Sickle cell disease

Pathophysiology & Genetics - A Sickle Situation

• Genetic Defect: Autosomal recessive point mutation in the β-globin gene (HBB).
  • A single base substitution replaces hydrophilic glutamic acid with hydrophobic valine.
  • This results in the formation of abnormal Hemoglobin S (HbS).
• Mechanism:
  • Under low O₂ conditions (e.g., infection, dehydration, acidosis), HbS polymerizes into rigid, insoluble fibers.
  • This deforms RBCs into a sickle shape, causing:
    • Vaso-occlusion: Blockage of microvasculature → ischemic pain, organ damage.
    • Hemolysis: Premature destruction (lifespan 10-20 days) → chronic anemia, jaundice.

⭐ Heterozygotes (HbAS, Sickle Cell Trait) are typically asymptomatic and exhibit resistance to Plasmodium falciparum malaria.

Clinical Features & Diagnosis - Spotting the Sickle

• Vaso-Occlusive Crisis (VOC): Hallmark of SCD.
  • Dactylitis: Swelling of hands/feet; often the first sign in infants.
  • Acute Pain: Excruciating pain in bones, chest (Acute Chest Syndrome), abdomen.
  • Stroke: High risk, even in children.
• Chronic Manifestations:
  • Functional Asplenia: ↑ risk of infection from encapsulated organisms (e.g., S. pneumoniae).
  • Avascular necrosis (hip, shoulder), leg ulcers, priapism.
• Diagnosis:
  • Screening: Newborn screening is standard.
  • Labs: Normocytic anemia, ↑ reticulocytes.
  • Confirmatory: Hb electrophoresis shows predominantly HbS.

⭐ Acute Chest Syndrome: A leading cause of death. Defined by a new pulmonary infiltrate on CXR plus fever, cough, or chest pain. Often triggered by infection or fat embolism from bone marrow.

Complications - The Vaso-Occlusive Fallout

• General: Chronic hemolysis → bilirubin gallstones (cholelithiasis), aplastic crisis (Parvovirus B19).
• Organ-Specific Damage:
  • Brain: Stroke (ischemic > hemorrhagic).
  • Lungs: Acute Chest Syndrome (ACS) - new infiltrate + fever/respiratory symptoms.
  • Kidney: Papillary necrosis → hematuria; renal medullary carcinoma.
  • Bone: Avascular necrosis (femoral/humeral head), osteomyelitis (📌 Salmonella > S. aureus).
  • Spleen: Autosplenectomy → ↑ risk of encapsulated bacteria (S. pneumo, H. flu, N. meningitidis).
  • GU: Priapism.

⭐ Exam Favorite: While S. aureus is the most common cause of osteomyelitis in the general population, Salmonella species are classically associated with osteomyelitis in patients with sickle cell disease.

Management - Taming the Crisis

• Acute Vaso-occlusive Crisis (VOC):
  • 📌 HOP to it: Hydration (IVF), Oxygen (if SpO₂ <94%), Pain control (opioids).
  • Vigorously search for and treat infectious triggers.
• Chronic Management & Prevention:
  • Hydroxyurea: ↑ HbF, reducing sickling and crisis frequency.
  • Folic acid supplementation (due to high RBC turnover).
  • Routine vaccinations (esp. S. pneumoniae, H. influenzae, N. meningitidis).
  • Transfusions for severe anemia or stroke prevention.

⭐ Hydroxyurea is a cornerstone of chronic management but can cause myelosuppression (neutropenia, anemia, thrombocytopenia), requiring regular blood count monitoring.

High‑Yield Points - ⚡ Biggest Takeaways

• Autosomal recessive point mutation in the β-globin gene (glutamic acid to valine) causes HbS.
• Hallmarks are vaso-occlusive crises (VOC), causing severe pain, and chronic hemolytic anemia.
• Acute chest syndrome is the leading cause of death in adults; presents with fever, cough, and chest pain.
• Functional asplenia increases susceptibility to encapsulated organisms like S. pneumoniae.
• Aplastic crisis is most commonly precipitated by Parvovirus B19 infection.
• Hydroxyurea is the primary disease-modifying therapy; it works by increasing fetal hemoglobin (HbF).