Iron overload occurs when excess iron accumulates in the body. Those receiving iron therapy are vulnerable to iron overload as we lack major mechanisms for iron excretion (minor ones are cell desquamation and occult blood loss). Excess iron is deposited in body organs - heart, liver and endocrine glands in particular- causing organ damage. Probably, iron saturates the liver first, and then accumulates in other organs.¹

Aetiology²

• Hereditary haemochromatosis:
  • This is a genetic condition where individuals show increased iron absorption and organ deposition. There are various types, including the HFE gene mutations, which are relatively common in Northern European populations.
• Repeated red blood cell transfusions:
  • Iron excess can occur from as little as 10 transfusions. It is a common problem in transfusion-dependent patients; for example, those with thalassaemia major, sickle cell disease and myelodysplastic syndromes.³ Beta thalassaemia major patients may have the greatest iron overload because their iron absorption is also increased.¹
• Other causes of iron overload:
  • Liver disease
  • Excessive iron intake or supplementation
  • Porphyria cutanea tarda
  • Aceruloplasminemia (rare)

Presentation

• Usually there are no symptoms until organ damage (possibly irreversible) has occurred. Therefore awareness and monitoring of those at risk are important (below).
• Early symptoms of hereditary haemochromatosis include fatigue and arthritis (often arthritis of the hands, particularly the index and middle fingers).⁴
• In patients with thalassaemia, cardiac iron overload may present as reduced exercise tolerance or with features of right-sided heart failure.
• May present as an incidental finding, e.g. unexplained raised serum ferritin levels or unexplained liver disease may trigger investigation for haemochromatosis.

Investigations

Identifying the cause

• This may be known, e.g. multiple transfusions.
• See separate article Hereditary Haemochromatosis, which details investigation of suspected hereditary haemochromatosis.

Assessment of iron load^1,5

• Ferritin levels give an indication of body iron stores. However, they are also affected by other conditions (ferritin is an acute-phase protein), so trends are more important than individual measurements.
• Liver iron may be assessed by:
  • MRI scan, either with the R2 (Ferriscan®) method, or using the T2* (pronounced "T2-star") technique.
  • Liver biopsy (invasive)
• Cardiac investigations:
  • T2* MRI scan is a new and useful technique for evaluating cardiac iron overload. It is important because cardiac iron load does not always correlate with liver iron or ferritin levels. Measurement of cardiac iron enables appropriate adjustment of chelation treatment, which should help to prevent cardiac complications.
  • Echocardiography (ECHO) and electrocardiography (ECG) - to monitor cardiac function and detect complications early.
  • Where MRI is not available, monitor ferritin levels, liver iron status, ECHO and ECG carefully.

Management

Hereditary haemochromatosis can be treated by venesection to remove iron (see related article). In those with refractory anaemias where repeated venesection is not an option, iron chelation can be used. Chelating agents form chelator-iron complexes which are then safely excreted in urine or stools.

Chelation treatment should normally be managed by a consultant haematologist with experience in this field. Detailed guidance is available.^5,6 The following is an overview for non-specialists:

Chelation drugs

Iron chelators currently used are desferrioxamine, deferiprone and desferasirox:

• Desferrixoamine has been important first-line treatment for chronic iron overload over the last 30 years. It is usually given subcutaneously over 8-12 hours, 3-7 times a week, often with a pump at night-time. It has led to significant life expectancy gains for those with conditions such as thalassaemia major.³ However, the infusion regime is demanding and so compliance can be difficult.
• Deferiprone and desferasirox are newer, oral chelators with slightly different chelating properties.⁷ Deferiprone is more efficient in removing cardiac iron than desferrioxamine. Less is known about the effect of desferasirox on cardiac iron.¹
• New strategies have emerged involving combination therapy. Using desferrioxamine and deferipone together has advantages above monotherapy, e.g. in reducing cardiac iron load.^8,9

General principles of chelation therapy⁶

• The goal is prevention rather than rescue.
• Choice of chelator (or combinations) depends on the clinical situation, the tolerability/side-effects of each drug, cost and patient preference. Further guidance is available.^5,6
• Management decisions are best directed by results of ferritin levels and additional liver/cardiac investigations (see monitoring chelation below).
• Current evidence suggests that those with cardiac iron loading or cardiac problems should receive deferiprone as part of their treatment (if licensed for their age and tolerated).
• For patients with acute cardiac decompensation, e.g. cardiac failure or arrythmias:
  • Standard treatment is intensive chelation with continuous, intravenous desferrioxamine.
  • If this is not possible, combined desferrioxamine and deferiprone is an alternative.⁵
  • On recovery, combination therapy should be considered.
• Efforts should be made to improve adherence to desferrioxamine (where used) by the use of disposable pre-filled infusors and suitable needles.
• Vitamin C (ascorbic acid) is taken with desferrioxamine infusions, to increase iron excretion.

Some important side-effects of chelators⁵

Desferrioxamine:

• Poor growth
• Sensorineural hearing loss
• Zinc deficiency
• Infections - due to the high iron load and/or desferrioxamine treatment, patients are more prone to overwhelming infection with:
  • Yersinia spp. (presents with fever, diarrhoea and abdominal pains)
  • Klebsiella spp.
  • Therefore, advise patients that with fever or infection symptoms, they should stop treatment and seek medical advice.

