Thalassaemia

Synonyms: Mediterranean anaemia and Cooley's anaemia

The normal haemoglobin molecule has a haem base surrounded by two pairs of globin chains. The types of globin are called alpha (α), beta (β), gamma (γ) and delta (δ). Most types of haemoglobin have two α chains and two other identical types. HbA, the most common form of adult haemoglobin, has two α and two β chains. Fetal haemoglobin (HbF) has two α and two γ components (this is the predominant type of Hb before birth). HbA2 is present in smaller amounts, with two α and two δ chains.

The thalassaemias are a group of recessively autosomal inherited conditions characterised by decreased or absence of synthesis of one of the two polypeptide chains (α or β) that form the normal adult human haemoglobin molecule (HbA, α₂/β₂), which results in reduced haemoglobin in red cells, and anaemia. β-globin gene defects may give rise to β thalassaemia, while mutations of the α globin gene may cause α thalassaemia¹. There are many forms (over 300 mutations giving rise to thalassaemia have been identified) and its clinical severity varies enormously. Thalassaemia major, intermedia and minor refer largely to disease severity.

Epidemiology¹²

• 1.5% (80-90 million people) of the world's population are carriers of β thalassaemia and about 5% are carriers of α thalassaemia.

• β thalassaemia is prevalent in areas around the Mediterranean, in the Middle East, in Central, South and Southeast Asia, and in Southern China.

• More than 100 genetic forms of α-thalassemia have been identified. α thalassaemia is prevalent in Southeast Asia, Africa and India.

• Increasing migration of populations at risk to non-endemic countries has resulted in increasing prevalence of thalassaemia gene mutations in all parts of the world.

Classification¹

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.

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.

α thalassaemia

• Normal: genotype α,α/α,α.

• α+ thalassaemia heterozygous (genotype α,-/α,α): borderline haemoglobin level and mean corpuscular volume (MCV), low mean corpuscular haemoglobin (MCH); clinically asymptomatic.

• α+ thalassaemia homozygous (genotype α,-/α,-): slightly anaemic, low MCV and MCH; clinically asymptomatic.

• αo thalassaemia heterozygous (genotype α,α/,--): slightly anaemic, low MCV and MCH; clinically asymptomatic.

• HbH disease (genotype α,-/-,-): HbH. Anaemic, very low MCV and MCH; splenomegaly, variable bone changes.

• α thalassaemia major (genotype -,-/-,-): Hb Bart's. Severe non-immune intrauterine haemolytic anaemia. Hb Bart's hydrops fetalis, usually fatal.

β thalassaemia

• Normal: genotype β₂/β₂.

• β-thalassaemia trait (genotype -/β₂): HbA₂ >4%. Slightly anaemic, low MCV and MCH; clinically asymptomatic.

• β thalassaemia intermedia (genotype -/βo or β+/β+): high HbF, variable. Anaemic (symptoms usually develop when the haemoglobin level remains below 7.0 g/dL), very low MCV and MCH; splenomegaly, variable bone changes, variable transfusion dependency.

• β thalassaemia major (genotype -o/-o): HbF >90% (untransfused). Severe haemolytic anaemia, very low MCV and MCH; hepatosplenomegaly, chronic transfusion dependency.

Presentation

The stage of presentation depends upon the severity of the disease. In most patients with either α-thalassaemia or β-thalassaemia traits there are no signs or symptoms. Symptoms of haemolytic anaemia (eg, pallor and hepatosplenomegaly) at birth in α thalassaemia, or from several months after birth in β thalassaemia, indicate severe disease, especially if microcytic anaemia is present¹.

α thalassaemia

• 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 three of four genes (aa/ao). Patients are haematologically normal, except for occasional low RBC indices. This diagnosis cannot be made on haemoglobin 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 red blood cell (RBC) indices. This condition is typically caused by the deletion of two 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.

• HbH 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 (HbH). HbH is unstable and precipitates in the erythrocyte, giving it the appearance of a golf ball.

β 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.

• Presentation of β thalassaemia major in infancy often includes failure to thrive, vomiting feeds, sleepiness, stunted growth and irritability.

• Ineffective erythropoiesis creates a hypermetabolic state with fever.

