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Background
Homocysteine (Hcy), a sulphur-containing amino acid, is formed from the conversion of methionine into cysteine. It is usually rapidly metabolized via one of two pathways: (i) a vitamin B12- and folate-dependent re-methylation pathway that regenerates methionine, or (ii) a vitamin B6-dependent trans-sulphuration pathway that converts Hcy to cysteine. Thus, low levels of these vitamins/co-factors are associated with hyper-homocysteinemia, which can be classified as moderate (15 to 30 micromol/L), intermediate (31 to 100 micromol/L), or severe (greater than 100 micromol/L). Measurements of Hcy levels are usually performed after fasting; levels of 12 micromol/L are considered normal, and levels below 10 micromol/L are considered desirable. Increases in plasma Hcy concentration (pHcy) can arise from various causes: (i) genetic defects in the enzymes involved in Hcy metabolism, (ii) nutritional deficiencies in vitamin co-factors, and (iii) other factors such as chronic conditions/diseases (e.g., obesity, smoking, physical inactivity, hypertension, hypercholesterolemia, diabetes mellitus, and chronic kidney failure) and medications (e.g., fenofibrate, methotrexate, and nicotinic acid) (Rosenson and Kang, 2007).
The most common form of genetic hyper-homocysteinemia results from production of a thermo-labile variant of methylene tetrahydrofolate reductase (MTHFR) with reduced enzymatic activity. The gene encoding for this variant contains an alanine-to-valine substitution at amino acid 677 (C677T). The responsible gene is common, with a population frequency estimated between 5 to 14 %. Homozygosity for the thermo-labile variant of MTHFR (TT genotype) is a relatively common cause of mildly elevated pHcy in the general population, often occurring in association with low serum folate levels (Rosenson and Kang, 2007). Harmon and colleagues (1996) quantified the contribution of the thermo-labile mutation to the hyper-homocysteinemic phenotype in a working male population (n = 625). Serum folate and vitamin B12 concentrations were measured and their relationship with Hcy status and MTHFR genotype were assessed. They found that 11.5 % of the subjects were homozygous for the TT genotype. However, for those in the top 5 to 10 % of pHcy, the frequency rose to 48 % and 36 %, respectively. Homozygotes also had the lowest serum folate concentrations.
However, the role of screening for MTHFR variants during pregnancy to ascertain risks of neural tube defects (NTDs) and/or recurrent pregnancy loss is unclear.
Role of Hcy in 5,10-MTHFR Abnormalities:
Finnell and associates (2002) stated that despite the fact that NTDs are the most common congenital malformations of the central nervous system, investigators have yet to identify responsible gene(s). Research efforts have been productive in the identification of environmental factors, such as peri-conceptional folic acid supplementation that modulate risk for the development of NTDs. Studies of the folic acid biosynthetic pathway led to the discovery of an association between elevated levels of Hcy and NTD risk. Researchers subsequently identified single nucleotide polymorphisms in the gene coding for the enzyme 5,10-MTHFR. Association studies suggested it was a potential risk factor for NTDs, because the thermo-labile form of the enzyme led to elevated pHcy when folic acid intake is low. Numerous studies analyzing MTHFR variants have resulted in positive associations with increased NTD risk only in certain populations, suggesting that these variants are not large contributors to the etiology of NTDs. With limited understanding of the genes involved in regulating NTD susceptibility, the paucity of data on how folic acid protects the developing embryo as well as the observed decrease in birth prevalence of NTDs following folic acid supplementation and food fortification, it makes little sense for prospective parents to be tested for MTHFR variants, or for variants of other known folate pathway genes.
Makino and co-workers (2004) studied whether polymorphisms of MTHFR and the endothelial nitric oxide synthase (eNOS) are associated with recurrent pregnancy loss (RPL). They concluded that the nitric oxide concentration but not the polymorphism of MTHFR and eNOS gene and hyper-homocysteinemia are associated with RPL.
