Sickle-Cell Anemia - Assignment Example

Sickle-cell Anemia Introduction: Sickle-cell anemia is a term that de s a group of genetic disorders caused by sickle shaped hemoglobin Hgb S or Hb S. In patients with this disease the human red blood cells take a different shape upon deoxygenation because of polymerization of the abnormal sickle hemoglobin. This process causes damage to the red blood cell membrane and sometimes the red blood cells get attached in blood vessels. This attachment or adherence of the red blood cells deprives the tissues of oxygen causing ischemia and infarction.The disease is chronic with periodic painful attacks,damage of internal organs with complications of strokes and subsequent shortened lifespan.The average life span of sickle cell patients is just 40 years. Sickle-cell anemia is common in population in Saharan Africa and their descendants from parts of the world. Sickle-cell disease can occur in any individual of any race or ethnicity across the globe."Sickle-cell anemia" is a specific form of sickle-cell disease caused by a homozygous mutation forming Hgb S. Other forms of sickle-cell disease include sickle-haemoglobin C disease,sickle beta-plus-thalassemia,sickle beta-zero-thalassemia and hemoglobin ss causesd by heterozygous genes (Orah , 2000)..The origin of the mutation that led to the sickle cell gene was initially thought to be in the Arabian region spreading to Asia and Africa. It is now confirmed from evaluation of chromosome structures that there should have been at least four independent mutational events spanning over 70000 to 150000 years, three in Africa and a fourth in either Saudi Arabia or central India.The evolution of sickle-cell anaemia is understood and explained as an example of Baldwinian phylogeny whereby humans modify their environment and thus change the selective pressures. Disease Symptoms Patients with sickle cell anaemia exhibit anaemia with typical hemoglobin levels of 6-9 g/dl. Evaluation of reticulocytes reflects new red blood cells replacing the rapidly destroyed older cells because of a drastic reduction in red blood cell life span. Reticulocytes are immature red blood cells, typically comprising about 1% of the red cells in the human body. Reticulocytes develop and mature in the bone marrow and then circulate for about a day in the blood stream before developing into mature red blood cells.Reticulocytes do not have a nucleus. They are called reticulocytes because of a reticular or mesh-like network of ribosomal RNA.Reticulocytes appear slightly bluer than other red cells when looked at with the normal Romanowsky staining procedure. Evaluation of the white blood cell and platlet counts indicate vaso-occlusion( Kinney et al.1999). Complications of Sickle cell Anemia Vaso-occlusive crises Most patients with sickle cell disease suffer intensely painful episodes called vaso-occlusive crises The frequency, severity, and duration of these crises vary tremendously. Such painful crises are treated with hydration and analgesics.A vaso-occlusive crisis is a condition caused by sickle-shaped red blood cells that obstruct capillaries and restrict bloodflow to an organ often resulting in pain,ischemia and and organ damage. The Spleen is frequently affected due to narrow blood vessels and its metabolic function in clearing defective red blood cells. It is usually in infracted state before even the end of childhood in sickle-cell anemia cases(Orah , 2000). This causes autosplenectomy.Autosplenectomy occurs when the spleen is damaged to such an extent that it is non-functioning and hence equivalent to the spleen having been surgically removed .This further increases the risk of infection from encapsulated organisms. Prophylactic antibiotics and vaccinations are recommended for those with such asplenia.Asplenia refers to the absence of normal spleen function and is associated with infection risks.Asplenia increases the risk of septicaemia especially due to infection with Pneumococcus,Haemophilus and Meningococcal bacterial species which can kill within a few hours. Hyposplenism is another condition where the spleen is poorly-functioning but not as severely affected as with asplenism.Hepatic failure is also common in such patients.Bones, are a common target of vasoocclusive damage. Acute chest crisis Acute chest crisis is a condition characterized by fever, chest pain, breathing difficulties and pulmonary infiltrates in Sickle cell anemia cases.Aplastic crisis is an acute deteriotation of the patient's baseline anemia with typical pallor, tachycardia, and fatigue. This crisis has been found to be enhanced by a parvovirus which directly affects the production of red blood cells or erythropoiesis. In acute chest crisis reticulocte counts drop dramatically during the illness with a drop in hemoglobin(Hebbel, 2000). Splenic sequestration crisis is an acute, painful enlargement of the spleen with a hard bloated abdomen. It can be triggered by pain crisis, respiratory infection, bone-marrow embolization, or by atelectasis. Prolonged and progressive vascular occlusion prevents oxygen from reaching the parts of the brain causing stroke and cerebral hemorrhage in adults( Kinney et al.1999).Cerebral infarction is common in children.Prolonged occlusion leads to hemolysis and ecessive bilirubin precipitation causing Gallstone formation.in such patients. Avascular necrosis also known as the aseptic bone necrosis of the hip,depleted immune response due to spleen dysfunction,Priapism and penis infraction and Osteomyelitis are the other common complications of Sickle cell anemia( Kinney et al.1999). Diagnosis Although there is no gold standard for diagnosis of sickle cell anemia.clinical diagnosis is based on the symptoms of anemia and jaundice coupled with hemolysis.Diagnosis on pain crisis depends on the patients pain description.Electropheretic seperation of blood hemoglobin can help abnormal hempglobin forms based on the band seperation. Sickle cell hemoglobin HbSS and Hemoglobin C with sickling HbSC bands can be identified by gel electrophoresis. Pathophysiology and Genetics Sickle-cell anemia is due to a missense mutation in the -globin chain of hemoglobin where the amino acid glutamic acid is replaced with the less polar amino acid valine at the sixth position of the chain .The adherence of two wild type -globin subunits with two mutant -globin subunits forms the hemoglobin S.Hemoglobin S can polymerise under low levels of oxygen causing distortion of red blood cells and destroying their elasticity.New red cells are quite elastic ( Kinney et al.1999). But as the cells sickle, they form a region of low oxygen concentration and more red blood cells sickle. Repeated sickling causes