• 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.

Signs

Presentation varies with severity. Thalassaemia minor rarely has any physical abnormalities with haemoglobin ≥9 g/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 restriction is common even with well-controlled chelation therapy.

• Iron overload can cause endocrinopathy with diabetes, thyroid, adrenal and pituitary disorders.

Screening

• Pre-conceptual testing for haemoglobinopathies is recommended in at-risk groups³.

• Policies for antenatal and neonatal screening vary throughout the UK. Public Health England recommends that all pregnant women are offered screening for thalassaemia. All biological fathers are offered screening if the pregnant woman is a genetic carrier for thalassaemia⁴.

• Laboratories performing antenatal screening should utilise methods capable of detecting significant variants and be capable of quantitating haemoglobins A₂ and F.

Differential diagnosis

• Other causes of microcytic anaemia - eg, iron-deficiency anaemia, sideroblastic anaemia and anaemia of chronic disease⁵.

• Acute leukaemia may require bone marrow aspiration to differentiate.

• Rhesus incompatibility is rare now and post-mortem haemoglobin electrophoresis should differentiate in cases of hydrops fetalis.

• Diamond-Blackfan 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.

Investigations

Blood

• FBC shows a microcytic, hypochromic anaemia (β-thalassaemia carrier status is often confused with iron deficiency due to reduced MCV and MCH). In the severe forms of thalassaemia, the haemoglobin level ranges from 2-8 g/dL. White blood cell (WBC) count is usually elevated from the haemolytic process. Platelet count may be depressed in splenomegaly.

• Serum iron level is elevated, with saturation as high as 80%. Ferritin is also raised.

• Haemoglobin electrophoresis usually reveals the diagnosis. Normal HbA₂ is between 1.5 and 3.0% whilst HbA2 >3.5% is diagnostic.

• DNA testing is only available in specialised laboratories. DNA analysis should be offered to identify and confirm couples at risk, in prenatal testing and in pre-implantation genetic diagnosis¹.

If microcytosis is found, appropriate tests for iron deficiency and anaemia of chronic disease should be performed and testing for thalassaemia considered in patients of appropriate family origin. Some laboratories use various formulae to decide when to initiate testing for thalassaemia but these formulae are unreliable in children, pregnant women and in sick patients. Haemoglobinopathy investigations should therefore be considered in any unexplained microcytosis, even if the red cell indices are not typical of thalassaemia or any other haemoglobinopathy³.

Establishing the diagnosis of the α-thalassemia trait requires measuring either the α-β chain synthesis ratio or performing genetic tests of the α globin cluster - eg, using polymerase chain reaction (PCR) assay tests.

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.

  • CXR may show an enlarged heart and cardiac failure.

• 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 desferrioxamine 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.

Staging

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.

Management

The general principles of management include¹:

• Asymptomatic carriers: require no specific treatment but should be protected from detrimental iron supplementation, which should only be given after confirmation of iron deficiency.

• Thalassaemia intermedia or HbH disease:
  

  • Need to be closely monitored for progression of complications induced by chronic haemolytic anaemia.

  • Occasional blood transfusion may be required during periods of rapid growth, infection-associated aplastic or hyperhaemolytic crises, and in pregnancy.

  • Indications for regular transfusion include growth impairment and skeletal deformities.

  • If hypersplenism develops, splenectomy may be considered, although this carries severe risks of life-threatening infections, pulmonary hypertension, and thrombosis.

• Thalassaemia major:
  

  • Regular hypertransfusion to maintain a haemoglobin level higher than 9.5 g/dL.

  • Iron chelation to prevent overload syndrome.

  • Care by a multidisciplinary team (including haematologist, specialised nurse, social worker, psychologist, genetic counsellor, cardiologist and liver specialist).

National haemoglobinopathy cards are available for affected, carrier and normal individuals following haemoglobinopathy screening. It is considered good practice to issue haemoglobinopathy cards to those with a major haemoglobinopathy and also to carriers where a definitive diagnosis can be made³.

Non-drug

• Education and psychological support⁶.

• 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 haemoglobin fall below 9.5 g/dL. Transfused blood should be leukocyte-poor. This is especially important if a bone marrow transplant may be considered at a future stage.

