homocysteine i.e. mild b12 deficiency as disease marker of vegetarians

7/28/2019 Homocysteine i.e. Mild B12 Deficiency as Disease Marker of Vegetarians

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by Jack Norris, RD &Ginny Messina,

MPH, RDFor Updates: Follow @JackNorrisRD or subscribe to JackNorrisRD.com

Mild B12 Deficiency - Cardiovascular Disease &Homocysteine

Last updated J uly, 2012

Summary: Vegetarians who do not supplement their diet with vitamin B12 tend to have elevated homocysteinelevels. Elevated homocysteine is associated with early mortality, heart disease, stroke, dementia, and birthdefects. There is evidence that lowering homocysteine levels in otherwise healthy people can prevent death fromstroke. A 2012 study found that vitamin B12 supplements improved cardiovascular function in vegetariansindependently of lowering homocysteine levels. Vegetarians who follow B12 recommendations will minimizeany elevated homocysteine problems due to a low B12 intake.

Contents

Introduction Background on Homocysteine Homocysteine in Vegans and Lacto-ovo Vegetarians Homocysteine and Disease Elevated Homocysteine is Associated with Increased Mortality Homocysteine's Association with Cardiovascular Disease Vitamin B12 Supplementation in Lacto-ovo Vegetarians and Cardiovascular Markers Lowering Homocysteine with Vitamins in Non-vegetarians

Secondary Prevention of Cardiovascular Disease by Lowering Homocysteine Primary Prevention of Stroke But Aren't Vegans Protected From Cardiovascular Disease? B12, Homocysteine, and Dementia Homocysteine and Birth Defects What Level of B12 Should You Aim For? Should Vegans have their Homocysteine or B12 Levels Checked? References

Introduction

Most vegans are probably aware of the need to ensure a reliable source of vitamin B12 to prevent nerve damagein cases of severe depletion. Around 2000, research uncovered another dangerous condition that can result fromless severe B12 depletion: elevated homocysteine.

Background on Homocysteine

Methionine is an essential amino acid obtained from protein in the diet. Some methionine is turned intohomocysteine. The body turns much of this homocysteine back into methionine with the help of vitamin B12. Ifsomeone is B12-deficient, homocysteine levels will increase because this reaction cannot take place.

Homocysteine appears to be a nerve and vessel toxin, promoting mortality, cardiovascular disease (CVD),stroke, and dementia. High homocysteine levels are also associated with birth defects. These will each bediscussed below.

Normal serum homocysteine levels are from 2.2 to 13.2 mol/l (2). Levels of homocysteine in typical Westernpopulations are about 12 mol/l (3).

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.

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In most non-vegetarians with elevated homocysteine, folate is more of a problem than is B12. Since vegetariandiets are typically high in folate, elevated homocysteine levels in vegetarians are normally due to a low B12intake (click here for a list of plant sources of folate).

Homocysteine in Vegans and Lacto-ovo Vegetarians

At least 14 studies have measured the homocysteine levels in vegetarians. Figure 1 shows the blood B12 levelsof the participants of 13 of those studies (one did not report B12 levels (16)).

Figure 1: Serum B12 Levels in Homocy steine Studies on Vegetarians (pg/ml)

A - Most of these vegetarians did not supplement their diets with B12.

USA '985, USA '99 (averaged 5.6 g B12/day)6, Australia '997, Chile '998, Chile '009, Slovak

Republic '0010, India '0111, Germany '0112, Taiwan '0213, Italy '0214, Germany '0215, Taiwan

'0317, Germany '0318, Germany '03 (took "B vitamins", amounts not reported)18

Normal B12 levels are from 200 to 900 pg/ml. Figure 1 shows that vegans had the lowest B12 levels, followed bylacto-ovo-vegetarians, and then non-vegetarians. P lease note that the USA vegans had an average B12 intake,through fortified foods and supplements, of 5.6 g/day. Some of the vegetarians in the 2003 Germany studywere probably supplementing with B12, but amounts were not given. The vegetarians in the other studies did notsupplement their diets with B12.

Figure 2 shows the blood homocysteine levels in the vegetarians who did not eat B12 fortified foods or takesupplements.

Figure 2: Homocysteine Levels in Vegetarians (Mostly or Al l) Not Supplementingwith B12 (mol/l)

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1998 USA5, 1999 Australia7, 1999 Chile8, 2000 Chile9, 2000 Slovak Republic10, 2001 India11,

2001 Germany12 2002 Taiwan11, 2002 Italy14, 2002 Germany15, 2002 United Kingdom16, 2003

Taiwan17

, 2003 Germany18

The results in Figure 2 are the mirror opposite as those shown in Figure 1, with vegans having the highesthomocysteine levels, lacto-ovo-vegetarians having the next highest, and non-vegetarians having the lowest. Theconsistency of this finding indicates that in vegetarians, B12 levels are inversely related to homocysteine levels.

Figure 3 shows the homocysteine levels in vegetarians who either supplement with B12 or after a B12 injection(as indicated).

Figure 3: Homocy steine Levels in Vegetarians Receiving B12 (mol/l)

98 USA - 500 g/day for 2 months5; B12 levels increased to 553 pg/ml

99 USA - averaged 5.6 g B12/day6

00 CHILE - 1,000 g intramuscular injection9




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02 ITALY - B12 amount not reported14

03 GER - Germany; B12 amount not reported18

Neither the B12 levels nor the B12 intakes of the vegetarians in Italy were reported, and it is not clear why theirhomocysteine levels were so high. But the vegetarians in Chili, and the vegans in the USA, show very healthyhomocysteine levels compared to those in Figure 2.

