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Causes of meghlaboblastic anemia point wise

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Here are the causes of megaloblastic anemia, organized point-wise:

Causes of Megaloblastic Anemia

The common theme across all causes is impaired DNA synthesis, leading to defective nuclear maturation and ineffective hematopoiesis.

A. Vitamin B₁₂ (Cobalamin) Deficiency

1. Decreased Intake
  • Inadequate diet
  • Strict vegetarianism / veganism (B₁₂ found only in animal products)
2. Impaired Absorption
  • Intrinsic factor (IF) deficiency:
    • Pernicious anemia (autoimmune destruction of gastric parietal cells → no IF)
    • Gastrectomy (total or partial)
  • Malabsorption states:
    • Diffuse intestinal disease (e.g., lymphoma, systemic sclerosis)
    • Ileal resection or ileitis (terminal ileum is the site of B₁₂ absorption)
    • Crohn's disease
3. Competitive / Parasitic Uptake
  • Fish tapeworm infestation (Diphyllobothrium latum)
  • Bacterial overgrowth in blind loops and diverticula of the bowel

B. Folic Acid Deficiency

1. Decreased Intake
  • Inadequate diet (most common cause of folate deficiency)
  • Chronic alcoholism (poor diet + impaired absorption)
  • Infancy (especially with goat's milk feeding)
2. Impaired Absorption
  • Malabsorption states
  • Intrinsic intestinal disease (e.g., celiac disease, tropical sprue)
  • Drugs: anticonvulsants (phenytoin), oral contraceptives
3. Increased Loss
  • Hemodialysis (folate is dialyzable)
4. Increased Requirement
  • Pregnancy
  • Infancy (rapid growth)
  • Disseminated cancer
  • Markedly increased hematopoiesis (e.g., hemolytic anemias)
5. Impaired Utilization
  • Folic acid antagonists (e.g., methotrexate, trimethoprim, pyrimethamine)

C. Unresponsive to Vitamin B₁₂ or Folate Therapy

  • Metabolic inhibitors of DNA synthesis and/or folate metabolism:
    • Methotrexate (dihydrofolate reductase inhibitor)
    • Hydroxyurea (ribonucleotide reductase inhibitor)
    • 5-Fluorouracil
    • Cytarabine (Ara-C)
    • 6-Mercaptopurine
  • These drugs cause megaloblastic changes independent of B₁₂/folate levels

D. Other / Rare Causes

  • Nitrous oxide (N₂O) abuse — inactivates vitamin B₁₂ irreversibly
  • Transcobalamin II deficiency — congenital defect in B₁₂ transport
  • Orotic aciduria — inborn error of pyrimidine synthesis
  • Thiamine-responsive megaloblastic anemia — rare genetic syndrome
  • Acute megaloblastic anemia — can occur rapidly with N₂O exposure or intensive care patients on total parenteral nutrition without folate supplementation
Key mechanism: B₁₂ and folate are both required for thymidine synthesis (a DNA base). Deficiency → deranged DNA synthesis → delayed/blocked cell division → large, abnormal cells (megaloblasts) with nuclear-cytoplasmic dyssynchrony.
— Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 608; Goldman-Cecil Medicine, p. 1735
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