Safety and Efficacy of Iron Supplements in Malaria-Endemic Areas

Abstract

Where malaria surveillance and health care is inadequate, iron supplements given without food can increase the severity of malarial infections. The likely explanation is that the rate of iron influx into the plasma from high-dose oral supplements exceeds the rate of iron binding to transferrin and a quantity of non-transferrin-bound iron (NTBI) is formed. It is proposed that NTBI increases the intensity of malarial infections by increasing the sequestration of malaria-infected red cells in the capillaries of the brain and intestine, causing more cerebral malaria and further increasing the permeability of the intestinal barrier to the passage of pathogens. Bacteremia is frequently reported in children with severe malaria. At the same time, high iron doses stimulate the growth of pathogenic bacteria in the stool, further increasing the potential for bacteremia. The normal immune response to malaria, as well as other infections and inflammatory disorders, is to prevent further microbial growth by stimulating hepcidin synthesis and preventing the passage of iron into the plasma. Iron absorption is decreased and the efficacy of the iron interventions would be expected to be lower in the presence of infections.

Background

Infants and young children in the developing world are often iron deficient due to low iron stores at birth, high requirements for growth, and a low intake of bioavailable iron. The recommended intervention strategy to prevent or treat iron deficiency in infants and young children in the developing world is iron supplementation. In recent years, however, the safety and efficacy of iron supplementation for infants and young children living in areas of widespread infection has been questioned. The innate immune response to infection is to initiate a series of reactions, via acute-phase proteins and cytokines, which reduces microbial growth by withholding iron [1]. The concern over the efficacy then arises because the increase in hepcidin with infection and inflammation decreases iron absorption [2]. The current concern over the safety of iron supplements in malaria-endemic areas arose following a trial in Pemba, Tanzania, which reported that young children receiving daily iron and folate supplements were more likely to die or be treated for adverse events than those not receiving supplements [3]. It has long been known, however, that providing iron intravenously to subjects with infections can increase the severity of the infection [4].

Safety of Iron Supplements in Malaria-Endemic Areas

The negative effects of iron supplements have been reported previously [5] and they appear to be specifically linked to malarial infections. The Pemba trial, with 30,000 children, was much bigger than previous trials and reported a significantly higher incidence of all-cause morbidity and mortality with iron. Malaria adverse events were more frequent than other infections. An almost identical trial carried out in Nepal [6], a region of low malaria prevalence, reported no adverse events in the children receiving iron-folate supplements, thus implicating malaria as the main safety concern. Although a recent Cochrane meta-analysis [7] concluded that oral iron supplements given to children living in malaria-endemic areas were safe, this was only when regular malaria surveillance and health services were available, which is not the case in many developing countries.

The mechanism by which iron supplements increase the severity of malarial infections is likely to be linked to the formation of non-transferrin-bound iron (NTBI) when large amounts of supplemental iron are ingested without food [8]. NTBI was first observed in b-thalassemia where the binding capacity of transferrin had been exceeded [9], although more recently it was reported in subjects consuming oral iron supplements [10,11], even though their transferrin was far from saturated. The likely explanation is that the rate of iron influx into the plasma from a high oral iron dose exceeded the rate of iron binding to transferrin.

There is no indication that NTBI can enter erythrocytes and increase parasite growth. Plasmodium falciparum merozoites within the red blood cell obtain their iron from an intracellular iron pool derived from heme catabolism [12]. NTBI, however, can be taken up by hepatocytes [13] and may stimulate the formation of merozoites during the liver stage of the P. falciparum life cycle. It seems most likely, however, that NTBI increases the severity of malarial infections by increasing the sequestration of malaria-infected erythrocytes in the capillaries of the brain and intestine, leading to more cerebral malaria and a breach of the intestinal barrier leading to bacteremia [14].

During the second day of their 48-hour reproduction cycle, P. falciparum merozoites modify the surface of the infected erythrocytes so that they bind to capillary walls and avoid removal by the spleen [15]. The infected erythrocytes can bind to a variety of host ligands including intercellular adhesion molecule-1 (ICAM-1) and vascu- lar adhesion molecule-1 (VCAM-1) [16]. These adhesion molecules are upregulated on endothelia during malarial infection as a normal immune response to attract white blood cells but, by also facilitating the sequestration of the infected erythrocytes in the microvasculature of organs such as the intestine and the brain, can lead to serious health problems. The suggested effect of NTBI is to increase the levels of ICAM-1 and VCAM-1 on the surface of the endothelial cells [17].

Under normal circumstances, the gastrointestinal tract protects the body from invading pathogens; however, nontyphi Salmonella bacteremia is frequently described in children with severe malaria [18]. Intestinal cells are the favored site for sequestration of malaria-infected erythrocytes and the small capillaries at the tip of the villus bear the majority of the sequestration burden [19]. It seems likely, therefore, that malaria alone, or more effectively with iron supplements, could weaken the intestinal barrier and result in a systemic invasion by pathogenic organisms. It has recently been reported that pathogens, including Salmonella, drastically increased in the stool of children consuming iron-fortified biscuits [20].

Efficacy of Iron Interventions in Areas of Widespread Infections

Iron supply for erythropoiesis enters the plasma via three different routes, binds to transferrin, and is transported to the bone marrow. The main iron supply is from recycled red cells and this enters via the macrophages. A smaller supply comes from absorbed iron which enters the plasma through the mucosal cell and, when needed, storage iron can be provided from ferritin stored in the hepatocytes. Entry into the plasma from all three cell types is via the transport protein ferroportin. The entry is controlled by the protein hepcidin which degrades ferroportin and blocks the passage of iron into the plasma when the iron status is adequate. However, the innate immune response to infection and inflammation is also to increase hepcidin and block the entry of iron into the plasma [2]. Doherty et al. [21]demonstrated that the absorption of oral iron supplements was doubled after treatment of young Gambian children with uncomplicated malaria and that the hemoglobin response to iron supplements in the malaria-treated children was far greater than in a control group of similarly anemic children. It appeared that the iron from the malaria-hemolyzed red cells, which had been blocked in the macrophages during the infection, was released after treatment. Cercamondi et al. [22] also reported that iron absorption from a fortified sorghum porridge by Beninese women with asymptomatic malarial parasitemia was increased after treatment. In this study, the decreased absorption with malarial parasitemia was explained by increased levels of IL6, other cytokines, and increased hepcidin.

All diseases and inflammatory conditions which increase hepcidin would therefore be expected to decrease iron absorption and presumably the efficacy of iron interventions. However, there is as yet no published evidence to support this.

Disclosure Statement

The author has nothing to disclose