Journal of Advances in Medicine and Medical Research

33(8): 70-78, 2021; Article no.JAMMR.66724 ISSN: 2456-8899 (Past name: British Journal of Medicine and Medical Research, Past ISSN: 2231-0614, NLM ID: 101570965)

An Overview of Metabolism in Health and Disease

Nabiyev Abdusamat Utkurovich1*

1Republican Specialized Scientific and Practical Medical Center of Pediatrics, Uzbekistan.

Author’s contribution

The sole author designed, analysed, interpreted and prepared the manuscript.

Article Information

DOI: 10.9734/JAMMR/2021/v33i830888 Editor(s): (1) Dr. Ashish Anand, GV Montgomery Veteran Affairs Medical Center, USA. Reviewers: (1) Kalinca da Silva Oliveira, Federal University of Health Sciences of Porto Alegre (UFCSPA), Brazil. (2) Thomas Rolf Erdmann, Universidade Federal de Santa Catarina, Brazil. Complete Peer review History: http://www.sdiarticle4.com/review-history/66724

Received 25 January 2021 Review Article Accepted 30 March 2021 Published 13 April 2021

ABSTRACT

Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease. states are the reason for a decrease in working capacity, an increase in susceptibility to viral diseases, especially in children and cause growth and development retardation. Iron overload and poisoning lead to the activation of processes that can cause cell death. Timely diagnosis of disorders of iron metabolism and subsequent monitoring of treatment require knowledge of not only pathophysiological mechanisms, but also methodological capabilities and correct interpretation of clinical and biochemical parameters of iron metabolism.

Keywords: Diagnosis; iron deficiency anemia; hemochromatosis; hepcidin; hemosiderin; transferring; .

1. INTRODUCTION excess iron accumulation causes organ dysfunction through the production of reactive Iron is an essential metal for oxygen species (ROS). The total amount of body synthesis of erythrocytes, oxidation–reduction iron is approximately 3–4 g, two-thirds of which is reactions, and cellular proliferation, whereas composed of red blood cell (RBC) iron and ______

*Corresponding author: E-mail: [email protected];

Utkurovich; JAMMR, 33(8): 70-78, 2021; Article no.JAMMR.66724

recycled iron by RBC destruction; the remainder HFE (hereditary hemochromatosis protein), is stored in ferritin/hemosiderin, while only 1–2 hemouvelin, transferrin receptor 2. Hepcidin is mg of iron are absorbed in the intestinal tract and excreted in the urine, where it was first excreted. circulated in the blood (Fig. 1) [1]. An excess of iron induces the synthesis of hepcidin by hepatocytes. Hepcidin inhibits The key regulator of iron metabolism is the intestinal absorption of iron, blocks the transport hepatic bactericidal protein (hepcidin), a of iron everywhere, including internal epithelium, hormone synthesized primarily in the liver. macrophages, placenta and other cell types, and Hepcidin contains 25 amino acids, is rich in the transfer of iron across the placenta [2]. cysteine, with 4 disulfide bridges. Human hepcidin is derived from the portion of 84-amino Hepcidin induces the immersion of ferroportin acid precursor. The synthesis and secretion of into the cell cytoplasm, blocking the only pathway hepcidin is controlled by three proteins: for iron transport from the cell (Fig. 2).

Fig. 1. The intestinal tract and circulated in the blood

Fig. 2. Role of hepcidin in iron metabolism Hepcidin is secreted by hepatocytes and Kupffer cells of the liver during iron overload and inflammation. Hepcidin causes the immersion of ferroportin into the cytoplasm of the cell, blocking the only pathway of iron transport from the cell

