Thalassemia

Key Features

Essentials of Diagnosis

• Microcytosis out of proportion to degree of anemia

• Positive family history or lifelong personal history of microcytic anemia

• Normal or elevated red blood cell (RBC) count

• Abnormal RBC morphology with microcytes, hypochromia, acanthocytes, and target cells

• In beta-thalassemia, elevated levels of hemoglobin A₂ and F

General Considerations

• Hereditary disorders characterized by reduction in synthesis of globin chains (alpha or β), causing reduced hemoglobin synthesis and eventually hypochromic microcytic anemia

• Normal adult hemoglobin is primarily hemoglobin A, a tetramer of two alpha-chains and two beta-chains (alpha2beta2)

• Thalassemias are described as

  • Trait, when there are laboratory features without clinical impact

  • Intermedia, when there is a RBC transfusion requirement or other moderate clinical impact

  • Major, when the disorder is life-threatening

• Alpha-thalassemia syndromes are determined by the number of functional alpha-globin genes

  • Normal (four alpha-globin genes, normal hematocrit)

  • Silent carrier (three alpha-globin genes, normal hematocrit)

  • Alpha-thalassemia minor or trait (two alpha-globin genes, hematocrit 28–40%, mean cell volume [MCV] 60–75 fL)

  • Hemoglobin H disease (one alpha-globin gene, hematocrit 22–32%, MCV 60–70 fL)

  • Hydrops fetalis (0 alpha-globin genes, fatal in utero)

• Beta-thalassemia: Reduced beta-globin chain synthesis results in relative increase in proportions of hemoglobins A₂ and F compared with hemoglobin A, because beta-like globins (delta and gamma) substitute for missing beta-chains

• With reduced beta-chains

  • Excess alpha-chains precipitate, causing hemolysis

  • Bone marrow becomes hyperplastic, resulting in bony deformities, osteopenia, and pathologic fractures

Demographics

• Alpha-thalassemia occurs primarily in persons from southeast Asia and China and, less commonly, in blacks and persons of Mediterranean origin

• Beta-thalassemia affects persons of Mediterranean origin (Italian, Greek) and to lesser extent Asians and blacks

Clinical Findings

Symptoms and Signs

• Alpha-thalassemia silent carriers: asymptomatic

• Alpha-thalassemia trait: clinically normal with mild microcytic anemia

• Hemoglobin H disease

  • Chronic hemolytic anemia of variable severity

  • Pallor

  • Splenomegaly

• Hydrops fetalis

  • Only hemoglobin species made is called hemoglobin Bart's (γ4)

  • All four alpha-globin genes are deleted, no normal hemoglobin is produced and the affected fetus is stillborn

• Heterozygotes for beta-thalassemia (thalassemia minor): mild microcytic anemia

• Homozygotes for mild beta-thalassemia (thalassemia intermedia): chronic hemolytic anemia

• Homozygotes for major beta-thalassemia (thalassemia major)

  • Severe anemia requiring transfusion

  • Growth failure

  • Bony deformities (abnormal facial structure, pathologic bone fractures)

  • Hepatosplenomegaly and jaundice

Differential Diagnosis

• Iron deficiency anemia (thalassemia has lower MCV, normal iron studies, more normal RBC count, more abnormal peripheral blood smear at modest levels of anemia, and usually reticulocytosis)

• Other hemoglobinopathy (eg, sickle thalassemia, hemoglobin C disorders)

• Sideroblastic anemia

• Anemia of chronic disease

Diagnosis

Laboratory Tests

Alpha-thalassemia trait

• Mild or no anemia (hematocrit 28–40%) with strikingly ...