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Anemia ofchronic disease 173
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Infrequently, anemia of inflammation can be severe
enough to exacerbate underlying cardiac or pulmonary disease and cause cardiac ischemia. In this acute setting, erythrocyte transfusion can rapidly improve oxygen delivery and
the manifestations of ischemia. More commonly, anemia is
moderate, and its treatment is less urgent. Erythropoietin
with or without high- dose parenteral iron can be useful for
anemia symptoms that cannot be reversed by treating the
causative disease. High doses of parenteral iron may be
required to overwhelm the hepcidin- induced retention of
iron in macrophages, and possibly to expand erythrocyte
precursor populations that produce a hepcidin- suppressing
factor. In each patient, the potential side effects of erythropoietin and iron must be weighed against the anticipated
benefits, and the clinical effectiveness of the drugs. The continued need for therapy should be evaluated regularly and
critically.
Future treatments
Improved understanding of the pathogenesis of anemia of
targeting the cytokine pathways that mediate increased hepcidin production, or targeting hepcidin itself, its interaction
with ferroportin, or the ferroportin internalization pathway.
If successful, such interventions should reverse the iron
block and provide sufficient iron for normal erythropoiesis.
Mechanisms ofhypoferremia
Kawabata, H., Tomosugi, N., Kanda, J. etal. (2007). Anti- interleukin 6
receptor antibody tocilizumab reduces the level of serum hepcidin in
patients with multicentric Castleman’s disease. Haematologica 92:
857–858.
Kemna, E., Pickkers, P., Nemeth, E. etal. (2005). Time-
of hepcidin, serum iron, and plasma cytokine levels in humans
injected with LPS. Blood 106: 1864–1866.
Nemeth, E., Rivera, S., Gabayan, V. etal. (2004). IL-
remia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Investig. 113: 1271–1276.
Rivera, S., Nemeth, E., Gabayan, V. et al. (2005). Synthetic hepcidin
causes rapid doseferroportin-
Stefanova, D., Raychev, A., Arezes, J. etal. (2017). Endogenous hepcidin
and its agonist mediate resistance to selected infections by clearing
non-
transferrin- bound iron. Blood 130 (3): 245–257.
dependent hypoferremia and is concentrated in
containing organs. Blood 106: 2196–2199.
course analysis
6mediates hypofer-
Hepcidin andanemia
Gardenghi, S., Renaud, T.M., Meloni, A. etal. (2014). Distinct roles for
hepcidin and interleukin- 6 in the recovery from anemia in mice
injected with heat- killed Brucella abortus. Blood 123: 137–145.
Heeney, M.M. and Finberg, K.E. (2014). Iron- refractory iron deficiency
anemia (IRIDA). Hematol. Oncol. Clin. North. Am. 28: 637–652.
Kim, A., Fung, E., Parikh, S.G. etal. (2014). A mouse model of anemia
of inflammation: complex pathogenesis with partial dependence on
hepcidin. Blood 123: 1129–1136.
Roy, C.N., Mak, H.H., Akpan, I. etal. (2007). Hepcidin antimicrobial
peptide transgenic mice exhibit features of the anemia of inflammation. Blood 109: 4038–4044.
Further reading
General
Ganz, T. (2019). Anemia of inflammation. N. Engl. J. Med. 381:
1148–1157.
Diagnosis
Braga, F., Infusino, I., Dolci, A., and Panteghini, M. (2014). Soluble
transferrin receptor in complicated anemia. Clin. Chim. Acta 431:
143–147.
Hastka, J., Lasserre, J.J., Schwarzbeck, A. et al. (1993). Zinc protopor-
phyrin in anemia of chronic disorders. Blood 81: 1200–1204.
Clinical studies
Cash, J.M. and Sears, D.A. (1989). The anemia of chronic disease: spec-
trum of associated diseases in a series of unselected hospitalized
patients. Am. J. Med. 87: 638–644.
Cazzola, M., Ponchio, L., de Benedetti, F. et al. (1996). Defective iron
supply for erythropoiesis and adequate endogenous erythropoietin
production in the anemia associated with systemic- onset juvenile
chronic arthritis. Blood 87: 4824–4830.
Cercamondi, C.I., Stoffel, N.U., Moretti, D. etal. (2021). Iron homeosta-
sis during anemia of inflammation: a prospective study of patients
with tuberculosis. Blood 138 (15): 1293–1303.
