Chronic Inflammation and Iron Metabolism

Iron is an essential component of almost all biological systems. It is required for energy production, oxygen transport and utilization, cellular proliferation, and destruction of pathogens. The biological properties of iron stem from the variability of its Fe2+/Fe3+ redox potential. Protein ligands adapt these redox potentials to meet various biological requirements. Iron containing proteins are essential to many biochemical functions including oxygen transport by the hemoproteins hemoglobin and myoglobin. Other hemoproteins include the activators of molecular oxygen; cytochrome oxidases, peroxidases, catalases, and cytochrome P450s as well as the cytochromes that transfer electrons from substrate oxidation to cytochrome c oxidase. Iron sulfur proteins are another class of iron containing proteins that mediate one electron redox processes as integral components of the respiratory chain in mitochondria. They are also involved in the control of gene expression, DNA damage recognition and repair, oxygen and nitrogen sensing, and the control of cellular iron acquisition and storage. The vital importance of maintaining iron supply is most obvious in children. Children, unlike adults, have high iron requirements because of significant cellular metabolic demands due to the high growth rates of their developing tissues and the rapid expansion of their red cell mass. The human brain at birth is the most highly metabolic organ, consuming ~50% of the body’s energy needs1. Highly metabolic organs need a plentiful supply of substrates, including iron, that support energy metabolism. This metabolic need is reflected in the different physiologic iron absorption requirements (per kilogram) at varying stages of development to maintain normal hemoglobin concentrations as the red cell volume expands with growth and for normal iron delivery to tissues. Per the Food and Nutrition Board of the Institutes of Medicine, the recommended dietary allowance for enteral iron starts at 0.27mg/day in the birth to 6 month age group, increases to 11mg/day in 7 to 12 month old infants, and then is 7mg/day in the 1 to 3 year age group. Women of child-bearing age require 18 mg/day and this value increases to 27mg/day during pregnancy2. Failure to maintain iron sufficiency during fetal life and in early childhood causes long-term alterations to developing organs, most importantly the brain3. Thus, ensuring adequate iron delivery to children during rapid growth phases is essential. Although maintaining iron delivery to children is vital to support their growth and neurodevelopment, there exists a conundrum in that there are potential negative consequences of iron supplementation in certain contexts such as infectious states. Iron supports the growth and differentiation of other rapidly growing cells including infectious agents. Bacteria are able to form biofilms and grow more rapidly when iron is abundant4–5. Bacteria have evolved mechanisms to acquire iron in low iron environments that include the secretion and reuptake of iron-binding organic molecules termed siderophores. Pathogens have developed the ability to acquire iron from host iron-binding proteins like hemoglobin, lactoferrin, and transferrin4. The body has evolved a finely tuned mechanism to limit iron availability during infection. In the short-term, this is advantageous and promotes basic survival by protecting from overwhelming infection. In the long-term, anemia of inflammation, also known as the anemia of chronic disease, can place the child’s growth and future development at risk by limiting iron availability. Given the potential for long lasting effects, we will discuss the important inter-relationships between chronic disease and iron metabolism.. Although there remain few pediatric specific examples in the literature, the mechanisms gleaned from the adult literature strongly suggest some of the same iron regulation events that take place with acute inflammation and iron metabolism apply to chronic disease in children. Therefore, we will: (1) provide background to explain the importance of the supply and demand and regulatory proteins involved in iron metabolism; (2) review how these regulation principles apply to anemia of inflammation; and (3) propose how these principles apply to anemia of chronic disease and provide clinically relevant examples.