Medicine › Rheumatology

Folate and B Vitamins Research

Works Count: 70222

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This cluster of papers explores the role of homocysteine in various health conditions, including cardiovascular disease, neural tube defects, cognitive impairment, and endothelial dysfunction. It also investigates the impact of folate, vitamin B12, and one-carbon metabolism on homocysteine levels and associated diseases.

Keywords

Homocysteine; Folate; Vitamin B12; Cardiovascular Disease; Neural Tube Defects; Methylation; One-Carbon Metabolism; Cognitive Impairment; Folic Acid; Endothelial Dysfunction

The Biochemistry of Folic Acid and Related Pteridines.

1970-01-01

Raymond L. Blakley

Construction of a genetic linkage map in man using restriction fragment length polymorphisms.

1980-05-01

David Botstein , R. White , Mark H. Skolnick +1 more

Betaine in human nutrition

2004-11-01

Stuart Craig

A Second Genetic Polymorphism in Methylenetetrahydrofolate Reductase (MTHFR) Associated with Decreased Enzyme Activity

1998-07-01

Ilan Weisberg , Pamela V. Tran , Benedicte Christensen +2 more

A Quantitative Assessment of Plasma Homocysteine as a Risk Factor for Vascular Disease

1995-10-04

Carol J. Boushey

<h3>Objective.</h3> —To determine the risk of elevated total homocysteine (tHcy) levels for arteriosclerotic vascular disease, estimate the reduction of tHcy by folic acid, and calculate the potential reduction of coronary … <h3>Objective.</h3> —To determine the risk of elevated total homocysteine (tHcy) levels for arteriosclerotic vascular disease, estimate the reduction of tHcy by folic acid, and calculate the potential reduction of coronary artery disease (CAD) mortality by increasing folic acid intake. <h3>Data Sources.</h3> —MEDLINE search for meta-analysis of 27 studies relating homocysteine to arteriosclerotic vascular disease and 11 studies of folic acid effects on tHcy levels. <h3>Study Selection and Data Extraction.</h3> —Studies dealing with CAD, cerebrovascular disease, and peripheral arterial vascular disease were selected. Three prospective and six population-based case-control studies were considered of high quality. Five cross-sectional and 13 other case-control studies were also included. Causality of tHcy's role in the pathogenesis of vascular disease was inferred because of consistency across studies by different investigators using different methods in different populations. <h3>Data Synthesis.</h3> —Elevations in tHcy were considered an independent graded risk factor for arteriosclerotic vascular diseases. The odds ratio (OR) for CAD of a 5-μmol/L tHcy increment is 1.6(95% confidence interval [Cl], 1.4 to 1.7) for men and 1.8 (95% Cl, 1.3 to 1.9) for women. A total of 10% of the population's CAD risk appears attributable to tHcy. The OR for cerebrovascular disease (5-μmol/L tHcy increment) is 1.5 (95% Cl, 1.3 to 1.9). Peripheral arterial disease also showed a strong association. Increased folic acid intake (approximately 200 μg/d) reduces tHcy levels by approximately 4 μmol/L. Assuming that lower tHcy levels decrease CAD mortality, we calculated the effect of (1) increased dietary folate, (2) supplementation by tablets, and (3) grain fortification. Under different assumptions, 13 500 to 50 000 CAD deaths annually could be avoided; fortification of food had the largest impact. <h3>Conclusions.</h3> —A 5-μmol/L tHcy increment elevates CAD risk by as much as cholesterol increases of 0.5 mmol/L (20 mg/dL). Higher folic acid intake by reducing tHcy levels promises to prevent arteriosclerotic vascular disease. Clinical trials are urgently needed. Concerns about masking cobalamin deficiency by folic acid could be lessened by adding 1 mg of cobalamin to folic acid supplements. (<i>JAMA</i>. 1995;274:1049-1057)

