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Homocysteine Lowering does not Exclusively Mean Vitamin*Supplementation

The causes underlying hyperhomocysteinemia are varied. Many lifestyle factors, such as smoking and high alcohol intake, increase homocysteine levels by different mechanisms, as do some diseases and treatment with several drugs. While increased vitamin intake or vitamin supplementation may counteract the effects of these factors, changes in lifestyle, and approaches other than vitamin supplementation, should also be*considered.

It is obvious that one should aim for smoking cessation and reduction of alcohol intake, also for other reasons. To motivate the patient to opt for food rich in folate, primarily fresh vegetables and fruit, is likewise associated with other benefits. In addition to vitamins, other food components also influence remethylation of homocysteine and thereby homocysteine*levels.

Choline and Betaine, Present in Some Common Nutrients, Lower Plasma*Homocysteine

Recent publications focus on the impact of betaine- and choline-containing food on homocysteine levels in healthy individuals. Homocysteine can be remethylted, not only by the folate- and vitamin B12-dependent pathway, but also by a betaine-dependent pathway mediated by betaine-homocysteine methyltransferase (BHMT). This pathway is primarily active in the liver but also in the kidneys. Other tissues, including the brain, do not possess this BHMT system for remethylating homocysteine.

Two earlier open studies have suggested that supplementation with 6g of betaine daily may reduce fasting homocysteine levels by 8-9% (1,2). A new placebo-controlled study by Steenge and co-workers at the centre for Food Sciences and Health Programme in Wageningen, the Netherlands, has now investigated the effect of these nutrients on plasma homocysteine, both fasting and after methionine loading, in healthy men and women with mild elevation of fasting homocysteine levels. Mean levels were 12.7mol/L (range: 8-9-21.0mol/L).

Three groups of 12 subjects were each given daily doses of either 6g of betaine, 800g of folic acid plus 6g of placebo, or 6g of placebo only for 6 weeks. The effect of both fasting and post-methionine-loading (PML) homocysteine levels was determined. Before supplementation fasting and PML homocysteine levels did not differ between*groups.

After 6 weeks of intervention, fasting homocysteine had increased by 4% in the placebo group, whereas it had decreased by 11% in the betaine group (p=0.05 compared with placebo) and by 18% in the folic acid group (p=0.004 compared with placebo). After 6 weeks of betaine supplementation the 6h increment of PML homocysteine was 49% lower in the betaine than in the placebo group (p=0.04). Folic acid supplementation did not affect PML homocysteine levels significantly (3).

Choline is Another Nutrient Component of Critical*Importance

In the same journal, Zeisel and co-workers from the Department of Nutrition at University of North Carolina, report on the concentrations of betaine and choline in common foods*(4).

Choline is a precursor of betaine. Choline is also required for lipid transport and metabolism, and thereby affects cell and nerve signalling. Its importance for the brain development of the child has been demonstrated in many studies reviewed by Zeisel and co-workers*(5).

Choline can be synthesised endogenously but this synthesis is SAM-dependent, and is therefore dependent on folate and vitamin B12 supply. The SAM requirement for the synthesis may be higher than earlier thought. Recent studies in animals suggest that the SAM-dependent methylation in the liver of phosphatidyletanolamine to form phosphatidylcholine, a reaction that also generates S-adenosylhomocysteine and homocysteine, may be a major source of plasma homocysteine*(6).

Choline supplied by the diet may reduce the requirement of folate- and B12-dependent synthesis of SAM for methylation reactions by increasing betaine-mediated remethylation in the liver. This may be particularly important after protein-rich*meals.

Many Common Foods Contain Betaine and Choline

Multiple choline compounds and betaine can be supplied by the diet. Zeizel and co-workers (4) found that of the 145 foods that were analysed, the foods with the highest choline content (mg/100g) were beef liver (418), chicken liver (290), eggs (251), wheat germ (152), bacon (125), dried soy beans (116) and pork (103). (Frequent consumption of eggs is generally not recommended because of their very high cholesterol content (about 500 mg/100g). It is, however, interesting to note that when dietary confounders were considered, several studies have shown that consumption of up to one egg/day was not associated with increased CVD risk*(7).)

The foods richest in betaine (mg/100g) were wheat bran (1,339), wheat germ (1,241), spinach (645), pretzels (237), shrimps (218) and wheat bread (201). Another source of betaine is fish (Betaine monograph). One report cites about 10% lower fasting homocysteine levels in healthy subjects eating fish at least three times a week than in those eating fish less than once a month*(9).

Also fish oil, 12g/day for three weeks, is found to decrease fasting homocysteine significantly in hyperlipaemic men (10). A recent study showed that dietary supplementation with 6g/day of fish oil for 8 weeks resulted in a progressive decrease of fasting homocysteine levels without any changes in folate or vitamin B12 levels. The decrease of fasting homocysteine levels reached 20% after 8 weeks (11).

