Respiratory infections are a previously unsuspected cause of iron deficiency

Findings could re-orientate global programmes to prevent iron deficiency anemia

According to new research published in Science Advances, researchers in The Gambia have uncovered a hitherto unknown relationship between respiratory infections and iron deficiency in children living in poor environments.

According to the latest global burden of disease estimates, iron deficiency (ID) and its consequent anemia (IDA) are by far the most common micronutrient deficiencies worldwide; affecting about 1.25 billion people. The burden falls heavily on mothers and their young children.

Iron is especially critical for the developing brain and hence early-life deficiencies can have an irreversible impact on a child’s cognitive development and school performance. Iron is essential for numerous other biological functions with a key role in cellular immunity.

For decades, iron deficiency has been ascribed to poor diets with little diversity and low amounts of animal products, as well as to the effects of ‘antinutrients’ such as phytates in cereal foods. These bind iron and hinder its absorption by the intestine. The presence of intestinal helminths (that can consume iron and cause bleeding) and malaria (that breaks down red blood cells) also contribute to iron deficiency.

The new research, led by scientists at the Medical Research Council Unit The Gambia at the London School of Hygiene & Tropical Medicine, has exploited the recent discovery of the hormone hepcidin to uncover important new insights.

Hepcidin (discovered in 2002) is a vital hormone that acts as the master regulator of iron metabolism. It controls the absorption of iron and its distribution around the body. If tissues are short of iron, hepcidin levels are suppressed and this encourages iron to be absorbed more efficiently from food. In situations of iron overload, hepcidin rises and switches off iron absorption. Intriguingly, hepcidin also responds to infections and inflammation. When the threat of infection is sensed, hepcidin rises and switches off iron absorption and locks iron down in macrophages. This is to starve invading organisms of iron and has evolved to be a very effective natural innate defence (so-called ‘nutritional immunity’).

The researchers were able to measure hepcidin, multiple measures of iron status and markers of inflammation (mirroring the threat of infection) in over 400 young children who had tiny blood samples collected each week for 3 months.

The analysis revealed that – contrary to expectation – each child had a tendency to maintain a very characteristic level of hepcidin; some produced almost no hepcidin whilst others consistently produced very high levels. Previous studies in the same community had established threshold levels of hepcidin above which children did not absorb iron. Over half of the children in this new study had hepcidins above this threshold and hence were physiologically blocking iron absorption. Why?

As expected, hepcidin levels were strongly associated with measures of inflammation, but, very surprisingly, this association persisted even at very low levels of inflammation that would previously have been considered to be insignificant.

What is the source of this inflammation? Prior research has shown that these children – as with others living in unhygienic condition – have very damaged intestines; a phenomenon known as Environmental Enteric Disease (EED). This seemed a very likely culprit. However, the researchers could not detect any association between hepcidin and markers of gut damage; an inference supported by another study in Kenya.

To their surprise, the analysis revealed a very strong association between hepcidin and respiratory infections. This suggests that inflammation of the airways may be a key determinant of hepcidin-mediated iron blockade, and hence may constitute a previously unknown pathway to iron deficiency anemia.

Prof Andrew Prentice, senior author at the MRC Unit The Gambia at LSHTM said, “The discovery of hepcidin has given us new insights into how diets and infection interact to cause the iron deficiency anemia that affects over a billion under-privileged mothers and children globally. Past thinking was that the human gut is poorly evolved to absorb iron from non-meat foods, especially in young childhood. Our results show that, far from being poorly evolved, children are actually expending a lot of physiological effort to exclude iron from their bodies for fear that it will feed invading micro-organisms that could kill them. This shows why current approaches of giving large doses of iron to children usually fail and may be dangerous. Our research indicates that iron deficiency will be resolved if and when children can be freed from the ever-present cycle of infections. Reducing respiratory infections may be a critical step.”

The study was funded by the Medical Research Council and the Bill and Melinda Gates Foundation.