Homocysteine serum concentration

Wulffele MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van den Burg B, Donker AJM, Stehouwer CDA. Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus a randomized, placebo- controlled trial. J Intern Med 2003 254 455-63. 

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... 

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. 

Selhub J, Jacques PR, Rosenberg IH, et al. Semm total homocysteine concentrations in the Third National Health and Nutrition Survey (1991-1994) population reference ranges and contribution of vitamin status to high serum concentrations. Ann Intern Med 1999 131 331-339. 

In cooperation with vitamin B12, folic acid methylates homocysteine to methionine. Therefore, homocysteine is a suitable marker for the supply of folate. In the case of a deficiency, the serum concentration of this marker is clearly raised compared with the normal value of 8-lOpmol/ml, resulting in negative effects on health because higher concentrations of homocysteine are toxic. 

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.

Serum homocysteine concentration. The influence of nutritional factors associated... 

Metformin can cause reduced vitamin Bi2 absorption, reducing serum Bi2 concentrations and causing megaloblastic anemia (87), the prevalence of which was 9% in 600 patients with type 2 diabetes taking biguanides (phen-formin or metformin) for a mean of 12 years (88). In 353 patients with type 2 diabetes, treated with insulin, who took metformin for 16 weeks in a placebo-controlled study, metformin increased serum homocysteine concentrations by 4% and reduced serum folate by 7% and vitamin Bi2 by 14% (89). 

Some antiepileptic drugs have been associated with low serum and erythrocyte folate concentrations and high total plasma homocysteine concentrations in some patients. The concentrations of folate and homocysteine have been measured in 42 patients taking carbamazepine and 42 matched healthy controls (241). Patients taking carbamazepine had significantly lower serum and erythrocyte folate concentrations. There was hyperhomocystinemia (over 15 gmol/l) in 24% of the patients and 5% of the controls. 

Arnadottir M et al. The effect of high-dose pyridoxine and folic acid supplementation on serum lipid and plasma homocysteine concentrations in dialysis patients. Clin Nephrol 1993 40(4) 236-240. 

Patients with PAD have increased mortality risk from cardiovascular causes (4,5), which is significantly increased in the subgroup of patients with high serum homocysteine concentration (33,34). Association of a low ABI and high homocysteine level could be useful for identifying patients at excess risk for cardiovascular death (34). In spite of the efficacy in lowering homocysteine level with a folic acid supplement there is no evidence that reducing homocysteine concentration is beneficial in patients with CHD and PAD (26,35),... 

On the day of admission, the patient had developed a deep venous thrombosis in his right calf, a site not involved in the injury. In investigating the underlying cause of the deep venous thrombosis, serum homocysteine was measured and found to be 17.4 pmol/L (normal is < 14 pmol/I.).To distinguish between folic acid and vitamin B12 deficiencies, a serum methylmalonic acid (MMA) assay was performed it yielded a result of 0.59 pmol/I. MMA (normal is < 0.30 pmol/L). This confirmed the presence of vitamin B12 deficiency, despite a serum B12 concentration that was within the normal range. 

Indirect indicators of vitamin B12 deficiency include measurements of the metabolites homocysteine and methylmalonic acid (MMA) in serum and MMA in urine (see the Biochemical Perspectives section). Whereas the serum homocysteine concentration increases during folate or vitamin B12 deficiencies, the serum and urine MMA concentrations increase only in vitamin B12 deficiency. Therefore, MMA determinations can be used to differentiate vitamin B12 deficiency from folate deficiency. The normal concentration of MMA in serum ranges from 0.08 to 0.28 pmol/L. MMA is quantified using gas-liquid chromatography and mass spectrometry. Elevated concentrations of MMA and homocysteine in serum may precede the development of hematological abnormalities and reductions in serum vitamin B12 concentrations. One should be aware that other conditions, including renal in sufficiency and inborn errors of metabolism, can also result in elevated serum levels of MMA. 

