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Published in: International Journal of Hematology 1/2008

Open Access 01-07-2008 | Progress in Hematology

Body iron metabolism and pathophysiology of iron overload

Authors: Yutaka Kohgo, Katsuya Ikuta, Takaaki Ohtake, Yoshihiro Torimoto, Junji Kato

Published in: International Journal of Hematology | Issue 1/2008

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Abstract

Iron is an essential metal for the body, while excess iron accumulation causes organ dysfunction through the production of reactive oxygen species. There is a sophisticated balance of body iron metabolism of storage and transport, which is regulated by several factors including the newly identified peptide hepcidin. As there is no passive excretory mechanism of iron, iron is easily accumulated when exogenous iron is loaded by hereditary factors, repeated transfusions, and other diseased conditions. The free irons, non-transferrin-bound iron, and labile plasma iron in the circulation, and the labile iron pool within the cells, are responsible for iron toxicity. The characteristic features of advanced iron overload are failure of vital organs such as liver and heart in addition to endocrine dysfunctions. For the estimation of body iron, there are direct and indirect methods available. Serum ferritin is the most convenient and widely available modality, even though its specificity is sometimes problematic. Recently, new physical detection methods using magnetic resonance imaging and superconducting quantum interference devices have become available to estimate iron concentration in liver and myocardium. The widely used application of iron chelators with high compliance will resolve the problems of organ dysfunction by excess iron and improve patient outcomes.
Literature
2.
go back to reference McKie AT, Latunde-Dada GO, Miret S, et al. Molecular evidence for the role of a ferric reductase in iron transport. Biochem Soc Trans. 2002;30:722–4.CrossRefPubMed McKie AT, Latunde-Dada GO, Miret S, et al. Molecular evidence for the role of a ferric reductase in iron transport. Biochem Soc Trans. 2002;30:722–4.CrossRefPubMed
4.
go back to reference Sargent PJ, Farnaud S, Evans RW. Structure/function overview of proteins involved in iron storage and transport. Curr Med Chem. 2005;12:2683–93.CrossRefPubMed Sargent PJ, Farnaud S, Evans RW. Structure/function overview of proteins involved in iron storage and transport. Curr Med Chem. 2005;12:2683–93.CrossRefPubMed
5.
go back to reference Cabantchik ZI, Breuer W, Zanninelli G, Cianciulli P. LPI-labile plasma iron in iron overload. Best Pract Res Clin Haematol. 2005;18:277–87.CrossRefPubMed Cabantchik ZI, Breuer W, Zanninelli G, Cianciulli P. LPI-labile plasma iron in iron overload. Best Pract Res Clin Haematol. 2005;18:277–87.CrossRefPubMed
6.
go back to reference Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood. 1997;89:739–61.PubMed Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood. 1997;89:739–61.PubMed
7.
go back to reference Angelucci E, Brittenham GM, McLaren CE, et al. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med. 2000;343:327–31.CrossRefPubMed Angelucci E, Brittenham GM, McLaren CE, et al. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med. 2000;343:327–31.CrossRefPubMed
8.
go back to reference Ikuta K, Zak O, Aisen P. Recycling, degradation and sensitivity to the synergistic anion of transferrin in the receptor-independent route of iron uptake by human hepatoma (HuH–7) cells. Int J Biochem Cell Biol. 2004;36:340–52.CrossRefPubMed Ikuta K, Zak O, Aisen P. Recycling, degradation and sensitivity to the synergistic anion of transferrin in the receptor-independent route of iron uptake by human hepatoma (HuH–7) cells. Int J Biochem Cell Biol. 2004;36:340–52.CrossRefPubMed
9.
