1. Molecular Pathophysiology of Iron Disorders
Tomas Ganz, PhD, MD
Chaim Hershko, MD

2. Iron Economy
2400 mg
3- 4mg
The average adult contains about mg of iron. Of that about 2400 mg is in hemoglobin of erythrocytes, about 1000 mg is in storage mainly in the liver, and only about 3-4 mg circulates in the plasma iron pool. Iron is strictly conserved and recycled. Every day about 20 mg of iron is recovered by macrophages from senescent erythrocytes and returned to the plasma pool from where it is resused for the synthesis of hemoglobin and other ferroproteins. Under normal circumstances, the daily losses of iron from the body are small, only 1-2 mg, and are readily replaced by the absorption of similar amounts of iron from the diet.
1000 mg
With permission from Pietrangelo A. N Engl J Med. 2004;350:

3. Iron Concentration in Plasma Is Regulated
Range 2.5%–97.5% (μM/L)
Men
13.4–31.3 μM/L
Women
11.6–29.5 μM/L
Iron concentration in plasma is regulated to remain within the range of approximately uM. Persistently high concentrations of iron in plasma that exceed the binding capacity of transferrin lead to deposition of iron in tissues with resulting tissue and organ damage. Low plasma concentrations of iron limit iron delivery to cells and cause cellular dysfunction. Persistent limitation of iron supply to the bone marrow causes anemia.
Too much iron = tissue and organ damage
Too little iron = cellular dysfunction, anaemia
Lentner C (ed). Geigy Scientific Tables, Vol 3. Basel: Ciba-Geigy,1984.

4. Hepcidin—An Iron-Regulatory and Host Defense Peptide Hormone
Hepcidin 50 mg IP/mouse
Hepcidin is a small peptide that regulates iron absorption and distribution by inhibiting the release of intracellular iron into plasma. As illustrated in this graph, injection of hepcidin into mice causes the rapid development of severe hypoferremia that lasts for more than 48 hours.
Time (hours)
With permission from Rivera S, et al. Blood. 2005;106: 4

5. Ferroportin 12 (or 10) transmembrane segment protein
The only cellular iron exporter in vertebrates
Present in the macrophages, duodenum, hepatocytes, and the placenta N C 45 23 61
115 80 96
152
127
186
203
206
228
307
324
343
362
374
393
450
471
512
493
537
518
The molecular target of hepcidin is ferroportin, a transmembrane protein that is the only known iron exported in vertebrates. Ferroportin is present in all the cells and tissues that export iron into plasma, including macrophages, duodenal enterocytes, hepatocytes and the placenta.
Donovan A, et al. Nature. 2000;403: McKie AT, et al. Mol Cell. 2000;5:
Abboud S, et al. J Biol Chem. 2000;275:
Graphic courtesy of Tomas Ganz, PhD, MD.

6. How Hepcidin Regulates Iron
Spleen
Hepcidin
Hepcidin
Liver
Fpn
Fpn
Hepcidin
Plasma
Fe-Tf
Fpn
Hepcidin binds to ferroportin and induces its internalization and degradation. By this mechanism, the interaction of hepcidin with ferroportin regulates the flow of iron into plasma, and thereby regulates the distribution of iron in the body.
Bone marrow
and other sites
of iron usage
Duodenum
Nemeth E, et al. Science. 2004;306:
Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.

7. Iron-exporting cells (duodenal enterocytes, macrophages, hepatocytes)
Low Hepcidin
High Hepcidin
Iron uptake
Iron uptake
Iron-exporting cells (duodenal enterocytes, macrophages, hepatocytes)
ferritin
ferritin
Fpn
Fpn X
When hepcidin levels are low, iron-exporting cells, including duodenal enterocytes, macrophages, and hepatocytes display abundant ferroportin and release iron intro plasma. When hepcidin concentrations increase, hepcidin binds to ferroportin, ferroportin is degraded, and iron is retained within cells in cytoplasmic ferritin.
hepcidin
Iron release
into plasma Fe Fe
Nemeth E, et al. Science. 2004;306:
Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.

8. Diseases of Hepcidin Dysregulation
Iron
Hepcidin
Normal homeostasis
Dysregulation of hepcidin gives rise to a variety of iron disorders. In anemia of inflammation, iron-refractory iron deficiency anemia and hepcidin-secreting tumors, hepcidin production is inappropriately high, iron concentrations in plasma decrease and the supply of iron for is restricted, causing anemia. In hereditary hemochromatosis and iron-loading anemias hepcidin production is inappropriately low and iron absorption and cellular release are increased. Plasma iron concentrations are high causing tissue iron overload and iron toxicity.
Hereditary haemochromatosis
Iron-loading Anaemias
Anaemia of Inflammation
Iron-refractory iron-deficiency anaemia
Hepcidin-secreting tumors
Ganz T. J Am Soc Nephol. 2007;18:
Ganz T, Nemeth E. Am J Physiol Gastrointest Liver Physiol. 2006;290:G199-G203.
Courtesy of Tomas Ganz, PhD, MD.