In the early stages of reduced vitamin B12 absorption, the amount of vitamin B12 bound to TCII decreases rapidly (10-21 days) without any decrease in the total serum B12 level. The total vitamin B12 concentration begins to decline only when the saturation of TCII falls below 5%. Reduced saturation of TCII is thus one of the earliest indicators of reduced intake of vitamin B12 and is detectable in advance of clinical disease. This makes holo-TCII particularly valuable for use as a screening test in susceptible populations. Elevated serum and urine concentrations of homocysteine and MMA occur somewhat later and represent early evidence of cellular dysfunction that occurs when body (liver) stores have been greatly depleted. 

Concentrations of plasma homocysteine, plasma pyridoxal 5 -phosphate (active vitamin B6), serum folate, erythrocyte folate, and serum vitamin B12 have been measured both during fasting and after methionine in 60 epileptic patients (aged 14-18 years) and 63 sex- and age-matched controls before therapy and after 1 year of therapy with valproate or carbamazepine (33). After 1 year the patients who took valproate and carbamazepine had significantly increased plasma homocysteine concentrations compared with both baseline and control values and there was a significant fall in serum folate and plasma pyridoxal 5 -phosphate. Serum vitamin B12 and erythrocyte folate were unchanged. 

Reduced serum folate concentrations have been demonstrated in patients with homocystinuria taking pyridoxine. The mechanism of this effect may involve removal of substrate inhibition of the enzyme, A5-methyltetrahydrofolate homocysteine methyltransferase, due to pyridoxine-induced reduction of the substrate, homocysteine (27). 

A median increase in serum homocysteine of 50% (range 27-333%) was found in seven healthy male volnnteers after a 2-week course of trimethoprim 300 mg bd (59). Concomitantly, serum folate concentrations fell significantly. By day 50, baseline values of homocysteine and folate were regained. Since tetrahydrofolate serves as a methyl group carrier in the remethylation of homocysteine to methionine, the inhibitory effect of trimethoprim on dihydrofolate reductase may be most important, but other mechanisms could not be excluded. 

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. 

Although requirements for vitamins and trace elements are known in health (Table 30-1), the effects of illness on these requirements are poorly understood and quantified. However, it is now apparent that as an individual develops progressively more severe depletion in vitamin or trace element status, the person passes through a series of stages with biochemical or physiological consequences. The metabolic or physiological penalty of such suboptimal nutritional status is usually not clear, but the assumption remains that the suboptimal metabolism is likely to have detrimental effects (e.g., subclinical deficiency of folic acid is associated with an increase in serum homocysteine concentration, which is an independent risk factor for coronary artery disease—see Chapter 26). Similarly, subclinical deficiency of chromium may be associated with impaired glucose tolerance in certain types of diabetes. 

Indirect tests assess the functional adequacy of vitamin Bi2. Serum methylmalonic acid concentration is increased when a lack of adenyl-Cbl causes a block in the conversion of methylmalonyl-CoA to succinyl-CoA. It is a sensitive test of status, being often the first analyte to be raised in sub-clinical vitamin B12 deficiency. It has a further advantage in that it is unaffected by folate deficiency. Early methods for methylmalonic acid lacked sensitivity and specificity, a situation that has been resolved by the adoption of gas chromatographic-mass spectrometric methods,though these require specialized handling. Plasma total homocysteine concentration is a sensitive indicator of vitamin B status, because methyl-Cbl is required for the remethylation of... 

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. ... 

Stolzenberg-Solomon, R.Z., E.R. Miller 3rd, M.G. Maguire, J. Seihub, and L.J. Appel. 1999. Association of dietary protein intake and coffee consumption with serum homocysteine concentrations in an older population. Am. J. Clin. Nutr. 69(3) 467-475. 

Allen RH, Stabler SP, Savage DG, Lindenbaum J. Diagnosis of cobalamin deficiency I Usefulness of serum methylmalonic acid and total homocysteine concentrations. Am J Hematol 1990 34 90-98. 

Nilsson K, Gustafson L, Hultberg B. The plasma homocysteine concentration is better than that of serum methylmalonic acid as a marker for sociopsychological performance in a psychogeri-atric population. Clin Chem 2000 46 691-696. 

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