Total Plasma Homocysteine and Cardiovascular Risk Profile

1995-11-15

Ottar Nygård , Stein Emil Vollset , Helga Refsum +5 more

To estimate the relations between established cardiovascular risk factors and total homocysteine (tHcy) in plasma.Health examination survey by the Norwegian Health Screening Service in 1992 and 1993.General community, Hordaland County … To estimate the relations between established cardiovascular risk factors and total homocysteine (tHcy) in plasma.Health examination survey by the Norwegian Health Screening Service in 1992 and 1993.General community, Hordaland County of Western Norway.A total of 7591 men and 8585 women, 40 to 67 years of age, with no history of hypertension, diabetes, coronary heart disease, or cerebrovascular disease were included.Plasma tHcy level.The level of plasma tHcy was higher in men than in women and increased with age. In subjects 40 to 42 years old, geometric means were 10.8 mumol/L for 5918 men and 9.1 mumol/L for 6348 women. At age 65 to 67 years, the corresponding tHcy values were 12.3 mumol/L (1386 men) and 11.0 mumol/L (1932 women). Plasma tHcy level increased markedly with the daily number of cigarettes smoked in all age groups. Its relation to smoking was particularly strong in women. The combined effect of age, sex, and smoking was striking. Heavy-smoking men aged 65 to 67 years had a mean tHcy level 4.8 mumol/L higher than never-smoking women aged 40 to 42 years. Plasma tHcy level also was positively related to total cholesterol level, blood pressure, and heart rate and inversely related to physical activity. The relations were not substantially changed by multivariate adjustment, including intake of vitamin supplements, fruits, and vegetables.Elevated plasma tHcy level was associated with major components of the cardiovascular risk profile, ie, male sex, old age, smoking, high blood pressure, elevated cholesterol level, and lack of exercise. These findings should influence future studies on the etiology and pathogenesis of cardiovascular disease.

Vitamin Status and Intake as Primary Determinants of Homocysteinemia in an Elderly Population

1993-12-08

Jacob Selhub

<h3>Objective.</h3> —To describe the distribution of plasma homocysteine concentrations in an elderly population and to analyze the relationship between homocysteine level and intake of vitamins and serum levels of vitamins … <h3>Objective.</h3> —To describe the distribution of plasma homocysteine concentrations in an elderly population and to analyze the relationship between homocysteine level and intake of vitamins and serum levels of vitamins that serve as coenzymes in homocysteine metabolism. <h3>Design.</h3> —Cross-sectional analysis of homocysteine levels and vitamin blood levels and intake in elderly participants in the Framingham Study. <h3>Setting.</h3> —Population-based cohort in Framingham, Mass. <h3>Participants.</h3> —A total of 1160 adult survivors, aged 67 to 96 years, from the original Framingham Heart Study cohort. <h3>Main Outcome Measures.</h3> —Plasma homocysteine concentration correlated with plasma folate, vitamin B<sub>12</sub>, pyridoxal-5'-phosphate (PLP), and oral intakes of these vitamins, and the contribution of these vitamins to the prevalence of elevated homocysteine in the population. <h3>Results.</h3> —Homocysteine levels were positively correlated with age after controlling for vitamin concentrations. After controlling for age, sex, and levels of other vitamins, homocysteine exhibited a strong inverse association with plasma folate. When subjects were grouped by deciles of plasma folate, mean homocysteine was significantly higher in the lowest two folate deciles (15.6 and 13.7 μmol/L, respectively) than in the highest decile (11.0 μmol/L). Homocysteine demonstrated weaker, inverse associations with plasma vitamin B<sub>12</sub>and PLP. Similar inverse associations were demonstrated between homocysteine and intakes of folate and vitamin B<sub>6</sub>, but not vitamin B<sub>12</sub>. Prevalence of high homocysteine (>14 μmol/L) was 29.3% in this cohort, and was greatest among subjects with low folate status. Inadequate plasma concentrations of one or more B vitamins appear to contribute to 67% of the cases of high homocysteine. <h3>Conclusions.</h3> —These results indicate a strong association between homocysteine concentration and folate, vitamin B<sub>12</sub>, and vitamin B<sub>6</sub>status, as well as age. It is possible that a substantial majority of the cases of high homocysteine in this older population can be attributed to vitamin status. (<i>JAMA</i>. 1993;270:2693-2698)

Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis

2002-11-21

David S Wald

To assess whether the association of serum homocysteine concentration with ischaemic heart disease, deep vein thrombosis and pulmonary embolism, and stroke is causal and, if so, to quantify the effect … To assess whether the association of serum homocysteine concentration with ischaemic heart disease, deep vein thrombosis and pulmonary embolism, and stroke is causal and, if so, to quantify the effect of homocysteine reduction in preventing them.Meta-analyses of the above three diseases using (a) 72 studies in which the prevalence of a mutation in the MTHFR gene (which increases homocysteine) was determined in cases (n=16 849) and controls, and (b) 20 prospective studies (3820 participants) of serum homocysteine and disease risk.Odds ratios of the three diseases for a 5 micromol/l increase in serum homocysteine concentration.There were significant associations between homocysteine and the three diseases. The odds ratios for a 5 micromol/l increase in serum homocysteine were, for ischaemic heart disease, 1.42 (95% confidence interval 1.11 to 1.84) in the genetic studies and 1.32 (1.19 to 1.45) in the prospective studies; for deep vein thrombosis with or without pulmonary embolism, 1.60 (1.15 to 2.22) in the genetic studies (there were no prospective studies); and, for stroke, 1.65 (0.66 to 4.13) in the genetic studies and 1.59 (1.29 to 1.96) in the prospective studies.The genetic studies and the prospective studies do not share the same potential sources of error, but both yield similar highly significant results-strong evidence that the association between homocysteine and cardiovascular disease is causal. On this basis, lowering homocysteine concentrations by 3 micromol/l from current levels (achievable by increasing folic acid intake) would reduce the risk of ischaemic heart disease by 16% (11% to 20%), deep vein thrombosis by 25% (8% to 38%), and stroke by 24% (15% to 33%).

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Lowering Homocysteine in Patients With Ischemic Stroke to Prevent Recurrent Stroke, Myocardial Infarction, and Death

2004-02-03

James F. Toole , M.R. Malinow , Lloyd E. Chambless +6 more

ContextIn observational studies, elevated plasma total homocysteine levels have been positively associated with ischemic stroke risk. However the utility of homocysteine-lowering therapy to reduce that risk has not been confirmed … ContextIn observational studies, elevated plasma total homocysteine levels have been positively associated with ischemic stroke risk. However the utility of homocysteine-lowering therapy to reduce that risk has not been confirmed by randomized trials.ObjectiveTo determine whether high doses of folic acid, pyridoxine (vitamin B6), and cobalamin (vitamin B12), given to lower total homocysteine levels, reduce the risk of recurrent stroke over a 2-year period compared with low doses of these vitamins.DesignDouble-blind randomized controlled trial (September 1996–May 2003).Setting and Participants3680 adults with nondisabling cerebral infarction at 56 university-affiliated hospitals, community hospitals, private neurology practices, and Veterans Affairs medical centers across the United States, Canada, and Scotland.InterventionsAll participants received best medical and surgical care plus a daily multivitamin containing the US 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 pyridoxine, 0.4 mg of cobalamin, and 2.5 mg of folic acid; or the low-dose formulation (n = 1853), containing 200 µg of pyridoxine, 6 µg of cobalamin,and 20 µg of folic acid.Main Outcome MeasuresRecurrent cerebral infarction (primary outcome); coronary heart disease (CHD) events and death (secondary outcomes).ResultsMean reduction of total homocysteine was 2 µmol/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 = .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 homocysteine level and outcomes. A 3-µmol/L lower total homocysteine level was associated with a 10% lower risk of stroke (P = .05), a 26% lower risk of CHD events (P<.001), and a 16% lower risk of death (P = .001) in the low-dose group and a nonsignificantly lower risk in the high-dose group by 2% for stroke, 7% for CHD events, and 7% for death.ConclusionsIn this trial, moderate reduction of total homocysteine after nondisabling cerebral infarction had no effect on vascular outcomes during the 2 years of follow-up. However, the consistent findings of an association of total homocysteine with vascular risk suggests that further exploration of the hypothesis is warranted and longer trials in different populations with elevated total homocysteine may be necessary.

