Sickle cell disease, common in individuals of African descent, is an autosomal recessive genetic disorder characterised by the production of abnormal, sickle-shaped haemoglobin S, leading to recurrent vaso-occlusive crises and commonly identifiable on peripheral blood smear.
Description
Sickle Cell Disease (SCD) is a genetic condition characterised by the production of an abnormal form of haemoglobin, called haemoglobin S (HbS). The sickling of red blood cells results in vaso-occlusive crises and increased haemolysis, leading to anaemia. It’s part of the group of disorders known as haemoglobinopathies.
Pathogenesis
SCD arises from a single base mutation in the beta-globin gene (HBB) that results in a substitution of valine for glutamic acid at the sixth position of the beta-globin chain of haemoglobin. This creates HbS, which under conditions of low oxygen tension, polymerises into long, insoluble fibres that distort the red blood cells into a sickle shape. The sickled cells obstruct small blood vessels, causing acute painful crises and long-term damage to organs.
Subtype
- HbSS Disease: The most severe form of SCD, occurs when a child inherits copies of the haemoglobin S gene from both parents.
- SCD: Hb SS (homozygous) – Results in the most severe anaemia. It occurs when a child inherits copies of the haemoglobin S gene from both parents.
- Sickle cell-hemoglobin C disease: Hb SC results in mild anemia
- Sickle cell-α thalassemia: Hb S-α thal results in severe anemia
- Sickle cell-β thalassemia: Hb S-β thal results in mild to severe anemia
- Sickle cell trait: Hb SA (heterozygous gene carrier)
- Normal: Hb AA
Epidemiology, Risk Factors & Associations
- Highest prevalence in Sub-Saharan Africa, where up to 25% of the population may carry the sickle cell trait (HbAS).
- The disease is associated with a shortened lifespan.
- Increased risk of infection, particularly with encapsulated bacteria (Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis and Salmonella typhi), due to autosplenectomy.
Clinical Features
- Vaso-occlusive crises: Painful episodes caused by sickled red blood cells blocking blood flow.
- Anaemia: Characterised by fatigue, pallor and increased cardiac output.
- Jaundice: Due to increased haemolysis.
Complications
- Acute chest syndrome: A serious lung disease caused by infarction and infection. Also includes infarction of bony thoracic cage.
- Stroke: Resulting from sickle cells blocking cerebral blood vessels.
- Chronic kidney disease: Due to repeated renal infarction.
Pathological Features
Histopathology
- Macroscopic: Autopsy findings typically demonstrate enlarged, congested spleen and liver.
- Microscopic: Red blood cells appear as sickle shapes.
Serology
- Positive for HbS on haemoglobin electrophoresis.
Biochemistry
- Increased levels of lactate dehydrogenase and bilirubin due to haemolysis.
Radiological Features
General Features
- Characteristically demonstrates evidence of infarcts in various organs due to vaso-occlusion.
- Frequently seen osteopaenia, medullary expansion, and cortical thinning in long bones on plain radiographs due to red marrow hyperplasia.
XR
- Sunburst pattern of periosteal reaction in the skull due to marrow hyperplasia.
- Crew-cut or hair-on-end appearance (rare) and widened diploic space on skull radiographs due to marrow hyperplasia.
- Fish-mouth vertebrae – biconcave endplates on spinal radiographs representing marrow hyperplasia with bone softening
- H-shaped vertebrae – central endplate depressions on spinal radiographs representing small infarcts of the endplates
- Autoinfarcted spleen – may appear as calcified mass in left upper quadrant
- Diametaphyseal infarction – lucent or sclerotic serpiginous/geographic foci
- Epiphyseal infarctions (avascular necrosis) – Most common in humeral & femoral heads. Sclerosis, subchondral fracture, coxa magna
CT
- Non-contrast: May show evidence of infarcts in the brain and other organs.
- Contrast-enhanced: Liver and spleen may be enlarged. Autoinfarcted spleen may appear as calcified mass in left upper quadrant.
MRI
- Bone infarction: Marrow oedema with thin rim of enhancement around non-enhancing serpignious low signal intensity foci. Double-line sign – alternating bright and dark T2 serpiginous foci of chronic infarctions throughout medullary cavities & epiphyses.
- Osteomyelitis: Geographic, irregular marrow enhancement with contrast
- Red marrow hyperplasia: Bright yellow marrow is replaced by low T1 and intermediate T2 signal in nearly all long bones, with epiphyses and apophyses last to revert. Seen in chronic anaemia.
PET
- Tc-99m Sulfur Colloid: For confirmation of extramedullary haematopoiesis.
Grading and Staging
- WHO Functional Classification for Sickle Cell Disease: Classifies patients into four classes based on symptoms and complications.
Diagnosis
Diagnosis is confirmed by identification of HbS on haemoglobin electrophoresis.
Differential Diagnosis
- Thalassemia: Mediterranean descent, target cells on peripheral smear, confirmed with haemoglobin electrophoresis.
- Autoimmune haemolytic anaemia: Positive direct Coombs test, increased reticulocytes.
Management
- Supportive care: Includes pain management, hydration, and treatment of infections.
- Disease-modifying treatment: Hydroxyurea, blood transfusions, and stem cell transplantation.