Iron Overload, Toxicity and Treatments
Elizabeta Nemeth, PhD
UCLA David Geffen School of Medicine, Los Angeles, CA
E-mail: enemeth@mednet.ucla.edu
Iron Balance
During the last 15 years, there have been remarkable advances in the understanding of iron
homeostasis and its disorders1. Iron is poorly available in most natural settings, and as a result,
iron homeostasis evolved to conserve and recycle body iron. An average adult human male has
~ 4 g of total iron, but only less than 0.1% (1–2 mg) is lost from the body each day. Iron
excretion is not regulated and predominantly occurs through the shedding of iron-containing
cells from the gastrointestinal tract and the skin. Iron balance must therefore be maintained by
the regulation of dietary iron absorption. In humans, iron overload is most often caused by
genetic diseases that cause disruptions in the regulation of iron absorption or through blood
transfusions that bypass normal regulatory mechanisms1.
Iron absorption occurs in several successive steps: non-heme or heme iron is first transported
across the apical surface of enterocytes, and heme is degraded intracellularly to release iron.
Intracellular iron is then exported into plasma through a transporter ferroportin. In plasma, iron is
loaded onto transferrin for distribution to iron-consuming organs, chiefly the erythropoietic
compartment in the bone marrow.
Hepcidin, the iron-regulatory hormone produced by the liver, is the master regulator of iron
absorption1. Circulating hepcidin regulates iron absorption by binding to ferroportin on the
basolateral surfaces of enterocytes and inducing the endocytosis and degradation of ferroportin.
When hepcidin concentration is high, ferroportin is degraded and iron export from enterocytes
into plasma decreases. Conversely, low hepcidin concentrations result in export of iron from
enterocytes and delivery to plasma transferrin. Hepcidin is conserved in all the vertebrate
species examined so far (including human, rodents, bats and fish), except for birds where the
presence of hepcidin has been questioned. In contrast, ferroportin is widely expressed not only
in vertebrates but also in plants and invertebrates.
Human and mouse studies have demonstrated that alterations in hepcidin and ferroportin
expression, or in their interaction, lead to the development of several iron disorders ranging from
iron-restricted anemias to iron overload.
Hereditary hemochromatosis
Hereditary hemochromatosis, a disease of iron overload, is caused by homozygous disruption
of genes encoding hepcidin itself or hepcidin regulators (HFE, transferrin receptor 2 or
hemojuvelin). The resulting hepcidin deficiency leads to hyperabsorption of dietary iron and iron
overload of multiple tissues. The degree of iron overload correlates with the severity of hepcidin
deficiency. Hepatocytes are the predominant target of iron loading, but in severe hepcidin
deficiency prominent iron loading of endocrine organs and cardiac myocytes also occurs.
Excess iron is thought to cause organ toxicity by catalyzing generation of reactive oxygen
species. Reactive oxygen species damage cellular proteins, lipids and nucleic acids. Clinical
manifestations can include liver disease and hepatocellular carcinoma, skin pigmentation,
diabetes, arthropathy, impotence in males, heart failure or conduction defects.
Although a similar pattern of iron loading is observed in the mouse models of hereditary
hemochromatosis, mice seem to be resistant to iron toxicity and the resulting organ injury, for
reasons that are not well understood.
The standard treatment of iron overload in hereditary hemochromatosis is phlebotomy. Each 1
ml of blood that is removed eliminates 1 mg of iron from the body. As new red blood cells are
made, excess iron from other organs is mobilized and used for erythropoiesis. This treatment is
highly effective and inexpensive. However, repeated phlebotomy is inconvenient for many
patients and may be difficult for those with poor venous access or coexisting medical conditions.
Furthermore, once patients are iron-depleted, hepcidin is further decreased due to physiological
mechanisms, and this enhances iron absorption and increases the need for repeat phlebotomy.
