Infection, inflammation and hepcidin-mediated iron deficiency anaemia in African children

Iron deficiency (ID), and the more serious iron deficiency anaemia (IDA), causes multiple health problems especially in reproductive women and young children in low-income settings. Iron is crucial for neural development and early deficiencies during foetal and infant growth cause irreparable damage to brain development and cognition. Figures from the latest Global Burden of Disease analysis estimate that 1.225 billion people suffer from IDA worldwide and it is the fourth largest contributor to years lived with disability (YLD). This burden is concentrated in sub-Saharan Africa and South Asia.

It has been thought that IDA is largely caused by diets low in iron and by the effects of infections such as malaria and intestinal helminths. However carefully controlled trials of iron supplements have very poor efficacy in Africa. The recent discovery of the hormone hepcidin - which acts as the master regulator of iron - throws a new light on the causes of IDA and may guide future therapeutic pathways. We have recently discovered that even low-grade inflammation is a major contributor to IDA in rural African children because it up-regulates hepcidin levels with a consequent blockade of intestinal absorption of iron.

This project will try to identify the sources of this 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 inflammation-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 systemic and gut 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. It is likely that children will require major improvements in their environment achieved through intensive efforts to improve water, sanitation and hygiene (WASH++). If, as we speculate, the origins of IDA are more strongly determined by inflammation than by low dietary iron this would have important implications for future nutritional, agricultural and livestock policies.

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

The recently-published Global Burden of Disease estimates (Lancet, Sept 2017) estimates that 1.225 billion people suffer from iron deficiency anaemia (IDA) making it the fifth most prevalent health condition worldwide and fourth highest cause of YLDs (years lived with disability). The health cost of IDA outweighs all other nutritional deficiencies, haemoglobinopathies and haemolytic anaemias combined. The greatest burden is concentrated in West and Central Africa and South Asia. A 50% reduction in anaemia rates is one of WHO's 6 key Global Targets for 2025, but at current rates it would take another century to reach the target.
Our recent research has identified a key reason for the lack of efficacy of current iron supplementation programmes; namely hepcidin-mediated blockade of iron absorption/utilisation secondary to persistent low-grade inflammation. The work we propose here seeks to confirm this proposition, identify the infectious and possible other drivers of inflammation (eg gut dysbiosis) and better describe the metabolic pathways involving inflammation/EPO/erythroferrone/hepcidin interactions. Finally we will test two new strategies to circumvent the blockade with a specific goal of doubling the haemoglobin response to iron achievable by currently recommended interventions.

Iron deficiency of the foetus and young infant causes irreparable damage to the developing brain. If our hypothesis is correct it would explain why current interventional strategies have such low efficacy and could pave the way to a radically new approach that focuses on inflammation reduction rather than the current orthodoxy built solely upon augmentation of iron intake.

The evolution of a new strategy would first require the building of a strong evidence base to convince academic and clinical colleagues engaged in global health. The next step would be to devise and test alternative next-generation interventions against IDA and test them in larger field studies in multiple countries; a strategic priority for translation-focussed funders such as the Gates Foundation and CIFF. Finally such policies would need to be adopted by international bodies (primarily WHO with whom we engage closely) and by national governments. In the light of widespread frustration at the low efficacy of the current international guidance, and the consequent persistence of IDA as the leading micronutrient deficiency worldwide, any proven new approaches would be likely to have rapid uptake. Even if the ultimate solutions require complex interventions around improvements in water, sanitation and hygiene (WASH++) our work would have high value by signalling the need for a radical re-orientation of health investments in respect of combatting IDA.