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Abstract
Hyperhomocysteinemia is the result of a disturbed methionine metabolism. It results from enzyme and/or vitamin deficiency. Epidemiological studies have proven, that hyperhomocysteinemia is a risk factor for atherosclerotic cardiovascular diseases, stroke, peripheral arterial occlusive disease and venous thrombosis. Conflicting results come from prospective studies. Trials which are now in progress may clarify the “causality” of high homocysteine concentrations and will assess the value of homocysteine-lowering therapy. The induction of the atherogenic process by hyperhomocysteinemia seems to be associated with an alteration of endothelial and smooth muscle cell function leading to an accelerated formation of reactive oxygen species. An increased endothelial expression of adhesion molecules will then lead to an enhanced deposition of oxidized LDL in the vessel wall with the formation of foam cells. Additionally, hyperhomocysteinemia interferes with the coagulation system and thus also has prothrombotic effects. There is a high prevalence of hyperhomocysteinemia as a sign of a vitamin deficiency in elderly subjects which strongly increases with age. Elderly people have a high frequency of vitamin B 12 deficiency which can be diagnosed more reliably by the measurement of serum methylmalonic acid (MMA) level than by serum vitamin B 12 . Subjects following a strict vegetarian diet also have a high prevalence of hyperhomocysteinemia caused by functional vitamin B 12 deficiency (increased MMA level). Last but not least, hyperhomocysteinemia is a factor in the pathogenesis of neural tube defects and pre-eclampsia. An early diagnosis of vitamin B 12 deficiency is important for the prevention of neurological damages. Homocysteine should be measured in patients with a history of atherothrombotic vessel diseases, in patients with diabetes or hyperlipidemia, in renal patients, in obese subjects, in elderly people, in postmenopausal women, and in early pregnancy. A specific diagnosis of an underlying vitamin deficiency is important for adequate treatment. Individuals with homocysteine level >12 μmol/l should increase and/or supplement their dietary intake of vitamins.
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June 1, 2005
Abstract
In the past decade, moderately elevated homocysteine concentration has achieved wide-spread recognition as an independent risk factor for vascular diseases, such as stroke and peripheral vascular disease, as well as for an impaired nutritional status. In general, EDTA plasma is used for the determination of homocysteine. However, from the pre-analytical point of view it is important, that, when plasma is not separated from blood cells within 30 minutes, homocysteine levels increase in samples significantly by about 10% per hour. This 10% increase is very important, because the normal range is between 5 and 15 μmol/l and moderately elevated homocysteine concentrations above 15 μmol/l may signify an increased risk of vascular disease. These preliminary cut-off points show that there is only a small difference between normal and moderately elevated homocysteine concentrations. Most blood samples are obtained outside the hospital, and in these cases homocysteine concentrations will be falsely elevated, if no precautions are taken, such as immediate centrifugation and separation of plasma and cells. This aspect is critical both for clinical studies and in patient care outside the hospital. But even in the hospital it is difficult to separate plasma and cells within 30 minutes. In the past, different approaches were adopted to solve this problem. Potential stabilisers were sodium fluoride (4 g/l) and 3-deazaadenosine (100 μmol/l). Sodium fluoride initially increased the homocysteine concentration, which dropped below the initial values after 72 h. On the other hand, 3-deazaadenosine stabilised homocysteine concentrations for 24 h, but increased it within 72 h by roughly 10%. However, this stabiliser is restricted to HPLC technology but does not work reliably with immunoassays. Lysis of blood stabilised homocysteine, but homocysteine concentrations were systematically lower requiring totally new reference ranges. In addition, acidic citrate (0.5 mol/l) was evaluated, which seems to stabilise plasma homocysteine concentrations at ambient temperatures for several hours. However, small but systematic deviations at baseline are observed. This stabilisation procedure does not interfere with immunoassays. Because immunoassays will be the future method of choice for robust and easy to perform homocysteine measurements, because they easily allow the analyses of high sample numbers, homocysteine stabilisation in whole blood is still an important matter. It must be solved before homocysteine determinations are introduced as a general screening for vascular risk factors in non-specialist laboratories.
