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Sickle cell anaemia
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Sickle cell anaemia

Sickle cell anaemia (SCA) is a common genetic disease which 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 inflammation. The disease usually occurs in periodic painful attacks, eventually leading to damage of some internal organs, stroke, or anaemia, and usually resulting in early death.

Table of contents
1 Pathophysiology
2 Genetics
3 Complications
4 Vasoocclusive crises
5 Treatment
6 Situation of carriers
7 Related topics
8 References
9 External links

Pathophysiology

Sickle cell anaemia is caused by a mutation in the β-globin chain of hemoglobin that replaces valine with glutamic acid 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 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 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 early. Still, the disease has not died out. This is because carriers are 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.

So the illness continues and is especially prevalent 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 mosquitos 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.

Complications

Sickle cell anaemia can lead to various complications, including:

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, the spleen is frequently affected, and with recurrent episodes it may become functionless (infarction). Liver failure may also occur with time.

Vasoocclusive crises may also affect the central nervous system, resulting in cerebral infarction in children and hemorrhage in adults.

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.

Treatment

The first approved drug for the treatment of sickle cell anaemia, hydroxyurea, was shown to decrease the number and severeness of attacks in a study in 1995 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 cancer drug, 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'.

Related topics

References

External links


Health science - Medicine - Hematology
Hematological malignancy and White blood cells
Lymphoma (Hodgkin's disease;, NHL) - Leukemia (ALL, AML, CLL, CML) - Multiple myeloma; - MDS - Myelofibrosis - Myeloproliferative disease; (Thrombocytosis, Polycythemia) - Neutropenia
Red blood cells
Anemia - Hemochromatosis - Sickle-cell anemia; - Thalassemia - other hemoglobinopathies
Coagulation and Platelets
Thrombosis - Deep venous thrombosis; - Pulmonary embolism; - Hemophilia - ITP - TTP