PHYSIOLOGICAL, ENVIRONMENTAL, AND GENETIC INFLUENCES ON IRON HOMEOSTASIS

Abstract

Iron deficiency is the most widespread micronutrient deficiency globally, while elevated iron stores are also associated with an increased risk of adverse health outcomes. Iron homeostasis must be strictly maintained to ensure that adequate iron is available for metabolic functions and to avoid the toxicity that results from iron overload. The overall goal of this research was to investigate selected physiological (pregnancy), environmental (parasitic infections and iron supplementation) and genetic (ethnic differences in iron status) influences on iron homeostasis. Pregnancy places a significant strain on iron homeostasis. Surprisingly, there are very few longitudinal studies of hemoglobin concentrations across gestation and the norms that are used to define gestational anemia are based on limited evidence. To address a physiological determinant of iron homeostasis, this research provided a large normative analysis of determinants of maternal hemoglobin concentrations and identified factors associated with risk of maternal anemia in healthy U.S. pregnant women. Anemia was prevalent in otherwise healthy U.S. pregnant women even with the current universal iron supplementation recommendations. The existing CDC anemia cutoffs may overestimate the prevalence of anemia in late pregnancy based on our findings that were obtained in a significantly larger and more racially diverse population. Risk factors for anemia were identified as Black race, being underweight at entry into pregnancy, being multiparous or carrying a multiple birth pregnancy. Multiple environmental factors can influence iron status and risk of iron deficiency and iron deficiency anemia. Parasitic infections are one example of a common environmental factor that can cause anemia. To obtain more detailed information on the impact of parasitic infections and iron supplementation, stable iron isotopes were used to investigate iron absorption and change in erythrocyte iron isotope enrichment in a group of toddlers residing in a malaria and helminth endemic environment. Toddlers who received iron supplementation exhibited greater loss of erythrocyte iron isotope enrichment over time, which may be indicative of an increase in the size of the erythrocyte pool and increased erythropoietic drive due to the provision of iron among anemic or helminth infected toddlers. This study also summarized published literature on genetic determinants of iron status, characterized iron status in different ethnic populations, and statistically evaluated differences in iron status as a function of ethnicity using published data. A review of the literature identified multiple iron-related and non-iron related genes that have been associated with iron status. For the first time, these published data were used to statistically explore differences in iron status among various ethnic populations. East Asians had higher iron status compared to other racial groups yet this group also has the lowest prevalence of HFE mutations that are commonly associated with elevated iron stores. Future research using multidisciplinary approaches that consider physiological, environmental, and genetic factors is needed to better predict iron status at the individual and population level and to help develop the most effective interventions to maintain adequate iron status.