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June 1, 2005
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Increased concentrations of homocysteine probably contribute to the high cardiovascular morbidity and mortality in hemodialysed end-stage renal disease (ESRD) patients and are determined by a variety of factors such as age, residual renal function, and vitamin status. Fasting plasma concentrations of total homocysteine, methionine, cysteine, and cystathionine were determined by gas chromatography-mass spectrometry (GC-MS) in 131 ESRD patients receiving daily oral folate (160–320 μg) and vitamin B 6 (10–20 mg) supplements. Concentrations of homocysteine determined by GC-MS were compared with those measured by high-performance liquid chromatography (HPLC) and an immunofluorescence method (IMx analyzer) using Passing-Bablok regression analysis. Mean plasma concentration of total homocysteine determined by GC-MS (28.7±11.9 μmol/l [mean±SD]) was significantly lower than that determined by HPLC (34.0±14.5 μmol/l; p<0.001) or IMx (32.4±13.9 μmol/l; p<0.001). A close correlation existed between GC-MS and HPLC (r=0.931; y=1.203 x+0.279) and GC-MS and IMx (r=0.896; y=1.105 x+0.766). Linear regression analysis showed positive correlations between plasma concentrations of homocysteine and cysteine (r=0.434; p<0.001) and homocysteine and cystathionine (r=0.187; p=0.032). Plasma concentrations of homocysteine correlated negatively with folate (r=−0.281; p=0.001) and vitamin B 12 (r=−0.229; p=0.009). GC-MS proved to be a sensitive and reliable method for the determination of total plasma homocysteine and related amino acids. Despite vitamin supplementation, ESRD patients requiring chronic maintenance hemodialysis, have high plasma concentrations of homocyst(e)ine which seems to be metabolized mainly within the transsulfuration pathway, while remethylation to methionine seems to be disturbed.
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June 1, 2005
Abstract
Hyperhomocysteinemia is considered as a risk factor for cardiovascular diseases. Usually, an inverse relationship exists between homocysteine and folate levels, and supplementation with folate lowers homocysteine concentrations in patients. Therefore, hyperhomocysteinemia is mainly ascribed to the insufficient dietary intake of folate. Hyperhomocysteinemia has also been observed in infections and inflammatory diseases. Oxidative stress appears to be involved in the pathogenesis of these disorders, and associations have been found between homocysteine and e.g., neopterin concentration. Increased neopterin concentration indicates immune system activation and also allows an estimate of thus elicited oxidative stress. It may be relevant that the active cofactor, tetrahydrofolate, is very susceptible to oxidation. Immunologically induced oxidative stress could lead to folate depletion resulting in hyperhomocysteinemia. Thus, hyperhomocysteinemia in patients can be considered as an indirect consequence of hyperconsumption of antioxidant vitamins during prolonged states of immune activation.
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June 1, 2005
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Nutritional deficiency does not fit the view of life in an affluent society and in fact typical diseases resulting from a deficiency of vitamins are actually a rarity. On the other hand, elderly people must be regarded as an essential risk group for vitamin deficiency because of various influence factors. The frequency of lowered vitamin concentrations in the blood increases with age. However, knowledge on the consequences for this population is insufficient, especially for hyperhomocysteinemia. Investigations have yielded the following results: 1. Hyperhomocysteinemia often occurs with advanced age; 2. Impairment of physical condition or social situation seems to increase the risk of hyperhomocysteinemia; 3. Administration of the vitamins B 6 , B 12 and folate causes a significant decrease of elevated serum homocysteine concentrations in older persons. Homocysteine-lowering treatment should improve the prevention of chronic diseases. The question is which effects can be expected from such treatment in the elderly. Because of its great importance for both the persons concerned and society in general hyperhomocysteinemia in advanced age requires further systematic examination.
