Clinical Review - Haemoglobinopathies

The essentials 

- Haemoglobinopathies have global importance.

- Carriers of abnormal haemoglobin genes are more resistant to malaria.

- Sickle cell crises can be severe and ultimately fatal.

- The thalassaemias are caused by imbalance in alpha and beta globin.

- Babies with thalassaemia major get severe anaemia in their first year.

1. NORMAL HAEMOGLOBIN STRUCTURE AND FUNCTION

Haemoglobin (Hb) is responsible for the carriage of oxygen throughout the body. When Hb molecules are reduced in number (resulting in anaemia) or are abnormal in structure (due to haemoglobinopathy), characteristic symptoms and signs occur.

The term haemoglobinopathy is used here to loosely represent both structural abnormalities of the Hb molecule, such as sickle cell anaemia, and diseases where globin chains are imbalanced, such as in thalassaemia syndromes.

The Hb molecule The Hb molecule consists of four subunits, two alpha-like and two beta-like globins.

Different types of Hb are produced at various stages of life. Fetal haemoglobin (HbF) consists of two alpha globins and two gamma globins. As the name suggests, HbF is the predominant haemoglobin found in the fetus. The main adult haemoglobin is HbA (A for adult) which comprises two alpha globin and two beta globin polypeptide chains (a2b2 haemoglobin).

Even though they have different pathologies, sickle cell disease and thalassaemia share some features with other anaemias because a reduced oxygen-carrying capacity will have a similar effect, no matter what the underlying cause may be.

Features of anaemia

The features of anaemia either reflect the fact that less oxygen is being delivered to tissues or result from the compensatory mechanisms that try to restore oxygen delivery towards normal.

The body is highly adaptable and can cope with anaemia up to a point.

The symptoms of anaemia may be specific or non-specific (see box, below right).

There are a variety of physiological strategies involved, which explain why individuals with chronically reduced Hb may have few symptoms despite having a low haemoglobin.

If anaemia is of gradual onset, the body has ample time to adapt, and the patient can carry on working and leading a relatively normal life.

Anaemia of sudden onset, on the other hand, does not allow time for physiological adaptation and the patient will generally feel unwell.

The main adaptations to anaemia include an increase in 2,3 diphosphoglycerate.

This is a red cell molecule that helps offload oxygen from Hb to the tissues where it is required.

Blood is also diverted from less vital tissues such as the skin and kidneys to more essential organs such as the heart, brain and muscle. Cardiac output rises as the haemoglobin drops to below 7-8g/dl, with an increase in heart rate and stroke volume.

SYMPTOMS OF ANAEMIA

NON-SPECIFIC SPECIFIC

Tiredness. Pallor, for example,
palmar creases,
nail bed, conjunctivae
(notoriously unreliable).

Fainting. Tachycardia.

Shortness of breath. Bounding pulse.

Worsening of angina Systolic flow murmur.
or claudication in
older individuals.

Palpitations. Cardiac failure.

KEY POINTS

- Haemoglobinopathies relate to structural abnormalities of haemoglobin or globin chain imbalance.

- The haemoglobin molecule consists of two alpha-like and two beta-like globins.

- Sickle cell disease and thalassaemia share some features in common with other anaemias.

- The body can cope with severe degrees of anaemia if the onset is gradual.

2. DISORDERS IN HAEMOGLOBIN QUALITY

In sickle cell disease, sickle Hb is the result of an amino acid alteration in the beta globin molecule. This results in an abnormal Hb molecule, and when oxygen levels are low it forms long rods within the red cell.

The red cells then change shape and become crescent, or sickle, shaped.

The sickle cell gene is found widely throughout Africa and in countries with African immigrant populations, in some Mediterranean countries, the Middle East and parts of India. The mutation is found in one in 10 of the UK African-Caribbean population (for example, one in 10 are carriers).

Why is it widespread?

If this gene is so harmful, why is it so widespread? Carriers of the abnormal gene do not suffer any major ill-effects from the sickle globin, and have the bonus that they are more resistant to malaria than those with normal Hb molecules. Selective pressure is therefore maintaining the gene at a high level of distribution.

The same is true of thalassaemia - carriers are better off than normal individuals because of resistance to malaria. The downside of this benefit is that if both parents are carriers, a proportion of babies will be born with the full-blown disease, and will suffer significant morbidity and mortality as a result.

This is mostly because sickled red cells do not flow well through small blood vessels. This leads to blockage of the blood vessels and sickle cell crises. The carriers of the sickle gene are said to have the sickle cell trait, and have red cells that contain a mixture of normal HbA and sickle haemoglobin S (HbAS). Sickle cell carriers are not anaemic and have no clinical abnormalities.

