B12 and Disease: Homocysteine

Summary: 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, neural tube defects, and certain eye disorders. 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.

Introduction

Most vegans 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.

If homocysteine is a cause of the diseases with which it is associated, it is due to the body's prolonged exposure to homocysteine. People are now living longer, allowing homocysteine more time to do its damage. So, while it may seem unnatural to take a supplement, the need to do so may be at least partially caused by our increased longevity.

The most recent analysis of the Oxford Vegetarian Study was reported in 2002 in "Mortality in British Vegetarians."¹ Overall mortality was the same between vegetarians and non-vegetarians. But vegetarians had 2.2 times the death rate from mental and neurological diseases as non-vegetarians. (The finding barely reached statistical significance.) An obvious guess as to why is that vegetarians probably had higher homocysteine and lower B12 levels leading to more neurological problems. If we fix this problem, we will, hopefully, begin to see better mortality rates than non-vegetarians with similiar lifestyles.

Introduction References

1. Appleby PN, Key TJ, Thorogood M, Burr ML, Mann J. Mortality in British vegetarians. Public Health Nutr. 2002 Feb;5(1):29-36. Abstract

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.

Homocysteine appears to be a nerve and vessel toxin, promoting mortality, cardiovascular disease (CVD), stroke, Alzheimer's Disease, birth defects, recurrent pregnancy loss, and eye disorders. These will each be discussed below.

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 Although this is "normal," it is not necessarily healthy.

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 (click here for a list of plant sources of folate).

It is possible that free homocysteine is more harmful than protein-bound homocysteine.³ At this time, few studies on homocysteine and disease have distinguished between the two. Eventually, the research may focus on free homocysteine, although the treatment will probably be the same.

Background on Homocysteine References

1. Loehrer FM, Schwab R, Angst CP, Haefeli WE, Fowler B. Influence of oral S-adenosylmethionine on plasma 5-methyltetrahydrofolate, S-adenosylhomocysteine, homocysteine and methionine in healthy humans. J Pharmacol Exp Ther. 1997 Aug;282(2):845-50.
2. [No author.] Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. BMJ. 1998 Mar 21;316(7135):894-8.
3. Chambers JC, Ueland PM, Obeid OA, Wrigley J, Refsum H, Kooner JS. Improved vascular endothelial function after oral B vitamins: An effect mediated through reduced concentrations of free plasma homocysteine. Circulation. 2000 Nov 14;102(20):2479-83.

Homocysteine in Vegans and Lacto-Ovo-Vegetarians

To date, there have been 14 studies looking at homocysteine levels in vegetarians. Vegetarians refers to vegans and lacto-ovo-vegetarians. Figure 1 shows the blood B12 levels of the participants of 13 of those studies (1 study did not report B12 levels¹²).

Figure 1: Serum B12 Levels in Homocysteine Studies on Vegetarians^A (pg/ml)

A - Most of these vegetarians did not supplement their diets with B12 98 US - 1998 United States¹ 99 US - 1999 USA; averaged 5.6 µg B12/day² 99 AUS - 1999 Australia³ 99 CH - 1999 Chile⁴ 00 CH - 2000 Chile⁵ 00 SLR - 2000 Slovak Republic⁶	01 IND - 2001 India⁷ 01 GER - 2001 Germany⁸ 02 TAI - 2002 Taiwan⁹ 02 ITALY - 2002 Italy¹⁰ 02 GER - 2002 Germany¹¹ 03 TAI - 2003 Taiwan¹³ 03 GER - 2003 Germany¹⁴ 03 GER B-Vit - 2003 Germany; took "B vitamins" (amounts not reported)¹⁴

Normal B12 levels are from 200 to 900 pg/ml. Figure 1 shows that vegans had the lowest B12 levels, followed by lacto-ovo-vegetarians, and then non-vegetarians. Please note that the US vegans had an average B12 intake, through fortified foods and supplements, of 5.6 µg/day. Some of the vegetarians in the GER 03 study were probably supplementing with B12, but amounts were not given. The vegetarians in the other studies did not supplement their diets with B12.

