Sickle Cell Disease (SCD)
Sickle cell disease (SCD) is a collection of genetic blood disorders in which abnormal levels of hemoglobin, called hemoglobin S (HbS), occur. Hemolytic anemia and vaso-occlusion occur when RBCs become crescent or sickle-shaped and do not circulate through blood vessels efficiently.Types of Sickle Cell Disease
1. Sickle Cell Anemia (HbSS): A homozygous condition in which one is born with two HbS alleles.
2. Sickle Cell Trait (HbSA): Heterozygous disorder; often asymptomatic, but sometimes confers some immunity to malaria. Possible side effect: Painless hematuria due to papillary necrosis of the renal tubules.
3. Hemoglobin SC Disorder (HbSC): inherited from one HbS and one HbC allele.
4. Hemoglobin C Disease (HbCC): Caused by a point mutation in the ß-globin gene, which replaces glutamic acid with lysine.
Genetics of Sickle Cell Disease
1. Inheritance Pattern:
Sickle cell disease is autosomal recessive, meaning one needs to have two mutated copies of the ß-globin gene (one from each parent) to develop it.
2. Location of Mutation:
The mutation occurs on chromosome 11, a site for the gene that encodes the ß-globin subunit of hemoglobin.
Epidemiology of Sickle Cell Disease
1. Demographics:
Sickle cell disease is common among people of African descent.
It also occurs in areas where malaria is or was endemic, since HbS offers partial protection against malaria.
2. Risk Factors:
A family history of sickle cell trait or disease.
Pathophysiology of Sickle Cell Disease
Normal Hemoglobin Structure:
Normal hemoglobin (HbA) is made up of two -globin and two ß-globin units, which combine to form a soluble tetramer.
Mutant Hemoglobin (HbS):
The mutation in the ß-globin gene in SCD switches valine for glutamic acid at position 6 of the ß-globin chain. This creates HbS, which is poorly soluble in low-oxygen conditions.
RBCs in the shape of sickles: HbS polymerizes and spins RBCs into sickles, resulting in:
Occlusion and micro-blocked arteries, causing pain and scarring.
Increased hemorrhage (shortened RBC life to 17 days, instead of 120).
Production of reactive oxygen species (ROS), worsening cell damage.
Clinical Severity:
Clinically, SCD can be clinically severe, and may depend on other hemoglobin mutations (HbC, ß-thalassemia).
Sickle Cell Disease Clinical Features
2. Vaso-occlusive Crises (Anxiety Episodes): Short-term attacks of extreme pain, typically in the bones, joints, chest and abdomen, caused by stress, infection or temperature.
3. Dactylitis (Hand-Foot Syndrome): Stiff hands and feet — particularly in children.
4. Acute Chest Syndrome (ACS): Symptoms include fever, chest pain and pulmonary pleura, and are often caused by infection or embolism.
5. Cerebrovascular Accidents (Strokes): Involves the blockage of cerebral blood vessels, resulting in deficits.
6. Priapism: Excruciating long erections due to blocked blood flow.
7. Splenic Infarction: Causes functional asplenia by age 2-4, which increases vulnerability to infection.
8. Hematuria and renal failure after renal infarction.
2. Hemolytic Anemia: Less erythropoiesis and increased RBC depletion.
3. Growth Delay: Delays in childhood growth and development.
4. Renal Disease: A deterioration of kidneys that leads to decreased urine concentration leading to frequent urination and hematuria.
5. Neurologic Deficits: Stroke or TIAs that cause mental or motor impairment.
6. Infections: Higher vulnerability to infection, especially with capsulated organisms:
Pneumococcus (eg, sepsis and meningitis).
Salmonella species (common osteomyelitis).
Physical Examination and Imaging
1. Physical Exam Findings:
Splenomegaly: Spleen enlargement early in the course of the disease, followed by functional asplenia.
Bleeding: Due to hemolysis and increased bilirubin.
Pallor: Resulting from anemia.
Tenderness of Bone/Joint: Because of vaso-occlusive lesions and avascular necrosis.
2. Radiological Imaging:
Chest X-ray: If there is acute chest syndrome with pulmonary infiltrates.
MRI: Used to detect brain ischemia in stroke.
