by Jack Norris, RD • Last updated January 2019
- Background on Homocysteine
- Homocysteine in Vegetarians
- Cardiovascular Disease
- Birth Defects
- Bone Mineral Density
- What Level of B12 Should You Aim For?
- Should Vegans have their Homocysteine or B12 Levels Checked?
Vegans who don’t supplement their diet with vitamin B12 tend to have low vitamin B12 levels and elevated homocysteine. These conditions are especially linked with dementia and brain atrophy, but there is also evidence for birth defects, low bone mineral density, and possibly stroke. Vegans who follow our B12 recommendations will minimize any such problems due to a low B12 intake.
Most vegans are probably aware of the need to ensure a reliable source of vitamin B12 to prevent nerve damage resulting from severe deficiency. There are also problems with mild vitamin B12 deficiency, especially dementia. Some of these problems are related to elevated homocysteine while others may not to be. Because low vitamin B12 status and elevated homocysteine normally go together, it’s hard to separate one from the other.
Background on Homocysteine
Methionine is an essential amino acid obtained from protein in the diet. Some methionine is turned into homocysteine. The body turns much of this homocysteine back into methionine with the help of vitamin B12. If someone is B12-deficient, homocysteine levels will increase because this reaction cannot take place.
Keeping homocysteine at levels associated with lower rates of disease requires both adequate B12 and folate (also known as folic acid) status. Low vitamin B6 status can also cause elevated homocysteine in some people.
Normal serum homocysteine levels are from 2.2 to 13.2 µmol/l (2). Levels of homocysteine in typical Western populations are about 12 µmol/l (3). It is not clear what the ideal level of homocysteine is, but 10 µmol/l or lower appears to pose little harm.
Homocysteine in Vegetarians
In most non-vegetarians with elevated homocysteine, folate is more of a problem than is B12. Since vegetarian diets are typically high in folate, elevated homocysteine levels in vegetarians are normally due to a low B12 intake.
|Plant Sources of Folate (74)|
|Black beans||cooked||1/2 cup||128|
|Romaine lettuce||shredded||1 1/2 cup||114|
|Orange juice||1 cup||109|
|Refried beans||canned||1/2 cup||106|
|Navy beans||cooked||1/2 cup||82|
|Sunflower seeds||1/4 cup||76|
|Pinto beans||cooked||1/2 cup||72|
|Kidney beans||cooked||1/2 cup||63|
At least 14 studies have measured the vitamin B12 and homocysteine levels in vegetarians. The findings have been consistent: When vegetarians do not supplement their diets with vitamin B12 through fortified foods or supplements, their B12 levels drop over time and their homocysteine becomes elevated higher than omnivores, inversely related to their vitamin B12 levels (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18). While this finding is stronger in vegans, it is also true of lacto-ovo vegetarians. In these studies, the average homocysteine levels of vegans were between 14 and 20 µmol/l compared to about 8 to 12 µmol/l for omnivores.
In contrast, a 1998 study of vegans receiving 500 µg/day of vitamin B12 for 2 months showed them to have homocysteine levels below 5 µmol/l (5). A 1999 study showed vegans who averaged 5.6 µg/day of B12 to have homocysteine levels of 7.9 µmol/l, slightly lower than the omnivores (6).
In other words, vegans who make sure they have a reliable intake of vitamin B12 should have ideal homocysteine levels, other things being equal such as enough folate in the diet and not having a genetic variant found in 5-25% of people which increases their need for folate (more info on this in The Linus Pauling Institute’s article, Folate: Genetic variation in folate requirements).
During the late 1990s and 2000s, homocysteine was suspected of causing damage to nerves and blood vessels. In 2009, a group of researchers from the 1st Cardiology Department, Athens University Medical School in Greece wrote:
It is now widely accepted that, at a cellular level, [homocysteine] exerts a detrimental effect on vascular wall and especially on endothelial cells, by decreasing [nitric oxide] bioavailability, increasing intracellular oxidative stress, and by triggering multiple pro-atherogenic mechanisms. (52)
A number of prospective studies found an association between homocysteine and early death. A 1999 study from the USA (19), a 1999 study from Israel (20), and a 2001 study from Norway (22) all found a statistically significant increase in mortality in people with homocysteine levels of about 14 to 15 µmol/l.
The early deaths associated with homocysteine had long been thought to be due mainly to an increase in cardiovascular disease, especially stroke. In 2002, two meta-analyses of prospective studies examining homocysteine and cardiovascular disease found an increased risk associated with elevated homocysteine (23, 24), as did a 2008 meta-analysis of 24 cohort studies (45). A 2006 analysis (38) showed that a reduction in rates of death from stroke in both the USA and Canada paralleled the fortification of foods with folic acid.
At the same time, clinical trials using folate, vitamin B12, and vitamin B6 to lower homocysteine levels in patients were mostly failing to provide any benefit for heart disease (29, 49, 50, 53, 54, 55, 56 , 57, 37), although a number showed a benefit in preventing stroke (28, 58, 59, 60).
In 2010, Clarke et al. (62) published a meta-analysis of clinical trials of homocysteine-lowering therapy and after conducting many different analyses, concluded that there was no evidence, or even a hint, that lowering homocysteine reduces the risk of cardiovascular events, including stroke, even in the trials with large reductions in homocysteine over the course of five years.