The homozygous state

Homozygous individuals have the full-blown disease, and develop specific clinical features. These clinical manifestations (see box, left) are variable, and many patients have only a few symptoms despite having severe chronic anaemia. Others have severe and frequent sickle crises, with marked haemolytic anaemia.

Features of sickle cell disease

Newborn babies have a naturally occurring high level of HbF. This protects them during the first eight to 20 weeks of life. Symptoms start when HbF levels fall towards adult levels. This is the stage where adult Hb takes over as the oxygen carrier, but no normal molecules are produced since there is no normal beta globin. HbA is therefore not produced.

Infection in homozygous individuals has a high morbidity and mortality, whether due to bacterial or viral infection. Pneumococcal septicaemia due to Streptococcus pneumoniae is well recognised. Other bacteria involved are Neisseria meningitidis, Escherichia coli and Haemophilus influenzae. Because of recurrent splenic infarcts, patients are functionally hyposplenic, or even asplenic.

Anaemia is often severe in children and adults, with a Hb about 6.0-9.0 g/dl. Patients are generally well-adapted until an episode of decompensation, such as a severe infection, occurs.

KEY POINTS

- Sickle haemoglobin is the result of an amino acid alteration in the beta globin molecule.

- Sickled red cells do not flow well through small blood vessels, causing blockage and sickle cell crises.

- Homozygous individuals develop specific clinical features.

- Infection in homozygous individuals has a high morbidity and mortality.

SICKLE CELL DISEASE FEATURES

- Splenic atrophy.

- Chronic leg ulcers (from ischaemia).

- Jaundice (from haemolysis).

- Gallstones (from haemolysis).

- Priapism.

- Retinal artery occlusion.

3. SICKLE CELL CRISES AND THEIR MANAGEMENT

Sickle cell crises may be mild, life-threatening or even fatal, and are of several different types that are broadly termed vaso-occlusive, aplastic, haemolytic or sequestrative.

Vaso-occlusive disease

In the vaso-occlusive form, bone pain affects the long bones and spine, and is due to occlusion of small vessels. Abdominal pain also occurs. Attacks are often triggered by infection, dehydration, alcohol or menstruation, or have no obvious cause. They need urgent hospital admission.

Dactylitis occurs mainly in children who present with swollen, tender fingers and toes. The acute chest syndrome is fairly common and presents with a sudden onset pleuritic chest pain, fever and breathlessness and can be confused with infection, infarction or embolism. Transfer to an intensive care unit is needed if the pO2 cannot be kept above 70 mmHg, and there is a mortality of 10 per cent. Triggers include infection, dehydration, cold, hypoxia and acidosis.

Growth retardation is common in children, and sexual maturity may be delayed. Avascular necrosis of the head of the femur or humerus, arthritis and Salmonella osteomyelitis can cause locomotor problems. Chronic ulceration due to ischaemia occurs, and genitourinary problems include renal papillary necrosis, with haematuria and renal tubular defects.

Priapism occurs in about 60 per cent of men and may result in impotence.

Gallstones may follow chronic haemolysis.

In the cardiovascular system there may be murmurs and tachycardia. Proliferative retinopathy, retinal artery occlusion and retinal detachment may affect the eye and cause blindness. If the CNS is affected, convulsions, TIAs, strokes and sensory hearing loss can occur. Patients may also become depressed and socially withdrawn.

Laboratory features

Haemoglobin levels are about 6.0-9.0 g/dl, often with a high reticulocyte count (10-20 per cent) because of high red cell turnover. Anaemic symptoms are usually mild, since HbS has a reduced affinity for oxygen and it is given up to the tissues more easily. A blood film will show prominent sickle cells and target cells.

The sickle cell test, where sodium dithionate produces a turbid appearance with sickle cell Hb, will be positive, but does not discriminate between carriers and homozygotes. Hb electrophoresis showing 80-95 per cent sickle Hb confirms the diagnosis.

Management

Early treatment of crises in hospital is essential. IV fluids combat dehydration due to poor fluid intake and loss from fever. Antibiotics should be given if infection is suspected, even before culture results from blood, urine or sputum are reported. Analgesia in the form of opiates such as pethidine is often needed initially. Between attacks, patients should have prophylactic penicillin and long-term folic acid. Hydroxyurea may elevate HbF levels, resulting in milder and less frequent crises.

Prevention

Parents in at-risk groups should be screened in early pregnancy, and if they and their partners are carriers, can be offered prenatal or neonatal diagnosis. Once the diagnosis is made, babies should have penicillin daily and be immunised against Strep pneumoniae, H influenzae type B and N meningitides.

Parents should seek medical advice on any suspicion of infection.

KEY POINTS

- Sickle cell crises may be vaso-occlusive, aplastic, haemolytic or sequestrative.

- Vaso-occlusive attacks require urgent hospital treatment.