O'Leary and colleagues (2005) stated that methionine synthase reductase (MTRR) regenerates methylated cobalamin levels from the oxidized cob(II)alamin form and in so doing plays a crucial role in maintaining the active state of methionine synthase (MTR), which is an essential enzyme catalyzing the conversion of Hcy to methionine. Single nucleotide polymorphisms (SNPs) within the MTRR gene may potentially compromise MTR activity leading to elevated pHcy, a known risk factor for NTDs. These researchers studied the MTRR polymorphisms I22M (66A-->G), S175L (524C-->T), and K350R (1049A-->G) as potential NTD risk factors in a large homogeneous Irish NTD population. Degree of risk was assessed via case/control comparison, log-linear analysis, and transmission disequilibrium testing. No association was found between NTDs and I22M in mothers (p = 0.16, OR 1.14 [0.95 - 1.38], n = 447) or cases (p = 0.13, OR 1.15 [0.96 - 1.38], n = 470) compared to controls (n = 476). A dominant I22M paternal effect was found through case/control comparison and log-linear modeling (p = 0.019) (goodness-of-fit, p = 0.91, OR 1.46 [1.10 - 1.93], n = 423). No significant NTD association was found with S175L or K350R in cases or their parents and no interactions were observed between these polymorphisms and the D919G variant of MTR or the A222V variant of 5,10-MTHFR. These investigators also compared the frequencies of I22M, S175L, and K350R in African-Americans versus American-Caucasians. The frequencies of I22M and K350R differed significantly between the two groups (p = 0.0005 and p = 0.0001, respectively). These findings do not support an important role for these MTRR variants in NTDs.
Role of Hcy in Coronary Heart Disease or Stroke Risk:
While Hcy has been reported to exhibit atherogenic and prothrombotic properties, and histopathological hallmarks of Hcy-induced vascular injury include intimal thickening, elastic lamina disruption, smooth muscle hypertrophy, marked platelet accumulation, and the formation of platelet-enriched occlusive thrombi, its role in coronary heart disease and stroke is unclear. In randomized trials, reduction in Hcy levels has failed to lower overall risk for cardiovascular disease (CVD).
Genest and colleagues (2000) noted that the epidemiological evidence linking total plasma Hcy to atherosclerosis is mainly derived from case-control studies, however the strength of this association is weak in prospective studies. Thus, the causal relationship between total plasma Hcy and heart disease is not as strong as one would like to make recommendations regarding screening and treatment for the prevention of CVD.
In a double-blind, randomized controlled trial, Toole and associates (2004) examined if high doses of folic acid, vitamin B6, and vitamin B12, given to lower total Hcy levels would reduce the risk of recurrent stroke over a 2-year period compared with low doses of these vitamins. A total of 3680 adults with non-disabling cerebral infarction were included in this study. Subjects received best medical and surgical care plus a daily multi-vitamin containing the United States Food and Drug Administration's reference daily intakes of other vitamins; patients were randomly assigned to receive once-daily doses of the high-dose formulation (n = 1827), containing 25 mg of vitamin B6, 0.4 mg of vitamin B12, and 2.5 mg of folic acid; or the low-dose formulation (n = 1853), containing 200 microg of vitamin B6, 6 microg of vitamin B12 and 20 microg of folic acid. Main outcome measures were recurrent cerebral infarction (primary outcome); coronary heart disease (CHD) events and death (secondary outcomes). Mean reduction of total Hcy was 2 micromol/L greater in the high-dose group than in the low-dose group, but there was no treatment effect on any end point. The unadjusted risk ratio for any stroke, CHD event, or death was 1.0 (95 % confidence interval [CI], 0.8 - 1.1), with chances of an event within 2 years of 18.0 % in the high-dose group and 18.6 % in the low-dose group. The risk of ischemic stroke within 2 years was 9.2 % for the high-dose and 8.8 % for the low-dose groups (risk ratio, 1.0; 95 % CI, 0.8 - 1.3) (p = 0.80 by log-rank test of the primary hypothesis of difference in ischemic stroke between treatment groups). There was a persistent and graded association between baseline total Hcy level and outcomes. A 3- micromol/L lower total Hcy level was associated with a 10 % lower risk of stroke (p = 0.05), a 26 % lower risk of CHD events (p < 0.001), and a 16 % lower risk of death (p = 0.001) in the low-dose group and a non-significantly lower risk in the high-dose group by 2 % for stroke, 7 % for CHD events, and 7 % for death. The authors concluded that in this trial, moderate reduction of total Hcy after non-disabling cerebral infarction had no effect on vascular outcomes during the 2 years of follow-up. However, the consistent findings of an association of total Hcy with vascular risk suggested that further exploration of the hypothesis is warranted and longer trials in different populations with elevated total Hcy may be necessary.
