Evidence-Based Nutrient Recommendations

Subclinical B12 Deficiency and Homocysteine in Vegans


More Information on Vitamin B12

Contents

Summary

If someone has little or no vitamin B12 intake for a period of years, severe deficiency can result which manifests as overt symptoms of nerve damage and anemia. It’s also possible to obtain enough B12 to ward off overt deficiency symptoms while not meeting recommendations, resulting in a subclinical deficiency.

There’s evidence that subclinical B12 deficiency increases the risk of cognitive decline, cardiovascular disease (especially stroke), early mortality, and possibly low bone mineral density.

The mechanisms for how subclinical B12 deficiency harms people haven’t been fully elucidated. A lack of B12 for optimal nerve maintenance may take a toll after many years. It’s also possible that homocysteine, which becomes elevated in subclinical B12 deficiency, can directly harm nerves and vessels.

Homocysteine also becomes elevated in folate and vitamin B6 deficiency and it’s not clear whether homocysteine is the primary cause of the damage or merely a marker for vitamin deficiencies. It could be a combination of both.

Vegans who don’t regularly supplement with B12 tend to have low B12 levels and elevated homocysteine levels. It’s important for vegans to follow B12 recommendations to prevent subclinical B12 deficiency.

Background on Homocysteine

Methionine is an essential amino acid obtained from protein in the diet. As a byproduct of metabolism, some methionine is converted to homocysteine. The body turns much of this homocysteine back into methionine with the help of vitamin B12, but if someone is B12-deficient, homocysteine levels will increase.

Normal serum homocysteine levels are from 2.2 to 13.2 µmol/l (Loehrer, 1997). Levels of homocysteine in typical Western populations are about 12 µmol/l (Homocysteine Lowering Trialists’ Collaboration, 1998). According to the European Food Safety Commission (2015), there’s no consensus on a desirable cut-off value for homocysteine, acceptable upper reference limits from 9 to 16 μmol/l have been proposed by a range of researchers, and 15 μmol/l is frequently used as an indicator of hyperhomocysteinemia in adults.

Some people have a genetic variant in folate metabolism, the MTHFR polymorphism, that might require supplementation with 5-methyl-THF though research is currently inconclusive (see the National Institutes of Health article Folate).

Many clinical trials have investigated the impact of pharmacological doses of B12, folic acid, and vitamin B6 in treating diseases associated with elevated homocysteine. To date, they haven’t shown much promise, with some exceptions noted below.

Homocysteine in Vegetarians and Vegans

In most non-vegetarians with elevated homocysteine, folate is more of a problem than is B12. Vegetarians tend to have an advantage regarding folate as many plant foods are good sources. The RDA for adults is 400 µg.

Plant Sources of Folate
Food Preparation Serving µg
Lentils cooked 1/2 cup 179
Black beans cooked 1/2 cup 128
Romaine lettuce shredded 1 1/2 cup 114
Orange juice 1 cup 109
Spinach cooked 1/2 cup 103
Refried beans canned 1/2 cup 106
Garbanzo beans
(aka chickpeas)
cooked 1/2 cup 80
Navy beans cooked 1/2 cup 82
Broccoli cooked 1 cup 78
Sunflower seeds 1/4 cup 76
Pinto beans cooked 1/2 cup 72
Kidney beans cooked 1/2 cup 63
Taken from Wardlaw GM. Perspectives in Nutrition, 4th Ed. Boston, MA: McGraw-Hill; 1999.

Since vegetarian diets are typically high in folate, elevated homocysteine levels in vegetarians are normally due to a low B12 intake.

At least 14 studies have measured the vitamin B12 and homocysteine levels in vegetarians. The findings have been consistent: when vegetarians don’t supplement their diets with B12 their homocysteine levels rise to unhealthy levels (Bissoli, 2002; Crane, 1998; Haddad, 1999; Herrmann, 2001; Herrmann, 2003; Huang, 2003; Hung, 2002; Krajcovicova-Kudlackova, 2000; Krivosikova, 2009; Mann, 1999; Mezzano, 1999; Mezzano, 2000; Obeid, 2002; Refsum, 2001). While this finding is stronger in vegans, it’s also true of lacto-ovo vegetarians.

