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Chapter 35 Pathophysiology of Iron Homeostasis 473

the erythrocyte in a phagosomal vacuole known as an erythropha- Under normal circumstances, the macrophages in the liver, spleen,
golysosome, the erythrocyte membrane is lysed. The hemoglobin and bone marrow that are dedicated to reprocessing hemoglobin iron
within then undergoes oxidative precipitation and rapid catabolism from senescent erythrocytes maintain an equilibrium between iron
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into heme (see Fig. 35.5). Heme is then transported from the storage and release. Synthesis of cytosolic ferritin is induced in
erythrophagolysosome into the cytosol via the heme transporter response to erythrophagocytosis, and, in the absence of iron defi-
HRG1 (SLC48A1), a heme-transporting permease. 16 ciency, a portion of the iron derived from the ingested erythrocyte is
A small proportion of aged or damaged erythrocytes undergo retained within the macrophage as soluble cytosolic ferritin. With
intravascular hemolysis. With normal erythropoiesis, this portion increasing amounts of storage iron within the macrophage, an
of the total iron flux is minor but can increase substantially in increasing proportion of iron is stored within amorphous, insoluble
disorders with increased ineffective erythropoiesis or intravascular masses as hemosiderin. On the basis of studies with heat-damaged
hemolysis. The hemoglobin released into plasma is then rapidly erythrocytes labeled with radioactive iron, it is known that the frac-
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bound by haptoglobin, a glycoprotein synthesized in the liver. The tion of radioiron sequestered within the macrophage can vary from
hemoglobin−haptoglobin complex (M r 150,000) is too large to be virtually none in association with iron deficiency to a maximum of
filtered by the kidneys, a feature that helps restrict the renal loss almost 80% in the presence of bone marrow aplasia and a fully satu-
of iron with hemoglobinemia. Macrophages (and hepatocytes; see rated plasma transferrin.
later) remove the haptoglobin−hemoglobin complex from plasma by
binding through the cluster of differentiation 163 (CD163) receptor
and after endocytosis digest the complex in lysosomes, liberating LIVER REGULATION OF SYSTEMIC IRON HOMEOSTASIS
heme. In an analogous fashion, any heme released into plasma by AND IRON STORAGE
intravascular hemolysis complexes with hemopexin and is removed
by macrophages (and hepatocytes) expressing the low-density lipo- The liver (Fig. 35.6) is both the central site for control of systemic
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protein receptor−related protein 1 (LRP1). In macrophages, heme iron homeostasis, as the principal source of plasma hepcidin, and a
from all these sources is degraded by an enzymatic complex contain- major iron storage organ, sequestering iron in cytosolic ferritin and
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ing nicotinamide adenine dinucleotide phosphate−cytochrome c hemosiderin within hepatocytes and macrophages (Kupffer cells).
reductase, the microsomal enzyme heme oxygenase 1, and biliverdin The dual blood supply of the liver from the portal and systemic
reductase, yielding carbon monoxide (the sole physiologic source circulation is a vital feature, allowing monitoring of both plasma
in the body), bilirubin, and iron (see Fig. 35.5). Both DMT1 and iron in the systemic circulation and newly absorbed iron in the
natural resistance−associated macrophage protein 1 (NRAMP1; portal circulation. Hepatocytes can acquire iron from plasma trans-
SLC11A1), a divalent metal transporter expressed within the late ferrin via the transferrin cycle, from hemoglobin−haptoglobin and
endosomal and phagolysosomal membranes of iron-recycling heme−hemopexin complexes via endocytosis after binding to CD163
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macrophages, seem to be involved in efficient recycling of this and LRP1 receptors, respectively; from lactoferrin, apparently by
iron. 16,17 Macrophages also can acquire iron from plasma transferrin receptor-mediated endocytosis; and from plasma nontransferrin-
via the transferrin cycle, but this is a minor portion of their total bound iron (Fig. 35.6). Plasma non-transferrin-bound iron forms
iron flux. when the rate of iron influx into plasma exceeds the rate of iron
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Ferroportin is the conduit for the outpouring of iron from mac- acquisition by transferrin. Plasma non-transferrin-bound plasma
rophages in the bone marrow, liver, and spleen to plasma apotransfer- iron enters specific cells independently of the transferrin mechanism,
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rin, normally the largest single flux of iron from cells in the body. particularly hepatocytes, pancreatic acinar cells, cardiomyocytes, and
