Disease relevance of Hyperhomocysteinemia

• CONCLUSIONS: The results strongly suggest that alcohol may modulate both apoptotic and fat synthetic gene expression through homocysteine-induced ER stress in chronic alcoholic mouse liver and that correction of hyperhomocysteinemia by betaine or other approaches may be useful to prevent alcoholic liver disease [1].
• BACKGROUND & AIMS: Cystathionine beta-synthase (CBS) deficiency causes severe hyperhomocysteinemia, which confers diverse clinical manifestations, notably liver disease [2].
• Normalization of hyperhomocysteinemia with L-thyroxine in hypothyroidism [3].
• Elevated plasma homocysteine (hyperhomocysteinemia) is associated with occlusive vascular disease [4].
• Methylenetetrahydrofolate reductase (MTHFR) mutations are commonly associated with hyperhomocysteinemia, and, through their defects in homocysteine metabolism, they have been implicated as risk factors for neural tube defects and unexplained, recurrent embryo losses in early pregnancy [5].

Psychiatry related information on Hyperhomocysteinemia

• For folate deficiency and hyperhomocysteinemia, the association with depressive disorders was substantially reduced after adjustment for functional disability and cardiovascular disease, but for vitamin B(12) this appeared independent [6].
• Independently of hyperhomocysteinemia and other confounders, low folate concentrations (< or = 11.8 nmol/L) were also associated with an increased risk of both dementia (1.87; 95% CI: 1.21, 2.89; P = 0.005) and AD (1.98; 95% CI: 1.15, 3.40; P = 0.014), whereas the association was not significant for vitamin B-12 [7].
• The effects of folate deficiency include hyperhomocysteinemia, megaloblastic anemia, and mood disorders [8].
• Further, since hyperhomocysteinemia may promote oxidative stress, and we had previously found evidence of oxidative stress in brain following sleep deprivation, we also searched for evidence of systemic oxidative stress by measuring glutathione and thiobarbituric acid reactive substance levels [9].
• In addition, new strategies for stroke prevention have been identified, including encouragement of a diet high in fruits, vegetables, whole grains, and omega-3 fatty acids, the use of vitamins B12, B6, and folic acid in hyperhomocysteinemia, and moderate alcohol consumption [10].

High impact information on Hyperhomocysteinemia

• Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins [11].
• CONTEXT: Hyperhomocysteinemia is caused by genetic and lifestyle influences, including low intakes of folate and vitamin B6 [12].
• Hepatic steatosis is common in patients having severe hyperhomocysteinemia due to deficiency for cystathionine beta-synthase [13].
• Hence, mild hyperhomocysteinemia due to reduced CBS expression impairs endothelium-dependent vasodilation, likely due to impaired nitric oxide bioactivity, and increased oxidative stress apparently contributes to inactivating nitric oxide in chronic, mild hyperhomocysteinemia [14].
• Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (> or = 40 micromol/liter). The Hordaland Homocysteine Study [15].

Chemical compound and disease context of Hyperhomocysteinemia

• Pretreatment with antioxidant vitamin E and ascorbic acid blocks the effects of hyperhomocysteinemia, suggesting an oxidative mechanism [11].
• BACKGROUND & AIMS: Alcohol-induced hyperhomocysteinemia has been reported in rats and humans [1].
• Nonetheless, hyperhomocysteinemia due to this compound heterozygosity is correctable by oral folic acid therapy [16].
• Such studies have not distinguished the effects of excess dietary methionine from those of hyperhomocysteinemia [4].
• Demonstration of rapid onset vascular endothelial dysfunction after hyperhomocysteinemia: an effect reversible with vitamin C therapy [17].

Biological context of Hyperhomocysteinemia

• Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice [18].
• Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition [19].
• Molecular defects in the intestinal absorption of dietary folates that precipitate low blood folate levels and hyperhomocysteinemia have not been investigated previously [20].
• Acute methionine load-induced hyperhomocysteinemia enhances platelet aggregation, thromboxane biosynthesis, and macrophage-derived tissue factor activity in rats [21].
• We used a combination of differential display and cDNA arrays to analyze differential gene expression in association with elevated hepatic homocysteine levels in CBS-deficient mice, a murine model of hyperhomocysteinemia [22].

Anatomical context of Hyperhomocysteinemia

• Recent studies have shown that a common mutation (nucleotide 677 C-->T) in the methylenetetrahydrofolate reductase (MTHFR) gene may contribute to mild hyperhomocysteinemia and, therefore, to the incidence of coronary artery disease [23].
• Because homocysteine has been found to be damaging to endothelial cells in animal and cell culture studies, we evaluated the association between hyperhomocysteinemia and arterial endothelial dysfunction (a marker of early atherosclerosis) in asymptomatic adult subjects [24].
• Such hypertrophy may reflect a smooth muscle proliferation induced by hyperhomocysteinemia and represent a promising target for testing vascular effects of therapeutic measures to lower homocysteine [25].
• Low levels of serum folate and the 677TT methylene tetrahydrofolate reductase were associated with hyperhomocysteinemia, but in a multivariate model hyperhomocysteinemia only was associated with an increased risk of cerebral vein thrombosis [26].
• This has been linked to the toxic effects of hyperhomocysteinemia in uremic erythrocytes; however, treatment aimed at abating homocysteine levels did not lead to significant reductions in plasma protein damage [27].

Gene context of Hyperhomocysteinemia

• Patients with severe MTHFR deficiency have hyperhomocysteinemia, hypomethioninemia, and a range of neurological and vascular findings with a variable age at onset [28].
• Severe hyperhomocysteinemia in its most frequent form, is caused by a homozygous enzymatic deficiency of cystathionine beta-synthase (CBS) [29].
• We tested the hypothesis that heterozygous disruption of the Mthfr gene sensitizes mice to diet-induced hyperhomocysteinemia and endothelial dysfunction [18].
• Methionine synthase reductase (MSR) deficiency is an autosomal recessive disorder of folate/cobalamin metabolism leading to hyperhomocysteinemia, hypo- methioninemia and megaloblastic anemia [30].
• Biallelic expression of H19 has been observed in renal disease patients with hyperhomocysteinemia, a cardiovascular disease risk factor [31].

Analytical, diagnostic and therapeutic context of Hyperhomocysteinemia

• We also did not detect resistance of plasma FV to APC in hyperhomocysteinemic mice deficient in cystathionine beta-synthase (plasma tHcy, 93 +/- 16 microM) or in human volunteers with acute hyperhomocysteinemia (plasma tHcy, 45 +/- 6 microM) [32].
• A dose of 30 or 60 mg of folic acid per day was compared with 15 mg/d in an attempt to normalize hyperhomocysteinemia in 150 hemodialysis patients [33].
• Coronary endothelial function in hyperhomocysteinemia: improvement after treatment with folic acid and cobalamin in patients with coronary artery disease [34].
• We assessed the prevalence and potential determinants of fasting and postmethionine-loading hyperhomocysteinemia in 29 stable renal transplant recipients and 58 age- and sex-matched, population-based controls free of renal disease with serum creatinine levels of 1.5 mg/dL or less [35].
• We conclude that hyperhomocysteinemia reduces rat skeletal muscle arteriolar dilations in response to ACh and histamine, and enhances constrictions to NE, alterations that are likely to be caused by the reduced mediation of these responses by NO [36].

References