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Serum hepcidin levels, iron status, and HFE gene alterations during the first year of life in healthy Spanish infants

Abstract

The aims of this study were to describe hepcidin levels and to assess their associations with iron status and the main variants in the HFE gene in healthy and full-term newborns during the first year of life, as a longitudinal study conducted on 140 infants. Anthropometric and biochemical parameters, hepcidin, hemoglobin (Hb), serum ferritin (SF), transferrin saturation (TS), mean corpuscular volume (MCV), and C-reactive protein (CRP), were assessed in 6- and 12-month-olds. Infants were genotyped for the three main HFE variants: C282Y, H63D, and S65C. Hepcidin levels increased from 6 to 12 months of age (43.7 ± 1.5 to 52.0 ± 1.5 ng/mL; p < 0.001), showing higher levels in infants with better iron status compared to those with iron deficiency (ID) (44.8 ± 1.5 vs 37.9 ± 1.3 ng/mL, p < 0.018, and 54.3 ± 1.5 vs 44.0 ± 1.4 ng/mL, p < 0.038, in 6- and 12-month-olds, respectively). In multivariate linear regression models, iron status was found to be associated with hepcidin levels in infants with wild-type HFE gene (p = 0.046 and p = 0.048 in 6- and 12-month-olds, respectively). However, this association was not found in HFE-alteration-carrying infants. Hepcidin levels increased in healthy infants during the first year of life and were positively associated with iron levels only in infants with wild-type HFE gene, a situation that requires further investigation.

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References

  1. 1.

    Durá T, Díaz L (2002) Prevalencia de la deficiencia de hierro en lactantes sanos de 12 meses de edad. An Esp Pediatr 57(3):209–214. https://doi.org/10.1016/s1695-4033(02)77907-1

    Article  Google Scholar 

  2. 2.

    McLean E, Cogswell M, Egli I, Wojdyla D, de Benoist B (2009) Worldwide prevalence of anaemia, WHO vitamin and mineral nutrition information system, 1993–2005. Public Health Nutr 12(04):444–454. https://doi.org/10.1017/s1368980008002401

    Article  PubMed  Google Scholar 

  3. 3.

    Roncagliolo M, Garrido M, Walter T, Peirano P, Lozoff B (1998) Evidence of altered central nervous system development in infants with iron deficiency anemia at 6 mo: delayed maturation of auditory brainstem responses. Am J Clin Nutr 68(3):683–690. https://doi.org/10.1093/ajcn/68.3.683

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Lozoff B, Beard J, Connor J, Barbara F, Georgieff M, Schallert T (2006) Long-lasting neural and behavioral effects of iron deficiency in infancy. Nutr Rev 64:S34–S91

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Thomas DG, Grant SL, Aubuchon-Endsley NL (2009) The role of iron in neurocognitive development. Dev Neurophsychol 34(2):196–122. https://doi.org/10.1080/87565640802646767

    Article  Google Scholar 

  6. 6.

    Beard J (2007) Recent evidence from human and animal studies regarding iron status and infant development. J Nutr 137(2):524S–530S. https://doi.org/10.1093/jn/137.2.524S

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Chaparro CM (2008) Setting the stage for child health and development: prevention of iron deficiency in early infancy. J Nutr 138(12):2529–2533. https://doi.org/10.1093/jn/138.12.2529

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Moráis A, Dalmau J (2011) Importancia de la ferropenia en el niño pequeño: Repercusiones y prevención. An Pediatr 74(6):415.e1–415.e10. https://doi.org/10.1016/j.anpedi.2011.01.036

    Google Scholar 

  9. 9.