3. Diagnostic Studies
Newborn Screening:
In many jurisdictions, they are required to be screened – typically through high-performance liquid chromatography (HPLC), DNA analysis, or isoelectric focusing.
4. Laboratory Studies:
CBC: Low hemoglobin and hematocrit, elevated reticulocyte count.
Peripheral Blood Smear:
Sickle cells and Howell-Jolly bodies (nuclear residues in RBCs, evidence of functional asplenia).
Fetal HbF levels tend to be slightly elevated.
5. Differential Diagnosis:
Beta-thalassemia: Characterised by microcytic anemia (lower RBC count) and lack of sickled cells on the smear.
Treatment of Sickle Cell Disease
2. Medical Management:
Adequate care during emergencies (hydration, oxygen, pain management).
Hydroxyurea: Stimulates HbF levels, preventing painful crises and hospital stays.
Exchange transfusions: used in extreme emergencies to lessen sickle cell count.
3. Surgical Treatment:
Hematopoietic stem cell transplant (HSCT): The only curative treatment, though not common.
1. Functional Asplenia: Increased vulnerability to bacterial infections, due to depletion of the spleen.
2. Aplastic Crisis: Caused by parvovirus B19 infection or splenic sequestration.
3. Chronic Lung Disease and Pulmonary Hypertension: Associated with acute chest syndrome.
4. Renal Disease: May result in an inability to concentrate urine, leading to frequent urination and hematuria
5. Retinopathy: Caused by a blocked retinal artery.
6. Cardiomyopathy: Most often left-sided diastolic dysfunction caused by anemia, hypoxemia, and elevated cardiac output.
7. Cholelithiasis: Gallstones caused by prolonged hemolysis.
8. Sickle Hepatic Crisis: Enlargement of the liver and increased mortality, particularly in the womb.
Conclusion
Sickle cell disease is an incurable, lifelong illness that must be managed appropriately. Early detection, supportive care and prevention can improve quality of life and lessen complications. Treatment advances, such as stem cell transplants, have the potential to cure some patients.
Genetics of Sickle Cell Disease
1. Inheritance Pattern:
Sickle cell disease is autosomal recessive, meaning one needs to have two mutated copies of the ß-globin gene (one from each parent) to develop it.
2. Location of Mutation:
The mutation occurs on chromosome 11, a site for the gene that encodes the ß-globin subunit of hemoglobin.
Epidemiology of Sickle Cell Disease
1. Demographics:
Sickle cell disease is common among people of African descent.
It also occurs in areas where malaria is or was endemic, since HbS offers partial protection against malaria.
2. Risk Factors:
A family history of sickle cell trait or disease.
Pathophysiology of Sickle Cell Disease
Normal Hemoglobin Structure:
Normal hemoglobin (HbA) is made up of two -globin and two ß-globin units, which combine to form a soluble tetramer.
Mutant Hemoglobin (HbS):
The mutation in the ß-globin gene in SCD switches valine for glutamic acid at position 6 of the ß-globin chain. This creates HbS, which is poorly soluble in low-oxygen conditions.
RBCs in the shape of sickles: HbS polymerizes and spins RBCs into sickles, resulting in:
Occlusion and micro-blocked arteries, causing pain and scarring.
Increased hemorrhage (shortened RBC life to 17 days, instead of 120).
Production of reactive oxygen species (ROS), worsening cell damage.
Clinical Severity:
Clinically, SCD can be clinically severe, and may depend on other hemoglobin mutations (HbC, ß-thalassemia).
Sickle Cell Disease Clinical Features
Acute Events:
1. Anemia: The disease is caused by the pre-release of sickled RBCs.
1. Anemia: The disease is caused by the pre-release of sickled RBCs.
2. Vaso-occlusive Crises (Anxiety Episodes): Short-term attacks of extreme pain, typically in the bones, joints, chest and abdomen, caused by stress, infection or temperature.
3. Dactylitis (Hand-Foot Syndrome): Stiff hands and feet — particularly in children.
4. Acute Chest Syndrome (ACS): Symptoms include fever, chest pain and pulmonary pleura, and are often caused by infection or embolism.