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June 1, 2005
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The genes for the enzymes methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MS), methionine synthase reductase (MSR) and cytathionine-Β-synthase (CBS) play an important role in homocysteine metabolism. Rare mutations in these genes cause severe hyperhomocysteinemia and clinical symptoms. Growing interest has focused on common mutations with moderate effects on homocysteine levels. We studied 280 subjects of different age groups for the following mutations: MTHFR677C→T and 1298A→C, MS2756A→G, MSR66A→G and the 68 bp insertion in the CBS gene. The median value for homocysteine increased significantly with age (median homocysteine levels: 7.5, 12.4 and 16.5 μmol/l in the age groups 20–43, 65–75 and 85–96 years, respectively). The genotypes of the MTHFR677C→T mutation were associated with differences in plasma homocysteine levels, but without reaching significance. Individuals homozygous for the MTHFR677C→T mutation had a 2.3 μmol/l higher median homocysteine level compared to individuals with the wild-type allele. This effect was pronounced in combination with low folate levels and abolished with higher folate in plasma. For the other three mutations no association with homocysteine values could be determined. The analysis of homocysteine metabolite cystathionine by backward regression analysis revealed a significant correlation of the MS2756A→G mutation with cystathionine level. This increase could indicate a disturbed remethylation. In summary, larger and homogeneous study populations are necessary to quantify the small effects of common mutations on homocysteine levels. This may also be the reason that no effects of genetic interactions between two genotypes were observed.
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June 1, 2005
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Among individuals with severe hyperhomocysteinaemia, there is a striking heterogeneity in the severity of the clinical features. This observation demonstrates that factors must exist that modulate the relationship between hyperhomocysteinaemia and clinical disease. Investigations of the association between mild-to-moderate hyperhomocysteinaemia and atherothrombotic disease also suggest heterogeneity in the association between plasma homocysteine levels and 1) clinical disease; 2) angiographic and echographic estimates of the extent of atherosclerosis; 3) arterial stiffness; 4) endothelial function; and 5) procoagulant status. The commonly held view that homocysteine is a vasculotoxic substance that promotes atherogenesis by causing endothelial damage is incomplete, because it cannot explain this heterogeneity. I suggest that homocysteine may have both prothrombotic and proatherogenic properties, but that there are strong, as yet unidentified enhancing and protective factors, the prevalence of which may differ among populations. This concept could account for some of the observed heterogeneity. Identifying these factors would be of major clinical importance and would provide crucial mechanistic insights.
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June 1, 2005
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Classical homocystinuria is associated with arterial vascular diseases and venous thrombosis. In the last decade, several studies have been published indicating that even mild hyperhomocysteinemia is a risk factor for venous thrombosis. The 677C→T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is an important cause of mild hyperhomocysteinemia, but this polymorphism does not seem to be a risk factor for venous thrombosis. Studies on the interaction between hyperhomocysteinemia and other thrombotic risk factors are conflicting. Little is known about the pathophysiology of venous thrombosis in hyperhomocysteinemia. Several mechanisms proposed for vascular disease may be applied to venous thrombosis as well. However, up to now there is no satisfying model which might explain a thrombophilic state at plasma homocysteine concentrations in the range of mild hyperhomocysteinemia. The results of a first clinical intervention study are expected in 2002. As the results are pending, clinicians could perform homocysteine measurements in patients with venous thrombosis if screening for thrombophilia is indicated. Vitamin supplementation could be prescribed if homocysteine levels are elevated. However, the patient should be informed about the uncertainty of the benefits of vitamin supplementation.
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June 1, 2005
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In the Western world, cardiovascular disease is still the most common cause of death. Over the past decade it has become clear that apart from common risk factors, high concentrations of total homocysteine are relavant to the process of atherosclerosis, especially in the development of premature vascular disease. Hyperhomocysteinaemia (HHC) can be found in 25–32% of the patients with premature peripheral arterial occlusive disease (PAD). Retrospective and prospective studies, evaluating the clinical course of patients with PAD, showed significant associations between high concentrations of total homocysteine and the severity of atherosclerosis and with a more rapid disease progression and mortality rates. HHC can be treated with vitamin B 6 and folic acid. Although there may be indications that there is a protective effect of treatment, prospective randomized clinical trials are urgently needed to unravel the role of HHC and its treatment in patients with premature PAD.
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June 1, 2005
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There is some evidence from recent observational studies that hyperhomocysteinemia is a risk factor for cognitive dysfunction, including Alzheimer's disease and vascular dementia. There are only a few intervention studies, and the results are disappointing for such a frequent disease. Prospective double-blind and placebo-controlled intervention studies are not available. If homocysteine-lowering therapy will be in the running for the prevention and treatment of dementia, we must be able to diagnose the disease at a preclinical stage ( i.e. 5 or 10 or 20 years before the disease becomes clinically overt for Alzheimer's disease). At the moment, there are insufficient data to support a vitamin B 12 , B 6 or folate therapy in the prevention or treatment of patients with dementia.
