Vegetarians, Vitamin B12 and Homocysteine
by Jack Norris, R.D.
Readers of Health Science are probably aware of the need for vegans to ensure a reliable source of vitamin B12 to prevent nerve damage in cases of severe depletion. Recent research has uncovered another dangerous condition that can result from less severe B12 depletion: elevated 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.
Homocysteine (HCY) appears to be a nerve and vessel toxin, promoting cardiovascular disease (CVD), stroke, Alzheimer’s Disease, neural tube defects, recurrent pregnancy loss, and overall mortality.
Normal serum homocysteine levels are from 2.2 to 13.2 µmol/l. 1 Levels of homocysteine in typical Western populations are about 12 µmol/l.2
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. 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.
To date, there have been eight studies looking at homocysteine levels in vegetarians. 3,,4,5,6,7,8,9,10Figure 1 shows the blood B12 levels of the participants of those studies. Normal B12 levels are from 200 to 900 pg/ml. As can be seen from Figure 1, vegans had the lowest B12 levels, followed by lacto-ovo-vegetarians, and then non-vegetarians. Please note that the USA vegans had an average B12 intake, through fortified foods and supplements, of 5.6 µg/day. The vegetarians in the other studies did not supplement their diets with B12.
Figure 1. Serum B12 levels (pg/ml) in non-vegetarians (NV), lacto-ovo-vegetarians (LOV), and vegans in homocysteine studies. Numbers for vegetarians in the Italy study were not reported.
Figure 2 shows the blood homocysteine levels in the vegetarians who did not eat B12-fortified foods or take supplements. As you can see, the results are almost the exact opposite as those shown in Figure 1, with vegans having the highest homocysteine levels, lacto-ovo-vegetarians having the next highest, and non-vegetarians having the lowest. This indicates that in vegetarians, B12 levels seem to be inversely, and directly, related to homocysteine levels.
Figure 2. Homocysteine levels (µmol/l) in non-vegetarians (NV), lacto-ovo-vegetarians (LOV), and vegans not supplementing with vitamin B12 through fortified foods or vitamins.
Figure 3 shows the homocysteine levels in vegetarians who either supplement with B12 or after a B12 injection (as indicated). The B12 levels or intakes of the vegetarians in Italy were not reported, and it is not clear why their homocysteine levels were so high. But the vegetarians in Chile, and the vegans in the USA, show very healthy homocysteine levels compared to those in Figure 3.
Figure 3. Homocysteine levels (µmol/l) in lacto-ovo-vegetarians (LOV) and vegans supplementing with vitamin B12 through fortified foods or vitamins. IMI = intramuscular injection.
Thus, vegans and vegetarians who supplement with B12 have homocysteine levels that are considered healthy, while vegans and vegetarians who do not supplement with B12 tend to have high homocysteine levels — higher than those in non-vegetarians. But, does this really matter?
Elevated homocysteine levels are associated with many diseases. However, there is a question about whether elevated homocysteine causes, or is simply a result, of those diseases. Studies on homocysteine and disease can be divided into two types:
• Cross-sectional – The homocysteine levels in people with diseases are measured and compared to those without diseases. These can only show an association, but do not give evidence of cause. For this reason, such studies are not reviewed here in any depth.
• Prospective – Homocysteine levels are measured for a large population and that population is followed. The people who get diseases are compared to those who do not to see if there were originally differences in homocysteine levels. If the people with higher homocysteine levels get the disease at higher rates, it could be that homocysteine causes the disease.
Figure 4 shows the results of the three prospective studies11,12,13 of homocysteine and mortality in which the subjects were free of known disease at the beginning of the study. They included a total of 8,847 people. The results indicate that a homocysteine level of about 15 µmol/l is associated with a 50 to 100% increase in mortality when compared to levels of about 5 to 9 µmol/l. All of the studies adjusted their results for the blood pressure of the participants. The Norway and USA studies also adjusted for cholesterol levels.
Figure 4. Homocysteine levels and increased risk for mortality.
Cardiovascular disease (CVD) includes ischemic heart disease (IHD) (heart attack), coronary artery disease (CAD; plaque obstruction of the coronary arteries to the heart), and stroke. In October and November of 2002, two meta-analyses of prospective studies examining homocysteine and CVD were published.
The Homocysteine Studies Collaboration (HSC) included 11 prospective studies of IHD and 8 of stroke. 14 It compiled data from 9,025 people. HSC’s analysis was geared mainly towards how much disease could be reduced through lowering homocysteine levels by 25% (about 3 µmol/l). After adjusting for age, sex, smoking, systolic blood pressure, and total cholesterol levels, a 25% lower homocysteine level reduced the risk of IHD by 11%, and the risk of stroke by 19%.
