Elevated Homocysteine Concentrations Research Articles

A new chromatographic method for the determination of cysteine, glutathione, homocysteine and Nɛ-homocysteinyllysine isopeptide in human plasma

Cysteine and glutathione can be applied as therapeutic targets in civilization diseases such as diabetes mellitus and cancers. On the other hand, an elevated concentration of homocysteine, and its metabolites such as homocysteine thiolactone and Nɛ-homocysteinyllysine result in health problems and has been indicated as an independent risk factor for cardiovascular disease and accelerated atherosclerosis. This work describes the first simplified HPLC-UV method that allows simultaneous determination of Nɛ-homocysteinyllysine isopeptide, cysteine, glutathione and homocysteine in human plasma. The assay is based on reversed-phase high performance liquid chromatography with UV detection and simultaneous reduction of disulfide bound with tris(2-carboxyethyl)phosphine and the selective pre-column derivatization of the thiol group with 1-benzyl-2-chloropyridinium bromide. Linearities of the detector responses for plasma samples were observed in ranges: 0.1–10.0 nmol/mL for Nɛ-homocysteinyllysine, 2.0–60.0 nmol/mL for glutathione and homocysteine, 20.0–600.0 nmol/mL for cysteine. The proposed method reduces the number of steps, shortens the total time of sample preparation, and limits the amount of single-use polypropylene laboratory materials.

Association of multiple metabolic and cardiovascular markers with the risk of cognitive decline and mortality in adults with Alzheimer's disease and AD-related dementia or cognitive decline: a prospective cohort study.

There is a scarcity of data stemming from large-scale epidemiological longitudinal studies focusing on potentially preventable and controllable risk factors for Alzheimer's disease (AD) and AD-related dementia (ADRD). This study aimed to examine the effect of multiple metabolic factors and cardiovascular disorders on the risk of cognitive decline and AD/ADRD. We analyzed a cohort of 6,440 participants aged 45-84 years at baseline. Multiple metabolic and cardiovascular disorder factors included the five components of the metabolic syndrome [waist circumference, high blood pressure (HBP), elevated glucose and triglyceride (TG) concentrations, and reduced high-density lipoprotein cholesterol (HDL-C) concentrations], C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), factor VIII, D-dimer, and homocysteine concentrations, carotid intimal-medial thickness (CIMT), and urine albumin-to-creatinine ratio (ACR). Cognitive decline was defined using the Cognitive Abilities Screening Instrument (CASI) score, and AD/ADRD cases were classified using clinical diagnoses. Over an average follow-up period of 13 years, HBP and elevated glucose, CRP, homocysteine, IL-6, and ACR concentrations were significantly associated with the risk of mortality in the individuals with incident AD/ADRD or cognitive decline. Elevated D-dimer and homocysteine concentrations, as well as elevated ACR were significantly associated with incident AD/ADRD. Elevated homocysteine and ACR were significantly associated with cognitive decline. A dose-response association was observed, indicating that an increased number of exposures to multiple risk factors corresponded to a higher risk of mortality in individuals with cognitive decline or with AD/ADRD. Findings from our study reaffirm the significance of preventable and controllable factors, including HBP, hyperglycemia, elevated CRP, D-dimer, and homocysteine concentrations, as well as, ACR, as potential risk factors for cognitive decline and AD/ADRD.

