Differentials
Congenital dyserythropoietic anemia (CDA)
SIGNS / SYMPTOMS
There may be no differences in signs and symptoms, but it is likely there will be no family history of thalassemia, and the child may not be of an ethnic background noted for beta-thalassemia (Mediterranean, Southeast Asian, Middle Eastern).
INVESTIGATIONS
Anemia in CDA is usually macrocytic as opposed to the microcytic anemia found in classical beta-thalassemia syndromes. Hemoglobin analysis in CDA may show an elevated Hb F, but most of the hemoglobin is Hb A, whereas in beta-thalassemia major or intermedia there is minimal or no Hb A.
Pyruvate kinase (PK) deficiency
SIGNS / SYMPTOMS
Usually presents in the neonatal period with prolonged and severe hyperbilirubinemia. Anemia is profound, and hepatosplenomegaly and skeletal changes may develop in infancy. Moderate icterus is almost always present.
INVESTIGATIONS
Anemia in PK deficiency is usually not microcytic as in thalassemia. The peripheral smear is remarkable for the very large number of nucleated red cells; fewer such cells are seen in beta-thalassemia. Hemoglobin analysis in PK deficiency shows a preponderance of Hb A, whereas in beta-thalassemia major or intermedia there is minimal to no Hb A.
Mild iron deficiency anemia
SIGNS / SYMPTOMS
The clinical presentation of beta-thalassemia trait is similar to that of mild iron deficiency anemia. Symptoms of anemia may be mild or absent in both. In iron deficiency anemia, there may be a history/finding of blood loss (overt or occult, usually chronic) and/or a history of a diet poor in iron-rich foods. Otherwise the diagnosis must be made based on laboratory tests.
INVESTIGATIONS
In beta-thalassemia trait, fasting serum iron and transferrin saturation are usually normal, whereas both are low in iron deficiency states. There is a mild microcytic anemia in both, but the red cell distribution width (RDW) is usually elevated only in iron deficiency.[24] The Mentzer index has also been used to distinguish the two conditions.[25] An index >13 is highly suggestive of iron deficiency anemia.
Hemoglobin analysis will confirm the diagnosis of beta-thalassemia trait.
Alpha-gene mutations (alpha-thalassemia major, hemoglobin H disease, hemoglobin Constant Spring)
SIGNS / SYMPTOMS
Alpha-thalassemia major generally presents as hydrops fetalis at birth or may be diagnosed in the intrauterine period on routine ultrasound. These patients/families usually have Chinese ancestry.
Hemoglobin H disease may have the same clinical presentation as beta-thalassemia intermedia, with chronic moderate to severe microcytic anemia, elevated bilirubin levels, and propensity for developing gallstones.
Hemoglobin Constant Spring has the same phenotype as alpha-thalassemia major.
INVESTIGATIONS
The clinical presentation of alpha-thalassemia major and hemoglobin Constant Spring are quite different from that of beta-thalassemia. Hemoglobin H disease may be distinguished based on the hemoglobin analysis, which will show some hemoglobin A and a specific band of hemoglobin H (tetramer of 4 beta-globin chains).
Hemolytic anemia
SIGNS / SYMPTOMS
Presents with acute or subacute development of fatigue or jaundice, and may include orthostasis and mild splenomegaly. Common causes include autoantibodies, medications, and underlying malignancy. If the course is insidious and the anemia is longstanding, beta-thalassemia trait or intermedia may be considered in patients of the appropriate ethnicity.
INVESTIGATIONS
CBC will show normocytic anemia with elevated mean corpuscular hemoglobin concentration (MCHC), whereas in beta-thalassemia, the anemia is microcytic and the MCHC is low. Direct antiglobulin test (Coombs) is important for differentiating immune from nonimmune etiologies of hemolysis. Peripheral smear review is important in identifying underlying cause.
Anemia of chronic disease
SIGNS / SYMPTOMS
History of acute and chronic infections, autoimmune disorders, major trauma and surgery, and critical illness, with physical examination findings of the underlying disorder. May consider beta-thalassemia trait in such situations.
INVESTIGATIONS
The degree of anemia is typically mild to moderate (Hb 8-11 g/dL) and normocytic. WBC and differential and platelet count may be elevated due to associated infection or inflammation. In beta-thalassemia trait, the anemia is microcytic and the hemoglobin analysis is abnormal with elevated hemoglobin A2 and often hemoglobin F as well.
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