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Hepcidin has antibacterial activity to gram- Transferrin is synthesized in liver cells and in negative, gram-positive bacteria and antifungal small amounts in lymphoid tissue, mammary activity. Like other antibacterial peptides, gland, testes and ovaries. It consists of one hepcidin is able to rupture the bacterial polypeptide chain and two hydrocarbon side membrane, which is due to its structure: regions. The normal serum concentration is Hydrophilic (positively charged) and hydrophobic about 2-4 g / L, which corresponds to about 4% (negatively charged) [3]. of the total plasma protein. In addition to blood serum, under physiological conditions, transferrin Hepcidin is capable of destroying bacterial is determined in lymph and tissue fluid, and membranes, affecting the accumulation of iron by under pathological conditions - in urine and macrophages. In this case, microorganisms are effusion. Disorders of iron metabolism in patients deprived of the necessary component for the can be associated with both its deficiency and production of superoxide dismutase, which, in overload. Iron deficiency is clinically manifested turn, protects them from the host's oxygen by iron deficiency anemia, overload - by radicals. Decreased is an important hemochromatosis [7]. defense mechanism to avoid inflammatory organ damage. In , this is also part of the The main cause of iron deficiency in pathology is immune strategy. Hepcidin inhibits the synthesis blood loss, usually from the gastrointestinal tract, of IL-6 and TNF α in macrophages, and thus has urinary tract, especially in women, and relatively an anti-inflammatory effect [4]. rarely - as a result of bleeding from the kidney or bladder. The clinical picture of latent or manifest Bacteria and pathogen-specific macromolecules iron deficiency resulting from blood loss can be act on macrophages, including hepatic Kupffer easily identified from the patient's history or cells, and induce increased production of IL-6. during a diagnostic examination. Men who This cytokine, in turn, initiates the synthesis of donate blood 4 or more times and women who hepcidin by hepatocytes through the induction of donate 2 or more times a year should be tested its mRNA. Simultaneously with increased for ferritin once a year. expression of hepcidin, it increases serum ferritin and IL-6 levels. The same situation is observed Iron deficiency can result from malabsorption in with tumors: Anemia develops, hepcidin, ferritin the intestine (after extensive resection of the and IL-6 levels increase [5]. small intestine, with chronic enteritis). Violation of the acid and enzyme-forming function of the The opposite situation occurs with anemia and stomach (atrophic gastritis) may be an additional hypoxia. The suppressive effect of hemolytic cause of the development of iron deficiency. Iron anemia on the production of hepcidin is observed deficiency in adolescents, especially girls, is even when the body is overloaded with iron, thus aggravated by fasting. A limited diet often leads confirming that the requirements of to the fact that only about half of the erythropoiesis in the gland are a stronger recommended amount of iron is consumed with stimulus than an excess of iron, which should food and this, naturally, when combined with the cause hepcidin induction. This hierarchy of onset of menstruation, leads to iron deficiency. effects explains why hemosiderosis develops in Endogenous iron deficiency can occur in hemolytic anemias. Since in such cases, a chronic infections (tuberculosis), intoxications, decrease in hepcidin production leads to an hypovitaminosis (especially Chypovitaminosis) overload of the body with iron, only chelation and malignant neoplasms [8]. therapy can prevent the increasing excess of iron [6]. Rarely, iron deficiency develops due to a lack of transferrin (hereditary atransferrinemia). People with hepcidin-producing adenomas Latent iron deficiency is typically found in long- develop iron deficiency anemia that is resistant to distance swimmers. Occupational physical iron therapy. Mutations in the hepcidin gene are overload is, apparently, additional factors of the cause of hemochromatosis. Overproduction hemolysis. of hepcidin during and inflammation may be responsible for anemia of inflammation Most often, it becomes necessary to differentiate or anemia of chronic disease. Inflammatory iron deficiency anemia from chronic anemias anemia is caused primarily by hepcidin-induced associated with tumors, infections, sideroblastic iron deposition in macrophages. anemia, or thalassemia (Table 1).