Elevated Serum Homocysteine Concentrations in Severe Preeclampsia and Eclampsia

Background & objective: Preeclampsia, a pregnancy-specific syndrome, is a major cause of maternal and perinatalmorbidity and mortality all over the world. Several studies have indicated that homocysteine concentrations areincreased in women with preeclampsia. However, there is still conflicting evidence on the extent to which elevatedmaternal homocysteine contributes to this deadly complication of pregnancy. The present study was, therefore,intended to see the association between serum homocysteine and preeclampsia. Methods: This cross-sectional study was carried out in the Department of Obstetrics and Gynaecology, Dhaka MedicalCollege Hospital, Dhaka over a period of 2 (two) years from July 2007 to June 2009. Pregnant women with gestationalage ranging between 24 – 40 weeks having preeclampsia or eclampsia were considered as cases, while gestationalage-matched pregnant women without preeclampsia and eclampsia were considered as controls. However, pregnancywith diabetes mellitus, known renal or hepatic disease, urinary tract infection, cardiovascular disease, and takinganti-epileptics were excluded from the study. A total of 100 pregnant women – 50 cases and 50 controls were selectedfor the study. Among the cases, 16 had mild preeclampsia, 17 had severe preeclampsia, and 17 had eclampsia. Result: Two-thirds of the cases and 60% of the controls were in their 3rd decade of life with no significant differencebetween the study groups (p = 0.651). There was no significant difference between the groups in terms of gravidityand gestational age. However, the past history of PE demonstrated its more significant presence in the case group thanthat in the control group (p = 0.030). Out of 50 cases, 30(60%) had severe proteinura (+++), 15(30%) had moderateproteinuria (++) and 5(10%) had mild proteinuria. The mean serum homocysteine level was significantly higher inmild PE (7.2±1.2 μmol/L) than that in normal pregnant women (5.3±1.0 μmol/L). The concentration of homocysteineincreases with the increase in severity of preeclampsia (p = 0.004) and turning preeclampsia into eclampsia (p =0.027). The data show as the grade of proteinuria increases progressively (from mild to severe) the concentrations ofhomocysteine level also increase progressively from 6.3 ± 1.6 μmol/L in mild proteinuria to 11.4 ± 3.7 μmol/L insevere proteinuria. Conclusion: The serum homocysteine level is significantly elevated in mild PE than that in normal pregnant women.The concentration of homocysteine increases further with the increase in the severity of preeclampsia and ineclampsia. Ibrahim Card Med J 2022; 12 (2): 10-14

Ischaemic stroke with multi-focal venous and arterial thrombosis due to hyperhomocysteinemia: anabolic androgenic steroid use and MTHFR c.667 C > T variant – a case report

BackgroundSeverely elevated serum homocysteine is a rare cause of ischaemic stroke and extra-cranial arterial and venous thrombosis. Several factors can lead to mild elevation of homocysteine including dietary folate and B12 deficiency, and genetic variants of the methylenetetrahydrofolate reductase (MTHFR) enzyme. The use of Anabolic androgenic steroid (AAS) is under-reported, but increasingly linked to ischaemic stroke and can raise homocysteine levels.Case ReportWe present a case of a man in his 40s with a large left middle cerebral artery (MCA) territory ischaemic stroke and combined multifocal, extracranial venous, and arterial thrombosis. His past medical history was significant for Crohn’s disease and covert use of AAS. A young stroke screen was negative except for a severely elevated total homocysteine concentration, folate and B12 deficiencies. Further tests revealed he was homozygous for the methylenetetrahydrofolate reductase enzyme thermolabile variant (MTHFR c.667 C > T). The etiology of this stroke was a hypercoagulable state induced by raised plasma homocysteine. Raised homocysteine in this case was likely multifactorial and related to chronic AAS use in combination with the homozygous MTHFR c.677 C > T thermolabile variant, folate deficiency and, vitamin B12 deficiency.ConclusionIn summary, hyperhomocysteinemia is an important potential cause of ischaemic stroke and may result from genetic, dietary, and social factors. Anabolic androgenic steroid use is an important risk factor for clinicians to consider, particularly in cases of young stroke with elevated serum homocysteine. Testing for MFTHR variants in stroke patients with raised homocysteine may be useful to guide secondary stroke prevention through adequate vitamin supplementation. Further studies looking into primary and secondary stroke prevention in the high-risk MTHFR variant cohort are necessary.

Association Between Plasma Homocysteine Level and Mortality: A Mendelian Randomization Study.

