Thalassemia

Overview

Disease characteristics

• Thalassemias are hereditary hemoglobin (Hb) disorders of α- or β-globin genes. Defects in these genes lead to abnormal hemoglobin and RBC structure and function.
• Presents as microcytic hypochromic anemia:
  • Mild cases can be asymptomatic.
  • Severe cases may lead to splenomegaly, hemolysis, and skeletal abnormalities.

Epidemiology

• Worldwide prevalence: 
  • α-Thalassemia: 5%; most common in Africa and Asia
  • β-Thalassemia: 3%; most common in the Mediterranean
• Equal incidence in men and women

Etiology

• Autosomal recessive disorder
• α-Thalassemia: 2 α genes (HbA₁ and HbA₂) = 4 alleles (αα/αα)
  • Chromosome 16: deletion error
  • 4 types of disease variations:
    • Minima: deletion of 1 α gene
    • Minor: deletion of 2 α genes (same chromosome = cis, opposite chromosomes = trans)
    • HbH disease: deletion of 3 α genes
    • Hb Barts: deletion of 4 α genes 
• β-Thalassemia: 1 β gene (HbB) = 2 alleles
  • Chromosome 11: 
    • Splicing mutation (β⁺: decreased expression) or
    • Nonsense mutation (β⁰: absent expression)
  • 2 types of disease variations:
    • Thalassemia minor: heterozygous, approximately 50% decreased synthesis
    • Thalassemia major: homozygous, no production of β globulin, increase in HbA₂(α₂δ₂) and HbF(α₂γ₂), no HbA

Pathophysiology

• Defective Hb formation: leads to Hb aggregation that damages RBC membranes
• Damaged RBCs undergo hemolysis, resulting in: 
  • Anemia
  • Pigmented gallstones
• Ineffective erythropoiesis (due to lack of normal Hb components) leads to: 
  • Anemia → high-output heart failure
  • Bone marrow expansion
  • Extramedullary hematopoiesis → hepatomegaly and/or splenomegaly
• Iron overload (from multiple transfusions to account for damaged native RBCs)
  • Compensatory increase in the GI uptake of iron
  • Endocrinopathies

Clinical Presentation

Diagnosis

Initial studies

• Take a full medical and family history (screen in high-risk areas).
• Order CBC with erythrocyte indices and peripheral blood smear.
• On CBC:
  • Hb → usually < 11 g/dL or < 6 g/dL in Cooley’s anemia
  • MCV → microcytic (< 70 fL) in thalassemias
  • MCH → low in thalassemias
  • Red-cell distribution width → not very useful in thalassemias (can be normal or elevated)
• On peripheral blood smear:
  • Target cells (most common)
  • Howell-Jolly body: blue spot in RBC (DNA remnant)
  • Anisocytosis: RBCs of unequal size
  • Inclusion bodies: seen only in hemoglobin H (HbH) disease (4 β aggregation)
  • Heinz bodies: red spot at the periphery of RBCs (denatured Hb)
  • Basophilic stippling
  • To recall the features seen on a peripheral blood smear of a patient with thalassemia, remember the mnemonic THAL:
    • Target cells (most common)
    • Howell-Jolly body
    • Anisocytosis
    • Low MCH, MCV, and Hb
• If hemolysis is suspected, order LDH:
  • If LDH is elevated and hemolysis is suspected, order a reticulocyte count: elevated in HbH disease.
• Order iron studies: normal in thalassemias, abnormal in other causes of anemia

Confirmatory studies

• If iron studies are normal, order Hb electrophoresis.
• Normal Hb electrophoresis studies show:
  • HbA: 95%
  • HbA₂: 3%–5%
  • HbF: minimal amount
  • No HbH or Hb Barts with normal Hb electrophoresis
• In α-thalassemia:
  • Minima: normal percentage of HbA and HbA₂
  • Minor (trait): normal percentage of HbA and HbA₂, but CBC shows anemia
  • HbH disease: β-tetrad (i.e., Hb electrophoresis will show only a β band)
  • Hb Barts: γ-tetrad (i.e., Hb electrophoresis will show only a γ band)
• In β-thalassemia
  • Minor: 
    • ↓ HbA (93%)
    • ↑ HbA₂ (5%)
    • ↑ HbF (2%)
  • Major: 
    • No HbA
    • ↑ HbF (90%)
    • ↑ HbA₂ (10%)
• Other ancillary studies:
  • X-ray will show osteopenia and skull with “hair on end” appearance.
  • An echocardiogram may show a reduction in the left ventricular ejection fraction.

Management

Minor α- and β-thalassemia

• Patients are usually asymptomatic and no chronic therapy is indicated.
• Periodic folate supplementation may be helpful during physiologic stress (e.g., pregnancy).
• Provide genetic counseling regarding risk to the offspring.

Cooley’s anemia and HbH disease

• Transfusions: 
  • Patients are transfusion dependent.
  • Target Hb level > 10 g/dL
  • Folate supplementation, if not transfused
• Splenectomy and cholecystectomy: 
  • Splenectomies reduce transfusion requirements.
  • Post-splenectomy vaccinations (encapsulated organisms)
    • Pneumococcal polyvalent
    • Haemophilus influenzae type b
    • Pneumococcal conjugate
  • Cholecystectomy to prevent recurrent gallstones
• Iron chelation:
  • Reduces serum iron levels
  • Deferoxamine (IV)
  • Deferiprone/deferasirox (oral formulations)
• Endocrine therapy:
  • Administer deficient hormones.
  • Bisphosphonates to prevent osteopenia and osteoporosis
  • Fertility agents
• Definitive therapy: allogeneic stem cell transplantation 
• Genetic counseling

Differential Diagnosis

The differential diagnosis includes other conditions associated with microcytic anemia or target cells.

• Iron-deficiency anemia: the other major cause of microcytic hypochromic anemia besides thalassemia. Patients may present with pallor and easy fatigability. Iron studies are required to obtain the diagnosis. Findings of the iron study will indicate decreased iron levels and an increased total iron-binding capacity. Treatment is with oral iron supplementation.
• Anemia of chronic disease (“anemia of chronic inflammation”): secondary to inflammatory, infectious, or malignant disease. Patients present with findings similar to those of iron deficiency, namely, pallor and easy fatigability. Iron studies will reveal low levels of serum iron and transferrin; however, ferritin levels will be normal or increased. Treatment is targeted toward resolving the underlying chronic disease.
• Liver disease: Target cells can be seen on the peripheral blood smear of patients with liver disease. These target cells, having a large and targetoid appearance, are formed due to excess membrane lipids.
• Post-splenectomy patients: Target cells and Howell-Jolly bodies appear in the peripheral blood smear of patients after splenectomy. Patients may also have a mild-to-marked increase in platelet count (thrombocytosis).