- Clinical science
Thalassemias are a heterogeneous group of hereditary blood disorders characterized by faulty globin chain synthesis resulting in defective hemoglobin, which can lead to anemia. Based on the defective globin chain, they are classified as either alpha or beta subtypes. Thalassemias are generally more frequent in areas where malaria is endemic; alpha thalassemias occur most commonly in patients of Asian or African origin, whereas beta thalassemias are predominant in patients of Mediterranean descent. Beta thalassemia can be further divided into a heterozygous minor and a homozygous major variant. The minor variant features only a low risk of hemolysis; however, the major variant presents with severe anemia as early as infancy and often causes growth retardation. The severity of alpha thalassemias varies as well, with significant anemia generally first arising with a deletion of three of the four alleles (HbH disease). Deletion of all four α-globin alleles (Hb Bart disease) is usually fatal in utero or shortly after birth. In all forms of thalassemia, insufficient erythropoiesis can lead to extramedullary hematopoiesis as well as bone marrow hyperplasia. The latter frequently results in periosteal reactions that are observed as the classic "hair-on-end" sign on skull radiographs. Diagnosis is confirmed via electrophoresis or DNA analysis. If a patient with thalassemia requires transfusion therapy, it is important to consider the possible development of secondary iron overload, which should be treated with chelating agents (e.g., deferoxamine).
- Beta thalassemia: most commonly seen in people of Mediterranean descent
- Alpha thalassemia: most commonly seen in people of Asian and African descent
- Thalassemia provides partial resistance against malaria.
Alpha thalassemia is common in Asia and Africa!
Epidemiological data refers to the US, unless otherwise specified.
- Cause: gene mutations
- Inheritance pattern: autosomal recessive
- Beta thalassemia minor (trait): one defective allele
- Beta thalassemia major (Cooley's anemia): two defective alleles
In a normal cell, the α-globin chains are coded by a total of four alleles. Thus, there are four forms of the disease. The severity of alpha thalassemia depends on the number of defective α-globin alleles.
- Silent carrier (minima form): one defective allele (-α/αα)
Alpha thalassemia trait (minor form)
- Two defective alleles (-α/-α or --/αα)
- Cis-deletion is common amongst Asian populations, whereas trans-deletions are more common in African populations
- Hemoglobin H disease: three defective alleles (--/-α) → results in excessive production of pathologically altered HbH
- Hemoglobin Bart disease (major form): four defective alleles (--/-‑) → results in excessive production of pathologically altered Hb Bart
Anemia results from a combination of inefficient erythropoiesis and increased hemolysis. The degree to which both mechanisms contribute to the severity of the disease depends on a patient's exact genotype.
Inefficient erythropoiesis → anemia
- Beta thalassemia minor and major: faulty β-globin chain synthesis → ↓ → ↑ γ-,δ-chains → ↑ HbF and ↑ HbA2
- Alpha thalassemia major (HbH disease) and Bart disease: faulty α-globin chain synthesis → ↓ → ↑ β-, γ-chains → ↑ HbH, ↑ Hb-Bart's
- In minor and minima forms, production of the affected chain is reduced, but enough is produced to prevent severe anemia.
- Increased hemolysis: One of the chains (either α or β) is reduced → compensatory overproduction of other chains → excess globin chains precipitate and form inclusions within RBCs → erythrocyte instability with hemolysis
- Anemia → ↑ erythropoietin → bone marrow hyperplasia and skeletal deformities
- Minor variant (heterozygous): unremarkable symptoms (low risk of hemolysis, rarely splenomegaly)
- Major variant (homozygous)
- Silent carrier: asymptomatic
- Alpha thalassemia trait: mild hemolytic anemia with normal RBC and RDW
- Hemoglobin H disease
- Hb-Bart's hydrops fetalis syndrome (most severe variant of alpha thalassemia)
Microcytic hypochromic anemia
- Iron deficiency anemia (IDA) usually presents with a low RBC count and a high RDW, whereas patients with thalassemia minor or thalassemia trait usually have a normal RDW and a higher RBC, and a relatively low MCV compared to IDA. IDA usually only becomes microcytic once the hemoglobin is less than 10 g/dL.
- Signs of hemolysis (↓ haptoglobin, ↑ LDH, ↑ indirect bilirubin, ↑ reticulocytes)
- Microcytic hypochromic anemia
- Blood smear: target cells; , teardrop cells
- Bone marrow biopsy: reactive hyperplasia
- Confirmatory tests
- Skeletal deformities; (e.g., high forehead, prominent zygomatic bones and maxilla) can be seen on all imaging modalities.
- X-ray: hair-on-end (“crew cut”) sign
Family history plays an important role in diagnosing patients with clinically silent thalassemia. The possibility of thalassemia in these patients may only be investigated once a family member is diagnosed with a more severe form!
Minor and minima variants
- Usually no therapy required
- Supplementation of iron or folic acid may be indicated in some patients.
Major variants and hemoglobin H disease
- Curative: allogeneic stem cell transplantation
- Symptomatic treatment