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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 regulating iron absorption from the gut and iron release from macrophages.

  • Name and prioritize the causes of iron deficiency.

  • Describe the key clinical and laboratory features of iron deficiency.

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

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The metallic element iron is essential for the growth and survival of all organisms from bacteria to man. 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. Not only is iron required for the biological activity of heme proteins such as hemoglobin, myoglobin, and cytochromes, but it also is a key cofactor in a number of enzymes spanning a wide range of metabolic activities. 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, for iron to fulfill its biological functions safely, an exquisite degree of control is required.

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In this chapter, we will first review the basic elements of iron homeostasis: absorption, transport, utilization, recycling, and excretion. Over 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 mice and zebrafish with genetic defects leading to abnormal iron metabolism. We will then turn to 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. A number of proteins play critical roles in iron metabolism. This section of the chapter focuses on the function and regulation of three proteins in particular:

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  • Transferrin receptor, which enables the uptake of iron-bound transferrin from the plasma through the transferrin cycle

  • Ferritin, which provides a bioavailable intracellular storage depot for iron, protecting the cell from toxicity

  • Hepcidin, which is a circulating hormone that controls both the absorption of dietary iron from the gut and release of recycled iron from macrophages

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IRON ABSORPTION

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The dietary sources of iron vary considerably according to geographic location, cultural tastes, and economic status. Iron in food is found in inorganic salts and in organic complexes derived from plants as well as heme from animal sources. Digestion of grains, vegetables, and fruits in the stomach and duodenum results in the release of ferric ...

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