Lewis et al (2005) stated that despite the statistical association of Hcy with vascular events, a causal association is unproven, and there is no convincing biological mechanism by which small increases in pHcy would promote CVD. Hankey (2006) noted that there is insufficient evidence to confirm that Hcy is a modifiable causal risk factor for stroke, or to recommend routine screening for, or treatment of, raised plasma total Hcy levels with folic acid and other vitamins, to prevent ischemic stroke. Moreover, the Thrombosis Interest Group of Canada (Houston et al, 2006) stated that there is no evidence to support routine measurement of Hcy in patients with arterial or venous disease. The Group also noted that fasting plasma or serum Hcy concentrations may be measured as a part of the investigation of selected patients with venous thrombo-embolism, especially those with idiopathic thrombosis, recurrent thrombosis, and thrombosis at a young age or at an unusual site. The finding of elevated Hcy by itself would not influence management, as it is a relatively weak risk factor for thrombosis and has not been shown to increase the risk of recurrence. The rationale for its measurement is that the risk associated with elevated Hcy augments the risk associated with other thrombophilic disorders such as Factor V Leiden, and a longer duration of anti-coagulation may be warranted in patients with multiple thrombophilias.
The B-Vitamin Treatment Trialists' Collaboration (2006) reviewed the design and statistical power of 12 randomized trials assessing the effects of lowering Hcy with vitamin B supplements on risk of CVD. The authors concluded that the strength of association of Hcy with risk of CVD may be weaker than had previously been believed. Extending the duration of treatment in these trials would allow any effects associated with prolonged differences in Hcy concentrations to emerge. Establishing a prospective meta-analysis of the ongoing trials of Hcy lowering should ensure that reliable information emerges about the effects of such interventions on CVD outcomes.
Lonn (2007) summarized observational studies linking Hcy to ischemic heart disease, stroke, and venous thrombo-embolism. These studies support weak associations between Hcy and vascular risk. A number of recent large randomized controlled studies failed to demonstrate benefit for Hcy lowering with B vitamin supplements in the prevention of cardiovascular events and venous thrombosis. However, these trials may have been insufficiently powered to detect modest but clinically important treatment benefits. Thus, completion of ongoing large randomized studies is essential. The author concluded that the status of Hcy as a target for intervention in the prevention of athero-thrombotic arterial and venous disease is uncertain. Current evidence does not support the use of B vitamin supplements to reduce vascular risk. Ongoing large randomized studies will provide further clarity on this subject.
Lazzerini et al (2007) examined the relationship between Hcy and CVD in patients affected with autoimmune diseases (ADs), reviewing the most recent literature data and also providing their experience. Although the large amount of available studies showed that mild hyper-homocysteinemia represents a common finding in patients affected with several autoimmune diseases, the actual role of Hcy in the development of CVD in the course of AD is still unclear, perhaps, with the only exception of the systemic lupus erythematosus. In the other conditions, the role of Hcy in the pathogenesis of vascular complications is still a matter of debate, as the result of conflicting reports and/or lack of an adequate body of investigation.
In a double-blind, randomized controlled trial, Jamison et al (2007) examined if high doses of folic acid and B vitamins administered daily would reduce mortality in patients with chronic kidney disease (CKD). Median follow-up was 3.2 years for 2056 participants aged 21 years or older with advanced CKD (estimated creatinine clearance less than or equal to 30 mL/min) (n = 1305) or end-stage renal disease (n = 751) and high Hcy levels (greater than or equal to 15 micromol/L). Subjects received a daily capsule containing 40 mg of folic acid, 100 mg of vitamin B6, and 2 mg of vitamin B12 or a placebo. The primary outcome was all-cause mortality. Secondary outcomes included myocardial infarction (MI), stroke, amputation of all or part of a lower extremity, a composite of these 3 plus all-cause mortality, time to initiation of dialysis, and time to thrombosis of arterio-venous access in hemodialysis patients. Mean baseline Hcy level was 24.0 micromol/L in the vitamin group and 24.2 micromol/L in the placebo group. It was lowered 6.3 micromol/L (25.8 %; p < 0.001) in the vitamin group and 0.4 micromol/L (1.7 %; p = 0.14) in the placebo group at 3 months, but there was no significant effect on mortality (448 vitamin group deaths versus 436 placebo group deaths) (hazard ratio [HR], 1.04; 95 % CI, 0.91 - 1.18). No significant effects were demonstrated for secondary outcomes or adverse events: there were 129 MIs in the vitamin group versus 150 for placebo (HR, 0.86; 95 % CI, 0.67 - 1.08), 37 strokes in the vitamin group versus 41 for placebo (HR, 0.90; 95 % CI, 0.58 - 1.40), and 60 amputations in the vitamin group versus 53 for placebo (HR, 1.14; 95 % CI, 0.79 - 1.64). In addition, the composite of MI, stroke, and amputations plus mortality (p = 0.85), time to dialysis (p = 0.38), and time to thrombosis in hemodialysis patients (p = 0.97) did not differ between the vitamin and placebo groups. The authors concluded that treatment with high doses of folic acid and B vitamins did not improve survival or reduce the incidence of vascular disease in patients with advanced CKD or end-stage renal disease.
