Homocysteine stroke

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. 

Elevated homocysteine level (still under study, but may be related to stroke risk)... 

The response-to-injury hypothesis states that risk factors such as oxidized LDL, mechanical injury to the endothelium, excessive homocysteine, immunologic attack, or infection-induced changes in endothelial and intimal function lead to endothelial dysfunction and a series of cellular interactions that culminate in atherosclerosis. The eventual clinical outcomes may include angina, myocardial infarction, arrhythmias, stroke, peripheral arterial disease, abdominal aortic aneurysm, and sudden death. 

Prescribing perspective is to recognize that the previously acceptable counts, on treatment, between (500-650) X (f are hazardous since microvas-cular occlusion, including stroke, remain risks. The concurrent role of aspirin continues to be defined. Thus, while this has a sound theoretical benefit and is recommended to decrease platelet-endothelial cell interaction, occasional gastrointestinal tract bleeding may be found. Furthermore, associated hypercoagulability may be found and determinations of proteins C and S, mutations of factor V and II or elevated homocysteine, as well as the presence of anti-cardiolipin syndrome or lupus anticoagulant should not be overlooked. 

Homocysteine Studies Collaboration (2002) Homocysteine and risk of ischemic heart disease and stroke a meta-analysis. JAMA 288 2015-2022... 

Neurotoxins produced by the body. Some normal body constituents are neurotoxic in excess. These incluse quinolinic acid (Fig. 25-11),889 3-hydroxykynurenine (Fig. 25-11 p. 1444),890 and homocysteine.891 Elevated levels of homocysteine are also associated with vascular disease and stroke (Chapter 24). 3-Hydroxykynurenine is a precursor to ommochrome pigments of insects and an intermediate in conversion of tryptophan into the nicotinamide ring of NAD in humans (Fig. 25-11). 6-Hydroxydopamine (Fig. 30-26), which may be formed in the body, is severely toxic to catecholaminergic neurons.892... 

There may be an added benefit for adults. N 5-methyltetrahydrofolate is required for the conversion of homocysteine to methionine (Figure 33-1 Figure 33-2, reaction 1). Impaired synthesis of N 5-methyltetrahydrofolate results in elevated serum concentrations of homocysteine. Data from several sources suggest a positive correlation between elevated serum homocysteine and occlusive vascular diseases such as ischemic heart disease and stroke. Clinical data suggest that the... 

Moderately elevated plasma homocysteine, defined as levels between 15 and 30 jimol/L (5), has emerged as a new risk factor for ischemic heart disease and stroke (6). 

Many studies published during the last few decades have suggested that hyperhomocysteinemia is a risk factor for coronary artery disease (CAD), stroke, and thromboembolic disease. The Homocysteine Studies Collaboration metaanalysis of 30 studies concluded that elevated tHcy is a moderate risk factor for ischemic heart disease a level 3 xmol/L lower reduces the risk with an odds ratio of 0.89 (95% Cl = 0.83-0.96). The same was true for homocysteine as a risk factor for stroke (odds ratio = 0.81 95%5CI = 0.69-0.95) (6). A meta-analysis of 40 studies of the MTHFR 677 C > T polymorphism demonstrated a mildly increased risk of coronary heart disease with an odds ratio of 1. 16 (95% Cl = 1.05-1.28) (25). 

In the Heart Outcomes Prevention Evaluation 2 (HOPE-2) study, 5522 patients aged 55 or older with vascular disease or diabetes were randomized to treatment with either placebo or a combination 2, 5 mg of folic acid, 50 mg vitamin B6, and I mg vitamin B 2, for an average of five years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, and stroke. Mean plasma homocysteine levels decreased by 2.4 jimol/L in the treatment group and increased by 0.8 jimol/L in the placebo group. The primary outcome occurred in 18.8% of patients assigned to active therapy and in 19.8% of those assigned to placebo (relative risk = 0.95 95% Cl = 0.84-1.07 P = 0.41) (68). 

IboleJF etal. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004 291 (5) 565-575. 

Fallon UB, Elwood P, Ben Shiomo Y, Ubbink JB, Greenwood R, Smith GD. 2001. Homocysteine and ischaemic stroke in men the Caerphilly study. J Epidemiol Community Health 55 91-96. 

Fallon UB, Virtamo J, Young I, et al. 2003. Homocysteine and cerebral infarction in Finnish male smokers. Stroke 34 1359-1363. 

Like cholesterol, tHcy appears to be a graded risk factor, and even mild hyperhomocysteinemia confers an increased risk of cardiovascular events. A meta-analysis concluded that a 25% elevation in plasma tHcy (about 3 ftmol/L) is predictive of about a 10% increased risk of myocardial infarction and a 20% increased risk of stroke (Homocysteine Studies Collaboration, 2002). 

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... 

Dusitanond et al. 2005). However, a recent systematic review of all randomized trials of homocysteine lowering does suggest a modest reduction in stroke risk (Wang et al. 2007). 

Homocysteine-lowering treatment with folic acid, cobalamin and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction or hypercoagulability in patients with previous transient ischemic attack or stroke a randomized substudy of the VITATOPS trial. Stroke 36 144-146... 

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... 

Perry IJ, Refsum H, Morris RW, et al. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995 346 1395-8. 

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. 

Homocysteine—still under study, but hyperhomocysteinemia may be related to increased stroke risk Asymptomatic carotid stenosis Subclinical disease—aortic arch atheromas Multiple Risk Factors—Stroke Is Increased by the Presence of Multiple Risk Factors Framingham profile... 

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