Microcytic anaemias in childhood and iron‐refractory iron deficiency anaemia

In this issue, Bhatia et al (2017) report a study from India in which iron deficiency anaemia was found to be resistant to oral iron therapy in over 10% of 550 young children: those resistant were subsequently investigated for the phenotype of iron refractory iron deficiency anaemia (IRIDA) and, where this was present, whether TMPRSS6 gene variations might explain this finding. Their work draws attention to the approach to the diagnosis of microcytic anaemias, and how new understanding of the molecular pathways involved in systemic and cellular iron metabolism (comprehensively reviewed by Hentze et al, 2010) may change this. Microcytic anaemias accompany reduced haemoglobin production in developing red cells. This in turn results from failure of either haem synthesis (most commonly from lack of availability of iron but rarely from failure of protoporphyrin synthesis or of iron incorporation into the porphyrin ring in sideroblastic anaemias), or of globin synthesis in the thalassaemia disorders. Many young children have minimal or no iron stores as assessed by low serum ferritin concentrations and are at particular risk of developing iron deficiency anaemia, by far the commonest cause of childhood anaemia: in the UK National Diet and Nutrition Surveys, up to a third of children aged 1 5–4 5 years had serum ferritin values below the World Health Organization cut off values (Scientific Advisory Committee on Nutrition, 2010). Iron deficiency in such children is usually the result of a combination of the increased iron requirements of growth and limited availability of iron in the diet, particularly if the latter is predominantly vegetarian, though chronic blood loss (e.g. from intestinal hookworm infestation) and exposure to cow’s milk may be important in many parts of the world. Chronic disease may also give rise to microcytic red cells as a result of iron malutilisation rather than any reduction in total body iron and may impair the response to iron therapy. Contributions from multiple causes in a single patient may sometimes cause diagnostic difficulty, and interpretations of individual laboratory measures of iron status need to consider whether they are appropriate to the overall clinical context. For example, a ‘normal’ plasma ferritin in the presence of anaemia may be inappropriate in the sense that, together, the measures imply an overall reduction of total body iron, as may a ‘normal’ plasma hepcidin in the presence of iron deficiency (Girelli et al, 2016). In most cases iron deficiency anaemia responds rapidly to oral iron, but less common alternative diagnoses must be considered, especially if there is an inadequate response. Such refractoriness may result from failure of absorption: mucosal damage in coeliac disease has long been recognised as a potential cause for this, and more recently has been joined by Helicobacter pylori infection, at least in adults, where it is most probably the result of reduction in the gastric acid secretion needed to solubilise dietary iron (Hershko & Camaschella, 2014). However, rarer inherited defects may lead to impaired iron availability or utilisation and inappropriately low amounts of iron absorption (Donker et al, 2014). Foremost among inherited defects leading to impaired iron absorption are those resulting in loss of function of the TMPRSS6 gene and of the ferroportin gene, SLC40A1, though the latter leads to macrophage iron retention and loading rather than a microcytic anaemia. TMPRSS6 codes for the serine protease, matriptase-2 (also termed transmembrane protease, serine 6, TMPRSS6), which inhibits the transcription of hepcidin within hepatocytes. Hepcidin is the major systemic regulator of internal iron exchange, downregulating iron release via the membrane transporter, ferroportin, from cells (enterocytes, macrophages and hepatocytes) that donate iron to circulating transferrin and thus make it available for incorporation into haemoglobin by developing erythroblasts (Hentze et al, 2010). Matriptase-2 modulates hepcidin synthesis by interrupting the main iron-responsive signal transduction pathway. It cleaves the membrane protein haemojuvelin (HJV), one of several coreceptors, including transferrin receptor 2 (TFR2) and haemochromatosis (HFE) protein, for the bone morphogenetic protein (BMP) receptor. The BMP receptor complex initiates signal transduction after interaction with BMPs, particularly BMP6: the production of BMP6 is regulated at mRNA level by iron (Meynard et al, 2009) and is therefore related to intracellular iron levels, particularly in liver nonparenchymal cells (Rausa et al, 2015). Diferric (iron Correspondence: Professor Martin J. Pippard, University of Dundee School of Medicine, Ninewells Hospital, Dundee DD1 9SY, UK. E-mail: m.j.pippard@dundee.ac.uk editorial comment