    Demircioglu F, Gorunmez G, Dagıstan E et al (2014) Serum hepcidin levels and iron metabolism in obese children with and without fatty liver: case-control study. Eur J Pediatr 173:947–951. https://doi.org/10.1007/s00431-014-2268-8

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Galesloot TE, Janss LL, Burgess S et al (2015) Iron and hepcidin as risk factors in atherosclerosis: what do the genes say? BMC Genet 16(7):79. https://doi.org/10.1186/s12863-015-0246-4

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Pechlaner R, Kiechl S, Mayr M, Santer P, Weger S, Haschka D, Bansal SS, Willeit J, Weiss G (2016) Correlates of serum hepcidin levels and its association with cardiovascular disease in an elderly general population. Clin Chem Lab Med 54(1):151–161. https://doi.org/10.1515/cclm-2015-0068

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Berglund S, Lonnerdal B, Westrup B, Domellof M (2011) Effects of iron supplementation on serum hepcidin in low birth weight infants. Am J Clin Nutr 94(6):1553–1561. https://doi.org/10.3945/ajcn.111.013938

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Ganz T, Olbina G, Girelli D, Nemeth E, Westerman M (2008) Immunoassay for human serum hepcidin. Blood 112(10):4292–4297. https://doi.org/10.1182/blood-2008-02-139915

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Ganz T, Nemeth E (2012) Hepcidin and iron homeostasis. Biochim Biophys Acta 1823(9):1434–1443. https://doi.org/10.1016/j.bbamcr.2012.01.014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Dogan A, Alioglu B, Dindar N, Dallar Y (2013) Increased serum hepcidin and ghrelin levels in children treated for iron deficiency anemia. J Clin Lab Anal 27(1):81–85. https://doi.org/10.1002/jcla.21566

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Galesloot TE, Vermeulen SH, Geurts-Moespot AJ, Klaver SM, Kroot JJ, van Tienoven D, Wetzels JFM, Kiemeney LALM, Sweep FC, den Heijer M, Swinkels DW (2011) Serum hepcidin: reference ranges and biochemical correlates in the general population. Blood 117(25):218–226. https://doi.org/10.1182/blood-2011-02-337907

    Article  Google Scholar 

  17. 17.

    Rochette L, Gudjoncik A, Guenancia C, Zeller M, Cottin Y, Vergely C (2015) The iron-regulatory hormone hepcidin: a possible therapeutic target? Pharmacol Ther 146:35–52. https://doi.org/10.1016/j.pharmthera.2014.09.004

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Aranda N, Viteri FE, Fernández-Ballart J, Murphy M, Arija V (2007) Frequency of the hemochromatosis gene (HFE) 282C→Y, 63H→D, and 65S→C mutations in a general Mediterranean population from Tarragona, Spain. Ann Hematol 86:17–21. https://doi.org/10.1007/s00277-006-0179-0

    Article  PubMed  Google Scholar 

  19. 19.

    Papanikolaou G, Tzilianos M, Christakis JI, Bogdanos D, Tsimirika K, MacFarlane J, Goldberg YP, Sakellaropoulos N, Ganz T, Nemeth E (2005) Hepcidin in iron overload disorders. Blood 105(10):4103–4105. https://doi.org/10.1182/blood-2004-12-4844

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Fairbanks VF, Klee GG (1999) Biochemical aspects of haematology, 3rd edn. Saunders, Philadelphia

    Google Scholar 

  21. 21.

    Aranda N, Viteri FE, Montserrat C, Arija V (2010) Effects of C282Y, H63D, and S65C HFE gene mutations, diet, and life-style factors on iron status in a general Mediterranean population from Tarragona, Spain. Ann Hematol 89(8):767–773. https://doi.org/10.1007/s00277-010-0901-9

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Hollingshead AB (2011) Four factor index of social status. Yale J Sociol 8:21–52 http://www.yale.edu/sociology/yjs/yjs_fall_2011.pdf. Accessed 19 March 2017

    Google Scholar 

  23. 23.

    Choi HS, Song SH, Lee JH, Kim HJ, Yang HR (2012) Serum hepcidin levels and iron parameters in children with iron deficiency. Korean J Hematol 47(4):286–292. https://doi.org/10.5045/kjh.2012.47.4.286

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Muller KF, Lorenz L, Poets CF, Westerman M, Franz AR (2012) Hepcidin concentrations in serum and urine correlate with iron homeostasis in preterm infants. J Pediatr 160(6):949–953. https://doi.org/10.1016/j.jpeds.2011.12.030

    Article  PubMed  Google Scholar 

  25. 25.