go back to reference Liuzzi JP, Aydemir F, Nam H, Knutson MD, Cousins RJ. Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells. Proc Natl Acad Sci USA. 2006;103:13612–7.CrossRefPubMedPubMedCentral Liuzzi JP, Aydemir F, Nam H, Knutson MD, Cousins RJ. Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells. Proc Natl Acad Sci USA. 2006;103:13612–7.CrossRefPubMedPubMedCentral
10.
go back to reference Schranzhofer M, Schifrer M, Cabrera JA, et al. Remodeling the regulation of iron metabolism during erythroid differentiation to ensure efficient heme biosynthesis. Blood. 2006;107:4159–67.CrossRefPubMed Schranzhofer M, Schifrer M, Cabrera JA, et al. Remodeling the regulation of iron metabolism during erythroid differentiation to ensure efficient heme biosynthesis. Blood. 2006;107:4159–67.CrossRefPubMed
11.
12.
go back to reference Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276:7806–10.CrossRefPubMed Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276:7806–10.CrossRefPubMed
13.
go back to reference Inamura J, Ikuta K, Jimbo J, et al. Upregulation of hepcidin by interleukin-1beta in human hepatoma cell lines. Hepatol Res. 2005;33:198–205.CrossRefPubMed Inamura J, Ikuta K, Jimbo J, et al. Upregulation of hepcidin by interleukin-1beta in human hepatoma cell lines. Hepatol Res. 2005;33:198–205.CrossRefPubMed
15.
go back to reference 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;361:669–73.CrossRefPubMed 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;361:669–73.CrossRefPubMed
16.
17.
go back to reference Gardenghi S, Marongiu MF, Ramos P, et al. Ineffective erythropoiesis in β-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin. Blood. 2007;109:5027–35.CrossRefPubMedPubMedCentral Gardenghi S, Marongiu MF, Ramos P, et al. Ineffective erythropoiesis in β-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin. Blood. 2007;109:5027–35.CrossRefPubMedPubMedCentral
18.
go back to reference Cazzola M, Huebers HA, Sayers MH, MacPhail AP, Eng M, Finch CA. Transferrin saturation, plasma iron turnover, and transferrin uptake in normal humans. Blood. 1985;66:935–9.PubMed Cazzola M, Huebers HA, Sayers MH, MacPhail AP, Eng M, Finch CA. Transferrin saturation, plasma iron turnover, and transferrin uptake in normal humans. Blood. 1985;66:935–9.PubMed
19.
go back to reference Breuer W, Hershko C, Cabantchik ZI. The importance of non-transferrin bound iron in disorders of iron metabolism. Transfus Sci. 2000;23:185–92.CrossRefPubMed Breuer W, Hershko C, Cabantchik ZI. The importance of non-transferrin bound iron in disorders of iron metabolism. Transfus Sci. 2000;23:185–92.CrossRefPubMed
20.
go back to reference Koorts AM, Viljoen M. Ferritin and ferritin isoforms I: structure-function relationships, synthesis, degradation and secretion. Arch Physiol Biochem. 2007;113:30–54.CrossRefPubMed Koorts AM, Viljoen M. Ferritin and ferritin isoforms I: structure-function relationships, synthesis, degradation and secretion. Arch Physiol Biochem. 2007;113:30–54.CrossRefPubMed
21.
go back to reference Harrison PM, Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta. 1996;1275:161–203.CrossRefPubMed Harrison PM, Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta. 1996;1275:161–203.CrossRefPubMed
23.
go back to reference Jacobs A, Miller F, Worwood M, Beamish MR, Wardrop CA. Ferritin in the serum of normal subjects and patients with iron deficiency and iron overload. Br Med J. 1972;4:206–8.CrossRefPubMedPubMedCentral Jacobs A, Miller F, Worwood M, Beamish MR, Wardrop CA. Ferritin in the serum of normal subjects and patients with iron deficiency and iron overload. Br Med J. 1972;4:206–8.CrossRefPubMedPubMedCentral
24.
go back to reference Piperno A. Classification and diagnosis of iron overload. Haematologica. 1998;83:447–55.PubMed Piperno A. Classification and diagnosis of iron overload. Haematologica. 1998;83:447–55.PubMed
25.
go back to reference Saito H, Hayashi D, Ohya T, Ohya F, Yamada H. Clinical evaluation on serum ferritin (author’s transl). Rinsho Ketsueki. 1979;20:1317–25.PubMed Saito H, Hayashi D, Ohya T, Ohya F, Yamada H. Clinical evaluation on serum ferritin (author’s transl). Rinsho Ketsueki. 1979;20:1317–25.PubMed
