BIOCHEMICAL REMEDY FOR SICKLE CELL DISEASE - Project Topics & Materials - Gross Archive

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Sickle cell disease is a hereditary condition that result from a single glutamic acid to valine substitution of position 6 of the beta globin polypeptide chain. It is inherited as an autosomal recessive trait. This glutamic aicd being subsituted by valine is characterized by drastic reduction in the solubility of sickle cell haemoglobin (Hbs) when deoxygenated. Under these conditions, the Hbs molecules polymerize to form long crystalline intracellular mass of fibres which are responsible for the deformation of the bioconcave disc shaped erythrocyte into a sickle shape. First line clinical management of sickle disease involves the use of hydroxyurea (hydroxycarbamide) folic acid, amino acids supplementation and antimalarial prophylaxis to manage the condition and blood transfusions to stabilize the patients’s haemoglobin level. Alternative therapy involves the use of phytomedicines such as Nicosan preparation, ciklavit  preparation and Zanthoxylum-Zanthoxyloids. Phytomedicine have been proven to not only reduce crisis but also reverse sickling. The immense benefits of these phytomedicine include their efficacy, less expensive to procure and absence of side effects.

1.0    INTRODUCTION    -    -    -    -    -    -    1
1.1    Epidemiology of Sickle Cell Disease    -    -    -    2
1.2    Aetiology of Sickle Cell Disease    -    -    -    -    3
1.3    Pathophysiology of Sickle Cell Disease    -    -    5
1.4    Pathogenesis of Sickle Cell Disease    -    -    -    6
1.5    Clinical Features of the Homozygous Disease    -    7
1.5.1 Vaso-oclusive Crisis    -    -    -    -    -    -    7
1.5.2 Visceral Sequestration Crisis    -    -    -    -    8
1.5.3 Aplastic Crisis    -    -    -    -    -    -    -    9
1.5.4 Haemolytic Crisis    -    -    -    -    -    -    10
1.5.5 Other Clinical Features    -    -    -    -    -    10
1.6    Investigation    -    -    -    -    -    -    -    11
HAEMOGLOBIN (Hbs)    -    -    -    -    -    12
2.1    Homozygous and Heterozygous (Hbs)    -    -    13
2.2    Abnormalities Associated with (Hbs)    -    -    -    14
2.3    Mechanism of Sickling in Sickle-cell Disease    -    15
2.4    Sticky Patches and Formation of
Deoxyhaemoglobin Fibre    -    -    -    -    -    15
2.5    Sickle-Cell Trait Provides Resistance to Malaria -    16
2.6    Diagnosis of Sickle-Cell Haemoglobin (Hbs)    -    18
2.6.1 Sickling Test    -    -    -    -    -    -    -    18
2.6.2 Electrophoresis    -    -    -    -    -    -    18

3.1    Prophylaxis    -    -    -    -    -    -    -    19
3.2    Other Drug Treatment    -    -    -    -    -    20
3.3    Transfusion    -    -    -    -    -    -    -    22
3.3.1 Kinds of Transfusion    -    -    -    -    -    23
3.3.2 Complications of Transfusion Therapy    -    -    24
3.4    Bone Marrow or Stem Cell Transplantation    -    26
3.5    Nicosan Preparation    -    -    -    -    -    -    28
3.6    Zanthoxylin-Zanthoxybides    -    -    -    -    28
3.7    Ciklavit Preparation    -    -    -   
4.1    Conclusion
4.2    Recommendation
References    -   
Sickle-cell disease is a hereditary condition that results from a single glutamic acid to valine substitution at position 6 of the beta globin polypeptide chain. It is inherited as an autosomal recessive trait. Homozygotes only produce abnormal beta chain that make haemoglobin S (Hbs, termed SS), and this result in the clinical syndrome of sickle-cell disease. Heterozygotes produce a mixture of normal Haemoglobin (HbA) and abnormal haemoglobin (HbS), and this result in the clinically asymptomatic sickle cell trait. Normal haemoglobin is comprised of two alpha and two non-alpha globin chains. Alpha globin chains are produced throughout life, so, severe mutations may cause intrauterine death. Production of non-alpha chains varies with age; fetal haemoglobin (HbF-/yy) has two gamma chains while the predominant adult haemoglobin (HbA-/) has two beta chains. Thus disorders affecting the beta chains do not present until after 6-months of age (Davidson, 2010).
The homozygous sickle cell anaemia (HbSS) is the most common severe syndrome while the double heterozygote conditions of HbSC and HbSthal also cause sickling disease. HbS is insoluble and forms crystal when exposed to low oxygen tension. Deoxygenated sickle haemoglobin polymerizes into long fibres, each consisting of seven intertwined double strands with cross-linking (Davidson, 2010).

