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Sickle+Cell+anemia
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is a group of
Genetic Disorders caused by
Sickle Hemoglobin (Hgb S or Hb 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 , which may cause organ damage, such as
Stroke . The disease is chronic and lifelong. Individuals are most often well, but their lives are punctuated by periodic painful attacks. Life-expectancy is shortened, but contemporary survival data is lacking. Older studies indicated that sufferers could live to an average of 40 to 50 years, with the average age for males being 42 and the average age for females being 48. Sickle-cell disease occurs more commonly in people (or their descendants) from parts of the world such as
Sub-Saharan Africa , where
Malaria is or was common, but it also occurs in people of other ethnicities. As a result, those with sickle cell disease are resistant to malaria since the red blood cells are not conducive to the parasites. The mutated
Allele is
Recessive , meaning it must be inherited from each parent for the individual to have the disease.
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
Anaemia . 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.
1
The disease was named "sickle-cell anaemia" by of a runaway slave. The African medical literature reported this condition in the 1870s where it was known locally as ''ogbanjes'' ('children who come and go') because of the very high infant mortality in this condition. And a history of the condition tracked reports back to 1670 in one Ghanaian family.Konotey-Ahulu FID. Effect of environment on sickle cell disease in West Africa: epidemiologic and clinical considerations. In: Sickle Cell Disease, Diagnosis, Management, Education and Research. Abramson H, Bertles JF, Wethers DL, eds. CV Mosby Co, St. Louis. 1973; 20; cited in
2 Also, the practice of using tar soap to cover blemishes caused by sickle cell sores was prevalent in the African American community.
Proof that sickle-cell disease was associated with an alteration of hemoglobin was published in 1949 by
Linus Pauling and coworkers. This was the first time a genetic disease was linked to a mutation of a specific protein, a milestone in the
History Of Molecular Biology .
The origin of the mutation that led to the sickle cell gene was initially thought to be in the
Arabian Peninsula , spreading to Asia and Africa. It is now known, from evaluation of chromosome structures, that there have been at least four independent mutational events, three in Africa and a fourth in either Saudi Arabia or central India.
3 These independent events occurred between 3,000 and 6,000 generations ago, approximately 70,000-150,000 years.
"Sickle-cell anaemia" is the name of a specific form of sickle-cell disease in which there is
Homozygosity for the
Mutation that causes Hgb S. Sickle cell anaemia is also referred to as "SS disease," "Hemoglobin S," or permutations thereof. Other forms of sickle-cell disease include:
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 Allele . "Sickle-cell anaemia" is a synonym for "sickle-cell disease".
The term "disease" is applied here since the inherited abnormality causes a pathological condition that can lead to death and severe complications. Not all inherited variants of
Hemoglobin are detrimental, a concept known as
Genetic Polymorphisms .
Hemoglobin is one of the best-characterized proteins in terms of inherited variants; some variants manifest as severe
Thalassaemia , such as beta-zero-
Thalassaemia , and other variants manifest as a milder thalassaemia, such as beta-plus-
Thalassaemia .
Patients with sickle-cell anemia can have symptoms that vary in severity, with typical hemoglobin levels of 6-9 g/dl.
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 .
A vaso-occlusive crisis is caused by sickle-shaped red blood cells that obstruct capillaries and restrict blood flow 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 ;
45 preventive antibiotics and vaccinations are recommended for those with such
Asplenia .
Bone s, especially weight-bearing bones, are also a common target of vaso-occlusive damage. This is due to bone ischemia.
A recognised type of sickle crisis is the ''acute chest crisis'', a condition characterised by fever, chest pain, hard breathing, and pulmonary infiltrate on chest X-ray. Given that pneumonia and intrapulmonary sickling can both produce these symptoms, the patient is treated for both conditions. Treatment consists of admission, oxygen, close monitoring, and intravenous
Antibiotics .
- are acute worsenings of the patient's baseline anaemia producing pallor, tachycardia, and fatigue. This crisis is triggered by Parvovirus B19 , which directly affects Erythropoiesis (production of red blood cells). Parvovirus infection nearly completely prevents red blood cell production for 2-3 days. In normal individuals this is of little consequence but the shortened red cell life of sickle-cell patients results in an abrupt, life-threatening situation. 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.
- are acute, painful enlargements of the spleen. The abdomen becomes bloated and very hard. Management is supportive, sometimes with blood transfusion.
Sickle-cell anaemia can lead to various complications, including:
- 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. Incentive spirometry, a technique to encourage deep breathing to minimise the development of Atelectasis , is recommended.
- Acute Chest Syndrome is a life-threatening condition characterised by chest pain, shortness of breath, fever, hypoxaemia and pulmonary infiltrates on chest X-ray. It can be triggered by pain crisis, respiratory infection, bone-marrow embolization, or possibly by atelectasis, such as can be caused by opiate administration, or surgery.
