Thalassemia (α & β)

Summary

Thalassemia is an inherited (autosomal recessive) microcytic, hypochromic anemia caused by decreased production of either the α-globin chains (α-thalassemia) or β-globin chains (β-thalassemia) of hemoglobin. It is one of the most common genetic disorders worldwide and is highly prevalent in Mediterranean, Middle Eastern (including Jordan), African, and Southeast Asian populations.

• α-thalassemia → caused by gene deletion on chromosome 16 (4 α-genes total).
• β-thalassemia → caused by point mutations on chromosome 11 (2 β-genes total).
• Severity depends on how many globin genes are affected.
• Clinical spectrum ranges from a silent carrier to a transfusion-dependent child with severe anemia and skeletal deformities.
• Diagnosis: CBC (low MCV, normal/high RBC count, normal RDW), peripheral smear (target cells), Hb electrophoresis, and genetic testing.
• Management: chronic transfusion + iron chelation in severe disease; the only cure is hematopoietic stem cell transplant.

Definition and Genetics

Normal adult hemoglobin (HbA) is made of 2 α-chains and 2 β-chains (α₂β₂). Thalassemia is a quantitative defect — the globin chains produced are normal in structure but reduced in amount, leading to:

• Decreased hemoglobin per RBC → hypochromia and microcytosis.
• Imbalance of chains → excess of the unaffected chain precipitates inside the RBC → ineffective erythropoiesis and hemolysis.

Genetic basis:

• α-thalassemia: 4 α-globin genes (2 on each chromosome 16). Caused mainly by gene deletions.
• β-thalassemia: 2 β-globin genes (1 on each chromosome 11). Caused mainly by point mutations (splicing/promoter defects).
• Inheritance is autosomal recessive.

Pathophysiology

The same general mechanism applies to both types, but the excess chain determines the clinical picture.

• β-thalassemia: ↓ β-chains → excess α-chains precipitate inside RBC precursors in the bone marrow → cell membrane damage → ineffective erythropoiesis (cells die before leaving the marrow) + peripheral hemolysis.
• α-thalassemia: ↓ α-chains → excess β or γ chains form abnormal tetramers:
  • Excess β₄ = HbH (adult).
  • Excess γ₄ = Hb Barts (fetal).
• Chronic anemia → kidney releases erythropoietin → massive marrow expansion → skeletal deformities and extramedullary hematopoiesis (hepatosplenomegaly).
• Increased intestinal iron absorption + repeated transfusions → iron overload (the main cause of mortality in β-thalassemia major).

Look for target cells, nucleated RBCs, and Pappenheimer bodies on the smear as the morphologic footprint of this process.

Alpha Thalassemia

α-thalassemia is caused by deletion of one or more of the 4 α-globin genes. Because the α-chain is needed for fetal Hb (HbF, α₂γ₂) and adult Hb (HbA, α₂β₂), severe forms present in utero or soon after birth.

Key high-yield points:

• Cis deletion (both α-genes lost from the same chromosome) → Asian population → dangerous for offspring.
• Trans deletion (one α-gene from each chromosome) → African population → safer.
• In α-thalassemia, Hb electrophoresis is normal in trait/minor (since α-chain is needed for HbA, HbA2, and HbF — all are decreased proportionately).

Beta Thalassemia

β-thalassemia results from point mutations (splicing or promoter defects) in one or both β-globin genes on chromosome 11. Two key alleles:

• β⁺ = reduced β-chain production.
• β⁰ = absent β-chain production.

Symptoms appear after 6 months of age, because HbF (α₂γ₂) — which does not need β-chains — is replaced by HbA (α₂β₂) during the first months of life. Once HbF declines, the β-chain defect is unmasked.

Clinical Features

Clinical signs depend on severity of anemia and the body's compensatory response (marrow expansion + iron overload).

• General signs of anemia: pallor, fatigue, poor exercise tolerance, tachycardia.
• Hemolysis signs: jaundice, scleral icterus, dark urine, pigment gallstones.
• Marrow expansion (only in severe forms):
  • Frontal bossing and prominent maxilla → "chipmunk facies".
  • "Crew-cut" / "hair-on-end" appearance on skull X-ray.
  • Pathologic fractures, growth retardation.
• Extramedullary hematopoiesis → hepatosplenomegaly.
• Iron overload (from chronic transfusions + ↑ intestinal absorption): bronze skin, cardiomyopathy, diabetes, cirrhosis, hypogonadism, hypothyroidism, hypoparathyroidism — the same picture as secondary hemochromatosis.