Deferiprone:

• Agranulocytosis and neutropenia - so patients need advice about fever/infection symptoms and a letter to present to A&E.
• The risk of agranulocytosis may be higher in patients with Diamond-Blackfan anaemia. Deferiprone should not be used in patients with bone marrow disorders, e.g. Diamond Blackfan anaemia, aplastic anaemia.⁶
• Risk of neurological disorders, including cerebellar syndrome, with high doses.¹⁰

Desferasirox:

• This is the newest chelator, so there is less experience with its use. Important adverse effects reported are:
  • Common - raised serum creatinine and/or intermittent proteinuria. This may stabilise, but the possibility of causing renal damage cannot be excluded at present.
  • Less common - lens opacities, sensorineural hearing loss, drug induced hepatitis, hepatic failure, gastrointestinal (GI) ulceration, GI haemorrhage.

Monitoring chelation⁶

All patients:

• Monthly biochemistry (creatinine and liver function tests)
• 3-monthly clinic visit and serum ferritin
• Annual audiometry and ophthalmology
• MRI monitoring (recommended from age 8 in thalassaemia patients)⁵:
  • T2* MRI for cardiac iron
  • R2 or T2* MRI for liver iron

If taking deferiprone, also need:

• Weekly neutrophil counts
• Education about the risk of agranulocytosis; letter to present to A&E if unwell with fever

If taking desferasirox, also need:

• Serum creatinine in duplicate before commencing therapy, and eGFR.
• Monitor creatinine, liver enzymes and urine protein on dipstix weekly for the first month, then monthly. Dose reduction or discontinuation required if there is a trend of increasing creatinine.

Combination therapy (desferrioxamine plus deferiprone) also need:

• The risks of agranulocytosis and desferrioxamine toxicity are probably increased, so need more intensive monitoring including:
  • Weekly blood counts
  • 3-monthly zinc levels
  • 6-monthly T2* MRI and audiometry

Complications

• Cardiac disease:
  • Cardiac failure:
    • In thalassaemia, tends to present with gradually reduced physical activity, and features of right ventricular dysfunction, e.g. fatigue and abdominal pain.¹
  • Arrhythmias
  • Pericarditis
• Liver damage
• Endocrine disorders, including diabetes
• Infections - Yersinia and Klebsiella (as above)

Prognosis

The prognosis depends on the underlying condition and the degree of iron overload, for example:

• For thalassaemia major (one of the most severe forms of iron overload):
  • Without chelation the iron overload causes death in the teenage years or 20s.
  • With chelation treatment, life expectancy is vastly improved. With optimal treatment, heart failure usually presents in the 30s or 40s.¹
  • Recent developments in chelation may improve the prognosis. One estimate gives an average life expectancy of 63 years.¹¹
• For hereditary haemochromatosis:
  Early treatment can confer normal life expectancy.
  Untreated patients tend to develop complications during their 40s (with a wide age range).

Some complications can be reversed, e.g:

• Recent experience with thalassaemia patients found that intensive chelation can in some cases reduce cardiac iron overload, and may even completely remove it, together with resolution of heart failure.¹
• Some complications of hereditary haemochromatosis are reversible after venesection treatment.⁴

Document references

1. Aessopos A, Berdoukas V, Tsironi M; The heart in transfusion dependent homozygous thalassaemia today--prediction, prevention and management. Eur J Haematol. 2008 Feb;80(2):93-106. Epub 2007 Dec 10. [abstract]
2. Harrison H, Adams PC; Hemochromatosis. Common genes, uncommon illness? Can Fam Physician. 2002 Aug;48:1326-33. [abstract]
3. Roberts DJ, Rees D, Howard J, et al; Desferrioxamine mesylate for managing transfusional iron overload in people with transfusion-dependent thalassaemia. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD004450. [abstract]
4. Haemochromatosis Society UK
5. Standards of clinical care for children and adults with thalassaemia in the UK. United Kingdom Thalassaemia Society, 2008.
6. UK Forum for Haemoglobin Disorders; Consensus view on choice or iron chelation therapy in transfusional iron overload for inherited anaemias. June 2007.
7. Neufeld EJ; Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassemia major: new data, new questions. Blood. 2006 May 1;107(9):3436-41. [abstract]
8. Tanner MA, Galanello R, Dessi C, et al; A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Circulation. 2007 Apr 10;115(14):1876-84. Epub 2007 Mar 19. [abstract]
9. Daar S, Pathare AV; Combined therapy with desferrioxamine and deferiprone in beta thalassemia major patients with transfusional iron overload. Ann Hematol. 2006 May;85(5):315-9. Epub 2006 Feb 1. [abstract]
10. Beau-Salinas F, Guitteny MA, Donadieu J, et al; High doses of deferiprone may be associated with cerebellar syndrome. BMJ. 2009 Jan 22;338:a2319. doi: 10.1136/bmj.a2319.
11. Zeuner D, Ades AE, Karnon J, et al; Antenatal and neonatal haemoglobinopathy screening in the UK: review and economic analysis. Health Technol Assess. 1999;3(11):i-v, 1-186.

Internet and further reading

• McLeod C, Fleeman N, Kirkham J, et al; Deferasirox for the treatment of iron overload associated with regular blood transfusions (transfusional haemosiderosis) in patients suffering with chronic anaemia: a systematic review and economic evaluation. Health Technol Assess. 2009 Jan;13(1):iii-iv, ix-xi, 1-121. [abstract]
• Wood MJ, Skoien R, Powell LW; The global burden of iron overload. Hepatol Int. 2009 Jul 29. [abstract]
• Toliyat T, Jorjani M, Khorasanirad Z; An extended-release formulation of desferrioxamine for subcutaneous administration. Drug Deliv. 2009 Jul 30. [abstract]
• Haemochromatosis Society UK
• UK Thalassaemia Society

Acknowledgements