Oxidative Nucleobase Modifications Leading to Strand Scission

1998-04-01

Cynthia J. Burrows , James G. Muller

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTOxidative Nucleobase Modifications Leading to Strand ScissionCynthia J. Burrows and James G. MullerView Author Information Department of Chemistry, University of Utah, 315 S. 1400 East, Salt Lake … ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTOxidative Nucleobase Modifications Leading to Strand ScissionCynthia J. Burrows and James G. MullerView Author Information Department of Chemistry, University of Utah, 315 S. 1400 East, Salt Lake City, Utah 84112-0850 Cite this: Chem. Rev. 1998, 98, 3, 1109–1152Publication Date (Web):April 1, 1998Publication History Received18 December 1997Revised20 February 1998Published online1 April 1998Published inissue 7 May 1998https://pubs.acs.org/doi/10.1021/cr960421shttps://doi.org/10.1021/cr960421sresearch-articleACS PublicationsCopyright © 1998 American Chemical SocietyRequest reuse permissionsArticle Views6532Altmetric-Citations1513LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Adducts,Genetics,Guanine,Nucleobases,Oxidation Get e-Alerts

Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage

1997-04-01

Benjamin C. Blount , M. M. Mack , Carol M. Wehr +6 more

Folate deficiency causes massive incorporation of uracil into human DNA (4 million per cell) and chromosome breaks. The likely mechanism is the deficient methylation of dUMP to dTMP and subsequent … Folate deficiency causes massive incorporation of uracil into human DNA (4 million per cell) and chromosome breaks. The likely mechanism is the deficient methylation of dUMP to dTMP and subsequent incorporation of uracil into DNA by DNA polymerase. During repair of uracil in DNA, transient nicks are formed; two opposing nicks could lead to chromosome breaks. Both high DNA uracil levels and elevated micronucleus frequency (a measure of chromosome breaks) are reversed by folate administration. A significant proportion of the U.S. population has low folate levels, in the range associated with elevated uracil misincorporation and chromosome breaks. Such breaks could contribute to the increased risk of cancer and cognitive defects associated with folate deficiency in humans.

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A Second Common Mutation in the Methylenetetrahydrofolate Reductase Gene: An Additional Risk Factor for Neural-Tube Defects?

1998-05-01

N.M.J. van der Put , F. Gabreëls , E M Stevens +5 more

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Prevention of neural tube defects: Results of the Medical Research Council vitamin study

1992-06-01

Nicholas Wald , Jean Sneddon , J. W. Densem +2 more

Plasma Homocysteine as a Risk Factor for Dementia and Alzheimer's Disease

2002-02-14

Sudha Seshadri , Alexa Beiser , Jacob Selhub +5 more

In cross-sectional studies, elevated plasma homocysteine levels have been associated with poor cognition and dementia. Studies of newly diagnosed dementia are required in order to establish whether the elevated homocysteine … In cross-sectional studies, elevated plasma homocysteine levels have been associated with poor cognition and dementia. Studies of newly diagnosed dementia are required in order to establish whether the elevated homocysteine levels precede the onset of dementia or result from dementia-related nutritional and vitamin deficiencies.