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Table 1. Laboratory indicators of primary and secondary iron deficiency

Iron Trance Saturation Ferritin Soluble ferrin transferrin transferrin receptors Primary iron deficiency in: Reduced Increased Reduced Reduced Increased - lack of food - impaired absorption - iron loss Secondary iron deficiency in: Reduced Normal or Reduced or Increased Normal -infections reduced normal -inflammation -tumors -continuous dialysis

The human body is not able to actively excrete Hereditary hemochromatosis is characterized by iron. If the ability of these proteins to bind iron is clinical polymorphism due to excessive iron load exceeded, it begins to be deposited in the to one degree or another in all organs and parenchymal organs. Iron poisoning, unlike iron tissues. Therefore, these stages of the disease deficiency, is relatively rare. This is a serious are conditional. Dysfunction and the condition that can be life threatening. An corresponding clinical manifestation occur with increased ferritin content always accompanies advanced morphological changes in organs, after iron overload. However, ferritin cannot be a decompensation occurs. Laboratory diagnostics differential diagnostic indicator of primary or of the disease should be early, in connection with secondary hemochromatosis. At the same time, which widespread introduction of screening tests the cause of the iron overload must be is necessary (hemogram in combination with a established, as it is necessary for informed complete study of iron metabolism). If hereditary treatment [9]. hemochromatosis is suspected, HLA typing and liver biopsies should be performed. In order to Primary hemochromatosis: Hereditary remove excess iron from the body, patients are hemochromatosis is a serious disease with a treated with desferal and regular bloodletting genetically determined disorder of iron [10]. metabolism. The primary functional defect in hereditary hemochromatosis is an abnormality in Secondary acquired hemochromatosis: the regulation of iron uptake by the cells of the Hemosiderosis (secondary hemochromatosis) is gastrointestinal mucosa (there is no limitation of possible with hemolytic anemias, with ineffective absorption), which leads to a massive intake of a erythropoiesis (including with sideroblastic and trace element into the body, followed by the aplastic anemia, thalassemia), malaria, deposition of iron in various organs (liver, spleen, intoxication (lead, tin, etc.), alcoholic cirrhosis, heart, pancreas, gonads, adrenal glands). A chronic viral hepatitis, some types of porphyria , close relationship with the HLA-A locus was after repeated blood transfusions. found. Primary hemochromatosis occurs about 10 times more often in men than in women. Therefore, only with prolonged chronic iron Usually clinical manifestations are observed at overload conditions arise for the development of age 35 - 55 years old, there are liver diseases of iron accumulation with damage to dysfunctions up to cirrhosis, diabetes mellitus, organs [11]. pigmented dermatosis, cardiomyopathy and heart rhythm disturbances. The classic triad of The duration of chronic iron overload is a primary hemochromatosis is melasma, liver determining factor in organ pathology in cirrhosis, diabetes mellitus. Sometimes secondary hemochromatosis. symptoms of secondary hypogonadism and adrenocortical insufficiency occur. Hepatocellular Iron, which enters the body during blood carcinoma develops in about 15% of transfusions, brings a significant addition to the cases. iron that has already entered the intestine.

