Sickle-shaped red blood cells
Sickle cell anemia (American English), sickle cell anaemia (British English) or sickle cell disease is a genetic disease in which red blood cells may change shape under certain circumstances. This causes the cells to become stuck in capillaries which deprives the downstream tissues of oxygen and causes ischemia and infarction. The disease usually occurs in periodic painful attacks, eventually leading to damage of internal organs, stroke, or anemia, and usually resulting in decreased lifespan. It is common in people from countries with a high incidence of malaria, and especially in West Africa.
Signs and symptoms
Patients have baseline anemia that varies in severity, with hemoglobin levels of 7-9 mg/dl typical. Often white blood cell counts are elevated simply due to marrow hyperactivity. Reticulocyte counts are elevated, reflecting new red blood cells replacing the rapidly cleared older cells - red blood cell life span is markedly reduced in this disease.
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 infarcted before the end of childhood in individuals suffering from sickle cell anaemia. This autosplenectomy increases the risk of infection from encapsulated organisms; preventive antibiotics & vaccinations are recommended for those with such asplenia. 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 acute chest crisis, a condition characterized by fever, chest pain, and pulmonary infiltrate on chest x-ray. Given that pneumonia and intra-pulmonary sickling can both produce these symptoms, the patient is treated for both conditions. Treatment consists of admission, oxygen, close monitoring, and intravenous antibiotics.
Other sickle cell crises
Aplastic crisis - acute worsening of the patient's baseline anemia producing pallor, tachycardia, and fatigue. This crisis is triggered by parvovirus B19, which directly affects erythropoiesis (production of red blood cells). Reticulocyte counts drop dramatically during the illness and the rapid turnover of red cells leads to the drop in hemoglobin. Most patients can be managed supportively, some need blood transfusion.
Splenic sequestration crisis - acute enlargement of the spleen causing pain. Management is supportive, sometimes with blood transfusion.
Sickle cell anaemia can lead to various complications, including:
Attacks are diagnosed clinically, i.e. there is no gold standard diagnostic test. Hemolysis (anemia and jaundice) is often present, although for painful crises the diagnosis depends essentially on how the patient describes the pain.
Abnormal hemoglobin forms are detected on hemoglobin electrophoresis , a form of gel electrophoresis on which the various types of hemoglobin move at varying speed. Sickle cell hemoglobin (HbSS) and Hemoglobin C with sickling (HbSC)--the two most common forms--can be identified from there. Genetic testing is rarely performed.
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.
New red blood cells are quite elastic, which allows the cells to deform to pass through capillaries. Repeated episodes of sickling causes loss of this elasticity and the cells fail to return to normal shape when oxygen concentration increases. These rigid red blood cells are unable to flow through narrow capillaries, causing vessel occlusion and ischemia.
The allele responsible for sickle cell anaemia is 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 (U to A) of the β-globin gene, which results in glutamic acid to be substituted for valine at position 6. Hemoglobins with this mutation are referred to as HbS, as opposed to the more normal adult HbA. The genetic disorder is due to the mutation of a single nucleotide, to a GAG to GTG codon mutation. 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 of sickling hemoglobin), 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. Carriers only have symptoms if they are deprived of oxygen (for example, while climbing a mountain) or while severely dehydrated. For those afflicted with the disease, however, vasocclusive events can be a painful part of life (normally they occur 0.8 times per year per patient). The occurs when HbS becomes deoxygenated it undergoes an abnormal change in shape and consistency which can lead to a change in the shape and plasticity in the cell well of the RBC, an occurrence called sickling.
The sufferers of the illness have a reduced life span. It is believed that carriers (sickle cell trait) are relatively resistant to malaria. Since the gene is incompletely recessive, carriers have a few sickle red blood cells at all times, not enough to cause symptoms, but enough to give resistance to malaria. Because of this, heterozygotes have a higher fitness than either of the homozyogotes. This is known as heterozygote advantage.
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 12 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.
See the Price equation article for a simplified mathematical model of the genetic evolution of sickle cell anemia.
Children with fever are screened for bacteremia - complete blood count, reticulocyte count and blood culture. Younger children (varies from center to center) are admitted for intravenous antibiotics while older children with reassuring white cell counts are managed at home with oral antibiotics. Children with previous bacteremic episodes should be admitted.
Painful (vaso-occlusive) crises
While a small subset of patients have frequent pain crises, most require less than one acute care visit per year. Painful 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, fentanyl, diamorphine (heroin - not available in the US) are used commonly; this has unfortunately led to a high rate of opioid addiction amongst sickle-cell patients, although this issues is much less common in children and adolescents. Some patients require inpatient management for intravenous opioids; patient-controlled analgesia (PCA) devices are commonly used in this setting. Diphenhydramine is effective for the itching associated with the opioid use.
Acute chest crisis
Management is similar to general painful crises with the addition of antibiotics (usually a third generation cephalosporin), oxygen supplementation for hypoxia, and close observation. Should the pulmonary infiltrate worsens or the oxygen requirements increase, simple blood transfusion or exchange transfusion is indicated. The latter involve the exchange of a significant portion of the patients red cell mass for normal red cells, which decreases the percent hemoglobin S in the patient's blood.
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 counseling 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 has risks, 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".
The cause of this collection of clinical findings was unknown until the description of the sickle cells in 1910 by the Chicago cardiologist and professor of medicine James B. Herrick (1861-1954) whose intern Ernest Edward Irons (1877-1959) found "peculiar elongated and sickle shaped" cells in the blood of Walter Clement Noel , a 20 year old first year dental student from Grenada after Noel was admitted to the Presbyterian Hospital in December 1904 suffering from anemia. Noel was readmitted several times over the next three years for "muscular rheumatism" and "bilious attacks" while an undergraduate. Noel completed his studies and returned to capital of Grenada (St. George's) to practice dentistry. He died of pneumonia in 1916 and is buried in the Catholic cemetery at Sauteurs in the north of Grenada.
The disease is very occasionally called "Herrick's syndrome" for this reason.
The disease was named "sickle cell anemia" by Vernon Mason in 1922. In retrospect some elements of the disease had been recognized earlier: a paper in the Southern Journal of Medical Pharmacology in 1846 described the absence of a spleen in the autopsy of a runaway slave. The African medical literature reported this condition in the 1870's where it was known locally as ogbanjes ('children who come and go') because of the very high infant mortality in this condition. Also, the practice of using tar soap to cover blemishes caused by sickle cell sores was prevelent in the African American community.
- Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, Orringer E, Bellevue R, Olivieri N, Eckman J, Varma M, Ramirez G, Adler B, Smith W, Carlos T, Ataga K, DeCastro L, Bigelow C, Saunthararajah Y, Telfer M, Vichinsky E, Claster S, Shurin S, Bridges K, Waclawiw M, Bonds D, Terrin M. 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;332:1317-22. PMID 12672732.
- Savitt TL, Goldberg MF. Herrick's 1910 case report of sickle cell anemia. The rest of the story. JAMA. 1989;261:266-271. PMID 2642320.