Impairment of the Developing Human Brain in Iron Deficiency: Correlations to Findings in Experimental Animals and Prospects for Early Intervention Therapy.

Veronika Markova,Anja Pinborg,Lars Thomsen,Charlotte Holm,Torben Moos

doi:10.3390/ph12030120

Abstract

Due to the necessity of iron for a variety of cellular functions, the developing mammalian organism is vulnerable to iron deficiency, hence causing structural abnormalities and physiological malfunctioning in organs, which are particularly dependent on adequate iron stores, such as the brain. In early embryonic life, iron is already needed for proper development of the brain with the proliferation, migration, and differentiation of neuro-progenitor cells. This is underpinned by the widespread expression of transferrin receptors in the developing brain, which, in later life, is restricted to cells of the blood–brain and blood–cerebrospinal fluid barriers and neuronal cells, hence ensuring a sustained iron supply to the brain, even in the fully developed brain. In embryonic human life, iron deficiency is thought to result in a lower brain weight, with the impaired formation of myelin. Studies of fully developed infants that have experienced iron deficiency during development reveal the chronic and irreversible impairment of cognitive, memory, and motor skills, indicating widespread effects on the human brain. This review highlights the major findings of recent decades on the effects of gestational and lactational iron deficiency on the developing human brain. The findings are correlated to findings of experimental animals ranging from rodents to domestic pigs and non-human primates. The results point towards significant effects of iron deficiency on the developing brain. Evidence would be stronger with more studies addressing the human brain in real-time and the development of blood biomarkers of cerebral disturbance in iron deficiency. Cerebral iron deficiency is expected to be curable with iron substitution therapy, as the brain, privileged by the cerebral vascular transferrin receptor expression, is expected to facilitate iron extraction from the circulation and enable transport further into the brain.

Highlights

Iron deficiency is the most common type of malnutrition in humans [1,2,3,4]
This review aims to summarize the current evidence on the significance of iron for the developing brain, how iron deficiency may impair functioning of the central nervous system (CNS) in the human brain and brains of experimental animals, and which therapeutic advances available can prevent damage to the developing CNS
The human brain develops throughout the gestational period, ranging from the formation and proliferation of neuroprogenitor cells, to their later migration, and later differentiation into fully developed neurons and glial cells

Summary

Introduction

Iron deficiency is the most common type of malnutrition in humans [1,2,3,4]. Iron deficiency occurs due to an inadequate intake, excess loss, or increased need, and gradually leads to insufficient functions of many organs, including the bone marrow, and as a consequence, iron deficiency leads to iron deficiency anemia [5,6,7]. According to the WHO, anemia affects 1.8 billion people worldwide, equivalent to approximately 25% of the world’s population. Among this group, approximately 0.5 billion are women of a reproductive age, and in developing countries, the incidence of anemia is even higher and varies during pregnancy from 35% to 56% for Africa, 37% to 75% in Asia, and 37% to 52% in Latin America. Women of a reproductive age are at risk for developing iron deficiency due to menstrual bleeding and pregnancy. When the maternal iron stores exceed this threshold, the placenta actively transports iron into the fetal circulation to ensure adequate iron supply to the fetus [9]

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