I have committed to teaching the juniors next week on sickle cell disease. In my 35 years at Bournemouth I had only one patient plus some visiting students who had this disease, so I can hardly pose as an expert.
But it is one of the most common genetic diseases worldwide and in America occurs in 1 in 2400 live births. Among African Americans the incidence is 1 in 400. In some places in Britain everybody has a screening test for it at birth, but Bournemouth is not one of them, malaria being quite rare here.
The abnormality is due to the substitution of valine for glutamic acid at position 6 in the beta chain of hemoglobin. Hb S is insoluble and forms crystals when exposed to low oxygen tension. It then polymerizes into long fibers, each consisting of seven intertwined double strands with cross linking.
It is only when the sickle gene is inherited from both parents that the full picture emerges. The features are of a severe hemolytic anemia punctuated by crises. Hb S releases oxygen to tissues more easily than Hb A so the anemia is often more severe than its symptoms. Interestingly some patients live fairly normal lives without incident.
The crises may be painful, visceral, aplastic or hemolytic.
Most common are painful crises caused by the occlusion of small blood vessels. They are precipitated by such factors as infection, acidosis, dehydration or any condition causing low oxygenation (altitude, anesthetic, obstetric delivery or, violent exercise), exposure to cold or vascular stasis. The occlusions may occur in bones (hips, shoulders and vertebrae are most common), the lungs and spleen. The most serious events occur in the brain. In children the hand-foot syndrome is common when occlusions occur in the small bones. It may lead to digits of varying length.
Visceral crises are due to sickling within organs. The most common occurs in the lungs with infiltrates in the lungs causing severe respiratory distress and is the commonest cause of death. Sickling in the liver and spleen can also cause severe illness.
Aplastic crises occur either because parvovirus puts a halt to red cell production or because the body runs out of folic acid.
Hemolytic crises often accompany other types of crisis and are associated with a fall in Hb with a reticulocytosis.
Other clinical features include splenomegaly in infancy, but splenic infarction means that most adults have signs of hyposplenism. Leg ulcers are common.
Treatment is to avoid things that precipitate crises, especially dehydration, anoxia, infections, stasis of the circulation and cooling of the skin surface. Patients should receive folic acid 5mg a day as prophylaxis, they should be vaccinated against pneumococcus as children and adults should receive prophylactic penicillin like other people without a spleen. Good hygiene and nutrition should be practised.
Crises are treated with rehydration, antibiotics, if appropriate, and bicarbonate if there is acidosis. Strong pain relief is often necessary, but some patients do become dependent on opiates. Blood transfusion is only needed for severe symptomatic anemia (normal oxygenation is achieved with hemoglobin lower than in patients with Hb A). Exchange transfusion may be needed if there is neurological damage or visceral crisis, or if painful crises are common. The aim should be to achieve a Hb S level of less than 30%.
Transfusion is often necessary during pregnancy and a Hb S level of less than 30% should be achieved by delivery. Careful anesthetic technique is required to avoid hypoxemia or acidosis
Iron overload may become a problem in patients requiring frequent transfusions.
In carefully selected patients, stem cell transplant may be indicated.
Sicklers in Saudi Arabia often have high Hb F levels and this seems to prevent the worst complications. Drugs have been used to raise Hb F levels, particularly hydroxyurea (called hydroxycarbamide more recently).
Hydroxyurea is a type of chemotherapy used in polycythemia and before Gleevec for CML. It is regarded as very safe, though it can suppress the platelets, Hb and neutrophils, and therefore has to be regularly monitored with a CBC. There has been a randomized clinical trial in patients with sickle cell disease and this showed a 44% reduction in pain episodes, a longer time to the first painful crisis, fewer episodes of acute chest syndrome and fewer transfusions or admission to hospital. In long term follow up, mortality rates were 40% lower.
There have been several less convincing studies which have suggested that Hb F levels can be raised to 20% without significant toxicity, that neurologic function and splenic function improves, and that hydroxyurea does not lead to a higher incidence of second malignancies. This has been a worry since there has been a suggestion of a higher incidence on acute leukemia in patients with polycythemia who take hydroxyurea. It is not clear however whether it is safe to take during pregnancy, and there have been reports of reduced sperm production in men on the drug.
There are a number of experimental treatment being tested. I noticed viagra on the list.
If the sickle cell gene is inherited from only one parent it is completely benign, unless it occurs in association with another hemoglobinopathy. The picture is then that of sickle cell disease, but patients have large spleens. Patients with HbSC disease are particularly prone to thrombosis and pulmonary emboli - especially in pregnancy. and they have a high incidence of retinal problems.
Homozygous Hb C disease, which is common in West Africa, is due to the substitution of lysine for glutamic acid ant position 6 on the beta chain. It tends to form rhomboidal crystals in red cells. It causes a mild hemolytic anemia with many target cells. Splenomegaly is prominent.
Homozygous Hb D disease is a mild hemolytic anemia. Homozygous Hb E disease is the commonest hemoglobinopathy in South East Asia and resembles a mild thalassemia.