In a randomized, double-blind, placebo-controlled study, Albert and colleagues (2008) examined if a combination of folic acid, vitamin B6, and vitamin B12 would lower risk of CVD among high-risk women with and without CVD. A total of 5442 women who were United States health professionals aged 42 years or older, with either a history of CVD or 3 or more coronary risk factors, received a combination pill containing folic acid (2.5 mg), vitamin B6 (50 mg), and vitamin B12 (1 mg) or a matching placebo, and were treated for 7.3 years. Main outcome measures were a composite outcome of myocardial infarction, stroke, coronary re-vascularization, or CVD mortality. Compared with placebo, a total of 796 women experienced a confirmed CVD event (406 in the active group and 390 in the placebo group). Patients receiving active vitamin treatment had similar risk for the composite CVD primary end point (226.9/10,000 person-years versus 219.2/10,000 person-years for the active versus placebo group; relative risk [RR], 1.03; 95 % CI, 0.90 - 1.19; p = 0.65), as well as for the secondary outcomes including myocardial infarction (34.5/10,000 person-years versus 39.5/10,000 person-years; RR, 0.87; 95 % CI, 0.63 - 1.22; p = 0.42), stroke (41.9/10,000 person-years versus 36.8/10,000 person-years; RR, 1.14; 95 % CI, 0.82 - 1.57; p = 0.44), and CVD mortality (50.3/10,000 person-years versus 49.6/10,000 person-years; RR, 1.01; 95 % CI, 0.76 - 1.35; p = 0.93). In a blood substudy, geometric mean pHcy was decreased by 18.5 % (95 % CI, 12.5 % - 24.1 %; p < 0.001) in the active group (n = 150) over that observed in the placebo group (n = 150), for a difference of 2.27 micromol/L (95 % CI, 1.54 - 2.96 micromol/L). The authors concluded that after 7.3 years of treatment and follow-up, a combination pill of folic acid, vitamin B6, and vitamin B12 did not reduce a combined end point of total cardiovascular events among high-risk women, despite significant Hcy lowering.
In an editorial that accompanied the afore-mentioned article, Lonn (2008) stated that currently vitamin B supplements can not be recommended for the prevention of CVD events with the exception of rare genetic disorders, and there is no role for routine screening for elevated Hcy levels.
Role of Hcy in Multiple Sclerosis:
Vrethem and colleagues (2003) examined if multiple sclerosis (MS) is associated with vitamin B12 deficiency. These researchers measured serum vitamin B12, plasma folate, serum methylmalonic acid (MMA), pHcy as well as cerebrospinal fluid (CSF) MMA and Hcy in 72 patients with MS and 23 controls. The mean pHcy level was significantly increased in MS patients (11.6 micromol/L) compared with controls (7.4 micromol/L) (p = 0.002). Seven patients showed low serum vitamin B12 levels but only 1 of them had concomitant high pHcy. None of them showed high serum MMA. Plasma or blood folate levels did not differ between MS patients and controls. These researchers found no significant differences in mean values or frequency of pathological tests of serum B12, serum MMA, mean corpuscular volume (MCV), hemoglobin concentration, CSF Hcy or CSF MMA between patients and healthy subjects. There were no correlations between CSF and serum/plasma levels of MMA or Hcy. Serum vitamin B12, serum MMA, pHcy, CSF Hcy or CSF MMA were not correlated to disability status, activity of disease, duration of disease or age. The authors concluded that the relevance of the increased mean value of pHcy thus seems uncertain and does not indicate functional vitamin B12 deficiency. However, they can not exclude the possibility of a genetically induced dysfunction of the Hcy metabolism relevant for the development of neuro-inflammation/degeneration. These findings indicated that, regardless of a significant increase in pHcy in MS patients, the disease is not generally associated with vitamin B12 deficiency since they did not find any other factors indicating vitamin B12 deficiency. Analysis of CSF MMA and CSF Hcy, which probably reflects the brain vitamin B12 status better than serum, are not warranted in MS. The authors concluded that B12 deficiency, in general, is not associated with MS.
