New Insights into Iron Deficiency Anemia in Children: A Practical Review

Carla Moscheo, Maria Licciardello, Piera Samperi, Milena La Spina, Andrea Di Cataldo, Giovanna Russo, Carla Moscheo, Maria Licciardello, Piera Samperi, Milena La Spina, Andrea Di Cataldo, Giovanna Russo

Abstract

Iron deficiency anemia (IDA) is the most frequent hematological disorder in children, with an incidence in industrialized countries of 20.1% between 0 and 4 years of age and 5.9% between 5 and 14 years (39 and 48.1% in developing countries). Although IDA has been recognized for a long time, there are still uncovered issues and room for improving the management of this condition. New frontiers regarding its diagnosis and therapeutic options emerge every day; recently, innovative formulations of iron have been launched, both for oral and parenteral administration, with the aim of offering treatment schedules with higher efficacy and lower toxicity. As a matter of fact, glycinate and liposomal preparations, while maintaining a satisfying efficacy profile, have significantly fewer side effects, in comparison to the traditional elemental iron salts; parenteral iron, usually considered a second-choice therapy reserved to selected cases, may evolve further, as a consequence of the production of molecules with an interesting clinical profile such as ferrocarboxymaltose, which is already available for adolescents aged >14 years. The present article reports the clinically relevant latest insights regarding IDA in children and offers a practical guide to help pediatricians, particularly to choose the most appropriate prevention and therapy strategies.

Keywords: anemia; bis-glycinate iron; iron deficiency prevention; iron therapy; iron-deficiency; liposomal iron; pediatric.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Diagnostic workup in case of IDA. EGD-scopy, esophagogastroduodenoscopy; RC-scopy, rectoscopy; Pos, positive; Neg, negative; H.pylori, Helicobacter pylori; IDA, iron deficiency anemia.
Figure 2
Figure 2
Role of hepcidin in the homeostasis of iron.
Figure 3
Figure 3
Intestinal iron absorption is influenced by diet composition.

References

    1. Nutritional Anaemias: Tools for Effective Prevention and Control. WHO; Geneva, Switzerland: 2017. [(accessed on 25 February 2022)]. Available online: .
    1. Cerami C. Iron Nutriture of the Fetus, Neonate, Infant, and Child. Ann. Nutr. Metab. 2017;71:8–14. doi: 10.1159/000481447.
    1. Sangkhae V., Nemeth E. Regulation of the Iron Homeostatic Hormone Hepcidin. Adv. Nutr. Int. Rev. J. 2017;8:126–136. doi: 10.3945/an.116.013961.
    1. Donovan A., Roy C.N., Andrews N. The Ins and Outs of Iron Homeostasis. Physiology. 2006;21:115–123. doi: 10.1152/physiol.00052.2005.
    1. Gkouvatsos K., Papanikolaou G., Pantopoulos K. Regulation of iron transport and the role of transferrin. Biochim. Biophys. Acta (BBA) Gen. Subj. 2012;1820:188–202. doi: 10.1016/j.bbagen.2011.10.013.
    1. Saito H. Metabolism of iron stores. Nagoya J. Med. Sci. 2014;76:235–254.
    1. Wang Y., Wu Y., Li T., Wang X., Zhu C. Iron Metabolism and Brain Development in Premature Infants. Front. Physiol. 2019;10:463. doi: 10.3389/fphys.2019.00463.
    1. Parodi E., Aurucci M.L., Stella B., Russo G., Ramenghi U. Anemia sideropenica nel III millennio. “Nuovi” parametri di monitoraggio della risposta tapeutica. Med. Bambino. 2015;34:515–519.
    1. Duque X., Moran S., Mera R., Medina M., Martinez H., Mendoza M.E., Torres J., Correa P. Effect of Eradication of Helicobacter pylori and Iron Supplementation on the Iron Status of Children with Iron Deficiency. Arch. Med. Res. 2010;41:38–45. doi: 10.1016/j.arcmed.2009.11.006.
    1. Russo-Mancuso G., Branciforte F., Licciardello M., La Spina M. Iron deficiency anemia as the only sign of infection with Helicobacter pylori: A report of 9 pediatric cases. Int. J. Hematol. 2003;78:429–431. doi: 10.1007/BF02983815.