In previous studies, high homocysteine levels were associated with high cardiovascular mortality. However, these results were inconsistent with those of randomized controlled trials. We aimed to evaluate the causal role of homocysteine on all-cause and cardiovascular mortality using Mendelian randomization (MR) analysis. This study included the 10,005 participants in the Namwon Study. In conventional observational analysis, age, sex, survey years, lifestyles, body mass index, comorbidities, and serum folate level were adjusted using multivariate Cox proportional regression. MR using 2-stage least squares regression was used to evaluate the association between genetically predicted plasma homocysteine levels and mortality. Age, sex, and survey years were adjusted for each stage. The methylenetetrahydrofolate reductase (MTHFR) polymorphism was used as an instrumental variable for predicting plasma homocysteine levels. Observed homocysteine levels were positively associated with all-cause (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.26-1.54) and cardiovascular (HR, 1.62; 95% CI, 1.28-2.06) mortality when plasma homocysteine levels doubled. However, these associations were not significant in MR analysis. The HRs of doubling genetically predicted plasma homocysteine levels for all-cause and cardiovascular mortality were 0.99 (95% CI, 0.62-1.57) and 1.76 (95% CI, 0.54-5.77), respectively. This MR analysis did not support a causal role for elevated plasma homocysteine concentrations in premature deaths.

694 DRUG INDUCED KIDNEY INFARCTION: A CASE REPORT

Abstract Isotretinoin (ISO) is a synthetic analog of vitamin A. Notwithstanding the well-known long-term efficacy in the treatment of severe resistant cystic acne, ISO induces several side effects too. Dyslipidemia, increased liver enzymes, as well as reduction of biotidinase have been already reported [1]. Homocysteine (HCY), a sulfur-containing amino acid, is recycled into methionine by a transmethylation reaction requiring folate and vitamin B12. Given that during ISO treatment elevated liver enzymes (SGOT, SGPT) are often observed, it has been hypothesized that iatrogenic liver dysfunction could affect cystathionine-b-synthase, an enzyme involved in HCY metabolism, [2]. Several studies have highlighted that elevated plasma HCY concentrations are associated with an increased risk of premature occlusive vascular disease. We hereby report a case of drug-induced kidney infarction after ISO therapy. A previously healthy 18-year-old male, on therapy with 40 mg/die isotretinoin for acne, was admitted to the Emergency Unit for abdominal pain, nausea and vomiting and dyspnea. A trans-thoracic echocardiogram showed dilated and hypocontractile left ventricle. During the hospitalization he had a total body CT that showed the presence of an ischemic lesion on left kidney without other pathological findings. He started therapy with 12 IU/kg UFH as soon as a surgical emergency was excluded. Subsequently, he underwent a coronary angiogram that resulted unremarkable. Cardiac MRI showed extensive delayed gadolinium late enhancement with intramural linear pattern. In the hypothesis of drug-induced vasculitis, an extensive serological testing was performed. Elevation of serum liver enzymes (SGOT, SGPT), CRP, LDH was found. Mutations on MTHFR gene and Leiden Factor were not detected, neither alteration in coagulation parameters. Finally the dosage of plasmatic HCY resulted over the range of normality and ISO was discontinued. The patient was discharged on optimized medical therapy for heart failure. He is currently managed as outpatient. HCY levels could be found elevated in patients with ischemic events during ISO treatment. Given the widespread use of this drug for acne, it could be reasonable to dose HCY in patients with suspected liver dysfunction. Physicians should be aware of this scenario and should act swiftly to avoid uneventful outcomes. [1] Schulpis KH et al. Elevated plasma homocysteine levels in patients on isotretinoin therapy for cystic acne. Int J Dermatol. 2001 Jan;40(1):33-6. [2] Polat M, et al. Plasma homocysteine level is elevated in patients on isotretinoin therapy for cystic acne: a prospective controlled study. J Dermatolog Treat. 2008;19(4):229-32.

The Effects of Proton Pump Inhibitors in Acid Hypersecretion-Induced Vitamin B12 Deficiency: A Systematic Review (2022).

