Homocysteine and Health

The little known amino acid homocysteine has been the subject of great interest in the medical community since the early 1990s as evidence accumulated that even moderately elevated levels went hand in hand with increased risk of heart diseas, birth defects, dementia, depression and death. Independent studies in Israel, USA, Norway and Holland have shown homocysteine to be strongly associated with mortality from all causes combined and thus a potentially greater risk factor than cholesterol: every 10% increase in homocysteine is associated with a 8% increase in mortality from all causes and a one year reduction in life expectancy.

Apart from kidney disease and certain rare genetic defects, low intakes of any of three vitamins (folate, vitamin B12 and vitamin B6) can cause homocysteine levels to rise. Supplementation trials using folate, B12 and B6 to reduce homocysteine showed a reduction in symptoms of heart disease, including the rate of progression of atherosclerosis. Supplementation with 4 mg per day of folate reduced the incidence of neural tube defects such as spina bifida by about 70% while 0.8 mg of folic acid plus 4 micrograms (µg) of B12 reduced neural tube defects by 100%.

Serum homocysteine, micromol per litre (graph)

At first, there was considerable optimism that on a plant-based diet homocysteine levels would be lower, due to high folate levels, and a recent trial showed that homocysteine levels decreased within a week of switching from a typical Western diet to a vegan diet with plenty of vegetables. However, other studies have shown that many long-term vegans have blood homocysteine levels around 15 µmol/l compared with desirable levels below 10 µmol/l, while other vegetarians averaged about 12 µmol/l. This trend is not found in vegans ensuring B12 intakes of 3 µg or more per day, who show the expected benefit from high folate and plentiful B6 with homocysteine levels around 8 µmol/l compared with a Western average of about 10 µmol/l. The bar graph shows the results of recent studies on homocysteine and diet.

With the exception of one study in the USA in 1999, the highest levels of homocysteine were observed in vegans, with lacto-vegetarian levels also higher than meat eaters. The critical role of B12 can be seen from the comparisons of B12 and folate intakes in the same studies. The B12 levels of vegans were generally the lowest, while the B12 levels of other vegetarians fell between those of vegans and meat eaters. In contrast, the vegan folate levels were generally higher than or similar to the other groups. In the 1999 USA study, the vegan B12 levels matched those of the meat eaters and so did the homocysteine levels. To remove any shadow of doubt as to the cause of the high homocysteine levels, the Chilean study subsequently monitored the effect of B12 supplementation: the homocysteine levels of the Chilean vegetarians dropped from 13 to 8 µmol/l with no other dietary changes.

Average vegan homocysteine levels are about 15 µmol/l. Based on studies in the general population, this degree of excess homocysteine could be associated with a 40% increase in mortality, particularly from causes other than cancer. Low vegan cholesterol levels would be expected to reduce heart disease deaths by about 50% compared with meat-eaters, so the overall result would be expected to be 30% less heart disease but 40% increased mortality from other causes, with little difference overall. This is almost exactly the pattern observed in the only study to report direct observations of vegan mortality (UK, USA and Germany 1999). The table shows the relative risk of death per year. Regular meat eaters (eating meat once or more per week) are taken as the reference point. The results are highly consistent with mortality expectations based on reduced cholesterol and elevated homocysteine combined.

	Regular meat eaters	Occasional meat eaters	Fish eaters	Vegetarians	Vegans
Heart disease	1.00	0.8	0.66	0.66	0.74
Other non-cancer causes	1.00	0.84	0.85	0.95	1.33
All causes	1.00	0.84	0.82	0.84	1.00

The evidence suggests that getting adequate B12 could result in vegans living about 4 years longer than meat eaters and 2 years longer than lacto-vegetarians. It should be noted that the "regular" meat-eaters in this study ate less meat than the general population in their countries and none of the groups included many smokers. Mortality in the general population is about 1.6 in terms of the above table, so although the vegans studied lived no longer than the other groups they were already living about five years longer than their more typical compatriots.

