Megaloblastic Anemia

MA is associated with an abnormal appearance of the BM erythroblasts in which nuclear development is delayed and nuclear chromatin has a lacy open appearance. There is a defect in DNA synthesis, usually caused by deficiency of Vitamin B12 or Folate.

 Vit B12 deficiency

  1. Adult daily requirement for B12 is 1ug (normal mixed diet=10-15ug)
  2. It is present only in foods of animal origin eg meat, fish, eggs, milk, butter; it is absent from vegetables eg cereals and fruits, unless contaminated by microorganisms.
  3. Normal body stores of B12, largely in the liver with an enterohepatic circulation, are sufficient to last for 2-4 years.
  4. Dietary B12 after release from food and gastric (R) binder combines with intrinsic factor (IF) secreted by gastric parietal cells. IF-B12 complex attaches to ileal receptors and B12 is absorbed.
  5. Passive absorption (about 0.1% of oral B12) occurs through buccal, gastric and duodenal mucosae.
  6. Absorbed B12 attaches to transcobalamin II which carries B12 in plasma to the liver, bone marrow, brain and other tissues. Most B12 in plasma is attached to a second B12 binding protein, transcobalamin I, and is functionally inactive. Transcobalamin I is synthesized by granulocytes and their precursors.
  • The role of Vit B12 is conversion of 5-methyltetrahydrofolate to tetrahydrofolate which is required as substrate for folate polyglutamate synthesis.
  • The reaction which requires methionine synthase involves conversion of homocysteine to methionine which is converted to S-adenosylmethionine involved in numerous methylation reactions.
  • 5,10-methylenetetrahydofolate plays a key part in DNA synthases by adding as coenzyme for synthesis of thymidine monophosphate from deoxyuridine monophosphate.

Causes of B12 deficiency:
  1. Inadequate diet: vegans, infants born to B12 deficient mothers and breastfed by them.
  2. Malabsorption
    - gastric causes: Pernicious anemia; other organ specific autoimmune diseases (eg myoectema, thyrotoxicosis, vitiligo, Addison disease, hypothyroidism); gastrectomy, congenital IF deficiency
    - intestinal causes: bacterial colonization of small intestine, stagnant loop syndromes, congenital & acquired defects of the ileum
Folate deficiency and other macrocytic anemias
  • Occur in most foods, esp liver and green vegetables. Normal daily diet contains 200-250ug of 50% is absorbed.
  • Daily requirements are about 100ug; body stores are sufficient for 4 months.
  • Absorbed through the duodenum with conversion of all natural forms to 5-methyltetrahydrofolate.
Causes of deficiency:
  1. Poor dietary intake esp old age, institutions, poverty.
  2. Malabsorption in gluten-induced enteropathy, dermatitis herpetiformis, tropical sprue.
  3. Increased utilization eg pregnancy, lactation, prematurity, hemolytic anemia, severe chronic inflammatory and malignant diseases.
  4. Excess urinary folate loss in CHF, chronic dialysis (folate is loosely bound to plasma proteins)
  5. Drugs: anticonvulsants, sulphasalazine
  6. Mixed: liver disease, alcoholism

Other causes of MA:
  • Defects of B12 / folate metabolism
  • Antifolate drugs (inhibitors of DHF reductase)
  • Cytotoxic drug therapy
  • Inborn errors eg orotic anemia

Causes of macrocytosis
  • Alcohol
  • MCV is not usually as high as in severe MA
  • White cell & platelet counts are normal; red cells are circular rather than oval; hypersegmented neutrophils are absent; marrow is normoblastic

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