Malaria and the Safety of Iron Supplements and Iron Fortification
Condition: Iron Deficiency
MeSH terms: Malaria; Anemia, Iron-Deficiency; Iron Deficiencies
Study type: Interventional

Summary: 
      The primary study hypothesis of the investigators is that administration of an iron
      supplement between meals at a dose like that used in the Pemba trial (~1 mg Fe/kg) during P.
      falciparum parasitemia will increase plasma non-transferrin-bound iron. A key subsidiary
      hypothesis is that iron administered with meals in amounts used in food fortification (~0.1
      mg Fe/kg) will not produce plasma non-transferrin-bound iron.

      This research will be carried out at the Hospital for Tropical Diseases, Mahidol University,
      Bangkok, Thailand. The studies are intended to help understand how giving iron and folic acid
      to preschool children in Pemba, Zanzibar, Tanzania, (the "Pemba trial") in the doses
      recommended by the World Health Organization, could have resulted in an increase in
      hospitalizations and deaths. The investigators will examine the most likely explanation, that
      the dose of iron supplements used in the Pemba trial produced iron in the blood not bound to
      the usual carrier for iron (a protein called "transferrin"), that is called
      "non-transferrin-bound iron", abbreviated as NTBI. In children with malaria, this NTBI might
      favor the growth of malarial parasites or other causes of infection. At present, no studies
      have been carried out to see if NTBI is present after giving iron to patients with malaria.
      Using non-radioactive forms of iron (called "stable isotopes"), the investigators will study
      iron absorption and NTBI after giving a single dose of iron (like that used in the Pemba
      trial) one day after treatment for malaria has been started, while patients still have
      malaria parasites in the blood, and then again two weeks later, after the malaria has been
      cured. The investigators will study adults admitted to the Hospital for Tropical Diseases in
      Bangkok, Thailand, with malaria. For reasons of safety, the investigators have chosen to
      study adults in the hospital rather than children living in an area like Pemba but the
      results should also apply to children. The outcome of this research will help us design ways
      of safely giving iron in malarious areas to adults and children to prevent or treat iron
      deficiency.
    

Detailed description: 
      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:

        1. 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;

        2. 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;

        3. 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.
    

Intervention name(s): Ferrous sulfate; Ferrous sulfate; Ferrous sulfate; Ferrous sulfate
Intervention type(s): Dietary Supplement; Dietary Supplement; Dietary Supplement; Dietary Supplement
Intervention description(s): Ferrous sulfate, ~1 mg Fe/kg body weight, given as a single dose in the fasting state.; Ferrous sulfate, ~1 mg Fe/kg body weight, given as a single dose with a standard Thai rice meal.; Ferrous sulfate, ~1 mg Fe/kg body weight, given as a single dose with a standard Thai rice meal with added oil.; Ferrous sulfate, ~0.1 mg Fe/kg body weight, given as a single dose with a standard Thai rice meal.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Non-transferrin-bound iron; Iron stable isotopes; Iron deficiency; Malaria; Iron supplementation; Iron fortification