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 - higherthan those in non-vegetarians.

Homocysteine and Disease

After reviewing the research on each of the following topics, Antoniades et al. (2009) write (52):

It is now widely accepted that, at a cellular level, [homocysteine] exerts a detrimental effect onvascular wall and especially on endothelial cells, by decreasing [nitric oxide] bioavailability,increasing intracellular oxidative stress, and by triggering multiple pro-atherogenic mechanisms. Inthis context, epidemiological studies have clearly demonstrated that plasma [homocysteine] is anindependent risk factor for atherosclerosis.

Elevated Homocysteine is Associated with Increased Mortality

A 1999 prospective study from the USA (19), a 1999 prospective study from Israel (20), and a 2001 prospectivestudy from Norway (22) all found a statistically significant increase in mortality in people with homocysteine levels

of about 14 to 15 mol/l. A 2001 prospective study from Norway found an increased risk of mortality but that wasnot statistically significant, although the analysis only tested for significance between people above and below 14mol/l (21); had they tested against people with less than 10 mol/l, the finding would have been stronger.

All of the studies adjusted their results for the blood pressure of the participants. The USA, Norway, andNetherlands studies also adjusted for cholesterol levels.

These studies show a considerable risk in mortality associated with high homocysteine levels. If you average thetwo studies that calculated a risk of death per 5 mol/l, you get an increased risk of 33% per 5 mol/l increase inhomocysteine.

Homocysteine's Association with Cardiovascular Disease

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 2002, two meta-analyses ofprospective studies examining homocysteine and CVD were published.

The Homocysteine Studies Collaboration (HSC) included 11 prospective studies of IHD and 8 of stroke (23). Itcompiled data from 9,025 people. HSC's analysis was geared mainly towards how much disease could bereduced through lowering homocysteine levels by 25% (about 3 mol/l). After adjusting for age, sex, smoking,systolic blood pressure, and total cholesterol levels, a 25% lower homocysteine level reduced the risk of IHD by11%, and the risk of stroke by 19%.

The second meta-analysis (24) examined 16 prospective studies of IHD. A 5 mol/l increase in homocysteineincreased risk 23%. In 8 prospective studies on stroke, a 5 mol/l increase in homocysteine increased risk 42%.The results were adjusted for age, sex, smoking, cholesterol, and blood pressure (except for one study whichadjusted only for age and sex).

In 2008, Humphrey et al. (45) conducted a meta-analysis which included 24 cohort studies. They found that eachincrease of 5 mol/L in homocysteine level increases the risk of CHD events by approximately 20%, independentof traditional CHD risk factors.

Vitamin B12 Supplementation in Lacto-ovo Vegetarians and Cardiovascular

Markers

A 2012 randomized, placebo-controlled, crossover clinical trial tested B12 supplementation's effects on flow-mediated dilation (FMD) of the brachial artery and intima-media thickness (IMT) of the carotid artery, both ofwhich are markers of cardiovascular disease (1). The study was done in Hong Kong and there were 50vegetarians, two of whom were vegan. Twelve subjects (24%) had serum vitamin B-12 between 203-406 pg/mland 35 subjects (70%)


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Lowering Homocysteine with Vitamins in Non-vegetarians

It is clear that most people with slightly elevated (or higher) homocysteine levels can lower them through takingfolate and vitamin B12. In 1998, the British Medical J ournal published an analysis of 12 studies and concludedthat folic acid in the range of 500-5,000 g/day reduced homocysteine by 25%, and that B12 supplements(average intake of 500 g/day) reduced it a further 7%. Vitamin B6 supplements (average of 16.5 mg/day) didnot reduce homocysteine further.

500 g B12/day is a lot more than necessary. In one study reported in the BMJ , only 100 g B12/day (combinedwith folate and B6) was successful in reducing homocysteine from 7.2 to 5.8 mol/l (3). In another, only 20 g

B12/day (combined with folate and B6) resulted in reducing homocysteine from 11.9 to 7.8 mol/l (3). Smalleramounts of B12 were not tested.

People with kidney problems should not take large doses of cyanocobalamin, as they often cannot metabolizethe cyanide efficiently. For more information, please see the Chronic Kidney Failure section ofPeople WhoShould Not Take the Cyanocobalamin Form of B12. In fact, there is evidence that cyanocobalamin is noteffective at lowering homocyesteine in people with kidney disease (61).

Secondary Prevention of Cardiovascular Disease by LoweringHomocysteine

There have been a lot of clinical trials to see if lowering homocysteine through vitamin supplementation willdecrease cardiovascular events in people already diagnosed with cardiovascular disease. Although most trialshave shown no benefit (29, 49, 50, 53, 54, 55, 56 , 57, 37), some have shown benefit in preventing stroke (28,58, 59, 60).

In their 2009 review, Antoniades et al. (52) conclude:

The existing data support that low-dose folate treatment (achieved by folate food fortification) mayreduce cardiovascular risk, but any pharmacological treatment with folates on top of that is unlikelyto achieve any additional benefit in subjects with plasma [homocysteine] within the 'normalrange' [


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Afman et al. (42) (2001, The Netherlands) found that low levels of a particular measure of B12 activityincreased 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 hadchildren 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 B12deficiency, 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 reducethe chances of NTDs.

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 cutoff for keeping homocysteine at a healthy level. These levelscan be accomplished by following the recommendations listed here.

Should Vegans have their Homocysteine or B12 Levels Checked?

Click here to see the Should I Get My B12 Status Tested?

References

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51. See the section How Recommendations were Formulated of Vitamin B12: Are You Getting It?




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homocysteine i.e. mild b12 deficiency as disease marker of vegetarians

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