In the 14 studies above, the average homocysteine levels of vegans were 14 to 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 B12 for 2 months showed them to have homocysteine levels below 5 µmol/l (Crane, 1998). 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 (Haddad, 1999).

In other words, vegans who make sure they have a reliable intake of 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.

Cognition

Vitamin B12 is important for nerve function and people who become severely deficient exhibit neurological and cognitive problems. This has raised concerns that mild B12-deficiency over many years could contribute to cognitive impairment, Alzheimer’s Disease, or other forms of dementia.

The research related to these subjects is vast and inconsistent due to wide variability in methodology. Below, we review what appears to be the most relevant research for vegans.

With respect to B12, only omnivores who don’t regularly meet the Recommended Dietary Allowance for B12 appear to be at risk; vegans should meet VeganHealth’s minimum recommendations (5 µg per day for most adults) to provide the same amount of absorbed B12.

With respect to homocysteine, it’s best to keep levels below 10 µmol/l but this could be more related to folate status than B12.

B12 Status and Prospective Studies of Cognitive Decline

Zhang et al. (2020) conducted a meta-analysis of studies measuring the association between plasma levels of vitamins B12, B6, folate and cognitive function. Among 6 cross-sectional studies, higher B12 levels (OR = 0.77, 95% CI = 0.61–0.97) and folate (OR = 0.68, 95% CI = 0.51–0.90) were associated with better cognition. However, among 5 prospective studies, there was no association between higher B12 levels (OR = 1.27, 95% CI = 0.97–1.67) or intake (1.10, 95% CI = 0.85–1.42) and better cognition. Also among prospective studies, there was no association between folate concentration or intake and better cognition. This finding strongly suggests that poor B12 status in the cross-sectional studies was more likely a result, rather than a cause, of cognitive decline.

The Effects and Mechanism Investigation of Cholesterol and Oxysterol on Alzheimer’s disease (EMCOA) study from China wasn’t included in Zhang et al.’s meta-analysis above and it might be especially relevant to vegans due to the low B12-intake categories (An, 2019). The study included 2,533 people aged 50-70 years with normal cognitive functioning at baseline. After 2 years, compared to the upper two quartiles of B12 intake (2.1–3.4 and 3.4–37 µg/day) the lowest quartile of B12 intake (0–1.3 µg/day) was associated with accelerated cognitive decline across all domains, and the second quartile of B12 intake (1.3–2.1 µg/day) was associated with decline in most cognitive domains. The two lowest B12 intake quartiles were below the U.S. Recommended Dietary Allowance of 2.4 µg/day.

EMCOA conducted a subgroup case-control analysis among those diagnosed with Mild Cognitive Impairment (MCI). Among cases of MCI, they found higher homocysteine and lower folate levels, but not lower B12 intakes or B12 serum levels. They also found disturbances of B-vitamin metabolism and an imbalance of antioxidant-to-free radical ratio among cases. This suggests a larger role for folate than B12 with regard to developing MCI over the course of 2 years.

B12 Metabolites and Brain Volume

A study from the Chicago Health and Aging Project measured B12 metabolites and cognition scores in 121 older adults (Tangney, 2011). Baseline methylmalonic acid (MMA) and homocysteine levels, but not serum B12, were associated with lower total brain volume as measured by an MRI 4.6 years later. Despite the seemingly prospective nature of this study, it’s not clear that reverse causality can be ruled out since MRI measurements weren’t taken at baseline.

Randomized Controlled Trials of B-Vitamins, Cognitive Decline, and Brain Atrophy

The Cochrane Database of Systematic Reviews is a leading journal and database for systematic reviews in healthcare. They conducted a review of randomized clinical trials using B vitamins to slow cognitive decline in people diagnosed with mild cognitive impairment but without overt vitamin deficiencies (McCleery, 2018). Five trials with 879 participants qualified, though one used only folic acid. They concluded that there was probably little or no effect of B vitamins taken for 6 to 24 months on episodic memory, executive function, speed of processing, or quality of life.

The Cochrane review included the VITACOG trial, using a daily dose of folic acid (0.8 mg), B12 (500 µg), and vitamin B6 (20 mg) for 2 years and found evidence for a slower rate of brain atrophy (Douaud, 2013).

