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Mechanisms of iron loading and toxicity

Gregory J. Anderson*
Iron Metabolism Laboratory, Queensland Institute of Medical Research, Brisbane Queensland, Australia

Normal iron homeostasis is a nely balanced system that reects iron absorption, loss and utilization. The
body has no mechanism for the active excretion of iron, so body iron levels are controlled at the point of
absorption in the small intestine. Disturbances in this equilibrium, such as those leading to enhanced
absorption, can have signicant clinical consequences. Continued excessive iron uptake is followed by
iron deposition in various tissues, ultimately leading to tissue damage, and possibly end-organ failure. In
this review, current concepts in normal iron homeostasis, and iron loading are explained. The clinical consequences as well as the differences between primary and secondary iron loading are also reviewed, and
C 2007 Wiley-Liss, Inc.
some future research priorities are discussed. Am. J. Hematol. 82:11281131, 2007. V

Iron Homeostasis in the Body


The amount of iron in the body is regulated predominantly by the control of dietary iron absorption [1]. Each
day 12 mg of iron from dietary sources is absorbed by the
proximal small intestine, with the precise amount reecting
body iron requirements. The iron absorbed is distributed to
various body tissues and organs bound to the plasma protein transferrin (Tf) [2]. Quantitatively, most iron is incorporated into erythrocytes for heme synthesis, but all body
cells require some iron to meet their metabolic requirements. Iron in excess of immediate metabolic needs is
stored, predominantly in hepatocytes and the macrophages
of the reticuloendothelial system [2]. There is a dynamic
cycle of iron utilization and recycling within the body, and
the amount of iron trafcked internally each day far
exceeds dietary iron absorption and loss [2,3]. Much of the
iron recycling is mediated by macrophages, which engulf
senescent erythrocytes and return heme-derived iron to the
circulation [4]. Small amounts (12 mg) of iron are also lost
daily from the body by processes such as sloughing of intestinal mucosal and skin cells, and in the urine and bile.
Women have additional losses associated with menstruation, and consequently their daily iron requirements are
somewhat higher than those of men [13].
The delivery of iron to cells involves a number of specialized transport systems and membrane carriers, some of
which are depicted in Fig. 1. Iron delivery to most cells,
and to erythroid cells in particular, involves binding of diferric transferrin (Fe2Tf) to a specic cell surface receptor,
TfR1 [5]. A homolog of TfR1, TfR2, is also found on some
cells (notably hepatocytes). While it is able to mediate the
uptake of Tf-bound iron, its major function appears to be as
a regulatory protein [3,6]. The Fe2Tf-TfR1 complex is internalized by receptor-mediated endocytosis, and the iron is
released from Tf through a process that involves acidication of endosomes and likely reduction of the iron via the
enzyme Steap3 [5,7]. Divalent metal ion transporter 1
(DMT1) carries the released iron across the endosomal
membrane into the cytoplasm of the cell [8], where it can
be utilized for metabolic purposes. Internalized iron not
required immediately for biosynthesis is sequestered within
the cytosolic protein ferritin (Ft) [2,9]. Most tissues are able
to divest themselves of iron, a process mediated predominantly by the iron transporter ferroportin (FPN) [10].
The epithelial cells lining the proximal small intestine are
specically adapted for the absorption of dietary iron. Most
iron in the diet is in the oxidized or ferric (Fe3) form, but

