Supplements homocysteine levels

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. 

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. 

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),... 

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... 

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, an amino acid associated with eoronary heart disease as a risk factor is elevated in folate deficiency (discussed earlier and also see Chapter 17). If the elevation of plasma homoeysteine is due to folate deficency, supplementation of folate corrects the plasma homocysteine level and may deerease the morbidity and mortality from atherosclerotie disease which can lead to heart attack and stroke. Vitamin Be and Vitamin B12 defieencies can also cause elevated plasma homocysteine levels. 

Myelosuppression increased in patients with elevated cystathioneine or homocysteine concentrations. Folic acid and vitamin B12 supplementation decrease myelosuppression by decreasing elevated cystathionine and homocysteine levels. 

Homocysteine is an intermediate in biosynthesis of cysteine, methionine, and in the breakdown of methionine. Recent research has indicated that elevated levels of homocysteine may correlate with increased incidence of vasuclar disease. Supplementation of diets with folic acid, cobalamin and pyridoxine appear to provide protection by lowering homocysteine levels in the blood. 

Chauveau P, Chadefaux B, Coude M, Aupetit J, Kamoun P, lungers P. Long-term folic acid (but not pyridoxine) supplementation lowers elevated plasma homocysteine level in chronic renal failure. Miner Electrolyte Metab 1996 22 106-1()9. 

The homocysteine hypothesis of vascular disease has attracted considerable interest since homocysteine levels are readily lowered by daily dietary supplementation with folic acid, vitamin Bg and vitamin B12 (Homocysteine Lowering Trialists Collaboration 2005), raising the prospect that dietary supplementation with these B vitamins could prevent vascular disease. Indeed, dietary supplementation with B vitamins to lower homocysteine levels of affected individuals is remarkably effective for the prevention of cardiovascular disease and other complications of homocystinuria (Yap et al. 2001). This review examines the evidence from the observational studies of homocysteine and vascular disease and from the randomized trials of B vitamin supplementation for the prevention of vascular disease. 

Although the observational studies suggested modest associations of homocysteine with risk of vascular disease that were biologically plausible, such studies could not establish if these associations were causal. The randomized trials assessed the effectiveness of dietary supplementation with B vitamins to lower homocysteine levels on risk of cardiovascular morbidity and mortality. The initial trials were designed in the mid-1990s before the results of the Homocysteine Studies Collaboration meta-analysis (Homocysteine Studies Collaboration 2002) were reported in 2002. Consequently, few of the individual trials had sufficient statistical power to confirm or refute the 10% difference in... 

Many studies have found that elderly and cognitively impaired patients may have high homocysteine levels in spite of normal blood concentration of folate and vitamin B12. Hence, serum homocysteine is a more sensitive indicator of low vitamin B12 and folate status at tissue level. It is further supported by the fact that homocysteine levels can often be normalized by supplementing the diet with vitamin B12 and folate (Diaz-Arrastia 2000). 

Mucosal lesions (Fig. 1), nausea, and diarrhea are also consequences of MTX therapy. At doses of 15 to 25 mg used for arthritis, nausea has been reported by 40% to 60% of patients and diarrhea over 10% of the time (94,95). Stomatitis had also been reported in over 10% of cases from another series (96). This appears to be dose related, with no difference between placebos for any of these effects in a randomized trial of MTX for sarcoidosis (35). However, in a larger series of sarcoidosis, some sarcoidosis patients did discontinue MTX because of nausea (8,97). The hematologic and G1 toxicity of MTX can be minimized by the use of low-dose folic acid supplement (1-mg folic acid per day) (98) without affecting the efficacy of MTX. MTX leads to decreased homocysteine levels that can be reversed with folic acid supplementation (99). 

A deficiency of folate, vitamin B12, or vitamin Bg may increase the level of homocysteine, an amino acid normally found in the blood. Evidence indicates that a high homocysteine level increases the risk for CVD and stroke, possibly by either damaging coronary arteries or making it easier for blood platelets to clump together and form a clot. However, no evidence is available to suggest that lowering homocysteine through vitamin supplementation will reduce the risk of CVD. Clinical intervention trials to test the effects of vitamin supplementation on CVD and stroke are needed. 

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]. 

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. 

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. 

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. 

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. 

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. 

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. 

Folic acid is one of the B vitamins. Research has established that consuming about 800 micrograms by way of foods and supplements, along with vitamins B6 and B12, reduces levels of the amino acid homocysteine, another risk factor for heart disease. Now recent... 

A consequence of these studies is that the Food and Drug Administration (fTDA) has recomtnended that commercially available flour and cereal products be fortified w ith folic acid 1-4 tug folic acid/kg flour) for preventing NTDs (Tucker cf ai, 1996). The consumer interested in the folate level in any particular food can view the label on the package. Folic acid supplements have the effect of reducing the level of homocysteine in the blood. This homocysteine effect appears directly relevant to the prevention of atherosclerosis, but may also be relevant to neural tube defects. The reader interested in continuing developments regarding neural tube defects and folate should take note of the relationship between folate and homocysteine, presented in the Vitamin 8 section. 

A study of 2K human subjects revealed that treatment with three vitamins together (folate, vitamin and vitamin Bu) can provoke a decline of plasma homt>cysteine from an initial level of about 12 piM to the lower level of 8 xM (Naurath ei a]., 1995). A study of 100 men with moderate levels of plasma homocysteine (18-40 pM) involved separate supplements of placebo, folic acid, vitamin 15i2, or vitamin E. Folic add alone resulted in a 40% decline in plasma homocysteine. Vitamin B] alone provoked a 15% decrease in the amino acid, while vitamin... 

Vitamin Bjj deficiency is a dearly defined condition that tends to be somewhat common in the older population, due to gastric atrophy and pernicious anemia. Moderate increases in plasma homocysteine can ciccur with B j deficiency, and these levels can be cut in half by supplements of this vitamin (Brattstrom el al, 1988 Sumner el ai., 1996). Researchers interested in the mechanisms by which plasma homocysteine can influence metabolism need to con.sider the possible effects of other sulfhydryl compounds (K—Sf f) that occur in plasma. These sulf-hydryl compounds include cysteine (10-100 pM) (Hiramatsu et ai, 1994 Fuka-gawa, 1996), glutathione (2 pAi in humans 20 pM in rats) (Halliwell and Gut-teridge, 1990), and the free sulfhydryl in albumin (640 pM) (E>eMaster et al., 1995). The micromolar levels of cysteine, glutathione, and the albumin in plasma are indicated. 

---