Vitamin B12

Functions

• Cofactor for enzymes:
  1. Methionine synthase: Converts homocysteine to methionine (requires folate). Deficiency leads to ↑ homocysteine and traps folate as methyl-THF, impairing DNA synthesis.
  2. Methylmalonyl-CoA mutase: Converts methylmalonyl-CoA to succinyl-CoA. Deficiency leads to ↑ methylmalonic acid (MMA), which is neurotoxic and impairs myelin synthesis.
     • Deficiency leads to impaired myelin synthesis: the buildup of Methylmalonyl-CoA disrupts myelin
  • Hydroxocobalamin (precursor of vitamin B12) is used to treat Cyanide poisoning

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Epidemiology

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Etiology

Attention

The liver can store approximately 1,000 times the daily vitamin B12 requirement; deficiency develops only after the complete absence of intake or absorption for 3-4 year

• 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

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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

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Clinical features

• Signs of anemia (e.g., fatigue, pallor)
• Subacute combined degeneration
• Glossitis

Tip

Always consider vitamin B12 deficiency when evaluating patients with dementia.

Folate deficiency

Feature	Vitamin B12 (Cobalamin) Deficiency	Folate (Vitamin B9) Deficiency
Primary Unique Role	Neurological function (myelin sheath)	Neural tube development (in fetus)
Primary Sources	Animal products	Leafy greens, legumes, fortified foods
Body Stores	Large (Years)	Small (Months)
Absorption	Terminal Ileum (Requires Intrinsic Factor)	Duodenum/Jejunum (No Intrinsic Factor)
Key Unique Causes	Pernicious anemia, vegan diet, gastric surgery	Poor diet, alcoholism, pregnancy needs
Neurologic Symptoms	PRESENT (Paresthesias, gait issues, cognitive changes)	ABSENT
Key Lab Marker	Elevated Methylmalonic Acid (MMA)	Normal Methylmalonic Acid (MMA)
Treatment Danger	Folate alone masks anemia, allows neuro damage to progress	Less critical interaction (though diagnosis is key)

Link to original

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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.

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Treatment

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