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Sickle cell anaemia

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Sickle-shaped red blood cells

Sickle cell anaemia (SCA) is a genetic disease which, under certain circumstances, causes the red blood cells of a sufferer to be shaped like sickles, instead of the normal rounded shape. This causes the cells to become stuck in capillaries which deprives the body of oxygen and causes ischemia and infarction of downstream tissue. The disease usually occurs in periodic painful attacks, eventually leading to damage of some internal organs, stroke, or anaemia, and usually resulting in decreased lifespan. It is common in countries with a high incidence of malaria, and especially in West Africa.

Contents

1 Pathophysiology

2 Genetics

3 Disease symptoms

3.1 Vasoocclusive crises
3.2 Complications

4 Treatment

4.1 Painful crises
4.2 Hydroxyurea

5 Situation of carriers

6 Related topics

7 References

8 External links

Pathophysiology

Sickle cell anaemia is caused by a mutation in the β-globin chain of hemoglobin, replacing glutamic acid with less polar valine at the sixth amino acid position. The association of two wild type α-globin subunits with two mutant β-globin subunits forms hemoglobin S , which polymerises under low oxygen conditions causing distortion of red blood cells and a tendency for them to lose their elasticity.

At the onset of the disease, red blood cells are capable of regaining their original shape and elasticity when oxygen concentration increases. However, with repeated bouts of low oxygen conditions, red blood cells permanently lose their elasticity. These rigid red blood cells are unable to flow through narrow capillaries, causing vessel occlusion and ischemia.

Genetics

The allele responsible for sickle cell anaemia is incompletely (autosomal) recessive. A person who receives the defective gene from both father and mother develops the disease; a person who receives one defective and one healthy allele remains healthy, but can pass on the disease and is known as a carrier. If two parents who are carriers have a child, there is a 1-in-4 chance of their child developing the illness and a 1-in-2 chance of their child just being a carrier.

The gene defect is a known mutation of a single nucleotide of the β-globin gene. Hemoglobins with this mutation are referred to as HbS, as opposed to the more normal adult HbA. This is normally a benign mutation, causing no apparent effects on the secondary, tertiary, or quaternary structure of hemoglobin. What it does allow for, under conditions of low oxygen concentration, is the polymerization of the HbS itself. In people heterozygous for HbS (carriers), the polymerization problems are minor. In people homozygous for HbS, the presence of long chain polymers of HbS distort the shape of the red blood cell, from a smooth doughnut-like shape to ragged and full of spikes, making it fragile and susceptible to breaking within capillaries.

The sufferers of the illness usually die young, and according to the theory of evolution, the disease should have been eliminated from the gene pool. Still, the disease has not died out; this is because carriers are relatively resistant to malaria. Carriers of the allele have an unsymptomatic condition called sickle cell trait. Since the gene is incompletely recessive, carriers have a few sickle red blood cells at all times but not enough to cause symptoms. Only if they are deprived of oxygen (for example, climbing a mountain) will they develop symptoms.

The malaria parasite has a complex life cycle and spends part of it in red blood cells. In a carrier, the presence of the malaria parasite causes the red blood cell to rupture, making the plasmodium unable to reproduce. Further, the polymerization of Hb affects the ability of the parasite to digest Hb in the first place. Therefore, in areas where malaria is a problem, people's chances of survival actually increase if they carry sickle cell anaemia.

Due to the above phenomenon, the illness is still prevalent, especially among people with recent ancestry in malaria-striken areas, such as Africa, the Mediterranean, India and the Middle East. In fact, sickle-cell anaemia is the most common genetic disorder among African Americans; about 1 in every 13 is a carrier.

The evolution of sickle-cell anaemia is probably an example of Baldwinian evolution, whereby humans modify their environment and thus change the selective pressures. As humans in tropical areas in Africa and elsewhere developed agriculture and animal husbandry, they expanded the niche for Anopheles mosquitoes that could transmit the malaria parasite.

