E.A. Lukina, A.V. Dezhenkova
Hematology Research Center under the Ministry of Health of the Russian Federation, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167
For correspondence: Elena Alekseevna Lukina, DSci, Professor, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-09-23; e-mail: elenalukina02@gmail.com
For citation: Lukina EA, Dezhenkova AV. Iron Metabolism in Normal and Pathological Conditions. Clinical oncohematology. 2015;8(4):355–361 (In Russ).
DOI: 10.21320/2500-2139-2015-8-4-362-367
ABSTRACT
This review describes modern conceptions of the physiological and pathological roles of iron, as well as the main mechanisms of iron metabolism regulation. In recent years, it has been shown that both deficiency and excess of iron can have damaging effects on the body, and the existence of homeostatic mechanisms controlling the total iron content of the body has been proved. The body of an average healthy adult human contains 3 to 5 g iron, most of which is contained in blood cells, bone marrow and liver; it is bound to proteins and this is important for prevention of cytotoxic effects of free iron ions. This review summarizes data on the main proteins involved in iron metabolism and their role in iron homeostasis. The processes of iron recirculation and the functional role of hepcidin, the key protein regulating extracellular iron concentration, are emphasized. The review provides brief data on pathogenic mechanisms of functional iron deficiency development and its role in anemia of chronic disease, as well as the pathogenesis, diagnostics and management of secondary iron overload.
Keywords: iron metabolism, ferritin, hepcidin, iron recirculation, anemia of chronic disease, iron overload.
Received: July 1, 2015
Accepted: November 9, 2015
REFERENCES
- Петров В.Н. Физиология и патология обмена железа. Львов: Наука, 1982. 224 c.
[Petrov VN. Fiziologiya i patologiya obmena zheleza. (Physiology and pathology of iron metabolism.) L’vov: Nauka Publ.; 1982. 224 p. (In Russ)] - Finch CA, Huebers HA. Iron metabolism. Clin Physiol Biochem. 1986;4:5–15.
- Richardson DR. Role of iron in cell cycle progression and cellular proliferation. Book of Abstracts. BioIron; 2005:7.
- Roetto A, Camaschella C. New insights into iron homeostasis through the study of non-HFE hereditary haemochromatosis. Best Pract Res Clin Haematol. 2005;18:235–50. doi: 10.1016/j.beha.2004.09.004.
- Sussman HH. Iron in cancer. Pathobiology. 1992;60:2–9. doi: 10.1159/000163690.
- Идельсон Л.И., Воробьев А.И. Железодефицитная анемия. Руководство по гематологии. Под ред. А.И. Воробьева. В 3 томах. М.: Ньюдиамед, 2005. Т. 2. С. 171–90.
[Idel’son LI, Vorob’ev AI. Iron-deficiency anemia. In: Vorob’ev AI, ed. Rukovodstvo po gematologii. (Manual of Hematology.) In 3 vol. Moscow: Newdiamed Publ.; 2005. Vol. 2. p. 171–90. (In Russ)] - Porter JB. Monitoring and treatment of iron overload: state of the art and new approaches. Sem Hematol. 2005;42(2 Suppl. 1):14–8. doi: 10.1053/j.seminhematol.2005.01.004.
- Kuntz E, Kuntz H-D. Haemochromatosis. In: Hepatology – Principles and Practice. Berlin: Springer-Verlag; 2002. p. 556–65.
- Ilickstein H, El RB, Shvartsman M, Cabantchik ZY. Intracellular labile iron pools as direct targets of iron chelators: a fluorescence study of chelator action in living cells. Blood. 2005;106:3242–50. doi: 10.1182/blood-2005-02-0460.
- Corce V, Renaud St, Cannie I, et al. Tumoral vectorization of new iron chelators for antiproliferative activity: biological properties of polyaminoquinolines. The abstract book of 5th Congress of the International Bioiron Society; 2013. Poster #230.
