Homocysteine supplementation

Methyl-tetrahydro folic acid is furthermore, together with vitamin B12 and B6, required to regenerate homocysteine (see Vitamin B12, Fig. 1). Homocysteine results when methionine is used as a substrate for methyl group transfer. During the last few years, homocysteine has been acknowledged as an independent risk factor in atherosclerosis etiology. Folic acid supplementation can help reduce elevated homocysteine plasma levels and is therefore supposed to reduce the risk of atherosclerosis as well [2]. 

Supplements of 400 Ig/d of folate begun before conception result in a significant reduction in the incidence of neural mbe defects as found in spina bifida. Elevated blood homocysteine is an associated risk factor for atherosclerosis, thrombosis, and hypertension. The condition is due to impaired abihty to form methyl-tetrahydrofolate by methylene-tetrahydrofolate reductase, causing functional folate deficiency and resulting in failure to remethylate homocysteine to methionine. People with the causative abnormal variant of methylene-tetrahydrofolate reductase do not develop hyperhomocysteinemia if they have a relatively high intake of folate, but it is not yet known whether this affects the incidence of cardiovascular disease. 

Elevated homocysteine concentrations have been associated with an increased risk for cardiovascular disease in both epidemiologic and clinical studies.43 Several studies have evaluated the benefit of lowering homocysteine levels with folic acid supplementation. One study reported a reduction in major cardiac events with the combination of folic acid, vitamin B12, and vitamin B6 following PCI.44 However, a more recent study found an increased risk of instent restenosis and the need for target-vessel revascularization with folate supplementation following coronary stent placement.45 The role of folate in the management of IHD is currently unclear. 

There is usually no need to supplement with specific vitamins. Patients should be encouraged to eat a well balanced diet and should also take a multivitamin and mineral supplement. Some clinicians recommend vitamins C and E for their antioxidant properties however, no significant improvements have been shown compared to placebo. Encourage patients to eat a diet rich in vitamin C and E (i.e., bright colored fruits and vegetables, nuts, and whole grains). Metabolism of levodopa may cause elevated homocysteine concentrations that... 

A newer therapeutic approach is the administration of betaine (6-12 g daily), which lowers homocysteine levels by favoring remethylation [33], A theoretical hazard of betaine treatment is increasing the blood methionine, sometimes to an extravagant degree ( 1 mmol/1). Experience to date indicates that betaine administration is safe, with no major side effects except for a fishy odor to the urine. Other therapeutic approaches have included the administration of salicylate to ameliorate the thromboembolic diathesis. Patients also have been treated with dietary supplements of L-cystine, since the block of the transsulfura-tion pathway in theory could diminish the synthesis of this amino acid. 

The fibroblasts do not convert cyanocobalamin or hydroxocobalamin to methylcobalamin or adenosyl-cobalamin, resulting in diminished activity of both N5-methyltetrahydrofolate homocysteine methyltransferase and methylmalonyl-CoA mutase. Supplementation with hydroxocobalamin rectifies the aberrant biochemistry. The precise nature of the underlying defect remains obscure. Diagnosis should be suspected in a child with homocystinuria, methylmalonic aciduria, megaloblastic anemia, hypomethioninemia and normal blood levels of folate and vitamin B12. A definitive diagnosis requires demonstration of these abnormalities in fibroblasts. Prenatal diagnosis is possible. 

The question therefore arose about the fate of the methyl group from methionine. When minimal amounts of methionine were used to supplement the diet of rats given homocysteine as their main source of sulfur, the rats did not usually thrive, and at death had fatty accumulations in their livers. Best and his co-workers had earlier reported the efficacy of choline as a lipotropic agent, facilitating the mobilization of fat from the liver. Du Vigneaud therefore tried supplementing homcys-... 

Homocysteine blood levels (>15 jtmol/L) promote atherosclerosis, perhaps by stimulating proliferation of arterial wall smooth muscle cells. Supplementing the diet with folic acid can reduce high levels. Lpa is a mod-ihed LDL particle that is both atherogenic and pro-thrombic. 

Homocysteine, which initiates proatherogenic changes in endothelium, can be reduced in many patients by restriction of total protein intake to the amount required for amino acid replacement. Supplementation with folic acid plus other vitamins is indicated in severe homocyteinemia. 

