Homocysteine elevated plasma concentrations

Schwaninger M, Ringleb P, Winter R, Kohl B, Fiehn W, Rieser PA, Waiter-Sack I. Elevated plasma concentrations of homocysteine antiepileptic drug treatment. Epilepsia 1999 40(3) 345-50. 

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). 

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). 

Amino acids (AA) have also been studied on microdevices for development of microclinical analysis devices. In urine, normal ranges for standard amino acids and their metabolites range from 0 to 24 mM, with abnormal concentrations indicative of a number of disease states. Plasma concentrations of certain amino acids can also be used for disease detection. Elevated homocysteine levels in plasma is an independent risk factor for cardiovascular disease. Microdevices employing end-column amperometric detection were used for the determination... 

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... 

McGregor DO, Dellow WJ, Lever M, George PM, Robson RA, and Chambers ST (2001) Dimethylglycine accumulates in uremia and predicts elevated plasma homocysteine concentrations. Kidney International 59,2267-72. 

Homocysteine arises from dietary methioiiine. High levels of homocysteine (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 homocysteine. Elevated homocysteine levels have been associated also with ischemic stroke (9). The mechanism by which high levels of homocysteine produce vascular damage are, as of yet, not completely understood. Interaction of homocysteine with platelets or endotheHal cells has been proposed as a possible mechanism. Clinically, homocysteine levels can be lowered by adrninistration of vitamin B, vitamin B 2j foHc acid. 

Nilsson, K., Gustafson, L., and Hultberg, B. 2007. Elevated plasma homocysteine concentration in elderly patients with mental illness is mainly related to the presence of vascular disease and not the diagnosis. Dement. Geriatr. Cogn. Disord. 24 162-168. 

The diagnosis of homocystinuria is based on the recognition of the clinical phenotype in conjunction with the identification of an elevated total plasma homocysteine and elevated plasma methionine concentrations (via quantitative plasma amino acid analysis). Low cystine and low cystathionine are also seen (Box 14.3). In addition, increased urinary excretion of homocysteine as well as cysteine-homocysteine disulfide can be identified on urine amino acid analysis. Confirmation of the diagnosis can be done via enzyme assay, typically performed on cultured skin fibroblasts, lymphocytes, or liver tissue, or via molecular studies. 

Epidemiological studies. Epidemiology is the study of the distribution and determinants of disease frequency in human populations and the application of this study to control health problems. Therefore, epidemiological studies harvest valid and precise information about the causes, prevention and treatments for disease. Types of epidemiological studies are experimental studies and observational studies (cohort and case-control studies). Homocysteine. Homocysteine is a sulfur-containing amino acid that occurs naturally in all humans. Elevated plasma homocysteine concentration is linked to an increased risk of ischemic stroke. Lowering homocysteine plasma levels is linked to increasing the intake of folic acid and vitamins Bg and Bi2-... 

In vitamin B12 deficiency, methionine synthase is inhibited causing increased levels of homocysteine and SAH. SAH in turn inhibits SAM mediated methylation, thereby leading to toxic levels of homocysteine causing direct damage to the vascular endothelium and inhibition of iV-methyl-o-aspartate receptors (NMDA) (Moretti et al. 2008). Homocysteine is produced entirely from the methylation cycle, as it is totally absent from any dietary source (Pietrzik and Bronstrup 1997). Hence, an elevated plasma homocysteine concentration is a sensitive marker for vitamin B12 and folate deficiency (Pametti et al. 1997). In addition, it can be due to increased frequency of impaired genetic capacity to metabolize homocysteine (Nilsson et al. 1996). 

Elevated concentrations of plasma homocysteine (HCY) are related to an increased risk of cardiovascular disease, which exists in numerous forms in plasma, with the main form existing as a disulfide with itself, cysteine, or albumin. Therefore, the first step in the measurement involves treatment with a reducing agent, in this case dithiothreitol (DTT), to obtain HCY in its free form (Eq. 16.34). Some amino acids (e.g., L-cysteine and L-methionine) are present in human plasma at higher molar concentrations than HCY and may interfere with this assay. To avoid this possible interference, the highly selective enzymatic conversion of HCY to S-adenosyl-L-homocysteine (SAH), as shown in Eq. 16.34, is used. Both reactions (reduction and conjugation) are accomplished in 30 min at 34 °C. 

The role of folic acid in the metabolism of homocysteine has received increased interest recently. Elevations of plasma homocysteine concentrations have been shown to be independent risk factors for coronary artery disease and probably cerebrovascular disease (see Chapter 26). The involvement of folate in its coenzyme forms with homocysteine and methionine metabolism is summarized in Figure 30-22. Folate is the principal micronutrient determinant of homocysteine status, and supplementation with folate has been used as a treatment modality to reduce circulating homocysteine concentrations. Primary (fasting) homo-cystinemia can be treated with 0.5 to 5.0mg/day of folic... 

Elevated serum MMA and tHcy concentrations can be considered alternative specific metabolic parameters of cobalamin deficiency. Measurement of functional metabolite MMA requires sophisticated equipment and is, therefore, unsuitable for routine use. Total homocysteine is a more sensitive analyte than tfii2 in diagnosing subclinical vitamin B12 deficiency because its plasma levels increase before clinical symptoms appear. However, the lack of specificity of this analyte represents a serious limit to its use. Total homocysteinemia depends on genetic or physiological factors, life style, diseases in progress, and drugs. HHCY is caused by folate or vitamin Bg deficiency and renal failure. 

Epilepsy. From the Greek, epilepsia (attack, seizure). A term applied to a group of brain disorders characterized by attacks of epileptic seizures (fits). Hyperhomocysteinemia. Designates a state with elevated concentration of plasma homocysteine, above the normal range. 

Vitamin B12 deficiency is generally assessed based on serum vitamin B12 concentration, plasma homocysteine concentration and serum methylmalonic acid (MMA) concentration (Savage et al. 1994). Serum vitamin B12 concentration has been reported by many researchers, including us, to be similar in patients with CKD and healthy individuals (Koyama et al. 2002). However, plasma total homocysteine level is elevated in an inverse relationship with the reduction in renal function (Bostom and Lathrop 1997). 

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