Gastroesophageal reflux disease (GERD) is the most common disease, for which proton pump inhibitors (PPIs) are a widely used class of drugs. Due to their efficacy and relative safety profile, PPIs are used chronically by GERD patients. Although it is a safe drug, particular attention focuses on the long-term adverse effects of PPI. The association with vitamin deficiencies has received additional focus since chronic PPI treatment increases the incidence of vitamin B12 deficiency, especially in the elderly. However, numerous studies regarding the establishment of an association between PPI and vitamin B12 status revealed conflicting results. In this systematic review, we systematically examined observational studies that focused on the impact of chronic PPI effects on vitamin B12 absorption and diagnostic biomarkers of vitamin B12 deficiency. Our review showed significant changes in diagnostic biomarkers of vitamin B12 status in long-term PPI users, including elevated homocysteine and methylmalonic acid (MMA) concentration levels defining cellular vitamin B12 deficiency. Although there is uncertainty regarding the exact mechanism, it supports the concept that long-term intake of PPI can have clinical implications for vitamins.

Homocysteine as a Predictor of Early Neurological Deterioration in Acute Ischemic Stroke

Background: Ischemic stroke (AIS) is on the rise owing in part to a longer average life expectancy. It's called early neurological deterioration (END) when symptoms deteriorate immediately after the stroke, and it's connected with a decreased probability of recovery. As homocysteine levels rise, so does the risk of neurotoxicity and other conditions that contribute to thrombosis. There are a number of ways that homocysteine may be hazardous, including direct toxicity and endothelium damage, according to experiments. If homocysteine could predict early neurological impairment after an ischemic stroke, this research would have been a success. Patients with acute ischemic stroke were included in the trial at Mataria teaching Hospital (AIS). The participants in the study were, on average, 63 years old and 12 months old. Two-thirds of the participants were men (60.0 percent ). The majority of individuals had hypertension (86.0 percent). One-fifth of research participants had diabetes mellitus (52.0 percent ) More over a third of the participants admitted to smoking cigarettes (44.0 percent ). More than one-third of the participants had dyslipidemia and coronary artery disease (approximately a quarter). The average HbA1c level in this research was 5.8%, with a standard variation of 1.3 percentage points.. It varied from a low of 2 to a high of 176, with an average of 11.5. Some 42.0 percent of the participants had elevated homocysteine concentrations. Age (P-value = 0.657), gender (P-value = 0.368), hypertension (P-value = 0.075), diabetes mellitus (P-value = 0.086), smoking (P-value = 0.171), and dyslipidemia (P-value = 0.726) were found to be non-significant variations across the groups. There was a statistically significant association between early neurological deterioration and a higher median CRP (47.5) compared to those with no decrease (10). Homocysteine levels were greater in individuals with early neurological degeneration (786%) than in those without deterioration (278%) (P = 0.001). Age (P=0.056), gender (P=0.815), high blood pressure (P=0.009), diabetes mellitus (P=0.603), or high cholesterol (P=0.863) were not linked to low homocysteine levels. HbA1C (P=0.507), CRP (P=0.643), or elevated lipid profiles (P=0.603) did not vary across the groups. Because of our investigation, we discovered a substantial connection between elevated levels of homocysteine and END. Homocysteine levels in acute stroke patients might be used as a prognostic indicator for such individuals.

Homocysteine, Vitamins B6 and Folic Acid in Experimental Models of Myocardial Infarction and Heart Failure-How Strong Is That Link?

Cardiovascular diseases are the leading cause of death and the main cause of disability. In the last decade, homocysteine has been found to be a risk factor or a marker for cardiovascular diseases, including myocardial infarction (MI) and heart failure (HF). There are indications that vitamin B6 plays a significant role in the process of transsulfuration in homocysteine metabolism, specifically, in a part of the reaction in which homocysteine transfers a sulfhydryl group to serine to form α-ketobutyrate and cysteine. Therefore, an elevated homocysteine concentration (hyperhomocysteinemia) could be a consequence of vitamin B6 and/or folate deficiency. Hyperhomocysteinemia in turn could damage the endothelium and the blood vessel wall and induce worsening of atherosclerotic process, having a negative impact on the mechanisms underlying MI and HF, such as oxidative stress, inflammation, and altered function of gasotransmitters. Given the importance of the vitamin B6 in homocysteine metabolism, in this paper, we review its role in reducing oxidative stress and inflammation, influencing the functions of gasotransmitters, and improving vasodilatation and coronary flow in animal models of MI and HF.