Homocysteine rises significantly long before B12 stores drop to the level associated with classical B12 deficiency. Current UK Government recommendations of 1.5 µg per day are based on reliably preventing classical deficiency and are more than adequate for that purpose. However, they do not take into account B12 requirements to minimise homocysteine. At least 3 µg per day are required to achieve this by maintaining blood B12 levels at 300 pmol/l or more. If the main source of B12 is a supplement taken daily, at least 10 µg should be taken. If it is taken weekly, 2000 µg is required. The variation in recommended weekly intake is because absorption of B12 is best at small doses below 0.5 µg, where about 70% of available B12 is absorbed. As the dose approaches 10 µg, the amount absorbed flattens off at about 1.5 µg and only about 0.5% of further increases in dose are absorbed. The absorbed amount from 2000 µg is therefore little more than 10 µg, which is just enough for one week, while the same absorbed amount can be obtained from 3 µg per day spread across several meals or from a daily supplement of 10 µg.

A single weekly supplement of 2000 µg has the advantage that absorption does not rely on intrinsic factor in the small intestine, which is required for efficient absorption of small amounts of B12 and is occasionally absent, particularly in the elderly. All forms of fortified foods and supplements avoid the more common B12 absorption problem in the elderly, namely inability (usually due to declining stomach acidity) to separate the B12 in meat from the proteins to which it is bound. B12 supplements should be chewed to ensure reliable absorption.

From conception to death, elevated homocysteine casts its shadow, but the risk can be straightforwardly minimised by ensuring an adequate intake of vitamin B12 from fortified foods or supplements and consuming a varied plant-based diet with plenty of fruit and vegetables. This should allow the full potential of the vegan diet to shine through, giving vegans a clear lead over other dietary groups.

Germany 2002: Abstract 18, Loma Linda Conference on Vegetarian Nutrition, Cobalamin and homocysteine status of vegans – results of the German Vegan Study, Jochen Koschizke

Italy 2002: Annals of Nutrition and Metabolism, 2002; 46: 73-79, Effect of vegetarian diet on homocysteine levels, L Bissoli et al.

Germany 2001: Clinical Chemistry, 2001; 47: 1094-1101, Total homocysteine, Vitamin B12, and total antioxidant status in vegetarians, Wolfgang Herrmann et al.

Taiwan 2001: Journal of Nutrition, 2001; 132: 152-158, Plasma homocysteine levels in Taiwanese vegetarians are higher than those of omnivores, Chien-Jung Hung et al.

Czechoslovakia 2000: Annals of Nutrition and Metabolism, 2000; 44: 135-138, Homocysteine levels in vegetarians versus omnivores, M. Krajcovicova-Kudlackova et al.

Australia 1999: European Journal of Clinical Nutrition, 1999; 53: 895-899, The effect of diet on plasma homocysteine concentrations in healthy male subjects, NJ Mann et al.

Chile 1999: Thrombosis and Haemostasis, 1999; 81: 913-917, Vegetarians and cardiovascular risk factors: hemostasis, inflammatory markers and plasma homocysteine, Diego Mezzano et al. (plus reduction of homocysteine by B12 supplementation) Thrombosis Research, 2000; 100: 153-160, Cardiovascular risk factors in vegetarians: normalisation of hyperhomocysteinemia with vitamin B12 and reduction of platelet aggregation with n-3 fatty acids, Diego Mezzano et al.

USA 1999: American Journal of Clinical Nutrition, 1999; 70: 586S-593S, Dietary intake and biochemical, hematologic, and immune status of vegans compared with nonvegetarians, Ella H Haddad et al.

UK, USA and Germany 1999: American Journal of Clinical Nutrition, 1999; 70: 516S-524S, Mortality in vegetarians and nonvegetarians: detailed findings from a collaborative analysis of 5 prospective studies, Timothy J Key et al.