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June 1, 2005
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Hyperhomocysteinemia is a risk factor for obstructive large-vessel disease. Here, we studied plasma concentrations of homocysteine and vitamins in patients suffering from subcortical vascular encephalopathy (SVE), a cerebral small-vessel disease leading to dementia. These results were compared to the homocysteine and vitamin plasma concentrations from patients with cerebral large vessel disease and healthy control subjects. Plasma concentrations of homocysteine, vascular risk factors and vitamin status (B 6 , B 12 , folate) were determined in 82 patients with subcortical vascular encephalopathy, in 144 patients with cerebral large-vessel disease and in 102 control subjects. Patients with SVE, but not those with cerebral large-vessel disease, exhibited pathologically increased homocysteine concentrations in comparison with control subjects without cerebrovascular disease. Patients with SVE also showed lower vitamin B 6 values in comparison to subjects without cerebrovascular disease. Logistic regression analysis showed that homocysteine is associated with the highest risk for SVE (odds ratio 5.7; CI 2.5–12.9) in comparison to other vascular risk factors such as hypertension, age and smoking. These observations indicate that hyperhomocysteinemia is a strong independent risk factor for SVE.
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June 1, 2005
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Elevated plasma homocyst(e)ine is currently accepted as a major, independent risk factor for atherosclerosis and venous thrombosis. Even moderate hyperhomocyst( e)inemia is prospectively associated with increased risk of mortality in patients with cardiovascular disease. However, the underlying mechanisms resulting in vascular damage are not clearly defined. The endothelium exerts fundamental control on the vascular tone, coagulation and fibrinolysis. Injury to the endothelium followed by dysfunction is an early key event preceding manifestation of vessel pathology. Acute and chronic exposure of endothelium to homocyst(e)ine induces impairment of endothelial function associated with altered homeostasis and morphologic changes of the vessel wall. Investigations of the role of homocyst(e)ine in the endothelium-dependent function in healthy subjects and cardiovascular patients have recently added important clinical insight with implications for the treatment of cardiovascular disease. Importantly, the damaging effects of hyperhomocyst(e)inemia on endothelial function are, at least in part, reversible in patients with established vascular disease, supporting further the hypothesis that homocyst(e)ine-lowering through vitamin supplementation may have vasoprotective effects.
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June 1, 2005
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A moderate increase in plasma total homocysteine (tHcy) is considered to be an independent risk factor for cardiovascular disease (CVD) in the general population. Almost all chronic renal failure (CRF) patients have plasma concentration of tHcy that is elevated 3 to 4 times above normal. The prevalence of CVD, diabetes mellitus, malnutrition and hypoalbuminemia is high in CRF patients. Previous investigations have focused on the role of vitamin status on plasma tHcy in CRF patients, but little information exists on the influence of nutritional status and hypoalbuminemia on plasma tHcy in CRF, although a substantial fraction of tHcy (>70%) is protein-bound, mainly to albumin. Our study in patients with end-stage renal disease showed that more than 90% of the patients had elevated plasma tHcy levels, which were higher in patients with normal nutritional status than in malnourished patients. Moreover, plasma tHcy was inversely correlated with subjective global nutritional assessment (high values denote malnutrition) and positively correlated with serum albumin and protein intake. Hence, it seems likely that serum-albumin is a strong determinant of plasma tHcy in CRF patients and this may contribute to the lower tHcy levels in malnourished patients. Patients with diabetes mellitus had lower serum-albumin and plasma tHcy than non-diabetic patients, irrespective whether they were malnourished or not. Patients with CVD had lower (although still elevated) plasma tHcy levels than those without CVD. An explanation may be that the prevalence of diabetes mellitus, malnutrition and hypoalbuminema, i.e. factors that decrease tHcy, was higher in patients with CVD, which may explain why they had less elevated values. Assuming that hyperhomocysteinemia carries an independent risk of CVD, this implies that almost all CRF patients are exposed to this risk. CRF patients with CVD had a higher prevalence of malnutrition, hypoalbuminemia and diabetes mellitus, which was associated with a lower plasma Hcy level. This may explain why plasma tHcy was lower (although still abnormally high) in patients with CVD than in patients without CVD. The lower tHcy levels in CVD patients do not contradict the assumption that hyperhomocysteinemia is a risk factor for CVD since almost all patients are exposed to this risk, and other factors might be present that confound the relationship between the absolute tHcy levels and CVD. Our findings imply that nutritional status and serum albumin, as well as the presence of diabetes mellitus, should be taken into consideration when evaluating tHcy as a risk factor for CVD in CRF patients.