Elevated homocysteine and depression outcomes in patients with comorbid medical conditions in rural primary care

We examined the association of elevated concentration of total homocysteine (tHcy) with the severity of depression in patients diagnosed with depression and comorbid chronic medical conditions in rural primary care settings in Karnataka. Participants were included from the control arm of a cluster-randomized controlled trial designed to evaluate the effects of using a collaborative care model to integrate screening and treatment of primary health center patients. tHcy was assayed at baseline, and depression severity scores were assessed using the Patient Health Questionnaire (PHQ-9) 6 months later. There was no difference in the mean PHQ-9 score between those with (mean PHQ = 7.4) and without (mean PHQ = 7.6) elevated tHcy levels (P = 0.67).

Development and validation of a prediction model of deep venous thrombosis for patients with acute poisoning following hemoperfusion: a retrospective analysis.

ObjectiveTo develop and confirm an individualized predictive model to ascertain the probability of deep venous thrombosis in patients with acute poisoning after undergoing hemoperfusion.MethodsThree hundred eleven patients with acute poisoning who were admitted to a hospital in China between October 2017 and February 2019 were included in the development group. Eighty patients with acute poisoning who were admitted between February and May 2019 were included in the validation group. The independent risk factors for deep venous thrombosis were examined. An individualized predictive model was developed using regression coefficients.ResultsThe number of catheter indwelling days, having a catheter while being transported, elevated serum homocysteine concentrations, and dyslipidemia were independent risk factors for deep venous thrombosis following hemoperfusion in patients with acute poisoning. The areas under the receiver operating characteristic curve of the development and validation groups were 0.713 and 0.702, respectively, which suggested that the prediction model had good discrimination capacity. The calibration belts of the two groups were ideal.ConclusionsOur prediction model has a moderate predictive effect for the occurrence of deep venous thrombosis in patients with acute poisoning. In clinical practice, this model could be combined with a common thrombosis risk assessment model.

The Relationship of Cobalamin and/or Folate to the Patient-Centred Outcomes in Multiple Sclerosis: A Systematic Review and Meta-analysis.

Background: To examine the relationship of vitamin B12 and folate concentrations to cognitive function, fatigue measures, physical function, quality of life (patient-centred outcomes) and homocysteine plasma concentrations (intermediate marker of cobalamin and folate deficiency) for patients with Multiple Sclerosis (MS). Methods: Systematic searches for eligible articles of MEDLINE, CINAHL, EMBASE, Scopus, Web of Science and OpenGray databases were conducted from 1983 in March 2021. Heterogeneity, Weighted Mean Difference (WMD) and Confidence Intervals (CI) calculated using Random Effects Model. Results: Sixteen studies were included involving; 616 MS patients and 655 healthy controls. 14 of these had acceptable or better quality but there was high heterogeneity. No difference was found between MS, healthy controls for folate and cobalamin concentrations; WMD 0.00ug/L (95% CI: -0.01, 0.01) and WMD 7.01pmol/L (95% CI: -25.54, 39.55) respectively. MS group showed mild-to-moderate disability WMD was 2.78 (95% CI: 2.00, 3.56). MS may be associated with elevated plasma homocysteine concentrations on average 2.47µmol/L more than healthy controls. Discussion: Physical ability of MS group was worse than healthy controls, but there was no difference in folate and cobalamin concentrations. This suggests folate and cobalamin are not influential factors in worsening physical function. There may be an association between worse cognitive function, and increased homocysteine concentrations. Results were inconclusive due to high heterogeneity and limited number of studies. A core outcome set would enable easier synthesis of future results.

Changes of Serum Level of Homocysteine and Oxidative Stress Markers by Metformin and Inositol in Infertile Women with Polycystic Ovary Syndrome: A Double Blind Randomized Clinical Trial Study.