Iron-loading anemias
Iron overload also develops in the setting of hereditary or acquired anemias, such as betathalassemia or congenital dyserythropoietic anemias. In humans, iron overload develops most
commonly when patient anemia is treated with chronic erythrocyte transfusions, as each unit of
blood contains 200 ml of packed erythrocytes or around 200 mg of iron, equivalent to more than
100 days of normal iron absorption. With transfusions, iron initially accumulates in macrophages
that phagocytose damaged or senescent erythrocytes, but iron eventually also accumulates in
other cell types and tissues in which it causes cell injury and organ dysfunction, including
cardiac complications, diabetes, and endocrine and metabolic abnormalities.
Iron overload can also develop in the absence of transfusions, as a consequence of ineffective
erythropoiesis. Exuberant erythropoietic activity leads to hepcidin suppression and the
hyperabsorption of dietary iron, similarly to hereditary hemochromatosis. Iron overload is the
main cause of morbidity and mortality in iron-loading anemias.
Iron overload in ineffective erythropoiesis cannot be treated by phlebotomy as patients are
anemic and many require transfusions. Rather, iron chelation is employed, but patient
adherence to treatment must be rigorous for the treatment to be effective. For decades,
chelation was administered by continuous intravenous or subcutaneous infusion, however, more
recently orally available chelators have been introduced. Although iron chelators are relatively
safe, serious adverse effects may occur in rare cases.
Novel treatments for iron overload
Because hepcidin deficiency causes or contributes to iron overload disorders, therapeutic
approaches that mimic the function of hepcidin, or that potentiate endogenous synthesis of
hepcidin, may be able to prevent systemic accumulation of iron. The development of both types
of therapeutics is in progress.
Hepcidin agonists - Minihepcidins are peptide-based hepcidin agonists that were rationally
designed based on the region of hepcidin that interacts with ferroportin. Minihepcidin are based
on the 7-9 amino acid segment from the N-terminal region of hepcidin, which has been further
engineered to increase resistance to proteolysis and prolong the half-life in circulation. Their
effectiveness has been demonstrated in mouse models of hereditary hemochromatosis and
beta-thalassemia.
Stimulators of hepcidin production – A protease TMPRSS6 is a negative regulator of hepcidin.
Knockdown of Tmprss6 with RNA-based therapeutics has been demonstrated to be a promising
approach in mouse models of iron overload. Other approaches for increasing hepcidin
production may include stimulation of the bone morphogenetic protein pathway, which is critical
for hepcidin expression in the liver. However, the BMP pathway plays a role in many other
biological processes and clinical application of these agents in iron disorders will require
extensive further research.
Iron overload in animal species
Iron overload has also been reported in numerous captive animal species2;3, including birds
(birds-of-paradise, toucans, mynahs and others) and mammals (browsing rhinoceroses, tapirs,
fruit bats, lemurs, sea lions, dolphins and others). However, neither the pathogenesis nor the
clinical relevance of iron overload is well understood, especially as compared to mice and
humans. Iron overload is likely to be directly associated with morbidity and mortality in animals,
but frequently it is only reported as a finding at necropsy. The primary cause of iron overload
among affected animal species is thought to be the higher amount and bioavailability of iron in
captive diets. However, these species may have evolved to consume iron-restricted diets and
likely have inefficient regulatory mechanisms to prevent excessive iron absorption.
Based on the similarity of humans and mice with respect to iron absorption and its regulation, it
is likely that iron absorption in most vertebrates is regulated in a similar manner, through the
interaction of hepcidin and ferroportin. If so, the analysis of the hepcidin regulation and activity
in animal species susceptible and resistant to iron overload in captivity may reveal the causative
mechanisms.
Reference List
1. Ganz T, Nemeth E. Hepcidin and disorders of iron metabolism. Annu.Rev.Med.
2011;62:347-360.
2. Klasing KC, Dierenfeld ES, Koutsos EA. Avian iron storage disease: variations on a
common theme? J Zoo.Wildl.Med. 2012;43:S27-S34.
3. Clauss M, Paglia DE. Iron storage disorders in captive wild mammals: the comparative
evidence. J Zoo.Wildl.Med. 2012;43:S6-18.