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June 1, 2005
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Moderate hyperhomocysteinemia is very frequent in renal patients. Aside from homocysteine (HCY) itself, the metabolites methylmalonic acid (MMA) and cystathionine (CYS) supply further information about disturbances in HCY metabolism. In two groups of renal patients, transplant and hemodialysis patients, we measured HCY, MMA and CYS and evaluated their diagnostic value for impaired HCY metabolism due to vitamin deficiency and renal insufficiency. We investigated serum samples from 63 transplant patients and 38 patients undergoing hemodialysis. HCY, MMA and CYS were assayed by gas chromatography-mass spectrometry, vitamin B 6 by HPLC, B 12 and folate by chemiluminescence immunoassay. The determination of HCY, MMA, and CYS in renal patients provides specific information about intracellular disturbances of HCY metabolism. The frequency of increased metabolite levels in renal patients was much higher than the frequency of lowered vitamin concentrations in serum. Furthermore, the metabolite levels in transplant patients were only moderately increased, whereas they were strongly increased in patients on hemodialysis (HCY 19.2 vs. 28.8 μmol/l, MMA 292 vs. 1025 nmol/l, CYS 733 vs. 2711 nmol/l). Our findings may support the use of MMA determination in the diagnosis of vitamin B 12 deficiency in renal patients. Compared to vitamin B 12 deficiency, renal dysfunction itself appears to cause only a modest elevation in serum MMA. Regression analysis revealed that the moderate elevation of HCY and CYS in transplant patients is mainly a consequence of impaired remethylation of HCY to methionine with activated transsulfuration, whereas the mildly elevated MMA level is attributable to renal dysfunction. In patients on hemodialysis, all three metabolites were markedly elevated, indicating a strongly disturbed HCY metabolism. Based on a backward regression, we discovered that the HCY metabolism was strongly disturbed by renal insufficiency and vitamin deficiency. The markedly elevated HCY level was mainly attributable to functional vitamin B 12 deficiency indicated by high MMA, and the strong CYS elevation was due to renal dysfunction and inhibition of this pathway by low levels of vitamin B 6 . In conclusion, besides HCY, the determination of MMA and CYS levels supports an early diagnosis of B-vitamin deficiency in renal patients. MMA is a more sensitive indicator of intracellular vitamin B 12 deficiency than vitamin B 12 in serum.
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June 1, 2005
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Glomerular filtration is one of the major determinants of plasma total homocysteine (tHcy). To evaluate the respective roles of residual glomerular filtration (by measuring a specific protein marker, cystatin C), genetic polymorphisms and nutritional status in tHcy blood levels in end-stage renal disease patients (ESRD) under hemodialysis and supplemented with folate, we measured tHcy, folate, vitamin B 12 (B 12 ), creatinine, cystatin C, albumin and C-reactive protein and determined the polymorphism of methylenetetrahydrofolate reductase (MTHFR) (C677T and A1289C) and of methionine synthase (MS) (A2756G) in 114 ESRD patients before hemodialysis and 76 control subjects. All patients received a folate supplementation of 700 μg/day. Hyperhomocysteinemia was observed in all patients and exceeded the upper normal limit by 2-fold in 52.4% of the patients. Serum folate was significantly increased and the B 12 level was not different from controls. Folate, Cystatin C and creatinine were significantly correlated to tHcy, while no correlation was found between tHcy, albumin and C-reactive protein. No difference in genotype frequency between ESRD patients and controls was found for MTHFR A1289C and MS A2756G. The MTHFR 677TT genotype was less frequent and was associated with a significantly higher tHcy level in patients. Folate and residual glomerular filtration estimated by cystatin C and creatinine levels were two independent determinants of tHcy in ESRD patients. These data suggest that hyperhomocysteinemia is a consequence as well as a complicating factor of renal failure.