Corwin, H.L. and Krantz, S.B. (2000). Anemia of the critically ill:
“acute” anemia of chronic disease. Crit. Care Med. 28: 3098–3099.
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Chapter13
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metabolism
Molecular basis ofiron
Jodie L. Babitt1 and Tomas Ganz
1
Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
2
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Introduction, 175
Mechanisms of iron transport, 175
Sites of iron storage, 178
Regulation of iron homeostasis, 178
2
Introduction
Iron is one of several metals that are essential for normal cellular processes. Its primary role in mammalian biology is to
bind oxygen in hemoglobin and myoglobin, and to catalyze
the enzymatic transfer of electrons by iron- dependent
enzymes, including cytochromes, peroxidases, ribonucleotide reductases, and catalases. When iron is deficient, the
synthesis of iron- containing proteins is impaired, with
adverse consequences for oxygen delivery and cellular
metabolism. However, the same properties that make iron
useful for these functions can also lead to cellular damage
when iron is present in excess. Normally, several binding
proteins constrain the activity of iron, but when their ironbinding capacity is exceeded, iron promotes the formation of
reactive oxygen species that attack cellular lipids, proteins,
and nucleic acids. Thus, iron balance must be carefully maintained to avoid the deleterious effects of iron deficiency and
iron overload. All known disorders of iron metabolism can
be considered abnormalities of iron balance.
There is no physiological excretion mechanism for iron:
iron losses result only from bleeding and exfoliation of skin
and mucosal cells. Under normal conditions, iron enters the
body exclusively by dietary absorption, and absorption is
closely regulated to balance the small losses. Iron balance is
disrupted when intake and losses are not matched. Iron deficiency occurs when the dietary iron supply is inadequate,
when losses are increased (primarily because of bleeding), or
when both of these circumstances are present. Iron overload
results when iron absorption is inappropriately increased due
to genetic defects in iron regulatory proteins, or when
repeated blood transfusions create a substantial iron burden.
Iron disorders, 181
Conclusions, 185
Further reading, 185
Our understanding of the molecular processes of iron
metabolism has advanced considerably over the last two
decades as new techniques in genetics and molecular biology have been applied to problems in this field. Much of
what we have learned has come from the study of patients
with diseases of iron metabolism and from investigation of
animals with spontaneous and induced mutations in genes
important for the transport and storage of iron. Most features of iron metabolism are very similar among mammalian species, validating the use of rodent models. More
recently, important insights into iron disorders in humans
have also come from the study of iron metabolism in
zebrafish and even yeast.
Mechanisms ofiron transport
General principles
Iron is a large charged ion that cannot freely diffuse across
cellular membranes. Transmembrane transfer requires
specific carrier proteins. There are two general ways in
whichcells transport iron. Some cells, such as intestinal epithelial cells, hepatocytes, macrophages, kidney tubule cells,
and placental trophoblast, are equipped both to take in
(import) iron and to release (export) it. These cell types are
involved in the acquisition, storage, and mobilization of iron
for the entire organism. Many other cells import iron but do
not release it unless the cells are destroyed. An intermediate
group of cells, including erythrocyte precursors, pulmonary
arterial smooth muscle cells, and cardiac myocytes, export
iron primarily to maintain cellular homeostasis, but the
released iron contributes little to systemic iron needs.
Molecular Hematology, Fifth Edition. Edited by Drew Provan and Hillard M. Lazarus.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
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175
176 Molecular Hematology
Tf
Na
?
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Approximately 25 mg of iron is needed every day to support hemoglobin production in maturing erythrocytes. This
amount is much greater than the 1–2 mg entering the body
each day through the intestine. The iron for erythropoiesis is
largely provided by splenic and hepatic (reticuloendothelial)
macrophages recycling iron from old erythrocytes and making it available to developing erythroid precursors.
Cells use at least three mechanisms to take up iron.
Intestinal absorptive cells have cell surface transporters that
carry ferrous (Fe2+) ions directly across the membrane.
Erythroid precursors use membrane receptors to take up
iron bound to a protein carrier, concentrate the iron in a subcellular compartment, and then transfer it across the membrane of that compartment into the cytoplasm. Hepatocytes
use both of these mechanisms. Finally, recycling macrophages acquire iron through the phagocytosis of aged or
damaged erythrocytes, lysing the cells, and extracting the
iron from their hemoglobin.