- Laboratory tests show anaemia, reticulocytosis and sickle cells

- Haemoglobin electrophoresis will confirm the diagnosis.

4. DISTRIBUTION AND DIAGNOSIS OF THALASSAEMIAS

The thalassaemias are caused by an imbalance in alpha and beta globin protein production. Because normal Hb contains an equal mixture of alpha and beta, a deficiency of one type will lead to excess of the other. This imbalance makes red cells that are small, pale and poorly formed.

Patients suffer chronic anaemia, and the body attempts to correct this by increasing its production of red cells. This leads to typical bone changes, with expansion of the marrow in an attempt to increase red cell production. Splenomegaly occurs because the spleen also attempts to over-produce red cells. There are several types of thalassaemia, but the most important is beta thalassaemia.

Distribution

Thalassaemia is distributed throughout parts of Africa, the Mediterranean region, the Middle East, the Indian subcontinent, and South East Asia and occurs sporadically in all racial groups. As with sickle cell anaemia, it persists because carriers have been protected against malaria.

Children with the full-blown disease are severely affected. Carrier parents have a one in four chance of having a homozygous child.

Heterozygotes for beta thalassaemia (the thalassaemia trait) have no symptoms but they do have hypochromic microcytic red cells that may resemble iron deficiency, a frequent misdiagnosis.

Thalassaemia trait or iron-deficient?

Hb electrophoresis will help tell thalassaemia trait from iron deficiency.

One way of distinguishing them on a blood count is that the mean corpuscular volume (MCV) in thalassaemia trait is much lower than would be seen in iron deficiency with an equivalent Hb level.

Patients are usually diagnosed because of antenatal testing or when a blood count is carried out for an unrelated reason. Using a formula may help. For example, suspect thalassaemia trait if the MCV divided by the red blood count (RBC) in millions is less than 13. For example, if the RBC is 7.3 million per cubic mm (7.3x1012/l) and the MCV is 59fl, the result is 8.08 and strongly suggestive of thalassaemia trait.

KEY POINTS

- In thalassaemia the red cells are small, pale and poorly formed.

- Splenomegaly occurs because the spleen attempts to over-produce red cells.

- Heterozygotes have no symptoms, but blood films resemble iron deficiency.

- Suspect thalassaemia if the MCV divided by the red blood count in millions is less than 13.

5. BETA THALASSAEMIA MAJOR

Homozygotes for beta thalassaemia develop severe anaemia in the first year of life. This results from a major deficiency of beta globin chains.

Excess alpha chains precipitate in the red cell precursors, causing damage and early destruction. Hypertrophy of the ineffective bone marrow leads to skeletal changes, and there is variable hepatosplenomegaly. The HbF level is always raised. If these children are transfused, the excess marrow activity is switched off, and growth and development may become normal.

But sufferers then accumulate iron and may die later from damage to the myocardium, pancreas, or liver. Patients are also prone to infection and folic acid deficiency.

Presentation and clinical features

The disease presents in childhood with anaemia and recurrent bacterial infection. There is extramedullary haemopoiesis (blood cell production in organs other than the bone marrow, such as the spleen and liver) with the development of hepatosplenomegaly and skeletal deformities.

Other clinical features include bone deformities such as skull bossing and maxillary deformities, wasting, growth retardation and gallstones.

There is moderate to severe anaemia, with haemoglobin levels between 3.0 and 9.0g/dl, and the MCV and the mean corpuscular haemoglobin concentration are reduced, and the reticulocyte count is raised.

The blood film is bizarre and shows marked anisopoikilocytosis, target cells and nucleated red cells. Hb electrophoresis shows an absence of the normal HbA, with mainly HbF. HbA2 may be normal or mildly elevated.

Prevention and treatment

Pregnant women of appropriate racial groups should be screened. If a woman is found to be a carrier, her partner should be tested and the couple counselled.

Prenatal diagnosis by chorionic villus sampling can be carried out between weeks nine and 13 of pregnancy. If diagnosis is confirmed, the patient should be treated by regular blood transfusion, with surveillance for hepatitis C and related infections.

KEY POINTS

- Hypertrophy of the ineffective bone marrow leads to skeletal changes.

- Extramedullary haemopoiesis in the spleen and liver occurs.

- Skull bossing, maxillary deformities, wasting, growth retardation and gallstones are seen.

- Diagnosis is by chorionic villus sampling.

FURTHER RESOURCES

Further reading

Oxford Handbook of Clinical Haematology by Drew Provan et al, Oxford University Press, 2004.

ABC of Clinical Haematology, 2nd edition, edited by D Provan. BMJ Publications.

Weatherall D J, Provan A B. Inherited anaemias. Lancet 2000; 355: 1,169-75.

WEBSITES

See Medicine on the Web, page 57

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