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

Figure 2: Homocysteine Levels in Vegetarians (Mostly or All) Not Supplementing with B12 (µmol/l)

98 US - 1998 United States¹ 99 AUS - 1999 Australia³ 99 CH - 1999 Chile⁴ 00 CH - 2000 Chile⁵ 00 SLR - 2000 Slovak Republic⁶ 01 IN - 2001 India⁷ 01 GER - 2001 Germany⁸	02 TAI - 2002 Taiwan⁹ 02 IT - 2002 Italy¹⁰ 02 GER - 2002 Germany¹¹ 02 UK - 2002 United Kingdom¹² 03 TAI - 2003 Taiwan¹³ 03 GER - 2003 Germany¹⁴

The results in Figure 2 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. The consitency 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: Homocysteine Levels in Vegetarians Receiving B12 (µmol/l)

98 USA - 500 µg/day for 2 months¹; B12 levels increased to 553 pg/ml 99 USA - averaged 5.6 µg B12/day² 00 CHILE - 1,000 µg intramuscular injection⁵ 02 ITALY - B12 amount not reported¹⁰ 03 GER - Germany; B12 amount not reported¹⁴

Neither the B12 levels nor the B12 intakes of the vegetarians in Italy were reported, and it is not clear why their homocysteine levels were so high. But the vegetarians in Chili, and the vegans in the USA, show very healthy homocysteine 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 – higher than those in non-vegetarians. But, does this really matter?

Notes for Homocysteine in Vegans and Vegetarians

1. Crane MG, Register UD, Lukens RH, Gregory R Cobalamin (CBL) studies on two total vegetarian (vegan) families. Vegetarian Nutrition. 1998; 2(3):87-92.

2. Haddad EH, Berk LS, Kettering JD, Hubbard RW, Peters WR. Dietary intake and biochemical, hematologic, and immune status of vegans compared with nonvegetarians. Am J Clin Nutr. 1999;70(suppl):586S-93S.

3. Mann NJ, Li D, Sinclair AJ, Dudman NP, Guo XW, Elsworth GR, Wilson AK, Kelly FD. The effect of diet on plasma homocysteine concentrations in healthy male subjects. Eur J Clin Nutr. 1999 Nov;53(11):895-9.

4. Mezzano D, Munoz X, Martinez C, Cuevas A, Panes O, Aranda E, Guasch V, Strobel P, Munoz B, Rodriguez S, Pereira J, Leighton F. Vegetarians and cardiovascular risk factors: hemostasis, inflammatory markers and plasma homocysteine. Thromb Haemost. 1999 Jun;81(6):913-7.

5. Mezzano D, Kosiel K, Martinez C, Cuevas A, Panes O, Aranda E, Strobel P, Perez DD, Pereira J, Rozowski J, Leighton F. Cardiovascular risk factors in vegetarians. Normalization of hyperhomocysteinemia with vitamin B(12) and reduction of platelet aggregation with n-3 fatty acids. Thromb Res. 2000 Nov 1;100(3):153-60.

6. Krajcovicova-Kudlackova M, Blazicek P, Kopcova J, Bederova A, Babinska K. Homocysteine levels in vegetarians versus omnivores. Ann Nutr Metab. 2000;44(3):135-8.

7. Refsum H, Yajnik CS, Gadkari M, Schneede J, Vollset SE, Orning L, Guttormsen AB, Joglekar A, Sayyad MG, Ulvik A, Ueland PM. Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. Am J Clin Nutr. 2001 Aug;74(2):233-41.

8. Herrmann W, Schorr H, Purschwitz K, Rassoul F, Richter V. Total homocysteine, vitamin b(12), and total antioxidant status in vegetarians. Clin Chem. 2001 Jun;47(6):1094-101.

9. Hung CJ, Huang PC, Lu SC, Li YH, Huang HB, Lin BF, Chang SJ, Chou HF. Plasma Homocysteine Levels in Taiwanese Vegetarians Are Higher than Those of Omnivores. J Nutr. 2002 Feb;132(2):152-158.

10. Bissoli L, Di Francesco V, Ballarin A, Mandragona R, Trespidi R, Brocco G, Caruso B, Bosello O, Zamboni M. Effect of vegetarian diet on homocysteine levels. Ann Nutr Metab. 2002;46(2):73-9.

11. Obeid R, Geisel J, Schorr H, Hubner U, Herrmann W. The impact of vegetarianism on some haematological parameters. Eur J Haematol. 2002 Nov;69(5-6):275-9.