Intestinal iron transport
Our current understanding of intestinal non- heme iron
transport is illustrated in Figure13.1. Iron absorption takes
place in an acidic environment in the proximal small intestine, just distal to the gastric outlet. Most non- heme dietary
iron is in the ferric (Fe3+) form, whose very limited solubility
is enhanced by the low pH. It is reduced to Fe2+ by a brush
border ferrireductases, including the duodenal cytochrome
b (DCYTB). The Fe2+ ions pass through divalent metal trans-
porter 1 (DMT1, formerly called Nramp2, DCT1), a membrane protein that allows iron to traverse the apical bilayer.
DMT1 requires an acidic environment for its activity because
it cotransports protons with iron atoms. The requisite protons are generated by apical Na+/H+ exchangers, predominantly NHE3. Once it crosses the membrane, some of the
iron is retained within the absorptive intestinal cells (enterocytes), and some is exported through the basolateral membrane through the action of a distinct transporter, ferroportin.
A multicopper oxidase protein, hephaestin, facilitates basolateral transport, perhaps by oxidizing Fe2+ to Fe3+ to allow it
to exit from ferroportin and to bind to the plasma iron carrier protein, transferrin.
The expression of ferroportin on the basolateral membrane of enterocytes is the principal mechanism controlling
the rate of iron flux through this transport system. The more
ferroportin on the basolateral membranes, the more iron
from enterocytes is passed into the plasma. The resultant
depletion of enterocyte iron activates iron- dependent
hypoxia- inducible factor transcription factors, which
increase expression of proteins involved in the iron uptake
machinery, further regulating the iron supply. Iron retained
within the enterocytes is lost from the body when these cells
finish their short lifespan and slough into the gut lumen. The
partitioning of iron (i.e. the process that governs how much
enters the plasma and how much is retained within cells) is
regulated by the hormone hepcidin through posttranslational degradation of ferroportin. The hepcidin–
ferroportin interaction plays an important role in determining the overall efficiency of iron absorption.
In humans and other meat- eating organisms, direct
absorption of heme contributes importantly to total iron
absorption. The pathways involved in heme absorption are
not well understood and may not be present in mice.
–
Fe
3+
Fe
Ferritin
3+
Fe
2
Blood
Lumen
Figure13.1 Intestinal non- heme iron absorption. The cartoon shows an absorptive enterocyte from the duodenal epithelium, joined to adjacent
cells by iron- impermeable tight junctions. The apical brush border is on the luminal side (left) and the basolateral surface is on the blood side
(right). Dietary Fe3+ iron is reduced by the ferrireductase DCYTB and other mechanisms to produce Fe2+ ion for transport. Fe2+ crosses the apical
membrane through the action of DMT1 to enter the cell. There, iron is partitioned between storage and export; stored iron is ultimately lost from
the body when the epithelial cells senesce and exfoliate into the gut lumen. Meanwhile, a fraction of the iron is exported across the basolateral
membrane by ferroportin. The iron hormone hepcidin binds to ferroportin and causes its degradation, thereby inhibiting iron efflux, proportionally
to hepcidin concentration. Hephaestin is a ferroxidase- like protein that aids in iron export, probably by oxidizing the Fe2+ iron leaving ferroportin
to the Fe3+ form, which binds to plasma transferrin (TF).
Fe
Heme
Fe
3+
Fe
Ferrireductases
2+
Fe
+
DMT1
H
+
H
NHE3
+
Hephaestin
Fe
Fe
HO
Enterocyte
2+
e
Ferroportin
2+
Fe
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Other iron uptake mechanisms
Transferrin receptor
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Upon entry into the plasma, iron attaches to transferrin, an
abundant plasma protein that binds iron with extremely high
affinity. Transferrin serves three important functions. Firstly,
it keeps iron in solution. In an aqueous, neutral pH environment, iron exists as Fe3+ ion, which is almost insoluble.
Secondly, it renders iron non- reactive, and allows it to circulate in a safe non- toxic form. Thirdly, transferrin facilitates
the delivery of iron to cells bearing transferrin receptors on
their surfaces.
Most differentiated cell types express few, if any, transferrin receptors, but there are three important exceptions:
tumor cells, activated lymphocytes, and erythroid precursors. Tumor cells presumably use transferrin receptors to
optimize iron uptake to support rapid proliferation. The
same may be true for activated lymphocytes. However, the
greatest demand for iron is by erythroid precursors, to support the large- scale production of hemoglobin. In normal
adults, about two- thirds of the total body iron endowment is
found in hemoglobin, distributed among erythroid precursor cells and circulating erythrocytes.
