vitamin B12

**Biochemistry / Functions** - Cofactor for 2 reactions: 1. Methionine synthase (homocysteine → methionine): uses methylcobalamin and N5-methyl-THF as methyl donor. Regenerates THF, which is needed for purine/thymidine synthesis. B12 deficiency causes the "methyl-folate trap" (folate trapped as N5-methyl-THF), so DNA synthesis is impaired. 2. Methylmalonyl-CoA mutase (methylmalonyl-CoA → succinyl-CoA): uses adenosylcobalamin. Part of odd-chain fatty acid and branched-chain amino acid catabolism. Deficiency raises MMA and impairs myelin synthesis, causing neurologic damage.

**Absorption (high-yield pathway)** 1. Dietary B12 is released from food proteins by pepsin and stomach acid. 2. It binds haptocorrin (R-binder) from saliva in the stomach. 3. Pancreatic proteases degrade haptocorrin in the duodenum, and B12 transfers to intrinsic factor (IF, from gastric parietal cells). 4. The IF–B12 complex is absorbed in the terminal ileum by cubam receptors (cubilin/amnionless). 5. In blood, B12 is carried by transcobalamin II and stored in the liver. Stores last 3–5 years, so deficiency develops slowly.

**Sources**: Animal products only (meat, fish, eggs, dairy), and also synthesized by gut bacteria (not absorbed in colon). Strict vegans need supplementation.

**Causes of deficiency** - Pernicious anemia: autoimmune destruction of parietal cells (anti-parietal cell and anti-intrinsic factor antibodies; type A chronic atrophic gastritis). It is associated with other autoimmune disease (e.g., Hashimoto thyroiditis, type 1 DM, vitiligo) and increases gastric adenocarcinoma risk. - Terminal ileum disease/resection: Crohn disease, celiac disease (less so), ileal resection. - Gastrectomy/bariatric surgery (loss of IF and acid). - Atrophic gastritis, chronic PPI/H2 blocker use (decreased release from food) and metformin (decreased absorption). - *Diphyllobothrium latum* (fish tapeworm) competes for B12. - Pancreatic insufficiency (failure to cleave haptocorrin). - Strict vegan diet or exclusively breastfed infants of vegan mothers. - Nitrous oxide exposure (inactivates cobalamin). - Imerslund-Gräsbeck syndrome (cubam defect), a rare cause.

**Clinical features** - Hematologic: megaloblastic (macrocytic) anemia with high MCV, hypersegmented neutrophils (>5 lobes), macro-ovalocytes, pancytopenia in severe cases, and ineffective erythropoiesis (↑ LDH, ↑ indirect bilirubin). - Neurologic (not seen in folate deficiency): subacute combined degeneration with demyelination of the dorsal columns (↓ vibration/proprioception, sensory ataxia), lateral corticospinal tracts (spastic paresis, upper motor neuron signs), and spinocerebellar tracts. Also peripheral neuropathy, paresthesias, dementia, depression, and psychosis ("megaloblastic madness"). - GI: glossitis (smooth, beefy red tongue), diarrhea.

**Diagnosis** - ↓ Serum B12 (if borderline, check MMA/homocysteine). - ↑ Homocysteine AND ↑ methylmalonic acid (B12 deficiency). Folate deficiency has ↑ homocysteine with NORMAL MMA. - Anti-intrinsic factor antibodies (most specific for pernicious anemia); anti-parietal cell antibodies are more sensitive but less specific. - Schilling test (historical) localized the cause of malabsorption.

**Treatment** - Intramuscular or deep SC cyanocobalamin/hydroxocobalamin is used for pernicious anemia and malabsorption. High-dose oral B12 is also effective, since ~1% is absorbed passively without IF. - **Do not treat with folate alone**: it corrects the anemia but allows neurologic damage to progress. - Monitor potassium early in treatment: brisk erythropoiesis can cause hypokalemia. - Neurologic damage may be irreversible if treatment is delayed.

**Other high-yield points** - Elevated homocysteine raises the risk of thrombosis and atherosclerosis. Treatment is not proven to reduce cardiovascular events. - Hydroxocobalamin is used for cyanide poisoning, because it binds cyanide to form cyanocobalamin. - Prenatal B12 is not a neural tube defect preventive (folate is), but deficiency can still cause problems. - Cobalt is the central metal ion in cobalamin.