Vitamins and minerals, whose main dietary sources are other than fruits and vegetables, are also likely to play a significant role in the prevention and repair of DNA damage, and thus are important to the maintenance of long-term health. Vitamin B12 is found in animal products, and deficiencies of B12 cause a functional folate deficiency, accumulation of the amino acid homocysteine (a risk factor for heart disease),46 and chromosome breaks. B12 supplementation above the RDA was necessary to minimize chromosome breakage.47 Strict vegetarians are at increased risk for developing vitamin B12 deficiency. 

The homocystinurias are a group of disorders involving defects in the metabolism of homocysteine. The diseases are inherited as autosomal recessive illnesses, characterized by high plasma and urinary levels of homocysteine and methionine and low levels of cysteine. The most common cause of homocystinuria is a defect in the enzyme cystathionine /3-synthase, which converts homocysteine to cystathionine (Figure 20.21). Individuals who are homozygous for cystathionine [3-synthase deficiency exhibit ectopia lentis (displace ment of the lens of the eye), skeletal abnormalities, premature arte rial disease, osteoporosis, and mental retardation. Patients can be responsive or non-responsive to oral administration of pyridoxine (vitamin B6)—a cofactor of cystathionine [3-synthase. Bg-responsive patients usually have a milder and later onset of clinical symptoms compared with B6-non-responsive patients. Treatment includes restriction of methionine intake and supplementation with vitamins Bg, B, and folate. 

Stulc T, Melenovsky V, Grauova B, Kozich V, Ceska R. Folate supplementation prevents plasma homocysteine increase after fenofibrate therapy. Nutrition 2001 17(9) 721-3. 

Supplementation with the antioxidant vitamins ascorbic acid (250 mg) and mixed natural tocopherols (50 IU on alternate days) may be beneficial. Higher doses may vitiate the impact of lipid lowering therapy. Other naturally occurring antioxidants such as resveratrol, 3-catechin, selenium, and various carotenoids found in a variety of fruits and vegetables may provide additional antioxidant defense. Homocysteine, which initiates proatherogenic changes in endothelium, can be reduced in many patients by restriction of total protein intake to the amount required for amino acid replacement. Daily supplementation with up to 2 mg of folic acid plus other B vitamins is also recommended. 

Homocysteine is a nonprotein-building amino acid formed as a metabolite in the methionine cycle. It was first associated with disease in 1962 (1,2). Individuals with a mutation in cystathionine-(3-synthase (CBS) develop classical homocystin-uria with extremely elevated plasma tHcy (> 100 xmol/L) (3). Homocystinuria is characterized by early atherosclerosis and thromboembolism as well as mental retardation and osteoporosis and is ameliorated by vitamin supplementation aimed at reducing the blood concentration of homocysteine (4). 

In vitro studies have shown that homocysteine can undergo autoxidation, leading to the formation of oxygen free radicals (30-32). Homocysteine is involved in oxidative modification of low-density lipoprotein in vitro (33). Increased lipid peroxidation in humans with hyperhomocysteinemia has been reported (34,35). However, vitamin supplementation that resulted in substantial reduction of tHcy concentrations did not normalize either the homocysteine redox status or the increased lipid peroxidation in CAD patients (35,36). 

Homocysteine decreases the bioavailability of nitrous oxide (NO) via a mechanism involving glutathione peroxidase (37). Tawakol et al. (38) reported that hyperhomocysteinemia is associated with impaired endothelium-dependent vasodilation in humans. Homocysteine impairs the NO synthase pathway both in cell culture (39) and in monkeys with hyperhomocysteinemia, by increasing the levels of asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor (40). Elevation of ADMA may mediate endothelial dysfunction during experimental hyperhomocysteinemia in humans (41). However, Jonasson et al. (42) did not find increased ADMA levels in patients with coronary heart disease and hyperhomocysteinemia, nor did vitamin supplementation have any effect on ADMA levels in spite of substantial plasma tHcy reduction,... 

