Malaria and the Safety of Iron Supplements and Iron Fortification

This research will determine the effects of acute infection with Plasmodium falciparum on the absorption, pharmacokinetics and metabolism of iron from iron supplements and other iron preparations in non-immune adults in Thailand. Our project will combine measurements of iron absorption during and after successful treatment of acute uncomplicated falciparum malaria with characterization of the pharmacokinetics of the appearance of plasma nontransferrin-bound iron (NTBI) and measurements of the iron regulatory hormone, hepcidin, and other proteins of iron metabolism. We will examine iron supplements like those used in the Pemba supplementation trial (Sazawal et al., Lancet 2006; 367, 133-143) as well as alternative iron interventions that could minimize or avoid the formation of plasma non-transferrin-bound iron. This research has three specific aims:

• to characterize the pharmacokinetics of the appearance of non-transferrin bound iron in the systemic circulation after oral administration of an iron supplement or other iron intervention;
• to determine the effect of acute uncomplicated falciparum malaria on absorption of iron from iron supplements and other iron interventions, using erythrocyte incorporation of stable isotopes of iron;
• to assess the effects of acute uncomplicated falciparum malaria on iron metabolism by repeated measurements of serum hepcidin, transferrin receptor, ferritin, haptoglobin, and concentrations of pro- (Th-1) and anti- (Th-2) inflammatory cytokines, erythrocyte zinc protoporphyrin, and the complete blood count with absolute reticulocyte count and reticulocyte hemoglobin content (CHr).

These studies of the effects of infection with P. falciparum on iron absorption and metabolism will further our basic understanding of the interaction of iron supplements with malaria and other infections. The results could help guide the choice of optimal means for the prevention and treatment of iron deficiency in regions endemic for malaria. Characterization of the pharmacokinetics of changes in plasma iron produced by administration of conventional iron supplements could lead to the design and development of new formulations of supplemental iron that would maximize iron absorption while minimizing risks associated with non-transferrin-bound plasma iron. Because of the public health importance of assuring iron sufficiency in mothers, our studies are focused on women of childbearing age but the results should be broadly applicable to the optimal means of providing iron to infants and children.

Inclusion criteria

• men or premenopausal woman, 18 to 50 years of age;
• peripheral blood positive for asexual forms of P. falciparum (this criterion not applicable to uninfected healthy control subjects);
• women not pregnant by self-report and not planning pregnancy;
• body weight <65 kg.

Exclusion criteria

• presence of severe or complicated malaria as defined by WHO criteria;
• clinical evidence of ill health or a history of chronic disorders;
• treatment for mental illness;
• imprisonment;
• institutionalization.