- Guyader CD, Thirouard A-S, Erdtmann L, et al. Liver iron is surrogate marker of severe fibrosis in chronic hepatitis. J Hepatol. 2007;46:587–96. doi: 10.1016/j.jhep.2006.09.021.
- Camaschella C. Iron and hepcidin: a story of recycling and balance. Hematol Am Soc Hematol Educ Program. 2013;2013:1–8. doi: 10.1182/asheducation-2013.1.1.
- Sikorska K, Romanowski T, Stalke P, et al. Association of Hepcidin mRNA Expression With Hepatocyte Iron Accumulation and Effects of Antiviral Therapy in Chronic Hepatitis C Infection. Hepat Mon. 2014;14(11):e21184. doi:10.5812/hepatmon.21184.
- Raha AA, Vaishnav RA, Friedland RP, et al. The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer’s disease. BMC Neuroscience. 2015;16(1):24. doi: 10.1186/2051-5960-1-55.
- Xu X, Pin S, Gathinji M, et al. Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostais. Ann N Y Acad Sci. 2004;1012:299–305. doi: 10.1196/annals.1306.024.
- Moreau C, Devedjian J, Kluza J, et al. Targeting brain chelatable iron as therapeutic strategy for parkinson’s disease. Translational and clinical studies. The abstract book of 5th Congress of the International Bioiron Society; 2013. Podium #52.
- Collingwood J, Finnegan M, Visanji N, et al. Brain iron and MRI in Alzheimer’s disease, Parkinson’s disease, and Multiple System Atrophy. The abstract book of 5th Congress of the International Bioiron Society; 2013. Podium #67.
- Долгов В.В., Луговская С.А., Почтарь М.Е. Лабораторная диагностика нарушений метаболизма железа. СПб.: Vital Diagnostics, 2002. 51 c.
[Dolgov VV, Lugovskaya SA, Pochtar’ ME. Laboratornaya diagnostika narushenii metabolizma zheleza. (Laboratory diagnosis of impaired iron metabolism.) Saint Petersburg: Vital Diagnostics Publ.; 2002. 51 p. (In Russ)] - Cabantchik ZY, Brener W, Zanninelili G. LPI-labile plasma iron in iron overload. Best Pract Res Clin Haematol. 2005;18:277–87. doi: 10.1016/j.beha.2004.10.003.
- Cheng Y, Zak O, Aisen P, et al. Structure of the human transferring receptor-transferrin complex. Cell. 2004;116:483–5. doi: 10.1016/s0092-8674(04)00130-8.
- Левина А.А., Андреева А.П., Замчий А.А. Определение концентрации ферритина в сыворотке крови радиоиммунным методом. Гематология и трансфузиология. 1984;5:57–60.
[Levina AA, Andreeva AP, Zamchii AA. Evaluation of serum ferritin levels using radioimmunoassay technique. Gematologiya i transfuziologiya. 1984;5:57–60. (In Russ)] - Lukina EA, Levina AA, Mokeeva NA. The diagnostic significance of serum ferritin indices in patients with malignant and reactive histiocytoses. Br J Haematol. 1993;83:326–9. doi: 10.1111/j.1365-2141.1993.tb08289.x.
- Denz H, Orth B, Huber P, et al. Immune activation and anemia of chronic disorders. Blood. 1993;81:1404–9.
- Gunshin H, Mackenzie B, Berger UV, et al. Cloning and characterization of mammalian proton-coupled metal-ion transporter gene. Nature. 1997;388:482–8. doi: 10.1038/41343.
- Mims MP, Guan Y, Pospisilova D, et al. Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload. Blood. 2005;105(3):1337–42. doi: 10.1182/blood-2004-07-2966.
- Napier I, Ponka P, Richardson DR. Iron trafficking in the mitochondrion: novel pathways revealed by disease. Blood. 2005;105:1867–974. doi: 10.1182/blood-2004-10-3856.
- D’Angelo G. Role of hepcidin in the pathophysiology and diagnosis of anemia. Blood Res. 2013;48(1):10–5. doi: 10.5045/br.2013.48.1.10.
