Homocysteine and B12: what your level means and when B vitamins help

What is homocysteine?

Homocysteine is formed when the body processes the amino acid methionine from dietary protein. It is an intermediate in the methylation cycle, which is used to make DNA, nerve tissue and brain signalling molecules. sundhed.dk (Lægehåndbogen) sundhed.dk (Lægehåndbogen)

To stop homocysteine from building up, it must either be recycled back to methionine or converted onward to cysteine. That requires three B vitamins: folate (B9) and B12 for the first route and B6 for the second. If you lack any of them, blood homocysteine rises. This is why homocysteine works as a sensitive but non-specific marker of B vitamin status. sundhed.dk (Lægehåndbogen) sundhed.dk (Lægehåndbogen)

Homocysteine is also affected by sex, age, muscle mass and kidney function. Men generally have higher levels than women, and levels rise with age. sundhed.dk (Lægehåndbogen) sundhed.dk (Lægehåndbogen)

Normal homocysteine levels

Reference ranges vary slightly between laboratories, so always use the range printed on your result. The table shows Rigshospitalet's ranges and the degrees of elevation used in the Danish medical handbook (Lægehåndbogen). sundhed.dk (Lægehåndbogen)

You will often see 'optimal' targets below 7–9 µmol/L in longevity circles. These come from population studies in which low levels go with lower risk, but no trial shows a benefit from pushing levels that low with supplements. sundhed.dk (Lægehåndbogen)

Why is homocysteine raised?

There are many possible causes, and often several at once. The priority is to find a treatable cause such as B12 deficiency or kidney disease. sundhed.dk (Lægehåndbogen) sundhed.dk (Lægehåndbogen) sundhed.dk (Lægehåndbogen)

The Danish medical handbook no longer recommends homocysteine as a routine test when investigating cardiovascular disease or dementia. It is mainly used when inherited homocystinuria is suspected and in work-ups for an increased tendency to blood clots. sundhed.dk (Lægehåndbogen) sundhed.dk (Lægehåndbogen) sundhed.dk (Lægehåndbogen)

• B12 or folate deficiency, the most common treatable cause
• Reduced kidney function
• Medicines: metformin, methotrexate, some anti-epileptic drugs, L-dopa, theophylline and ciclosporin
• Underactive thyroid
• Smoking, heavy drinking and a lot of coffee
• Cirrhosis and chronic liver disease
• MTHFR gene variants, especially with low folate intake
• Older age, male sex, excess weight and high muscle mass (normal variation)

B12 and folate: how to read the tests

If homocysteine is high, the next step is to measure B12 and folate. Blood B12 is not always precise, so in the grey zone the lab measures methylmalonic acid (MMA). MMA rises only in B12 deficiency, while homocysteine rises in both B12 and folate deficiency. MMA can, however, be falsely raised when kidney function is reduced. sundhed.dk (Lægehåndbogen) sundhed.dk (Lægehåndbogen)

B12 deficiency affects an estimated 3–5% of people over 70. It develops slowly and can cause anaemia, a sore smooth tongue, tingling and numbness in the feet, unsteady walking and memory problems. Nerve damage can become permanent if treatment comes too late, so it is worth acting on. sundhed.dk (Lægehåndbogen) sundhed.dk (Lægehåndbogen)

Homocysteine and the heart: a risk marker, not a treatment target

In population studies, high homocysteine is linked to several cardiovascular diseases. A large analysis of 30 studies found that a 25% lower homocysteine level, about 3 µmol/L, was associated with an 11% lower risk of ischaemic heart disease and a 19% lower risk of stroke. The authors called homocysteine at most a modest independent risk factor. PMID 12387654 PMID 20937919 PMID 28816346 PMID 25771069

Then came the trials. In eight large randomised trials with 37,485 people, folic acid lowered homocysteine by an average of 25%, yet after five years there was no difference in heart attacks, strokes, cancer or death. The 2017 Cochrane review of 15 trials and more than 71,000 participants also found no effect on heart attack or death, but a small reduction in stroke (4.3% vs 5.1%). PMID 12387654 PMID 20937919 PMID 28816346 PMID 25771069