In 2013, the Cochrane Collaboration performed a meta-analysis of 12 clinical trials (63). Homocysteine-lowering interventions did not significantly reduce heart disease, stroke, or mortality (though stroke was close to significant with a risk ratio of 0.91, 0.82-1.0). Regarding primary intervention—preventing events in people who had not previously had one—the researchers believed that it had been conclusively proven that lowering homocysteine could not reduce the risk of cardiovascular events by 20% or more. However, an updated Cochrane review in 2017 found that among 10 high-quality, clinical trials homocysteine-lowering treatment reduced the risk of stroke by 10% (75).
A 2012 randomized, placebo-controlled, crossover clinical trial studied the impact of vitamin B12 supplements on cardiovascular markers in vegetarians (mostly lacto-ovo) (1). The study was done in Hong Kong and there were 50 vegetarians, two of whom were vegan. Twelve subjects (24%) had serum vitamin B12 between 203-406 pg/ml and 35 subjects (70%) < 203 pg/ml. After 12-week periods of 500 µg of B12 per day, blood flow improved after vitamin B12 treatment but not after placebo. These positive effects appeared to be better correlated with the correction of vitamin B12 deficiency than with the lowering of homocysteine.
In terms of cardiovascular disease, it is still possible that vitamin B12 could prevent long-term damage in vegans, with most of the benefit coming in the form of stroke prevention, though it is not as much of a concern as it once was.
People who become severely B12-deficient typically exhibit neurological and often cognitive problems. This has raised concerns that mild B12-deficiency over many years could contribute to various forms of deficiency. In some cases, B12-deficient dementia may be misdiagnosed as Alzheimer’s disease (68), but the data is mixed (66).
A 2002 report from the Oxford Vegetarian Study (71) showed that while overall mortality was the same between vegetarians and non-vegetarians, vegetarians had 2.2 times the death rate from mental and neurological diseases (the finding barely reached statistical significance). Given the research above, a low vitamin B12 intake seems like a possible explanation for this finding in vegetarians.
Two literature reviews from 2000 (64, 65) note that people with Alzheimer’s disease have elevated homocysteine, elevated methylmalonic acid (a metabolite indicating low B12 status), low B12 levels, or low folate levels. A 2009 meta-analysis of prospective studies showed elevated homocysteine to be associated with risk of Alzheimer’s disease (67). A 2017 prospective study found that higher homocysteine levels were associated with cognitive decline over the course of three years in middle-aged people (76).
A 2011 study from Chicago Health and Aging Project, found that poor vitamin B12 status in older age is frequently missed by measuring serum vitamin B12 levels alone (72). Their findings suggested that methylmalonic acid (MMA) may affect cognition by reducing total brain volume, whereas the effect of elevated homocysteine on cognition may be caused by increasing white matter hyperintensity volume and strokes.
A 2013 study from the University of Oxford found that B-vitamin treatment significantly reduced brain atrophy, in older subjects at risk for dementia with homocysteine levels above 11 µmol/l, over the course of 2 years (73). They believed that vitamin B12 supplementation (500 µg/day) was the main factor in preventing the atrophy. Some of the authors on this paper had a conflict of interest in that they hold patents to certain vitamin B therapies.
Despite the association between poor B12 status and elevated homocysteine levels with cognitive decline and dementia, trails of vitamin B12 and folate supplementation have shown mixed results for improving cognitive function, or slowing decline, in people with normal or mildly impaired cognition (69, 77). Results are even less promising in people diagnosed with dementia (70).
At this time, it’s prudent for vegans to make sure they’re meeting the recommendations for vitamin B12 to prevent possible cognitive decline or dementia. A mild, long-term deficiency does not appear to be easily corrected by taking B12 once cognitive difficulties are discovered.
Folic acid intake in the weeks before and after conception has been shown to decrease the number of neural tube defects (NTD), such as spina bifida, in at least four studies (39). While the focus has been primarily on folate deficiency, there has been increasing interest in B12’s part, which would be important to vegans:
- Molloy et al. (44) (2009, Ireland) conducted three separate case-control studies and found that women with a serum B12 level of less than 300 pg/ml were significantly more likely to have a baby born with neural tube defects.
- Kirke et al. (41) (1993, Ireland) studied folate and B12 in 328 pregnant women. There was a statistically significant difference between B12 levels of women who had an infant with a NTD (243 pg/ml) and those who did not (296 pg/ml).
- Afman et al. (42) (2001, The Netherlands) found that low levels of a particular measure of B12 activity increased the risk of having a baby with a NTD by 5 times.
- Wald et al. (43) (1996, UK) studied 135 women, 27 of whom had a baby with a NTD. The women who had children with NTDs had B12 levels an average of 38 pg/ml lower in the first trimester than controls. However, after adjusting for folate levels, there was no independent association for B12 and NTDs.
On the other hand, I am unaware of any reports of birth defects in babies born to vegan women with B12 deficiency, and it seems like this would have been reported in the scientific literature by now if it were a problem.
To be safe, ensuring adequate B12 (and folic acid) intake in the weeks before and after conception may reduce the chances of NTDs.
Bone Mineral Density
Taking vitamin B12 might also be important for bone mineral density. Two studies have linked low B12 status in vegetarians to poorer bone health.
For more information, see the Vitamin B12 and Bone Mineral Density.
What Level of B12 Should You Aim For?
Based on data from the National Health and Nutrition Examination Survey (NHANES) III, Selhub et al. (4) determined that 300 pmol/l (405 pg/ml) was the minimum B12 level required to prevent elevated homocysteine. These levels can be achieved by following the B12 recommendations in Daily Needs.
Should Vegans have their Homocysteine or B12 Levels Checked?
Click here to see the article Should I Get My B12 Status Tested?
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