Ramsaransing and associates (2006) stated that there is evidence that Hcy contributes to various neurodegenerative disorders, and elevated pHcy levels have been observed in patients with MS. These investigators examined if and why pHcy levels are increased in MS, and whether they play a role in the disease course. They compared pHcy in 88 patients with MS and 57 healthy controls. In the MS group, 28 had a benign course, 37 were secondary progressive, and 23 primary progressive. To explore the underlying mechanisms, these investigators measured serum levels of vitamins B6 and B12, folate, interleukin (IL)-12, tumor necrosis factor (TNF)-alpha, leukocyte nitric oxide production, and plasma diene conjugate levels (measure of oxidative stress). Mean pHcy was higher in patients (13.8 micromol/L) than in controls (10.1 micromol/L; p < 0.0001). However, there were no significant differences in Hcy levels between the three clinical subgroups of MS. Serum concentrations of vitamin B6, vitamin B12, and folate were not different between patients with MS and controls. In the MS group, there were no correlations between pHcy and the serum levels of IL-12 or TNF-alpha, leukocyte nitric oxide production, or plasma diene conjugate levels. The authors concluded that elevated pHcy occurs in both benign and progressive disease courses of MS, and seems unrelated to immune activation, oxidative stress, or a deficiency in vitamin B6, vitamin B12, or folate.
Role of Hcy in Polycystic Ovary Syndrome:
Badawy and colleagues (2007) examined the relationship between insulin resistance and increased serum Hcy in women with polycystic ovarian syndrome (PCOS). A total of 90 PCOS women as a study group and 35 women with infertility due to other causes as a control group were enrolled in this study. Outcome measures included serum Hcy levels in the presence and absence of insulin resistance in PCOS patients. Homocysteine levels were significantly higher in PCOS patients than in the controls. Considering 11 micromol/l as the cut-off level for a normal Hcy level, 41.1 % of PCOS patients (37 out of 90) and 2.9 % of control group (1 out of 35) had high Hcy levels. With regard to insulin resistance, 23 % of PCOS patients without insulin resistance (9 out of 39) had a high Hcy level, while 47 % of PCOS patients with insulin resistance (24 out of 51) had high Hcy level, thus demonstrating the effect of insulin resistance on the Hcy level. The authors concluded that there is a strong association between serum Hcy and insulin resistance in women with PCOS that contributes to the long-term complications of PCOS.
On the other hand, Schachter et al (2007) reported that in women with insulin-resistant PCOS, pHcy were significantly reduced by both B vitamins and metformin, but to a greater degree by B vitamins, and higher pregnancy rates were associated with vitamin B treatment. Also, Carlsen et al (2007) reported that metformin treatment in women with PCOS does not increase serum Hcy levels in the non-pregnant or the pregnant state. There is currently a lack of evidence regarding the association of monitoring of Hcy levels in women with PCOS and "fertility". Furthermore, Battaglia et al (2008) noted that PCOS is a condition associated with an increased vascular risk, however, the use of Hcy testing for assessing the risk of CHD has not been established.
Role of Hcy in Osteoporosis/Fractures:
High Hcy levels in adults have been associated with osteoporotic fractures in some, but not all, studies. However, it is unclear if high levels of Hcy have a direct effect on bone or if the effect is mediated through another factor, such as poor nutrition (Rosenson and Kang, 2007).
