Snapshot A 55-year-old man is brought to his primary care physician by his wife for increased confusion. He forgets to turn off the stove after cooking and frequently misplaces his keys. He fell approximately 1 week ago while walking in the dark. His physical examination is notable for impaired short-term memory, decreased vibration and proprioception sensation, and patellar hyperreflexia. On laboratory testing, he has a macrocytic anemia, reticulocytopenia, and low serum vitamin B12. Introduction Overview vitamin B12 (cobalamin) is a water-soluble vitamin that is involved in the formation of hematopoietic cells and maintainance of myelin integrity vitamin B12 deficiency results in a megaloblastic anemia reversible dementia subacute combined degeneration Etiology decreased oral intake strict vegan diet breastfeeding in a vitamin B12 deficiency mother decreased animal product intake decreased absorption gastrointestinal surgeries bariatric surgery grastrectomy illness Crohn disease celiac disease pancreatic insufficiency Diphyllobothrium latum (fish tapeworm) gastric atrophy medications proton pump inhibitors histamine receptor antagonist metformin autoimmune disease pernicious anemia autoantibodies against intrinsic factor or gastric parietal cells Pathophysiology absorption protein-bound vitamin B12 is released from protein by pepsin gastric acid converts pepsinogen to pepsin R-binder binds to vitamin B12 to prevent its degradation by gastric acid R-binder is produced in the salivary glands proteases in the duodenum separate R-binder and vitamin B12, allowing vitamin B12 to bind to intrinsic factor intrinsic factor is produced by gastric parietal cells proteases in the duodenum are produced by the pancreas intrinsic factor bound to vitamin B12 is absorbed in the terminal ileum DNA synthesis vitamin B12 serves as a coenzyme for methionine synthase to produce methionine serves a vital role in methylation reactions tetrahydrofolate serves a vital role in DNA synthesis myelin stabilization methionine is converted to S-adenosylmethionine associated with myelin stabilization vitamin B12 serves as a coenzyme for methylmalonyl-CoA mutase to convert methylmalonyl-CoA (produced from methylmalonic acid) to succinyl-CoA decreased methylmalonic acid is associated with myelin stabilization vitamin B12 deficiency impaired DNA synthesis significantly affects rapidly dividing cells (e.g., hematopoietic precursor cells) and leads to megaloblastic changes, which is cased by slowing of nuclear division due to nuclear-cytoplasmic dyssynchrony ineffective erythropoiesis (intramedullary hemolysis) erythropoietic precursor cells within the bone marrow prematurely die results in a reticulocytopenia impair neuronal function mechanism is not fully clear but hypothesized to be due to decreased methylation of neuronal lipids and proteins (e.g., myelin basic protein) Prognosis atrophic gastritis increases risk of gastric cancer Presentation Symptoms anemia fatigue dyspnea gastrointestinal glossitis neurologic cognitive decline Physical examination subacute combined degeneration lateral corticospinal tracts weakness spasticity hyperreflexia dorsal columns decreased vibration and proprioception sensation gait difficulties spinocerebellar tracts gait difficulties ataxia decreased proprioception sensation impaired proprioception information from the spinal cord to the cerebellum Labs Serum labs macrocytic and megaloblastic anemia decreased serum B12 level reticulocytopenia ↑ serum methylmalonic acid and homocysteine levels anti-intrinsic factor and parietal antibodies seen in pernicious anemia Peripheral blood and marrow smear show hypersegmented neutrophils and megalocytes Differential Folate anemia differentiating factors no neurological manifestations methylmalonic acid levels are not elevated Treatment Medical intramuscular vitamin B12 indication first-line for vitamin B12 deficiency Complications Irreversible neurological damage if untreated