Iron- loaded transferrin binds with high affinity to transferrin receptors. Of the two forms of the receptor, transferrin
receptor 1 (TFR1) appears to be critical for cellular iron
uptake, but both TFR1 and transferrin receptor 2 (TFR2) are
involved in systemic iron homeostasis. Transferrin receptors,
carrying their iron- transferrin cargo, undergo endocytosis
(Figure13.2). Portions of the cell membrane bearing transferrin receptors invaginate into the cytoplasm and bud off as
intracellular vesicles (endosomes). Protons are pumped into
the endosomes to lower their internal pH, leading to the
release of iron from transferrin. The liberated iron then
leaves the endosome to enter the cytoplasm. This also
requires a transmembrane transport step, which is probably
mediated by DMT1 and facilitated by the low endosomal
pH. The process is assisted by one or more essential ferrireductases, in erythroid cells principally Steap3 (six transmembrane epithelial antigen of the prostate 3), that convert
ferric to ferrous iron. Within the cytoplasm, ferrous iron is
shuttled to sites of use and storage. Two iron chaperones,
poly(rC)- binding proteins (PCRB) 1 and 2have been shown
to escort iron to ferritin and several other proteins that
require or transport iron. Meanwhile, transferrin and transferrin receptor proteins return to the cell surface, where
transferrin is released, and the receptors become available for
further cycles of iron delivery.
Why should cells have evolved the complicated transferrincycle when it is possible to take up iron directly? There
are atleast two likely answers. Firstly, tight binding of iron
totransferrin is advantageous while iron is in the circulation,
but it complicates the transport of iron into cells. The
pH- dependent release of iron, occurring in a controlled
Molecular basis ofiron metabolism 177
DMTI
+
H
+
H
Erythroid precursor
.
Fe
transferrin
2
–Apo-transferrin
Figure13.2 The transferrin cycle. The transferrin cycle of receptormediated endocytosis is initiated by binding of diferric (Fe2)- transferrin
to a cell surface transferrin receptor. The ligand–receptor complex is
internalized by invagination of clathrin- coated pits to form specialized
endosomes. Influx of protons into the endosome decreases its pH
toapproximately 5.5, facilitating release of iron from transferrin.
Theiron is then transferred to the cytoplasm by DMT1.
Apo- transferrin and transferrin receptor return to the cell surface
forfurther cycles of iron uptake.
intracellular environment, solves the problem of liberating
the iron. Secondly, binding of iron- loaded transferrin to
transferrin receptors serves to concentrate iron in the vicinity of DMT1, probably achieving much higher local iron
concentrations than would be possible without such a mechanism. This allows more efficient iron uptake by cells with
large needs (erythroid precursors, tumor cells, activated lymphocytes) without exposing other cells to unnecessary iron.
Undoubtedly, other cell types use these and other schemes
for assimilating iron. Hepatocytes and macrophages are particularly important in iron homeostasis and their iron uptake
mechanisms, though not well understood, deserve mention.
Hepatocytes express both types of transferrin receptor and
likely take up iron via the transferrin cycle. Hepatocytes also
avidly take up non- transferrin- bound iron (NTBI) when the
plasma iron concentration exceeds the binding capacity of
transferrin. This is an abnormal situation, except perhaps in
the portal circulation after an iron- rich meal, because there
are usually about three times as many transferrin ironbinding sites as are needed (i.e. transferrin is normally about
30% saturated with iron). However, patients with iron overload may have more iron than transferrin can accommodate,
and this excess iron appears to be rapidly removed from the
circulation by hepatocytes. The molecular mechanism for
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178 Molecular Hematology
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hepatic NTBI uptake uses the SLC39A14 (also called ZIP14)
transporter, and in the absence of this transporter, NTBI is
no longer taken up by hepatocytes in mice. Hepatocytes
express ferroportin and release iron at least in part by a
hepcidin- controlled ferroportin- dependent mechanism.
As discussed earlier, reticuloendothelial macrophages
obtain iron by phagocytosing and breaking down erythrocytes. This process takes place in discrete phagocytic vesicles
within the cells, and likely involves the action of heme oxygenase, an enzyme that catalyzes the degradation of heme.