    Mupfudze TG, Stoltzfus RJ, Rukobo S, Moulton LH, Humphrey JH, Prendergast AJ (2014) Hepcidin decreases over the first year of life in healthy African infants. Br J Haematol 164(1):150–153. https://doi.org/10.1111/bjh.12567

    Article  PubMed  Google Scholar 

  26. 26.

    Uijterschout L, Swinkels DW, Domellof M et al (2014) Serum hepcidin measured by immunochemical and mass-spectrometric methods and their correlation with iron status indicators in healthy children aged 0.5–3 y. Pediatr Res 76(4):409–414. https://doi.org/10.1038/pr.2014.109

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Viatte L, Vaulont S (2009) Hepcidin, the iron watcher. Biochimie 91:1223–1228. https://doi.org/10.1016/j.biochi.2009.06.012

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Dahlfors G, Stal P, Hansson EC et al (2015) Validation of a competitive ELISA assay for the quantification of human serum hepcidin. Scand J Clin Lab Invest 75(10):652–658

    PubMed  Google Scholar 

  29. 29.

    Domellöf M, Dewey KG, Lönnerdal B, Cohen RJ, Hernell O (2002) The diagnostic criteria for iron deficiency in infants should be reevaluated. J Nutr 132(12):3680–3686. https://doi.org/10.1093/jn/132.12.3680

    Article  PubMed  Google Scholar 

  30. 30.

    Emond AM, Hawkins N, Pennock C, Golding J (1996) Haemoglobin and ferritin concentrations in infants at 8 months of age. Arch Dis Child 74(1):36–39. https://doi.org/10.1136/adc.74.1.36

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Yalçin SS, Dut R, Yurdakok K, Ozmert E (2009) Seasonal and gender differences in hemoglobin value in infants at 5–7 months of age. Turk J Pediatr 51(6):572–577

    PubMed  Google Scholar 

  32. 32.

    Sherriff A, Emond A, Bell JC, Golding J (2001) Should infants be screened for anaemia? A prospective study investigating the relation between haemoglobin at 8, 12, and 18 months and development at 18 months. Arch Dis Child 84(6):480–485. https://doi.org/10.1136/adc.84.6.480

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Domellof M, Hernell O (2002) Iron-deficiency anaemia during the first two years of life. Scand J Nutr 46(1):20–30. https://doi.org/10.1080/110264802753704091

    Article  Google Scholar 

  34. 34.

    Makrides M, Leeson R, Gibson RA, Simmer K (1998) A randomized controlled clinical trial of increased dietary iron in breastfed infants. J Pediatr 133(4):559–562. https://doi.org/10.1016/S0022-3476(98)70069-1

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Hay G, Sandstad B, Whitelaw A, Borch-Iohnsen B (2004) Iron status in a group of Norwegian children aged 6-24 months. Acta Paediatr 93(5):592–598. https://doi.org/10.1111/j.1651-2227.2004.tb02983.x

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Beristain R, Pasquetti A, Meléndez G, Sánchez-Escobar O, Cuevas-Covarrubias S (2010) Evaluation of iron status in healthy six-month-old infants in Mexican population: evidence of a high prevalence of iron deficiency. e- Spen, Eur e-J Clin Nutr Metab 5(1):37–39. https://doi.org/10.1016/j.eclnm.2010.01.001

    Article  Google Scholar 

  37. 37.

    Trowbridge F, Martorell R (2002) Forging effective strategies to combat iron deficiency. Summ Recomm J Nutr 132(4 Suppl):875S–879S

    CAS  Google Scholar 

  38. 38.

    Male C, Persson LA, Freeman V, Guerra A, van't Hof MA, Haschke F (2001) Prevalence of iron deficiency in 12-mo-old infants from 11 European areas and influence of dietary factors on iron status (Euro-Growth study). Acta Paediatr 90(5):492–498. https://doi.org/10.1080/080352501750197601

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Vila Sanchez M et al (2003) Population screening for hemochromatosis: a study in 5370 Spanish blood donors. J Hepatol 38(6):745–750. https://doi.org/10.1016/S0168-8278(03)00123-5

    Article  Google Scholar 

  40. 40.

    Altes A, Ruiz A et al (2004) Frequency of the C282Y and H63D mutations of the hemochromatosis gene (HFE) in a cohort of 1,000 neonates in Madrid (Spain). Genet Test. Winter 8:407–410

    CAS  Article  Google Scholar 

  41. 41.

