Iron Supplementation and Copper Homeostasis: Evidence for Potential Copper Depletion, Biomarker Challenges, and Clinical Implications.

Iron deficiency remains a major nutritional problem, particularly among women of reproductive age, pregnant women, infants, and children. Oral iron supplementation is the principal strategy for prevention and treatment, but the biological interdependence of iron and copper metabolism raises concern that prolonged or excessive iron exposure may impair copper availability in susceptible individuals. This review summarizes human and animal evidence linking iron supplementation or high dietary iron intake to altered copper homeostasis, with emphasis on underlying mechanisms, biomarker limitations, and clinical implications. Human studies report inconsistent changes in serum copper and ceruloplasmin, suggesting that baseline mineral status, physiological demand, iron dose, treatment duration, inflammation, and biomarker selection may influence responses. Animal studies provide stronger mechanistic evidence that high iron intake can reduce intestinal copper absorption and copper-dependent ferroxidase activity, promote tissue iron sequestration, and contribute to anemia, impaired growth, cardiac enlargement, dyslipidemia, gastrointestinal alterations, and disrupted maternal-offspring copper transfer. However, the clinical relevance of these findings remains uncertain because standardized diagnostic criteria and sensitive biomarkers for marginal copper deficiency are lacking. Iron intervention should remain guided by confirmed iron status, while dose, duration, and treatment response warrant careful consideration. Evaluation of copper status may be particularly relevant when hematological recovery is inadequate despite sufficient iron stores or when additional risk factors for copper deficiency are present. Prospective human studies incorporating functional biomarkers are needed to identify susceptible populations and clinically relevant exposure conditions.