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Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay

2005-01-27

Nikki Parker , Mary Jo Turk , Elaine Westrick +3 more

The Effect of Folic Acid Fortification on Plasma Folate and Total Homocysteine Concentrations

1999-05-13

Paul F. Jacques , Jacob Selhub , A G Bostom +2 more

In 1996, the Food and Drug Administration issued a regulation requiring all enriched grain products to be fortified with folic acid to reduce the risk of neural-tube defects in newborns. … In 1996, the Food and Drug Administration issued a regulation requiring all enriched grain products to be fortified with folic acid to reduce the risk of neural-tube defects in newborns. Fortification (140 microg per 100 g) began in 1996, and the process was essentially complete by mid-1997.To assess the effect of folic acid fortification on folate status, we measured plasma folate and total homocysteine concentrations (a sensitive marker of folate status) using blood samples from the fifth examination (January 1991 to December 1994) of the Framingham Offspring Study cohort for baseline values and the sixth examination (January 1995 to August 1998) for follow-up values. We divided the cohort into two groups on the basis of the date of their follow-up examination: the study group consisted of 350 subjects who were seen after fortification (September 1997 to March 1998), and the control group consisted of 756 subjects who were seen before fortification (January 1995 to September 1996).Among the subjects in the study group who did not use vitamin supplements, the mean folate concentrations increased from 4.6 to 10.0 ng per milliliter (11 to 23 nmol per liter) (P<0.001) from the baseline visit to the follow-up visit, and the prevalence of low folate concentrations (<3 ng per milliliter [7 nmol per liter]) decreased from 22.0 to 1.7 percent (P< 0.001). The mean total homocysteine concentration decreased from 10.1 to 9.4 micromol per liter during this period (P<0.001), and the prevalence of high homocysteine concentrations (>13 micromol per liter) decreased from 18.7 to 9.8 percent (P<0.001). In the control group, there were no statistically significant changes in concentrations of folate or homocysteine.The fortification of enriched grain products with folic acid was associated with a substantial improvement in folate status in a population of middle-aged and older adults.

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Relation Between Folate Status, a Common Mutation in Methylenetetrahydrofolate Reductase, and Plasma Homocysteine Concentrations

1996-01-01

Paul F. Jacques , Andrew G. Bostom , Roger R. Williams +5 more

Background Methylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate, the major carbon donor in remethylation of homocysteine to methionine. A common MTHFR mutation, an alanine-to-valine substitution, renders the enzyme thermolabile and may cause … Background Methylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate, the major carbon donor in remethylation of homocysteine to methionine. A common MTHFR mutation, an alanine-to-valine substitution, renders the enzyme thermolabile and may cause elevated plasma levels of the amino acid homocysteine. Methods and Results To assess the potential interaction between this mutation and vitamin coenzymes in homocysteine metabolism, we screened 365 individuals from the NHLBI Family Heart Study. Among individuals with lower plasma folate concentrations (<15.4 nmol/L), those with the homozygous mutant genotype had total fasting homocysteine levels that were 24% greater ( P <.05) than individuals with the normal genotype. A difference between genotypes was not seen among individuals with folate levels ≥15.4 nmol/L. Conclusions Individuals with thermolabile MTHFR may have a higher folate requirement for regulation of plasma homocysteine concentrations; folate supplementation may be necessary to prevent fasting hyperhomocysteinemia in such persons.

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Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection

