B12

**Source & absorption:** Found only in animal products (meat, dairy, eggs); made by bacteria. Dietary B12 is released from food by gastric acid/pepsin, binds haptocorrin (R-binder, from saliva), then pancreatic proteases cleave it and it binds intrinsic factor (IF) from gastric parietal cells. The B12–IF complex is absorbed in the terminal ileum (cubilin receptor), then transported in blood by transcobalamin II. Body stores (liver) last 3–5 years, so deficiency develops slowly.

**Biochemical roles (2 reactions):** 1. Homocysteine → methionine (methionine synthase; requires methyl-THF and B12). Deficiency causes "methylfolate trap" → functional folate deficiency → impaired thymidine/DNA synthesis → megaloblastic anemia. ↑ Homocysteine. 2. Methylmalonyl-CoA → succinyl-CoA (methylmalonyl-CoA mutase). Deficiency → ↑ methylmalonic acid (MMA) → abnormal fatty acids incorporated into myelin → neurologic damage.

**Causes of deficiency:** - Pernicious anemia (autoimmune atrophic gastritis; anti-intrinsic factor and anti-parietal cell antibodies; ↑ risk of gastric adenocarcinoma; associated with other autoimmune disease, e.g., Hashimoto, type 1 DM, vitiligo) - Terminal ileum disease/resection (Crohn disease), celiac less commonly - Diphyllobothrium latum (fish tapeworm) competes for B12 - Strict vegan diet, exclusively breastfed infants of vegan mothers - Gastrectomy/bariatric surgery (loss of IF/acid), chronic PPI/H2 blocker use, metformin (reduced absorption) - Chronic pancreatitis (impaired protease cleavage of R-binder) - Nitrous oxide exposure (inactivates B12)

**Clinical features:** - Megaloblastic (macrocytic) anemia: ↑ MCV, macro-ovalocytes, hypersegmented neutrophils (>5 lobes), pancytopenia possible, ↑ LDH/indirect bilirubin (ineffective erythropoiesis) - Neurologic (NOT seen in folate deficiency): subacute combined degeneration — demyelination of dorsal columns (↓ vibration/proprioception), lateral corticospinal tracts (spastic weakness, UMN signs), and spinocerebellar tracts (ataxia); also peripheral neuropathy (paresthesias), dementia, depression - Glossitis, fatigue, pallor

**Diagnosis:** - Low serum B12 (borderline → check MMA and homocysteine) - ↑ Homocysteine AND ↑ MMA in B12 deficiency (vs. folate deficiency: ↑ homocysteine with NORMAL MMA) - Pernicious anemia: anti-intrinsic factor antibodies (most specific), anti-parietal cell antibodies (more sensitive); Schilling test historically - Gastric findings: ↑ gastrin, ↓ acid (achlorhydria), atrophic gastritis of body/fundus

**Treatment:** IM or high-dose oral B12 (cyanocobalamin, hydroxocobalamin); lifelong parenteral/high-dose oral therapy for pernicious anemia. Important pitfall: do NOT treat with folate alone — it corrects the anemia but allows neurologic damage to progress. Monitor potassium early in treatment (hypokalemia due to brisk erythropoiesis). Neurologic deficits may be irreversible if treatment is delayed.

**Other high-yield points:** Hydroxocobalamin is used as an antidote for cyanide poisoning. Elevated MMA also seen in methylmalonic acidemia (inborn error). Compare to folate (B9): found in leafy greens, absorbed in jejunum, stores last only months, no neurologic findings, normal MMA. Folate deficiency is also seen with phenytoin, methotrexate, and trimethoprim. In pregnancy, folate supplementation prevents neural tube defects.