Homocysteine: Cause Or Effect Of CVD?

Human DNA is programmed to incorporate 20 different amino acids into proteins. Other proteins are formed by chemical modification of some of the DNA-encoded amino acids after they are incorporated into polypeptide chains. An example is the n-octanoic acid (eight carbon atoms) ester of serine found in the recently discovered peptide hormone ghrelin that is involved in regulating body weight.1,2 Other amino acids are formed as metabolic intermediates that are not found in proteins, and are seen to have no apparent significant physiological role in humans. Perhaps the best-known example is homocysteine, a metabolic intermediate in the biochemical pathway from methionine to cysteine.

Despite this seemingly innocuous role, homocysteine is a major factor in human health. In recent years, moderately elevated homocysteine levels in the blood have been shown to be a significant risk factor for cardiovascular disease3,4 and stroke5,6 as well as being implicated as a risk factor for Alzheimer's disease.7 Even levels as low as 20-30 per cent above normal (the upper limit of normal is perhaps 14 or 15 micromoles per litre) are associated with increased risk of various forms of cardiovascular disease (CVD).8

Homocysteine's Role In CV
Homocysteine was first suggested to be involved in CVD by Kilmer McCully, MD,9 and then David E Wilcken, MD,10 in the late 1960s to mid-1970s. Since then, more than 100 studies supporting a link between homocysteine and CVD have been reported. A widely cited meta-analysis published in 1995 evaluated all studies reported prior to that year and concluded that elevated blood homocysteine levels are a significant independent risk factor for CVD.11

Despite the extensive evidence implicating homocysteine as a clear risk factor, the conclusion that homocysteine may be a cause of CVD, rather than an effect, is less clear, and the subject of much current debate.4,12 A strong argument in favour of cause rather than effect has recently come from researchers at Barts and the London School of Medicine.13 The meta-analysis evaluated 72 studies (n=16,849 cases plus controls) of a genetic variation producing high blood homocysteine levels, and 20 prospective studies (n=3,820 participants) comparing serum homocysteine levels and disease events. The authors concluded that since the two types of studies are based on different biological factors and sources of error, but show quantitatively similar association between elevated homocysteine and CVD, homocysteine must be a cause rather than an effect of CVD. Despite this fairly strong evidence, the debate will likely continue.

In fact, a recent comprehensive meta-analysis conducted by the Homocysteine Studies Collaboration—a group of nearly 100 international collaborators—of all articles published from January 1966 until January 1999 concluded that elevated homocysteine is 'at most a modest independent predictor' of heart disease in healthy populations.14 The Collaborative study included many more recent prospective trials that found weaker associations, which now seems to be the generally accepted view of experts on both sides of the Atlantic.15

It is not surprising then that the mechanism by which elevations in homocysteine might promote CVD are not known, even though a number of studies have investigated possible causes. To shed some light on this question, researchers at Tufts University recently analysed various hemostatic (arresting blood flow within the vessels) risk factors in 3,216 individuals free of CVD, who participated in the Framingham Offspring Study. The researchers concluded that elevated homocysteine levels increase the potential for thrombosis (clotting within blood vessel) as a plausible mechanism.16

The Nutrient Connection
Homocysteine is a by-product of a critical biochemical process involving the addition of a one-carbon methyl group (methylation) to many key molecules by S-adenosylmethionine (SAMe), including RNA, DNA and various proteins, as well as the methylation of norepinephrine to epinephrine and phosphatidylethanolamine to phosphatidylcholine.17 This last conversion may be the source of perhaps half the homocysteine produced in the body.18

Fortunately, nature has provided healthy individuals with two independent processes for controlling homocysteine levels in the body. One process is by conversion to the amino acid cysteine. The first step in this pathway utilizes vitamin B6 as a co-factor. Homocysteine levels in the body are influenced by the availability of vitamin B6.19 The second process is by re-methylation of homocysteine back to methionine. In the body, re-methylation is enzymatically carried out in all tissues by methyltetrahydrofolate (methyl-THF) in the presence of vitamin B12 as a co-factor. Methyl-THF is derived from folic acid, and is the predominate form (greater than 90 per cent) of folic acid in the body. Vitamin B12, a complex molecule containing a cobalt atom at its core, also plays a key role in this step. The methyl group on methyl-THF is first transferred to the cobalt atom of vitamin B12 to boost the chemical reactivity of the methyl group, and then onto the sulfur atom of homocysteine.20

