim. Biophys. Acta 1275, 161-203.
227. Torti, F.M. and Torti, S.V., 2002. Regulation of ferritin genes and protein. Blood 99, 3505-3516.
228. Beaumont, C., Leneuve, P., Devaux, I., Scoazec, J.-Y., Berthier, M., Loiseau, M.-N., Grandchamp, B., and Bonneau, D., 1995. Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinaemia and cataract. Nat. Genet. 11, 444-446.
229. Roetto, A., Bosio, S., Gramaglia, E., Barilaro, M.R., Zecchina, G., and Camaschella, C., 2002. Pathogenesis of hyperferritinemia cataract syndrome. Blood Cells Mol. Dis. 29, 532-535.
230. Allerson, C.R., Cazzola, M., and Rouault, T.A., 1999. Clinical severity and thermodynamic effects of iron-responsive element mutations in hereditary hyperferritinemia-cataract syndrome. J. Biol. Chem. 274, 26439-26447.
231. Levi, S., Girelli, D., Perrone, F., Pasti, M., Beaumont, C., Corrocher, R., Albertini, A., and Arosio, P., 1998. Analysis of ferritins in lymphoblastoid cell lines and in the lens of subjects with hereditary hyperferritinemia-cataract syndrome. Blood 91, 4180-4187.
232. Guyader, D., Jacquelinet, C., Moirand, R., Turlin, B., Mendler, M.H., Chaperon, J., David, V., Brissot, P., Adams, P., and Deugnier, Y., 1998. Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis. Gastroenterology 115, 929-936.
233. Sebastiani, G. and Alberti, A., 2006. Non invasive fibrosis biomarkers reduce but not substitute the need for liver biopsy. World J. Gastroenterol. 12, 3682-3694.
234. Sandrin, L., Fourquet, B., Hasquenoph, J.M., Yon, S., Fournier, C., Mal, F., Christidis, C., et al., 2003. Transient elastography: A new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med. Biol. 29, 1705-1713.
235. Castera, L., Vergniol, J., Foucher, J., Le Bail, B., Chanteloup, E., Haaser, M., Darriet, M., Couzigou, P., and De Ledinghen, V., 2005. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 128, 343-350.
236. Ziol, M., Handra-Luca, A., Kettaneh, A., Christidis, C., Mal, F., Kazemi, F., de Ledinghen, V., et al., 2005. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology 41, 48-54.
237. Adhoute, X., Foucher, J., Laharie, D., Terrebonne, E., Vergniol, J., Castera, L., Lovato, B., et al., 2008. Diagnosis of liver fibrosis using FibroScan and other noninvasive methods in patients with hemochromatosis: A prospective study. Gastroenterol. Clin. Biol. 32, 180-187.
238. Smith, B.C., Gorve, J., Guzail, M.A., Day, C.P., Daly, A.K., Burt, A.D., and Bassendine, M.F., 1998. Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C. Hepatology 27, 1695-1699.
239. Martinelli, A.L., Franco, R.F., Villanova, M.G., Figueiredo, J.F., Secaf, M., Tavella, M.H., Ramalho, L.N., Zucoloto, S., and Zago, M.A., 2000. Are haemochromatosis mutations related to the severity of liver disease in hepatitis C virus infection? Acta Haematol. 102, 152-156.
240. Bonkovsky, H.L., Troy, N., McNeal, K., Banner, B.F., Sharma, A., Obando, J., Mehta, S., Koff, R.S., Liu, Q., and Hsieh, C.C., 2002. Iron and HFE or TfR1 mutations as comorbid factors for development and progression of chronic hepatitis C. J. Hepatol. 37, 848-854.
241. Tung, B.Y., Emond, M.J., Bronner, M.P., Raaka, S.D., Cotler, S.J., and Kowdley, K.V., 2003. Hepatitis C, iron status, and disease severity: Relationship with HFE mutations. Gastroenterology 124, 318-326.
242. Erhardt, A., Maschner-Olberg, A., Mellenthin, C., Kappert, G., Adams, O., Donner, A., Willers, R., Niederau, C., and Haussinger, D., 2003. HFE mutations and chronic hepatitis C: H63D and C282Y heterozygosity are independent risk factors for liver fibrosis and cirrhosis. J. Hepatol. 38, 335-342.
243. Kazemi-Shirazi, L., Datz, C., Maier-Dobersberger, T., Kaserer, K., Hackl, F., Polli, C., Steindl, P.E., Penner, E., and Ferenci, P., 1999. The relation of iron status and hemochromatosis gene mutations in patients with chronic hepatitis C. Gastroenterology 116, 127-134.