    Ropero P, Briceño O, Mateo M, Polo M, Mora A, González FA, Villegas A (2006) Frequency of the C282Y and H63D mutations of the hemochromatosis gene (HFE) in a cohort of 1,000 neonates in Madrid (Spain). Ann Hematol 85(5):323–326. https://doi.org/10.1007/s00277-006-0094-4

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Hentze MW, Muckenthaler MU, Galy B, Camaschella C (2010) Two to tango: regulation of mammalian iron metabolism. Cell 142(1):24–38. https://doi.org/10.1016/j.cell.2010.06.028

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Rossi E (2005) Hepcidin—the iron regulatory hormone. Clin Biochem Rev 26:47–49

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Sdogou T, Tsentidis C, Gourgiotis D, Marmarinos A, Gkourogianni A, Papassotiriou I, Anastasiou T, Kossiva L (2015) Immunoassay-based serum hepcidin reference range measurements in healthy children: differences among age groups. J Clin Lab Anal 29(1):10–14. https://doi.org/10.1002/jcla.21719

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Schaap CC, Hendriks JC, Kortman GA et al (2013) Diurnal rhythm rather than dietary iron mediates daily hepcidin variations. Clin Chem 59(3):527–535. https://doi.org/10.1373/clinchem.2012.194977

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Kroot JJ, Hendriks J, Laarakkers CM et al (2009) Pre-analytical imprecision, between-subject variability, and daily variations in serum and urine hepcidin: implications for clinical studies. Anal Biochem 389(2):124–129. https://doi.org/10.1016/j.ab.2009.03.039

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Cangemi G, Pistorio A, Miano M, Gattorno M, Acquila M, Bicocchi MP, Gastaldi R, Riccardi F, Gatti C, Fioredda F, Calvillo M, Melioli G, Martini A, Dufour C (2013) Diagnostic potential of hepcidin testing in pediatrics. Eur J Haematol 90(4):323–330. https://doi.org/10.1111/ejh.12081

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Bhatia P, Marathe R, Hegde A, Bhardwaj D, Jain R (2017) Plasma hepcidin levels in healthy children from Chandigarh, Northern India. Indian Pediatr 54(7):599–600. https://doi.org/10.1007/s13312-017-1078-2

    Article  PubMed  Google Scholar 

  49. 49.

    Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, Beaumont C, Kahn A, Vaulont S (2002) The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 110(7):1037–1044. https://doi.org/10.1172/JCI0215686

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Cherian S, Forbes DA, Cook AG, Sanfilippo FM, Kemna EH, Swinkels DW, Burgner DP (2008) An insight into the relationships between hepcidin, anemia, infections and inflammatory cytokines in pediatric refugees: a cross-sectional study. PLoS ONE 3(12):e4030. https://doi.org/10.1371/journal.pone.0004030

    Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Vujić M (2014) Molecular basis of HFE-hemochromatosis. Front Pharmacol 5:42. https://doi.org/10.3389/fphar.2014.00042

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Verga Falzacappa MV, Vujic Spasic M, Kessler R, Stolte J, Hentze MW, Muckenthaler MU (2007) STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood 109(12):353–358. https://doi.org/10.1371/journal.pone.0004030

    Article  PubMed  Google Scholar 

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Funding

This study was supported by a grant from Institut d’Investigació Sanitària Pere Virgili (2010/IISPV/12).

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Correspondence to Monica Tous.

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Informed consent was obtained from all families according to the Helsinki declaration—prior to enrolment—and the study was approved by the ethics committee of the Hospital Universitari Sant Joan de Reus.

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The authors declare that they have no conflict of interest.

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Informed consent was obtained from all families included in the study.

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Aranda, N., Bedmar, C., Arija, V. et al. Serum hepcidin levels, iron status, and HFE gene alterations during the first year of life in healthy Spanish infants. Ann Hematol 97, 1071–1080 (2018). https://doi.org/10.1007/s00277-018-3256-2

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Keywords

  • Hepcidin levels
  • HFE gene
  • Infants
  • Iron status