Thalassaemia

Contributed by Dr Paul Telfer and Dr Banu Kaya, consultants in adult and paediatric haematology, haemoglobinopathy, Royal London Hospital.

1. Aetiology and epidemiology

The thalassaemias are genetic disorders of haemoglobin production that abolish or severely reduce the output of globin chains, resulting in anaemia and an expanded but ineffective erythroid marrow.

Thalassaemia genes are prevalent in many ethnic minority groups in the UK. The highest prevalence is in Cypriots, Indians, Pakistanis, Bangladeshis, Chinese and other Asian groups. However, as the UK population becomes more diverse, the affected population is changing.

Common disorder
Beta-thalassaemia, which affects beta-globin chains, is a relatively common genetic disorder in the UK, with more than 700 patients and 214,000 carriers.

The gene is recessive, so the carrier state is harmless, but patients with two copies of the beta-thalassaemia gene that can develop a transfusion-dependent anaemia is defined as thalassaemia major. A less severe anaemia that does not require regular transfusions is defined as thalassaemia intermedia.

Severe thalassaemia
Alpha-zero thalassaemia, the most serious form of alpha-thalassaemia, causes foetal anaemia and stillbirth (Barts Hydrops) in cases where four out of the four alpha-globin genes are affected by the mutation.

Patients with only one affected gene are silent carriers. Those with two affected genes are may have slight anaemia.

Those patients with three affected genes develop haemoglobin H disease, which presents as moderately severe anaemia.

Antenatal screening
In areas of England where the foetal prevalence of sickle cell disease is greater than 1.5 per 10,000 births, all women are offered screening for sickle cell disease and thalassaemia.

In English areas where sickle cell disease prevalence is less than 1.5 per 10,000 births and in Wales, parents in the high risk groups are offered screening for thalassaemia, sickle cell disease and other haemoglobin variants. No screening decisions have been made for Scotland and for Northern Ireland where prevalence is low.

Genetic counselling
The thalassaemia gene carriers should be identified and offered counselling about genetic risk before conceiving. Parents of babies with suspected thalassaemia need specialist counselling.

2. Diagnosis

Thalassaemia becomes clinically apparent at age three to six months, when adult haemoglobin (HbA) takes over from foetal haemoglobin (HbF). The diagnosis is usually straightforward, and can be confirmed by a haemoglobin analysis showing reduced or absent HbA.

Severe anaemia
Infants with thalassaemia become progressively pale and irritable, feed poorly and stop growing. Bone expansion affecting the skull and facial bones may become obvious.

On examination, the liver and spleen are enlarged. Blood tests reveal severe anaemia with unusually low haemoglobin levels in the red blood cells and microcytosis. There is also often a large number of circulating immature nucleated red cells.

Detecting carriers
Blood tests can be used to detect carriers of thalassaemia genes. A patient with a beta-thalassaemia trait condition, who carries one thalassaemia gene and one normal beta-globin gene, will typically have hypochromic microcytic red cells, combined with a relatively high red cell count and a mildly decreased haemoglobin level.

Haemoglobin analysis will show that a minor component of normal haemoglobin, HbA2, is increased generally up to a level of 4-6 per cent of total haemoglobin.

Difficult diagnosis
Alpha-zero thalassaemia trait is difficult to diagnose. In these patients, red cells are hypochromic and microcytic, but there is no abnormality in the haemoglobin components. It is difficult to distinguish this condition from iron deficiency anaemia or the milder alpha-plus thalassaemia.

Carriers of beta-thalassaemia who inherit another disorder affecting beta-globin production develop a thalassaemia phenotype. These can include haemoglobin E, delta-beta thalassaemia, Lepore haemoglobin and haemoglobin Knossos. Carriers who also inherit haemoglobin S will develop a clinical phenotype characteristic of sickle cell disease rather than thalassaemia.

Diagnostic markers

Points for identifying alpha-zero thalassaemia:

  • It is most common in people with family origins in South East Asia and the Eastern Mediterranean. It is not usually found in South Asians or Africans.
  • The mean corpuscular haemoglobin is less than 25pg.
  • Iron deficiency should be excluded, but this should not delay genetic evaluation.

3. Treatment

The majority of affected patients are managed in specialised clinics. This is particularly important for identifying and counselling carrier couples in low prevalence areas, especially those at risk of having thalassaemic children.

Life expectancy
The outlook for a child with thalassaemia is much more optimistic than it was even 10 years ago.

Parents should be advised that life expectancy is in excess of 50 years and that, with advances in iron chelation therapy, treatment should no longer be burdensome.

Apart from the inconvenience of treatment and monitoring, patients with thalassaemia should now be able to live full and productive lives.

Transplants and tranfusions
Children who have a histocompatible sibling can now be offered an allogeneic bone marrow transplant. This is currently the only cure for thalassaemia. However, most thalassaemic children will need regular transfusions indefinitely.

Transfusions are given every three to four weeks to maintain a haemoglobin level of 9.5-10g/dl.

Common complications
Endocrine complications are usually managed jointly by haematology and endocrinology specialists. In general, endocrine disease is irreversible, but hormone supplementation is generally effective.

There are many thalassaemic patients who have now had successful fertility treatment.

Infections are the second most common cause of death in patients with thalassaemia.

The bacteria yersinia and klebsiella require an iron-rich environment and their growth is facilitated by desferrioxamine, commonly used to treat iron overload.

Osteoporosis of the hip and spine is common in young adults and predisposes to fracture of the hip and crush fracture of the vertebrae.

A proportion of adult thalassaemics who received transfusions before hepatitis C virus screening was introduced into the transfusion programme have become infected.

Iron overload
Iron overload is the inevitable consequence of long-term regular transfusions and a major preventable cause of morbidity and mortality.

The anterior pituitary is very sensitive to iron in early childhood, and damage to it causes growth hormone and gonadotrop in deficiency. This manifests as short stature, delayed or absent pubertal development and infertility.

Hypothyroidism, hyperparathyroidism and glucose intolerance are later complications, and the most severe consequence of iron overload and commonest cause of death for thalassaemics in the developed world, is cardiac disease.

Chelating therapy
Iron overload can be both treated and prevented with a chelating agent. Three chelating agents are currently available in the UK, desferrioxamine, deferiprone and deferasirox.

Desferrioxamine is given by continuous subcutaneous infusion and the standard regimen is 30-50mg per kg given five to six nights per week over 10-12 hours using a syringe driver pump. A lower dosage is used in young children.

Improved compliance
The use of desferrioxamine over the past 25 years has improved life expectancy and reduced rates of endocrine complications.

However it is an impractical regime, and around half of patients are unlikely to be able to adhere to treatment adequately even with practical aids, such as disposable infuser pump, and psychological support.

Deferiprone and deferasirox can be taken orally and are associated with improved compliance and better quality of life in patients who are unable to adhere to desferrioxamine therapy.

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