loss of this elasticity and the cells fail to return to their normal shape when oxygen concentration increases. These rigid red blood cells cause vessel occlusion and ischemia as they are unable to flow through narrow blood capillaries. Genetically, an autosomal recessive allele is responsible for sickle cell anemia. A child who receives the defective genes from both father and mother only develops the disease.A progeny who receives one defective and one healthy allele remains healthy.But such heterozygous individuals pass on the disease and is known as a carrier.Thus,if two carrier parents 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 respectively.This genetic defect is because of a single nucleotide in the A -T sequence of the -globin gene, which results in positionong of valine instead of glutamic acid at 6th position.Hemoglobin S with mutation are referred to as HbS, as against the normal adult HbA. The genetic disorder here is due to the codon mutation of a single nucleotide from a GAG to GTG sequence(Hebbel, 2000).This is a benign mutation and cause no apparent effects on the aecondary,tertiary or quarternary hemoglobin structure.But under low oxygen levels,causes the polymerization of of the HbS itself. A hydrophobic patch on the protein between the E and F helices is exposed by deoxy form of hemoglobin.The hydrophobic residues of the valine at position 6 of the beta chain in hemoglobin bind to the hydrophobic patch and cause hemoglobin S molecules to form fibrous precipitates. In heterozygous carriers for HbS sickling hemoglobin, the polymerization problems are minor. In homozygous individuals for HbS, the presence of long chain polymers of HbS distort the shape of the red blood cell (Hebbel, 2000).Carriers can also exhibit sickle cell symptoms if they are low of oxygen in situations like high altitudes or dehydration.In homozygous individuals vasocclusive events are a painful part of life. It is a fact that heterozygous carriers show strong resistance to malaria.The heterozygous gene is incompletely recessive and carriers have a few sickle red blood cells at all times that are possibly not enough to cause sickle symptoms, but enough to give resistance to malaria. This is sometimes referred to as heterozygous advantage. Sickle cell anemia is thus inherited from parents in much the same way as blood type, hair color and texture, eye color and other physical traits. The types of sicle cell hemoglobin a person has in the red blood cells depend upon what hemoglobin genes the person inherits from his parents. Treatment Treatment for sickle cell anemia includes the treatment of the various disease symptoms like Febrile illness,vasoocclusive pain crisis,chest crisis and other associated conditions.Children and patients with fever should be screened screened for bacteremia for the presence of bacterial pathogens in blood. Complete blood count, reticulocyte count and blood culture are mandatory. Younger children are treated with intravenous antibiotics while older children are managed at home with oral antibiotics. Children with previous bacteremic episodes should be hospitalized and monitored.Painful vaso-occlusive crises is typical of sickle cell anemia with intensely painful episodes. The frequency, severity, and duration of these crises vary and can be treated symptomatically with analgesics and opioid administration at regular intervals. For milder crises NSAIDS like diclofenac are effective.Severe crises patients require inpatient management for intravenous opioids and ptient controlled analgesia devices. Diphenhydramine has been found effective in treating itching associated with the opioid use. Management of Acute chest crisis is similar to vaso-occlusive crises in combination with a third generation cephalosporin like antibiotics.Oxygen supplementation is done in case of hypoxia.Blood transfusion and exchange transfusion is done if the pulmonary infiltrate worsens or the oxygen is depleted. Exchange transfusion 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.Hydroxyurea was the first approved drug for the causative treatment of sickle cell anemia and has been shown to decrease the number and severity of attacks (Charache et al,1995 ) achieved by reactivating fetal hemoglobin production in place of the hemoglobin S that causes sickle cell anaemia.But hydroxyurea has longterm risks.Gene therapy is under active investigations with research on Hemoglobin switching ,use of phytochemicals like Nicosan. Conclusion Carriers of the disease are advised to undergo genetic counseling before they plan for a child. Testing the unborn for the disease is done with blood sample or amniotic fluid. The classical view of sickle cell anemia explains the primary genetic defect namely the abnormal sickle hemoglobin that polymerizes when deoxygenated. The interaction of the red cells, damages, stimulations of the vascular endothelium and surrounding tissues and cells is of great interest that gives a hypothesis that the sticky, stiff, oxidizing sickle red cell is an irritant that provokes an inflammatory response as it obstructs flow. Thus, according to this view, the tissues are not only under-perfused, but also exposed to inflammatory cytokines, growth factors, and the actions of the activated cells that respond to and produce them. This also explains the role reperfusion injury plays in sickle pathophysiology and provides new insights that contribute to this broader view of the disease process (Orah S. Platt, 2000). Young reticulocytes periodically adhere to endothelial cells in the vascular beds of organs and cause a transient logjam of relatively rigid deoxygenating mature red cells.. As the obstruction eventually clears, the reperfusion pathophysiology plays out, escalating the likelihood of additional rounds of reticulocyte adhesion to the inflamed endothelium that is becoming increasingly decorated with large unyielding leukocytes (Orah , 2000). Current understanding of the pathophysiology of adult Acute chest crisis is limited but suggests that ACS may be a specific form of acute lung injury that can progress to the acute respiratory distress syndrome (ARDS) caused by multiple exogenous insults or triggers superimposed upon the genetic-based pathophysiology (Markt. gladwin, 1999). Works cited Castro, O. et al.1994. The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease. Blood. 84:643-649.[Abstract/FreeFullText] 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 Garner, C. et al.2000. 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Laboratory profile of sickle cell disease: a cross-sectional analysis. The Cooperative Study of Sickle Cell Disease. J. Clin. Epidemiol. 45:893-909.[Medline] Read More