Thalassaemia

Synonyms: Mediterranean anaemia and Cooley's anaemia.

The name thalassaemia is derived from the Greek word thalassa meaning sea and by implication Mediterranean Sea. This emphasises its high prevalence around the eastern Mediterranean but it is also prevalent in the Indian subcontinent and may be found anywhere in the world.

Thalassaemia is an inherited abnormality of haemoglobin production. There are many forms (over 300 mutations giving rise to thalassaemia have been identified) and its clinical severity varies enormously.¹ Thalassaemia major, intermedia and minor refer largely to disease severity.

The normal haemoglobin (Hb) molecule has a haem base surrounded by 2 pairs of globin chains. The types of globin are called alpha, beta, gamma and delta. Most types of haemoglobin have 2 α chains and 2 other identical types.

• HbA, the commonest form of adult haemoglobin, has two α and two β chains.
• Fetal haemoglobin has 2 α and 2 γ components and is called HbF. This is the predominant type before birth.
• HbA2 is present in smaller amounts, with 2 α and 2 δ chains.

A decreased rate of production of any of these chains will lead to an imbalance between the amounts of the various forms of Hb in the erythrocytes leading to instability and haemolysis.

The thalassaemias are classified according to which chain of the globin molecule is affected. In α thalassaemia, the production of α globin is deficient and in β thalassaemia the production of β globin is defective.

Thalassaemia is carried by 150 million or 3% of the world population and is clinically apparent in 15 million people. The predominant type of thalassaemia varies with geography:

• Beta thalassaemia is the most common form around the Mediterranean, North Africa, the Middle East, India, and Eastern Europe.
• Alpha thalassaemia is more common in Southeast Asia, India, the Middle East, and Africa.

With population movement, thalassaemia is increasingly common in Northern and Western Europe. Prevalence of carriers in the UK is about 1 in 1,000 of the general population. Actual prevalence rates will be heavily influenced by local ethnic population mix as carrier prevalence varies:

• 1 in 7 Cypriots
• 1 in 12 Greeks
• 1 in 10 Gujeratis
• 1 in 10 Sindis
• 1 in 20 South Indians
• 1 in 25 Pakistanis
• 1 in 15 to 1 in 30 Punjabis and Bangladeshis

The stage of presentation depends upon the severity of the disease. In most patients with either α or β thalassaemia traits there are no signs or symptoms.

Alpha thalassaemia

There are two α genes on each chromosome 16, giving α thalassaemia the unique feature of gene duplication. There is only one β-globin gene on chromosome 11.

• Severe homozygous α thalassaemia is usually lethal in utero. It should be considered when hydrops fetalis is diagnosed as rhesus incompatibility has become a much rarer cause.
• Silent carrier α thalassaemia is a fairly common type of subclinical thalassaemia, usually found incidentally. In the silent carrier state, one of the α genes is usually absent, leaving only 3 of 4 genes (aa/ao). Patients are haematologically normal, except for occasional low RBC indices. This diagnosis cannot be made on Hb electrophoresis, as results are usually normal in all α thalassaemia traits. More sophisticated tests are necessary to confirm the diagnosis.
• α thalassaemia trait is characterised by mild anaemia and low RBC indices. This condition is typically caused by the deletion of 2 α (a) genes on one chromosome 16 (aa/oo) or one from each chromosome (ao/ao). It is found mainly in Southeast Asia, the Indian subcontinent, and some parts of the Middle East.
• Hb H disease results from the deletion or inactivation of three α globin genes (oo/ao). It represents a thalassaemia intermedia, with mildly to moderately severe anaemia, splenomegaly, jaundice, and abnormal RBC indices. When peripheral blood films stained with supravital stain or reticulocyte preparations are examined, unique inclusions in the RBCs are usually observed. These inclusions are called Heinz bodies and represent β chain tetramers (Hb H). Hb H is unstable and precipitates in the erythrocyte giving it the appearance of a golf ball.

Beta thalassaemia

In β thalassaemia, symptoms of anaemia start when the γ chain production ceases and the β chains fail to form in adequate numbers. This is usually in the latter part of the first year of life but can be as late as 5 years old because of delay in stopping HbF production.

Symptoms

• Presentation of β thalassaemia major in infancy often includes:
  • Failure to thrive
  • Vomiting feeds
  • Sleepiness
  • Stunted growth
  • Irritability
• Symptoms are related to the severity of anaemia and vary along a spectrum. In untreated β thalassaemia major they tend to be extremely debilitating but may be mild or absent in those with milder forms of disease.
• Ineffective erythropoiesis creates a hypermetabolic state with fever.

Signs

Presentation varies with severity. Thalassaemia minor rarely has any physical abnormalities with Hb ≥9g/dL. In patients with the severe forms the findings on physical examination vary widely depending on how well the disease is controlled.

