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Recent advances in the treatment of iron overload


Pierre Brissot
Professor of Medicine/Head of Liver Disease Unit
Liver Disease Department
Inserm U-522 and IFR 140
University Hospital Pontchaillou
E:[email protected]

The field of iron overload encompasses two main pathological situations: genetic haemochromatosis and acquired (or secondary), mainly post-transfusional, iron excess. Before considering the remarkable therapeutic advances made in the treatment of secondary iron overload and foreseen for genetic �haemochromatosis, it is of interest to describe briefly the different iron overload entities.

The new landscape of chronic iron overload

Genetic iron overload
This group of diseases corresponds to four types of haemochromatosis that have recently been defined:(1)

  • Haemochromatosis type 1(2) is the “classical”,and by far the most frequent, form of genetic haemochromatosis and is due to a major HFE mutation (located on chromosome 6), called C282Y. It is a recessive disease, thus two C282Y mutations (received from each parent) are necessary to cause the disease (the patient is said to be homozygote for the C282Y mutation).
  • Haemochromatosis type 2 is a rare disease affecting young people (less than 30 years old), also named juvenile haemochromatosis. It is due to mutations of the haemojuvelin(2,3) or hepcidin(4) genes (chromosome 1).
  • Haemochromatosis type 3(5) is an exceptional disease, mimicking type 1. It is due to mutations of the transferrin receptor 2 (chromosome 7).
  • Haemochromatosis type 4(6,7) is less rare than types 2 and 3 and is related to mutations of ferroportin (chromosome 3). It is also called ferroportin disease.

Acquired iron overload
It is mainly observed in haematological diseases such as thalassaemia major(8) and myelodysplastic syndromes.(9)

Clinical consequences of iron overload
Whatever the underlying disease, chronic iron overload may be responsible for very similar complications dominated by chronic fatigue, hepatic hypertrophy leading to cirrhosis and liver cancer, diabetes due to pancreatic damage, cardiomyopathy, endocrine dysfunction, and bone and joints symptoms. In their major forms, these diseases are life-threatening.

Pathophysiological mechanisms of iron overload
For genetic haemochromatosis (at least for types 1, 2 and 3), deficiency in hepcidin is the key factor accounting for iron excess.(10) Indeed, this “iron hormone”, when deficient, leads both to increased entry of digestive iron through the duodenum (intestinal hyperabsorption) and to increased release of iron from the macrophages into the plasma. The subsequent increased levels of plasma iron are responsible for progressive tissue iron deposition.

In the case of secondary iron overload, the main mechanism accounting for iron overload is represented by repeated transfusions needed by severe chronic anaemia. However, dyserythropoiesis is also partly responsible.

Novel therapeutic approaches

Acquired iron overload

The treatment of acquired iron overload is based upon chelation therapy.(11,12)

For a long time, desferrioxamine (Desferal(R)),(13) an excellent hexadentate chelator, was the only available compound. The main limitation of this drug, however, is the need for parenteral administration, as it cannot undergo intestinal absorption and therefore cannot be used orally. Moreover, the very short half-life of desferrioxamine requires that it is administered by subcutaneous infusion through a portable device, usually 12 hours a day and five days a week.

Then came deferiprone (Ferriprox(R)).(14) This drug, also named L1 or CP20, belongs to the class of hydroxypyridinones and is a bidentate chelator. It was the first available oral iron chelator and, at the time of its release, it represented a real breakthrough, answering the hopes of many patients, especially young thalassaemic individuals who badly tolerated the constraints associated with desferrioxamine. Another advantage of deferiprone was its cardioprotective effects.(12) However, limited absorption through the digestive system means that large daily doses must be administered, which can lead to erosive arthritis (up to 20% of patients) and can cause, exceptionally but in an unpredictable way, agranulocytosis (up to 0.5% of patients). The beneficial effect of combining desferrioxamine and deferiprone has been reported.(15)

Deferasirox (ICL 670, Exjade(R))(16) has been launched recently. This drug constitutes a major advance in the treatment of transfusional iron overload. This compound, which is a tridentate iron chelator (N-substituted bis-hydroxyphenyltriazole), is highly absorbed through the digestive tube, and its 12-13 hours half-life allows a single daily dose. Large international studies on more than 800 adult or paediatric patients with b-thalassaemia, rare anaemias and sickle cell disease treated for 48 weeks have documented its tolerability and efficacy.

Side-effects consist of digestive symptoms (approximately 25% of patients), skin rash (generally spontaneously resolving) and a moderate increase in serum creatinine (most of the values remaining within the normal range). This creatinine increase occurred in approximately one-third of patients; deferasirox dosage needs to be reduced in approximately one-fifth of these patients and, to date, has never been the cause for discontinuation of treatment. Provided that the dosage is appropriate (20-30mg/kg), deferasirox can make the iron balance negative, as shown by the decrease in serum ferritin levels and hepatic iron concentration.

A beneficial effect on liver status has also been observed in terms of serum transaminase levels and histological scores of activity. Whether combining deferasirox with other chelators might provide an additive effect needs to be demonstrated.

Genetic haemochromatosis
Venesections (ie, repeated phlebotomies) remain the reference method for treating iron excess in these diseases. However, this approach requires multiple venous punctures throughout the patient’s life, and it is not pathophysiologically relevant once iron excess has been eliminated. Indeed, venesections tend to increase intestinal iron absorption, which is one of the mechanisms accounting for iron excess in these diseases.

Therefore, therapeutic research is now based upon designing forms of hepcidin that could be administered to patients in order to counteract hepcidin deficiency, which causes iron excess. Such a therapeutic approach would be ideal to avoid both iron excess reconstitution (after iron depletion has been obtained by initial venesections) or to prevent the development of body iron excess in case of early diagnosis.

Another therapeutic way would be to find drugs counteracting digestive iron hyperabsorption and/or excessive iron release out of the macrophages by inhibiting membrane iron transporters.

Whether deferasirox could be an adjunct or even replace venesections in genetic haemochromatosis needs to be evaluated.

The new oral chelator deferasirox, which is now available in many countries worldwide, represents a major improvement in the management of patients with post-transfusional iron overload. For genetic haemochromatosis, doctors and patients are eagerly awaiting new compounds that can normalise body hepcidin levels.


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  2. Pietrangelo A. Hereditary hemochromatosis � a new look at an old disease. N Engl J Med 2004;350:2383-97
  3. Papanikolaou G, Samuels ME,Ludwig EH, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis.Nat Genet 2004;36:77-82.
  4. Roetto A, Papanikolaou G,Politou M, et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis.Nat Genet 2003;33:21-2.
  5. Camaschella C, Roetto A, Cali A, et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 2000;25:14-5.
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  7. Njajou OT, Vaessen N, Joosse M,et al. A mutation in SLC11A3 is associated with autosomal �dominant hemochromatosis. Nat Genet 2001;28:213-4.
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  13. Porter JB, Rafique R, Srichairatanakool S, et al. Recent insights into interactions of deferoxamine with cellular and plasma iron pools: Implications for clinical use. Ann N Y Acad Sci 2005;1054:155-68.
  14. Hider RC, Zhou T. The design of orally active iron chelators. Ann N Y Acad Sci 2005;1054:141-54.
  15. Kattamis A, Ladis V, Berdousi H, et al. Iron chelation treatment with combined therapy with deferiprone and deferioxamine: a 12-month trial. Blood Cells Mol Dis 2006;36:21-5.
  16. Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood 2006;107:3455-62.

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