Benefits and Risks of Iron Supplementation in Anemic Neonatal Pigs

Iron deficiency is a common health problem. The most severe consequence of this disorder is iron deficiency anemia (IDA), which is considered the most common nutritional deficiency worldwide. Newborn piglets are an ideal model to explore the multifaceted etiology of IDA in mammals, as IDA is the most prevalent deficiency disorder throughout the early postnatal period in this species and frequently develops into a critical illness. Here, we report the very low expression of duodenal iron transporters in pigs during the first days of life. We postulate that this low expression level is why the iron demands of the piglet body are not met by iron absorption during this period. Interestingly, we found that a low level of duodenal divalent metal transporter 1 and ferroportin, two iron transporters located on the apical and basolateral membrane of duodenal absorptive enterocytes, respectively, correlates with abnormally high expression of hepcidin, despite the poor hepatic and overall iron status of these animals. Parenteral iron supplementation by a unique intramuscular administration of large amounts of iron dextran is current practice for the treatment of IDA in piglets. However, the potential toxicity of such supplemental iron implies the necessity for caution when applying this treatment. Here we demonstrate that a modified strategy for iron supplementation of newborn piglets with iron dextran improves the piglets’ hematological status, attenuates the induction of hepcidin expression, and minimizes the toxicity of the administered iron.Iron deficiency is the most frequent cause of anemia in humans,¹ and iron deficiency anemia (IDA) is most prevalent in the neonatal period and early childhood.² Early postnatal iron deficiency is also a widespread phenomenon in other mammalian species. Indeed, IDA has long been recognized as a serious iron disorder in livestock, especially in suckling piglets.³ In contrast to humans and mice, the complex molecular regulation of body iron homeostasis⁴ has been the subject of few studies in pigs.^5,6,7 Our knowledge of iron homeostasis in newborn pigs is mostly based on physiological concepts stemming from the early 1990s. Although the pig is a major biomedical mammalian model for human studies,⁸ its contribution to understanding the molecular pathophysiological mechanisms of human iron disorders has so far been small.⁹The common reason for iron deficiency in newborn piglets is their rapid growth, particularly the increase in blood volume and the number of red blood cells (RBCs). Indeed, erythroid precursors in the bone marrow use most of the iron found in the plasma for the synthesis of hemoglobin. As sow’s milk largely provides piglets with iron below their daily requirements,¹⁰ an exogenous source of iron is essential to prevent the reduction in RBC hemoglobin level. Intramuscular administration of large amounts of iron dextran (FeDex) on days 3 to 6 postpartum is current practice in the swine industry,^3,11 and has been proven to rectify the hematological status of piglets. However, it seems unlikely that 100 to 200 mg of iron (a commonly applied dose) given in a single injection to a piglet with only about 40 to 50 mg of iron in its body at birth,¹² is efficiently metabolized and detoxified. Moreover, high parenteral intake of supplemental iron may easily perturb the tight control of systemic iron metabolic processes. In this context, iron supplementation in piglets raises the question of the role of hepcidin (Hepc)—the systemic iron-regulatory hormone¹³ in the regulation of natural intestinal iron absorption, especially under conditions of morphological and functional rebuilding of the pig small intestinal mucosa that occurs within 21 days of birth.¹⁴In this study we examined the expression of proteins involved in iron absorption and its regulation in newborn piglets during the first 2 weeks of life. We also tested a modified strategy for iron supplementation of anemic piglets and demonstrated its ability to improve their hematological status, regulate Hepc expression and minimize the toxicity of supplemental iron.