Functions

• Cofactor for enzymes:
  • Methionine synthase: Methylcobalamin is required for the transfer of methyl groups (e.g., in DNA synthesis).
    • Deficiency leads to impaired DNA synthesis
  • Methylmalonyl-CoA mutase (e.g., in odd-chain fatty acid metabolism)
    • Deficiency leads to impaired myelin synthesis: the buildup of Methylmalonyl-CoA disrupts myelin
  • Hydroxocobalamin (precursor of vitamin B12) is used to treat Cyanide poisoning

Epidemiology

Etiology

• Malabsorption
  • ↓ Intrinsic factor (IF)
    • Atrophic gastritis due to
      • Autoimmune atrophic gastritis: most common cause of vitamin B12 deficiency
      • H. pylori infection
    • Gastrectomy
  • Reduced uptake of IF-vitamin B12 complex in terminal ileum due to:
    • Alcohol use disorder
    • Crohn disease, celiac disease
    • Pancreatic insufficiency (e.g. Chronic pancreatitis)
      • Pancreatic proteolytic enzymes are needed to release vitamin B12 from the vitamin B12–R protein complex (R protein is also known as transcobalamin I or haptocorrin), a necessary step that enables vitamin B12 to bind intrinsic factor, which ultimately facilitates terminal ileal absorption.
    • Surgical resection of the ileum
    • Diphyllobothrium latum (tapeworm) infection
    • Bacterial overgrowth
    • Enteritis
    • Achlorhydria
• Malnutrition
  • Anorexia nervosa
  • Strict vegan diets: occurs only after years of a strict diet that excludes all animal products (unlike folate deficiency, which occurs within a few months of insufficient intake)
    • Found almost exclusively in animal products (except yeast extract)
• Increased demand: e.g., during pregnancy, breastfeeding, fish tapeworm (Diphyllobothrium latum) infection, and leukemia
• Drugs: metformin

Pathophysiology

Dysfunctional biochemical reactions

• Dysfunctional methionine synthase (normally converts homocysteine to methionine, thereby demethylating N5-methyl-THF to THF)
  • ↓ Tetrahydrofolate (THF; cofactor in purine synthesis) → ↓ DNA synthesis → large, nucleated hematopoietic cells, including megaloblasts → megaloblastic precursors undergo apoptosis or are phagocytosed by macrophages → pancytopenia (including megaloblastic anemia)
  • ↓ Methionine → neuropathy
  • ↑ Homocysteine → endothelial damage → predisposes to cardiovascular disease
  • Can also cause secondary folate deficiency
• Dysfunctional methylmalonyl CoA mutase
  • Methylmalonyl CoA cannot be converted to succinyl CoA → accumulation of methylmalonyl CoA and its precursor propionyl CoA, as well as their associated odd-chain fatty acids, which cannot be completely metabolized
  • Propionyl CoA replaces acetyl CoA in neuronal membranes → demyelination → neurological manifestations

Pernicious anemia

• A type of vitamin B12 deficiency caused by autoantibodies against intrinsic factor and/or gastric parietal cells (type II hypersensitivity reaction)
  • Antiparietal cell antibodies: target gastric parietal cells
    • Causes ↓ acid production and atrophic gastritis
      • In turn increases gastrin level
    • ↓ Intrinsic factor production → ↓ vitamin B12 absorption in terminal ileum
  • Anti-IF antibodies: bind intrinsic factor and block the vitamin B12 binding site
• Associated with other autoimmune diseases (e.g., hypothyroidism, vitiligo)
• Increases the risk of gastric cancer

Clinical features

• Signs of anemia (e.g., fatigue, pallor)
• Neurological disturbances are generally symmetrical
  • Peripheral neuropathy: tingling, numbness, pins-and-needles sensation, coldness (especially in the lower extremities)
  • Subacute combined degeneration of spinal cord: symmetrical demyelination of the spinal cord tracts occurs in vitamin B12 deficiency due to insufficient vitamin B12-dependent fatty acid synthesis and production/maintenance of myelin
    • It manifests with the following symptoms:
      • Paresthesia, impaired proprioception, loss of vibratory sensation, tactile sensation, and position discrimination due to demyelination of the dorsal columns
      • Spastic paresis due to demyelination of the lateral corticospinal tracts (axons of upper motor neurons)
      • Gait abnormalities (spinal ataxia) resulting from the damage of spinocerebellar tracts and dorsal columns, Romberg test (+)
    • Long-term deficiency can lead to irreversible neurological damage.
  • Neuropsychiatric disease (e.g., reversible dementia, depression, paranoia)
  • Worsening vision
  • Autonomic dysfunction: impotence and incontinence
• Glossitis

Diagnostics

• If vitamin B12 serum levels are normal:
  • Measure homocysteine: elevated in both vitamin B12 deficiency and folate deficiency
  • Measure methylmalonic acid (MMA) to help rule out folate deficiency (MMA is normal in folate deficiency and elevated in vitamin B12 deficiency)
    • Without vitamin B12, methylmalonyl CoA mutase cannot break down methylmalonyl CoA, which leads to the accumulation of MMA.

Treatment