    1. Srivaths L., Minard C.G., O’Brien S.H., Wheeler A.P., Mullins E., Sharma M., Sidonio R., Jain S., Zia A., Ragni M.V., et al. The spectrum and severity of bleeding in adolescents with low von Willebrand factor-associated heavy menstrual bleeding. Blood Adv. 2020;4:3209–3216. doi: 10.1182/bloodadvances.2020002081.
    1. Gichohi-Wainaina W.N., Towers G.W., Swinkels R.W., Zimmermann M.B., Feskens E.J., Melse-Boonstra A. Inter-ethnic differences in genetic variants within the transmembrane protease, serine 6 (TMPRSS6) gene associated with iron status indicators: A systematic review with meta-analyses. Genes Nutr. 2015;10:442. doi: 10.1007/s12263-014-0442-2.
    1. Casu C., Aghajan M., Oikonomidou P.R., Guo S., Monia B.P., Rivella S. Combination of Tmprss6- ASO and the iron chelator deferiprone improves erythropoiesis and reduces iron overload in a mouse model of beta-thalassemia intermedia. Haematologica. 2016;101:e8–e11. doi: 10.3324/haematol.2015.133348.
    1. Zhao N., Nizzi C.P., Anderson S.A., Wang J., Ueno A., Tsukamoto H., Eisenstein R.S., Enns C.A., Zhang A.-S. Low Intracellular Iron Increases the Stability of Matriptase-2. J. Biol. Chem. 2015;290:4432–4446. doi: 10.1074/jbc.M114.611913.
    1. Frýdlová J., Přikryl P., Truksa J., Falke L.L., Du X., Gurieva I., Vokurka M., Krijt J. Effect of Erythropoietin, Iron Deficiency and Iron Overload on Liver Matriptase-2 (TMPRSS6) Protein Content in Mice and Rats. PLoS ONE. 2016;11:e0148540. doi: 10.1371/journal.pone.0148540.
    1. Zhang A.-S., Anderson S.A., Wang J., Yang F., DeMaster K., Ahmed R., Nizzi C.P., Eisenstein R.S., Tsukamoto H., Enns C.A. Suppression of hepatic hepcidin expression in response to acute iron deprivation is associated with an increase of matriptase-2 protein. Blood. 2011;117:1687–1699. doi: 10.1182/blood-2010-06-287292.
    1. Joo E.Y., Kim K.Y., Kim D.H., Lee J.E., Kim S.K. Iron deficiency anemia in infants and toddlers. Blood Res. 2016;51:268–273. doi: 10.5045/br.2016.51.4.268.
    1. Baker R.D., Greer F.R., Committee on Nutrition Diagnosis and Prevention of Iron Deficiency and Iron-Deficiency Anemia in Infants and Young Children (0–3 Years of Age) Pediatrics. 2010;126:1040–1050. doi: 10.1542/peds.2010-2576.
    1. Lozoff B., Georgieff M.K. Iron Deficiency and Brain Development. Semin. Pediatr. Neurol. 2006;13:158–165. doi: 10.1016/j.spen.2006.08.004.
    1. Lopez A., Cacoub P., Macdougall I.C., Peyrin-Biroulet L. Iron deficiency anaemia. Lancet. 2016;387:907–916. doi: 10.1016/S0140-6736(15)60865-0.
    1. Bregman D.B., Morris D., Koch T.A., He A., Goodnough L.T. Hepcidin levels predict nonresponsiveness to oral iron therapy in patients with iron deficiency anemia. Am. J. Hematol. 2013;88:97–101. doi: 10.1002/ajh.23354.
    1. Nemeth E., Ganz T. Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis. Int. J. Mol. Sci. 2021;22:6493. doi: 10.3390/ijms22126493.
    1. Donovan A., Brownlie A., Zhou Y., Shepard J., Pratt S.J., Moynihan J., Paw B.H., Drejer A., Barut B., Zapata A., et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 2000;403:776–781. doi: 10.1038/35001596.
    1. Abboud S., Haile D.J. A Novel Mammalian Iron-regulated Protein Involved in Intracellular Iron Metabolism. J. Biol. Chem. 2000;275:19906–19912. doi: 10.1074/jbc.M000713200.