12. Cappuccio FP, Bell R, Perry IJ, Gilg J, Ueland PM, Refsum H, Sagnella GA, Jeffery S, Cook DG. Homocysteine levels in men and women of different ethnic and cultural background living in England. Atherosclerosis. 2002 Sep;164(1):95-102.

13. Huang YC, Chang SJ, Chiu YT, Chang HH, Cheng CH. The status of plasma homocysteine and related B-vitamins in healthy young vegetarians and nonvegetarians. Eur J Nutr. 2003 Apr;42(2):84-90.

14. Herrmann W, Schorr H, Obeid R, Geisel J. Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians. Am J Clin Nutr. 2003 Jul;78(1):131-6.

Homocysteine and Disease

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. Because the disease could cause elevated homocysteine levels, these studies only show an association; they do not give evidence of a 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 a fdisease at higher rates, it could be that homocysteine causes the disease.

Homocysteine and Mortality

The table below shows the results of the 4 prospective studies^1,2,3,4 of homocysteine and mortality. They included a total of 9,298 people. Unless otherwise noted, the findings were statistically significant (less than a 5% chance of being due to random chance).

Homocysteine and Increased Risk for Mortality^A
Homocysteine level (µmol/l)	Increased mortality rate

1999, USA, Framingham Study¹ 1,933 people age 59-91 after 10-13 years follow-up
< 14.26^B	controls
> 14.26^B	1.54
Adjusted for: age, sex, diabetes, smoking, BP, cholesterol.

1999, Israel² 1,788 people age ≥ 50 after 9-11 years follow-up
≤ 8.52	controls
11.90-14.69	1.53
≥ 14.7	1.97
Adjusted for: age, BP, serum glucose, health status, serum creatinine. A SS association between plasma homocysteine and increased risk of mortality was found for all deaths, CVD, CHD, and all other causes, but not for cancer.

2000, Netherlands³ 811 people age 50-70 (at entry) after 5 years follow-up
< 14.0	controls
> 14.0	1.34^NS
5 µmol/l increase	1.17^NS
In subjects without Type II diabetes. Adjusted for cholesterol, BP, age, sex, smoking, and albumin. From data given, it appears that if subjects > 14 were compared to subjects with < 10, there would have been a SS difference.

2001, Norway⁴ 4,766 people age 65-67 after a median of 4.1 years follow-up
5.1-8.9	controls
15.0-19.9	2.10
20.0-137	1.64
5 µmol/l increase	1.49
For those with no history of heart attack, stroke, angina, diabetes, or high BP treatment; and adjusted for total cholesterol, blood pressure, smoking, body mass index, physical activity, age, and gender.
A - For example, "1.54" means that group of people had a 54% higher rate of death than the control group B - Average and median for the group were not reported BP – Blood pressure NS - Not statistically significant

All of the studies adjusted their results for the blood pressure of the participants. The USA, Norway, and Netherlands studies also adjusted for cholesterol levels. These studies show a considerable risk in mortality associated with high homocysteine levels. If you average the two studies that calculated a risk of death per 5 µmol/l, you get an increased risk of early death of 33% per 5 µmol/l increase in homocysteine. Using this figure, lowering homocysteine from about 15 to about 8 µmol/l would be associated with a 46% lower risk of early death.

Notes for Homocysteine and Mortality

1. Bostom AG, Silbershatz H, Rosenberg IH, Selhub J, D'Agostino RB, Wolf PA, Jacques PF, Wilson PW. Nonfasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women. Arch Intern Med. 1999 May 24;159(10):1077-80.

2. Kark JD, Selhub J, Adler B, Gofin J, Abramson JH, Friedman G, Rosenberg IH. Nonfasting plasma total homocysteine level and mortality in middle-aged and elderly men and women in Jerusalem. Ann Intern Med. 1999 Sep 7;131(5):321-30.

3. Hoogeveen EK, Kostense PJ, Jakobs C, Dekker JM, Nijpels G, Heine RJ, Bouter LM, Stehouwer CD. Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes: 5-year follow-up of the Hoorn Study. Circulation. 2000 Apr 4;101(13):1506-11.

4. Vollset SE, Refsum H, Tverdal A, Nygard O, Nordrehaug JE, Tell GS, Ueland PM. Plasma total homocysteine and cardiovascular and non cardiovascular mortality: the Hordaland Homocysteine Study. Am J Clin Nutr. 2001 Jul;74(1):130-6.