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June 1, 2005
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Autoimmune thyroiditis with hypothyroidism is frequently accompanied by symptoms of psychiatric disorders and atherogenic changes in lipid metabolism. Recent studies suggest that some neuroactive steroids and homocysteine are involved in the pathophysiology of both disorders. Homocysteine metabolism may be affected by some steroids. We were interested if the treatment of hypothyroidism would affect the above factors. We studied plasma concentrations of allopregnanolone, pregnenolone sulfate, dehydroepiandosterone and its sulfate, progesterone, estradiol and homocysteine in 14 patients (12 women, 2 men) during the 3-month treatment with levothyroxine. Steroids and thyroid function were monitored by measuring thyrotropin, free triiodothyronine, free thyroxine and levels of thyroid antimicrosomal antibodies and antibodies to thyroglobulin. We have found that with the restoration of the thyrotropin level, free triiodothyronine, free thyroxine and homocysteine levels decreased, but the levels of steroids were not significantly altered. Steroid concentrations correlated negatively with the level of thyroid antimicrosomal antibodies.
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June 1, 2005
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Mild hyperhomocysteinaemia has been identified as a risk factor for arterial disease and venous thrombosis. In 1991, elevated homocysteine concentrations were also suggested to be associated with neural tube defects (NTD). Since then this relationship has been reported frequently, as well as the relationship between NTD and the 677 C→T mutation in the methylenetetrahydrofolate reductase ( MTHFR ) gene. Meanwhile, disturbances in the homocysteine metabolism have also been reported as a risk factor for early pregnancy loss and for other congenital birth defects. However, besides embryonic or foetal consequences, hyperhomocysteinaemia has also been described as a cause of maternal obstetric complications such as pre-eclampsia. This review is concerned with the role of hyperhomocysteinaemia in human reproduction.
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June 1, 2005
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Homocysteine (Hcy) has been shown to damage the vascular endothelial cells, contributing to atherothrombosis. The increase in plasma Hcy levels with natural menopause suggests a close relationship between Hcy metabolism and estrogen status and proposes one of the mechanisms through which menopause unfavorably affects cardiovascular disease risk in women. In addition to the prevention of osteoporosis, hormone replacement therapy (HRT) lowers Hcy levels in postmenopausal women. The first report by van der Mooren et al., demonstrated in an uncontrolled study a significant reduction (11%) in fasting serum Hcy level after 6 months of treatment with sequentially combined estradiol-dydrogesterone therapy in 21 healthy postmenopausal women. This effect was particularly evident in women with initially elevated baseline serum Hcy concentrations. Similar results were found in other studies in which women were treated with various transdermal as well as oral HRT regimens, although two studies could not confirm these findings. All these studies were uncontrolled, and three of them consisted of a relatively small number of participants. Therefore, they remained inconclusive. Three randomized controlled trials on HRT and Hcy were published to date, confirming that postmenopausal HRT reduces circulating levels of Hcy. Current and recent HRT use is associated with a slight increased risk of breast cancer. As a result of this, research has centered on finding compounds that can prevent the consequences of estrogen deficiency, without the potential risk of HRT. Raloxifene, referred to as a Selective Estrogen Receptor Modulator (SERM), has the potential as a viable alternative to HRT. Recently, two randomized controlled trials demonstrated that raloxifene lowers plasma Hcy levels in postmenopausal women, similar to the reduction obtained with HRT. Little is known about the mechanisms underlying the HRT-associated lowering of plasma Hcy. Proposed mechanisms relate to an increase in kidney methionine synthase activity or may be related to the transamination of methionine. We conclude that HRT decreases plasma Hcy levels in postmenopausal women and that the strongest reductions can be achieved in women with the highest concentrations.
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June 1, 2005
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In a pilot study we measured the effect of three different combinations of the vitamins B 6 , folate and B 12 on the serum concentrations of homocysteine, cystathionine and methylmalonic acid in five healthy young men without hyperhomocysteinemia. The results indicate that there are still undescribed interactions between vitamin B 6 and folate, suggesting that these two vitamins should be given together to avoid depletion of the one not given. With regard to the well known metabolic pathways of methionine and cysteine, this confirms the hypothesis that a combined supplementation with the vitamins B 6 and folate (and B 12 ) is superior to folate alone in order to lower homocysteine.
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