    1. McKie A.T., Marciani P., Rolfs A., Brennan K., Wehr K., Barrow D., Miret S., Bomford A., Peters T.J., Farzaneh F., et al. A Novel Duodenal Iron-Regulated Transporter, IREG1, Implicated in the Basolateral Transfer of Iron to the Circulation. Mol. Cell. 2000;5:299–309. doi: 10.1016/S1097-2765(00)80425-6.
    1. Vela D., Vela-Gaxha Z. Differential regulation of hepcidin in cancer and non-cancer tissues and its clinical implications. Exp. Mol. Med. 2018;50:e436. doi: 10.1038/emm.2017.273.
    1. Qiao B., Sugianto P., Fung E., Del Castillo-Rueda A., Moran M.J., Ganz T., Nemeth E. Hepcidin-Induced Endocytosis of Ferroportin Is Dependent on Ferroportin Ubiquitination. Cell Metab. 2012;15:918–920. doi: 10.1016/j.cmet.2012.03.018.
    1. Donovan A., Lima C.A., Pinkus J.L., Pinkus G.S., Zon L.I., Robine S., Andrews N.C. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab. 2005;1:191–200. doi: 10.1016/j.cmet.2005.01.003.
    1. Zhang Z., Zhang F., Guo X., An P., Tao Y., Wang F. Ferroportin1 in hepatocytes and macrophages is required for the efficient mobilization of body iron stores in mice. Hepatology. 2012;56:961–971. doi: 10.1002/hep.25746.
    1. Burke R.M., Leon J.S., Suchdev P.S. Identification, Prevention and Treatment of Iron Deficiency during the First 1000 Days. Nutrients. 2014;6:4093. doi: 10.3390/nu6104093.
    1. Dallman P.R., Siimes M.A. Percentile curves for hemoglobin and red cellvolume in infnacy and childhood. J. Pediatr. 1979;94:26–31. doi: 10.1016/S0022-3476(79)80344-3.
    1. Pereira A.D.S., de Castro I.R.R., Bezerra F.F., Neto J.F.N., da Silva A.C.F. Reproducibility and validity of portable haemoglobinometer for the diagnosis of anaemia in children under the age of 5 years. J. Nutr. Sci. 2020;9:e3. doi: 10.1017/jns.2019.43.
    1. Camaschella C. New insights into iron deficiency and iron deficiency anemia. Blood Rev. 2017;31:225–233. doi: 10.1016/j.blre.2017.02.004.
    1. Cancelo-Hidalgo M.J., Castelo-Branco C., Palacios S., Haya- Palazuelos J., Ciria-Recasens M., Manasanch J., Pérez-Edo L. Tolerability of different oral iron supplements: A systematic review. Curr. Med. Res. Opin. 2013;29:291–303. doi: 10.1185/03007995.2012.761599.
    1. Buchanan G.R. Paucity of clinical trials in iron deficiency: Lessons learned from study of VLBW infants. Pediatrics. 2013;131:e582–e584. doi: 10.1542/peds.2012-3365.
    1. Tolkien Z., Stecher L., Mander A.P., Pereira D.I.A., Powell J.J. Ferrous Sulfate Supplementation Causes Significant Gastrointestinal Side-Effects in Adults: A Systematic Review and Meta-Analysis. PLoS ONE. 2015;10:e0117383. doi: 10.1371/journal.pone.0117383.
    1. Moretti D., Goede J.S., Zeder C., Jiskra M., Chatzinakou V., Tjalsma H., Melse-Boonstra A., Brittenham G., Swinkels D.W., Zimmermann M.B. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood. 2015;126:1981–1989. doi: 10.1182/blood-2015-05-642223.
    1. Stoffel N.U., Cercamondi C.I., Brittenham G., Zeder C., Geurts-Moespot A.J., Swinkels D.W., Moretti D., Zimmermann M.B. Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: Two open-label, randomised controlled trials. Lancet Haematol. 2017;4:e524–e533. doi: 10.1016/S2352-3026(17)30182-5.
    1. Muñoz M., Gómez-Ramírez S., Bhandari S. The safety of available treatment options for iron-deficiency anemia. Expert Opin. Drug Saf. 2018;17:149–159. doi: 10.1080/14740338.2018.1400009.
    1. Powers J.M., Buchanan G.R., Adix L., Zhang S., Gao A., McCavit T.L. Effect of Low-Dose Ferrous Sulfate vs Iron Polysaccharide Complex on Hemoglobin Concentration in Young Children With Nutritional Iron-Deficiency Anemia. JAMA. 2017;317:2297–2304. doi: 10.1001/jama.2017.6846.
