What is the mechanism of action that causes macrocytosis in vitamin B12 (B12) deficiency?

Mechanism of Action Causing Macrocytosis in B12 Deficiency

Vitamin B12 deficiency causes macrocytosis primarily through impaired DNA synthesis, leading to disordered cell division, maturation arrest, and ineffective early erythropoiesis. 1

Primary Pathophysiological Mechanism

• In vitamin B12 deficiency, DNA synthesis is significantly impaired while RNA and protein synthesis continue normally, creating an asynchrony between nuclear and cytoplasmic maturation 1
• This impairment leads to erythroblasts undergoing apoptosis during their rapid division phase in early erythropoiesis 1
• The result is ineffective erythropoiesis with maturation arrest, producing fewer but larger red blood cells (macrocytosis) 1

Biochemical Pathway

• B12 serves as a cofactor for methionine synthase, which transfers methyl groups to form methionine from homocysteine 2
• This reaction is critical for the synthesis of purines and pyrimidines, which are essential building blocks for DNA 2, 3
• B12 deficiency creates a "methyl trap" where 5-methyltetrahydrofolate accumulates and cannot participate in one-carbon transfer reactions 2
• This leads to functional folate deficiency even when folate levels appear normal, further impairing DNA synthesis 4, 2

Cellular Manifestations

• Morphologically, B12 deficiency causes oval macrocytosis in peripheral blood 5
• Hypersegmented neutrophils are another characteristic finding, reflecting the same DNA synthesis defect in myeloid cells 5
• The mean corpuscular volume (MCV) typically exceeds 100 fL, though exceptions can occur 6
• Bone marrow examination reveals megaloblastic changes with enlarged, immature precursors 7, 3

Clinical Presentation Variations

• While macrocytic megaloblastic anemia is the classical presentation, B12 deficiency can sometimes present with:
  • Macrocytosis without anemia (early stage) 7
  • Normocytic normochromic anemia with low reticulocyte count 7
  • Rarely, microcytic hypochromic anemia when concurrent iron deficiency exists 7, 8
• Pancytopenia may develop in severe cases due to ineffective hematopoiesis affecting all cell lines 5

Important Clinical Considerations

• Neurological manifestations of B12 deficiency can occur even without hematological abnormalities 7, 3
• Cognitive difficulties and memory impairment may result from myelin sheath damage and elevated homocysteine levels 2
• Screening for B12 deficiency should include both serum B12 levels and functional markers like homocysteine and methylmalonic acid 1, 4
• Patients with more than 20-30 cm of distal ileum resection require B12 supplementation, as this is the site of B12 absorption 1

Treatment Implications

• Parenteral B12 supplementation (1000 μg monthly) is the standard treatment for patients with ileal resection >20 cm 1
• Oral supplementation (1200-2400 μg daily) may be effective but is less established in clinical practice 1
• Correction of B12 deficiency typically results in rapid reticulocytosis and improvement of hematological indices 5
• Concurrent folate supplementation may be necessary, especially in patients on medications like methotrexate or sulfasalazine that affect folate metabolism 1, 4