Download Iron Restriction, Associated Pathology, and Points of Therapeutic

Iron Restriction, Associated Pathology and Points of Therapeutic Intervention
Tomas Ganz, PhD, MD
Departments of Medicine and Pathology, David Geffen School of Medicine at UCLA
Los Angeles, CA ([email protected])
Introduction
Iron is an essential component of heme and hemoglobin, and an important regulator of
erythropoiesis. Limitation of iron delivery to erythrocyte precursors can therefore decrease the
production of red blood cells. Such iron restriction occurs in several common clinical situations,
including total body iron deficiency, iron sequestration (trapping of iron in macrophages),
functional iron deficiency (kinetic imbalance between increased iron demand of the stimulated
erythroid marrow and iron supply) and hereditary disorders with impaired iron transport and
utilization (Table 1). Although the pathophysiology of iron restriction has mainly been
systematically studied in humans and in laboratory rodents, early experiments were also done in
dogs. More recently, zebrafish have been used for the study of iron metabolism1 and
erythropoiesis2 showing a remarkable similarity to the key molecules and systems to those
studied in mice and men. Although some details such as blood volumes, red cell lifespan, sites
of baseline and stress erythropoiesis, and the relative flows of iron from iron absorption vs
recycling vary from one animal species to another, the general principles described in this
presentation are thought to apply to mammals and even to other vertebrates.
Table 1: Types and causes of iron restriction in human diseases and mouse models3
Total body iron deficiency
Blood loss
Iron-deficient diet
Decreased iron absorption
Iron sequestration
Inflammation
Hepcidin-producing adenomas
Iron-refractory iron deficiency anemia (genetic)
Functional iron deficiency
Treatment with erythropoiesis-stimulating agents
Genetic disorders
Divalent Metal Transporter 1 (DMT1) mutations
Hypotransferrinemia
Ferroportin mutations (loss of function)
Aceruloplasminemia
Heme Oxygenase Deficiency
Pathophysiology4
The delivery of iron for erythropoiesis involves a concerted action of multiple
transporters, enzymes and chaperones. Iron uptake in the red blood cell precursors is nearly
completely dependent on the plasma iron carrier protein transferrin. In erythroblasts, iron-loaded
transferrin is taken up by endocytosis of transferrin receptors (transferrin receptor 1, TfR1)
together with bound iron-transferrin, ferric iron then is released from transferrin in acidified
endocytic vesicles, converted to ferrous iron by the action of the ferric reductase STEAP3,
transported to the cytoplasm across the endosomal membrane by DMT1 (divalent metal
transporter 1) and delivered to mitochondria where it is inserted by the enzyme ferrochelatase
into protoporphyrin IX to form heme. Heme is exported into the cytoplasm where it is
incorporated into hemoglobin of red cells.
When red cells in circulation come to the end of their lifespan (120 days in humans and about
40 days in mice), they accumulate markers of senescence that cause them to be phagocytosed
by macrophages in the liver and the spleen. The macrophages degrade the red cell hemoglobin
and release iron from its heme by the action of the enzyme heme oxygenase-1. Ferrous iron is
exported from macrophages to plasma via the sole known iron exporter, ferroportin, converted
to ferric iron by the ferroxidase ceruloplasmin and delivered to plasma transferrin where it
becomes available for erythropoiesis. Recycled iron is the main source of iron for erythropoiesis
in humans and other large animals but intestinal iron absorption contributes also, especially in
small animals who consume a larger amount of food relative to body mass. Enterocytes absorb
nonheme dietary iron via the apical proton-coupled importer DMT-1, the same molecule used by
erythroblasts to export iron from endocytic vesicles. Ferrous iron is exported from enterocytes to
plasma via basolateral ferroportin and is oxidized by the ferroxidase hephaestin before loading
onto plasma transferrin. The absorption of heme iron, important especially in carnivores, is not
well understood. Lesions in any of these steps and processes can affect erythropoiesis.
Total body iron deficiency (also called absolute iron deficiency or just iron deficiency)
is a condition where all sites of iron storage are depleted, including macrophages in the spleen,
liver and the marrow as well as hepatocytes. Under these circumstances the influx of iron into
the plasma compartment is insufficient to maintain normal plasma iron concentrations and the
low serum iron causes inhibition of erythropoiesis, manifested initially as smaller and paler red
cells (microcytosis, hypochromia). The diagnostic hallmarks include low serum iron, low
transferrin saturation and low serum ferritin concentrations. When the bone marrow is sampled,
macrophages lack stainable iron on Perls’ stain. Absolute iron deficiency often results from
acute or chronic blood loss because the red blood cells of mammals and other vertebrates are
extremely iron-rich, e.g. contain about 1 mg of iron per ml of RBC in humans or mice. In
comparison, the baseline daily absorption of iron is only 1-2 mg in the average human adult,
and the amount of iron in the typical human diet is only 10 mg/day. Without iron
supplementation, the ability to compensate for acute or chronic blood loss is therefore very
limited. Iron deficiency is particularly common in situations where dietary iron intake is low, or
where intestinal infections or parasites cause blood loss and malabsorption of iron. Iron
imbalance is also worsened by pregnancies with attendant transfer of iron to the fetuses and
placentas, blood loss during delivery, and the iron demands of lactation.