Fasting and PML Homocysteine Levels are Independently Associated with*Disease

Fasting plasma homocysteine levels and PML levels are considered to constitute independent risk factors for CVD, although the strength of the association with PML values has been quantified only in a few studies. The relationship was found to be gradual and of similar strength as observed for fasting homocysteine*(12).

Betaine supplementation is used therapeutically in combination with high vitamin doses for the treatment of severe hyperhomocysteinemia (homocystinuria), a consequence of severe inborn enzyme defects, but its importance in healthy subjects has received little*attention.

The preventive effect of a combination of betaine (or its precursor choline), alone or in combination with vitamins, of CVD and other homocysteine-related disorders/complications has not yet been studied in subjects with moderately elevated plasma homocysteine. A possible confounding effect of varying intake of these food components in studies has also not been investigated. As choline and betaine may alter methyl group availability, varying dietary intake of these components might affect study*results.

Several Underlying Factors Offer Many Intervention*Approaches

Even if low vitamin status is very often found in hyperhomocysteinemic subjects, other factors may often contribute. Some of these cannot be modified genetic defects, diseases and sometimes drug treatment. Others lifestyle, including smoking, alcohol and coffee consumption, little exercise, and poor nutrition can be*modified.

A daily intake of folate of 400g up to 800g is generally recommended. It may be difficult to motivate a patient to make such changes in his/her diet to increase folate intake sufficiently. It was recently shown in female volunteers that a switch from 1 serving/day of both vegetables and berries (with a calculated mean folate content of 221g) to at least 7 daily servings (with a calculated mean content of 596g), resulted in a 13% decrease of fasting homocysteine after 5 weeks (13). Even 800g of folic acid, however, did not significantly decrease PML homocysteine levels and even higher doses do not seem to modify PLM levels much*(3).

When considering the dietary modifications, increased consumption of betaine/choline-rich foods, such as fish, may increase the homocysteine-lowering effect of increased vitamin consumption, in particular by reducing peaks after protein-rich meals, and might be considered. Whether betaine/choline supplements may be considered in the future for intervention in addition to folic acid, vitamin B12 and B6 supplementation remains to be*documented.

An alternative or additional approach to homocysteine-lowering in poor responders to dietary and other measures may be N-acetylcysteine therapy. This was recently found to dose-dependently decrease fasting homocysteine levels in healthy subjects (14). The homocysteine-lowering effect of N-acetylcysteine, however, is likely to be due to increased renal excretion, rather than increased endogenous*recycling.

Christina Bolander-Gouaille
November 2003


Folate and vitamin B12 reduce homocysteine levels by contributing to remethylation of homocysteine to SAM.

Homocysteine can also be remethylated to SAM by using betaine as methyl donor.

Betaine and its precursor choline are found in many common foods.

Choline can also be synthesized in the liver, but this reaction requires SAM as methyl donor and generates homocysteine.

Betaine supplementation, in contrast to folic acid, reduces both fasting levels of homocysteine and after methionine load.

Consumption of choline/betaine-rich food may have a positive effect for homocysteine monitoring.

(Recent references are highlighted)

Brouwer IA et al. Betaine supplementation and plasma homocysteine in healthy volunteers. Arch Intern Med, 2000;160:2546-7.

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

Steenge GR et al. Betaine supplementation lowers plasma homocysteine in healthy men and women. J Nutrition, 2003;133:1291-5.

Zeisel SH et al. Concentrations of choline-containing compounds and betaine in common foods. J Nutrition, 2003;133:1302-7.

Zeisel SH. Choline: Needed for normal development of memory. J Am College Nutrition, 2000;19:528S-531S.

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

Kritchewsky SB, Kritchewsky D. Egg consumption and coronary heart disease: an epidemiologic overview. J Am Coll Nutr, 2000;19:549S-555S.

Betaine Monograph (No authors listed). Altern Med Rev, 2003;8:193-6.

Vollset SE et al. Cross-sectional associations of dietary habits to plasma homocysteine. Int Conf Prev Card, Oslo 1993. Abstr 250.

Olszewski A, McCully K. Fish oil decreases serum homocysteine in hyperlipemic men. Coron Artery Dis, 1993;4:53-60.

Piolot A et al. Effect of fish oil on LDL oxidation and plasma homocysteine concentrations in health, J Lab Clin Med, 2003;141:41-9.

Verhoef P et al. Plasma total homocysteine, B-vitamins and risk of coronary atherosclerosis. Arterioscler Thromb Vasc Biol, 1997;17:989-95.

Silaste ML et al. Plasma homocysteine concentration is decreased by dietary intervention. Br J Nutrition, 2003;89:295-301.

Ventura P et al. Urinary and plasma homocysteine and cysteine levels during prolonged oral N-acetylcysteine therapy. Pharmacology, 2003;68:105-14.