Diagnosis

Workup is stepwise: CBC → peripheral smear → iron studies → Hb electrophoresis → genetic testing.

1. CBC

• ↓ Hb / Hct (severity varies).
• ↓ MCV (microcytic, often very low < 70 fL).
• Normal or HIGH RBC count — a key clue that distinguishes thalassemia from iron deficiency.
• Normal RDW (the cells are uniformly small).

2. Peripheral smear

Classic findings: target cells, microcytic-hypochromic RBCs, basophilic stippling, teardrop cells, nucleated RBCs, and reticulocytosis.

3. Iron studies

Normal or elevated iron, ferritin, and transferrin saturation (because iron is not the problem). This excludes iron deficiency.

4. Hemoglobin electrophoresis (HPLC)

• β-thalassemia minor → ↑ HbA2 (>3.5%), slight ↑ HbF.
• β-thalassemia major → ↑↑↑ HbF, ↑ HbA2, very little HbA.
• α-thalassemia minor/trait → normal electrophoresis (diagnosis is by exclusion or genetic testing).
• HbH disease → fast-migrating HbH (β₄) band.

5. Genetic testing

Required to confirm α-thalassemia and for prenatal diagnosis / genetic counseling.

Quick reference comparing thalassemia with the other key microcytic anemias: IDA vs α-thal minor vs β-thal minor.

Differential Diagnosis

Any patient with a low MCV is essentially in this differential. The fastest discriminator is the RBC count and RDW:

• Iron deficiency anemia (IDA) → low RBC count, high RDW, low ferritin. (Most common pitfall — don't give iron to a thalassemia patient!)
• Anemia of chronic disease → ↑ ferritin, ↓ TIBC.
• Sideroblastic anemia / lead poisoning → ↑ iron, ringed sideroblasts; basophilic stippling.

Mentzer index = MCV ÷ RBC count.

• < 13 → Thalassemia
• > 13 → Iron deficiency

Management

Treatment is matched to the disease severity.

Minor / Trait

• No treatment needed.
• Genetic counseling for the patient and their partner is the most important step (especially in Jordan, where consanguineous marriage is common).
• Do NOT give iron unless iron deficiency is proven by labs — iron supplementation can worsen iron overload.

Intermedia

• Folic acid supplementation.
• Occasional transfusions for symptomatic anemia or growth failure.
• Monitor ferritin; chelate if iron overload develops.

Major (and severe HbH disease)

1. Chronic transfusion therapy — maintain Hb > 9–10 g/dL to suppress erythropoiesis and prevent skeletal deformities.
2. Iron chelation — start once ferritin > 1000 ng/mL or after ~10–20 transfusions. Agents:
   • Deferoxamine (IV/SC).
   • Deferasirox (oral, first-line).
   • Deferiprone (oral).
3. Folic acid daily (increased demand from chronic hemolysis).
4. Splenectomy — if transfusion requirement rises sharply or hypersplenism develops. Vaccinate against encapsulated organisms first (S. pneumoniae, H. influenzae, N. meningitidis).
5. Allogeneic hematopoietic stem cell transplant (HSCT) — the only curative therapy; best results in young patients with HLA-matched sibling donor.
6. Luspatercept — newer drug that improves erythroid maturation; reduces transfusion need in adults.
7. Gene therapy — emerging option for transfusion-dependent patients.

Complications

• Iron overload (hemosiderosis) — from chronic transfusions + increased intestinal absorption:
  • Cardiac: dilated cardiomyopathy, arrhythmias, heart failure (most common cause of death).
  • Endocrine: diabetes mellitus, hypogonadism (delayed puberty), hypothyroidism, hypoparathyroidism.
  • Liver: cirrhosis, hepatocellular carcinoma.
  • Skin: bronze/grey pigmentation.
• Skeletal: bone deformity (chipmunk facies, frontal bossing), pathologic fractures, osteopenia, growth retardation.
• Hematologic: chronic hemolysis → pigment gallstones, folate deficiency, aplastic crisis (parvovirus B19).
• Hypersplenism: worsening anemia, leukopenia, thrombocytopenia.
• Transfusion-related: alloimmunization, infections (HBV, HCV, HIV — risk now low with screening), allergic reactions.
• Extramedullary hematopoiesis — paravertebral masses can compress the spinal cord (rare but high-yield).
• Increased thrombotic risk, especially after splenectomy.

Mnemonics

Key Points for Exams