Macrocytic/Megaloblastic Anemia

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

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General Principles

Definition

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.

Etiology

  • Vitamin B12 (cobalamin) deficiency occurs insidiously over several years because daily vitamin B12 requirements are low compared to total body stores. Vitamin B12 is absorbed in the terminal ileum.
    • 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, celiac disease, medications (metformin, proton pump inhibitors, nitrous oxide), and intestinal parasites (Diphyllobothrium latum).
  • Folate deficiency results from a negative folate balance arising from malnutrition, malabsorption, or increased requirement (pregnancy, hemolytic anemia). In contrast to B12 deficiency, it can develop more rapidly (weeks to months) given limited body stores. Folate is mainly absorbed in the upper third of small intestine.
    • Folate deficiency is now rare in the US 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 can occur secondary to celiac disease or bariatric surgery.
      • Drugs that can interfere with folate absorption include ethanol, trimethoprim, methotrexate, 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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General Principles

Definition

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.

Etiology

  • Vitamin B12 (cobalamin) deficiency occurs insidiously over several years because daily vitamin B12 requirements are low compared to total body stores. Vitamin B12 is absorbed in the terminal ileum.
    • 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, celiac disease, medications (metformin, proton pump inhibitors, nitrous oxide), and intestinal parasites (Diphyllobothrium latum).
  • Folate deficiency results from a negative folate balance arising from malnutrition, malabsorption, or increased requirement (pregnancy, hemolytic anemia). In contrast to B12 deficiency, it can develop more rapidly (weeks to months) given limited body stores. Folate is mainly absorbed in the upper third of small intestine.
    • Folate deficiency is now rare in the US 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 can occur secondary to celiac disease or bariatric surgery.
      • Drugs that can interfere with folate absorption include ethanol, trimethoprim, methotrexate, 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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