Ferroportin transcription increases in response to both iron and anterior pituitary cells, producing toxic accumulations in some forms
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heme. Ferroportin (FPN1A) levels are also regulated posttranscrip- of iron overload (see Chapter 36). In mice, the ZRT/IRT-like protein
tionally through an iron-responsive element in the 5′ untranslated 14 (ZIP14; SLC39A14) is reported to be the major route for cel-
region, with increases in cytosolic iron resulting in increased ferro- lular uptake of plasma non-transferrin-bound iron by hepatocytes
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portin translation. Iron export through ferroportin requires ferroxi- and pancreatic acinar cells. In the heart, ZIP14 is not required
dase activity, provided by the multicopper oxidase ceruloplasmin in for uptake of plasma non-transferrin-bound iron and iron loading;
2+
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macrophages and by hephaestin in duodenal enterocytes (see later). L- or T-type Ca channels or SLC39A8 are possible alternative
Ceruloplasmin oxidation may generate a concentration gradient that transporters. 21
drives the ferric iron out of the macrophage. In the absence of The liver functions as the central controller of systemic iron
3
ceruloplasmin, macrophage ferroportin is rapidly internalized and homeostasis by being the predominant synthetic source of hepcidin.
degraded. Unsaturated transferrin is not required for the release of The biologically active 25-amino acid peptide is produced by proteo-
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iron from the macrophages; apotransferrin does not enter the mac- lytic processing of an 84-amino acid prepropeptide by furin. After
rophage and accepts iron only after the exit of iron through ferroportin secretion, hepcidin circulates in plasma bound to α 2 -macroglobulin
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and oxidation by ceruloplasmin. The ferric iron can then be bound and is rapidly cleared by the kidneys or degraded after binding to
4
by transferrin and transported back to erythroid and other iron- ferroportin. As detailed earlier, hepcidin controls the entry of iron
requiring tissues. into plasma by decreasing the number of ferroportin channels avail-
Plasma hepcidin regulates iron efflux from macrophages by able for iron export from macrophages, hepatocytes, and duodenal
decreasing the number of ferroportin channels available for iron enterocytes. Plasma hepcidin concentrations increase with elevations
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export. The multimeric composition of ferroportin has not been in iron in plasma and in hepatocytes, and with infection and inflam-
determined definitively, but a dimeric structure seems most likely, mation, decreasing plasma iron. Plasma hepcidin concentrations
based both on the available evidence and on the autosomal dominant decrease with iron deficiency, hypoxia, and increased erythropoietic
2
inheritance of ferroportin mutations responsible for iron overload requirements for iron, increasing plasma iron. The hepatocyte
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(see Chapter 36). For the most part, ferroportin mutations either coordinates the congruent or conflicting influences of iron, infection,
interfere with iron export by decreasing the amount of functional and erythropoietic demand to determine hepcidin secretion and
ferroportin on the cell surface, resulting in retention and accumula- thereby the systemic supply of iron. Because the amount of plasma
tion of macrophage iron, or produce ferroportin resistance to inter- iron is small and is replaced every 2 to 3 hours, changes in plasma
nalization and degradation by hepcidin, resulting in loss of control hepcidin are followed rapidly by changes in plasma iron.
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of macrophage iron export that leads to parenchymal iron loading. Regulation of hepcidin seems to be entirely transcriptional, inte-
Homozygous ferroportin mutations are likely lethal. While the grating signals for induction and inhibition of synthesis both from
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precise pathway of degradation remains uncertain, ferroportin must within and outside the hepatocyte. Intensive investigation has
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bind hepcidin for internalization and ubiquitination to occur. Fol- revealed a complex signaling network for transcriptional regulation
lowing ubiquitination, ferroportin is degraded after entering the of hepcidin (summarized graphically in Fig. 35.7) that remains
multivesicular body that fuses with lysosomes. incompletely characterized and with some features that still require