After crossing the phagosomal membranes, cytoplasmic iron
is stored in ferritin. Macrophages export ferrous iron through
their abundant ferroportin, assisted by the plasma ferroxidase ceruloplasmin, so that ferric iron is delivered to plasma
transferrin. Similar to intestinal cells and hepatocytes, reticuloendothelial macrophages partition their iron content into
retained and released portions. This process is regulated in
response to the iron needs of the body by the hepatic hormone hepcidin, which induces the internalization and degradation of macrophage ferroportin. While there is currently
no direct way to measure how much iron is retained and how
much is released, commonly used laboratory tests provide
some information. The concentration of serum iron (and
hence transferrin saturation) is determined by two factors:
macrophage iron release and erythroid iron utilization.
When erythropoiesis occurs at a steady rate, transferrin saturation is determined primarily by the rate of macrophage
iron release, increasing when there is increased iron export
and decreasing when iron is retained or when less iron is
being recycled from erythrocytes. In contrast, the concentration of serum ferritin roughly correlates with the amount of
storage iron in the body. Serum ferritin appears to be derived
primarily from reticuloendothelial macrophages and hepatocytes. However, serum ferritin is not a very accurate indicator because levels are increased by inflammation, tissue
damage, and rare congenital hyperferritinemia disorders.
Nonetheless, a low serum ferritin value invariably indicates
depleted iron stores.
Sites ofiron storage
Iron is stored within cells in the cavities of ferritin protein
multimers. There are two types of ferritin subunit, L and H,
both approximately 20 kDa in size. These subunits assemble
in varying proportions into 24- subunit cage- like structures.
Up to several thousand iron atoms can be stored in each ferritin multimer. Like transferrin, ferritin’s function is to prevent iron from reacting with other cellular constituents, and
allow controlled iron release in response to increased cellular
needs. The molecular details of iron incorporation into and
release from ferritin are not fully understood, but it now
appears that iron is released by ferritinophagy, a regulated
process in which nuclear receptor coactivator 4 (NCOA4)
binds to ferritin under low iron conditions and delivers ferritin to the autophagy pathway, culminating in degradation
of ferritin in lysosomes and the release of iron into the cytoplasm. Under some circumstances, ferritin and other cellular
components are partially degraded and conglomerated to
form hemosiderin, a heterogeneous iron- containing substance that probably serves little purpose but to keep iron
from causing harm. Both ferritin and hemosiderin accumulate in iron- overloaded tissues.
The liver serves as the primary depot for iron in excess of
immediate needs. It has a very large capacity for storing iron,
though this capacity is ultimately exceeded in iron overload
disorders. While other tissues (myocardium, pancreas) also
fill up with iron in iron overload, the liver is frequently the
first site where damage from iron overload becomes apparent. Hepatocytes avidly take up NTBI from the plasma, and
the liver is the first organ exposed to dietary iron via the portal circulation.
Reticuloendothelial macrophages are also important for
iron storage, but their iron comes from degraded erythrocytes. Patients treated with frequent transfusions typically
accumulate excess iron in macrophages first, and only later
in other tissues. This pattern of iron accumulation has been
referred to as “siderosis” to distinguish it from hemochromatosis, which is primary iron loading of parenchymal cells.
Regulation ofiron homeostasis
Iron homeostasis requires the coordinated regulation of iron
transport and iron storage so that tissues will have adequate
amounts to meet their needs, but will not become overloaded
with iron. Regulation must involve the control of cellular
iron import, export, and partitioning. Over the last decade, a
better understanding of regulation at each of these steps has
emerged.
There are at least four known regulators of intestinal iron
absorption (Figure13.3): iron stores, erythropoietic demand,
hypoxia, and inflammation. The stores regulator modulates
absorption severalciency and decreasing absorption in iron overload. The
erythroid regulator is more potent: it can increase iron
absorption many- fold when erythropoiesis becomes iron
restricted. The hypoxia regulator is not well characterized,
but its effects may be at least partly distinct from those of the
erythroid regulator. This regulator increases iron absorption
in response to hypoxia. Finally, an inflammation regulator
decreases iron absorption in response to inflammation from
a variety of causes.