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Serum ferritin concentration closely correlates removal of four carboxyl groups from the with the corresponding degree of iron overload in carboxymethyl side chains of the reticuloendothelial system. uroporphyrinogen to form coproporphyrinogen. Ineffective erythropoiesis: 6. Formation of protoporphyrinogen IX: The mitochondrial enzyme coproporphyrinogen Stages of heme synthesis: oxidase catalyzes the removal of the carboxyl group and two hydrogen atoms 1. Formation of 5-aminolevulinic acid: 5- from the propionic groups of the pyrrole Aminolevulinate synthase, the first enzyme rings A and B of coproporphyrinogen with on the heme biosynthesis pathway, the formation of vinyl groups at these catalyzes the condensation of glycine with positions. succinyl coenzyme A to form 5- 7. Formation of protoporphyrin IX: The aminolevulinic acid. This enzyme is oxidation of protoporphyrinogen IX to localized on the inner mitochondrial protoporphyrin IX is catalyzed by membrane; its cofactor is pyridoxal-5- protoporphyrinogen oxidase, which phosphate. In the cells of the erythroid and removes 6 hydrogen atoms from the non-erythroid series, synthase is encoded porphyrinogen core. by different genes. 8. The last stage of heme biosynthesis is 2. Formation of porphobilinogen: Under the reduced to the incorporation of iron into action of aminolevulinate dehydratase (this protoporphyrin IX. This reaction is enzyme is localized in the cytosol), two catalyzed by the mitochondrial enzyme molecules of 5-aminolevulinic acid are ferrochelatase. converted into mono-pyrrolporfobilinogen with the release of two water molecules. The rate-limiting enzyme that determines the Lead inhibits aminolevulinate dehydratase, intensity of porphyrin synthesis in all organs is displacing zinc, which is necessary for the the enzyme 5-aminolevulinate synthase. Heme enzyme to function. The most potent (as well as hematin) is able to inhibit the activity inhibitor is succinylacetone (a structural of 5-aminolevulinate synthase. Since heme is not analogue of aminolevulinic acid), which is a direct product of the reaction with the present in the urine and blood of patients participation of 5-aminolevulinate synthase, the with hereditary tyrosinemia. inhibition appears to be due to the steric effect 3. Formation of hydroxymethylbilane: [12]. Porphobilinogen deaminase catalyzes the condensation of four porphobilinogen Nevertheless, this effect is a negative feedback molecules to form a linear tetrapyrrole - mechanism that controls the hemoglobin content hydroxymethylbilane. In the absence of the in the circulation system. About 100 different next enzyme, uroporphyrinogen drugs and metabolites are known that can affect cosynthase III, hydroxymethylbilane the activity of 5-aminolevulinate synthase, in spontaneously cyclizes with the formation particular 3,5-dicarbethoxy-1,4-dihydrocollidine of the first tetrapyrrole, uroporphyrinogen I. 40 times increases the activity of the enzyme in There are two isoforms of porphobilinogen the experiment. deaminase; one is present only in non- erythroid cells. These isozymes are Porphyrin metabolism disorders manifest encoded by different messenger RNAs, clinically as porphyrias. Porphyrias are hereditary which are transcribed from the same gene, and acquired anemias associated with impaired but in different ways and undergo different porphyrin synthesis, characterized by splicing. hypochromia, high serum iron, and organ 4. The formation of uroporphyrinogen III from hemosiderosis [13]. hydroxymethylbilane is catalyzed by uroporphyrinogen III-cosyntase. This stage A form of the disease associated with a violation consists in intramolecular rearrangement, of the synthesis of 5-aminolevulinic acid is affecting only the D ring of the porphyrin observed relatively more often. Violation of the "large ring". formation of protoporphyrin causes the 5. Formation of coproporphyrinogen: impossibility of binding iron and, as a result, its Cytosolic enzyme uroporphyrinogen accumulation in the body. In young people, decarboxylase catalyzes the sequential anemia in most cases is not expressed (80-90 g /