there is extensive evidence to show that it must be reduced


to the ferrous (Fe2) form before it can be absorbed. The
iron regulated ferric reductase, duodenal cytochrome B
(Dcytb) is predicted to be involved in this process [11] but
its role has yet to be fully dened. Mice in which the gene
encoding Dcytb has been deleted do not show disturbed
systemic iron homeostasis [12], but the animals were not
studied under conditions where the role of Dcytb in iron
absorption could be evaluated denitively [13]. Ferrous iron
is transported across the brush border membrane into the
enterocyte via the ferrous iron transporter DMT1 [1,8]. The
mechanism by which the brush border iron uptake components DMT1 and Dcytb are regulated is not well understood, although the expression of both is increased under
conditions that stimulate iron absorption [14]. The imported
iron can be stored within the enterocytes in Ft, but if it is
required by the body it is transported across the basolateral
membrane, and into the circulation. This process involves
the iron exporter FPN, and the iron oxidase hephaestin, but
the precise relationship between these two proteins is
unclear [15]. Under certain conditions it has been demonstrated that the circulating hephaestin homolog ceruloplasmin can also play a role in iron release from enterocytes [16].
Regulation of Iron Homeostasis
Role of hepcidin
The amount of iron entering the body, and that released
from storage sites, is tightly regulated according to body
iron requirements. It has become apparent in recent years
that much of this regulation is orchestrated by a liverderived peptide known as hepcidin [3]. Hepcidin regulates
the entry of iron into the plasma by binding directly to the
iron exporter FPN on basolateral membranes of enterocytes, the plasma membranes of macrophages, and other
cell types [3,17,18]. The binding of hepcidin leads to the
internalization and degradation of FPN, thereby blocking
cellular iron export, and reducing plasma iron [17]. Hepcidin
*Correspondence to: Dr. Gregory J. Anderson, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Brisbane Queensland 4029,
Australia. E-mail: Greg.Anderson@qimr.edu.au
Received for publication 20 July 2007; Accepted 20 August 2007
Am. J. Hematol. 82:11281131, 2007.
Published online 26 October 2007 in Wiley InterScience (www.interscience.
wiley.com).
DOI: 10.1002/ajh.21075

C 2007 Wiley-Liss, Inc.


V

American Journal of Hematology

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http://www3.interscience.wiley.com/cgi-bin/jhome/35105

Figure 1. Cellular iron transport and uptake. Tf, transferrin; Fe2Tf, diferric transferrin; TfR1, transferrin receptor 1;
DMT1, divalent metal ion transporter 1; FPN, ferroportin.
[Color gure can be viewed in the online issue, which is
available at www.interscience.wiley.com.]

thus acts as a suppressor of cellular iron release. When


iron demands are high, hepcidin levels are low and this
favors increased iron absorption and elevated iron release
from macrophages and tissues stores. During iron excess,
the liver secretes more hepcidin which decreases the
export of iron from enterocytes and iron release from tissues [3,18].
Systemic factors that regulate iron entry
into the plasma
Any factor that leads to alterations in iron requirements
has the potential to inuence iron entry into the plasma.
Some of the best-known factors include body iron stores,
changes in the rate of erythropoiesis, and hypoxia [1]. For
example, when body iron stores are low, iron absorption
will increase, as will the amount of iron released from the
reticuloendothelial system. The opposite occurs under conditions of iron sufciency. Changes in the rate of erythropoiesis will also increase or decrease iron entry into the
plasma, with increased erythropoiesis leading to increased
iron absorption and elevated iron release from macrophages and other storage sites. A number of important
genetic abnormalities also lead to altered iron trafcking. In
all of these situations, whether the changes in iron homeostasis result from physiological stimuli or genetic abnormalities, the alterations in iron trafcking ultimately result from
modulation of hepcidin expression [3,19].
Causes of Iron Overload
Sources of excess body iron
Excess body iron may be derived from either enteral (i.e.
iron absorption) or parenteral sources. Excess intestinal
iron absorption usually results from inherited disturbances
of iron metabolism (see below) but long-term medicinal iron
also can lead to excessive intake. Parenteral sources that
lead to iron overload include blood transfusions or, less
commonly, therapeutic iron dextran. In some situations
(e.g. in b-thalassemia) both elevated iron absorption, and
transfusional iron loading may coexist.
Iron loading disorders
Iron overload can be classied as primary or secondary,
depending on the underlying mechanism [19]. Some of the

