Peripheral Effects of Iron Deficiency

The estimated prevalence of iron deficiency in the world suggests that there should be widespread negative consequences of this nutrient deficiency in both developed and developing countries. In considering the reality of these estimates, the Belmont Conference seeks to reconsider the accepted relationships of iron status to physiological, biochemical and neurological outcomes. This review focuses on the biological processes that we believe are the basis for alterations in the immune system, neural systems, and energy metabolism and exercise. The strength of evidence is considered in each of the domains and the large gaps in knowledge of basic biology or iron-dependent processes are identified. Iron is both an essential nutrient and a potential toxicant to cells; it requires a highly sophisticated and complex set of regulatory approaches to meet the demands of cells as well as prevent excess accumulation. It is hoped that this review of the more basic aspects of the biology of iron will set the stage for subsequent in-depth reviews of the relationship of iron to morbidity, mortality and functioning of iron-deficient individuals and populations.

The increasing prevalence of multiple comorbidities among anemic patients with chronic kidney disease has made the use of serum ferritin and transferrin saturation more challenging in diagnosing iron deficiency. Because serum ferritin is an acute-phase reactant and because the inflammatory state may inhibit the mobilization of iron from reticuloendothelial stores, the scenario of patients with serum ferritin >800 ng/ml, suggesting iron overload, and transferrin saturation <20%, suggesting iron deficiency, has become more common. This article revisits the basis for the Kidney Disease Outcomes Quality Initiative recommendations regarding the use of serum ferritin and transferrin saturation in guiding iron therapy, then explores some of the newer alternative markers for iron status that may be useful when serum ferritin and transferrin saturation are insufficient. These newer tests include reticulocyte hemoglobin content, percentage of hypochromic red cells, and soluble transferrin receptor, all of which have shown some promise in limited studies. Finally, the role of hepcidin, a hepatic polypeptide, in the pathophysiology of iron mobilization is reviewed briefly.

The causal relationship between iron deficiency and physical work capacity is evaluated through a systematic review of the research literature, including animal and human studies. Iron deficiency was examined along a continuum from severe iron-deficiency anemia (SIDA) to moderate iron-deficiency anemia (MIDA) to iron deficiency without anemia (IDNA). Work capacity was assessed by aerobic capacity, endurance, energetic efficiency, voluntary activity and work productivity. The 29 research reports examined demonstrated a strong causal effect of SIDA and MIDA on aerobic capacity in animals and humans. The presumed mechanism for this effect is the reduced oxygen transport associated with anemia; tissue iron deficiency may also play a role through reduced cellular oxidative capacity. Endurance capacity was also compromised in SIDA and MIDA, but the strong mediating effects of poor cellular oxidative capacity observed in animals have not been demonstrated in humans. Energetic efficiency was affected at all levels of iron deficiency in humans, in the laboratory and the field. The reduced work productivity observed in field studies is likely due to anemia and reduced oxygen transport. The social and economic consequences of iron-deficiency anemia (IDA) and IDNA have yet to be elucidated. The biological mechanisms for the effect of IDA on work capacity are sufficiently strong to justify interventions to improve iron status as a means of enhancing human capital. This may also extend to the segment of the population experiencing IDNA in whom the effects on work capacity may be more subtle, but the number of individuals thus affected may be considerably more than those experiencing IDA.