Much of the stroke effect comes from China's CSPPT trial of more than 20,000 people with high blood pressure, in which folic acid plus blood pressure medication led to 21% fewer first strokes. China does not fortify foods with folic acid, and many participants had low folate intake. Denmark does not fortify flour either, but the result cannot be directly applied to well-nourished Europeans. PMID 12387654 PMID 20937919 PMID 28816346 PMID 25771069

The bottom line: use homocysteine as a hint of B vitamin deficiency, but focus on blood pressure, cholesterol, smoking and blood sugar if you want to prevent cardiovascular disease. PMID 12387654 PMID 20937919 PMID 28816346 PMID 25771069

Homocysteine and the brain: what did VITACOG show?

The Oxford VITACOG trial gave 271 people over 70 with mild cognitive impairment either placebo or 0.8 mg folic acid, 0.5 mg B12 and 20 mg B6 daily for two years. Among those who had MRI scans, the brain shrank by 0.76% a year in the B vitamin group versus 1.08% on placebo. In participants with homocysteine above 13 µmol/L at baseline, atrophy was 53% slower than on placebo, while the effect was small in those with low levels. PMID 20838622 PMID 24965307

The result is interesting but limited: it is a single trial, the main outcome was brain volume rather than dementia, and one researcher holds patents on folic acid for Alzheimer's. A pooled analysis of 11 trials with 22,000 participants found no effect of B vitamins on memory or cognitive ageing in older people in general. PMID 20838622 PMID 24965307

The reasonable reading is that B vitamins probably help the brain only if your B vitamin status is low or homocysteine clearly raised. That argues for testing and treating deficiency, not for everyone over 60 taking high-dose B vitamins. See our dementia prevention article for the bigger picture. PMID 20838622 PMID 24965307

MTHFR: should you get the gene tested?

MTHFR is an enzyme that converts folate into its active form. The C677T variant is common, and about one in ten Europeans carry two copies (TT). They have slightly higher homocysteine, but mainly when their folate intake is also low. sundhed.dk (Lægehåndbogen) PMID 25771069

There is no Danish recommendation to test healthy people for MTHFR, and the result rarely changes treatment. If you get enough folate from food, its significance is small. The claim that people with MTHFR variants cannot use ordinary folic acid and need expensive methylfolate is not supported by large trials. The Danish medical handbook simply lists MTHFR as one of many causes of mildly raised homocysteine. sundhed.dk (Lægehåndbogen) PMID 25771069

What to do in practice

If you have had a high homocysteine result, or belong to a risk group for B12 deficiency, work through the steps below with your doctor. sundhed.dk (Lægehåndbogen) sundhed.dk (Lægehåndbogen)

Avoid starting high-dose folic acid on your own if you might be B12 deficient. Folic acid can correct the anaemia while the nerve damage from B12 deficiency continues unnoticed. See your GP if you develop increasing tingling in the feet, unsteady walking or confusion, and call emergency services (112 in Denmark) for sudden weakness or speech problems. sundhed.dk (Lægehåndbogen) sundhed.dk (Lægehåndbogen)

• Have B12, folate, blood count and kidney function (eGFR) measured. If B12 is in the grey zone, ask for methylmalonic acid.
• If you are deficient: doctors usually recommend 1 mg of oral B12 daily, or injections for nerve symptoms or absorption problems.
• Eat folate-rich foods every day: dark green vegetables, cabbage, pulses, wholegrains and citrus fruit.
• B12 occurs naturally only in animal foods such as fish, meat, milk and eggs. On a vegan diet you need a supplement or fortified products.
• Pregnant women and women planning pregnancy are advised to take 400 µg of folic acid daily.
• If you take metformin, have your B12 checked every two years.
• Repeat homocysteine after 2–3 months of treatment if your doctor wants to track the effect, not as a yearly check in healthy people.