American Journal of Hematology DOI 10.1002/ajh

main clinical disorders of iron overload are shown in Table


I. Primary (hereditary) iron loading results from increased
absorption of dietary iron by the small intestine. In some
cases (e.g. ferroportin disease), there also may be redistribution of iron between tissues.
The most common type of primary iron overload is HFErelated hemochromatosis [2,19]. This autosomal recessive
disorder is most commonly caused by a homozygous mutation within the HFE gene on chromosome 6 leading to the
C282Y substitution. HFE-related hemochromatosis is particularly prevalent in populations of Northern European origin [20]. Other, less common, genetic disorders of primary
iron overload result from mutations in the genes encoding
TfR2, hepcidin, and hemojuvelin, but all show a similar histological pattern of iron deposition to that seen in HFErelated disease [19,20]. This excessive iron loading may
ultimately lead to irreversible organ damage with complications such as hepatic cirrhosis, diabetes, cardiac dysfunction, and arthritis [21]. A common feature of each of these
disorders is that circulating hepcidin levels are inappropriately low relative to body iron load and this can explain the
increased iron absorption associated with these conditions.
How disruption of HFE and TfR2 leads to altered hepcidin
expression is not understood, but recent evidence indicates
that hemojuvelin can alter hepcidin by signaling through the
BMP/SMAD pathway [22]. FPN-related hemochromatosis is
somewhat different in its histological appearance, but many
of the same pathological consequences are found; this is
the most common form of non-HFE hemochromatosis [23].
Secondary iron loading results mainly from iron accumulated as a result of blood transfusions that are administered
to treat diseases of the erythroid system [24]. These diseases include those associated with ineffective erythropoiesis (e.g. b-thalassemia, sideroblastic anemia), chronic hemolytic anemias (e.g. pyruvate kinase deciency, sickle cell
anemia), or hypoplastic anemias (e.g. chronic renal failure,
aplastic anemias). While transfusion is usually the major
source of the excess iron in these conditions, in some
cases, for example in b-thalassemia, there is also excessive iron absorption, so the excess body iron is acquired
from two different sources.

TABLE I. Classication of Iron Loading Disorders


Primary
HFE-related hemochromatosis (Type 1)
TfR2-related hemochromatosis (Type 3)
FPN-related hemochromatosis (Type 4)
Juvenile hemochromatosis (HJV-related) (Type 2A)
Juvenile hemochromatosis (hepcidin-related) (Type 2B)
Secondary
Ineffective erythropoiesis (e.g. b-thalassemia, sideroblastic anemias)
Chronic hemolytic anemias (e.g. pyruvate kinase deciency, sickle cell
anemia)
Hypoplastic anemias (e.g. chronic renal failure, aplastic anemias)
Other
Medicinal iron overload
African iron overload
Hereditary atransferrinemia
Hereditary aceruloplasminemia
Neonatal hemochromatosis
Chronic liver disease (e.g. ALD, IR-associated)
Porphyria cutanea tarda
Portacaval shunting
ALD, alcoholic liver disease; FPN, ferroportin; HJV, hemojuvelin; IRassociated, insulin resistance-associated; TfR2, transferrin receptor 2.

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There is also a range of miscellaneous forms of iron


