Thalassemia: alpha vs beta

Alpha thalassemia

1. One gene deleted: silent carrier
   • Usually normal CBC or minimal microcytosis.
   • No clinical anemia.
2. Two genes deleted: alpha-thalassemia trait
   • Mild microcytic anemia, usually asymptomatic.
   • Can occur in cis form (--/αα), more important for reproductive risk, or trans form (-α/-α).
   • Hemoglobin electrophoresis may be normal, so molecular genetic testing may be needed.
3. Three genes deleted: HbH disease
   • Moderate to severe hemolytic microcytic anemia.
   • Excess beta chains form HbH (β4) after birth.
   • May cause jaundice, splenomegaly, gallstones, and episodic worsening with infection or oxidant stress.
4. Four genes deleted: Hb Bart hydrops fetalis
   • Usually fatal in utero or shortly after birth without highly specialized care.
   • Excess gamma chains form Hb Bart (γ4).
   • Can cause severe fetal anemia, hydrops fetalis, and significant maternal pregnancy complications.

Beta thalassemia

1. Beta-thalassemia trait/minor
   • One abnormal beta-globin gene.
   • Mild microcytic anemia or microcytosis only.
   • Classically, HbA2 is elevated on hemoglobin analysis.
   • No transfusions are usually needed.
2. Beta-thalassemia intermedia
   • Variable moderate anemia.
   • May not require regular transfusions, though transfusions can be needed during illness, pregnancy, surgery, or worsening anemia.
   • Complications may include splenomegaly, thrombosis, bone disease, pulmonary hypertension, and iron overload even without many transfusions.
3. Beta-thalassemia major, also called transfusion-dependent thalassemia
   • Severe anemia develops in infancy, typically after fetal hemoglobin declines at about 6 months.
   • Untreated disease causes poor growth, marrow expansion with skeletal changes, hepatosplenomegaly, and severe anemia.
   • Requires regular red-cell transfusions and prevention/treatment of iron overload.

Diagnosis

• Low hemoglobin, low MCV, and low MCH
• Target cells and variable anisopoikilocytosis on blood smear
• Red-cell count often relatively high for the degree of anemia
• Iron studies that are normal unless iron deficiency coexists

• Ferritin and iron studies to exclude iron deficiency
• Hemoglobin electrophoresis or HPLC
  • Beta-thalassemia trait: usually raised HbA2, sometimes raised HbF
  • Alpha-thalassemia trait: may have normal adult electrophoresis
• Genetic testing, especially for alpha-thalassemia and for reproductive counseling

Management

• Carrier/trait: usually reassurance, avoid unnecessary iron, and offer genetic counseling.
• Non-transfusion-dependent disease: individualized follow-up, folate when appropriate, surveillance for anemia-related and iron-related complications.
• Transfusion-dependent beta thalassemia: scheduled red-cell transfusions plus iron chelation to prevent iron accumulation in the heart, liver, and endocrine organs.
• Potentially curative options: allogeneic hematopoietic stem-cell transplant for selected patients. In the United States, the FDA has also approved the cell-based gene therapy exagamglogene autotemcel (Casgevy) for eligible people aged 12 years or older with transfusion-dependent beta thalassemia. CDC treatment guidance

Genetic counseling: the practical distinction

• If both parents have beta-thalassemia trait, each pregnancy has a 25% chance of beta-thalassemia major.
• For alpha thalassemia, reproductive risk is particularly high when one or both parents carry a cis two-gene deletion (--/αα). Two such parents can conceive a fetus with Hb Bart hydrops fetalis.