Megaloblastic anemia mak

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  1. 1. Megaloblastic anemia Dr Mohamid Afroz Khan Moderator-Dr Namrata Shetty
  2. 2. Differential Diagnosis of Macrocytic Anaemia Megaloblastic Anemia Vitamin B12 deficiency Folate deficiency Drug Induced anemia Non megaloblastic Anemia Excess alcohol consumption Liver disease Hypothyroidism Aplastic anemia Paraprotenemia(Myeloma) Pregnancy Neonatal period
  3. 3. Megaloblastic Anemia Megaloblastic anemias are associated with defective DNA synthesis and therefore, abnormal RBC maturation in the bone marrow (a nuclear maturation defect) However, the primary defect in DNA replication is usually due to depletion of thymidine triphosphate which leads to retarded mitosis, and therefore retarded nuclear maturation The depletion of thymidine triphosphate is usually due to a deficiency of vitamin B12 or folic acid
  4. 4. RNA synthesis is less impeded than is DNA synthesis hence cytoplasmic maturation and growth continues accounting for enlargement of the cells Increase in total erythropoiesis that may be up to three times normal Decreased rate of appearance of iron in the Hb of circulating erythrocytes and reticulocytopenia indicate ineffective erythropoiesis Increased destruction of defective erythroid precursors in the marrow, survival of circulating erythrocytes is short, indicating hemolysis
  5. 5. Absorption and metabolism of vitamin B12
  6. 6. Role of B12 and Folic acid in DNA synthesis
  7. 7. Causes of Cobalamine Deficiency 1. Reduced intake 2. Malabsorption Addisonian pernicious anemia, Gastrectomy, pancreatic dysfunction, Tropical sprue, Zollinger Ellison syndrome 3. Food cobalamine malabsorption- Atrophic gastritis with achlorhydria 4. Abnormal transport protein- Tco I/II deficiency 5. Inborn error of cobalamine metabolism 6. Acquired drug effects
  8. 8. Causes of Folate Deficiency 1. Reduced Intake 2. Malabsorption- coeliac disease, tropical spure, small bowel resection, malabsorption syndrome 3. Drug Effect- Sulfa drugs, MTX, OCP, anticonvulsants 4. Increased folate turnover- pregnancy progressive fall, breastfeeding, skin disease(psoriasis & exfoliation), haemodylasis, PNH, haemoglobinopathy, autoimmune haemolytic anemia
  9. 9. MORPHOLOGY Certain morphologic features are common to all forms of megaloblastic anemia Bone Marrow 1. The bone marrow is markedly hypercellular and contains numerous megaloblastic erythroid progenitors Megaloblasts are larger than normal erythroid progenitors (normoblasts) and have delicate, finely reticulated nuclear chromatin (indicative of nuclear immaturity) As megaloblasts differentiate and acquire Hb, the nucleus retains its finely distributed chromatin and fails to undergo the chromatin clumping typical of normoblasts
  10. 10. Bone marrow is hypercellular with cellularity > 95%
  11. 11. Comparison of normoblasts (left) and megaloblasts (right)B M aspirate Megaloblasts are larger, have relatively immature nuclei with finely reticulated chromatin, and abundant basophilic cytoplasm
  12. 12. Megaloblasts Bone Marrow
  13. 13. 2. The granulocytic precursors also demonstrate NC asynchrony, yielding giant metamyelocytes The giant metamyelocyte is the most characteristic of the abnormal granulocyte 3. Megakaryocytes may also be abnormally large and have bizarre multilobed nuclei. Automated parameter on cell counters the mean platelet volume is decreased and there is increased platelet anisocytosis, as detected by the platelet distribution width (PDW)
  14. 14. Giant metamyelocytes
  15. 15. Periphral Blood Smears Macrocytic anemias associated with magaloblastosis differs from nonmegaloblastic macrocytic anemia in that macro-ovalocytes and giant hypersegmented neutrophils in blood Pancytopenia is the rule Anemia is macrocytic with an elevated MCV and extreme degree of anisocytosis and poikilocytosis Microcytes are common
  16. 16. Basophilic stippling, multiple Howell-Jolly bodies, nucleated red cells with karyorrhexis and cabots ring may be seen Leucopenia is present Thrombocytopenia usually seen, rarely sufficiently severe to be responsible for bleeding Neurologic symptoms may be present in the absence of anemia Reticulocytopenia, increased S.Fe and elevated S.LDH
  17. 17. Hypersegmented neutrophils Earliest change in periphral blood even before devlopment of anemia Increased lobe size as well as number of nuclear segments Neutrophil hypersegmentation can be defined as the presence of neutrophils with six or more lobes or the presence of more than >3% of neutrophils with at least five lobes
  18. 18. Diagnosis of Cobalamin Deficiency Established by one of methods 1. Therapeutic trial 2. Serum cobalamin assay 3. Methylmalonic Acid and Homocysteine Assay 4. Deoxyuridine Suppression test 5. Serum holotranscobalamin
  19. 19. Therapeutic trial With the patient on a diet low in cobalamin and folate Parenteral physiologic dose of cobalamin (10 g/day) is given Optimal hematologic response indicates deficiency and consists of reticulocytosis beginning on the third or fourth day, reaching a peak on the seventh day Erythropoiesis becomes normoblastic by 2 days, and leukopoiesis becomes normal by 12 to 14 days. Within a week, leukocyte and platelet counts have returned to normal, and the Hb concentration begins to rise
  20. 20. Serum Cobalamin Assay Reference values are 200900 ng/L In megaloblastic anemia due to cobalamin deficiency, serum cobalamin is usually less than 100 ng/L Individuals with folate deficiency and mild cobalamin deficiency have borderline values between 100 and 200 ng/L as in pregnancy Microbiological assay (Euglena gracilis), Radioisotopic dilution chemiluminescence assays
  21. 21. Methylmalonic Acid and Homocysteine Assays Cobalamin coenzyme is essential for the isomerization of methylmalonate to succinate Urine excretion of increased amounts of methylmalonate is found in cobalamin deficiency Plasma levels of methylmalonic acid and homocysteine are increased Interpreted with caution in patients with chronic renal failure
  22. 22. Deoxyuridine Suppression Test Measures the ability of marrow cells in vitro to utilize deoxyuridine in DNA synthesis Normally, in marrow cells, the major source of thymidine for DNA is de novo synthesis from deoxyuridine, which requires intact cobalamin and folate enzymes Tritium-labeled thymidine (3H-Tdr), normal