It is interesting that in the USA, where there is no endemic malaria, the incident of sickle cell anaemia amongst people of African descent is much lower than in West Africa and falling. Without endemic malaria from Africa, the condition is purely disadvantageous, and will tend to be bred out of the affected population.

Disease symptoms

Vasoocclusive crises

Vasoocclusive crises are caused by sickled red blood cells that obstruct capillaries and restrict bloodflow to an organ, resulting in ischemia, pain, and organ damage.

Because of its narrow vessels and function in clearing defective red blood cells, the spleen is frequently affected. It is usually (infacted) before the end of childhood in individuals suffering from sickle cell anaemia; they are subsequently at higher risk for infection from encapsulated organisms. Liver failure may also occur with time.

Bone is also a common target of vasoocclusive damage, especially when the bone is particularly weight-bearing. Such damage may result in avascular necrosis (especially of the femur) and bone deterioration. The pain experienced by sickle-cell patients is also due to the bone ischemia.

A recognised type of sickle crisis is the chest crisis, where a mild chest infection (to which patients are predisposed) triggers off a cascade of decreased oxygen, increased sickling in the pulmonary vascular bed, leading in turn to more severe hypoxia. Treatment is as a sickle crisis and pneumonia, but in recurrent chest crises, the patient will require penicillin (phenoxymethylpenicillin or penicillin V) oral prophylaxis, as well as vaccination against pneumococcus, meningococcus and Haemophilus influenzae bacteria, to prevent recurrence.

Complications

Sickle cell anaemia can lead to various complications, including:

Stroke - progressive vascular narrowing (occlusion) can prevent oxygen from reaching the brain, leading to stroke; cerebral infarction occurs in children, and cerebral hemorrhage in adults.
Anemia - sickling due to hemoglobin S polymerisation leads to hemolysis and a decreased red blood cell count
Cholelithiasis and cholecystitis - prolonged hemolysis may lead to excessive bilirubin production and precipitation, leading to gallstones
Avascular necrosis (aseptic bone necrosis) of the hip
Aplastic crisis after parvovirus B19 infection (due to arrest of erythropoiesis by the virus)
Decreased immune reactions due to hyposplenism (malfunctioning of the spleen)
Priapism and infarction of the penis (in men)
Salmonella osteomyelitis
Opioid addiction (see below)

Treatment

Painful crises

Painful sickle crises are treated symptomatically with analgesics; a subgroup of patients manages on NSAIDs (such as diclofenac or naproxen), but many require opioid administration at regular intervals until the crisis has settled. Morphine, pethidine and diamorphine are used commonly; this has unfortunately led to a high rate of opioid addiction amongst sickle-cell patients. In cases of severe hemolysis, exchange transfusion may be required; this is the removal of the patient's blood and replacing it with non-sickle donor blood. It removes HbS and decreases sickling, but has risks and complications of its own.

Hydroxyurea

The first approved drug for the causative treatment of sickle cell anaemia, hydroxyurea, was shown to decrease the number and severeness of attacks in a study in 1995 (Charache et al) and shown to increase survival time in a study in 2003. This is achieved by reactivating fetal hemoglobin production in place of the hemoglobin S that causes sickle cell anaemia. Hydroxyurea had previously been used as a chemotherapy agent, and there is some concern that long-term use may be harmful, but it is likely that the benefits outweigh the risks.

Situation of carriers

People who are known carriers of the disease often undergo genetic counselling before they have a child. A test to see if an unborn child has the disease takes either a blood sample from the unborn or a sample of amniotic fluid. Since taking a blood sample from a fetus is dangerous, the latter test is usually used.

After the mutation responsible for this disease was discovered in 1979, the U.S. Air Force required African American applicants to test for the mutation. It dismissed 143 applicants because they were carriers, even though none of them had the condition. It eventually withdrew the requirement, but only after a trainee filed a lawsuit. Now, some insurance companies are doing the same thing to eliminate, in their terminology, "unwise investments".

References

Charache S, Terrin ML, Moore RD, et al: Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995 May 18; 332(20): 1317-22 PMID 12672732 [1]