Homocysteine blood concentration

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). 

Folate status may be reliably assessed by direct measurement of serum and erythrocyte or whole blood concentrations, and its metabolic function as coen2yme assessed by metabolite concentrations, such as plasma homocysteine (see Chapters 20 and 26). Serum folate concentrations are considered indicative of recent intake and not of tissue stores, but serial measurements have been used to confirm adequate intake. Whole blood or erythrocyte folate concentrations are more indicative of tissue stores and have been shown to have a moderate correlation with liver folate concentrations taken through a biopsy. Because folate is taken up only by the developing erythrocyte in the bone marrow and not by the mature cell, erythrocyte concentrations reflect folate status over the 120-day lifespan of the ceU. Urine folate excretion is not considered to be a sensitive indicator of folate status. ... 

Homocysteine Lowering Trialists Collaboration, 2005. Dose-dependent effects of folic acid on blood concentrations of homocysteine a meta-analysis of the randomized trials. The American Journal of Clinical Nutrition. 82 806-812. 

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). 

Metabolism In a prospective controlled study in 74 patients taking isotretinoin for cystic acne, blood concentrations of homocysteine, vitamin B12, and folate were assessed before and after 45 days of isotretinoin therapy [39 ]. The control group consisted of 80 individuals. Homocysteine concentrations were significantly higher in those who took isotretinoin. The vitamins were unaffected, but serum lipids and liver enzymes increased significantly. These effects may have been due to inhibition of cystathionine-beta-synthase, an enzyme required for the metabolism of homocysteine by either the drug or liver dysfunction. Daily supplementation with vitamin B12 and folate can lower plasma concentrations of homocysteine, and the authors therefore recommended the use of these vitamins in patients taking isotretinoin. 

Distribution. Lead in blood partitions between plasma and red blood cells, with the larger fraction (90-99%) associated with red blood cells (Cake et al. 1996 DeSilva 1981 Everson and Patterson 1980 Manton and Cook 1984 Ong and Lee 1980a). Lead in plasma binds to albumin and y -globulins (Ong and Lee 1980a). The fraction that is not bound to protein exists largely as complexes with low molecular weight sulfhydryl compounds these may include cysteine, homocysteine, and cysteamine (Al-Modhefer et al. 1991). Approximately 75% was bound to protein when whole human blood was incubated with 50 ig/dL lead (as lead chloride) approximately 90% of the bound lead was associated with albumin (Ong and Lee 1980a). However, the fraction of lead in plasma bound to protein would be expected to vary with the plasma lead concentration. 

Figure 22.6 How various factors increase the risk of atherosclerosis, thrombosis and myocardial infarction. The diagram provides suggestions as to how various factors increase the risk of development of the trio of cardiovascular problems. The factors include an excessive intake of total fat, which increases activity of clotting factors, especially factor VIII an excessive intake of saturated or trans fatty acids that change the structure of the plasma membrane of cells, such as endothelial cells, which increases the risk of platelet aggregation or susceptibility of the membrane to injury excessive intake of salt - which increases blood pressure, as does smoking and low physical activity a high intake of fat or cholesterol or a low intake of antioxidants, vitamin 6 2 and folic acid, which can lead either to direct chemical damage (e.g. oxidation) to the structure of LDL or an increase in the serum level of LDL, which also increases the risk of chemical damage to LDL. A low intake of folate and vitamin B12 also decreases metabolism of homocysteine, so that the plasma concentration increases, which can damage the endothelial membrane due to formation of thiolactone.

When present in excess methionine is toxic and must be removed. Transamination to the corresponding 2-oxoacid (Fig. 24-16, step c) occurs in both animals and plants. Oxidative decarboxylation of this oxoacid initiates a major catabolic pathway,305 which probably involves (3 oxidation of the resulting acyl-CoA. In bacteria another catabolic reaction of methionine is y-elimination of methanethiol and deamination to 2-oxobutyrate (reaction d, Fig. 24-16 Fig. 14-7).306 Conversion to homocysteine, via the transmethylation pathway, is also a major catabolic route which is especially important because of the toxicity of excess homocysteine. A hereditary deficiency of cystathionine (3-synthase is associated with greatly elevated homocysteine concentrations in blood and urine and often disastrous early cardiovascular disease.299,307 309b About 5-7% of the general population has an increased level of homocysteine and is also at increased risk of artery disease. An adequate intake of vitamin B6 and especially of folic acid, which is needed for recycling of homocysteine to methionine, is helpful. However, if methionine is in excess it must be removed via the previously discussed transsulfuration pathway (Fig. 24-16, steps h and z ).310 The products are cysteine and 2-oxobutyrate. The latter can be oxidatively decarboxylated to propionyl-CoA and further metabolized, or it can be converted into leucine (Fig. 24-17) and cysteine may be converted to glutathione.2993... 

Gidal BE, Tamura T, Hammer A, Vuong A. Blood homocysteine, folate and vitamin B12 concentrations in patients with epilepsy receiving lamotrigine or sodium valproate for initial monotherapy. Epilepsy Res 2005 64 161-6. 

Hall, M Gamble, M Slavkovich, V. et al. (2007) Determinants of arsenic metabolism Blood arsenic metabolites, plasma folate, cobalamin, and homocysteine concentrations in maternal-newborn pairs. Environmental Health Perspectives, 115 (10), 1503-9. 

