Paper I
Question
Lab diagnosis and Pathogenesis of β thalassemia major.
Answer
Pathogenesis
- Mutation in the beta-globin gene results in absent (β0) or markedly reduced (β+) beta-globin chain synthesis
- Unpaired excess alpha-globin chains precipitate within red cell precursors, forming inclusion bodies that damage the cell membrane
- This causes premature intramedullary destruction of erythroid precursors (ineffective erythropoiesis) and shortened survival of the few mature red cells released into the periphery (peripheral haemolysis)
- Severe ineffective erythropoiesis triggers massive compensatory marrow expansion, causing skeletal deformities (frontal bossing, maxillary overgrowth, “hair-on-end” skull X-ray appearance) and extramedullary haematopoiesis (hepatosplenomegaly)
- Chronic transfusion dependence leads to secondary iron overload (haemosiderosis), affecting the heart, liver, and endocrine glands
Laboratory diagnosis
- Complete blood count: Severe microcytic hypochromic anaemia (low MCV, MCH)
- Peripheral smear: Marked anisopoikilocytosis, target cells, microcytes, nucleated red blood cells, basophilic stippling
- Reticulocyte count: Elevated but blunted relative to the severity of anaemia (ineffective erythropoiesis)
- Haemoglobin electrophoresis/HPLC (definitive test): Absent or markedly reduced HbA, markedly elevated HbF (usually >90%), variable HbA2
- Serum iron studies: Elevated serum ferritin, low TIBC (iron overload)
- Skull X-ray: “Hair-on-end” appearance
- Family/genetic studies: Beta-globin gene mutation analysis; parents typically show thalassaemia trait (minor) with elevated HbA2