Iron sequestration is a common consequence of inflammation wherein increased
cytokines, chiefly IL-6, stimulate the production of the iron-regulatory hormone hepcidin which
then blocks the release of iron from stores. The release of iron from stores (macrophages and
hepatocytes) into blood plasma takes place through the membrane iron exporter, ferroportin.
Hepcidin negatively regulates the levels of ferroportin on cell membranes by binding to
ferroportin and inducing its internalization and degradation, thus resulting in cellular iron
sequestration. High levels of hepcidin and inflammatory sequestration of iron commonly occur in
acute and chronic infections, autoimmune inflammatory diseases and certain cancers but are
also seen in chronic renal failure and extensive burns. Diagnostic hallmarks include low serum
iron and transferrin saturation but differ from absolute iron deficiency by normal or high serum
ferritin. Bone marrow biopsies or aspirates reveal macrophages containing Perls-stainable iron.
As in absolute iron deficiency, low serum iron concentrations inhibit erythropoiesis. Inflammatory
cytokines have additional effects on erythropoiesis that combine with the effect of iron restriction
to generate fewer but usually normal size red cells.
Functional iron deficiency reflects imbalance between iron demands of highly
stimulated erythropoiesis and the supply of iron to erythropoiesis. Intense stimulation of
erythropoiesis occurs after the administration of erythropoiesis-stimulating agents (ESAs, such
as erythropoietin and its derivatives). Functional iron deficiency is identified by a fall in serum
iron or transferrin saturation after the administration of ESAs, followed by evidence of ironrestricted erythropoiesis such as decreased reticulocyte hemoglobin content (CHr) measured by
specialized hematologic analyzers. When erythropoiesis is stimulated by endogenous
erythropoietin after blood loss, functional iron deficiency is countered by erythroferrone5,6, a
hepcidin-suppressing hormone whose production in erythroblasts is induced by erythropoietin.
This mechanism may be insufficient to counter the effect of large pharmacologic doses of ESAs.
Genetic disorders (Table) that cause iron restricted erythropoiesis impair at least one of
the steps required for iron delivery to erythroblasts: intestinal absorption of iron, iron recycling by
macrophages, release of iron from recycling macrophages, transport of iron in plasma or iron
uptake and utilization by erythroblasts.
Treatment3,7
Treatment of iron restrictive disorders is dictated by the cause of the iron deficit. In true iron
deficiency, the goal is to identify and treat the conditions that caused blood loss or inadequate
iron absorption and reverse the iron deficit with oral or parenteral iron preparations. Iron
sequestration is best treated by identifying and remediating the cause of increased hepcidin
production, usually an infection, an inflammatory disease, or a malignancy, but rarely also a
hepcidin-producing tumor or the genetic disease iron-refractory iron deficiency anemia. If this is
not possible and treatment of anemia is warranted by its severity, the combination of ESAs and
parenteral iron may be effective. New treatments targeting hepcidin, ferroportin or causative
cytokines are under development. Functional iron deficiency can be treated with iron
supplementation, usually parenteral, and by using ESA regimens that stimulate erythropoiesis in
a less pulsatile and more prolonged time-course. Genetic disorders can be treated by replacing
the missing factor when possible (transferrin, ceruloplasmin). Other lesions can give rise to
complex phenotypes in which iron is maldistributed. Here treatments are not adequately
validated due to the rarity of the patients.
Reference List
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metabolism. Front Pharmacol 5:33, 2014.
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anemia. Stem Cell Res Ther 3:55, 2012.
3. Goodnough LT, Nemeth E, Ganz T: Detection, evaluation, and management of ironrestricted erythropoiesis. Blood 116:4754, 2010.
4. Ganz T: Systemic iron homeostasis. Physiol Rev 93:1721, 2013.
5. Kautz L, Nemeth E: Molecular liaisons between erythropoiesis and iron metabolism. Blood
124:479, 2014.
6. Kautz L, Jung G, Valore EV, et al: Identification of erythroferrone as an erythroid regulator
of iron metabolism. Nat Genet 46:678, 2014.
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Haematologica 98:1667, 2013.