Similar influences also regulate the release of recycled iron
from reticuloendothelial macrophages. During inflammation or iron sufficiency, iron is retained in macrophages
fold, increasing absorption in iron defi-
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Molecular basis ofiron metabolism 179
(A) (B)
Duodenum
and other sites
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Liver
Hepcidin
Hepcidin
InammationHypoxia
Erythropoietic signal
Plasma
Fe-Tf
Liver
Hepcidin
Fpn
Fe
Hepcidin
Fpn
Fe
Fpn
Plasma
Fe-Tf
Spleen
Fe
Fe-Tf
Bone marrow
of iron usage
Iron signal
Figure13.3 Regulators of iron absorption, storage, and tissue distribution. (A) Iron stores, erythropoietic demand, hypoxia, and inflammation
modulate the hepatic production of hepcidin, an iron- regulatory hormone. Increased iron stores and inflammation both increase hepcidin
expression (↑), whereas increased erythropoietic demand and hypoxia decrease hepcidin expression (⊥). (B) Hepcidin controls the major flows of
iron in the body, including the efflux of iron into plasma from absorptive enterocytes, from splenic and hepatic macrophages involved in recycling
of iron from erythrocytes, and from hepatocytes that store iron. Plasma iron is destined for hemoglobin synthesis by erythrocyte precursors in the
bone marrow, and for other sites of iron utilization. Fe, Iron; Fpn, ferroportin; Tf, transferrin.
but is released in response to iron deficiency or erythroid
demand. The regulation of iron storage in hepatocytes is less
well understood, but it is clearly responsive to systemic iron
requirements.
The iron- regulatory hormone hepcidin is likely to be the
common effector of the stores, erythroid, hypoxia and
inflammation regulators (Figure 13.3). Hepcidin (also
called LEAP, HAMP) is produced by hepatocytes as a
25- amino acid peptide with four disulfide bonds from
an 84- amino acid precursor molecule, with the ultimatecleavage mediated the prohormone convertase furin.
Administration of synthetic hepcidin to mice results in
profound and prolonged hypoferremia. The hypoferremic
effect of hepcidin is due to its ability to inhibit the major
mechanisms that deliver iron to plasma: intestinal iron
absorption and the release of iron from recycling compartments and stores in the spleen and the liver. Continuing
consumption of iron by erythropoiesis and other ironrequiring processes then rapidly depletes the relatively
small plasma and extracellular iron compartment.
On the cellular and molecular level, hepcidin inhibits the
efflux of cellular iron into extracellular fluid or plasma,
exerting its effect on the major cell types involved in iron
transport, including enterocytes, macrophages, hepatocytes,
kidney tubule cells, and placental syncytiotrophoblast.
These iron- exporting cells express ferroportin, the sole
known cellular iron exporter. Hepcidin acts by binding
to ferroportin, inducing its internalization and lysosomal
degradation (Figure 13.4). The ferroportin degradation
pathway is similar to that of other receptors undergoing
ligand-
induced endocytosis, and is triggered by ubiquitination of a string of lysine residues in the cytoplasmic loop
connecting the twohalves of the molecule. The loss of ferroportin from cellmembranes proportionately reduces the
efflux of iron into extracellular fluid. Alternatively, at higher
concentrations, hepcidin directly occludes the channel
through which iron moves.
The production of hepcidin is increased in response to
dietary or parenteral iron loading, presumably as part of a
compensatory mechanism to decrease iron absorption and
decrease plasma iron (primarily derived from recycling
macrophages). On the contrary, iron deficiency reduces
hepcidin production, allowing more iron to enter the body
through the intestine and more iron to enter the plasma
from recycling macrophages. Hepcidin thus acts as the
store’s regulator. Based on recent studies in cellular models,
in genetically altered mice and in patients with genetic iron
disorders, hepcidin synthesis in hepatocytes is regulated by
iron sensors and signaling molecules that influence the
bone morphogenetic protein (BMP) signaling pathway
(Figure13.5). BMP signals increase the production of hepcidin by binding to the BMP receptor complex and the coreceptor hemojuvelin (HJV) on hepatocytes to activate
SMAD transcription factors, which bind directly to the hepcidin promoter. The primary BMP signals important for
iron homeostasis are BMP6 and BMP2. These BMP ligands
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180 Molecular Hematology
DMT1
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DMT1
Ferritin
Hepcidin
Ferritin
Ferroportin
Ferroportin
Hepcidin
Figure13.4 Regulation of cellular iron transport by hepcidin. Hepcidin regulates the release of iron from enterocytes (shown in the figure),
macrophages, and other cells by binding to ferroportin and inducing its internalization and degradation in lysosomes. At higher concentrations,
hepcidin also directly occludes the iron efflux pathway. Under the influence of hepcidin, iron export is decreased and iron accumulates in
cytoplasmic ferritin. In enterocytes, regulatory effects of increased cellular iron may result in decreased iron uptake.