5. Cerebrovascular Accidents (Strokes): Involves the blockage of cerebral blood vessels, resulting in deficits.
6. Priapism: Excruciating long erections due to blocked blood flow.
7. Splenic Infarction: Causes functional asplenia by age 2-4, which increases vulnerability to infection.
8. Hematuria and renal failure after renal infarction.
Chronic Events:
1. Chronic Pain: Because of organ degeneration and repeated vaso-occlusive episodes.
1. Chronic Pain: Because of organ degeneration and repeated vaso-occlusive episodes.
2. Hemolytic Anemia: Less erythropoiesis and increased RBC depletion.
3. Growth Delay: Delays in childhood growth and development.
4. Renal Disease: A deterioration of kidneys that leads to decreased urine concentration leading to frequent urination and hematuria.
5. Neurologic Deficits: Stroke or TIAs that cause mental or motor impairment.
6. Infections: Higher vulnerability to infection, especially with capsulated organisms:
Pneumococcus (eg, sepsis and meningitis).
Salmonella species (common osteomyelitis).
Physical Examination and Imaging
1. Physical Exam Findings:
Splenomegaly: Spleen enlargement early in the course of the disease, followed by functional asplenia.
Bleeding: Due to hemolysis and increased bilirubin.
Pallor: Resulting from anemia.
Tenderness of Bone/Joint: Because of vaso-occlusive lesions and avascular necrosis.
2. Radiological Imaging:
Chest X-ray: If there is acute chest syndrome with pulmonary infiltrates.
MRI: Used to detect brain ischemia in stroke.
3. Diagnostic Studies
Newborn Screening:
In many jurisdictions, they are required to be screened – typically through high-performance liquid chromatography (HPLC), DNA analysis, or isoelectric focusing.
4. Laboratory Studies:
CBC: Low hemoglobin and hematocrit, elevated reticulocyte count.
Peripheral Blood Smear:
Sickle cells and Howell-Jolly bodies (nuclear residues in RBCs, evidence of functional asplenia).
Fetal HbF levels tend to be slightly elevated.
5. Differential Diagnosis:
Beta-thalassemia: Characterised by microcytic anemia (lower RBC count) and lack of sickled cells on the smear.
Treatment of Sickle Cell Disease
1. Lifestyle and Prophylactic Treatments:
Folic acid supplementation per day for RBC production.
Antibiotics — Penicillin until 5 years to avoid infection.
Pneumococcal vaccination to defend against sepsis from enclosed organisms.
Folic acid supplementation per day for RBC production.
Antibiotics — Penicillin until 5 years to avoid infection.
Pneumococcal vaccination to defend against sepsis from enclosed organisms.
2. Medical Management:
Adequate care during emergencies (hydration, oxygen, pain management).
Hydroxyurea: Stimulates HbF levels, preventing painful crises and hospital stays.
Exchange transfusions: used in extreme emergencies to lessen sickle cell count.
3. Surgical Treatment:
Hematopoietic stem cell transplant (HSCT): The only curative treatment, though not common.
4. New Treatments
Phytochemicals (the chemical compounds found in Nigerian medicinal plants:. Two molecules, Phenanthrene-5,6-dione and Luteolin, exhibited particularly high binding affinities and stability relative to existing compounds.
Gene therapies to correct the genetic disorder and thus could be a paradigm-shifting cure. Gene therapy is a huge step from symptom management to treating the disease itself.
Complications of Sickle Cell Disease
1. Functional Asplenia: Increased vulnerability to bacterial infections, due to depletion of the spleen.
2. Aplastic Crisis: Caused by parvovirus B19 infection or splenic sequestration.
3. Chronic Lung Disease and Pulmonary Hypertension: Associated with acute chest syndrome.
4. Renal Disease: May result in an inability to concentrate urine, leading to frequent urination and hematuria
5. Retinopathy: Caused by a blocked retinal artery.
6. Cardiomyopathy: Most often left-sided diastolic dysfunction caused by anemia, hypoxemia, and elevated cardiac output.
7. Cholelithiasis: Gallstones caused by prolonged hemolysis.
8. Sickle Hepatic Crisis: Enlargement of the liver and increased mortality, particularly in the womb.
Conclusion
Sickle cell disease is an incurable, lifelong illness that must be managed appropriately. Early detection, supportive care and prevention can improve quality of life and lessen complications. Treatment advances, such as stem cell transplants, have the potential to cure some patients.
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