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l), but hemoglobin gradually decreases to 50-60 In clinical diagnostic laboratories, due to the ease g / l. The content of reticulocytes is normal or of implementation, TIBC is more often slightly reduced. Erythrocytes are hypochromic, determined instead of transferrin. Modern there is anisocytosis, poikilocytosis, single target methods for the determination of ferritin are erythrocytes. In the bone marrow - a sharp based on immunological analysis. Ferritin is irritation of the red sprout, increased basophilic present in serum at very low concentrations (0.2- polychromatophilic and decreased oxyphilic 7 x 10-12 mol / L). Therefore, test kits of the first normoblasts, many sideroblasts. The content of generation for the determination of ferritin were iron in the blood serum is significantly increased based on methods of indirect measurement - (up to 5.5 mg / l), transferrin is saturated with iron ELISA, RIA. In recent years, the sensitivity of by almost 100%. When examining the content of direct methods (turbidimetry, nephelometry), porphyrins in erythrocytes in some patients, a therefore, turbidimetric latex agglutination test, decrease in protoporphyrin to 3-9 μmol / l (norm ELISA-based ELISA kits, nephelometry, 18-90 μmol / l) and an increase in coproporphyrin fluorescence analysis, luminescence to 60-75 μmol / l (norm to 12 μmol / l) are found, immunoassay, RIA are used to determine ferritin. in some cases decreases both protoporphyrin Physicochemical and immunological differences and coproporphyrin. The content of 5- of isoferritins contribute to the fact that aminolevulinic acid and coproporphyrin in the radioimmunological methods or enzyme-linked urine is normal. Acquired disorders of porphyrin immunosorbent assay, depending on the type of synthesis are most often associated with lead antigens or antibodies used, can be poisoning or occur with a lack of vitamin B6. The accompanied by significant differences the patient's appearance is peculiar - an earthy pallor results of measuring the concentration of ferritin with a grayish tinge, associated with both anemia in serum. International contacts on a single and vasospasm and deposition of porphyrins in standard for ferritin were coordinated by the the skin, there may be a purple border on the World Health Organization (WHO), the gums. The hemoglobin content gradually International Committee for Standardization in decreases to 40-60 g / l, the color index is Hematology (ICSH), the International Federation sharply reduced, erythrocytes are sharply of Clinical Chemistry (IFCC), and the hypochromic, aniso-poikilocytosis is detected Standardization Committee of the International [14]. Union of Immunological Societies (IUIS). A standardized sample of human liver ferritin is 2. MATERIALS AND METHODS currently stored at the National Institute for Biological Standards and Control in London. The criteria for diagnostic kits for ferritin have been The quantitative determination of transferrin in worked out, which, in particular, must meet the serum is carried out by immunochemical safety requirements (tested for the absence of methods based on the antigen-antibody HIV infection), sensitivity, specificity and interaction reaction. The serum transferrin accuracy, could be used on automatic machines, concentration is high enough that the first and be commercially available. Ferritin, like reaction between antigen and antibody may be transferrin, does not have circadian rhythms. an agglutination or precipitation reaction. The Based on the fact that the vertical position of the result could be measured directly, often a body affects the composition of high-molecular- reaction to the eye. weight proteins, it is recommended to take samples for ferritin with a standard position of the Direct reactions can be quantified by methods body from a vein. Preferably, the same blood turbidimetry, nephelometry, radial sample is used for the determination of ferritin, immunodiffusion, radioimmunoassay, etc. transferrin and iron. Determining reference values for ferritin is always a challenge, as In contrast to these direct specific gender and age affect serum ferritin levels. For immunochemical methods for the determination example, the ferritin content in newborns of individual proteins, conventional chemical increases very sharply during the first month of methods allow an indirect and approximate life, since physiological hemolysis of erythrocytes determination of the concentration of transferrin takes place, then its concentration in serum by the total iron-binding capacity of serum decreases significantly, reaching minimum (TIBC). TIBC is the amount of iron that can values by 6 months of age, and then gradually bind transferrin to about limit volume of increases up to 15 years of age. In adult women serum. before menopause, the amount of iron and