In another letter to the editor (12) it was mentioned that the suspicion of partiality about the Committee on Toxicity becomes more plausible when one considers the issue of homocysteine. This intermediate metabolite may well turn out to be of greater importance as a risk factor for cardiovascular disease than cholesterol and blood pressure. Raised homocysteine concentrations appear to be accessible to treatment with pyridoxine (100 mg/day) together with vitamin B12 and foUc acid (13). Furthermore, the statement that there is no good evidence for the efficacy of pyridoxine in any disease, apart from depression, was criticized, because this ignores important studies in autism, pregnancy outcome, asthma, and sickle-cell anemia (12). 

Both direct and indirect (ftmctional) methods are available for assessing vitamin B status. The indirect tests include assays for urinary and serum concentrations of methylmalonic acid, plasma homocysteine, the deoxyuridine suppression test, and the vitamin B12 absorption test. Cyto-chemical staining of red blood cell (RBC) precursors and the test for IF blocking antibodies are also ancillary methods for assessing vitamin B12 status. 

Thiols can be oxidised at a variety of solid electrodes, such as noble metals, carbon and carbon with chemically modified surfaces. Mefford and Adams found that relatively high voltages, greater than -1-1 V, were required to oxidise GSH and cysteine at glassy carbon electrodes. Chemically modified surfaces can reduce the oxidation potentials required and hopefully increase specificity and sensitivity. Halbert and Baldwin used cyclic voltammetry to study the electrochemistry of cysteine, homocysteine, A -acetylcysteine and GSH at both unmodified and cobalt phthalocyanine-modified carbon paste electrodes. This non-chromatographic technique was used to measure the relatively high concentrations of GSH in whole blood. The electrochemistry of thiols has been reviewed. ... 

Another improvement implemented over the past years deals with sample preparation. In plasma and blood, only 5-15% of the total homocysteine is free. The rest is bound to disulfide bridges, either to other thiols or to various proteins. A reduction step is thus necessary for a meaningful monitoring of the homocysteine concentration. By switching from sodium borohydride to tris(2-carboxyethyljphosphine (TCEP), the disulfide reducing agent most widely used today [595], sample preparation was simplified. 

Since concentration measurements in blood may not reflect true vitamin status, the measurement of metabolites or activity of enzymes that use a coenzyme form of a B vitamin has been suggested. For example, the measurement of either homocysteine or methylmalonic acid has been suggested as a marker for cobalamin status, and the erythrocyte transaminase coefficient has been suggested as a marker for vitamin Bg status. However, there are no accepted definitions for the diagnosis of vitamin deficiency in the case of many vitamins. 

To assess the relationship of Hey concentrations with vascular disease risk, a meta-analysis of observational studies was carried out, showing that elevated Hey is at most a modest independent predictor of ischemic heart disease and stroke risk in healthy populations. Studies of the impact on disease risk of genetic variants that affect blood Hey concentrations will help determine whether Hey is causally related to vascular disease, as may large randomized trials of the effects on ischemic heart disease and stroke of vitamin supplementation to lower blood Hey concentrations (Homocysteine Studies Collaboration 2002). 

The results of prospective or cohort studies of homocysteine and vascular disease (where blood for homocysteine determinations was collected before the onset of disease in cases) in the late 1990s were less extreme than those of retrospective studies (where blood for homocysteine determinations was collected after the onset of vascular disease) (Danesh and Lewington 1998). In 1998, Danesh and Lewington reported that a 5 pmol/L higher measured homocysteine was associated with an odds ratio for CHD of 1.6 (1.4-1.7) in retrospective studies but only 1.3 (95%CI 1.1-1.5) in prospective studies (Danesh and Lewington 1998). The discrepancy between the results of retrospective and prospective studies was interpreted to indicate reverse causality i.e. the effect of vascular disease on homocysteine concentrations) (Danesh and Lewington 1998). 

In order to estimate reliably the associations of homocysteine with CHD and stroke outcomes, individual participant data were collected from all observational studies of homocysteine with CHD and stroke outcomes for the Homocysteine Studies Collaboration (Homocysteine Studies Collaboration 2002). With individual participant data, the Homocysteine Studies Collaboration meta-analysis was able to examine the shape and strength of association of homocysteine with vascular disease after adjustment for bias and confounding due to other risk factors (Homocysteine Studies Collaboration 2002). After excluding individuals with prior disease at enrolment and adjustment for smoking, blood pressure and cholesterol, a 25% lower usual i.e. longterm) homocysteine concentration (about 3 pmol/L, a difference typically achieved by folic add supplementation in populations without mandatory fortification of grain products with folic acid) was associated with an 11% (95% Cl 4-17%) lower risk of CHD and a 19% (5-31%) lower risk of stroke (Homocysteine Studies Collaboration 2002). 

Cystathionine synthase has pyridoxal phosphate as cofactor a radically different form of treatment was introduced in 1967 giving pyridoxine at a dosage level of 50 to 200 mg per day [40]. The concentrations of methionine and homocysteine in the blood, and of homocystine and homocysteine-cysteine mixed disulphide in the urine, fell sharply on such treatment in... 

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