    1. Parodi E., Giraudo M.T., Davitto M., Ansaldi G., Mondino A., Garbarini L., Franzil A., Mazzone R., Russo G., Ramenghi U. Reticulocyte parameters: Markers of early response to oral treatment in children with severe iron-deficiency anemia. J. Pediatr. Hematol. Oncol. 2012;34:e249–e252. doi: 10.1097/MPH.0b013e3182588996.
    1. Parodi E., Giraudo M.T., Ricceri F., Aurucci M.L., Mazzone R., Ramenghi U. Absolute Reticulocyte Count and Reticulocyte Hemoglobin Content as Predictors of Early Response to Exclusive Oral Iron in Children with Iron Deficiency Anemia. Anemia. 2016;2016:7345835. doi: 10.1155/2016/7345835.
    1. Kortman G.A.M., Boleij A., Swinkels D.W., Tjalsma H. Iron Availability Increases the Pathogenic Potential of Salmonella Typhimurium and Other Enteric Pathogens at the Intestinal Epithelial Interface. PLoS ONE. 2012;7:e29968. doi: 10.1371/journal.pone.0029968.
    1. Moazzen S., Dastgiri S., Dolatkhah R., Behrooz Z.A., de Bock G.H. Staple Food Fortification with Folic Acid and Iron and Gastrointestinal Cancers: Critical Appraisal of Long-Term National Fortification. Nutr. Cancer. 2021;73:1534–1538. doi: 10.1080/01635581.2020.1801778.
    1. Wurzelmann J.I., Silver A., Schreinemachers D.M., Sandler R.S., Everson R.B. Iron intake and the risk of colorectal cancer. Cancer Epidemiol. Biomark. Prev. 1996;5:503–507.
    1. Luo H., Zhang N.-Q., Huang J., Zhang X., Feng X.-L., Pan Z.-Z., Chen Y.-M., Fang Y.-J., Zhang C.-X. Different forms and sources of iron in relation to colorectal cancer risk: A case–control study in China. Br. J. Nutr. 2019;121:735–747. doi: 10.1017/S0007114519000023.
    1. Jung M., Mertens C., Tomat E., Brüne B. Iron as a Central Player and Promising Target in Cancer Progression. Int. J. Mol. Sci. 2019;20:273. doi: 10.3390/ijms20020273.
    1. Catania R., Scuderi M.G., Russo G., Miraglia V., Scalora L., Moscheo C., Musumeci A., Villari L., La Spina M., D’Amico S., et al. An Unusual Case of Severe Microcytic Anemia. J. Pediatr. Hematol. 2012;34:322. doi: 10.1097/MPH.0b013e31822031c6.
    1. Radulescu S., Brookes M.J., Salgueiro P., Ridgway R.A., McGhee E., Anderson K., Ford S.J., Stones D.H., Iqbal T.H., Tselepis C., et al. Luminal Iron Levels Govern Intestinal Tumorigenesis after Apc Loss In Vivo. Cell Rep. 2012;2:270–282. doi: 10.1016/j.celrep.2012.07.003.
    1. Giorgini E., Fisberg M., De Paula R.A., Ferreira A.M., Valle J., Braga J.A. The use of sweet rolls fortified with iron bis-glycinate chelate in the prevention of iron deficiency anemia in preschool children. Arch. Latinoam. Nutr. 2001;51:48–53.
    1. Szarfarc S.C., Núñez De Cassana L.M., Fujimori E., Guerra-Shinohara E.M., Vianna De Oliveira I.M. Relative effectiveness of iron bis-glycinate chelate (Ferrochel) and ferrous sulfate in the control of iron deficiency in pregnant women. Arch. Latinoam. Nutr. 2001;51:42–47.
    1. Pineda O., Ashmead H.D.W. Effectiveness of treatment of iron-deficiency anemia in infants and young children with ferrous bis-glycinate chelate. Nutrition. 2001;17:381–384. doi: 10.1016/S0899-9007(01)00519-6.
