Functional iron deficiency resulting mainly from inflammation driven diversion of iron trafficking. Inflammation results in profound alterations of iron homeostasis, which are characterized by low circulating iron and increased ferritin levels along with tissue iron retention, which frequently lead to anaemia of chronic disease (ACD). ACD is found in patients with immunity associated diseases such as infections, cancer, auto-immune disease, congestive heart or renal failure. Hypoferremia largely results from IL-1 and IL-6 mediated stimulation of hepcidin expression with consecutive iron retention in enterocytes and macrophages. Thus, inflammation causes a reduced dietary iron absorption and impaired transfer of recycled iron from macrophages to the circulation thereby limiting iron availability for erythropoiesis. This disturbance of iron trafficking is thought to arise from an immune defense strategy of the body, termed as nutritional immunity, which limits the availability of iron for invading pathogens. As described for the mammalian host, most pathogens, are dependent on a sufficient supply of iron which they need for their metabolism, pathogenicity and multiplication. Therefore, several infection resistance pathways of the body exert part of their anti-microbial activity by reducing the availability of iron to either intra or extracellular microbes.
The iron restriction strategies against extra- versus intracellular microbes are different and even contrasting. Currently we are lacking knowledge on the regulatory signals and pathways, which induce such pathogen specific metabolic networks with their subsequent also not very well studied effects on immune function. Consequently, we do not know how iron supplementation either by the oral or intravenous route may impact on the course of infections depending on the nature and localisation of the pathogen, an issue which is of utmost importance specifically in countries with a high environmental burden of infections where iron supplementation in nutrients is used to prevent negative effects of iron deficiency on the growth and mental development of children.