• Splenectomy may be indicated if hypersplenism causes a marked increase in transfusion requirements, but should be delayed for as long as possible because of potentially life-threatening infections, pulmonary hypertension and thromboembolic complications¹.

• The only cure for the disease is stem cell transplantation, which has better outcomes when offered at young ages¹.

• Gene therapy is a future prospect for treatment⁷⁸.

Drugs

• Desferrioxamine is given parenterally to aid iron excretion. The dose and means of delivery vary according to the needs of the patient⁹.

• Oral chelating agents have been developed and are now in use, including deferasirox and deferiprone¹⁰.

• Hydroxyurea may increase the expression of γ chains (HbF) and remove the excess α chains, which could potentially correct ineffective erythropoiesis¹.

• Folic acid and vitamin E deficiency may require treatment.

Management during pregnancy and pre-conception¹¹

• Women should be advised to use contraception despite the reduced fertility associated with thalassaemia.

• Iron chelators should be reviewed and deferasirox and deferiprone ideally discontinued three months before conception.

• Folic acid (5 mg) is recommended pre-conceptually to all women to prevent neural tube defects.

• Women should be offered an early scan at 7-9 weeks of gestation.

• In addition to the routine first-trimester scan (11-14 weeks of gestation) and a detailed anomaly scan at 18-20+6 weeks of gestation, women should be offered serial fetal biometry scans every four weeks from 24 weeks of gestation.

Full details of the guidance from the Royal College of Obstetrics and Gynaecology can be found by following the reference link below.

Complications

• Iron overload is one of the major causes of morbidity in severe forms of thalassaemia. Iron overload can occur even without transfusions, as absorption is increased and this increases with regular transfusions⁹. Excess iron is deposited in body organs, especially the pancreas, liver, pituitary and heart, causing fibrosis and eventual organ failure. Bleeding tendency and susceptibility to infection are also related to iron overload.

• Endocrine dysfunction secondary to iron overload is common in multiply transfused patients, manifesting as hypogonadotrophic hypogonadism, short stature, acquired hypothyroidism, hypoparathyroidism and diabetes mellitus¹².

• Glycated haemoglobin (HbA1c) is not a reliable indicator of diabetic control for people who also have diabetes because of the shortened lifespan of RBCs. A fructosamine blood test should be used instead.

• Repeated transfusions increase the risk of blood-borne diseases, including hepatitis B and hepatitis 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.

• Severe anaemia may cause high-output cardiac failure.

• Osteoporosis is common and apparently multifactorial in aetiology. Treatment strategies include bisphosphonates, with or without, hormone replacement therapy¹³.

• The long-term increased red cell turnover causes hyperbilirubinaemia and gallstones.

• Hyperuricaemia may lead to gout.

• With increasing length of survival, hepatocellular carcinoma is becoming an increasing problem¹⁴.

Desferrioxamine can cause toxicity:

• Local reaction at the site of injection can be severe.

• High-frequency hearing loss has been reported in 30-40% 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.

Prognosis

The prognosis depends on the severity of the disease and adherence to treatment:

α thalassaemia

• The prognosis is excellent for asymptomatic carriers.

• The overall survival for HbH disease is good overall but variable. Many patients survive into adulthood, but some patients have a more complicated course.

• Hydrops fetalis is incompatible with life.

β thalassaemia

• Thalassaemia minor (thalassaemia trait) usually causes mild, asymptomatic microcytic anaemia, with no effect on mortality or significant morbidity.

• Severe β thalassaemia major (also called Cooley's anaemia) has traditionally had a poor prognosis with 80% dying from complications of the disease in the first five years of life.

• Until recently, patients who received transfusions only did not survive beyond adolescence because of cardiac complications caused by iron toxicity. The introduction of chelating agents to remove excessive iron has increased life expectancy dramatically.

• The overall survival following stem cell transplantation has been shown to be 90% with a disease-free survival of 86% over a mean follow-up period of 15 years¹.

Prevention and screening

• A family origin questionnaire may be used to identify at-risk individuals⁴.

• Genetic counselling is available and, in areas of high prevalence, can be considered before marriage or conception.

• Early antenatal testing 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.