As early as the sixteenth and seventeenth centuries, chlorosis (iron deficiency anemia) was reported as a medical condition that could be treated with iron supplementation, but it was not until the turn of the twentieth century that our understanding of the essential nature of iron for heme synthesis slowly emerged (1). Since that time, the pace of discovery in the field of iron metabolism has accelerated to the current explosion in molecular information in the twenty-first century (2). This chapter highlights the most current concepts in iron homeostasis.

Iron exists in one of two oxidation states: the ferrous form (Fe²⁺) or the ferric form (Fe³⁺). This chemical property results in iron’s catalytic role in a multitude of redox reactions necessary to support basic metabolic functions for life. In fact, iron’s central role in oxygen and energy metabolism underscores the biologic significance of this element and helps to explain why it is one of the best-studied metals in nutrition and health. These same catalytic properties of iron also confer its well-known toxicity resulting from Fenton chemistry, a reaction that generates free radicals including superoxide. Thus, iron is an essential nutrient as well as a powerful toxicant, and it is important to understand how both features are kept in balance.

Total iron body content is estimated to be 3.8 g in men and 2.3 g in women. Most body iron is found as heme iron (Fig. 10.1). Heme iron is the essential constituent for oxygen transport in hemoglobin, oxygen storage in myoglobin, and electron transport for cytochrome function in aerobic respiration, and it is even necessary for signal transduction as a cofactor for nitric oxide synthase and guanylyl cyclase. The second largest pool of iron is found in its storage form ferritin (also hemosiderin). Ferritin is a large assembly of 24 protein subunits that form a large sphere around a mineralized ferric core of several thousands of iron atoms (3). In times of demand, iron is liberated from ferritin to fulfill essential functions in oxygen transport and energy metabolism. Damage generated by reactive oxygen species arising from redox-reactive free iron is prevented by its storage in ferritin.

In similar fashion, newly absorbed iron is bound by transferrin, thereby limiting its toxic effects as it is transported in serum. Transferrin-bound iron is destined to be taken up by the transferrin receptor in peripheral tissues for storage or utilization. Transferrin has two binding sites for one iron atom each. Under normal circumstances, 30% to 40% of these iron-binding sites are filled with approximately 4 mg of total body iron. Circulating transferrinbound iron represents a highly dynamic storage pool that can be drawn from to fulfill immediate demands. Hence the saturation state of serum transferrin plays a key role in the regulation of iron metabolism and is one of the indices used clinically to evaluate iron status.

Iron absorption, utilization, and storage are finely tuned to maintain the metal’s homeostasis. Unlike the situation with other essential elements, iron metabolism is subject to a high degree of conservation. Rather than eliminate excess iron that is not immediately required, iron is stored in ferritin for times of need, as described earlier. The nature of iron homeostasis reflects the metal’s key chemical role in oxygen and energy metabolism, processes that are necessary for life and must therefore rely on a substantial reservoir of iron to support the ultimate demands of human physiology. Approximately 20 to 25 mg of iron is turned over daily with the erythrophagocytosis of senescent red blood cells, and iron that is released from heme is captured for reutilization in the production of new erythrocytes. Small amounts of iron are lost in feces (˜0.6 mg/day), urine (<0.1 mg/day), and sweat (<0.3 mg/day). Menstruating women suffer an average blood loss of approximately 40 mL/cycle or 0.4 to 0.5 mg/day. Most losses are offset by the amount of iron provided in the diet, however, pathologic conditions associated with excessive blood loss such as hookworm infection or bleeding ulcers can result in greater iron demands. A key feature of iron homeostasis is that the body’s iron status is maintained at the level of dietary iron absorption to prevent toxic accumulation while adequate amounts are provided to offset losses. When iron is depleted from the body, dietary iron absorption increases to meet the demand for iron, although no known regulated pathway exists for excretion of excess iron.

Iron is absorbed from the diet as either heme or nonheme iron (see the following website: http://ods.od.nih .gov/factsheets/Iron-HealthProfessional). Heme iron is typically derived from hemoglobin or myoglobin and is contained in foods such as red meats, fish, and poultry. Various sources of nonheme iron, such as plant foods, are also available. This form of iron is also added to enrich and fortify foods such as cereals. Although nonheme iron is the predominant form in the diet, heme iron is more bioavailable (4). Approximately 15% to 35% of heme iron will be assimilated, compared with 2% to 20% nonheme iron absorption. As discussed earlier, the levels of stored iron in the body influence the extent of absorption. Under low-iron conditions, dietary absorption is promoted, whereas high-iron conditions reduce absorption. Many other dietary and endogenous factors can influence iron uptake (Table 10.1). For example, ascorbate can help to reduce ferric iron to the more bioavailable form of ferrous iron (5, 6). Polyphenols and phytates can interfere with nonheme iron uptake (6). Calcium blocks uptake of both heme and nonheme iron (7), whereas other metals can inhibit nonheme iron absorption by sharing the same pathway for absorption (4). In particular, not only is lead a competitive inhibitor for uptake, but also it can disrupt steps of iron metabolism required for heme synthesis (8). Because low iron status enhances metal absorption, lead poisoning is often associated with iron deficiency in children (9).

The recommended dietary allowances (RDAs) set for iron by the Institute of Medicine of the National Academy of Sciences are listed in Table 10.2. Iron is considered a micronutrient: adult men require 8 mg iron/day, and during their reproductive years, girls and women require 18 mg iron/day. The typical North American diet of 12 to 18 mg iron/day should be adequate to fulfill these needs, but the requirement for iron markedly increases to 27 mg/day during pregnancy, and iron supplements are often needed to match this high demand. Infants are born with a 4- to 6-month iron supply, and an RDA has not been established for this early age. An adequate intake (AI) of 0.27 mg/day is recommended, however. Beyond this age, iron content in milk cannot entirely meet the needs of the developing child, and food sources are
required to meet RDAs (7 mg/day at age 1 to 3 years and 10 mg/day at age 4 to 8 years). Iron toxicity can also pose a risk for children, and it commonly results from ingestion of excess iron supplements. Death occurs at levels of 200 to 300 mg/kg. The tolerable upper limits (UL) for iron intake are listed in Table 10.2.

The field of iron biology has made rapid advances since 2000. Many of the proteins involved in iron transport and homeostatic regulation have been identified, and their physiologic roles have been uncovered. Perhaps the most exciting breakthrough came with the discovery of iron regulatory hormone, hepcidin. Features of hepcidin regulation of iron metabolism have been compared to insulin action in glucose metabolism, thus creating a new field of iron endocrinology (10). How hepcidin regulates systemic iron homeostasis is a major focus of current investigation. At the cellular level, molecular insights into the regulation of iron-binding proteins have yielded information about regulation of iron transport, utilization, and storage that have important clinical considerations. Finally, transcriptional and posttranscriptional networks that may be activated by hepcidin-induced signaling are beginning to emerge and provide clues into the relationships between iron and inflammation.