In a double-blind, randomized controlled trial, Sato et al (2005) examined if treatment with folate and vitamin B12 would reduce the incidence of hip fractures in patients with hemiplegia following stroke. A total of of 628 consecutive patients aged 65 years or older with residual hemiplegia at least 1 year following first ischemic stroke were included in this study. Patients were assigned to daily oral treatment with 5 mg of folate and 1500 microg of vitamin B12, or double placebo; 559 completed the 2-year follow-up. Main outcome measure was incidence of hip fractures in the 2 patient groups during the 2-year follow-up. At baseline, patients in both groups had high levels of plasma Hcy and low levels of serum cobalamin and serum folate. After 2 years, pHcy decreased by 38 % in the treatment group and increased by 31 % in the placebo group (p < 0.001). The number of hip fractures per 1000 patient-years was 10 and 43 for the treatment and placebo groups, respectively (p < 0.001). The adjusted relative risk, absolute risk reduction, and the number needed to treat for hip fractures in the treatment versus placebo groups were 0.20 (95 % CI, 0.08 - 0.50), 7.1 % (95 % CI, 3.6 % -10.8 %), and 14 (95 % CI, 9 - 28), respectively. No significant adverse effects were reported. The authors concluded that in this Japanese population with a high baseline fracture risk, combined treatment with folate and vitamin B12 is safe and effective in reducing the risk of a hip fracture in elderly patients following stroke. An editorial that accompanied this article (van Meurs and Uitterlinden, 205) noted that the final proof of causality between circulating Hcy levels and fracture risk will have to come from elucidation of the biological mechanism underlying this relationship.
Selhub (2006) noted that elevated pHcy is associated with increased total and CVD mortality, increased incidence of stroke, increased incidence of dementia and Alzheimer's disease, increased incidence of bone fracture, and higher prevalence of chronic heart failure. This multitude of relationships between elevated plasma total Hcy (tHcy) and diseases that afflict the elderly point to the existence of a common denominator that may be responsible for these diseases. The author stated that whether this denominator is Hcy itself or whether Hcy is merely a marker remains to be determined.
In a population-based prospective study, Gjesdal et al (2007) examined if plasma levels of tHcy, folate, and vitamin B12 and the MTHFR 677C-->T and 1298C-->T polymorphisms predicted hip fracture. A total of 2639 women and 2127 men who were 65 to 67 years of age were included in this study. Cox proportional hazard regression was used to estimate fracture risk according to levels of plasma tHcy, folate, and vitamin B12 and for different genotypes. Over a median follow-up period of 12.6 years, hip fracture was recorded in 184 (7.0 %) women and 90 (4.2 %) men. The adjusted hazard ratio (95 % CI) for fracture in subjects with high (greater than or equal to 15 micromol) compared with low levels (less than 9.0 micromol) of tHcy was 2.42 (1.43 - 4.09) among women and 1.37 (0.63 - 2.98) among men. Dose-response analyses indicated a positive association between plasma tHcy and risk of fracture in both sexes and a negative association between plasma folate and risk of fracture among women only. Plasma vitamin B12 level or MTHFR genotype was not significantly related to risk of fracture after adjustments for confounding factors. The association between tHcy and risk of hip fracture was only slightly weakened by adjustments for plasma levels of vitamin B12 and folate. The authors concluded that tHcy seems to be a predictor for hip fracture among elderly men and women. Folate was a predictor among women only, whereas vitamin B12 and MTHFR genotype did not predict hip fracture. These findings corroborated the hypothesis that Hcy may play a role in the pathogenesis of osteoporotic fractures.
Role of Hcy in Recurrent Pregnancy Loss:
Hague (2003) stated hyper-homocysteinemia has been associated with vascular disease, although whether it is cause or effect is still a matter of debate. In normal pregnancy, Hcy concentrations fall. Disturbance of maternal and fetal Hcy metabolism has been associated with fetal NTDs, with various conditions characterized by placental vasculopathy, such as pre-eclampsia and abruption, and with recurrent pregnancy loss. Apart from folate supplementation, which has been clearly shown to halve the risk of fetal NTDs, no other strategies have been identified in relation to Hcy metabolism that will reliably reduce the frequency of these other common obstetric pathologies.
Krabbendam et al (2005) noted that thrombophilias are suggested to play a role in recurrent miscarriage. These researchers evaluated the literature of the past 10 years regarding the association between thrombophilias and recurrent miscarriage. They concluded that there is a large variety in applied study methodology. Thus, they defined criteria for an adequate study on the relationship of thrombophilias on recurrent pregnancy loss: (i) no exclusion criteria for patients or at least the same criteria for patients and controls; (ii) a clear definition of the gestational age at previous losses; (iii) a well-described control group; (iv) clear description of the test methods and moment of testing; and (v) a clear description of the (non) significant differences or odds ratio between cases and controls. Eleven out of 69 studies fulfilled these criteria. Their results show significant higher serum Hcy levels among women with a history of recurrent miscarriage. No relation was found between recurrent miscarriage and the MTHFR-C667T mutation. No relation was observed for the levels of antithrombin, protein C and protein S. Seven studies on the association of factor V Leiden (FVL) and/or pathologic activated protein C ratio (pAPCR) showed that FVL may play a role in second trimester losses, as do antiphospholipid antibodies. Studies on the prothrombin gene mutation yielded conflicting results. Consequently, large prospective studies according to the afore-mentioned criteria are needed to establish if there is a relationship between thrombophilias and recurrent miscarriage at all. At present, there is only justification for testing for Hcy levels, antiphospholipid antibodies and FVL in women with a history of recurrent miscarriage.
