Iron deficiency beyond erythropoiesis: should we be concerned?

Abstract

Objective: To consider the key implications of iron deficiency for biochemical and physiological functions beyond erythropoiesis.

Methods: PubMed was searched for relevant journal articles published up to August 2017.

Results: Anemia is the most well-recognized consequence of persisting iron deficiency, but various other unfavorable consequences can develop either before or concurrently with anemia. Mitochondrial function can be profoundly disturbed since iron is a cofactor for heme-containing enzymes and non-heme iron-containing enzymes in the mitochondrial electron transport chain. Biosynthesis of heme and iron-sulfur clusters in the mitochondria is inhibited, disrupting synthesis of compounds such as hemoglobin, myoglobin, cytochromes and nitric oxide synthase. The physiological consequences include fatigue, lethargy, and dyspnea; conversely, iron repletion in iron-deficient individuals has been shown to improve exercise capacity. The myocardium, with its high energy demands, is particularly at risk from the effects of iron deficiency. Randomized trials have found striking improvements in disease severity in anemic but also non-anemic chronic heart failure patients with iron deficiency after iron therapy. In vitro and pre-clinical studies have demonstrated that iron is required by numerous enzymes involved in DNA replication and repair, and for normal cell cycle regulation. Iron is also critical for immune cell growth, proliferation, and differentiation, and for specific cell-mediated effector pathways. Observational studies have shown that iron-deficient individuals have defective immune function, particularly T-cell immunity, but more evidence is required. Pre-clinical models have demonstrated abnormal myelogenesis, brain cell metabolism, neurotransmission, and hippocampal formation in iron-deficient neonates and young animals. In humans, iron deficiency anemia is associated with poorer cognitive and motor skills. However, the impact of iron deficiency without anemia is less clear.

Conclusion: The widespread cellular and physiological effects of iron deficiency highlight the need for early detection and treatment of iron deficiency, both to ameliorate these non-erythropoietic effects, and to avoid progression to iron deficiency anemia.

Keywords:

• DNA
• energy
• fatigue
• iron deficiency
• metabolism
• mitochondria
• immune

Transparency

Declaration of funding

This manuscript was funded by Vifor Pharma, Glattbrugg, Switzerland.

Declaration of financial/other interests

KM and AT have received honoraria from Vifor Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial relationships to disclose.

Acknowledgements

The authors would like to thank Clara Camaschella of the Vita-Salute San Raffaele University in Milan for her critical review of the manuscript. Editorial support was provided by a medical writer (C. Dunstall) funded by Vifor Pharma, Glattbrugg, Switzerland.