Growth Differentiation Factor-15 and Erythroferrone are Reliable Predictors of Iron Status among Iraqi Pregnant Women with Anemia: A Case-Control Study:

Shatha Mohammed Jawad Alkhateeb; Alea Farhan Salman; Eham Amer Ali; Walaa Ahmed Al-Jedda; Alaa Fadhill Alwan

doi:10.54133/ajms.v6i2.688

Authors

Shatha Mohammed Jawad Alkhateeb Department of Chemistry and Biochemistry, College of Medicine, Mustansiriyah University, Baghdad, Iraq
Alea Farhan Salman National Center of Hematology, Mustansiriyah University, Baghdad, Iraq https://orcid.org/0000-0002-6718-4321
Eham Amer Ali Department of Chemistry and Biochemistry, College of Medicine, Mustansiriyah University, Baghdad, Iraq https://orcid.org/0000-0003-0559-9406
Walaa Ahmed Al-Jedda Department of Chemistry and Biochemistry, College of Medicine, Mustansiriyah University, Baghdad, Iraq
Alaa Fadhill Alwan National Center of Hematology, Mustansiriyah University, Baghdad, Iraq https://orcid.org/0000-0003-4757-8064

DOI:

https://doi.org/10.54133/ajms.v6i2.688

Keywords:

Anemia, Erythroferrone, Growth Differentiation Factor-15, Pregnancy

Abstract

Background: It is estimated that more than half of pregnant women all over the world are anemic. The potential of erythroferrone (ERFE) and growth differentiation factor-15 (GDF15) as indicators for iron deficiency could be used to detect various types of anemia, cardiovascular and metabolic diseases. Objectives: To assess whether variations in erythroferrone and Growth Differentiation Factor-15 in blood levels among pregnant women might be used as a marker for anemia. Methods: A cross-sectional study recruited 120 pregnant women into a study group: 60 anemic pregnant women and 60 healthy pregnant controls. Their demographics, hematological indices, and biomarkers (growth differentiation factor-15, erythroferrone, serum ferritin and iron) were collected. Results: It has been found that anemic pregnant women have statistically higher levels of Growth Differentiation-15, Erythroferrone, and other iron status compared to healthy pregnant women. The average concentration of ERFE in anemic pregnant women was 5.6 ng/mL, while in healthy pregnant women, it was 2.2 ng/mL. For GDF-15, the average concentration was 457.27 pg/mL for anemic patients and 228.89 pg/mL for healthy pregnant women. The cutoff value of both GDF-15 and ERFE had the highest sensitivity and specificity in differentiating anemic pregnant women, 1.000 (p<0.0001) for the area under the curve in the case of healthy controls. Conclusions: The markers erythroferrone and GDF-15 have a significant correlation with iron indicators and are recommended for screening anemic pregnant women.

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References

Khalaf MA, Khider DM, Kamal BJ. Anemia in pregnant women in Kirkuk Governorate. J Kirkuk Med Coll. 2020;8(1):78-85. DOI: https://doi.org/10.32894/kjms.2020.169358

Salah-Aldeen OA, Ali EA, Hameed BH. Spexin as a marker of ovarian dysfunction in PCOS related infertility. Revista Latinoamericana de Hipertensión, 2023;18(2):77-83. doi: 10.5281/zenodo.8001514. DOI: https://doi.org/10.35600/25008870.2023.18.0291

Babker AM. The role of inherited blood coagulation disorders in recurrent miscarriage syndrome. Crit Rev. 2020;7(1):16-20. doi: 10.22159/jcr.07.01.04.

Delaney KM, Guillet R, Pressman EK, Ganz T, Nemeth E, O'Brien KO. Serum erythroferrone during pregnancy is related to erythropoietin but does not predict the risk of anemia. J Nutr. 2021;151(7):1824-1833. doi: 10.1093/jn/nxab093. DOI: https://doi.org/10.1093/jn/nxab093

Sangkhae V, Yu V, Coffey R, Ganz T, Nemeth E. Erythroferrone modulates iron distribution for fetal erythropoiesis. Blood. 2021;138(1):757. doi: 10.1182/blood-2021-153902. DOI: https://doi.org/10.1182/blood-2021-153902

Srole DN, Ganz T. Erythroferrone structure, function, and physiology: Iron homeostasis and beyond. J Cell Physiol. 2021;236(7):4888-4901. doi: 10.1002/jcp.30247. DOI: https://doi.org/10.1002/jcp.30247

Coffey R, Jung G, Olivera JD, Karin G, Pereira RC, Nemeth E, et al. Erythroid overproduction of erythroferrone causes iron overload and developmental abnormalities in mice. Blood. 2022;139(3):439-451. doi: 10.1182/blood.2021014054. DOI: https://doi.org/10.1182/blood.2021014054