26.
go back to reference Galanello R, Piga A, Forni GL, et al. Phase II clinical evaluation of deferasirox, a once-daily oral chelating agent, in paediatric patients with β-thalassaemia major. Haematologica. 2006;91:1343–51.PubMed Galanello R, Piga A, Forni GL, et al. Phase II clinical evaluation of deferasirox, a once-daily oral chelating agent, in paediatric patients with β-thalassaemia major. Haematologica. 2006;91:1343–51.PubMed
27.
go back to reference Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood. 2006;107:3455–62.CrossRefPubMed Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood. 2006;107:3455–62.CrossRefPubMed
28.
go back to reference Jensen PD, Jensen FT, Christensen T, Eiskjaer H, Baandrup U, Nielsen JL. Evaluation of myocardial iron by magnetic resonance imaging during iron chelation therapy with deferrioxamine: indication of close relation between myocardial iron content and chelatable iron pool. Blood. 2003;101:4632–9.CrossRefPubMed Jensen PD, Jensen FT, Christensen T, Eiskjaer H, Baandrup U, Nielsen JL. Evaluation of myocardial iron by magnetic resonance imaging during iron chelation therapy with deferrioxamine: indication of close relation between myocardial iron content and chelatable iron pool. Blood. 2003;101:4632–9.CrossRefPubMed
29.
go back to reference Takatoku M, Uchiyama T, Okamoto S, et al. Retrospective nationwide survey of Japanese patients with transfusion-dependent MDS and aplastic anemia highlights the negative impact of iron overload on morbidity/mortality. Eur J Haematol. 2007;78:487–94.CrossRefPubMed Takatoku M, Uchiyama T, Okamoto S, et al. Retrospective nationwide survey of Japanese patients with transfusion-dependent MDS and aplastic anemia highlights the negative impact of iron overload on morbidity/mortality. Eur J Haematol. 2007;78:487–94.CrossRefPubMed
30.
go back to reference Gattermann N. Guidelines on iron chelation therapy in patients with myelodysplastic syndromes and transfusional iron overload. Leuk Res. 2007;31(Suppl 3):S10–5.CrossRefPubMed Gattermann N. Guidelines on iron chelation therapy in patients with myelodysplastic syndromes and transfusional iron overload. Leuk Res. 2007;31(Suppl 3):S10–5.CrossRefPubMed
31.
go back to reference Olivieri NF, Brittenham GM, Matsui D, et al. Iron-chelation therapy with oral deferiprone in patients with thalassemia major. N Engl J Med. 1995;332:918–22.CrossRefPubMed Olivieri NF, Brittenham GM, Matsui D, et al. Iron-chelation therapy with oral deferiprone in patients with thalassemia major. N Engl J Med. 1995;332:918–22.CrossRefPubMed
32.
go back to reference Long JA Jr, Doppman JL, Nienhus AW, Mills SR. Computed tomographic analysis of beta-thalassemic syndromes with hemochromatosis: pathologic findings with clinical and laboratory correlations. J Comput Assist Tomogr. 1980;4:159–65.CrossRef Long JA Jr, Doppman JL, Nienhus AW, Mills SR. Computed tomographic analysis of beta-thalassemic syndromes with hemochromatosis: pathologic findings with clinical and laboratory correlations. J Comput Assist Tomogr. 1980;4:159–65.CrossRef
33.
go back to reference Brittenham GM, Farrell DE, Harris JW, et al. Magnetic-susceptibility measurement of human iron stores. N Engl J Med. 1982;307:1671–5.CrossRefPubMed Brittenham GM, Farrell DE, Harris JW, et al. Magnetic-susceptibility measurement of human iron stores. N Engl J Med. 1982;307:1671–5.CrossRefPubMed
34.
go back to reference Anderson LJ, Westwood MA, Holden S, et al. Myocardial iron clearance during reversal of siderotic cardiomyopathy with intravenous desferrioxamine: a prospective study using T2* cardiovascular magnetic resonance. Br J Haematol. 2004;127:348–55.CrossRefPubMed Anderson LJ, Westwood MA, Holden S, et al. Myocardial iron clearance during reversal of siderotic cardiomyopathy with intravenous desferrioxamine: a prospective study using T2* cardiovascular magnetic resonance. Br J Haematol. 2004;127:348–55.CrossRefPubMed
