Macrocytic/Megaloblastic Anemia

Macrocytic/Megaloblastic Anemia is a topic covered in the Washington Manual of Medical Therapeutics.

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General Principles


Megaloblastic anemia is a term used to describe disorders of impaired DNA synthesis in hematopoietic cells, but this also affects other normally proliferating cells such as in the GI tract.


  • Vitamin B12 deficiency occurs insidiously over several years because daily vitamin B12 requirements are low compared to total body stores.
    • Most cases of megaloblastic anemia are due to vitamin B12 deficiency.
    • Vitamin B12 deficiency occurs in up to 20% of untreated patients within 8 years of partial gastrectomy and in almost all patients with total gastrectomy or pernicious anemia (PA). Older patients with gastric atrophy may develop a food-bound vitamin B12 deficiency in which vitamin B12 absorption is impaired. In nonvegan adults, vitamin B12 deficiency is almost always due to malabsorption.
    • PA usually occurs in individuals older than 40 years (mean age of onset, 60 years). Up to 30% of patients have a positive family history. PA is an immune-mediated disorder associated with other autoimmune disorders (Graves disease 30%, Hashimoto thyroiditis 11%, and Addison disease 5%–10%). In patients with PA, 90% have antiparietal cell antibodies, and 60% have anti-intrinsic factor antibodies.
    • Other etiologies of vitamin B12 deficiency include pancreatic insufficiency, bacterial overgrowth, and intestinal parasites (Diphyllobothrium latum).
  • Folate deficiency results from a negative folate balance arising from malnutrition, malabsorption, or increased requirement (pregnancy, hemolytic anemia).
    • Folate deficiency is now rare in the United States because of fortification of grains with folic acid.
    • Patients on weight-losing diets, alcoholics, the elderly, and psychiatric patients are particularly at risk for nutritional folate deficiency.
    • Folate deficiency may be seen in several settings:
      • Pregnancy and lactation in which there is a three- to fourfold increased daily folate requirements.
      • Folate malabsorption secondary to celiac disease or bariatric surgery.
      • Drugs that can interfere with folate absorption include ethanol, trimethoprim, pyrimethamine, diphenylhydantoin, barbiturates, and sulfasalazine.
      • Dialysis-dependent patients require more folate intake because of increased folate losses.
      • Patients with hemolytic anemia, such as sickle cell anemia, require increased folate for accelerated erythropoiesis and can present with aplastic crisis (rapidly falling RBC counts) with folate deficiency.

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