Vitamin B12

Vitamin B12 (cobalamin) is a water-soluble, cobalt-containing vitamin essential for two mammalian enzyme reactions: methionine synthase (converting homocysteine to methionine, part of one-carbon metabolism) and methylmalonyl-CoA mutase (converting methylmalonyl-CoA to succinyl-CoA in branched-chain amino acid and odd-chain fatty acid catabolism). Through these reactions, B12 supports DNA synthesis, red blood cell maturation, myelin synthesis, and fatty acid metabolism.

Absorption complexity

B12 absorption is the most complex of any vitamin. Dietary B12 is released from food proteins by gastric acid and pepsin, binds to salivary haptocorrin in the stomach, is released by pancreatic proteases in the duodenum, binds to intrinsic factor (IF) secreted by gastric parietal cells, and is absorbed via cubilin receptors in the distal ileum. The B12-IF complex absorption pathway has a saturable limit of approximately 1.5-2 µg per single dose. Failure at any step — achlorhydria, gastrectomy, pernicious anemia (autoimmune destruction of parietal cells), ileal resection or disease, bacterial overgrowth — can cause deficiency.

Sources

B12 is synthesized only by certain bacteria and archaea. In the human food supply, it is found almost exclusively in animal-source foods where it accumulates from bacterial synthesis in animal gut flora. Per USDA FoodData Central: beef liver 70 µg per 100 g, clams 100 µg, oysters 28 µg, mackerel 19 µg, beef 2-5 µg, salmon 3 µg, milk 0.5 µg per 100 g, eggs 0.9 µg per 100 g. Plant foods contain essentially no bioavailable B12; trace amounts in some seaweeds and fermented foods are generally non-absorbable B12 analogues.

Deficiency

Deficiency manifestations include: (1) megaloblastic anemia with macrocytosis, hypersegmented neutrophils, and anisopoikilocytosis; (2) neurological symptoms — peripheral neuropathy, gait ataxia, paresthesias, cognitive impairment, and in severe cases subacute combined degeneration of the posterior and lateral spinal cord columns; (3) glossitis and gastrointestinal symptoms. Neurological manifestations can progress even when anemia is masked by adequate folate intake; for this reason, folic acid fortification programs must be paired with attention to B12 status.

At-risk populations

Populations at elevated risk of B12 deficiency: (1) vegans and strict vegetarians — supplementation is essential; (2) older adults (>50 years) — 10-30% have food-cobalamin malabsorption due to reduced gastric acid, and the 2005 NAM DRI recommends these individuals preferentially use fortified food or supplement sources; (3) long-term proton pump inhibitor users — impaired acid-mediated B12 release from food; (4) metformin users — mechanism incompletely understood, possibly reduced ileal absorption; (5) patients with gastric surgery, ileal disease (Crohn, resection), or pernicious anemia.

Laboratory assessment

Serum B12 is the primary marker but has limitations — borderline values (200-400 pg/mL) are nondiagnostic and functional deficiency can exist at "normal" B12 levels. Methylmalonic acid (MMA) and homocysteine are more sensitive functional markers: MMA elevation indicates B12 deficiency specifically (B12 is required for its metabolism); homocysteine elevates with both B12 and folate deficiency. Holotranscobalamin (active B12) is available in some laboratories.

Supplementation

Cyanocobalamin is the most common supplemental form, stable and well-absorbed; methylcobalamin and adenosylcobalamin are marketed as "active" forms but confer no demonstrated advantage in most patients. Doses of 1000 µg oral daily are effective for most deficiency states, including pernicious anemia, because a small fraction (~1-2%) is absorbed passively even without intrinsic factor. Intramuscular B12 (1000 µg weekly then monthly) remains first-line for severe neurological manifestations.