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CHAPTER 42 of dietary iron, and the release of iron from macrophages involved in iron

IRON METABOLISM recycling and storage and from hepatocytes that store iron. The cellular iron
exporter ferroportin serves as the receptor for hepcidin and is destroyed when
the complex is formed. This impairs transport from intestinal mucosal cells,
from macrophages and from hepatocytes into the plasma, and lowers iron
Tomas Ganz absorption and release from stores. Hepcidin decreases plasma iron levels by
causing iron to be sequestered within cells, predominantly in macrophages or
enterocytes, the latter of which are then shed along with their absorbed iron.
Once ferric iron enters the plasma, it is bound by transferrin, which, after form-
SUMMARY ing a complex with the transferrin receptor, transports the metal into cells. The
transferrin receptor is internalized together with bound transferrin and iron,
Iron is a component of nearly all living organisms. It plays an important met- and the iron is released inside the cell into an acidified vacuole. The transferrin
abolic role, particularly in electron transfer reactions. Most of the iron in the receptor then recycles to the cell surface.
human body is incorporated into the hemoglobin of circulating red cells, which Cellular iron homeostasis is largely achieved through posttranscriptional
contain approximately 1 mg of iron per 1 mL of packed cells. Smaller amounts regulation of key proteins involved in iron transport, storage and utiliza-
of iron are present in myoglobin and in many enzymes. Iron is stored within tion. The synthesis of these proteins is regulated by binding of one of the
cells inside ferritin and circulates in plasma bound to transferrin. Because lit- iron-regulatory proteins (IRPs) to iron-responsive elements (IREs) located
tle iron is lost from the body under normal circumstances, the iron content within stem loop structures of the corresponding messenger ribonucleic acids
of the body is controlled by modulating dietary iron absorption. Iron absorp- (mRNAs). IRP-1 is cytoplasmic aconitase that binds to the IRE when it is not
tion increases in the presence of iron deficiency and it decreases when there complexed with iron and does not bind when iron is present; IRP-2, a closely
is iron overload. The absorption of inorganic iron involves a ferrireductase related protein, is destabilized by the presence of iron. When IRPs bind to IREs
and a divalent iron transporter, DMT-1, on the gastrointestinal luminal api- at the 5′ end of the mRNA, they prevent translation; when they bind at the 3′
cal membranes of enterocytes, and ferroportin and hephaestin, located on end, they stabilize the mRNA.
the basolateral enterocyte membranes, in contact with blood. In contrast to
elemental iron, heme iron is absorbed by a distinct pathway, which is still not
well understood.
Systemic iron homeostasis is orchestrated by the hepatic peptide hor- DISTRIBUTION OF IRON IN THE
mone hepcidin, which regulates plasma iron concentrations, the absorption
AVERAGE PERSON

Table 42–1 summarizes the most important iron compartments.
Iron is a key element in the metabolism of nearly all living organisms.
Iron is a component of heme, which is the active site of electron trans- HEMOGLOBIN
port in cytochromes and cytochrome oxidase involved in mitochondrial Hemoglobin, which is 0.34 percent iron by weight, contains approxi-
energy generation. The heme moiety of hemoglobin and myoglobin mately 2 g of body iron in men and 1.5 g in women. One mL of packed
binds O , providing the means to transfer O from the lungs to tissues erythrocytes contains approximately 1 mg of iron. Because the life span
2
2
and to store it. Heme is also the active site of peroxidases that protect of human erythrocytes is approximately 120 days, every day 1/120 of
cells from oxidative injury by reducing peroxides to water or generate the iron in hemoglobin is recycled by macrophages and returned to the
microbicidal hypochlorite in granulocytes. DNA synthesis requires the plasma, from where it is largely delivered to marrow erythroblasts for
enzyme ribonucleotide reductase to convert ribonucleotides to deoxyri- incorporation into newly synthesized hemoglobin.
bonucleotides. Neither bacteria nor nucleated cells proliferate when the
supply of iron is insufficient. STORAGE COMPARTMENT
Iron is stored either as ferritin or as hemosiderin. The former is
water-soluble; the latter is water-insoluble. The protein ferritin is com-
Acronyms and Abbreviations: ABCB10, ATP-binding cassette (ABC) trans- posed of 24 similar or identical subunits arranged as 12 dimers forming
porter in the inner membrane of mitochondria; ALA synthase, aminolevulinic a dodecahedron that approximates a hollow sphere with a cavity capa-
1,2
acid synthase; BMP, bone morphogenetic protein; dcytb, duodenal cytochrome ble of storing up to 4500 Fe atoms as hydrous ferric oxide polymers.
b; DMT, divalent metal transporter; GDF15, growth differentiation factor 15; HFE, The ferritin subunits are of H (heavy) or L (light) type. H subunits have
human hemochromatosis protein; HRG1, heme transporter; IL, interleukin; ferroxidase activity, thereby enabling ferritin to take up or release iron
IRE, iron-responsive element; IRP, iron-regulatory protein; NADPH, nicotinamide quite rapidly. Ferritin that is rich in H subunits takes up iron more read-
adenine dinucleotide phosphate; Nramp1, natural resistance-associated macro- ily, but retains it less avidly than does ferritin composed predominantly
phage protein one; STEAP3, six-transmembrane epithelial antigen of prostate 3; of L subunits. Much of the storage iron in liver and spleen is in ferritin
TfR, transferrin receptor. containing mostly L subunits.
Ferritin is found in virtually all cells of the body and also in tis-
sue fluids. In plasma ferritin is present in minute concentrations. It is
glycosylated and largely composed of L subunits. Except under con-
In the previous edition, this chapter was written by Ernest Beutler and portions ditions of inflammation, the plasma (serum) ferritin concentration
of that chapter have been retained. usually correlates with total-body iron stores, making measurement

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