Sickle Cell Disease

 

• Background

  Pathophysiology

  • Autosomal recessive mutation in gene for the β-globin chain of haemoglobin.
  • Leads to an abnormally-shaped sickle cell haemoglobin (HbS), which (a) breaks down easily (haemolytic anaemia), (b) occludes the microvasculature, and (c) is sequestered in the liver and spleen, the latter causing splenic dysfunction and immunosuppression.
  • Lifespan of HbS is 20 days vs. 120 days of normal haemoglobin (HbA).
  • Homozygous (HbSS) inheritance causes sickle cell disease (aka sickle cell anaemia), while heterozygous (HbAS) sickle cell trait is usually an asymptomatic carrier state where most haemoglobin is HbA.
  • Other forms of sickle cell disease: HbS plus Hb C-E (compound heterozygotes), HbS plus thalassaemia.

  Epidemiology

  • 1/2500 UK newborns have sickle cell disease.
  • 1/200 UK Afro-Caribbeans have sickle cell disease, 1/10 are carriers.
  • Also increased risk if Middle Eastern, Mediterranean, or Indian.

• Signs and symptoms

  Chronic features:

  • Haemolytic anaemia: pallor, fatigue, jaundice.
  • Chronic pain.
  • Painful dactylitis: swelling of foot or hand bones. Often presents age 6-18 months, along with failure to thrive. Rare >2 years old.
  • Splenomegaly
  • Pigment gallstones from chronic haemolysis. Affects 70%.
  • High cardiac output: systolic flow murmur, cardiomegaly.

  Sickle cell crisis:

  • Triggers: cold, dehydration, stress, infection, pregnancy, acidosis, hypoxia.
  • Vaso-occlusive crisis: usually an acute painful crisis, affecting bones (especially limbs), abdomen, or chest. Other presentations: stroke, priapism, visual floaters (and eventual visual loss).
  • Acute chest syndrome: vaso-occlusion ± infection in lungs. Common in kids. Pneumonia-like presentation with chest pain (may be pleuritic), cough, SOB, fever, lung crackles, and tender ribs.
  • Aplastic crisis from parvovirus B19 infection.
  • Severe infection, especially from encapsulated bacteria.
  • Severe worsening of anaemia from increased sequestration or haemolysis.

  Pregnancy:

  • Worsens sickle cell disease.
  • High risk of obstetric complications: miscarriage, pre-eclampsia, IUGR, perinatal mortality.

• Investigations

  Diagnostic testing:

  • Usually neonatal, using Hb isoelectric focusing (IEF), capillary electrophoresis, or high-performance liquid chromatography (HPLC). Confirm diagnosis with 2 different methods.
  • In older patients, Hb analysis with electrophoresis or IEF. Confirm with HPLC or DNA test.

  Bloods:

  • Anaemia bloods: FBC (↓Hb, normal MCV), reticulocytes, blood film, iron studies.
  • U&E and LFTs for complications.

  Other investigations as indicated:

  • Lung: CXR (acute chest syndrome is defined by new infiltrates), lung function tests.
  • Neurological: CT/MRI, US.

• Management

  Preventative and lifestyle

  • Annual follow up to screen for complications. Includes transcranial doppler US in kids.
  • Avoid alcohol (dehydration triggers crisis) and smoking (triggers acute chest).
  • Lifelong antibiotic prophylaxis with phenoxymethylpenicillin (penicillin V).
  • Consider folic acid supplementation. High dose (5 mg) during pregnancy.
  • Extra immunizations: flu annually, hep B, pneumococcal every 5 years.
  • Consider medium or long-acting opiates for pain.

  Specific treatment

  Hydroxycarbamide (aka hydroxyurea) PO to reduce painful crises:

  • Mechanism: increases fetal Hb concentration, improves erythrocyte hydration.
  • Indication: recurrent crises.
  • Monitor with monthly FBC and reticulocytes.

  Crisis:

  • Supportive care including analgesia and cautious fluids.
  • Antibiotics if there is any sign of infection.

  Transfusion indications:

  • Symptomatic anaemia.
  • Life-threatening crises.
  • Stroke or sickle lung: partial exchange transfusions to keep HbS concentration down to prevent recurrence/progression. Also offer to those at high risk of stroke.
  • Iron chelation to prevent iron overload with regular transfusions.

  Surgery:

  • Hip replacement for avascular necrosis.
  • Splenectomy after 2 sequestration crises.
  • Cholecystectomy for recurrent gallstones.

  Bone marrow transplantation:

  • Used in severe, refractory disease.
  • Curative, but lack of donors.

• Complications and prognosis

  Chronic organ disease:

  • Bone: avascular necrosis of hip or shoulder.
  • Lung: sickle lung, pulmonary hypertension.
  • Brain: cognitive impairment, epilepsy.
  • Eyes: proliferative retinopathy, visual loss.
  • Kidney: CKD.

  Mortality:

  • One US study found most people with HbSS die before age 50.
  • Causes of death: stroke, sepsis, acute chest syndrome, pulmonary hypertension.