Thalassemia, Alpha

INTRODUCTION

Background: Alpha thalassemia, the most prevalent of all thalassemias, is the deficient or absent production of alpha-globin synthesis. Normally, alpha-globin chains bind with beta-globin chains to form the tetramer aa/bb in hemoglobin A. The imbalance of alpha- and beta-globin chains creates the pathology in thalassemia. The alpha thalassemic genetic abnormality primarily affects Southeast Asian and Mediterranean populations. However, the genetic trait is found in 30% of asymptomatic African Americans. The condition results in a variety of clinical syndromes depending on the degree of alpha chain deletion.

Pathophysiology: Normal adult hemoglobin contains a tetramer of globin chains a₂/b₂. Two conditions exist in the red blood cell when the alpha-globin synthesis decreases or is absent altogether. Intracellular precipitation of unmatched beta chains form inclusion bodies, causing damage to red blood cell precursors in the marrow and ineffective erythropoiesis.
Diminished hemoglobinization of individual red cells results in hypochromia and microcytosis.

The alpha-globin genes are duplicated on the short arm of chromosome 16. Each individual carries 4 separate loci, 2 from the paternal chromosome and 2 from the maternal chromosome. This results in 4 possible genotypes, each resulting in a different clinical syndrome.

Table 1. Alpha-Globin Genotypes and Clinical Syndromes

Frequency:
　

• In the US: The most common genotype in American blacks is -a/aa, with a prevalence of 30%. Hydrops fetalis and hemoglobin H are rare in blacks due to the low incidence of --/aa; the homozygous alpha+ thalassemia, a-/a-, is found in approximately 2-3%.

• Internationally: The highest frequency occurs in Southeast Asia and Africa, where as many as 30% of the general population have the condition. Other areas of increased incidence include Italy, the Middle East, Greece, North Africa, and the Mediterranean.

CLINICAL

History: Clinical courses and physical findings are different for each of the 4 genotypes. Concomitant beta chain hemoglobinopathies and beta thalassemia alter the clinical course.

• Silent carrier: Clinical symptoms and physical findings are not present.

• Homozygous alpha+ thalassemia (a-/a-) or heterozygous alpha0 thalassemia (--/aa): Clinical symptoms do not exist. This is diagnosed by incidental laboratory abnormalities (microcytosis) and family studies to characterize a relative.

• Hemoglobin H disease (--/a-)

• Chronic hemolytic anemia

• Splenomegaly occurs by age 1 year, with progression to jaundice and hepatosplenomegaly.

• Skeletal changes due to expanded erythropoiesis in the marrow affect one third of patients.

• Transfusions are not necessary unless concomitant illness exists.

• Acquired, not inherited, cases are observed in myeloproliferative diseases (eg, acute myelogenous leukemia, erythroleukemia, refractory sideroblastic anemia, acute lymphocytic leukemia).

• Hemoglobin Barts or hydrops fetalis (--/--)

• Premature infant or death in utero

• Pallor

• Edematous friable placenta

• Massive hepatomegaly secondary to extramedullary hematopoiesis

WORKUP

Lab Studies:
　

• Trait -a/aa

• Hemoglobin is within the reference range.

• Reticulocyte count is within the reference range.

• Mean corpuscular volume (MCV) is 75-85 fL.

• Mean corpuscular hemoglobin (MCH) is 26 pg.

• Alpha1 thalassemia minor

• Hemoglobin is within the reference range.

• Reticulocyte count is within the reference range.

• MCV is 65-75 fL.

• MCH is 22 pg.

• Hemoglobin H disease

• Hemoglobin is 7-10 g/dL.

• Reticulocyte count is 5-10%.

• MCV is 55-65 fL.

• MCH is 20 pg.

• The peripheral blood smear shows small misshapen red cells, hypochromia, microcytosis, and targeting.

• Brilliant cresyl blue stain demonstrates hemoglobin H inclusion bodies.

• Hydrops fetalis
• Hemoglobin is 4-10 g/dL.
• MCV is 110-120 fL.

  　

• The peripheral blood smear shows severe anisopoikilocytosis, severe hypochromia, and nucleated red blood cells.