Role of Hcy in Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency:
Homocystinuria is an inherited disorder in which patients are unable to properly process certain amino acids. The principal biochemical features of this condition are markedly elevated pHcy, tHcy, plasma concentrations of methionine as well as increased urinary concentration of Hcy. The most common form of homocystinuria is caused by the lack of cystathionine beta-synthase (CBS), a vitamin B6-dependent enzyme. Homocystinuria caused by CBS deficiency affects at least 1 in 200,000 to 335,000 people worldwide. Other forms of homocystinuria are much rarer. Moreover, the hallmarks of homocystinuria caused by CBS deficiency are developmental delay/mental retardation, ectopia lentis (dislocation of the ocular lens) and/or severe myopia, skeletal abnormalities as well as thrombo-embolism. There are two phenotypic variants of homocystinuria: (i) B6-responsive, and (ii) B6-non-responsive. The former is typically milder than the latter. In the majority of untreated affected individuals, ectopia lentis occurs by 8 years of age. Patients are often tall and slender with an asthenic habitus and are prone to osteoporosis. Thrombo-embolism is the major cause of early death and morbidity. Intelligence quotient (IQ) in individuals with homocystinuria usually ranges from 10 to 138; with the mean IQ of affected individuals with B6-responsiveness being 79 versus 57 for those who are B6-non-responsive. Other features that may occur include seizures, psychiatric problems, extra-pyramidal signs such as dystonia, hypo-pigmentation, pancreatitis, malar flush, and livedo reticularis (Picker and Levy, 2006).
Complications of homocystinuria should be treated appropriately (e.g., surgical intervention for ectopia lentis). Treatments should aim to correct the biochemical abnormalities, especially to control pHcy and prevent thrombosis. Individuals identified by newborn screening are treated shortly after birth to maintain pHcy below 11 micromol/L. For newborn screening, measurements of Hcy (plasma and/or urine) are performed only when hyper-methioninemia has been confirmed. Measurement of plasma concentrations of amino acids and Hcy in at-risk siblings immediately after birth ensures reduction of morbidity and mortality by early diagnosis and treatment. Prophylactic anti-coagulation during the third trimester of pregnancy and post-partum in women with homocystinuria is recommended to reduce risk of thrombo-embolism (Picker and Levy, 2006).
Role of Hcy in Other Conditions:
There is conflicting evidence regarding whether Hcy is an independent risk factor for dementia (e.g., Alzheimer's disease, Binswanger's disease) (Rosenson and Kang, 2007). Silbert et al (2008) examined the association of plasma Hcy and C-reactive protein (CRP) with cognition in patients scheduled for coronary artery bypass graft (CABG) surgery. Cognition was assessed in 264 patients using a standard battery of neuropsychological tests. Patients were classified as having pre-existing cognitive impairment (PreCI) by reference to a healthy control group or post-operative cognitive dysfunction (POCD) by reference to baseline test scores. PreCI was present in 37.3 % of patients, and POCD was present in 18.3, 12.1 and 13.6 % of patients at 1 week, 3 months and 12 months post-operatively. On multi-variate analysis, neither Hcy nor CRP was independently associated with cognition at any testing time but both were strongly associated with age and left ventricular function. The authors concluded that PreCI and POCD are present in a substantial proportion of patients undergoing CABG surgery but there is no independent association with either baseline Hcy or CRP levels. It is possible that cognitive impairment may result from the vascular disease rather than a direct association with either Hcy or CRP. Teper and O'Brien (2008) stated that the relationship between vascular disease and depression can not be solely explained by current established risk factors or the effects of treatment for depression. Other mechanisms must apply, and there is some evidence for common genetic factors. Promising future lines of investigation include Hcy, cytokines and endothelial dysfunction. They noted that more longitudinal studies combined with measurements of these biomarkers are needed.
Furthermore, there is insufficient evidence on the role of Hcy in any of the following conditions (not an all inclusive list):
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