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ferritin stores is significantly less than in men. In diagnosing the real cause of the violation of iron old age, the serum ferritin concentration is metabolism. To avoid an erroneous diagnosis, it approximately the same in men and women. It is is necessary to determine all clinical and recommended to set the boundaries of "normal biochemical parameters of iron metabolism and values" in the group of persons in whom latent interpret them on the basis of (patho) iron deficiency can be suspected - these are physiological laws. The cost of a comprehensive permanent donors and young women. Naturally, examination is much less compared to the people with a manifest form of iron deficiency consequences of erroneous (incorrect) therapy. and patients with infectious diseases should be Normally, at the stage of the middle excluded. An increased serum ferritin content, polychromatophilic normoblast, the Hb which does not correlate with the amount of concentration reaches a critical value, which deposited iron in the body, is often determined in almost completely stops DNA synthesis and Hodgkin's disease, acute leukemia, breast turns off the cell from the mitotic cycle. In this cancer, malignant gonadal tumors, melanoma case, the rate of Hb synthesis also slows down. and carcinoma of the gastrointestinal tract and Further maturation of red cells occurs without liver [15]. An increase in ferritin concentration division [17]. depends on the type and stage of the disease and can be caused by the following reasons: Cytochemical determination of iron: Sideroblasts increased synthesis of ferritin by tumor cells, and siderocytes Siderocytes are erythrocytes release of ferritin during their destruction, containing ferric iron, the reserves of which are nonspecific increase in serum ferritin not associated with hemoglobin. Sideroblasts are concentration. In patients with malignant tumors, the corresponding nucleated cells of the an increase in ferritin is due to a high erythrocyte series. Iron granules are detected in concentration of acidic isoferritins. Normal serum reaction with Prussian blue. ferritin concentration does not exclude malignant neoplasm. Therefore, ferritin is not used as a Principle: The interaction of iron ions (Fe + 3), screening indicator for early diagnosis of unbound with hemoglobin, with iron-cyanide tumors. In selected patients, an elevated potassium in a HCl solution is called the reaction serum ferritin concentration may be a useful of Prussian blue. parameter for detecting metastasis and relapse and, in part, for monitoring the effectiveness of 4 Fe + 3 + 3К4Fe (CN) 6 ----> Fe4 [Fe (CN) treatment. 6] 3 + 12 K +

3. RESULTS AND DISCUSSION 4. CONCLUSION

The value of ferritin determination in differential Iron is necessary for redox reactions during diagnosis causes of iron deficiency and anemia. energy production, peroxidation, oxygen transfer Extremely important when differential diagnosis and other critical processes. to distinguish iron deficiency anemia (primary) from other hypochromic anemias, since only with Both iron deficiency and excess cause severe iron deficiency anemia is treatment with iron disease. Functional dysfunctions at each of these preparations indicated. Similar treatment for stages can affect overall iron metabolism. other hypochromic anemias can cause Nevertheless, the multistage metabolism allows symptoms of secondary hemochromatosis. the body to compensate to a large extent for metabolic shifts. Therefore, clinically there are The most important diagnostic finding is the both latent and, to varying degrees, clinically amount of iron reserve, as measured by the expressed states of iron deficiency or excess in serum ferritin concentration. All anemias, with the the body. Moreover, blocking the utilization of exception of iron deficiency, have normal or iron at the stages of its utilization may be elevated ferritin levels. A combination of anemia accompanied by the development of a clinical of chronic diseases with iron deficiency anemia is picture of iron deficiency and laboratory possible. In cases of low ferritin content, indicators of its excess. Incorrect interpretation of treatment with iron preparations is indicated [16]. the results will be accompanied by incorrect It should be emphasized that the diagnostic prescription of iron-containing drugs and an even significance of individual indicators of iron greater deterioration in the patient's condition. metabolism under physiological conditions and Limited access of iron for infectious agents is one most pathological processes does not allow of the most effective mechanisms of infectious

