Thalassemia

Chapter: Thalassemia
McMaster Section Editor(s): Mark Crowther
McMaster Author(s): Marissa Laureano, Rebecca Rosart, Madeleine Verhovsek
Additional Information

Definition, Etiology, PathogenesisTop

Thalassemia is a chronic inherited anemia, most commonly caused by reduced (+) or absent (o) synthesis of alpha-globin and/or beta-globin chains, the key protein components of the adult hemoglobin (Hb) tetramer, HbA (alpha2beta2) (Table 7.3-1).

The thalassemias comprise the most common monogenetic disorder worldwide, resulting from inheritance of mutant or deleted copies of globin genes (2 alpha-globin genes on each chromosome 16 [4 genes], one beta-globin gene on each chromosome 11 [2 genes]). Thalassemia prevalence is highest in populations from Southeast Asia, the Middle East, North and Central Africa, and Mediterranean regions.

The imbalanced production of globin chains leads to excess of the unaffected globin chain (eg, excess alpha-globin chains in beta thalassemia), which is unstable, resulting in ineffective intramedullary erythropoiesis (decreased Hb production) and extramedullary hemolysis (reduced red blood cell [RBC] survival).

Clinical FeaturesTop

The clinical spectrum of thalassemia is broad, ranging from clinically silent (no symptoms or signs) to severe, lifelong, potentially fatal anemia (Table 7.3-1). Disease manifestations may include:

1) Anemia.

2) Ineffective erythropoiesis stimulating extramedullary hematopoiesis and leading to proliferation of marrow cavities (eg, frontal bossing), hepatosplenomegaly, and increased risk of osteoporosis.

3) Chronic hemolysis (jaundice, gallstones, splenomegaly, leg ulcers, aplastic crisis).

4) Increased intestinal iron absorption with or without chronic blood transfusions can result in iron overload (cirrhosis, cardiomyopathy, endocrinopathies including hypopituitarism, diabetes mellitus, testicular or ovarian failure).

5) Affected offspring.

DiagnosisTop

In patients with suspected thalassemia perform complete blood count (CBC), peripheral blood film, and Hb electrophoresis. The diagnosis of thalassemia is confirmed with globin gene testing (molecular studies).

Diagnostic Tests

1. CBC: Low Hb level, low mean corpuscular volume (MCV).

2. Peripheral blood film: Microcytosis, hypochromia, target cells, basophilic stippling, nucleated RBCs.

3. Hb electrophoresis: Increased levels of hemoglobin A2 (HbA2) >3.5% (beta thalassemia), hemoglobin H (HbH) preparation (presence of HbH inclusion bodies suggests alpha thalassemia); this test does not detect alpha-thalassemia silent carrier or trait (ie, a defect in 1 or 2 out of 4 genes; molecular testing is needed) but does detect thalassemic-variant Hbs (eg, HbE, Hb Constant Spring, Hb Lepore).

4. Molecular genetic testing for thalassemia.

5. Other studies: Ferritin, zinc protoporphyrin IX (normal in thalassemia, elevated in iron-deficient erythropoiesis) to distinguish thalassemia from iron deficiency anemia or anemia of chronic disease.

Differential Diagnosis

Iron deficiency, anemia of chronic disease, enzymopathies (pyruvate kinase deficiency).

TreatmentTop

Management should be tailored to the patient’s disease phenotype and clinical manifestations. Patients with thalassemia trait usually have a mild anemia that does not require hematology consultation or treatment. 

1. General measures:

1) Referral to a hematology center for individuals with moderate or severe anemia.

2) Genetic counselling and prenatal family planning.

2. RBC transfusions: Patients with thalassemia major require chronic transfusions. A pretransfusion Hb level target of 90 to 105 g/L is used with the aim of preventing extramedullary hematopoiesis. Patients with non–transfusion-dependent thalassemia may require transfusion support during acute illness or physiologic stress (eg, pregnancy).

3. Iron overload: Ferritin levels should be measured on a regular basis. Liver and myocardial iron content should be assessed. This can be done through biopsy or, preferably, by specialized noninvasive techniques such as R2 or T2* magnetic resonance imaging (MRI). Patients with non–transfusion-dependent thalassemia can also develop iron overload through increased intestinal iron absorption. Chelators used in the treatment of iron overload include deferoxamine, deferiprone, and deferasirox. Therapy should be tailored to individual patient characteristics, including the area of iron deposition, preferred route of chelator administration, and coexisting medical concerns. Chelator therapy is considered at the time of starting chronic transfusions or detecting marked elevations of ferritin or iron stores in organs that exceed predefined levels.

4. Splenectomy: Possible indications include a significant increase in transfusion requirements, symptomatic splenomegaly, and hypersplenism causing cytopenias. Splenectomy should only be considered in carefully selected patients given the risks that include infection, hypercoagulability, and pulmonary hypertension.

5. Allogeneic hematopoietic stem cell transplantation: This can be considered in selected patients as a curative therapy.

Follow-UpTop

Consider the following investigations for patients with thalassemia major and intermedia:

1. Annual blood tests: CBC, reticulocyte count, creatinine, urine albumin-to-creatinine ratio, ferritin, calcium, vitamin D, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (women), testosterone (men), fasting glucose, liver enzymes, HIV testing, and hepatitis B and C serologic testing.

2. Imaging studies:

1) Hepatic and cardiac MRI: Performed as needed for the assessment of iron overload.

2) Bone mineral density: Performed at baseline, then every 1 to 5 years as needed.

3) Echocardiography: Performed at baseline, then every 1 to 3 years as needed.

3. Regular audiometry and ophthalmology evaluations in patients treated with iron chelators.

TablesTop

Table 7.3-1. Examples of genotype and phenotype correlation in thalassemia

 

Phenotype

Genotype

Clinical manifestations

Beta thalassemia

Trait/minor

Beta/beta+

Mild microcytic anemia

Intermedia (non–transfusion-dependent thalassemia)

Beta+/beta0

Beta+/beta+

Moderate to severe microcytic anemia

Major (transfusion-dependent thalassemia)

Beta0/beta0

Severe anemia; transfusion-dependent

Alpha thalassemia

Carrier

-alpha/alpha alpha

Asymptomatic; MCV normal or mild microcytosis

Trait/minor

--/alpha alpha

-alpha/-alpha

Mild anemia with microcytosis

Hemoglobin H disease

--/-alpha

Mild to moderate microcytic anemia

Bart hydrops fetalis

--/--

May be fatal in utero or neonatal period

MCV, mean corpuscular volume.

 

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