are not produced by hepatocytes but byadjacent sinusoidal
endothelial cells, and their secretion reflects closely the
amounts of iron stored in the liver. One mechanism that
contributes to iron-
dependent BMP6 regulation during
high iron load is activation of the NRF2 transcription factor
pathway by reactive oxygen species. Two additional molecules that function as sensors of circulating iron levels are
TFR1 and TFR2. The transmembrane molecule HFE can
bind to both transferrin receptors but is displaced from
TFR1 when the receptor binds its main ligand, irontransferrin. Both HFE and TFR2 are thought to influence
hepcidin production by activating SMAD signaling, possibly by interacting with members of the BMP receptor complex. Under conditions of iron deficiency, transmembrane
protease, serine 6 (TMPRSS6), also called matriptase 2,
binds HJV and other components of the BMP receptor complex to reduce BMP- SMAD signaling and hepcidin expression. How all these cells and molecules interact to regulate
hepcidin is still an unfinished story.
In addition to its regulation by iron, hepcidin is suppressed by increased erythropoietic activity, sometimes
even in the face of systemic iron overload, confirming that
hepcidin is the ultimate erythroid regulator. How enhanced
erythropoiesis suppresses hepcidin production is not yet
fully understood. Recent studies indicate that erythropoietinstimulated erythroblasts secrete erythroferrone (also called
Fam132b), a member of the C1q-TNFα superfamily, which
suppresses hepcidin transcription by binding and sequestering BMP ligands. The production of hepcidin is also
decreased in hypoxia, suggesting that hepcidin is an ultimate effector of the hypoxia regulator. The effect of hypoxia
on hepcidin could be partly mediated by hypoxia- induced
erythropoietin acting on erythroblasts to increase erythroferrone secretion.
Finally, hepcidin expression is induced by inflammation,
probably through a direct action of the cytokine interleukin
(IL)- 6 and other inflammatory mediators on hepatocytes,
where hepcidin transcription is then modulated by the
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Molecular basis ofiron metabolism 181
https://t.me/med1917
Fe2 Transferrin
HFE
TFR1 TFR2
Fe
Mitochondrion
SMAD1/5/8
ROS
BMP2/6
HJV
neo
BMP receptor
NRF2
Nucleus
complex
P
SMAD1/5/8
BMP6
BMP2
Endothelial cell
TMPRSS6
Hepatocyte
SMAD4
Hepcidin
Nucleus
Figure13.5 Molecular regulation of hepcidin by iron. Increased tissue iron stores induce the production of BMP6 and BMP2in liver endothelial
cells, at least in part via activation of the transcription factor NRF2 by mitochondrial reactive oxygen species (ROS). Secreted BMP ligands bind to
the BMP receptor complex, including the co-receptor HJV and scaffold protein neogenin (neo), on the hepatocyte membrane to induce the
phosphorylation of SMAD1/5/8 proteins. Phosphorylated SMAD1/5/8 forms a complex with SMAD4 and translocates to the nucleus to induce
hepcidin transcription. Circulating iron in the form of Fe2- transferrin binds to TFR1, which displaces HFE. Fe2- transferrin binding also stabilizes
TFR2, which can interact with HFE. TFR2 and HFE enhance the activation of the SMAD signaling cascade and hepcidin transcription, possibly by
interacting with the BMP receptor complex. Pathways activated by iron are inhibited by iron deficiency. Additionally, iron deficiency increases
TMPRSS6 to interact with HJV and other BMP receptor complex proteins to inhibit SMAD pathway activation and hepcidin transcription.
JAK2- STAT3 regulatory pathway. In this case, induced hep-
Iron disorders
cidin expression leads to decreased intestinal iron absorption and decreased macrophage iron release, acting as an
inflammation regulator. There is growing evidence that, in
response to the inflammatory regulator, increased hepcidin
expression contributes to the abnormal iron homeostasis
observed in the anemia of chronic disease (also known as the
anemia of inflammation).