1987-01-01

Atsushi Araki , Yoshiyasu Sako

Plasma Homocysteine as a Risk Factor for Vascular Disease

1997-06-11

Ian M. Graham

<h3>Context.</h3> —Elevated plasma homocysteine is a known risk factor for atherosclerotic vascular disease, but the strength of the relationship and the interaction of plasma homocysteine with other risk factors are … <h3>Context.</h3> —Elevated plasma homocysteine is a known risk factor for atherosclerotic vascular disease, but the strength of the relationship and the interaction of plasma homocysteine with other risk factors are unclear. <h3>Objective.</h3> —To establish the magnitude of the vascular disease risk associated with an increased plasma homocysteine level and to examine interaction effects between elevated plasma homocysteine level and conventional risk factors. <h3>Design.</h3> —Case-control study. <h3>Setting.</h3> —Nineteen centers in 9 European countries. <h3>Patients.</h3> —A total of 750 cases of atherosclerotic vascular disease (cardiac, cerebral, and peripheral) and 800 controls of both sexes younger than 60 years. <h3>Measurements.</h3> —Plasma total homocysteine was measured while subjects were fasting and after a standardized methionine-loading test, which involves the administration of 100 mg of methionine per kilogram and stresses the metabolic pathway responsible for the irreversible degradation of homocysteine. Plasma cobalamin, pyridoxal 5'-phosphate, red blood cell folate, serum cholesterol, smoking, and blood pressure were also measured. <h3>Results.</h3> —The relative risk for vascular disease in the top fifth compared with the bottom four fifths of the control fasting total homocysteine distribution was 2.2 (95% confidence interval, 1.6-2.9). Methionine loading identified an additional 27% of atrisk cases. A dose-response effect was noted between total homocysteine level and risk. The risk was similar to and independent of that of other risk factors, but interaction effects were noted between homocysteine and these risk factors; for both sexes combined, an increased fasting homocysteine level showed a more than multiplicative effect on risk in smokers and in hypertensive subjects. Red blood cell folate, cobalamin, and pyridoxal phosphate, all of which modulate homocysteine metabolism, were inversely related to total homocysteine levels. Compared with nonusers of vitamin supplements, the small number of subjects taking such vitamins appeared to have a substantially lower risk of vascular disease, a proportion of which was attributable to lower plasma homocysteine levels. <h3>Conclusions.</h3> —An increased plasma total homocysteine level confers an independent risk of vascular disease similar to that of smoking or hyperlipidemia. It powerfully increases the risk associated with smoking and hypertension. It is time to undertake randomized controlled trials of the effect of vitamins that reduce plasma homocysteine levels on vascular disease risk.

Homocysteine and vascular disease

1999-07-01

Graeme J. Hankey , John W. Eikelboom

The natural history of homocystinuria due to cystathionine beta-synthase deficiency.

1985-01-01

S. Harvey Mudd , Flemming Skovby , Harvey L. Levy +7 more

Folate, Vitamin B12, and Serum Total Homocysteine Levels in Confirmed Alzheimer Disease

1998-11-01

Robert Clarke , A. David Smith , Kim A. Jobst +3 more

Recent studies suggest that vascular disease may contribute to the cause of Alzheimer disease (AD). Since elevated plasma total homocysteine (tHcy) level is a risk factor for vascular disease, it … Recent studies suggest that vascular disease may contribute to the cause of Alzheimer disease (AD). Since elevated plasma total homocysteine (tHcy) level is a risk factor for vascular disease, it may also be relevant to AD.To examine the association of AD with blood levels of tHcy, and its biological determinants folate and vitamin B12.Case-control study of 164 patients, aged 55 years or older, with a clinical diagnosis of dementia of Alzheimer type (DAT), including 76 patients with histologically confirmed AD and 108 control subjects.Referral population to a hospital clinic between July 1988 and April 1996.Serum tHcy, folate, and vitamin B12 levels in patients and controls at entry; the odds ratio of DAT or confirmed AD with elevated tHcy or low vitamin levels; and the rate of disease progression in relation to tHcy levels at entry.Serum tHcy levels were significantly higher and serum folate and vitamin B12 levels were lower in patients with DAT and patients with histologically confirmed AD than in controls. The odds ratio of confirmed AD associated with a tHcy level in the top third (> or = 14 micromol/L) compared with the bottom third (< or = 11 micromol/L) of the control distribution was 4.5 (95% confidence interval, 2.2-9.2), after adjustment for age, sex, social class, cigarette smoking, and apolipoprotein E epsilon4. The corresponding odds ratio for the lower third compared with the upper third of serum folate distribution was 3.3 (95% confidence interval, 1.8-6.3) and of vitamin B12 distribution was 4.3 (95% confidence interval, 2.1-8.8). The mean tHcy levels were unaltered by duration of symptoms before enrollment and were stable for several years afterward. In a 3-year follow-up of patients with DAT, radiological evidence of disease progression was greater among those with higher tHcy levels at entry.Low blood levels of folate and vitamin B12, and elevated tHcy levels were associated with AD. The stability of tHcy levels over time and lack of relationship with duration of symptoms argue against these findings being a consequence of disease and warrant further studies to assess the clinical relevance of these associations for AD.

‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease?*

2003-02-01

George Davey Smith , Shah Ebrahim

Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading, despite our best efforts to improve the design and analysis of studies. Mendelian randomization-the … Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading, despite our best efforts to improve the design and analysis of studies. Mendelian randomization-the random assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures. The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies. Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian randomization and are described. The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study, that polymorphisms may have several phenotypic effects associated with disease, the lack of suitable polymorphisms for studying modifiable exposures of interest, and canalization-the buffering of the effects of genetic variation during development. Nevertheless, Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.

Homocysteine and Cardiovascular Disease

1998-02-01

Helga Refsum , Per Magne Ueland , Ottar Nygård +1 more

An elevated level of total homocysteine (tHcy) in blood, denoted hyperhomocysteinemia, is emerging as a prevalent and strong risk factor for atherosclerotic vascular disease in the coronary, cerebral, and peripheral … An elevated level of total homocysteine (tHcy) in blood, denoted hyperhomocysteinemia, is emerging as a prevalent and strong risk factor for atherosclerotic vascular disease in the coronary, cerebral, and peripheral vessels, and for arterial and venous thromboembolism. The basis for these conclusions is data from about 80 clinical and epidemiological studies including more than 10,000 patients. Elevated tHcy confers a graded risk with no threshold, is independent of but may enhance the effect of the conventional risk factors, and seems to be a particularly strong predictor of cardiovascular mortality. Hyperhomocysteinemia is attributed to commonly occurring genetic and acquired factors including deficiencies of folate and vitamin B12. Supplementation with B-vitamins, in particular with folic acid, is an efficient, safe, and inexpensive means to reduce an elevated tHcy level. Studies are now in progress to establish whether such therapy will reduce cardiovascular risk.

Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease

2006-03-13

Eva Lonn , Salim Yusuf , Malcolm J Arnold +7 more

In observational studies, lower homocysteine levels are associated with lower rates of coronary heart disease and stroke. Folic acid and vitamins B6 and B12 lower homocysteine levels. We assessed whether … In observational studies, lower homocysteine levels are associated with lower rates of coronary heart disease and stroke. Folic acid and vitamins B6 and B12 lower homocysteine levels. We assessed whether supplementation reduced the risk of major cardiovascular events in patients with vascular disease.We randomly assigned 5522 patients 55 years of age or older who had vascular disease or diabetes to daily treatment either with the combination of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 or with placebo for an average of five years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, and stroke.Mean plasma homocysteine levels decreased by 2.4 micromol per liter (0.3 mg per liter) in the active-treatment group and increased by 0.8 micromol per liter (0.1 mg per liter) in the placebo group. Primary outcome events occurred in 519 patients (18.8 percent) assigned to active therapy and 547 (19.8 percent) assigned to placebo (relative risk, 0.95; 95 percent confidence interval, 0.84 to 1.07; P=0.41). As compared with placebo, active treatment did not significantly decrease the risk of death from cardiovascular causes (relative risk, 0.96; 95 percent confidence interval, 0.81 to 1.13), myocardial infarction (relative risk, 0.98; 95 percent confidence interval, 0.85 to 1.14), or any of the secondary outcomes. Fewer patients assigned to active treatment than to placebo had a stroke (relative risk, 0.75; 95 percent confidence interval, 0.59 to 0.97). More patients in the active-treatment group were hospitalized for unstable angina (relative risk, 1.24; 95 percent confidence interval, 1.04 to 1.49).Supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease. (ClinicalTrials.gov number, NCT00106886; Current Controlled Trials number, ISRCTN14017017.).

