is a general term for a group of
Genetic Disorders caused by sickle hemoglobin (Hgb S). In many forms of the disease, the
Red Blood Cell s change shape upon deoxygenation because of polymerization of the abnormal sickle hemoglobin. This process damages the red blood cell membrane, and can cause the cells to become stuck in blood vessels. This deprives the downstream tissues of
Oxygen and causes
Ischemia and
Infarction . The disease is chronic and lifelong. Individuals are most often well, but their lives are punctuated by periodic painful attacks. In addition to periodic pain, there may be damage of internal organs, such as
Stroke . Lifespan is often shortened. It is common in people from parts of the world where
Malaria is or was common, especially in
West Africa or in descendents of those peoples. Sickle cell disease can occur in any individual of any color or ethnicity, however.
"Sickle cell anemia" is the name of a specific form of sickle cell disease in which there is
Homozygosity for the mutation that causes Hgb S. Other forms of sickle cell disease include sickle-hemoglobin C disease, sickle beta-plus-
Thalassemia , and sickle beta-zero-thalassemia. Unlike sickle cell anemia, these other forms of sickle cell disease are compound heterozygous states in which the person has only one copy of the mutation that causes Hgb S and one copy of another abnormal
Hemoglobin Gene . It is important to know that "sickle cell anemia" is the proper name of a specific type of "sickle cell disease", and that "sickle cell disease" is a non-specific term. Because the different forms of sickle cell disease are quite different, one must be sure to specify the exact form of the disease in question.
The disease was originally called sickle-cell anemia but this name has fallen out of favor in medical contexts because anemia is not the only symptom of the disease.
Patients with sickle cell anemia have steady-state or baseline anemia that varies in severity, with hemoglobin levels of 6-9 g/dl typical.
Reticulocyte counts are elevated, reflecting new red blood cells replacing the rapidly destroyed older cells - red blood cell life span is markedly reduced in this disease. Often, the white blood cell and
Platelet counts are elevated, and these cells may contribute to vaso-
Occlusion .
Vasoocclusive crisis is caused by sickle shaped 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 anemia. This
Autosplenectomy increases the risk of infection from encapsulated organisms; preventive antibiotics and 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 recognized type of sickle crisis is the ''acute chest crisis'', a condition characterized by fever, chest pain, hard breathing, 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 .
- . An 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.
- . An acute, painful enlargement of the spleen. Management is supportive, sometimes with blood transfusion.
Sickle cell anemia 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.
anemia is caused by a
Mutation in the β-globin chain of
Hemoglobin , replacing
Glutamic Acid with less polar
Valine at the sixth position of the β chain . 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
Erythrocytes are quite elastic, which allows the cells to deform to pass through capillaries. Often a cycle occurs because as the cells sickle, they cause a region of low oxygen concentration which causes more red blood cells to sickle. 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 anemia 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 (A to T) of the β-globin gene, which results in
Glutamic Acid to be substituted by
Valine at position 6. Hemoglobin S 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 , from 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
Donut -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). This 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 wall of the RBC, an occurrence called sickling.
The sufferers of the illness have a reduced life span. It is believed that carriers () 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 homozygotes. 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 anemia.
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 anemia 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 incidence 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 i.e. complete blood count, reticulocyte count and blood culture taken. 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.
Most patients with sickle cell disease have intensely painful episodes called ''vaso-occlusive crises''. The frequency, severity, and duration of these crises vary tremendously, however. Painful crises are treated symptomatically with
Analgesic s; pain management requires
Opioid administration at regular intervals until the crisis has settled. For milder crises a subgroup of patients manage on
NSAID s (such as
Diclofenac or
Naproxen ). For more severe crises most 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.
Management is similar to vaso-occlusive crises with the addition of antibiotics (usually a third generation
Cephalosporin ), oxygen supplementation for
Hypoxia , and close observation. Should the pulmonary infiltrate worsen or the oxygen requirements increase, simple blood transfusion or exchange transfusion is indicated. The latter involves 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 severity 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.
Various approaches are being sought for preventing sickling episodes as well as for the complications of sickle-cell disease. Other ways to modify Hb switching are being investigated.
Nipoxan (or Hemoxin), previously Niprisan or Nix-0699, is a
Phytochemical (ethanol/water extract of ''
Piper Guineenses '' seeds, ''
Pterocapus Osum '' stem, ''
Eugenia Caryophyllum '' fruit, and ''
Sorghum Bicolor '' leaves) has received orphan drug status in the USA and Europe.
Gene Therapy is under investigation.
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.
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 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 prevalent 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.
- Chestnut, D. (1994). Perceptions of ethnic and cultural factors in the delivery of services in the treatment of sickle cell disease. Journal of Health and Social Policy, 5(3/4), 236.
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