Wischhusen J, Melero I, Fridman WH. Growth/differentiation factor-15 (GDF-15): from biomarker to novel targetable immune checkpoint. Front Immunol. 2020;11:951. doi: 10.3389/fimmu.2020.00951. DOI: https://doi.org/10.3389/fimmu.2020.00951

Andersson-Hall U, Joelsson L, Svedin P, Mallard C, Holmäng A. Growth-differentiation-factor 15 levels in obese and healthy pregnancies: relation to insulin resistance and insulin secretory function. Clin Endocrinol (Oxf). 2021;95(1):92-100. doi: 10.1111/cen.14433. DOI: https://doi.org/10.1111/cen.14433

Lockhart SM, Saudek V, O’Rahilly S. GDF15: A hormone conveying somatic distress to the brain. Endocr Rev. 2020;41(4):bnaa007. doi: 10.1210/endrev/bnaa007. DOI: https://doi.org/10.1210/endrev/bnaa007

Koenig MD, Tussing-Humphreys L, Day J, Cadwell B, Nemeth E. Hepcidin and iron homeostasis during pregnancy. Nutrients. 2014;6(8):3062-3083. doi: 10.3390/nu6083062. DOI: https://doi.org/10.3390/nu6083062

Hjort L, Wewer Albrechtsen NJ, Minja D, Rasmussen C, Møller SL, Lusingu J, et al. Cord blood FGF-21 and GDF-15 levels are affected by maternal exposure to moderate to severe anemia and malaria. J Endocr Soc. 2023;7(10):bvad120. doi: 10.1210/jendso/bvad120. DOI: https://doi.org/10.1210/jendso/bvad120

Stevens GA, Finucane MM, De-Regil LM, Paciorek CJ, Flaxman SR, Branca F, et al. Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and non-pregnant women for 1995-2011: a systematic analysis of population-representative data. Lancet Glob Health. 2013;1(1):e16-25. doi: 10.1016/S2214-109X(13)70001-9. DOI: https://doi.org/10.1016/S2214-109X(13)70001-9

Sharma R, Stanek JR, Koch TL, Grooms L, O'Brien SH. Intravenous iron therapy in non‐anemic iron‐deficient menstruating adolescent females with fatigue. Am J Hematol. 2016;91(10):973-977. doi: 10.1002/ajh.24461. DOI: https://doi.org/10.1002/ajh.24461

SAS.SAS/STAT Users Guide for Personal Computer. Release 9.13.SAS Institute, Inc., Cary, N.C., USA, 2010.MedCalc Statistical Software version 16.4.3 (MedCalc Software bvba, Ostend, Belgium; 2016. Available at: https://www.medcalc.org

Sunuwar DR, Singh DR, Chaudhary NK, Pradhan PMS, Rai P, Tiwari K. Prevalence and factors associated with anemia among women of reproductive age in seven South and Southeast Asian countries: Evidence from nationally representative surveys. PLoS One. 2020;15(8):e0236449. doi: 10.1371/journal.pone.0236449. DOI: https://doi.org/10.1371/journal.pone.0236449

WHO. Intermittent iron and folic acid supplementation during pregnancy in malaria endemic areas. WHO. Accessed in Jan 4, 2021. Available at: http://www.who.int/elena/titles/intermittent_iron_pregnancy_malaria/en

Hussein SI, Rabaty AA. Red cell distribution width’s role in differentiating iron deficiency anemia from other hypochromic microcytic anemias. Zanco J Med Sci. 2021;25(3):625-632. DOI: https://doi.org/10.15218/zjms.2021.028

Kumar KJ, Asha N, Murthy DS, Sujatha M, Manjunath V. Maternal anemia in various trimesters and its effect on newborn weight and maturity: an observational study. Int J Prev Med. 2013;4(2):193-199. PMID: 23543625.

Mei Z, Cogswell ME, Looker AC, Pfeiffer CM, Cusick SE, Lacher DA, et al. Assessment of iron status in US pregnant women from the National Health and Nutrition Examination Survey (NHANES), 1999-2006. Am J Clin Nutr. 2011;93(6):1312-1320. doi: 10.3945/ajcn.110.007195. DOI: https://doi.org/10.3945/ajcn.110.007195

Bothwell TH. Overview and mechanisms of iron regulation. Nutr Rev. 1995;53(9):237-245. doi: 10.1111/j.1753-4887.1995.tb05480.x. DOI: https://doi.org/10.1111/j.1753-4887.1995.tb05480.x

Zimmers TA, Jin X, Hsiao EC, McGrath SA, Esquela AF, Koniaris LG. Growth differentiation factor-15/macrophage inhibitory cytokine-1 induction after kidney and lung injury. Shock. 2005;23(6):543-548. PMID: 15897808.

Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P, Lee YT, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007;13(9):1096-1101. doi: 10.1038/nm1629. DOI: https://doi.org/10.1038/nm1629

Sangkhae V, Fisher AL, Ganz T, Nemeth E. Iron homeostasis during pregnancy: Maternal, placental, and fetal regulatory mechanisms. Annu Rev Nutr. 2023;43:279-300. doi: 10.1146/annurev-nutr-061021-030404. DOI: https://doi.org/10.1146/annurev-nutr-061021-030404

Klein AB, Kleinert M, Richter EA, Clemmensen C. GDF15 in appetite and exercise: Essential player or coincidental bystander? Endocrinology. 2022;163(1):bqab242. doi: 10.1210/endocr/bqab242. DOI: https://doi.org/10.1210/endocr/bqab242

Ganz T, Jung G, Naeim A, Ginzburg Y, Pakbaz Z, Walter PB, et al. Immunoassay for human serum erythroferrone. Blood. 2017;130(10):1243-1246. doi: 10.1182/blood-2017-04-777987. DOI: https://doi.org/10.1182/blood-2017-04-777987

Delaney K, Guillet R, Pressman E, Nemeth E, O'Brien K. Erythroferrone is associated with maternal erythropoietic drive during pregnancy. Curr Dev Nutr. 2020;4(Suppl 2):968. doi: 10.1093/cdn/nzaa054_040. DOI: https://doi.org/10.1093/cdn/nzaa054_040

Appleby S, Chew-Harris J, Troughton RW, Richards AM, Pemberton CJ. Analytical and biological assessment of circulating human erythroferrone. Clin Biochem. 2020;79:41-47. doi: 10.1016/j.clinbiochem.2020.02.001. DOI: https://doi.org/10.1016/j.clinbiochem.2020.02.001

Goodrich JA, Frisco DJ, Kim S, Holliday M, Rueda M, Poddar S, et al. The importance of lean mass and iron deficiency when comparing hemoglobin mass in male and female athletic groups. J Appl Physiol (1985). 2020;129(4):855-863. doi: 10.1152/japplphysiol.00391.2020. DOI: https://doi.org/10.1152/japplphysiol.00391.2020

Robach P, Gammella E, Recalcati S, Girelli D, Castagna A, Roustit M, et al. Induction of erythroferrone in healthy humans by micro-dose recombinant erythropoietin or high-altitude exposure. Haematologica. 2021;106(2):384-390. doi: 10.3324/haematol.2019.233874. DOI: https://doi.org/10.3324/haematol.2019.233874

Moretti D, Mettler S, Zeder C, Lundby C, Geurts-Moetspot A, Monnard A, et al. An intensified training schedule in recreational male runners is associated with increases in erythropoiesis and inflammation and a net reduction in plasma hepcidin. Am J Clin Nutr. 2018;108(6):1324-1333. doi: 10.1093/ajcn/nqy247. DOI: https://doi.org/10.1093/ajcn/nqy247

Kautz L, Jung G, Du X, Gabayan V, Chapman J, Nasoff M, et al. Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of β-thalassemia. Blood. 2015;126(17):2031-2037. doi: 10.1182/blood-2015-07-658419. DOI: https://doi.org/10.1182/blood-2015-07-658419

Salman AF, Issa AH, Hameed BH. The relation of soluble fms-like tyrosine kinase-1 and placental growth factor ratio with some oxidative stress markers in preeclampsia. Biochem Cell Arch. 2020;20(2):5649-5654. DOI: https://doi.org/10.36295/ASRO.2020.231361

Ali EA, Hameed BH, Salman AF. The value of neutrophil gelatinase-associated lipocalin and neutrophil/lymphocyte ratio in the diagnosis of preeclampsia and its severity. J Med Invest. 2021;68(3.4):321-325. doi: 10.2152/jmi.68.321. DOI: https://doi.org/10.2152/jmi.68.321

Nori W, Zina Hussein ZA, Salman AF, Hameed BH. The capacity of RDW and platelet indices in defining pre-eclampsia severity: a cases-control study. Ital J Gynaecol Obstet. 2023;35(2). doi: 10.36129/jog.2022.73. DOI: https://doi.org/10.36129/jog.2022.73

Ali EA, Albayati A, Alshaban SA, Althamer KA. Serum hepcidin and ferritin level changes in iraqi adult patients with non-transfusion dependent beta-thalassemia major and intermedia. Int J Pharm Res. 2020;13(1):1373–1378. doi: 10.31838/ijpr/2021.13.01.301. DOI: https://doi.org/10.31838/ijpr/2021.13.01.301