In severe, untreated cases there may be:

• Hepatosplenomegaly
• Bony deformities (frontal bossing, prominent facial bones, and dental malocclusion)
• Marked pallor and slight to moderate jaundice
• Exercise intolerance, cardiac flow murmur or heart failure secondary to severe anaemia

These features are absent in well treated patients but there are often still problems:

• Growth retardation is common even with well controlled chelation therapy.
• Iron overload can cause endocrinopathy with diabetes, thyroid, adrenal and pituitary disorders.

Antenatal screening

All pregnant women in the UK, irrespective of family origins or where they now live, are offered screening for thalassaemia as part of their routine antenatal care based upon routine red cell indices. Where the woman is found to be a carrier, the father is also offered testing. Where both are carriers, counselling is provided and prenatal diagnosis offered.

Neonatal testing

The bloodspot or heel prick test is taken between 5-8 days old. It primarily aims to identify babies affected by sickle cell disease and other haemoglobinopathies. Conditions that can be detected:

• Hb SS
• Hb SC
• Hb SDPunjab
• Hb SOArab
• Hb Sb Thalassaemia (b0, b+, db Thalassaemia, Lepore)
• Hb Eb Thalassaemia
• Large number of variants (carrier states)
• β Thalassaemia major but not carrier status

Since the introduction of universal newborn bloodspot screening in 2005, about 1 in 2000 babies has screened positive.²

• Iron deficiency anaemia also produces a hypochromic, microcytic anaemia but Fe and ferritin are low whilst iron binding capacity is high.
• Acute leukaemia may require bone marrow aspiration to differentiate.
• Rhesus incompatibility is rare now and post-mortem Hb electrophoresis should differentiate in cases of hydrops fetalis.
• Blackfan Diamond syndrome is a rare congenital cause of erythroid aplasia. It causes a severe normochromic, macrocytic anaemia usually in infancy and is often associated with craniofacial or upper limb anomalies.

Blood

• FBC shows a microcytic, hypochromic anaemia.
• In the severe forms of thalassaemia, the Hb level ranges from 2 to 8 g/dL.
• WBC count is usually elevated from the haemolytic process.
• Platelet count may be depressed in splenomegaly.
• Haemoglobin electrophoresis usually reveals the diagnosis.
• Serum iron level is elevated, with saturation as high as 80%.
• Ferritin is also raised.

Imaging

• Skeletal surveys show classical changes to the bones but only in patients who are not regularly transfused. They result from expansion of marrow spaces and usually disappear when marrow activity is reduced by regular transfusions.
  • Plain skull x-ray shows the classical "hair on end" appearance. The maxilla may overgrow, with overbite, prominence of the upper incisors, and separation of the orbit. These produce the characteristic facies of thalassaemia major.
  • Ribs, long bones, and flat bones may be deformed.
  • Chest x-ray shows cardiac size and shape.
• CT or MRI scan can be used to evaluate the amount of iron in the liver in patients on chelation therapy.

Other tests

• ECG and echocardiogram are used to monitor cardiac function.
• HLA typing is required where bone marrow transplantation is considered.
• Eye examinations, hearing tests and renal function tests are required in the monitoring of deferoximine therapy.
• Bone marrow aspiration is sometimes needed at diagnosis to exclude other conditions that may mimic thalassaemia major's presentation.
• Liver biopsy is used to assess iron deposition and the degree of haemochromatosis.
• Measurement of excretion of iron in the urine after a challenge test of desferrioxamine evaluates the need for chelation therapy.

1. Iron overload - this can occur even without transfusions as absorption is increased. Untransfused thalassaemics increase their dietary iron absorption by 2-5 g per year and with regular transfusions this increases to an excess of over 10 g of iron per year.³ Excess iron is deposited in body organs - pancreas, liver, pituitary and heart in particular - causing fibrosis and eventual organ failure.
2. Malaria - Haldane⁴ suggested that the thalassaemia gene may offer some protection against malaria and this would account for its geographical distribution. The exact protective mechanism is unclear but such a scenario is similar to that in sickle cell disease, in which being heterozygous is advantageous.