Re-methylation of homocysteine also occurs in the liver with betaine (trimethylglycine), an oxidation product of choline, using a B12-independent enzyme. However, this reaction is much less efficient, requiring plasma concentrations of several hundred mmol/L of betaine to influence the levels of homocysteine, versus microgram amounts of folic acid, vitamins B12 and B6.21

As might be suspected, sufficient quantities of folic acid, vitamin B12 and B6, as well as betaine, can lower the level of total plasma homocysteine in the body.4,21,22 The bad news is that many people are at risk of being deficient in one or more of these key molecules, especially folic acid and vitamin B12 in the poor and elderly. A number of studies have confirmed the inverse relationship between elevated plasma homocysteine and the risk of CVD and stroke with insufficient folic acid, vitamins B12 and B6.22,23,24

Folic acid deficiency is usually due to an inadequate diet, partly from inadequate consumption of fruits, vegetables and legumes. It is estimated that only 23 per cent of the US adult population consumes the recommended five daily servings of fruits and vegetables.25 In addition, significant amounts of dietary folic acid may be lost during the processing of food due to both its relatively high water solubility and limited heat and light stability.26 As a result, in 1998 the US Food and Drug Administration (FDA) mandated fortification of all flour and uncooked cereal grains with 140mcg folic acid per 100g grain.

Two recent studies from the University of Florida and Tufts suggest fortification has increased consumption of folic acid by about 200mcg/day relative to a recommended daily intake (RDI) of 400mcg/day.27,28 This is almost double the amount originally projected by FDA. As a result of the successful fortification programme, some vitamin experts such as Barry Shane, PhD, believe the current daily intake of folic acid in the US is very close to the RDI.29

Insufficient B12 Issues
It now appears that insufficient vitamin B12 is a cause for greater concern with regard to elevated homocysteine levels, especially since excess folic acid can mask a deficiency of vitamin B12.29 (However, there is no indication that this level of folic acid fortification is masking a B12 deficiency.) To be effectively absorbed into the body, vitamin B12 must be released from proteins in food, such as meat and dairy products, by stomach acid before it can be absorbed. An estimated 10-30 per cent of people over age 50 exhibit low stomach acid production and therefore have a potential risk of inadequate B12.30 This may also explain, in part, why homocysteine levels steadily increase with age.

Vegans are also at risk due to a diet low in B12. The current DRI is a mere 2.4mcg/day. A US Department of Agriculture survey estimated approximately 10 per cent of the US population consumes less than half of the vitamin B6 DRI (1.3-1.7mcg/day).31 Betaine is produced in the body, and is also widely distributed in plants and animals and is, therefore, not a factor. A recent Finnish study of betaine supplementation showed that a daily supplement of 6g betaine for 12 weeks reduced homocysteine values in healthy subjects by approximately 9 per cent.21

Based on the above considerations, it is logical to assume that supplementation of the diet with folic acid, vitamins B12 and B6, and higher levels of betaine, could reduce elevated levels of plasma homocysteine and the incidence of CVD, stroke and Alzheimer's disease. Many trials are now underway to affirm or disconfirm this hypothesis.32 In the meantime, a number of prominent nutritionists and medical doctors, such as Harvard's Walter Willett and Meir Stampfer, recommend supplements as a safeguard—especially for the poor and elderly.33

Guy A Crosby, PhD, is a consultant, writer and lecturer on food and nutrition chemistry. He has more than 30 years of experience as a scientist and executive in academia and industry, including vice president of R&D at Opta Food Ingredients and R&D director at FMC. He has written more than 50 scientific publications and holds 20 US patents.
[email protected]


1. Masayasu K, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402:656-60.

2. Cummings DE, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002;346:1623-30.

3. McCully KS, Homocysteine, folate, vitamin B6, and cardiovascular disease. JAMA 1998;279:392-3.

4. Graham I. Homocysteine in health and disease. Ann Intern Med 1999;131:387-8.

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10. Wilcken DEL, Wilcken B. The pathogenesis of coronary artery disease: a possible role for methionine metabolism. J Clin Invest 1976;57:1079-82.