In their own meta-analysis, Smith and Refsum, two of the researchers from the VITACOG study, argue that B-vitamins are likely to provide benefit only in populations whose baseline homocysteine levels are greater than 10–11 µmol/l (Smith, 2016). Smith and Refsum hold patents to certain B-vitamin therapies (Douaud, 2013).

Research on Vegetarians and Vegans

There’s no research studying cognitive decline among vegans. For what it’s worth, there have been some studies comparing the mortality from some diseases related to cognition between vegetarians and non-vegetarians.

A 2002 study (Appleby, 2002) on British mortality found vegetarians to have a barely statistically significant, higher risk of death from mental and neurological diseases (DRR 2.21, CI 1.02–4.78). However, in the EPIC-Oxford study (Appleby, 2016), vegetarian deaths from “mental and behavioral disorders” were not statistically different from non-vegetarians (HR 1.22, CI 0.78–1.91). The risk of mortality from neurologic disease in the Adventist Health Study-2 (Orlich, 2013) was also not statistically different for vegetarians compared to non-vegetarians (HR 0.93, CI 0.67-1.29).

Summary of B12 and Cognition

It appears that B12-related cognitive impairment is limited to people who would traditionally be considered at least mildly B12-deficient or with marginal B12 intakes.

It’s prudent for vegans to make sure they’re meeting VeganHealth’s minimum B12 recommendations in order to prevent possible cognitive decline or dementia. Once discovered, cognitive decline appears not to be easily corrected.

Mortality and Cardiovascular Disease

A number of prospective studies have found an association between elevated homocysteine and early death. Studies from the USA (Bostom, 1999), Israel (Kark, 1999), and Norway (Vollset, 2001) all found a statistically significant increase in mortality in people with homocysteine levels of about 14 to 15 µmol/l.

Among prospective, observational studies, three meta-analyses found that elevated homocysteine levels were associated with an increased risk of cardiovascular disease (Homocysteine Studies Collaboration, 2002; Wald, 2002; Humphrey, 2008). Also, a reduction in stroke deaths in both the USA and Canada paralleled the fortification of foods with folic acid (Yang, 2006).

More recently, Chen et al. (2020) conducted a meta-analysis of prospective, observational studies of B-vitamin intake and the risk of stroke. While higher intakes of folate and B6 were associated with a lower risk, B12 was not. Limitations of the analysis are that most studies didn’t adjust for dietary variables such as saturated fat intake, only a small percentage of participants were likely to have had B12 deficiency, and homocysteine levels weren’t analyzed.

The Cochrane Database of Systematic Reviews conducted a meta-analysis of pharmacological doses of B-vitamins for lowering homocysteine and preventing cardiovascular disease in people with and without pre-existing cardiovascular disease. Their analysis included 15 high-quality, randomized controlled trials involving 71,422 participants lasting 1 to 7 years. They found a reduced risk of stroke (RR 0.90, CI 0.82–0.99), but no reduction in overall mortality or heart attacks (Martí-Carvajal, 2017). It’s not clear to what degree the participants in these trials had elevated homocysteine levels with some trials not reporting levels; a meta-analysis comparing the impact of lowering homocysteine only in people with levels above a particular threshold might find a stronger effect.

A 2012 randomized, placebo-controlled, crossover trial from Hong Kong studied the impact of B12 supplements on cardiovascular markers in 50 vegetarians, including 2 vegans. 35 subjects (70%) had B12 levels <150 pg/ml. After 12-week periods of 500 µg of B12 per day, blood flow improved with B12 supplementation. The positive effects more closely correlated to the correction of B12 deficiency than to lowering homocysteine (Kwok, 2012).

Adequate folate status might be more important than B12 for the primary prevention of cardiovascular events in the general population. For vegans, it’s important to follow B12 recommendations in order to maintain homocysteine levels below 10 µmol/l to minimize the risk of cardiovascular disease.

Bone Mineral Density

Vitamin B12 might also be important for bone mineral density, and two studies have linked low B12 status in vegetarians to poorer bone health. For more information, see the Vitamin B12 and Bone Mineral Density.

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Last updated November 2021

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