Normal Range and Predictors of Serum Erythroferrone in Infants

Overview

Journal Pediatr Res

Specialties Biology
Pediatrics

Date 2023 Apr 17

PMID 37069224

Authors

Fredrik Backstrom

Anna Chmielewska

Magnus Domellof

Staffan K Berglund

Affiliations

Soon will be listed here.

Abstract

Background: Erythroferrone (ERFE) has been identified as a hepcidin-regulating hormone synthetized by erythroblasts correlating to the erythropoietic activity and the needs for iron substrate in bone marrow of adults. The present study aimed to assess the ERFE serum concentrations and its predictors in infants.

Methods: ERFE was explored at 4 time points during the first year of life in 45 healthy, breastfed, normal birth weight (NBW) infants, and 136 marginally low birth weight infants (LBW, 2000-2500 g) receiving iron (N = 58) or placebo (N = 78) between 6 weeks and 6 months of age.

Results: ERFE concentrations were low at birth, increasing gradually during the first year of life. In NBW infants, reference ranges (5th to 95th percentile) were at 6 weeks <0.005-0.99 ng/mL and at 12 months <0.005-33.7 ng/mL. ERFE was higher in LBW infants at 6 weeks but lower at 12 months compared to NBW and minimally affected by iron supplementation among LBW infants. Correlations of ERFE with erythropoietic and iron status markers were weak and inconsistent.

Conclusions: The role of ERFE in the crosstalk of erythropoiesis and iron homeostasis remains unclear in infants and further studies on ERFE in infants and older children are warranted within the framework of the erythropoietin-ERFE-hepcidin axis.

Impact: Normal range of erythroferrone in healthy infants is described for the first time. Erythroferrone in infants lacks correlation to iron status and markers of erythropoiesis. The findings indicate differences in infant regulation of iron homeostasis as compared to adults. The findings point to a need to study infant erythropoiesis separately from its adult counterpart. The findings may have clinical impact on management strategies of iron-loading anemia in infancy.

References

Berglund S, Domellof M . Iron deficiency in infancy: current insights. Curr Opin Clin Nutr Metab Care. 2021; 24(3):240-245. DOI: 10.1097/MCO.0000000000000749. View

Nemeth E, Tuttle M, Powelson J, Vaughn M, Donovan A, Ward D . Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004; 306(5704):2090-3. DOI: 10.1126/science.1104742. View

Sangkhae V, Nemeth E . Regulation of the Iron Homeostatic Hormone Hepcidin. Adv Nutr. 2017; 8(1):126-136. PMC: 5227985. DOI: 10.3945/an.116.013961. View

Kautz L, Jung G, Valore E, Rivella S, Nemeth E, Ganz T . Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet. 2014; 46(7):678-84. PMC: 4104984. DOI: 10.1038/ng.2996. View

Srole D, Ganz T . Erythroferrone structure, function, and physiology: Iron homeostasis and beyond. J Cell Physiol. 2020; 236(7):4888-4901. PMC: 8026552. DOI: 10.1002/jcp.30247. View

Hanudel M, Rappaport M, Chua K, Gabayan V, Qiao B, Jung G . Levels of the erythropoietin-responsive hormone erythroferrone in mice and humans with chronic kidney disease. Haematologica. 2018; 103(4):e141-e142. PMC: 5865435. DOI: 10.3324/haematol.2017.181743. View

Robach P, Gammella E, Recalcati S, Girelli D, Castagna A, Roustit M . Induction of erythroferrone in healthy humans by micro-dose recombinant erythropoietin or high-altitude exposure. Haematologica. 2020; 106(2):384-390. PMC: 7849588. DOI: 10.3324/haematol.2019.233874. View

Ganz T, Jung G, Naeim A, Ginzburg Y, Pakbaz Z, Walter P . Immunoassay for human serum erythroferrone. Blood. 2017; 130(10):1243-1246. PMC: 5606005. DOI: 10.1182/blood-2017-04-777987. View

El Gendy F, El-Hawy M, Shehata A, Osheba H . Erythroferrone and iron status parameters levels in pediatric patients with iron deficiency anemia. Eur J Haematol. 2017; 100(4):356-360. DOI: 10.1111/ejh.13021. View

10.

Delaney K, Guillet R, Pressman E, Ganz T, Nemeth E, OBrien K . Umbilical Cord Erythroferrone Is Inversely Associated with Hepcidin, but Does Not Capture the Most Variability in Iron Status of Neonates Born to Teens Carrying Singletons and Women Carrying Multiples. J Nutr. 2021; 151(9):2590-2600. PMC: 8417932. DOI: 10.1093/jn/nxab156. View

11.

Meznarich J, Draper L, Christensen R, Yaish H, Luem N, Pysher T . Fetal presentation of congenital dyserythropoietic anemia type 1 with novel compound heterozygous CDAN1 mutations. Blood Cells Mol Dis. 2018; 71:63-66. PMC: 5947870. DOI: 10.1016/j.bcmd.2018.03.002. View

12.

Bahr T, Ward D, Jia X, Ohls R, German K, Christensen R . Is the erythropoietin-erythroferrone-hepcidin axis intact in human neonates?. Blood Cells Mol Dis. 2021; 88:102536. PMC: 9107158. DOI: 10.1016/j.bcmd.2021.102536. View

13.

Berglund S, Westrup B, Domellof M . Iron supplements reduce the risk of iron deficiency anemia in marginally low birth weight infants. Pediatrics. 2010; 126(4):e874-83. DOI: 10.1542/peds.2009-3624. View

14.

Pasricha S, Tye-Din J, Muckenthaler M, Swinkels D . Iron deficiency. Lancet. 2020; 397(10270):233-248. DOI: 10.1016/S0140-6736(20)32594-0. View

15.

Lonnerdal B . Development of iron homeostasis in infants and young children. Am J Clin Nutr. 2017; 106(Suppl 6):1575S-1580S. PMC: 5701726. DOI: 10.3945/ajcn.117.155820. View

16.

Seldin M, Peterson J, Byerly M, Wei Z, Wong G . Myonectin (CTRP15), a novel myokine that links skeletal muscle to systemic lipid homeostasis. J Biol Chem. 2012; 287(15):11968-80. PMC: 3320944. DOI: 10.1074/jbc.M111.336834. View

17.

Berglund S, Lonnerdal B, Westrup B, Domellof M . Effects of iron supplementation on serum hepcidin and serum erythropoietin in low-birth-weight infants. Am J Clin Nutr. 2011; 94(6):1553-61. DOI: 10.3945/ajcn.111.013938. View

18.

Arezes J, Foy N, McHugh K, Quinkert D, Benard S, Sawant A . Antibodies against the erythroferrone N-terminal domain prevent hepcidin suppression and ameliorate murine thalassemia. Blood. 2020; 135(8):547-557. PMC: 7046598. DOI: 10.1182/blood.2019003140. View