Non-Drug

• All families should be offered genetic counselling.
• Avoid food rich in iron. Extra vitamin E, folic acid and some vitamin C may be beneficial. Tea and coffee can reduce the absorption of iron.
• Transfusion improves both quality and quantity of life in severe cases. The target is not to let Hb fall below 9 to 9.5 g/dL. Transfused blood should be leucocyte poor. This is especially important if a bone marrow transplant may be considered at a future stage.
• When hypersplenism occurs, splenectomy is often undertaken.
• Cure can be achieved with a bone marrow transplant⁵ from a compatible, usually related donor.
• Recently embryo selection has enabled the production of an immunologically compatible sib ('the saviour sibling') for this end. The ethical and legal issues of this have been considered widely.⁶

Drugs

• Desferrioxamine is given parenterally to aid iron excretion.⁷ The dose and means of delivery varies according to the needs of the patient.
• Oral chelating agents have been developed and are now in use, including deferasirox and deferiprone.⁸
• There is hope for new combination therapies e.g. oral deferiprone used in combination with desferrioxamine produces a greater effect than either alone.⁹ Together they increase iron excretion, decrease ferritin levels and improve glucose tolerance in borderline cases, suggesting some reversal of damage to the pancreas by iron.
• Folic acid and vitamin E deficiency may require treatment.

• Iron overload is one of the major causes of morbidity in severe forms of thalassaemia.
• Bleeding tendency, susceptibility to infection, and organ dysfunction are related to iron overload.
  Endocrine dysfunction,¹⁰ again secondary to iron overload is common in multiply transfused patients, manifesting as hypogonadotrophic hypogonadism, short stature, acquired hypothyroidism, hypoparathyroidism and diabetes mellitus.
• Repeated transfusions increase the risk of blood borne diseases, including hepatitis B and C, although all blood is screened for known blood-borne infections.
• Infection with rare opportunistic organisms may cause pyrexia and enteritis in patients with iron overload. Yersinia enterocolitica thrives with the abundant iron. Unexplained fever, especially with diarrhoea, should be treated with gentamicin and co-trimoxazole, even when cultures are negative.
• Osteoporosis is common and apparently multifactorial in aetiology but pamidronate is an effective treatment.¹¹
• Hyperuricaemia sometimes produces gout.
• With increasing length of survival, hepatocellular carcinoma is becoming an increasing problem.¹²

Desferrioxamine can cause toxicity:

• Local reaction at the site of injection can be severe.
• High-frequency hearing loss has been reported in 30 to 40% of patients. Colour and night blindness can occur. These complications may be reversible. Eye and hearing examinations should be performed every 6-12 months in patients on chelation therapy.

A staging system has been developed, based on history of blood transfusions and cardiac symptoms, to decide when to initiate chelation therapy.

• Stage I is patients who have received fewer than 100 units of packed RBCs. They are usually asymptomatic.The echocardiogram shows only slight left ventricular wall thickening, and both the radionuclide cineangiogram and the 24-hour ECG are normal.
• Stage II patients have received between 100 and 400 units of blood and may have some fatigue. Echocardiograms may show some left ventricular wall thickening and dilatation but the ejection fraction is normal. The radionuclide cineangiogram findings are normal at rest but show no increase or fall in ejection fraction during exercise. Atrial and ventricular ectopic beats are usually found on the 24-hour ECG.
• Stage III patients have symptoms ranging from palpitations to congestive heart failure. The ejection fraction on echocardiography is decreased. There is normal or decreased ejection fraction on cineangiogram at rest, and it falls on exercise. The 24-hour ECG reveals atrial and ventricular premature beats, often in pairs or in runs.

There is an alternative classification,⁵ developed in Italy, for patients with severe disease who are candidates for haematopoietic stem cell transplantation (HSCT). This classification uses risk factors to predict outcome and prognosis:

• The degree of hepatomegaly
• The presence of portal fibrosis in a liver biopsy sample
• Effectiveness of chelation therapy before transplantation

In class I patients with no unfavorable features, the event-free survival after HSCT is 90%. In class III with hepatomegaly and fibrosis and poor response to chelation, the rate is 56%.

This depends upon the severity of the disease:

• Severe β thalassaemia major (also called Cooley's anaemia) has traditionally had a poor prognosis with 80% dying in the first 5 years of life from complications of the disease.
• Until recently, patients who received transfusions only did not survive beyond adolescence because of cardiac complications caused by iron toxicity. The introduction of chelating agents¹³ to remove excessive iron has increased life expectancy dramatically
• More recent survival rates for β thalassaemia major:¹⁴
  • 5 years - 99%
  • 10 years -98%
  • 20 years - 90%
  • 40 years - 81%
  • 60 years - 71%

• A family origin questionnaire¹⁵ may be used to identify at risk individuals although screening (antenatal and neonatal) is not focussed on high risk populations for thalassaemia.
• Genetic counselling is available and in areas of high prevalence can be considered before marriage or preconception.
• Early antenatal testing¹⁶ with the option of termination for affected fetuses is available, enabling some reproductive choice. Acceptability of such an approach will vary.
• Gene therapy, particularly targeted at stem cells, is an attractive proposition for the future but is not currently feasible with concerns about vector safety.^17,18