Background:Hyperhomocysteinemia plays an important role in the anovulation in infertile women suffering from polycystic ovary syndrome (PCOS). However, long-term metformin therapy elevated homocysteine (Hcy) concentration in these individuals. Inositol increases serum insulin levels and improves ovulation. The aim of this study was to compare the effect of metformin and inofolic on the level of serum Hcy and oxidative markers in the infertile patients with PCOS.Materials and Methods:Eighty PCOS infertile women undergoing in vitro fertilization in the Umm-al-Banin clinical center, Dezful, Iran from December 2018 to September 2019 were invited to participate in this double blind randomized clinical trial. They were divided into two groups; group A who received metformin (1000 mg twice/day) and folic acid (400 μg /day) and group B who used inofolic (inositol+ olic acid 200 μg twice/day) for 3 months.Results:The mean Hcy levels increased significantly by metformin (P=0.02), but not by inofolic. There was a decrease in the total antioxidant capacity (TAC) after metformin administration (P=0.01). In both groups, a significant increase in folic acid levels was observed after treatment (P=0.04). Also, no significant change in vitamin B12 and malondialdehyde levels was observed in both groups (P=0.08).Conclusion:These findings indicate an increase in the serum Hcy levels as well as a remarkable decrease in TAC following metformin treatment. Given the rise in blood Hcy in PCOS patients, inofolic and other medications containing inositol can be prescribed instead of metformin (registration number: IRCT20190508043516N1).

The Relationship Between Folate, Vitamin B12 and Gestational Diabetes Mellitus With Proposed Mechanisms and Foetal Implications.

The incidence of gestational diabetes mellitus (GDM) is rising, which warrants attention due to the associated complications during pregnancy and in the long term for both mother and offspring. Studies have suggested a relationship between maternal folate (vitamin B9) and vitamin B12 status and GDM risk. Seemingly the most problematic scenario occurs when there is B-vitamin imbalance, with high folate and low vitamin B12. This nutritional state can occur in vitamin B12 deficient women who exceed the recommended folic acid supplementation. However, the pathological mechanisms behind this relationship are currently unclear and are explored in this review article. A high folate/low B12 can lead to a functional folate deficiency through the methyl-trap phenomenon, impairing re-methylation of homocysteine and regeneration of folates for DNA synthesis and repair. Consequently elevated homocysteine concentration leads to endothelial dysfunction and oxidative stress. Vitamin B12 deficiency also leads to an impairment of the conversion of methylmalonyl-CoA to succinyl-CoA, which has been associated with insulin resistance. Insulin resistance is thought to contribute to the etiology of GDM. More studies are needed to confirm the impact of these and other mechanisms on disease development. However, it highlights a potential avenue for GDM risk modification through a vitamin B12 supplement and improvement of maternal metabolic health.

Persistent Helicobacter pylori infection for more than 3years leads to elevated serum homocysteine concentration: A retrospective cohort study based on a healthy Chinese population.

The relationship between the Helicobacter pylori (H. pylori) infection and homocysteine is unclear. We evaluated the effect of H. pylori on serum homocysteine in a healthy Chinese population. A total of 21184 individuals aged over 18years underwent 13 C/14 C urease breath test (13 C/14 C-UBT) and blood tests and 5042 individuals with follow-up intervals greater than 6months. Homocysteine levels are classified according to the Chinese expert consensus. The rates of H. pylori infection of normal level, mild level, moderate level, and severe level were 40.9%, 43.8%, 45.8%, and 46.6%, respectively (P=0.000). H. pylori infection increased the risk of higher homocysteine concentration (OR=1.406, P=0.000). In the case-control study, the rates of persistent negative, new infection, persistent infection, and eradication infection were 43.6%, 11.2%, 22.9%, and 22.3%, respectively. The percentage of changes in serum homocysteine levels varied significantly among the different H. pylori infection statuses only in mild level (P=0.024). Mean changed homocysteine values were higher in the subgroup of persistent infection than in the persistent negative subgroup (P=0.004) and the eradication infection subgroup (P=0.034). Serum homocysteine values were elevated only in the subgroup with over 3years interval time and persistent infection (n=107, mean paired differences=1.1±4.6μmol/L, P=0.014). There is a relationship between H. pylori and serum homocysteine, and persistent infection leads to elevation of the latter.