Homocysteine and 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 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.¹ 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.² 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, the Table below shows reduced risks based on data provided by the American Heart Association.³ 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 rates of death from heart disease.⁴

Heart Attack and Stroke Rates Among Americans and Potential Reductions by Reducing Risk³

Chances of Heart Attack Between the Ages of 35 and 74 years old
	Average Risk:	Reducing Risk By:
	1 out of	11% (1 out of)	23% (1 out of)
Women
Black	3.6	4	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 Stoke Between the Ages of 45 and 74 years old
	Average Risk:	Reducing Risk By:
	1 out of	19% (1 out of)	42% (1 out of)
Women
Black	4.5	5.6	7.8
White	12.7	15.7	21.9
Men
Black	4.8	6	8.4
White	5.8	7.1	10

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 causality. 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.⁵ 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 with which it is associated, it is also likely that the true effect of elevated homocysteine levels is masked.

Notes for Homocysteine & Cardiovascular Disease

1. No author listed. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002 Oct 23-30;288(16):2015-22.

2. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002 Nov 23;325(7374):1202.

3. Raw data (first and recurrent cases per 1,000 people per decade) used to make calculations was provided by Nancy Haase, Biostatistics Consultant, Science and Medicine, National Center, American Heart Association, 7272 Greenville, Dallas, TX 75231-4596. December 2, 2002. Data for heart disease is from the Atherosclerosis Risk in Communities (ARIC) study of the National Heart, Lung, and Blood Institute (NHLBI), 1987-94. Data for stroke is from ARIC for ages 45-54 and 55-64; Cardiovascular Health Study (CHS) for 65-74.

4. Key TJ, Fraser GE, Thorogood M, Appleby PN, Beral V, Reeves G, Burr ML, Chang-Claude J, Frentzel-Beyme R, Kuzma JW, Mann J, McPherson K. Mortality in vegetarians and nonvegetarians: detailed findings from a collaborative analysis of 5 prospective studies. Am J Clin Nutr. 1999 Sep;70(3 Suppl):516S-524S.

5. Robert A.J.M. van Dijk, Jan A. Rauwerda, Mieke Steyn, Jos W.R. Twisk, and Coen D.A. Stehouwer. Long-Term Homocysteine-Lowering Treatment With Folic Acid Plus Pyridoxine Is Associated With Decreased Blood Pressure but Not With Improved Brachial Artery Endothelium-Dependent Vasodilation or Carotid Artery Stiffness: A 2-Year, Randomized, Placebo-Controlled Trial. Arterioscler Thromb Vasc Biol. 2001 21: 2072-2079.

Treatment of High Homocysteine with Folate, B12, & B6 in Non-vegetarians

The British Medical Journal published an analysis of 12 studies on the effectiveness of reducing homocysteine levels with folic acid and vitamin B12 and/or B6 supplements for 3-12 weeks.¹ 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.¹ In another, only 20 µg B12/day (combined with folate and B6) resulted in reducing homocysteine from 11.9 to 7.8 µmol/l.¹ Smaller amounts of B12 were not tested.

Notes for Treatment of High Homocysteine with Folate, B12, & B6 in Non-vegetarians

1. No author. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. BMJ. 1998 Mar 21;316(7135):894-8.

Reversing Carotid Artery Plaque Progression through Homocysteine Treatment

Hackam et al.¹ (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 vitamin B6, and 250 µg B12/day for about 2 years. The results were:

Results of Hackam et al.
In those with HCY:	HCY ≤ 14	HCY > 14
Number	50	51
HCY range (µmol/l)	4.7-13.9	14.3-69.4
Duration of vitamin therapy (yrs)	1.9 ± .9	1.8 ± .7
Carotid artery plaque progression before vitamin therapy (cm²/year)	.13 ± .24^A	.21 ± .41^B
Carotid artery plaque progression after vitamin therapy (cm²/year)	-.024 ± .29^A,C	-.049 ± .24^B,C
A, B - Statistically significant difference between groups with same letters. C - Not a statistically significant difference between groups with same letters. HCY - Homocysteine

Vitamin therapy actually reversed the amount of plaque in some of the patients, including some with a homocysteine level below 14 µmol/l. It should be noted that:

The vitamin therapy might have worked in ways other than by lowering homocysteine. (Post-treatment homocysteine levels were not measured.)
There was no control group, so the results might not have been due to the vitamin therapy.

