Thalassaemia

Synonyms: Mediterranean anaemia and Cooley's anaemia.

Thalassaemia is an inherited abnormality of haemoglobin production. There are many forms and clinical severity varies enormously.¹
The normal haemoglobin 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.

There are some other forms in early fetal life.

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.

The classification of thalassaemia major, thalassaemia minor and sometimes thalassaemia intermedia is based on clinical severity.

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.

Prevalence of carriers is about 1 in 1,000 in the indigenous UK population. Actual prevalence will be heavily influenced by immigration and local ethnic population.

• 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

It is carried by 150 million or 3% of the world population. It 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.

The stage of presentation depends upon the severity of the disease.

Alpha Thalassaemia

• Severe homozygous α thalassaemia is usually lethal in utero. It should be considered when hydrops fetalis is diagnosed as rhesus incompatibility is a rare cause nowadays.
• Silent carrier α thalassaemia is a fairly common type of subclinical thalassaemia, usually found by chance among various ethnic African children being investigated for some other condition. 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. 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 characterized 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 represent β chain tetramers (Hb H), which are unstable and precipitate in the erythrocyte, giving it the appearance of a golf ball. These inclusions are called Heinz bodies.

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 sometimes they are 3 to 5 years old because of delay in stopping HbF production.

In most patients with either α or β thalassaemia traits there are no signs or symptoms.

Symptoms

• In more severe forms, such as β thalassaemia major, the symptoms vary from extremely debilitating in non-transfused patients to mild or absent in those on regular transfusion regimes and closely monitored chelation therapy.
• Ineffective erythropoiesis creates a hypermetabolic state with fever and failure to thrive.

Signs

Presentation varies with severity. Thalassaemia minor rarely has any physical abnormalities with Hb over 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 including frontal bossing, prominent facial bones, and dental malocclusion are striking.
• Marked pallor and slight to moderate jaundice.
• Severe anaemia causes exercise intolerance, cardiac flow murmur, or even heart failure.

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 and adrenal disorders.

• Fe deficiency anaemia also produces a hypochromic, microcytic anaemia but in iron deficiency, Fe and ferritin are low whilst iron binding capacity is high.
• Acute leukaemia may require bone marrow aspiration to differentiate
• Hydrops fetalis is rarely due to rhesus incompatibility these days and post-mortem Hb electrophoresis is required
• Blackfan Diamond syndrome

Blood

• FBC shows a microcytic, hypochromic anaemia.
• In the severe forms of thalassaemia, the Hb level ranges from 2 to 8g/dL.
• WBC count is usually elevated from the haemolytic process.
• Platelet count may be depressed in splenomegaly.
• Haemoglobin electrophoresis usually gives 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 needed to monitor deferoxamine therapy.
• Bone marrow aspiration is sometimes needed at the time of diagnosis to exclude other conditions that may present as thalassaemia major.
• 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 deferrioxamine evaluates the need for chelation therapy.

Haemochromatosis can occur even without transfusions as absorption is increased. Nevertheless patients do much better for being adequately transfused.

In 1949, Haldane² suggested that the thalassaemia gene may offer some protection against malaria and this would account for its geographical distribution. The mechanism by which it might protect is unclear but such a scenario is similar to that for sickle cell disease, in which being heterozygous offers such protection.

Non-Drug

• All families should be offered genetic counselling. In mild cases no treatment is required but anaemia should not be treated with iron unless iron deficiency had been substantiated.
• 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 9.5g/dL. Transfused blood should be leucocyte poor. This is especially important if a bone marrow transplant is considered at some stage.

Drugs

Desferrioxamine is given parenterally to aid iron excretion.³ The dose and means of delivery varies according to the needs of the patient. Oral chelating agents⁴ are being developed. Oral deferiprone used in combination with desferrioximine produces a greater effect than either alone.⁵ 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 both need treating.

Surgical

• When hypersplenism occurs splenectomy is often undertaken.
• Cure can be achieved with a bone marrow transplant⁶ from a compatible, usually related donor.
• Recently embryo selection has been used to produce an immunologically compatible sib. While this induces horror in the expected quarters, the child is not simply a tissue culture but will be a loved and wanted member of the family. The ethical and legal issues have been discussed.⁷

• Iron overload is one of the major causes of morbidity in severe forms of thalassaemia even if they are not transfused.
• Bleeding tendency, susceptibility to infection, and organ dysfunction are related to iron overload.
• Repeated transfusions increase the risk of blood borne diseases including hepatitis B and hepatitis C although nowadays all blood is screened for these diseases.
• 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.⁸
• Hyperuricaemia sometimes produces gout.
• With increasing length of survival, hepatocellular carcinoma is becoming an increasing problem.⁹

Deferrioxamine 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 to 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,⁶ 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. In the severe β thalassaemia major, also called Cooley's anaemia, 80% die in the first 5 years of life from complications of the disease. Until recently, patients who received only transfusions did not survive beyond adolescence because of cardiac complications caused by iron toxicity. The introduction of chelating agents¹⁰ to remove excessive iron has increased life expectancy dramatically.

• Use family origin questionnaire¹¹ to identify at risk population for screening.
• Genetic counselling is available and in areas of high prevalence may be considered before marriage.
• Early antenatal testing¹² with a view to TOP is available. Even in populations such as Sardinia, the acceptance of screening¹³ including antenatal screening with a view to TOP, has brought great success.
• Gene therapy is an attractive proposition for the future but is not currently feasible.