- Overwhelming Post-(auto)splenectomy Infection is due to functional asplenia, caused by encapsulated organisms such as '' Streptococcus Pneumoniae '' and '' Haemophilus Influenzae ''. Daily Penicillin prophylaxis is the most commonly used treatment during childhood with some haematologists continuing treatment indefinitely. Patients benefit today from routine vaccination for ''H. influenzae'', ''S. pneumoniae'' and ''Neisseria meningitidis''.
- Stroke can result from a progressive vascular narrowing of blood vessels, preventing oxygen from reaching the Brain . Cerebral infarction occurs in children, and cerebral hemorrhage in adults.
- Cholelithiasis and Cholecystitis (gallstones) may result from excessive Bilirubin production and precipitation due to prolonged Haemolysis .
- Avascular necrosis ( Aseptic Bone Necrosis ) of the hip may occur as a result of ischemia.
- Decreased Immune Reactions due to Hyposplenism (malfunctioning of the spleen)
- Priapism and Infarction of the penis.
- Osteomyelitis (bacterial bone infection) - '' Salmonella '' is noted much more commonly than in the general population, although '' Staphylococcus '' is still the most common.
- Opioid tolerance can occur as a normal, physiologic response to the therapeutic use of opiates. Addiction to opiates occurs no more commonly among individuals with sickle cell disease than among other individuals treated with opiates for other reasons.
- Acute papillary necrosis in the kidneys
Attacks are diagnosed clinically, i.e. there is no
Gold Standard diagnostic test.
Haemolysis (causing
Anaemia 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 (HgbS) and
Hemoglobin C with sickling (HgbSC)—the two most common forms—can be identified from there.
Genetic Testing is rarely performed.
Sickle-cell anaemia is caused by a point
Mutation in the β-globin chain of
Hemoglobin , replacing the amino acid
Glutamic Acid with the less polar amino acid
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
Ischaemia .
In people
Heterozygous for HgbS (carriers of sickling hemoglobin), the polymerisation problems are minor. In people
Homozygous for HgbS, 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 . Normally these painful crises occur 0.8 times per year per patient.the sickle cell disease occurs when the 6th amino acid,glutamic acid is replaced by valine to change is structure and function.
]]
The gene defect is a known
Mutation of a single
Nucleotide (see
Single Nucleotide Polymorphism - SNP) (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 normal adult HbA. The genetic disorder is due to the
Mutation of a single nucleotide, from a GAG to GUG
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. The deoxy form of hemoglobin exposes a hydrophobic patch on the protein between the E and F helices. The hydrophobic residues of the valine at position 6 of the beta chain in hemoglobin are able to bind to the hydrophobic patch, causing hemoglobin S molecules to aggregate and form fibrous precipitates.
The
Allele responsible for sickle-cell anaemia is
Autosomal Recessive and can be found on the 11th chromosome. 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. 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 .
Due to the evolutionary advantage of the heterozygote, the illness is still prevalent, especially among people with recent ancestry in malaria-stricken areas, such as
Africa , the
Mediterranean ,
India and the
Middle East 6.
The
Price Equation is a simplified mathematical model of the genetic evolution of sickle cell anaemia.
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 trait (selection for the heterozygote).
In the
USA , where there is no endemic malaria, the incidence of sickle cell anaemia amongst
African Americans is lower (about 8%) than in
West Africa and is falling. Without endemic malaria from Africa, the condition is purely disadvantageous, and will tend to be breed out of the affected population.
- Sickle-cell conditions are inherited from parents in much the same way as blood type, hair color and texture, eye color and other physical traits.
- The types of hemoglobin a person makes in the red blood cells depend upon what hemoglobin genes the person inherits from his or her parents.
# If one parent has sickle-cell anaemia ("rr" in the diagram above) and the other is Normal (RR), all of their children will have sickle cell trait (Rr).
# If one parent has sickle-cell anaemia (rr) and the other has Sickle Cell Trait (Rr), there is a 50% chance (or 1 out of 2) of a child having sickle cell disease (rr) and a 50% chance of a child having sickle cell trait (Rr).
# When both parents have Sickle Cell Trait (Rr), they have a 25% chance (1 of 4) of a child having sickle cell disease (rr), as shown in the diagram above.
# Sickle-cell anemia is caused by a recessive allele. Two carrier parents have a one in four chance of having a child with the disease. The child will be homozygous recessive.
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.
Zinc is given as it stablises cell membrane.
Most people with sickle cell disease have intensely painful episodes called ''vaso-occlusive crises''. The frequency, severity, and duration of these crises, however, vary tremendously. 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 quinolone or macrolide, since wall-deficient
{Link without Title} bacteria are thought to contribute to the syndrome),
7 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'')
8
and shown to possibly increase survival time in a study in 2003 (Steinberg ''et al'')
9.
This is achieved, in part, by reactivating
Fetal Hemoglobin production in place of the hemoglobin S that causes sickle cell anaemia. Hydroxyurea's clinical benefits can actually precede the induction of
Fetal Hemoglobin , however. 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, including the use of
Phytochemicals such as
Nicosan .
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.
- 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.