1.1    Epidemiology of Sickle Cell Disease
Sickle cell disease is a hereditary condition. Several different variants of sickle cell disease exist (Charache et al, 1999). It is found in a number of ethnic groups mainly in populations that originate from tropical regions. In the UK, approximately 5000 people largely from the Afro-Caribbean population have sickle cell disease. The heterozygote frequency is over 20% in tropical Africa. In black American population sickle cell trait has a frequency of 80%. Individuals with sickle cell trait are relatively resistant to the lethal effects of falciparum malaria in early childhood; the high prevalence in equatorial Africa can be explained by the selectival survival advantage it confers in areas where falciparium malaria is endemic. However, homozygous patients with sickle cell anaemia do not have corresponding greater resistance to falciparium malaria (Hoffbrand and Moss, 2008).

1.2    Aetiology of Sickle Cell Disease
Patients with sickle cell disease have a different form of haemoglobin. Patients with the most common variant of sickle cell disease have haemoglobin S(HbS). Normal haemoglobin is usually designated HbA. Haemoglobin S has valine substituted for glutamic acid as the sixth amino-acid in the -polypeptide compared with normal haemoglobin. Patients with homozygous haemoglobin S develop many problem including anaemia (Charache et al, 1999).
Sickle cell trait is where a person is a carrier of the gene (heterozygous for sickle cell gene). These people are usually asymptomatic. Sickle cell trait provides some protection from malaria and is more common in those ethnic groups originating from geographical area that are endemic for malaria. The offspring from a father with the trait and a mother with the trait has a one in four chance of having sickle cell disease.
AA    =    Normal
AS    =    Sickle cell trait (heterozygous)
SS    =    Sickle cell disease (homozygous)
Inheritance patterns in sickle cell trait and sickle cell disease (Charache et al., 1999).
1.3    Pathophysiology of Sickle Cell Disease
The membrane of red cells containing haemoglobins is damaged, which leads to intracellular dehydration. In addition, when the patient blood is deoxygenated, polymerization of haemoglobins occurs, forming a semisolid gel. These two process had to the formation of crescent-shaped cells known as sickle cells. Sickle cells are less flexible than normal cell (flexibility allows normal cells to pass through the microcirculation). The inflexibility leads to impaired blood flow through the microcirculation, resulting in local tissue hypoxia (Beris et al., 2008). Anaemia result from an increased destruction (haemolysis) of red cells in the spleen. Some red cells in patient with sickle cell disease contains fetal haemoglobin (HbF). These cells do not become sickle cells (Beris et al, 2008).
1.4    Pathogenesis of Sickle Cell Disease
When haemoglobin S is deoxygenated, the molecules of haemoglobin polymerise to form pseudocrystalline structures known as tactoids. These distort the red cell membrane and produce characteristics sickle-shaped cell. The polymerization is reversible when reoxygenation occurs. The distortion of the red cell membrane, however, may become permanent and the red cell irreversible sickled. The greater the concentration of sickle-cell haemoglobin in the individual cell, the more easily tactoids are formed, but this process may be enhanced or retarded by the presence of other haemoglobin. Thus, the abnormal haemoglobin C variant participates in the polymerization more readily than haemolgobin A whereas haemoglobin F strongly inhibits polymerization (Hoffbrand and Moss, 2008).
1.5    Clinical Features of the Homozygous Disease
Clinical features are of severe haemolytic anaemia punctuated by crisis. The symptoms of anaemia are often mild in relation to the severity of the anaemia because HbS gives up oxygen (O2) to tissue relatively easily compared with HbA, its O2 dissociation curve being shifted to the right.
The clinical expression of HbSS is very variable, some patient having an almost normal life free of crises but others develop severe crises even as infants and many die in early childhood or a young adults. Crises may be vaso-occlusive, viscereal, aplastic or hemolytic.

