vitamin B12 (cobalamin)

see also:

• vitamins
• folic acid / folate

• a water soluble vitamin which can only be created naturally by bacteria and archaea as these have the enzymes required for its synthesis
• dietary reference intake for an adult ranges from 2 to 3 µg per day (USA), and 1.5 µg per day (UK)
• as 10-30% of older people may be unable to absorb naturally occurring vitamin B12 in foods, it is advisable for those older than 50 years old to take B12-fortified foods or B12 supplements to meet the recommended intake
• most dietary intake is from eating meat, fortified yeast, salmon, Greek yogurt, eggs, and clams
  • beef liver may contain ~71 μg per serving versus 0.5 μg per serving of egg.
• vegan diets contain very little biologically active B12
• cobalamin from food or supplements is activated through its conversion to methylcobalamin and adenosylcobalamin
• cyanocobalamin is a semi-synthetic form which does not occur in nature and must first be converted to cobalamin by detaching the cyanide group before activation.
  • mutations in B12 metabolic pathways may impair this conversion in a subset of individuals
  • cyanocobalamin storage in the liver is lower than that of natural vitamin B12
  • both cyanocobalamin and methylcobalamin effectively raise serum B12 levels although methylcobalamin may be the best option ¹⁾
• vitamin B12 deficiency is relatively common and can cause severe and irreversible damage, especially to the brain and nervous system, as well as megaloblastic anaemia
• even very high doses does not seem to cause toxicity however, there are some conditions in which it's pharmacologic use needs specific care
  • it's use may unmask polycythaemia rubra vera
  • it's use may mask folic acid / folate deficiency
  • it may cause hypokalaemia or gout in Rx of megaloblastic anaemia
  • cyanocobalamin is C/I in early Leber's disease as it can cause rapid optic atrophy

• ingested protein-bound vitamin B12 must be released from the proteins by the action of digestive proteases in both the stomach and small intestine
• gastric acid / pepsin releases the vitamin from food particles
• B12 then binds to the R-Proteins (from saliva) to avoid degradation of it in the acidic environment of the stomach
• proteases in the duodenum then digest the R-proteins releasing the B12
• intrinsic factor (IF), a protein synthesized by gastric parietal cells that is secreted in response to histamine, gastrin and pentagastrin, as well as the presence of food, binds to the released B12 in the duodenum
• the IF protects the B12 from catabolism by intestinal bacteria
• the B12 can then be absorbed in the terminal ileum, BUT only if it is bound to IF
  • maximum absorbed amount per meal is ~ 1.5 microgram irrespective of oral dose
  • NB. modern high efficiency oral preparations of B12 containing 0.5-1mg or more of B12, generally provide enough GIT absorption along the intestine via passive diffusion of 1-5% of dose even in the absence of IF, that parenteral B12 is probably no longer needed for most patients (exceptions include patients with cobalamin C disease, combined methylmalonic aciduria and homocystinuria)
• once absorbed into the portal circulation, it is bound to a protein transporter to form transcobalamin II (TC-II/B12), and stored in the body (2-5mg in adults) - 50% in the liver which can store several years worth of B12
• through very efficient enterohepatic circulation, only 0.1% of stores are lost through GIT /bile each day, and thus deficiency takes months or years to develop (although more rapidly in infants)
• if B12 levels in plasma exceed transport capacity, the excess is excreted in urine
• by age 75-80, 40% of people have a diminished ability to absorb food-bound vitamin B12

• serum vitamin B12 levels
• MMA test
  • measures levels of methymalonic acid, an acid produced during certain aspects of metabolism requiring adequate B12.
  • it can be elevated with even a mild B12 deficiency which may be contributing to cognitive dysfunction
• serum homocysteine levels
  • homocysteine is also a byproduct of metabolism requiring B12.
  • if only homocysteine levels are elevated, a folate deficiency may be the problem.
  • if both MMA and homocysteine are high, a B12 deficiency is the likely cause

• inadequate dietary intake (quite rare given the usually high liver stores)
  • eg. vegans
• achlorhydria:
  • thought to be the most common cause of low B12 in the elderly, who often have some degree of achlorhydria without being formally low in intrinsic factor
  • inhibition of gastric acid
    • long term use of proton pump inhibitors (PPIs) or H2-type antihistamines
• no intrinsic factor
  • autoimmune atrophic gastritis
  • gastrectomy
  • bariatric surgical procedures
  • Roux-en-Y gastric bypass surgery
• high levels of bacteria in bowel
  • blind loop syndrome
  • antibiotic use
• reduced terminal ileum absorption
  • inflammatory bowel disease (IBD)
  • surgical removal of terminal ileum
  • metformin
• defective plasma transporter
  • hereditary defects in production of the transcobalamins ⇒ infantile megaloblastic anemia

• impaired methionine synthesis from homocysteine resulting in:
  • impaired purine and thymidine synthesis and thus impaired DNA synthesis
    • megaloblastic anaemia pernicious anaemia
  • hyperhomocysteinaemia
  • impaired neurotransmitter synthesis
    • psychiatric symptoms
    • seizures
    • dementia
• impaired metabolism of methylmalonic acid and impaired production of succinyl-CoA, and high levels of methylmalonic acid which remains in neuronal myelin sheaths causing fragility resulting in:
  • peripheral neuropathy
  • subacute combined degeneration of spinal cord
    • loss of deep tendon reflexes
    • pathologic reflexes eg. Babinski
    • dorsal cord type ataxia
    • impaired perception of deep touch, pressure and vibration, loss of sense of touch
    • very annoying and persistent paresthesias