Iron Metabolism and Inherited Causes of Iron Deficiency Anemia

Iron metabolism is crucial for oxygen transport and enzymatic functions, with disruptions leading to iron deficiency anemia (IDA). While acquired IDA is common, inherited forms arise from genetic mutations affecting iron absorption, transport, and utilization. These include iron-refractory iron deficiency anemia (IRIDA), hypotransferrinemia, DMT1 deficiency, ferroportin disease, and congenital sideroblastic anemias, which often mimic acquired IDA. This chapter highlights the molecular mechanisms regulating iron homeostasis, emphasizing transferrin, DMT1, ferroportin, and hepcidin. Genetic mutations in TMPRSS6, TF, SLC11A2, ALAS2, and SLC25A38 disrupt iron balance, leading to anemia. A structured diagnostic approach incorporating iron markers (serum iron, ferritin, transferrin saturation [TSAT], soluble transferrin receptor [sTFR]), hepcidin levels, and genetic testing is essential for distinguishing between inherited iron deficiency anemia (IDA) and acquired cases. Management requires individualized treatment. IRIDA is refractory to oral iron and necessitates intravenous (IV) iron therapy, while hypotransferrinemia may need plasma or apotransferrin (apoTf) therapy. Vitamin B6 benefits some cases of sideroblastic anemia, and hematopoietic stem cell transplantation (HSCT) is curative for severe cases. Emerging therapies, such as hepcidin modulators, CRISPR-based gene therapy, and AI-driven precision medicine, may become promising alternatives. Future research focuses on genomic sequencing, non-invasive iron monitoring, and personalized iron chelation. Advances in gene-editing technologies and stem cell therapies may revolutionize treatment, improving patient outcomes. A deeper understanding of iron regulatory pathways and genetic determinants is key to early diagnosis and targeted therapy.