1.5.1 Vaso-Occlusive Crisis
These are the most frequent and are precipitated by such factors as infection, acidosis, dehydration or deoxygenation (eg. altitude, operations, obstetric delivery, stasis of the circulation, exposure to cold, violent exercise). Infarcts causing severe pain occur in the bones (lips, shoulders and vertebrae are commonly affected). The hand-foot syndrome (painful dactylitis caused by infarcts of the small bones) is frequently the first presentation of the disease and may lead to digit of varying lengths. Soft tissue affected include the lungs and the spleen. The most serious vaso-occlusive crisis is of the brain (a stroke occurs in 7% of all patients) or spinal cord. Transcranial Doppler ultrasonography detect abnormal blood flow indicative of arterial stenosis. This predicts for strokes in children. These can be largely prevented by regular blood transfusions in these cases.

1.5.2 Visceral Sequestration Crisis
These are caused by sickling within organs and pooling of blood often with a severe exacerbation of anaemia. The acute sickle chest syndrome is a feared complication and the most common cause of death after puberty. Patients present with dyspnoea, falling arterial PO2, chest pain and pulmonary infiltrates on chest x-ray. Treatment is with analgesia, oxygen, exchange transfusion and ventilator support if necessary. Hepatic and girdle sequestration crises and splemic sequestration may lead to severe illness requiring exchange transfusions. Splemic sequestration is typically seen in infants and presents with an enlarging spleen, falling haemoglobin and abdominal pain. Treatment is with transfusion and patients must be monitored at regular intervals as progression may be rapid. Attacks tend to be recurrent and splenectomy is often required.
1.5.3 Aplastic Crisis
These occur as a result of infection with parvovirus or from folate deficiency and are characterized by a sudden fall in haemoglobin, usually requiring transfusion. They are characterized by a fall in reticulocytes   as well haemoglobin.
1.5.4 Haemolytic Crisis
These are characterized by an increase rate of haemolysis with a fall in haemoglobin but rise in reticulocytes and usually accompany a painful crisis (Davidson, 2010).
1.5.5 Other Clinical Features
Ulcers of the lower legs are common as a result of vascular stasis and local ischaemia. The spleen is enlarged in infancy and early childhood but later is often reduced in size as a result of infarcts (antosplenectomy). Pulmonary hypertension detected by Doppler echocardiography and an increase tricuspid regurgitate velocity is common and increase the risk of death. A proliferative retinopathy and priapism are other complications. Chronic damage to the liver may occur through microinfarcts. Pigment (bilirubin) gallstones are frequent. The kidney are vulnerable to infarctions of the medulla with papillary necrosis. Failure to concentrate urine aggravates the tendency to dehydration and crisis and nocturnal enuresis is common. Osteomyelitis may also occur usually from Salmonella spp (Davidson, 2010).

1.6    Investigations
Patient with sickle cell disease have a compensated anaemia, usually around 60-80g/L. The blood film shows sickle cells, target cells and features of hyposplenism. A retculocytosis is present. The presence of HbS can be demonstrated by exposing red cells to a reducing agent such as sodium dithionite; HbA gives a clear solution, whereas HbS polymerises to produce a turbid solution. This form the basis of emergency screening tests before surgery in appropriate ethnic groups but cannot distinguish between sickle-cell trait and disease. The definitive diagnosis requires haemoglobin electrophoresis to demonstrate the absence of HbA, 2-20% HbF and the predominance of HbS. Both parents of the affected individual will have sickle-cell trait (Hoffbrand and Moss, 2008).


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