Vitamin B12 (Cobalamin)

Protects nerves

B12 is a large molecule built around a cobalt atom, and the human body uses it in only two enzymes. Both matter for nerves.¹

• Methionine synthase (as methylcobalamin) recycles homocysteine into methionine, which becomes SAM, the methyl donor used to tag myelin proteins and lipids and to make neurotransmitters.
• Methylmalonyl-CoA mutase (as adenosylcobalamin) is the last step in breaking down odd-chain fatty acids, cholesterol's side chain and the amino acids valine, isoleucine, methionine and threonine. All of them pass through methylmalonyl-CoA on their way into the TCA cycle.

Without B12, the spinal cord's long sensory and motor tracts lose their myelin first. This is subacute combined degeneration: numbness and tingling in the feet, lost vibration and position sense, an unsteady gait that's worse in the dark, and eventually stiffness and weakness. Peripheral nerves, the optic nerve and the brain are affected too, causing memory loss, depression and, rarely, psychosis.¹ The exact cause of the myelin damage is still debated. The two main explanations are low SAM starving myelin of methylation, and methylmalonyl-CoA buildup putting abnormal branched and odd-chain fatty acids into myelin lipids.

Nerve damage can happen without anaemia, and it can be permanent. About a quarter of people with B12-related nerve damage have a normal blood count. The longer symptoms go untreated, the less fully they recover. That's why numbness or balance problems in an at-risk person (see below) should prompt a B12 test with methylmalonic acid, even when the blood count is normal.¹

Builds red blood cells

B12's effect on red cells works through folate. Methionine synthase is the only enzyme that can take the methyl group off 5-methyl-THF, the form most folate is stored in. Without B12, folate gets stuck in that form: the methyl-folate trap. Blood folate can look normal or even high, but cells can't use it to make the thymidine and purines they need to copy DNA (see Folate).¹

Fast-dividing bone marrow cells keep growing but can't divide on time, so they come out large, misshapen and fragile: megaloblastic anaemia. It looks the same as folate-deficiency anaemia. That's the trap: high-dose folic acid can get around the block and correct the blood count while the nerve damage keeps getting worse. Check B12 before treating any large-cell anaemia with folate alone.¹

Tiredness from B12 deficiency comes from this anaemia. The mutase reaction is a minor fuel pathway, and extra B12 does nothing for energy in someone who isn't deficient.

Keeps homocysteine down

Every methyl group the body uses from SAM leaves homocysteine behind. B12-dependent methionine synthase, taking the methyl group from folate's 5-MTHF, turns it back into methionine. That keeps the methylation cycle running and homocysteine low (see Methionine). The other exit, through B6 to cysteine, can't keep up when B12 is short, so homocysteine rises.

Two blood markers come from B12's two enzymes:

• Homocysteine rises when methionine synthase stalls. It's sensitive but not specific, because folate, B6 and kidney function all affect it.
• Methylmalonic acid (MMA) rises when the mutase stalls. It's the most specific marker of B12 deficiency and often rises before serum B12 drops below the reference range.¹

As with folate and B6, lowering homocysteine with B vitamins hasn't reduced heart attacks in trials (see B6). The value of B12 here is correcting a deficiency, not lowering an already-normal homocysteine further.

Intake, absorption & who's at risk

The RDA is 2.4 mcg/day. Only animal foods (and fortified foods) contain meaningful B12. The liver stores several years' worth, which is why deficiency develops slowly and often goes unnoticed.

Absorption takes several steps, and any of them can fail:

1. Stomach acid and pepsin free B12 from food protein (see Chloride). Long-term PPIs and age-related stomach thinning block this step.
2. B12 binds intrinsic factor, a protein made by the stomach's parietal cells. In pernicious anaemia, an autoimmune disease, antibodies destroy those cells or the intrinsic factor itself.
3. The B12–intrinsic factor complex is absorbed in the last part of the small intestine (terminal ileum). Crohn's disease, ileal resection and bariatric surgery can disrupt this.

Metformin lowers B12 too. In a randomised trial it cut serum B12 by 19% over about 4 years, with a 7-point higher absolute rate of deficiency.² Vegans need a supplement or fortified foods.

Oral works, even without intrinsic factor. About 1% of a large oral dose is absorbed by passive diffusion, without intrinsic factor. In a randomised trial in deficient patients, 2,000 mcg/day by mouth corrected blood and nerve findings as well as monthly injections, and left higher B12 levels at 4 months.³

Very low toxicity. No upper limit has been set. Unexplained high serum B12, without supplements, can be a sign of liver disease or some blood cancers and is worth asking a doctor about.

Top foods

• Clams: about 84 mcg in 3 oz, about 35 days' worth
• Beef liver: about 70 mcg in 3 oz
• Oysters: about 15–25 mcg in 3 oz (see Oyster)
• Salmon or tuna: about 2.5–5 mcg in 3 oz
• Beef: about 1.5–2.5 mcg in 3 oz
• Milk or yogurt: about 1.2 mcg per cup; eggs about 0.5 mcg each

Deficiency effects

Large-cell anaemia with fatigue and paleness; numbness, tingling and balance problems; memory, mood and thinking changes; a smooth sore tongue; raised MMA and homocysteine. Nerve and cognitive changes can become permanent if deficiency goes uncorrected for too long.¹ Serum B12 alone misses some cases. When results are borderline, MMA settles it.