Thus, more studies are needed before lowering homocysteine can be said to reverse atherosclerosis.

Notes for Reversing Heart Disease through Homocysteine Treatment

1. Hackam DG, Peterson JC, Spence JD. What level of plasma homocyst(e)ine should be treated? Effects of vitamin therapy on progression of carotid atherosclerosis in patients with homocyst(e)ine levels above and below 14 micromol/L. Am J Hypertens. 2000 Jan;13(1 Pt 1):105-10.

But Aren't Vegans Protected From CVD?

Studies show that vegans have lower cholesterol levels¹ and blood pressure² 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, as noted, 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.

Unless there is a study that follows vegans with elevated homocysteine for many years, we will not know the effects with certainty. Because of the enormous cost, such a study will probably not be conducted. Since B12 succeeds in normalizing most vegans' homocysteine levels without any adverse effects, there is a simple solution and no reason to take any risk.

Notes for But Aren't Vegans Protected From CVD?

1. Appleby PN, Thorogood M, Mann JI, Key TJ. The Oxford Vegetarian Study: an overview. Am J Clin Nutr. 1999 Sep;70(3 Suppl):525S-531S.

2. Appleby PN, Davey GK, Key TJ. Hypertension and blood pressure among meat eaters, fish eaters, vegetarians and vegans in EPIC-Oxford. Public Health Nutrition. 2002;5:645-654.

B12, Homocysteine, & Alzheimer's Disease

Approximately 6-8% of all people older than 65 have Alzheimer's Disease (AD).¹ At least two recent literature reviews^1,2 and a letter to the editor³ 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.³ In some cases, B12-deficient dementia (which is a concern in itself) may be misdiagnosed as AD.⁴ There have been 2 prospective studies:

Seshadri et al.⁵ (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.⁶ (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.

Notes for B12, Homocysteine, & Alzheimer's Disease

1. Nourhashemi F, Gillette-Guyonnet S, Andrieu S, Ghisolfi A, Ousset PJ, Grandjean H, Grand A, Pous J, Vellas B, Albarede JL Alzheimer disease: protective factors. Am J Clin Nutr. 2000 Feb;71(2):643S-649S.

2. Selhub J, Bagley LC, Miller J, Rosenberg IH. B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr. 2000 Feb;71(2):614S-620S.

3. McCaddon A, Davies G, Hudson P. Nutritionally independent B12 deficiency and Alzheimer disease. Arch Neurol. 2000 Apr;57(4):607-8.

4. Rieder CR, Fricke D. Vitamin B(12) and folate in relation to the development of Alzheimer's disease. Neurology. 2001 Nov 13;57(9):1742-3.

5. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002 Feb 14;346(7):476-83.

6. Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin B(12) and folate in relation to the development of Alzheimer's disease. Neurology. 2001 May 8;56(9):1188-94.

B12, Folate, Homocysteine, & Birth Defects

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.¹ 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.² While the focus has been primarily on folate, there has been increasing interest in B12's part, which would be important to vegans:

Molloy et al.⁶ (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.³ (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.⁴ (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.⁵ (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 intakes in the weeks before and after conception may reduce the chances of NTDs.

Notes for B12, Folate, Homocysteine, & Birth Defects

1. Refsum H. Folate, vitamin B12 and homocysteine in relation to birth defects and pregnancy outcome. Br J Nutr. 2001 May;85 Suppl 2:S109-13.

2. Shaw GM, Velie EM, Schaffer DM. Is dietary intake of methionine associated with a reduction in risk for neural tube defect-affected pregnancies? Teratology. 1997 Nov;56(5):295-9.

3. Kirke PN, Molloy AM, Daly LE, Burke H, Weir DG, Scott JM. Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects. Q J Med. 1993 Nov;86(11):703-8.

4. Afman LA, Van Der Put NM, Thomas CM, Trijbels JM, Blom HJ. Reduced vitamin B12 binding by transcobalamin II increases the risk of neural tube defects. QJM. 2001 Mar;94(3):159-66.