35.
go back to reference Crichton RR, Wilmet S, Legssyer R, Ward RJ. Molecular and cellular mechanisms of iron homeostasis and toxicity in mammalian cells. J Inorg Biochem. 2002;91:9–18.CrossRefPubMed Crichton RR, Wilmet S, Legssyer R, Ward RJ. Molecular and cellular mechanisms of iron homeostasis and toxicity in mammalian cells. J Inorg Biochem. 2002;91:9–18.CrossRefPubMed
36.
go back to reference Yen AW, Fancher TL, Bowlus CL. Revisiting hereditary hemochromatosis: current concepts and progress. Am J Med. 2006;119:391–9.CrossRefPubMed Yen AW, Fancher TL, Bowlus CL. Revisiting hereditary hemochromatosis: current concepts and progress. Am J Med. 2006;119:391–9.CrossRefPubMed
37.
go back to reference Pietrangelo A. Hereditary hemochromatosis—a new look at an old disease. N Engl J Med. 2004;350:2383–97.CrossRefPubMed Pietrangelo A. Hereditary hemochromatosis—a new look at an old disease. N Engl J Med. 2004;350:2383–97.CrossRefPubMed
38.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
39.
go back to reference Franchini M. Hereditary iron overload: update on pathophysiology, diagnosis, and treatment. Am J Hematol. 2006;81:202–9.CrossRefPubMed Franchini M. Hereditary iron overload: update on pathophysiology, diagnosis, and treatment. Am J Hematol. 2006;81:202–9.CrossRefPubMed
40.
go back to reference Bonkovsky HL, Lambrecht RW, Shan Y. Iron as a co-morbid factor in nonhemochromatotic liver disease. Alcohol. 2003;30:137–44.CrossRefPubMed Bonkovsky HL, Lambrecht RW, Shan Y. Iron as a co-morbid factor in nonhemochromatotic liver disease. Alcohol. 2003;30:137–44.CrossRefPubMed
41.
go back to reference Zurlo MG, De Stefano P, Borgna-Pignatti C, et al. Survival and causes of death in thalassaemia major. Lancet. 1989;2:27–30.CrossRefPubMed Zurlo MG, De Stefano P, Borgna-Pignatti C, et al. Survival and causes of death in thalassaemia major. Lancet. 1989;2:27–30.CrossRefPubMed
42.
go back to reference McGowan JH, Cleland JG. Reliability of reporting left ventricular systolic function by echocardiography: a systematic review of 3 methods. Am Heart J. 2003;146:388–97.CrossRefPubMed McGowan JH, Cleland JG. Reliability of reporting left ventricular systolic function by echocardiography: a systematic review of 3 methods. Am Heart J. 2003;146:388–97.CrossRefPubMed
43.
go back to reference Anderson LJ, Holden S, Davis B, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J. 2001;22:2171–9.CrossRefPubMed Anderson LJ, Holden S, Davis B, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J. 2001;22:2171–9.CrossRefPubMed
44.
go back to reference Telfer PT, Prestcott E, Holden S, Walker M, Hoffbrand AV, Wonke B. Hepatic iron concentration combined with long-term monitoring of serum ferritin to predict complications of iron overload in thalassaemia major. Br J Haematol. 2000;110:971–7.CrossRefPubMed Telfer PT, Prestcott E, Holden S, Walker M, Hoffbrand AV, Wonke B. Hepatic iron concentration combined with long-term monitoring of serum ferritin to predict complications of iron overload in thalassaemia major. Br J Haematol. 2000;110:971–7.CrossRefPubMed
46.
go back to reference Fung EB, Harmatz PR, Lee PD, et al. Increased prevalence of iron-overload associated endocrinopathy in thalassaemia versus sickle-cell disease. Br J Haematol. 2006;135:574–82.CrossRefPubMed Fung EB, Harmatz PR, Lee PD, et al. Increased prevalence of iron-overload associated endocrinopathy in thalassaemia versus sickle-cell disease. Br J Haematol. 2006;135:574–82.CrossRefPubMed
Metadata
Title
Body iron metabolism and pathophysiology of iron overload
Authors
Yutaka Kohgo
Katsuya Ikuta
Takaaki Ohtake
Yoshihiro Torimoto
Junji Kato
Publication date
01-07-2008
Publisher
Springer Japan
Published in
International Journal of Hematology / Issue 1/2008
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-008-0120-5

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