• Alpha thalassemia combined with sickle cell anemia causes a higher hemoglobin concentration and improved red blood cell survival. The alpha gene deletion is associated with improved red cell deformability, but the improved rheologic benefits often are overcome by the greater viscosity of a higher hematocrit. Clinically, this is observed as a greater number of painful vaso-occlusive pain crises with the combination of alpha thalassemia and sickle cell disease. Interestingly, however, the incidence of stroke is lower than compared to sickle cell disease alone.

Imaging Studies:

• Imaging studies are not useful in these disorders.

Other Tests:
　

• Hemoglobin electrophoresis will separate hemoglobin into different types. Hemoglobin Barts is elevated at birth in patients with alpha thalassemia. For example, in hemoglobin H disease, 20-40% hemoglobin Barts is present; however, in the silent carrier alpha thalassemia condition, only 1-2% hemoglobin Barts with low and normal-to-decreased amounts of hemoglobin A₂ are present. Hemoglobin electrophoresis generally is not sufficiently sensitive to diagnose silent carrier alpha thalassemia.

• The imbalance between the quantity of alpha and beta chains initially was used to define the thalassemias. Beta-to-alpha synthetic ratios are altered in both alpha and beta chain thalassemias. Increasing ratios are observed in alpha2 thalassemia, alpha1 thalassemia, and hemoglobin H disease, respectively. Tests are performed by incubation of cells with radiolabeled amino acid and subsequently separating alpha- and beta-globin chains using urea carboxymethyl cellulose (CMC) chromatography.

• Currently, genetic testing is used to establish the diagnosis in patients with a suggestive family history and/or hematologic findings suggestive of alpha thalassemia.

• Recombinant DNA technology can be diagnostic, but it generally is a research tool.

• Gene mapping

• Polymerase chain reaction (PCR)

• Restriction endonucleases

• Anti-L globin monoclonal antibodies

Procedures:
　

• Bone marrow aspiration and biopsy are not helpful in establishing the precise diagnosis and are not indicated unless other confounding problems exist.

Histologic Findings: Review of the peripheral blood smear may reveal target cells, microcytosis, hypochromia, and anisopoikilocytosis as a clue to the presence of a thalassemic syndrome. Most individuals with alpha2 thalassemia (trait) have only mild microcytosis, which can be differentiated from other common causes of microcytosis because these people have a serum iron and ferritin concentration within the reference range.

TREATMENT

Medical Care:

• Avoid iron supplementation. It contributes to iron overload and does not affect hematologic values or cell morphology.

• Administer folate supplementation to provide adequate amounts of the vitamin for increased utilization resulting from the hemolytic process and high bone marrow turnover rate.

• Provide prompt attention to infection, especially in children who have had a splenectomy.

• Administer blood transfusions only if necessary.

• If chronic transfusion is needed (hemoglobin H disease), iron chelation therapy should be considered to avoid iron overloading.

Surgical Care:

• Hemoglobin H disease

• Perform a splenectomy if transfusion requirements are increasing.

• Surgical or orthodontic correction may be necessary to correct skeletal deformities of the skull and maxilla due to erythroid hyperplasia.

FOLLOW-UP

Prognosis:
　

• The prognosis is excellent for silent carriers.

• Because hydrops fetalis is incompatible with life, hemoglobin H (a-/--) is the most serious syndrome. The overall survival for hemoglobin H disease is variable; however, it generally is very good. Many patients survive into adulthood. However, some patients have a more complicated course and may not do as well.

Patient Education:
　

• Patients with a family history or known carrier state for alpha thalassemia gene mutations should obtain genetic counseling to determine genotype and risk to offspring. This especially is true in cases of suspected concomitant hemoglobinopathy.

MISCELLANEOUS

Medical/Legal Pitfalls:
　

• Alpha thalassemia frequently is mistaken for iron deficiency anemia because both disorders have microcytic red blood cells. Iron therapy is not required, and prolonged therapy may produce untoward effects from iron overload. Similarly, the procedures used to find a source of bleeding in patients with iron deficiency anemia have no value in patients with thalassemia. Measurements of serum iron and ferritin can provide laboratory evidence to exclude iron deficiency as the etiology for microcytosis