    1. Ferrari P., Nicolini A., Manca M.L., Rossi G., Anselmi L., Conte M., Carpi A., Bonino F. Treatment of mild non-chemotherapy-induced iron deficiency anemia in cancer patients: Comparison between oral ferrous bisglycinate chelate and ferrous sulfate. Biomed. Pharm. 2012;66:414–418. doi: 10.1016/j.biopha.2012.06.003.
    1. Jeppsen R., Borzelleca J. Safety Evaluation of Ferrous Bisglycinate Chelate. Food Chem. Toxicol. 1999;37:723–731. doi: 10.1016/S0278-6915(99)00052-6.
    1. Pisani A., Riccio E., Sabbatini M., Andreucci M., Del Rio A., Visciano B. Effect of oral liposomal iron versus intravenous iron for treatment of iron deficiency anaemia in CKD patients: A randomized trial. Nephrol. Dial. Transplant. 2015;30:645–652. doi: 10.1093/ndt/gfu357.
    1. Russo G., Guardabasso V., Romano F., Corti P., Samperi P., Condorelli A., Sainati L., Maruzzi M., Facchini E., Fasoli S., et al. Monitoring oral iron therapy in children with iron deficiency anemia: An observational, prospective, multicenter study of AIEOP patients (Associazione Italiana Emato-Oncologia Pediatrica) Ann. Hematol. 2020;99:413–420. doi: 10.1007/s00277-020-03906-w.
    1. Auerbach M., Ballard H. Clinical Use of Intravenous Iron: Administration, Efficacy, and Safety. Hematology. 2010;2010:338–347. doi: 10.1182/asheducation-2010.1.338.
    1. Huybrechts I., Lin Y., De Keyzer W., Matthys C., Harvey L., Meirhaeghe A., Dallongeville J., Sarria B., De Backer G., De Henauw S. Intake and dietary sources of haem and non-haem iron in Flemish preschoolers. Eur. J. Clin. Nutr. 2012;66:806–812. doi: 10.1038/ejcn.2012.16.
    1. Hurrell R., Egli I. Iron bioavailability and dietary reference values. Am. J. Clin. Nutr. 2010;91:1461S–1467S. doi: 10.3945/ajcn.2010.28674F.
    1. Holst B., Williamson G. Nutrients and phytochemicals: From bioavailability to bioefficacy beyond antioxidants. Curr. Opin. Biotechnol. 2008;19:73–82. doi: 10.1016/j.copbio.2008.03.003.
    1. Bryszewska M.A. Comparison Study of Iron Bioaccessibility from Dietary Supplements and Microencapsulated Preparations. Nutrients. 2019;11:273. doi: 10.3390/nu11020273.
    1. Silva A.D.P., Pereira A.D.S., Simões B.F.T., Omena J., Cople-Rodrigues C.D.S., de Castro I.R.R., Citelli M. Association of vitamin A with anemia and serum hepcidin levels in children aged 6 to 59 mo. Nutrition. 2021;91-92:111463. doi: 10.1016/j.nut.2021.111463.
    1. Jaiswal A., Lakshmi A.J. Maximising the bioaccessibility of iron and zinc of a complementary food mix through multiple strategies. Food Chem. 2021;372:131286. doi: 10.1016/j.foodchem.2021.131286.
    1. Singh A., Bains K., Kaur H. Effect of inclusion of key foods on in vitro iron bioaccessibility in composite meals. J. Food Sci. Technol. 2016;53:2033–2039. doi: 10.1007/s13197-015-2154-z.
    1. Chaparro C.M. Timing of umbilical cord clamping: Effect on iron endowment of the newborn and later iron status. Nutr. Rev. 2011;69:S30–S36. doi: 10.1111/j.1753-4887.2011.00430.x.
    1. Ziegler E.E. Consumption of cow's milk as a cause of iron deficiency in infants and toddlers. Nutr. Rev. 2011;69:S37–S42. doi: 10.1111/j.1753-4887.2011.00431.x.
    1. Position of the American Dietetic Association and Dietitians of Canada: Vegetarian diets. J. Am. Diet. Assoc. 2003;103:748–765. doi: 10.1053/jada.2003.50142.
    1. Yen C.-E., Yen C.-H., Huang M.-C., Cheng C.-H., Huang Y.-C. Dietary intake and nutritional status of vegetarian and omnivorous preschool children and their parents in Taiwan. Nutr. Res. 2008;28:430–436. doi: 10.1016/j.nutres.2008.03.012.

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