Differentials
Congenital dyserythropoietic anaemia (CDA)
SIGNS / SYMPTOMS
There may be no differences in signs and symptoms, but it is likely there will be no family history of thalassaemia, and the child may not be of an ethnic background noted for beta-thalassaemia (Mediterranean, Southeast Asian, Middle Eastern).
INVESTIGATIONS
Anaemia in CDA is usually macrocytic, as opposed to the microcytic anaemia found in classical beta-thalassaemia syndromes. Haemoglobin analysis in CDA may show an elevated Hb F, but most of the haemoglobin is Hb A, whereas in beta-thalassaemia 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 hyperbilirubinaemia. Anaemia is profound, and hepatosplenomegaly and skeletal changes may develop in infancy. Moderate icterus is almost always present.
INVESTIGATIONS
Anaemia in PK deficiency is usually not microcytic as in thalassaemia. The peripheral smear is remarkable for the very large number of nucleated red cells; fewer such cells are seen in beta-thalassaemia. Haemoglobin analysis in PK deficiency shows a preponderance of Hb A, whereas in beta-thalassaemia major or intermedia there is minimal to no Hb A.
Mild iron deficiency anaemia
SIGNS / SYMPTOMS
The clinical presentation of beta-thalassaemia trait is similar to that of mild iron deficiency anaemia. Symptoms of anaemia may be mild or absent in both. In iron deficiency anaemia, 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-thalassaemia trait, fasting serum iron and transferrin saturation are usually normal, whereas both are low in iron deficiency states. There is a mild microcytic anaemia 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 anaemia.
Haemoglobin analysis will confirm the diagnosis of beta-thalassaemia trait.
Alpha-gene mutations (alpha-thalassaemia major, haemoglobin H disease, haemoglobin Constant Spring)
SIGNS / SYMPTOMS
Alpha-thalassaemia 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.
Haemoglobin H disease may have the same clinical presentation as beta-thalassaemia intermedia, with chronic moderate to severe microcytic anaemia, elevated bilirubin levels, and propensity for developing gallstones.
Haemoglobin Constant Spring has the same phenotype as alpha-thalassaemia major.
INVESTIGATIONS
The clinical presentation of alpha-thalassaemia major and haemoglobin Constant Spring are quite different from that of beta-thalassaemia. Haemoglobin H disease may be distinguished based on the haemoglobin analysis, which will show some haemoglobin A and a specific band of haemoglobin H (tetramer of 4 beta-globin chains).
Haemolytic anaemia
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 anaemia is longstanding, beta-thalassaemia trait or intermedia may be considered in patients of the appropriate ethnicity.
INVESTIGATIONS
FBC will show normocytic anaemia with elevated mean corpuscular haemoglobin concentration (MCHC), whereas in beta-thalassaemia, the anaemia is microcytic and the MCHC is low. Direct antiglobulin test (Coombs') is important for differentiating immune from non-immune aetiologies of haemolysis. Peripheral smear review is important in identifying underlying cause.
Anaemia 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-thalassaemia trait in such situations.
INVESTIGATIONS
The degree of anaemia is typically mild to moderate (Hb 80-110 g/L [8-11 g/dL]) and normocytic. WBC and differential and platelet count may be elevated due to associated infection or inflammation. In beta-thalassaemia trait, the anaemia is microcytic and the haemoglobin analysis is abnormal with elevated haemoglobin A2 and often haemoglobin F as well.
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