Contents
Introduction
Sickle cell anaemia is an inherited, autosomal recessive haemolytic anaemia that is also a haemoglobinopathy. It is common in the black African population and occurs sporadically in the Mediterranean and Middle East. The presentation is usually in infancy
Pathology
Sickle cell anaemia is caused by a mutation in the beta chain of haemoglobin. The mutation is a switch of a GAG codon to a GTG codon for the sixth amino acid of the beta chain. This mutation results in a glutamate amino acid being replaced by a valine. The gene is located on chromosome eleven.
Glutamate is a hydrophilic amino acid whereas valine is hydrophobic. In deoxygenated conditions the sickle cell form of haemoglobin manifests abnormal bonding between these aberrantly positioned valine residues. This binding allows haemoglobin molecules to stack up into a helical fibre which has a diameter of 11.6nm and contains fourteen residues of haemoglobin.
Once the poor erythrocyte becomes stuffed with these stacks of duff haemoglobin it adopts a sickle shape. The sickled cells are more fragile than normal erythrocytes. In addition repeated cycles of sickling and desickling result in loss of surface membrane and the cell becomes stuck in a sickle shape. Sickled erythrocyte also agglutinate and can therefore block up small blood vessels.
Sickling can be precipitated by hypoxia, dehydration, acidosis, infection and surgery.
The defective form of haemoglobin is known as haemoglobin S. Normal adult haemoglobin is haemoglobin A. A haemoglobin A2 also exists. The form of haemoglobin used in the fetus is haemoglobin F.
Clinical Features
Full blown sickle cell anaemia produces a marked haemolytic anaemia. This is frequently accompanied by pigment
gallstones.
The anaemia itself is a significant burden but the disease has rather more diverse manifestations as a consequence of the ability of the sickle cells to agglutinate and clog up blood vessels.
The spleen suffers repeated infarction such that by the end of the first decade it is markedly atrophic. This is sometimes referred to as autosplenectomy. Patients are therefore susceptible to infection with encapsulated bacteria. The spleen may be vulnerable because it is the normal site of erythrocyte destruction.
The head of the femur can undergo aseptic / avascular necrosis. Less often the head of the humerus suffers this problem. The vertebrae can become deformed. More generally there can be bone infarcts and these can become secondarily infected. The bone marrow may become infarcted and rarely this can result in emboli being generated.
Chronic leg ulcers can develop.
The liver may be subjected to repeated episodes of infarction and in some patients this can result in fibrosis.
Microinfarcts occur in the kidney and cause a progressive loss of function. Renal papillary necrosis is found.
Some patients may develop priapism.
Retinal ischaemia can result in the development of proliferative retinopathy, retinal infarcts, vitreous haemorrhage or retinal detachment.
Sickle cell anaemia is not limited to chronic complications. Acute crises can be precipitated by infection, dehydration, cold or may even be without an apparent cause. There is widespread sickling in which small blood vessels become occluded by sickled cells. There is abdominal pain and bone pain.
The acute lung syndrome is due to blockage of pulmonary vessels by the sickle cells. Dyspnoea, pleuritic pain and fever occur.
Involvement of cerebral vessels in a sickle crisis produces transient ischaemic attacks, ischaemic cerebrovascular accidents, seizures or coma.
Sequestration crises tend to affect babies and children. There is sudden enlargement of the liver and spleen because of engorgement by erythrocytes. Many erythrocytes become trapped in these two organs and the patient thus becomes rapidly and markedly anaemic.
Aplastic crises reflect sudden failure of the bone marrow to manufacture erythrocytes. They can be caused by folate deficiency or infection with parvovirus B19. Parvovirus B19 can induce sudden suspension of erythropoiesis in normal people but the problem is usually transient and the existing red cells have sufficient durability for the pause not to be a problem. However, the short-lived erythrocytes of sickle cell anaemia mean that any temporary suspension of erythropoiesis results in anaemia.
Investigations
The anaemia of sickle cell disease is usually normochromic and normocytic.
The blood film may disclose sickle shaped cells.
A specific sickling test can be performed. Sodium metabisulphite is added to the blood to induce sickling then a reducing solution will make the blood become turbid due to the presence of haemoglobin S that was released by the sickling.
Haemoglobin electrophoresis should be undertaken because patients occasionally have other coeixsting haemoglobinopathies.
The vitamin B12 and folate levels should be measured.
Renal function should be assessed with the urea and electrolytes.
Treatment
The treatment of a sickle crisis requires intravenous fluids, oxygen, antibiotics and strong analgesia. Transfusions are reserved for sequestration crises or very severe anaemia. The pulmonary and neurological syndromes require exchange transfusion.
Sickle Cell Trait
The prevalance of sickle cell anaemia reflects the partial resistance that being heterozygous for haemoglobin S confers against malaria. The advantage of being heterozygous for haemoglobin S (sickle cell trait) ensured that the sickle cell gene persisted at a high frequency in the population. However, the price for this is that the frequency of homozygotes is high.
Sickle cell trait is largely asymptomatic. However, some of the renal problems can occur and severe dehydration or exhaustion can provoke a sickling crisis.