11. Boushey CJ, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995;274:1049-57.

12. Cleophas TJ, et al. Homocysteine, a risk factor for coronary artery disease or not? A meta-analysis. J Am Coll Cardiol 2000;86:1005-9.

13. Wald DS, et al. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002;325:1202-8.

14. Clarke R, et al. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002;288:2015-22.

15. Wilson PWF. Homocysteine and coronary heart disease: how great is the hazard? JAMA 2002;288:2042-43.

16. Tofler GH, et al. Association between increased homocysteine levels and impaired fibrinolytic potential: potential mechanism for cardiovascular risk. Thromb Haemost 2002;88:799-804.

17. Selub J, et al. Serum total homocysteine concentrations in the Third National Heath and Nutrition Survey (1991-1994): population reference ranges and contribution of vitamin status to high serum concentrations. Ann Intern Med 1999;131:331-9.

18. Noga AA, et al. Plasma homocysteine is regulated by phospholipid methylation. J Biol Chem 2003;278:5952-5.

19. Mennen LI, et al. Homocysteine, cardiovascular disease risk factors, and habitual diet in the French Supplementation with Antioxidant Vitamins and Minerals Study. Am J Clin Nutr 2002;76:1279-89.

20. Walsh C. Enzymatic Reaction Mechanisms, W.H. Freeman and Co., San Francisco 1979, pp 846-50.

21. Schwab U, et al. Betaine supplementation decreases plasma homocysteine concentrations but does not affect body weight, body composition, or resting energy expenditure in human subjects. Am J Clin Nutr 2002;76:961-7.

22. Selub J, et al. Relationship between plasma homocysteine and vitamin status in the Framingham Study population. Impact of folic acid fortification. Public Health Rev 2000;28:117-45.

23. Rimm EB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998;279:359-64.

24. Eikelboom JW, et al. Homocysteine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 1999;131:363-75.

25. Li R, et al. Trends in fruit and vegetable consumption among adults in 16 US states: Behavioral Risk Factor Surveillance System, 1990-1996. Am J Public Health 2000 May;90(5):777-81.

26. DeMan JM. Principles of Food Chemistry, Van Nostrand Reinhold, NY, NY, 1990, pp. 365-7.

27. Quinlivan EP, Gregory JF. Effect of food fortification on folic acid intake in the United States. Am J Clin Nutr 2003;77:221-5.

28. Choumenkovitch SF, et al. Folic acid intake from fortification in United States exceeds predictions. J Nutr 2002;132:2792-8.

29. Shane B. Folate fortification: enough already? Am J Clin Nutr 2003;77:8-9.

30. Shane B. Folic acid, vitamin B12, and vitamin B6, in Stipanuk MH, ed. Biochemical and Physiological Aspects of Human Nutrition, W.B. Saunders, Phila., 2000, Chapter 21, p. 508.

31. Wilson JW, et al. Data tables: combined results from USDA's 1994 and 1995 continuing survey of food intakes by individuals and 1994 and 1995 diet and health knowledge survey. 1997 USDA/ARS Food Survey Research Group, Beltsville Human Nutrition Research Center, Riverdale, MD.

32. Clarke R, Collins R. Can dietary supplements with folic acid or vitamin B6 reduce cardiovascular risk? Design of clinical trials to test homocysteine hypothesis of vascular disease. J Cardiovasc Risk 1998;5:249-55.

33. Willett WC, Stampfer MJ. What vitamins should I be taking, doctor? N Engl J Med 2002;345:1819-24.

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