What mechanism leads to anemia in patients with vitamin B12 deficiency and how is it classified?

Mechanism and Classification of Anemia in Vitamin B12 Deficiency

Vitamin B12 deficiency leads to macrocytic anemia through impaired DNA synthesis, causing maturation arrest and ineffective erythropoiesis due to apoptosis of rapidly dividing erythroblasts. 1

Pathophysiological Mechanism

• Vitamin B12 (cobalamin) is essential for DNA synthesis, hematopoiesis, and nucleoprotein and myelin synthesis 2
• When vitamin B12 is deficient, DNA synthesis becomes impaired, affecting rapidly dividing cells like erythroblasts 1
• The defective DNA synthesis leads to maturation arrest and ineffective early erythropoiesis 1
• Erythroblasts undergoing rapid division during erythropoiesis succumb to apoptosis (programmed cell death) 1
• This results in fewer cells completing maturation into functional red blood cells 1

Absorption and Causes of Deficiency

• Vitamin B12 absorption requires intrinsic factor produced by gastric parietal cells and an acidic environment in the stomach 2
• The most common cause of vitamin B12 deficiency is malabsorption due to:
  • Autoimmune chronic atrophic gastritis (pernicious anemia) with destruction of parietal cells 3
  • Decreased hydrochloric acid production and reduced availability of intrinsic factor 1
  • Food-bound cobalamin malabsorption due to achlorhydria, gastritis, or use of PPIs 3
• Vitamin B12 is bound to intrinsic factor in the stomach and absorption occurs in the terminal ileum in the presence of calcium 2
• Only about 1% of vitamin B12 is absorbed by simple diffusion, which is inadequate without supplementation in deficiency states 2

Classification of Anemia

• Vitamin B12 deficiency anemia is classified as a macrocytic anemia 1
• Characteristics include:
  • Mean corpuscular volume (MCV) > 100 fL 1
  • Megaloblastic features due to impaired DNA synthesis 1
  • Low reticulocyte index (RI), indicating decreased red blood cell production 1
• It is specifically a megaloblastic macrocytic anemia, characterized by:
  • Abnormally large erythrocyte precursors in the bone marrow 1
  • Nuclear-cytoplasmic asynchrony in developing red blood cells 4
  • Hypersegmented neutrophils on peripheral blood smear 4

Laboratory Findings

• Elevated serum methylmalonic acid and homocysteine levels (early markers of B12 deficiency) 4
• Decreased serum B12 levels, though approximately 50% of patients with subclinical disease may have normal B12 levels 4
• In severe cases, pancytopenia may develop 5
• Peripheral blood smear may show macrocytes, hypersegmented neutrophils, and occasionally schistocytes 5
• In rare cases, hemolytic anemia with features resembling thrombotic microangiopathy can occur 3, 5

Clinical Implications

• If left untreated, vitamin B12 deficiency can lead to:
  • Irreversible neurological damage including peripheral neuropathy and subacute combined degeneration of the spinal cord 2
  • Cognitive impairment and neuropsychiatric disorders 6
  • In severe cases, hyperhomocysteinemia which can increase thrombotic risk 5
• Early diagnosis and treatment with vitamin B12 supplementation can reverse hematological abnormalities and prevent progression of neurological damage 2, 6

Vitamin B12 deficiency should be considered in any patient presenting with macrocytic anemia, especially when accompanied by neurological symptoms or risk factors for malabsorption 6, 4.