Homocysteine and female fertility, pregnancy loss and offspring birthweight: a two-sample Mendelian randomization study.

Observational studies link elevated homocysteine concentrations (Hcy) with female fertility, pregnancy loss, and low offspring birthweight. Maternal rs1801133, a functional variant in MTHFR strongly associated with lifelong elevated Hcy, is associated with recurrent pregnancy loss and offspring birthweight in Asian women. We investigated if genetically elevated Hcy is associated with fertility, pregnancy loss, and offspring birthweight in European women. We performed a two-sample Mendelian randomization (MR) study using publicly available data. We obtained 18 genetic variants (five involved in Hcy metabolism) explaining up to 5.9% of the variance in Hcy from a genome-wide association meta-analysis of 44,147 European individuals (82% women). We investigated fertility (including age at menopause), pregnancy loss, and offspring birthweight in the UK Biobank (N = 194,174), EGG (N = 190,406), and ReproGen (N = 69,360-252,514) consortia using summary statistics. We calculated inverse-variance weighted, and several sensitivity MR regression statistics. rs1801133 was associated with a 7.45 months (95% CI: 4.09, 10.80) increase in age at menopause and 29.69 (12.87, 46.51) g decrease in offspring birthweight per SD increase in Hcy in the UK biobank, and confirmed in EGG and ReproGen. MR for Hcy metabolism alone (five variants in MTHFR, MTR, CBS) showed similar results for offspring birthweight across consortia. However, using all 18 variants resulted in no association for any of the outcomes across consortia. Hcy and suggestively vitamin B variants are most likely the drug targets for folate supplementation in pregnant women on the offspring birthweight, while Hcy variants related to renal function or diabetes are not involved.

A comparison of homocysteine, troponin, cobalamin and folate status in acute myocardial infarction patients and healthy subjects: A case–control study

Introduction: Homocysteine (HCY), troponin, cardiac markers, folic acid and Vitamin B12 are known as the potential biomarkers for acute myocardial infarction (AMI) diagnosis. This study was designed to evaluate these markers as candidate biomarkers in the diagnosis, prognosis and prevention of AMI. Materials and Methods: This study was carried out on 40 AMI patients and 40 healthy subjects. After taking blood, HCY level was measured by an enzymatic, troponin and Vitamin B12, while the level of folic acid was determined by the radioimmunoassay method. In addition, the cardiac enzyme markers and lipid profile were measured by commercial kits and spectrophotometric method. Results: The results showed that patients' HCY levels were significantly more than the control group. Furthermore, the level of troponin was significantly different in the two groups (P = 0.0001), while serum levels of cardiac enzyme markers were significantly higher in patients (P 0.05). A positive correlation was identified between HCY with cholesterol (r = 0.32, P < 0.04) and low-density lipoprotein cholesterol (LDL-C) (r = 0.38, P < 0.02) in the patients. Conclusion: Elevated fasting HCY and troponin concentration are related to the lower circulation of folate and Vitamin B12 levels in the patients. The deficiency of these vitamins plays a role as an independent factor in HCY metabolism. As our findings revealed, despite a decrease in high-density lipoprotein cholesterol, the level of LDL-C increased in the patients. It can be inferred that merging enzymatic and non-enzymatic biomarkers might be more valuable in the diagnosis of AMI.

Epigallocatechin Gallate Reduces Homocysteine-Caused Oxidative Damages through Modulation SIRT1/AMPK Pathway in Endothelial Cells.