- Hellman N, Gitlin JD. Ceruloplasmin metabolism and function. Ann Rev Nutr. 2002;22:439–58. doi: 10.1146/annurev.nutr.22.012502.114457.
- Fuqua B, Darshan D, Frazer D, et al. Severe defects in iron metabolism in mice with double knockout of the multicopper ferroxidases hephaestin and ceruloplasmin. The abstract book of 5th Congress of the International Bioiron Society; 2013. Podium #24.
- Krause A, Neitz S, Magert HJ, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibit antimicrobial activity. FEBS Lett. 2000;480(2):147–50. doi: 10.1016/s0014-5793(00)01920-7.
- Park CH, Valore EV, Waring AJ, et al. Hepcidin: a urinary antibacterial peptide synthesized in the liver. J Biol Chem. 2001;276:7806–10. doi: 10.1074/jbc.m008922200.
- Ganz T. Hepcidin – a regulator of intestinal iron absorption and iron recycling by macrophages. Best Pract Res Clin Haematol. 2005;18:171–82. doi: 10.1016/j.beha.2004.08.020.
- Pigeon C, Ilyin G, Courselaud B, et al. A new mouseт liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2001;276(4):7811–9. doi: 10.1074/jbc.m008923200.
- Hunter HN, Fulton DB, Vogel HJ. The solution structure of human hepcidin, a antibicrobial activity that is involved in iron uptake and hereditary hemochromatosis. J Biol Chem. 2002;277:37597–603. doi: 10.1074/jbc.m205305200.
- Harrison-Findik D, Lu S, Zmijewski E. Regulation of hepcidin transcription by reactive oxygen species and hypoxia. The abstract book of 5th Congress of the International Bioiron Society; 2013. Poster #6.
- Luo Q, Cheng Ch, Wang D, et al. Regulation of intracellular iron homeostasis under hypoxia. The abstract book of 5th Congress of the International Bioiron Society; 2013. Poster #166.
- Means RT, Krantz SB. Progress in understanding the pathogenesis of anemia of chronic disease. Blood. 1992;80:1639–44.
- Gardenghi S, Casu C, Renaud T, et al. Investigating the role of cytokines and hepcidin in anemia of inflammation. The abstract book of 5th Congress of the International Bioiron Society; 2013. Poster #138.
- Nairz M, Ferring-Appel D, Schroll A, et al. Iron regulatory proteins mediate macrophage innate immunity against salmonella. The abstract book of 5th Congress of the International Bioiron Society; 2013. Podium #34.
- Kautz L, Nemeth E, Ganz T. The erythroid factor erythroferrone and its role in iron homeostasis. The abstract book of 5th Congress of the International Bioiron Society; 2013. Podium #30.
- Frazer D, Wilkins S, Whitelaw N, et al. Hepcidin-independent iron recycling in a mouse model of haemolytic anaemia. The abstract book of 5th Congress of the International Bioiron Society; 2013. Podium #32.
- Gerhard G, Still Ch, Wood C, et al. Primary hepatic iron overload in extreme obesity is common and not associated with metabolic abnormalities. The abstract book of 5th Congress of the International Bioiron Society; 2013. Podium #58.
- Miyanishi K, Tanaka Sh, Kobune M, et al. Increased hepatic oxidative DNA damage in patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. The abstract book of 5th Congress of the International Bioiron Society; 2013. Poster #227.
- Kobune M, Kikuchi S, Iyama S, et al. Iron chelation therapy improves oxidative DNA damage in hematopoietic cells derived from transfusion-dependent myelodysplastic syndrome. The abstract book of 5th Congress of the International Bioiron Society; 2013. Poster #93.
- Jones E, Allen A, Evans P, et al. Differences in hepcidin regulation distinguish mild and severe phenotypes of e-beta thalassaemia. The abstract book of 5th Congress of the International Bioiron Society; 2013. Podium #27.