Increases in plasma S-AA levels have previously been reported in patients with coronary disease (57). S-AA and plasma intracellular adhesion molecule-1 were elevated in patients with CAD and hyperhomocysteinemia, but only S-AA decreased after vitamin supplementation (35). Homocysteine activates nuclear factor- in endothelial cells, possibly via oxidative stress (58), and increases monocyte chemoattractant protein-1 expression in vascular smooth muscle cells (59). Additionally, it stimulates interleukin-8 expression in human endothelial cultures (60). These inflammatory factors are known to participate in the development of atherosclerosis. Taken together, these reports suggest an association of elevated tHcy and low-grade inflammation in CAD. 

To conclude, hyperhomocysteinemia is associated with oxidative stress, inflammation, endothelial dysfunction, and dysfunction of coagulation in animals and in humans, but vitamin supplementation does not consistently normalize these changes in spite of large reductions in homocysteine. It still remains be seen whether homocysteine per se causes the pathological processes or whether it is simply an innocent bystander. 

The results of these three large trials are consistent and lead to the conclusion that there is no clinical benefit from vitamin supplementation in patients with cardiovascular disease (CVD). 4s suggested by Loscalzo (69), the results indicate that either homocysteine is not a important atherogenic determinant or the vitamin therapy might have other adverse effects that offset its homocysteine-lowering effects, such as cell proliferation through synthesis of thymidine, hypermethylation of DNA, or increased methylation potential leading to elevated levels of ADMA. 

Arnadottir M et al. The effect of high-dose pyridoxine and folic acid supplementation on serum lipid and plasma homocysteine concentrations in dialysis patients. Clin Nephrol 1993 40(4) 236-240. 

Jonasson T, et al. Plasma homocysteine and markers for oxidative stress and inflammation in patients with coronary artery disease-a prospective randomized study of vitamin supplementation, Clin Chem Lab Med 2005 43(6) 628-634. 

Patients with PAD have increased mortality risk from cardiovascular causes (4,5), which is significantly increased in the subgroup of patients with high serum homocysteine concentration (33,34). Association of a low ABI and high homocysteine level could be useful for identifying patients at excess risk for cardiovascular death (34). In spite of the efficacy in lowering homocysteine level with a folic acid supplement there is no evidence that reducing homocysteine concentration is beneficial in patients with CHD and PAD (26,35),... 

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

Homocysteine isn t harmless. Evidence from population studies indicates that high levels of homocysteine in the blood are correlated with heart disease. Folic acid supplements may prevent this problem by ensuring that the homocysteine is rapidly converted to methionine. Similarly, pregnant women generally take folic acid supplements to prevent their babies from being bom with neural tube defects. The mechanism for its action isn t known, but the folic acid may help decrease the level of homocysteine in this case as well. 

An alternative reaction for the remethylation of homocysteine to methionine can be accomplished by betaine homocysteine methyltrans-ferase, which uses betaine instead of 5-MTHF as the methyl donor. Unlike the MS reaction, which is believed to be ubiquitously present in all tissues, the betaine homocysteine methyl-transferase reaction occurs only in the liver and kidney. Betaine is not a required nutrient since the liver can synthesize betaine from choline. Betaine supplements, however, have been shown to lower plasma total homocysteine concentrations successfully in subjects with deficient homocysteine remethylation due to defects in MTHFR or MTRR and in those with deficient CBS activity. 

Dietary supplementation with B vitamins is also highly effective in lowering homocysteine in most individuals with mild or moderate hyperhomocysteinemia. A meta-analysis of 12 randomized trials performed prior to folic acid fortification concluded that treatment with folic acid (0.5 to 5 mg daily) decreased homocysteine levels by 25%, and that the addition of... 

Brattstrom L, Landgren F, Israelsson B, et al. Lowering blood homocysteine with folic acid based supplements—meta-analysis of randomised trials. BMJ 316 894-898,1998. 