Elevated plasma concentration of total homocysteine is a pathological condition that causes vascular endothelial injury and subsequently leads to the progression of endothelial apoptosis in atherosclerosis. Epigallocatechin gallate (EGCG), a well-known anti-oxidant in green tea, has been reported with benefits on metabolic and cardiovascular diseases. This study aimed to explore that EGCG ameliorates homocysteine-induced endothelial cell apoptosis through enhancing the sirtuin 1 (SIRT1)/AMP-activated protein kinase (AMPK) survival signaling pathway. Human umbilical endothelial cells were treated with homocysteine in the presence or absence of EGCG. We found that EGCG significantly increased the activities of SIRT1 and AMPK. EGCG diminished homocysteine-mediated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation by inhibiting protein kinase C activation as well as reactive oxygen species (ROS) generation and recovered the activity of the endogenous antioxidant enzyme, superoxidase dismutase (SOD). Besides, EGCG also restores homocysteine-mediated dephosphorylation of Akt and decreases endothelial NO synthase (eNOS) expression. Furthermore, EGCG ameliorates homocysteine-activated pro-apoptotic events. The present study shows that EGCG prevents homocysteine-induced endothelial cell apoptosis via enhancing SIRT1/AMPK as well as Akt/eNOS signaling pathways. Results from this study indicated that EGCG might have some benefits for hyperhomocysteinemia.

Homocysteine and Mitochondria in Cardiovascular and Cerebrovascular Systems.

Elevated concentration of homocysteine (Hcy) in the blood plasma, hyperhomocysteinemia (HHcy), has been implicated in various disorders, including cardiovascular and neurodegenerative diseases. Accumulating evidence indicates that pathophysiology of these diseases is linked with mitochondrial dysfunction. In this review, we discuss the current knowledge concerning the effects of HHcy on mitochondrial homeostasis, including energy metabolism, mitochondrial apoptotic pathway, and mitochondrial dynamics. The recent studies suggest that the interaction between Hcy and mitochondria is complex, and reactive oxygen species (ROS) are possible mediators of Hcy effects. We focus on mechanisms contributing to HHcy-associated oxidative stress, such as sources of ROS generation and alterations in antioxidant defense resulting from altered gene expression and post-translational modifications of proteins. Moreover, we discuss some recent findings suggesting that HHcy may have beneficial effects on mitochondrial ROS homeostasis and antioxidant defense. A better understanding of complex mechanisms through which Hcy affects mitochondrial functions could contribute to the development of more specific therapeutic strategies targeted at HHcy-associated disorders.

Adolescent/adult-onset homocysteine remethylation disorders characterized by gait disturbance with/without psychiatric symptoms and cognitive decline: a series of seven cases.

Homocysteine remethylation disorders are rare inherited disorders caused by a deficient activity of the enzymes involved in the remethylation of homocysteine to methionine. The adolescent/adult-onset remethylation disorders are rarely reported. We analyzed the clinical and genetic characteristics of seven cases with adolescent/adult remethylation disorders, including 5 cases of the cobalamin C disease (cblC) and 2 cases of the methylenetetrahydrofolate reductase deficiency. The average onset age was 21.1 (range 14 to 40) years. All patients complained of gait disturbances. Other common symptoms included psychiatric symptoms (5/7) and cognitive decline (4/7). Acute encephalopathy, dysarthria, anorexia, vomiting, ketoacidosis, anemia, cataract, and hand tremor were also observed. The mean total homocysteine in serum when the patients were diagnosed was 94.6 (range 53.1-154.5) mol/L. Electrophysiological studies revealed neuropathy in the lower limbs (6/7). The brain MRI showed reversible altered signal from the dorsal portions of the cerebellar hemispheres (1/7), periventricular hyperintensity (2/7), and delayed/impaired myelination (2/7). The sural nerve biopsy performed in one case showed a modest loss of myelinated fibers. Five patients showed heterozygous mutations of the MMACHC gene, including c.482G>A (5/5), c.609G>A (2/5), and c.658-660delAAG (3/5). Two patients showed heterozygous mutations of the MTHFR gene, including c.698C>A (2/2), c.698C>G (1/2), and c.236+1G>A (1/2). The patients responded well to the treatments with significant improvements. Adolescent/adult-onset remethylation disorders are easily misdiagnosed. We recommend testing the serum homocysteine concentrations in young/adult patients with unexplained neuro-psychotic symptoms. Furthermore, individuals with significantly elevated serum homocysteine concentrations should be further tested by organic acid screening and genetic analysis.