overload of varying etiologies, but most of these are
uncommon to rare. These include medicinal iron overload,
African iron overload, rare diseases of plasma protein
synthesis, such as congenital atransferrinemia and aceruloplasminemia, neonatal hemochromatosis, siderosis associated with chronic liver disease (e.g. dysmetabolic iron
loading syndrome), and porphyria cutanea tarda.
Mechanisms of Iron Toxicity
In hemochromatosis and other iron-loading states, the
iron binding capacity of plasma Tf may be exceeded, and
there is a marked increase in the proportion of free-iron in
the plasma. Such non-transferrin-bound iron (NTBI) [25,26]
can reach quite high concentrations (up to 20 lM under
some pathological conditions), and it is cleared very rapidly
from the plasma by the liver and other organs [27,28]. As a
consequence, there is the progressive accumulation of iron
in these tissues, and toxicity may result [29]. It is thought
that NTBI in the plasma per se is not unduly toxic, but
rather it is the unstable component of NTBI that enters cells
that is potentially damaging [26]. Esposito et al. have
recently dened labile plasma iron (LPI) as a component of
NTBI that is redox-active and chelatable, and capable of
permeating into organs and inducing tissue iron overload
[26]. In addition, intracellular labile iron can derive from the
degradation of the iron storage protein Ft.
The capacity of labile cellular iron to catalyze the formation of highly reactive oxygen radicals underlies its cellular
toxicity, as these radicals can damage a wide range of cellular macromolecules [30]. Although reactive oxygen species (ROS) are damaging, they are also generated during
normal metabolism in organelles such as mitochondria and
peroxisomes. Under normal circumstances the body uses a
range of defense strategies to protect against excessive
ROS accumulation and their effects. These include various
enzymes that will degrade the ROS, antioxidants, repair
processes (e.g. DNA repair), and iron storage mechanisms
[31]. The storage of intracellular iron within Ft and hemosiderin is particularly important in sequestering iron in its nontoxic form [9,32].
Several ROS exist including the superoxide anion, the
hydroxyl radical, alkoxyl radicals, peroxyl radicals, hypochlorous acid, and peroxynitrite. A wide range of damaging cellular processes can result from the action of these radicals
if they are not kept under control, and targets for radical
attack include DNA, proteins, and lipids. The peroxidation
of cell membrane and organelle lipids is a major pathway
of ROS-mediate damage. The hydroxyl radical is particularly reactive and can attack most biomolecules, but some
of the lipid hydroperoxide-derived radicals are also very important in promoting lipid peroxidation [30].
Clinical Consequences of Iron Overload
Target organs and organ dysfunction
The liver and heart are the major targets of damage
induced by reactive iron species, but other organs such as
the pancreas and endocrine organs are also sensitive to
the toxic effects of iron [21,33]. The liver is the major iron
storage organ in the body, and it is not surprising that hepatotoxicity is a major consequence of body iron loading
[34]. Iron-dependent damage to the liver can lead to brosis and cirrhosis and, in advanced cases, liver cancer. In
the heart, the formation of hydroxyl radicals by NTBI results
in impaired function of the mitochondrial respiratory chain
which leads to heart failure [33]. The more prominent cardiac effects (e.g. hypertrophy, ber degeneration, arrhyth-

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mias, and congestive heart failure) tend to be seen in situations where there is very rapid iron loading. For example,
cardiac complications are more common in the aggressive
juvenile forms of hemochromatosis than in adult onset
HFE-related disease, and cardiac damage often accompanies transfusional iron loading. Iron overload also affects
the endocrine system, in particular the pituitary gland and
the thyroid/parathyroid glands. Gonadal dysfunction is a
major secondary consequence of iron loading in the anterior pituitary. Arthritis is also very common in iron overload
and, in some cases there is an increased susceptibility to
certain infections. Other factors contributing to the extent of
iron-related tissue damage include the rate of iron accumulation (rapid loading is more damaging than slow loading),
the duration of elevated iron, the balance between parenchymal and reticuloendothelial cell loading (parenchymal
cells are more susceptible to oxidative damage), the presence of comorbidities (e.g. hepatotoxins such as alcohol
and viral hepatitis in the liver), and ascorbate levels.
Research Priorities
Despite major advances in our understanding of iron
loading and toxicity in recent years through the discovery of
new proteins, there are still many unanswered questions
that present challenges for iron homeostasis research. Of
foremost importance is understanding, in more detail, the
biology of the iron regulatory peptide hepcidin. Our knowledge of this central player in iron metabolism is expanding
rapidly, but we are still lacking fundamental information on
how hepcidin synthesis responds to changes in body iron
demand. In addition, an important priority for future
research is to design a simple, reliable plasma assay to
quantify the mature form of hepcidin. HFE and TfR2 are
upstream regulators of hepcidin, and dening the signal
transduction pathways linking these proteins to hepcidin
expression is another area deserving of signicant attention. Ultimately by learning more about the basic biology of
iron homeostasis and how it is regulated, we will be in a
much better position to understand the pathogenesis of various forms of iron loading, and to design novel therapies for
treating this important class of human disorders.
Acknowledgments
In preparation of this manuscript, the author received editorial/writing support that was funded by Novartis Oncology.
The author, however, was fully responsible for contents and
editorial decisions for this manuscript.
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