MEGALOBLASTIC ANAEMIA
It is caused by impaired DNA synthesis and is characterized by the distinctive abnormality in the hemopoietic precursors in bone marrow in which maturation of nucleus is delayed related to cytoplasm. Defective DNA synthesis is due to deficiency of vitamin B12 and folic acid.
ETIOLOGY:
I. Vitamin B12 deficiency
a. Inadequate dietary intake, e.g. strict vegetarians, breastfed infants.
b. Malabsorption
Gastric causes: Pernicious anemia, gastrectomy, congenital lack of intrinsic factor.
Intestinal causes: Tropical sprue, ileal resection, Crohn’s disease, intestinal blind loop syndrome, fish-tapeworm infestation.
II. Folate deficiency
a. Inadequate dietary intake, e.g. in alcoholics, teenagers, infants, old age, poverty.
b. Malabsorption, e.g. in tropical sprue, coeliac disease, partial gastrectomy, jejunal resection, Crohn’s disease.
c. Excess demand in
• Physiological: pregnancy, lactation, infancy.
• Pathological: malignancy, increased hematopoiesis, chronic exfoliative skin disorders, tuberculosis, rheumatoid arthritis.
d. Excess urinary folate loss, e.g. in active liver disease, congestive heart failure.
III. Other causes
a. Impaired metabolism, e.g. inhibitors of dihydrofolate reductase such as methotrexate and pyrimethamine; alcohol, congenital enzyme deficiencies.
b. Unknown etiology, e.g. in Di Guglielmo’s syndrome, congenital dyserythropoietic anemia, refractory megaloblastic anemia.
LAB DIAGNOSIS:
I. General Blood Parametres
- Decrease in RBC count and hemoglobin levels
- Increase in MCV and decrease in MCH.
- Reticulocyte count is normal
II. Peripheral Smear
- Red cells show anisopokilocytosis with presence of macrocytes and macrovalocytes, i.e. large oval RBCs.
- Presence of Howell-Jolly bodies, i.e. nuclear remnants left after nucleus is extruded and cabot rings (abnormal histone synthesis causes arginine rich histone to accumulate as rings in red cells)
- Neutrophil hypersegmentation is seen, i.e. greater than 5% of neutrophils more than 5 lobes or presence of atleast one sixed lobe cell.
III. Bone Marrow Examination
- It shows megaloblastic hyperplasia. Nuclei of erythroblasts are large with fine and open sieve like chromatin. Hemoglobinization of cytoplasm is of normal rate while nuclear maturation lag behind that of cytoplasm. This is known as nuclear-cytoplasmic asynchrony.
- Giant metamyelocytes and stab form are seen.
- Megakaryocytes may be large and abnormal.
IV. Biochemical Tests
- Serum vitamin B12 levels less than 200 pg/ml is indicative of vitamin B12 deficiency and serum folate levels less than 6 ng/ml indicates folate deficiency. Two methods are used to measure serum B12 microbiological and radioisotope assay.
- Radioisotope assay is the preferable method.
- Holotranscobalamin is considered active B12 and is the earliest biomarker for vitamin B12 deficiency.
- Elevated methylmalonic acid level indicates depletion of vitamin B12 stores.
- Isolated decreased levels of holotranscobalamin supports vitamin B12 deficiency and a combination of decreased Holotranscobalamin and increased methylmalonic acid and homocystine indicate a metabolically manifest B12deficiency.
- Schilling test:
It is useful for diagnosing intrinsic factor deficiency. It measure absorption of free radiolabelled vitamin B12. Radiolabelled vitamin B12 is given orally followed in 1 to 6 hours by 1000 mg of parenteral vitamin B12 which reduces uptake of radiolabelled vitamin B12 by liver. Absorbed radiolabelled vitamin B12 is excreted in urine, which is collected for 24 hours. The amount excreted is measured and the percentage of radiolabelled vitamin B12 is determined. If absorption is normal, i.e. ≥ 9% of the dose given appears in the urine. Reduced urinary excretion (if kidney function is normal) indicates inadequate vitaminB12 absorption.
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