Infection, inflammation and hepcidin-mediated iron deficiency anaemia in African children
Medical Research Council
London School of Hygiene and Tropical Medicine
The 2016 Global Burden of Disease analysis estimates that 1.225 billion people suffer from iron deficiency anaemia (IDA) and it is the fourth largest contributor to years lived with disability (YLD) globally. The burden is concentrated in sub-Saharan Africa and South Asia. Iron is crucial for neural development and early deficiencies during fetal and infant growth cause irreparable damage to brain development. Until now IDA has been largely attributed to diets low in iron and to infections such as malaria and intestinal helminths. However carefully controlled trials of iron supplements (often with deworming and malaria control) have very poor efficacy in Africa. The discovery of hepcidin - the master regulator of iron - throws a new light on the causes of IDA and may guide future therapeutic pathways. We have recently shown that even low-grade inflammation is a major contributor to ID in rural African children due to hepcidin/ferroportin-mediated blockade of intestinal absorption of iron. IDA is likely further exacerbated by EPO resistance. This project seeks to identify the sources of persistent low-grade inflammation in well and sick Gambian children. It will additionally try to understand the complex interacting mechanisms linking iron absorption, distribution and erythropoiesis to the effects of inflammation mediated through hepcidin, erythropoietin (EPO) and the newly discovered hormone erythroferrone (ERFE) which signals to the liver that the bone marrow requires iron. Finally we will conduct a randomised controlled trial to test whether it is possible to circumvent the hepcidin-induced blockade of iron absorption by administering iron in the form of haem. Another arm of this trial will be a proof-of-principle trial to assess the impact of reducing inflammation by co-administering azithromycin and galacto-oligosaccharides with iron. These studies, if successful, would suggest the need for a radical revision of current policies to combat IDA
2.1 Biological and endogenous factors / Research Grant