5. Wald NJ, Hackshaw AD, Stone R, Sourial NA. Blood folic acid and vitamin B12 in relation to neural tube defects. Br J Obstet Gynaecol. 1996 Apr;103(4):319-24.

6. Molloy AM, Kirke PN, Troendle JF, Burke H, Sutton M, Brody LC, Scott JM, Mills JL. Maternal vitamin B12 status and risk of neural tube defects in a population with high neural tube defect prevalence and no folic acid fortification. March 2, 2009. Pre-publication.

Homocysteine and Recurrent Early Pregnancy Loss

A number of retrospective, case-control studies have been performed looking at elevated homocysteine levels and recurrent first trimester pregnancy loss. Nelen et al.¹ (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.

Notes for Homocysteine and Recurrent Early Pregnancy Loss

1. Nelen WL, Blom HJ, Steegers EA, den Heijer M, Eskes TK. Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. Fertil Steril. 2000 Dec;74(6):1196-9.

Homocysteine and Eye Disorders

Though more work needs to be done before anything can be said definitively, two eye diseases have been associated with elevated homocysteine levels in at least one study:

Nonarteritic anterior ischemic optic neuropathy (NAION)¹

Retinal venous occlusive diseases (RVOD)^1,2,3

Notes for Homocysteine and Eye Disorders

1. Pianka P, Almog Y, Man O, Goldstein M, Sela BA, Loewenstein A. Hyperhomocystinemia in patients with nonarteritic anterior ischemic optic neuropathy, central retinal artery occlusion, and central retinal vein occlusion. Ophthalmology. 2000 Aug;107(8):1588-92.

2. Brown BA, Marx JL, Ward TP, Hollifield RD, Dick JS, Brozetti JJ, Howard RS, Thach AB. Homocysteine: a risk factor for retinal venous occlusive disease. Ophthalmology. 2002 Feb;109(2):287-90.

3. Weger M, Stanger O, Deutschmann H, Temmel W, Renner W, Schmut O, Quehenberger F, Semmelrock J, Haas A. Hyperhomocyst(e)inemia, but not methylenetetrahydrofolate reductase C677T mutation, as a risk factor in branch retinal vein occlusion. Ophthalmology. 2002 Jun;109(6):1105-9.

One Week of Vegan Diet (with B12) and Other Lifestyle Changes Lower Homocysteine

DeRose et al.¹ (2000, USA) placed 40 people with various diseases (heart disease, diabetes, hypertension, and high cholesterol) on a vegan-diet-based lifestyle program for 1 week. The program included:

No B vitamin supplements. However, the subjects had an average intake of .4 µg of B12/day. Personal communication with the author verified that this was from fortified foods.
Moderate physical exercise.
Stress management and spirituality enhancement sessions.
No caffeine, alcohol, or tobacco.

Homocysteine levels fell 13%, from 8.66 ± 2.7 to 7.53 ± 2.12 µmol/l. The researchers estimated that the subjects' folate intakes had gone from 301 µg for men and 226 µg for women (based on typical U.S. intakes) to 480 µg. The researchers did not think this could explain the entire homocysteine reduction. Other diet and lifestyle changes would probably explain the remaining reduction.

Please note that this study was not conducted on vegans and was only one week in duration. B12 intakes that low (.4 µg) or lower cannot be expected to keep homocysteine levels in check for long periods of time.

Notes for One Week of Vegan Diet (with B12) and Other Lifestyle Changes Lower Homocysteine

1. DeRose DJ, Charles-Marcel ZL, Jamison JM, Muscat JE, Braman MA, McLane GD, Keith Mullen J. Vegan diet-based lifestyle program rapidly lowers homocysteine levels. Prev Med. 2000 Mar;30(3):225-33.

What Level of B12 Should You Aim For?

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.¹ analyzed data from 8,083 people, including whites, blacks, and Hispanics. They 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%.² 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 by following the recommendations listed here.

Notes for What Level of B12 Should You Aim For?

1. Selhub J, Bagley LC, Miller J, Rosenberg IH. B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr. 2000 Feb;71(2):614S-620S.

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

Should Vegans Get their Homocysteine or B12 Levels Checked?

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

Homocysteine is Elevated in People with Kidney Disease

Homocysteine levels are often highly elevated in those with kidney disease. See Appendix: Homocysteine and Kidney Disease for more information.