Serum homocysteine

Levels correlate with serum homocysteine levels. 

Answer A. Pregnant woman with megaloblastic anemia and elevated serum homocysteine strongly suggests folate deficiency. Iron deficiency presents as microcytic, hypochromic anemia and would not elevate homocysteine. deficiency is not most likely in this presentation. 

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

Vitamin B12 Low serum cobalamin (< 150 pmol/L) accompanied by increased serum homocysteine (> 13 Nnol/L), and increased serum (> 0.4 -mol/L) and urine (> 3.6 mmol/mol creatinine) methylmalonic acid... 

A deficiency of vitamin B12 causes the accumulation of homocysteine due to reduced formation of methylcobalamin, which is required for the conversion of homocysteine to methionine (Figure 33-3, section 1). The increase in serum homocysteine can be used to help establish a diagnosis of vitamin B12 deficiency (Table 33-2). There is concern that... 

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). 

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... 

Murthy SN, et al. Rosiglitazone reduces serum homocysteine levels, smooth muscle proliferation, and intimal hyperplasia in Sprague-Dawley rats fed a high methionine diet. Metabolism 2005 54 5) 645-652. 

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. 

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... 

Lipoprotein fractionation Serum homocysteine Leukocyte a-galactosidase A Blood/cerebrospinal fluid lactate... 

Transcorrin II bound vitamin B12 Mean cell volume Serum methylmalonic acid Serum homocysteine Urine FIGLU more than 8 h after histidine load — <0.15 <0.22 >100 fL >1 i.mol/L >20 i.mol/L >50 [ig /mL ... 

Jakubowski, H. (2000). Calcium-dependent human serum homocysteine thiolactone hydrolase. A protective mechanism against protein N-homocysteinylation. J. Biol. Chem. 275 3957-62. 

It has been suggested that methotrexate increases mortality in patients with rheumatoid arthritis with cardiovascular co-morbidity (11). This assumption was based on a retrospective analysis of 632 patients with rheumatoid arthritis, of whom 73 died. The simultaneous presence of methotrexate and evidence of cardiovascular disease was an independent predictor of mortality. There was no such association with other DMARDs. The authors suggested that this effect may result from a methotrexate-induced increase in serum homocysteine, encouraging atherosclerosis. 

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. 

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. 

Vitamin B12 and folate are both required for conversion of homocysteine to methionine. Increased serum homocysteine may help define vitamin B12 or folate deficiency. Homocysteine levels can also be elevated in vitamin Bg deficiency, renal failure, hypothyroidism, and in persons with a genetic defect in cystathionine /S-synthase. Additionally, elevated levels have been caused by medications including nicotinic acid, theophylline, methotrexate, and L-dopa. 

It is of paramount importance to rule out vitamin B12 deficiency when folate deficiency is detected, as symptoms are similar. Laboratory changes associated with folate deficiency are similar to those seen in vitamin Bn deficiency, except vitamin Bn levels are normal. Decreases occur in the serum folate level (<3 ng/mL) within a few days of dietary folate limitations. The RBC folate level (<150 ng/mL) also declines and may be a better indicator of deficiency, as levels remain constant throughout the life span of the erythrocyte. Serum folate levels are sensitive to short-term changes such as dietary restrictions or alcohol intake, which may result in a short-term decline in serum levels with adequate tissue stores. It should be noted that an estimated 60% of patients with pernicious anemia have falsely low RBC folate levels, in all probability due to the requirement of cobal-amin for the normal transfer of methyltetrahydrofolate from plasma to cells. Additionally, if serum or erythrocyte folate levels are borderline, serum homocysteine is usually increased with a folic acid deficiency. If serum MMA levels are also elevated, vitamin B12 deficiency needs to be ruled out. 

In the type of homocystinuria in which the patient is deficient in cystathione 13-synthase, the elevation in serum methionine levels is presumed to be the result of enhanced rates of conversion of homocysteine to methionine, caused by increased availability of homocysteine (see Fig. 39.14). In type II and type HI homocystinuria, in which there is a deficiency in the synthesis of methyl cobalamin and of N -methyltetrahydrofolate, respectively (both required for the methylation of homocysteine to form methionine), serum homocysteine levels are elevated but serum methionine levels are low (see Fig. 39.14). 

A third way in which serum homocysteine levels can be elevated is by a mutated cystathinone-(3-synthase or a deficiency in vitamin B6, the required cofactor for that enzyme. These defects block the ability of homocysteine to be converted to cystathionine, and the homocysteine that does accumulate cannot all be accommodated by conversion to methionine. Thus, an accumulation of homocysteine results. 

Appel LJ, Miller EiR, 3rd, Jee SH, et al. Effect of dietary patterns on serum homocysteine results of a randomized, controlled feeding study. Circulation. 2000 102 852-857. 

Voutilainen, S. et al.. Functional COMT Vall58Met polymorphism, risk of acute coronary events and serum homocysteine The Kuopio Ischaemic Heart Disease Risk Factor Study, PloS ONE, 2 (1), el81, 2007. 

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. 

New evidence suggests that hyperhomocysteinemia may specifically contribute to AD pathology. Correlation exists between serum homocysteine levels and brain AP levels, but only in female mice. The increases in ApiO and Ap42 levels in APP /PS 1 /CBS female mice as compared to APP /PS1 mice were both significant. The mechanism leading to these gender differences is at this time unknown. 

In snmmary, individuals with elevated serum homocysteine are at increased risk of sporadic AD, bnt the mechanisms are controversial. This study shows that high serum homocysteine levels in female mice correlate with higher Ap peptide levels in the brain. Since Ap plays a central role in the pathogenesis of AD, the results advance a plansible mechanism underlying the higher risk for AD in hyperhomo-cysteinemia. On the basis of these results, future epidemiological studies should place emphasis on the gender differences noted. 

Krieg, E.F., Jr., and M.A. Butler. 2009. Blood lead, serum homocysteine, and neurobe-havioral test performance in the Third National Health and Nutrition Examination Survey. Neurotoxicology 30(2) 281-289. 

Note spelling increased serum homocysteine in homocystinuria. 

Cystathionine P-synthase deficiency is an autosomal recessive trait (Fig. 47.1). It is the most common cause of homocystinuria and is the second most treatable disorder of amino acid metabolism. Some patients respond to pyridoxine treatment but others are pyridoxine non-responsive. Orally administered betaine often lowers serum homocysteine concentrations. 

Nutrition Compared with immunosuppressive therapy based on ciclosporin, glucocorticoids, and mycophenolate, a regimen based on everolimus resulted in significantly lower serum homocysteine concentrations in renal transplant recipients [42 ]. 

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). 

Serum methylmalonic acid Serum homocysteine Serum methylmalonic acid... 

Laboratory indicators of low vitamin B status are serum homocysteine, methylmalonic acid and holotranscobalamin and CSF vitamin B12 and folate reflecting its functional status at tissue level. 

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