The second meta-analysis was Homocysteine and Cardiovascular Disease: evidence on causality from a meta-analysis. 15 In 16 prospective studies of IHD, a 5 µmol/l increase in homocysteine increased risk 23%. In 8 prospective studies on stroke, a 5 µmol/l increase in homocysteine increased risk 42%. The results were adjusted for age, sex, smoking, cholesterol, and blood pressure (except for one study which adjusted only for age and sex).
To get a ballpark idea of what lowering risks might mean for the typical person, Table 1 shows reduced risks based on data provided by the American Heart Association. 16 Particularly for stroke, the decreased rates are tangible. The greater effect of elevated homocysteine on stroke compared to heart disease could explain why vegetarians have not been shown to have lower rates of death from stroke, while they do have lower death rates from heart disease, than meateaters. 17
Table 1. Heart Attack and Stroke Rates Among Americans and Potential Reductions by Reducing Risk.16
Chances of Heart Attack Between the Ages of 35 and 74 years old
Reducing Risk by:
11% 23%
1 out of (1 out of) (1 out of)
Women
Black 3.6 4.0 4.6
Non-black 6.5 7.3 8.4
Men
Black 2.3 2.5 2.9
Non-black 2.2 2.5 2.9
Chances of Stroke Between the Ages of 35 and 74 years old
Reducing Risk by:
19% 42%
1 out of (1 out of) (1 out of)
Women
Black 4.5 5.6 7.8
White 12.7 15.7 21.9
Men
Black 4.8 6.0 8.4
White 5.8 7.1 10.0
Thus, both meta-analyses found that even after adjusting for blood pressure and cholesterol levels, homocysteine either causes IHD and stroke, or is strongly paired with an unknown factor that causes IHD and stroke.
A few caveats should be made about these studies:
• They do not prove casualty. However, they do show that homocysteine either promotes these diseases or is strongly associated with another factor that promotes these diseases.
• Elevated homocysteine might cause an increase in blood pressure. One study found that after folate (5 mg) and vitamin B6 (250 mg/d) therapy for 2 years, blood pressure went down in a group of 130 relatively healthy people, 65% of whom had elevated homocysteine at the beginning of the study. 18 If elevated homocysteine raises blood pressure, then adjusting disease risk for blood pressure will dilute the true effect of elevated homocysteine.
• People with high homocysteine at the beginning of these studies might have changed their diets or supplementation behaviors after the initial measurement of homocysteine. This would dilute the true effect of elevated homocysteine.
So, while it is true that the above studies do not prove that homocysteine causes the diseases it is associated with, it is also likely that the true effect of elevated homocysteine levels are masked.
The British Medical Journal published an analysis19 of 12 studies on the effectiveness of reducing homocysteine levels with folic acid and vitamin B12 and/or B6 supplements for 3-12 weeks. They concluded that folic acid in the range of 500-5,000 µg/day reduced homocysteine by 25%, and that B12 supplements (average intake of 500 µg/day) reduced it a further 7%. Vitamin B6 supplements (average of 16.5 mg/day) did not reduce homocysteine further.
500 µg B12/day is probably more than necessary. In one study reported in the BMJ, only 100 µg B12/day (combined with folate and B6) was successful in reducing homocysteine from 7.2 to 5.8 µmol/l. 19 In another, only 20 µg B12/day (combined with folate and B6) resulted in reducing homocysteine from 11.9 to 7.8 µmol/l. 19 Smaller amounts of B12 were not tested.
Reversing Heart Disease through Homocysteine Treatment
Hackam et al. 20 (2000, Canada) treated 100 patients with rapidly progressing atherosclerosis who had not responded well to a program of diet, exercise, smoking cessation, or drug treatment for high cholesterol and triglycerides. The treatment consisted of 2.5 mg folic acid, 25 mg of vitamin B6, and 250 µg B12/day for about 2 years. The results are shown in Table 2. Vitamin therapy actually reversed the amount of plaque in some of the patients, including some with a homocysteine level below 14 µmol/l.
Studies show that vegans have lower cholesterol levels21 and blood pressure22 than non-vegetarians. These, and possibly other factors in the vegan diet, have led some to believe that vegans are protected against these diseases so much that they do not need to care about homocysteine. However, the above studies on homocysteine and mortality and CVD were adjusted for differences in cholesterol levels and blood pressure. Therefore, vegans should not consider themselves completely protected, especially those vegans who are in the upper range of cholesterol and blood pressure.
Approximately 6-8% of all people older than 65 have Alzheimer’s Disease (AD). 23 At least two recent literature re-views23,24 and a letter to the editor25 note people with AD have elevated homocysteine, elevated methylmalonic acid (a metabolite indicating low B12 status), reduced B12, or reduced folate levels; although the data is somewhat mixed. 25 In some cases B12-deficient dementia (which is a concern in itself) may be misdiagnosed as AD. 26
There have been 2 prospective studies of note on this subject:
• Seshadri et al. 27 (2002, USA) conducted an 8-year prospective study of 1092 elderly people in which a 5 µmol/l increase in homocysteine increased the risk of AD by 40%.
