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INTRODUCTION

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LEARNING OBJECTIVES

After studying this chapter you should be able to:

  • Construct a flow diagram depicting iron homeostasis: absorption from the gut, transport in the plasma, incorporation into erythroid precursors, release from senescent red cells, and return to the plasma.

  • Explain the important role of hepcidin in iron absorption from the gut and release of iron from macrophages.

  • Name and prioritize the causes of iron deficiency.

  • Describe the key laboratory features of iron deficiency.

  • Identify the causes of iron overload and its clinical manifestations.

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In all organisms from bacteria to man, iron is by far the most important metallic element. Its outer shell of electrons is ideally poised for complex coordination chemistry, enabling the binding of ligands such as oxygen as well as participation in critical oxidation-reduction reactions. Iron is essential not only for the biological activity of heme proteins such as hemoglobin, myoglobin, and cytochromes but also as a key cofactor in a number of enzymes spanning a wide range of metabolism. However, because of iron's high degree of reactivity, it can catalyze the generation of oxygen free radicals and other toxic species, leading to cellular and tissue injury by way of protein cross-links, lipid peroxidation, and damage to DNA. Therefore, in order for iron to safely fulfill its biological functions, an exquisite degree of control is required. In this chapter we will review the basic elements of iron homeostasis: absorption, transport, utilization, recycling, and excretion. During the last decade, understanding of these processes has been enormously enhanced by the molecular cloning and characterization of critical genes, some of which were discovered by investigation of mutant mice and zebra fish whose phenotypes suggested perturbed iron metabolism.

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This chapter will begin with an overview of iron homeostasis, as this information is essential for understanding the pathogenesis, clinical features, and treatment of iron deficiency and iron overload.

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NORMAL IRON HOMEOSTASIS

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Safe and effective transport and utilization of iron are achieved by tight regulation at the level of both individual cells and the organism as a whole. The expression of a number of proteins that play critical roles in iron metabolism is regulated by the intracellular concentration of iron. This is achieved through a consensus stem loop sequence in the messenger ribonucleic acids (mRNAs) that encode these proteins. When iron is scarce, two iron regulatory proteins (IRPs) bind specifically to this stem loop and modify either the stability or rate of translation of the mRNAs, whereas when intracellular iron is abundant, the IRPs assume a conformation that precludes mRNA binding. Systemic iron metabolism is regulated by the circulating polypeptide hormone hepcidin, which controls both dietary iron absorption from the gut and release of recycled iron from macrophages. These two modes of regulation are described in detail later in this chapter.

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IRON ABSORPTION

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The dietary sources of iron vary considerably according to geographic location, ...

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