There is an association between the rare inborn recessive condition of homocystinemia and arterial and venous thrombosis, and observational data link coronary heart disease, stroke, and venous thromboembolism with increasing plasma homocysteine (Wald et al. 2002, 2004). This led to trials of foUc acid and pyridoxine supplementation to lower homocysteine levels (Hankey 2002 Hankey and Eikelboom 2005). Results from such trials have so far been disappointing the Vitamin Intervention for Stroke Prevention Study (VISP) and the Norwegian Vitamin Trial (NORVIT) (Toole et al. 2004 Bonaa et al. 2006) trials showed no treatment effect on recurrent stroke, coronary events or deaths. Preliminary results from the Study of Vitamins to Prevent Stroke (VITATOPS) trial have shown no evidence of reduced levels of iirflammation, endothelial dysfunction, or the hypercoagulability postulated to be increased by elevated homocysteine levels in patients with previous TIA or stroke treated with foUc acid, vitamin B12 and vitamin Bs... 

Homocysteine and cardiovascular disease evidence on causality from a meta-analysis. British Medical Journal 325 1202-1206 Wald DS, Law M, Morris JK (2004). The dose-response relationship between serum homocysteine and cardiovascular disease implications for treatment and screening. European Journal of Cardiovascular Prevention and Rehabilitation 11 250-253 Wang X, Qin X, Demirtas H et al. (2007). Efficacy of folic acid supplementation in stroke prevention a meta-analysis. Lancet 369 1876-1882... 

There is some evidence that riboflavin status affects the stability of the thermolab ile variant of methylene tetrahydrofolate reductase (Section 10.3.2.1), and that supplements of riboflavin may lower plasma homocysteine (Section 10.3.4.2) in people who are homozygous for the variant enzyme (McNulty et al., 2002). 

Epidemiological smdies suggest that hyperhomocysteineima is most significantly correlated with low folate status, but there is also a significant association with low vitamin Bg status (SeUiub et al., 1993). Trials of supplementation have shown that whereas folate supplements lower fasting homocysteine in moderately hyperhomocysteinemic subjects, supplements of 10 mg per day of vitamin Bg have no effect, although supplements do reduce the peak plasma concentration of homocysteine after a test dose of methionine (Ubbink et al., 1994 Ubbink, 1997 Dierkes et al., 1998). This can probably be explained on the basis of the kinetics of the enzymes involved the of cystathionine... 

Although folate is widely distributed in foods, dietary deficiency is not uncommon, and a number of commonly used drugs can cause folate depletion. Marginal folate status is a factor in the development of neural tube defects and supplements of 400 fj,g per day periconceptually reduce the incidence of neural tube defects significantly. High intakes of folate lower the plasma concentration of homocysteine in people genetically at risk of hyperhomo-cysteinemia and may reduce the risk of cardiovascular disease, although as yet there is no evidence from intervention studies. There is also evidence that low folate status is associated with increased risk of colorectal and other cancers and that folate may be protective. Mandatory enrichment of cereal products with folic acid has been introduced in the United States and other countries, and considered in others. 

Deficiency of vitamins Bg, B12, or folate are aU associated with elevated plasma homocysteine, with vitamin Bg deficiency as a result of impaired activity of cystathionine synthetase (Section 9.5.5) and folate and vitamin B12 as a result of impaired activity of methionine synthetase (Section 10.3.4). In subjects with apparently adequate intakes of vitamins Bg and B12, supplements of these two vitamins have little or no effect on fasting plasma homocysteine, although additional vitamin Bg reduces the plasma concentration of homocysteine after a test dose of methionine. By contrast, supplements of... 

Supplements of400 /xg per day of folic acid, begun before conception, halve the risk of neural tube defect (Section 10.9.4), and similar supplements reduce the plasma concentration of homocysteine in people homozygous for the ther-molabile variant of methylene-tetrahydrofolate reductase (Section 10.3.4.2), although it is not known whether or not this will reduce their risk of cardiovascular disease. A number of manufacturers voluntarily enrich foods with folic acid. In the United States and other countries, there is mandatory enrichment of cereal products with folic acid. 

Change A, Potier De Courcy G, Boisson F, Guilland JC, Barbe F, Perrin MO, Christides JP, Rabhi K, Pfister M, Galan P, Hercberg S, and Nicolas JP (2000b) 5,10-Meth-ylenetetrahydrofolate reductase common mutations, folate status and plasma homocysteine in healthy French adults of the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) cohort. British Journal of Nutrition 84, 891-6. 

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