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tolerance. This pathway is actively expressed in Menshikov, vol. 1, GEOTAR-Media; chronic pathology and is manifested by anemia 2012. of chronic diseases [18]. 5. Romanova LA, Lugovskaya SA. Other clinical laboratory diagnostics. 1999;9:6. Therefore, the comprehensive laboratory 6. Vorobiev PA. Anemic syndrome in analysis outlined in this study guide, aimed at clinical practice. M .: Newdiamed. analyzing the pathophysiological mechanisms of 2001;168. iron metabolism and the formation on this basis 7. Butler LI. Iron deficiency anemia. M.: of algorithms for laboratory diagnostics and Nyudiamed. 1998;40. monitoring of the effectiveness of treatment with 8. Durmanov ND, Filimonov AS. Diagnostics iron preparations. The offered laboratory and correction of iron metabolism technologies provide for the analysis of disorders in elite sports. M. 2010;84. biochemical, immunochemical, hematological, cytological, general clinical studies. 9. Nikulin BA. Clinical biochemistry manual. M .: GEOTARMedia. 2007;256. For adequate laboratory diagnostics, it is 10. Skurikhin IM, Nechaev AP. Everything necessary to introduce into practice and about food from the point of view of a laboratory research standards such significant chemist. M.: Higher School. 1991;287. indicators of iron metabolism as the 11. Shekhtman MM. Iron deficiency anemia determination of transferrin, ferritin, soluble and pregnancy. Clinical Lecture // transferrin receptors, hepcidin, cytochemical Gynecology. 2000;2(6). indicators for hemosiderosis. Modern therapeutic 12. Shcherbinina SP, Romanova EA, Levina approaches are able to significantly correct and AA. Other Diagnostic value of a normalize iron metabolism, but for this it is comprehensive study of indicators of necessary to carry out both screening studies in iron metabolism in clinical practice. groups prone to pathology of iron metabolism, Hematol and Transfusiol. 2005;50(5):23- and personalized laboratory studies of patients 28. with clinically expressed pathology [19]. 13. Joyce J. C. Kroot, Harold Tjalsma, Robert E. Fleming, Dorine W. Swinkels. Hepcidin CONSENT in human iron disorders: Diagnostic implications clinical chemistry. 2011;57: It is not applicable. 1650-1669. (Published October 11, 2011) ETHICAL APPROVAL 14. Hyoung Soo Choi, Sang Hoon Song, Jae Hee Lee, Hee-Jin Kim, Hye Ran It is not applicable. Yang. Serum hepcidin levels and iron parameters in children with iron COMPETING INTERESTS deficiency, serum hepcidin levels and iron parameters in children with iron Author has declared that no competing interests deficiency. Korean J Hematol. 2012;47(4): exist. 286-292. 15. Hyoung Soo Choi, Sang Hoon Song, REFERENCES Jae Hee Lee, Hee-Jin Kim, Hye Ran Yang. Korean J Hematol. 2012;47(4):286– 1. Andrews NC. Disorders of iron 292. metabolism. N Engl J Med. 1999;341: 16. Nemeth E, Preza GC, Jung CL, Kaplan J, 1986–95. Waring AJ, Ganz T. The Nterminus of 2. Dolgov VV, Lugovskaya SA, Morozova VT, hepcidin is essential for its interaction with Postman ME. Laboratory diagnostics of ferroportin: Structure-function study. Blood. anemias. M.-Tver. "Triad"; 2009. 2006;107:328–333. 3. Lugovskaya SA, Postman ME. 17. Lipiński P, Styś A, Starzyński R. Molecular Hematological atlas. M.-Tver, Triad; insights into the regulation of iron 2011. metabolism during the prenatal and early 4. National Guidelines for Clinical Laboratory postnatal periods. Cell Mol Life Sci. Diagnostics Ed. V. V. Dolgov, V. V. 2013;70(1):23–38.

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18. Nemeth E, Tuttle MS, Powelson J, Vaughn 19. Schaefer R, Gasche C, Huch R, Krafft A. MB, Donovan A, Ward DM, Ganz T, newsletter. Kaplan J. Hepcidin regulates cellular iron Recommendations for the treatment efflux by binding to ferroportin and of iron deficiency anemia. Hematol inducing its internalization. Science. and Transfusiol. 2004;49(4):40– 2004;306:2090–2093. 47. ______© 2021 Utkurovich; This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Peer-review history: The peer review history for this paper can be accessed here: http://www.sdiarticle4.com/review-history/66724

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