In most general terms, iron disorders represent a failure
ofhomeostatic mechanisms that match intestinal iron absorption and systemic iron distribution to the iron requirements
of erythropoiesis and other iron- consuming processes. Iron
homeostasis results in the maintenance ofnormal plasma and
extracellular iron concentrations (10–30 μmol/L in humans)
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and normal iron stores in macrophages and hepatocytes that
help buffer transient disturbances in the supply or demand
for iron. Either genetic or environmental causes, and often
both, can contribute to iron disorders.
Iron- deficiency disorders
Iron deficiency is a major public health problem and the
most common nutritional cause of anemia. Very rarely, iron
deficiency is genetic and is manifested as hypoferremia,
hypoferritinemia, and iron- restricted microcytic anemia
refractory to oral iron administration. Recent studies have
shown that homozygous or compound mutations in a gene
encoding TMPRSS6 are responsible for most cases of ironrefractory iron- deficiency anemia. TMPRSS6 negatively
regulates hepcidin by inhibiting the activity of the BMP
receptor complex. Although initial studies suggested
thatTMPRSS6 acts by cleaving membrane HJV, subsequent
studies provide evidence that HJV may not be the sole target
and proteolytic cleavage activity may not be essential for
TMPRSS6 function.
Most genetic disorders of iron metabolism result in iron
overload rather than iron deficiency. They are attributable to
mutations that affect the regulation of intestinal iron absorption and body iron distribution.
Iron overload disorders
It is now clear that there are many genetic iron overload disorders, affecting distinct components of the iron- regulatory circuitry. They can be generally classified as hemochromatosis
disorders (iron deposition in parenchymal cells) or siderosis
disorders (deposition of iron in reticuloendothelial macrophages). The known disorders and their genetic causes are
listed in Table13.1. Over the last 15 years, it has become clear
that the final common mechanism for most forms of hereditary hemochromatosis is relative or absolute hepcidin deficiency or, rarely, resistance to hepcidin. The lack of hepcidin or
the loss of its effect on ferroportin results in excessive or unrestrained absorption of dietary iron, as well as the depletion of
the macrophage iron storage compartment. The genetically
defective proteins in hereditary iron overload disease are hepcidin itself, regulators of hepcidin (HFE, TFR2, HJV), targets of
hepcidin (ferroportin), or molecules that convey iron to the
iron- sensing mechanism in hepatocytes (transferrin).
HFE- related hemochromatosis
The most common form of hemochromatosis was classically
described as the triad of cirrhosis, diabetes, and skin melanosis
(“bronze diabetes”), but fortunately such advanced disease is
Table13.1 Iron overload disorders (new classification based onthe 2022 consensus document ofthe Nomenclature Committee ofthe
International Society forthe Study ofIron inBiology andMedicine (BIOIRON Society).
Current classification Molecular pattern Note
HFE-
related p.Cys282Tyr homozygosity or compound
heterozygosity of p.Cys282Tyr with other rare
HFEpathogenic variants or HFE deletion
Non- HFE- related Rare pathogenic variants in “non- HFE” genes:
• HJV- related
• HAMP- related
• TFR2- related
• SLC40A1 (ferroportin gain- offunction)- related
b
Digenic
Molecularly undefined Molecular lesion unknown after sequencing of
a
Provided that iron overload is confirmed by MRI. If this is not available, close monitoring of hemoglobin level is needed to avoid anemia.
b
Caution is needed to interpret as digenic inheritance results from next-generation sequencing outputs reporting several variants in gene
panels. Whenever possible, strict criteria for defining pathogenic variants should be adopted and corroborated by family segregation and/or
functional studies.
Double heterozygosity and/or double homozygosity/
heterozygosity for mutations in 2 different genes
involved in iron metabolism (HFE and/or non- HFE)
known genes (provisional diagnosis)
Low penetrance; consider presence of host- related or
environmental cofactors for iron overload
In subjects with other HFE genotypes (e.g. p.
Cys282Tyr/His63Asp compound heterozygosity or
p.His63Asp homozygosity) consider second- line
genetic testing for rarer variants
Potentially, mutations in any hepcidin- regulatory
gene may be causative (the effects of novel
mutations should be confirmed through functional
and epidemiological studies)
Molecular subtypes characterization only at
specialized centers, but the diagnosis of non- HFE
related hemochromatosis is sufficient to start
phlebotomies at nonspecialized centers
More commonly, p.Cys282Tyr mutation in HFE gene
might coexist with mutation in other genes; rarely,
both mutations involve non- HFE genes
Patients should be referred (or DNA should be sent) to
specialized centers
a
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