Vitamin hyperhomocysteinemia

Homocysteine arises from dietary methionine. High levels of homocysteiae (hyperhomocysteinemia) are a risk factor for occlusive vascular diseases including atherosclerosis and thrombosis (81—84). In a controlled study, semm folate concentrations of <9.2 nmol/L were linked with elevated levels of plasma homocysteiae. Elevated homocysteine levels have beea associated also with ischemic stroke (9). The mechanism by which high levels of homocysteine produce vascular damage are, as of yet, aot completely uaderstood. lateractioa of homocysteiae with platelets or eadothehal cells has beea proposed as a possible mechanism. Clinically, homocysteine levels can be lowered by administration of vitamin B, vitamin B 2> foHc acid. 

As shown in the review of the homocysteine metabolism, vitamin B 2, vitamin B6, and folate are important cofactors in the metabolic pathways for homocysteine elimination, and consequently, deficiencies of these vitamins are characterized by elevated plasma concentrations of tHcy. Hyperhomocysteinemia is also frequently found in diseases such as renal failure, rheumatic and auto-immune diseases, hypothyroidism, and malignancies. Several drugs are also known to increase plasma tHcy concentrations (16-24). 

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. 

Measurement of blood tHcy is usually performed for one of three reasons (1) to screen for inborn errors of methionine metabolism (2) as an adjunctive test for cobalamin deficiency (3) to aid in the prediction of cardiovascular risk. Hyperhomocysteinemia, defined as an elevated level of tHcy in blood, can be caused by dietary factors such as a deficiency of B vitamins, genetic abnormalities of enzymes involved in homocysteine metabolism, or kidney disease. All of the major metabolic pathways involved in homocysteine metabolism (the methionine cycle, the transsulfuration pathway, and the folate cycle) are active in the kidney. It is not known, however, whether elevation of plasma tHcy in patients with kidney disease is caused by decreased elimination of homocysteine in the kidneys or by an effect of kidney disease on homocysteine metabolism in other tissues. Additional factors that also influence plasma levels of tHcy include diabetes, age, sex, lifestyle, and thyroid disease (Table 21-1). 

Homocysteine-lowering therapy is lifesaving for patients with severe hyperhomocysteinemia due to CBS deficiency. Approximately 50% of patients respond to treatment with pharmacological doses (100 to 800 mg daily) of pyridox-ine (a form of vitamin B6). Adjunctive therapy may include betaine (2 to 6 g daily), folic acid (5 to 10 mg daily), or cobalamin (0.05 to 1.0 mg daily), or methionine restriction. Long-term homocysteine-lowering therapy substantially decreases cardiovascular risk in these patients. 

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... 

The identification of hyperhomocysteinemia as an independent risk factor in atherosclerosis and coronary heart disease (Section 10.3.4.2) has led to suggestions that intakes of vitamin Be higher than are currently considered adequate to meet requirements may be desirable. Homocysteine is an intermediate in methionine metabolism and may undergo one of two metabolic fates, as shown in Figure 9.5 remethylation to methionine (a reaction that is dependent on vitamin B12 and folic acid) or onward metabolism leading to the synthesis of cysteine (trans-sulfuration). Therefore, intakes of folate, vitamin B12, and/or vitamin Be may affect homocysteine metabolism. 

Vitamin Be-Responsive Inborn Errors of MetaboUsm Indices of Vitamin Bg Nutritional Status Reference Intakes of Vitamin Bg Adverse Effects of Hyperhomocysteinemia Indices of Folate and Vitamin B12 Nutritional Status... 

Epidemiologiced studies suggest that hyperhomocysteinemia is most sig-nificemtly correlated with low folate status, but there is edso a significtmt tissoci-ation with low vitamin Be status (Selhub et al., 1993). Trials of supplementation have shown that whereas folate supplements lower fasting homocysteine in moderately hyperhomocysteinemic subjects, supplements of 10 mgper day of vitamin Be 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 ed., 1998). This cem probably be explained on the basis of the kinetics of the enzymes involved the Km of cystathionine... 

The reference values for human adults are in the range of 6 to 12 mM. Values exceeding 16 xM characterize hyperhomocysteinemia. Hyperhomocysteinemia can be fiuther subclassified as mild, intermediate, and severe [3,92]. Elevated homocysteine levels are found in 1-2% in the general population. Higher prevalence is associated with vascular diseases [3,93]. It increases with age. The vitamin deficiency, frequent in the elderly, contributes for the elevation of homocysteine levels [3,94]. Homocysteine levels increase in post-menopausal women, and are attenuated by hormone replacement therapy [3,94]. Hyperhomocysteinemia may result from [2,3,88,93] ... 

A. G. Bostom, D. Shemin and K. LaPane, High Dose B-Vitamin Treatment of Hyperhomocysteinemia in Dialysis Patients, Kidney International 49 (1996) 147-152. 

Vitamin B-6 is also required for the conversion of homocysteine to cysteine and hyperhomocysteinemia appears to be a risk factor for cardiovascular disease. 

Cravo ML, Gloria LM, Selhub J, Nadeau MR, Camilo ME, Resende MP et al. Hyperhomocysteinemia in chronic alcoholism correlation with folate, vitamin B-12, and vitamin B-6 status. Am J Clin Nutr... 

Yoburn D, Nadeau MR, et al. High dose-B-vitamin treatment of hyperhomocysteinemia in dialysis patients. Kidney Int 1996 49 147-52. 

Deficiencies of methionine adenosyltransferase, cystathionine 8-synthase, and cystathionine )/-lyase have been described. The first leads to hypermethioninemia but no other clinical abnormality. The second leads to hypermethioninemia, hyperhomocysteinemia, and homo-cystinuria. The disorder is transmitted as an autosomal recessive trait. Its clinical manifestations may include skeletal abnormalities, mental retardation, ectopia lentis (lens dislocation), malar flush, and susceptibility to arterial and venous thromboembolism. Some patients show reduction in plasma methionine and homocysteine concentrations and in urinary homocysteine excretion after large doses of pyridoxine. Homocystinuria can also result from a deficiency of cobalamin (vitamin B12) or folate metabolism. The third, an autosomal recessive trait, leads to cystathioninuria and no other characteristic clinical abnormality. 

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