9. Hereditary Haemochromatosis (Common)
HFE
TfR2
HJV
Liver
Spleen
Hepcidin deficiency, absolute or relative ×
Hepcidin ×
Hepcidin
RBC
Hepcidin
Plasma
Fe-Tf ×
The most common forms of hereditary hemochromatosis are due to the genetic disruption of hepcidin-regulating proteins HFE, transferrin receptor 2, hemojuvelin, or hepcidin itself. Hepcidin production is low and the lack of hepcidin results in unrestrained absorption of dietary iron, saturation of plasma transferrin, and toxic iron deposition in the liver and other organs.
Duodenum
Bone marrow
Piperno A, et al. Blood. 2007;110: Papanikolaou G, et al. Blood. 2005;105:
Nemeth E, et al. Blood.2005;105:
Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.

10. Hereditary Haemochromatosis (Rare)
HFE
TfR2
HJV
Liver
Spleen
Hepcidin = =
Hepcidin =
RBC
Hepcidin
Plasma
Fe-Tf
Ferroportin resistance to Hepcidin
Less commonly, hereditary hemochromatosis results from autosomal dominant ferroportin mutations that render ferroportin resistant to the effect of hepcidin. This also causes unrestrained iron absorption and excessive iron deposition in the liver and other tissues.
Duodenum
Bone marrow
Fernandes A, et al. Blood. 2008; in press.
Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.

11. Iron-loading Anaemias (-thal…)
Liver
Spleen
Erythroid Signal
Hepcidin deficiency
Hepcidin × ×
Hepcidin
RBC
Hepcidin
Plasma
Fe-Tf ×
In iron-loading anemias such as beta-thalassemia, hepcidin deficiency develops as a result of a suppressive signal generated by the greatly expanded erythroid precursor population. This also leads to excessive iron absorption and the development of iron overload even in patients who are not transfused. Although the hepcidin suppression is partially relieved by erythrocyte transfusions, the transfusions themselves add large amounts of exogenous iron again leading to iron overload.
Duodenum
Bone marrow
Nemeth E, Ganz T. Haematologica. 2006;91: Pak M, et al. Blood. 2006;108:
Papanikolaou G, et al. Blood. 2005;105: Tanno T, et al. Nat Med. 2007;13;
Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.

12. Anaemia of Inflammation
Liver
Spleen ×
Hepcidin ×
Hepcidin
RBC
Hepcidin
Plasma
Fe-Tf ×
The opposite problem develops in anemia of inflammation, also called anemia of chronic disease. Under the influence of inflammatory cytokines, hepcidin is overproduced and excessive hepcidin inhibits the release of recycled iron from macrophages, stored iron from hepatocytes, and absorbed iron from duodenal enterocytes. The iron supply for hemoglobin synthesis is restricted causing anemia.
Duodenum
Bone marrow
Nemeth E, et al. Blood. 2003;101:
Nemeth E, et al. J Clin Invest. 2004;113:
Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.

13. Iron-Refractory Iron-Deficiency Anaemia (IRIDA)
Iron deficiency despite adequate or increased iron intake
Partially corrected by parenteral iron
High hepcidin similar to anaemia of inflammation
Mutations in hepcidin-regulatory protease matriptase-2 (TMPRSS6)
Patients with iron-refractory iron-deficiency anemia have iron deficiency despite adequate or increased iron intake and are even partially resistant to parenteral iron. A major cause of this disorder is a genetic lesion in the gene encoding the membrane protease matriptase-2, also called TMPRSS-6.
Finberg KE, et al. Nat Genet. 2008;40: Du X, et al. Science. 2008;320:

14. Unfinished Business… How does extracellular iron regulate hepcidin?
Current model: holotransferrin + transferrin receptor 2 + transferrin receptor 1 + HFE + haemojuvelin + BMP receptor  transcription of hepcidin
How do intracellular iron stores regulate hepcidin?
Iron-regulatory proteins or other intracellular iron sensors?
How does matriptase-2 (TMPRSS6) participate in hepcidin regulation?

15. Mechanisms Regulating Hepcidin Production
Iron-driven
Increased by high transferrin saturation and decreased by low plasma iron
TMPRSS6: iron deficiency-driven suppression of hepcidin expression?
Erythropoiesis-driven
GDF15 suppression of hepcidin
Inflammation-driven
Independent of iron- and erythropoiesis-driven mechanisms
Triggered by IL-6 and other cytokines

16. Are There Compensatory Mechanisms That Limit Damage?
Hereditary haemochromatosis: surprising lack of severe infections despite harmful effects of excess iron on bacterial infections; cytokine-driven increased hepcidin?
Thalassaemia major: iron-driven increase of hepcidin production, limiting iron absorption?
Although compensatory mechanisms may limit possible damage to the organism, they are insufficient to prevent it

17. Mechanisms of Iron Homeostasis
Intracellular
Dominated by the IRE-IRP mechanism
Extracellular
Dominated by hepcidin/ferroportin interactions
Intracellular and extracellular mechanisms may interact

18. Future Hepcidin-Targeted Therapies
Limitations
Current therapies are effective and inexpensive; those targeting hepcidin are expected to be onerous and costly
Possible role
Hepcidin agonists and/or antagonists may be useful in treating more-complex disorders, such as beta-thalassaemia, iron-loading anaemias, IRIDA, and anaemia of inflammation