• Wang et al. 28 (2001, Sweden) studied 370 non-demented people for over 3 years. They found that having both a B12 level ≤ 203 pg/ml and a folate level ≤ 10 nmol/L increased risk for AD 2.3 times compared to those with folate and B12 above those levels (after adjusting for age, sex, and education). Homocysteine levels were not measured.
Thus, there is some preliminary evidence that elevated homocysteine can cause AD, although the question is far from resolved.
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. 29 The basis for this is not yet completely clear. It could be that when homocysteine cannot be converted back into methionine, there is not enough methionine available for normal closure of the neural tube. Some evidence for this is a case-control study in which women with the lowest methionine intakes had a higher rate of having a baby with a NTD. 30 While the focus has been primarily on folate, there has been increasing interest in B12’s part, which would be important to vegans. Kirke et al. 31 (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. 32 (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. 33 (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.
Ensuring adequate B12 and folic acid intake in the weeks before and after conception may reduce the chances of NTDs.
A number of retrospective, case-control studies have been performed, looking at elevated homocysteine levels and recurrent first trimester pregnancy loss. Nelen et al. 34 (2000) conducted a meta-analysis of the studies performed from 1992 to 1999. They found that women with elevated homocysteine levels (> 10-18.3 µmol/l) had a statistically significant, 170% greater chance of two or more pregnancy losses in the first trimester. They were not able to determine whether elevated homocysteine is a marker or a cause of the pregnancy loss.
Although homocysteine is not the only issue of concern in formulating recommendations for B12 levels, it is a fairly good proxy for other issues. Selhub et al. 35 analyzed data from 8,083 people, including whites, blacks, and Hispanics, and found that elevated homocysteine levels (> 11.4 µmol/l for men, > 10.4 µmol/l for women) were associated with B12 levels less than 338 pg/ml. A level of 430 pg/ml provides a safety factor for homocysteine and other potential problems.
In any given dose (at least six hours from ingestion of another dose of B12), the first 2 µg of B12 result in an absorption rate of 50%, or 1 µg. A dose of 5 µg will result in an additional .5 µg absorbed for a total of 1.5 µg. Any amount above 5 µg is absorbed at a rate of 1%.36 B12 levels of 350 to 430 pg/ml require 1 to 2.5 µg of B12 to be absorbed per day. This can be accomplished in many ways, but I recommend the following:
• 3 to 5 µg (i.e., about 50 to 80% of the Daily Value) from fortified foods in at least 2 servings, spaced 6 hours apart
• 10 to 100 µg from 1 supplement
• 5 µg from 2 supplements spaced at least 6 hours apart
If you are a vegetarian and have not had a regular source of B12 for some time, I recommend that you buy a bottle of sublingual B12. Place 2,000 µg under your tongue until the tablet(s) has dissolved, once a day, for 2 weeks. This should get your B12 back to a healthy level, if it is depleted. You can then follow the above advice. (Note: you can break the remaining sublingual tablets in halves or quarters for Step #2. It’s okay to take more than recommended.)
Vegans who supplement with vitamin B12 do not need to get their homocysteine or B12 levels checked merely because they are vegan. Rather, being vegan means that you should get a regular, reliable source of vitamin B12 from fortified foods and/or supplements.
Joel Fuhrman, M.D., 37 recommends that all adults over age 45 have their homocysteine levels checked in order to catch a genetic predisposition to high homocysteine, which can often be successfully treated. It is best to ensure a reliable source of B12 and folic acid for a few weeks prior to the test. Otherwise, a high homocysteine will not tell you whether you have a genetic predisposition, or if it was simply from a lack of B12 or folic acid in your diet. On the other hand, high homocysteine after a period of adequate B12 and folic acid intake shows that something else is a problem.
About 2% of people do not absorb B12 well. While this has nothing to do with being vegan, it is nice to know if you are such a person. You will not be able to tell unless you first have a reliable source of B12 for at least a few weeks before your B12 level is checked. Additionally, there are specific tests that measure B12 absorption.
If you get your B12 level checked, please note that eating seaweeds can falsely inflate B12 levels. Methods for determining B12 level do not distinguish between B12 and some inactive B12 analogues. Many seaweeds contain a variety of inactive B12 analogues. Someone who is eating large amounts of seaweed may have serum B12 levels well above normal, but much of it could be inactive B12 analogues.
Vegetarians who do not supplement their diet with vitamin B12 tend to have elevated homocysteine levels. Elevated homocysteine is probably a cause of early mortality, heart disease, stroke and recurrent pregnancy loss. It also may be a partial cause of Alzheimer’s disease and neural tube defects. Vegetarians who eat B12-fortified foods or supplements in amounts of 3 to 100 µg per day will minimize any elevated homocysteine problems due to a low B12 intake.
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©Copyright 2003. All Rights Reserved. Health Science is the publication of the National Health Association. This article reprinted from the Spring 2003 issue.