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A Prospective Study of Plasma Homocyst(e)ine and Risk of Myocardial Infarction in US Physicians

1992-08-19

Meir J. Stampfer

To assess prospectively the risk of coronary heart disease associated with elevated plasma levels of homocyst(e)ine.Nested case-control study using prospectively collected blood samples.Participants in the Physicians' Health Study.A total of … To assess prospectively the risk of coronary heart disease associated with elevated plasma levels of homocyst(e)ine.Nested case-control study using prospectively collected blood samples.Participants in the Physicians' Health Study.A total of 14,916 male physicians, aged 40 to 84 years, with no prior myocardial infarction (MI) or stroke provided plasma samples at baseline and were followed up for 5 years. Samples from 271 men who subsequently developed MI were analyzed for homocyst(e)ine levels together with paired controls, matched by age and smoking.Acute MI or death due to coronary disease.Levels of homocyst(e)ine were higher in cases than in controls (11.1 +/- 4.0 [SD] vs 10.5 +/- 2.8 nmol/mL; P = .03). The difference was attributable to an excess of high values among men who later had MIs. The relative risk for the highest 5% vs the bottom 90% of homocyst(e)ine levels was 3.1 (95% confidence interval, 1.4 to 6.9; P = .005). After additional adjustment for diabetes, hypertension, aspirin assignment, Quetelet's Index, and total/high-density lipoprotein cholesterol, this relative risk was 3.4 (95% confidence interval, 1.3 to 8.8) (P = .01). Thirteen controls and 31 cases (11%) had values above the 95th percentile of the controls.Moderately high levels of plasma homocyst(e)ine are associated with subsequent risk of MI independent of other coronary risk factors. Because high levels can often be easily treated with vitamin supplements, homocyst(e)ine may be an independent, modifiable risk factor.

Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction

2006-03-13

Kaare Harald Bønaa , Inger Njølstad , Per Magne Ueland +7 more

Homocysteine is a risk factor for cardiovascular disease. We evaluated the efficacy of homocysteine-lowering treatment with B vitamins for secondary prevention in patients who had had an acute myocardial infarction. Homocysteine is a risk factor for cardiovascular disease. We evaluated the efficacy of homocysteine-lowering treatment with B vitamins for secondary prevention in patients who had had an acute myocardial infarction.

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Impact of Folic Acid Fortification of the US Food Supply on the Occurrence of Neural Tube Defects

2001-06-20

Margaret A. Honein

Daily consumption of 400 microg of folic acid before conception and during early pregnancy dramatically reduces the occurrence of neural tube defects (NTDs). Before food fortification, however, only an estimated … Daily consumption of 400 microg of folic acid before conception and during early pregnancy dramatically reduces the occurrence of neural tube defects (NTDs). Before food fortification, however, only an estimated 29% of US reproductive-aged women were taking a supplement containing 400 microg of folic acid daily. The US Food and Drug Administration authorized addition of folic acid to enriched grain products in March 1996, with compliance mandatory by January 1998.To evaluate the impact of food fortification with folic acid on NTD birth prevalence.National study of birth certificate data for live births to women in 45 US states and Washington, DC, between January 1990 and December 1999.Birth certificate reports of spina bifida and anencephaly before fortification (October 1995 through December 1996) compared with after mandatory fortification (October 1998 through December 1999).The birth prevalence of NTDs reported on birth certificates decreased from 37.8 per 100 000 live births before fortification to 30.5 per 100 000 live births conceived after mandatory folic acid fortification, representing a 19% decline (prevalence ratio [PR], 0.81; 95% confidence interval [CI], 0.75-0.87). During the same period, NTD birth prevalence declined from 53.4 per 100 000 to 46.5 per 100 000 (PR, 0.87; 95% CI, 0.64-1.18) for women who received only third-trimester or no prenatal care.A 19% reduction in NTD birth prevalence occurred following folic acid fortification of the US food supply. However, factors other than fortification may have contributed to this decline.

Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials

1998-03-21

L.E. Brattstrom , Martin den Heijer , Henk J. Blom +5 more

<h3>Abstract</h3> <b>Objective:</b> To determine the size of reduction in homocysteine concentrations produced by dietary supplementation with folic acid and with vitamins B-12 or B-6. <b>Design:</b> Meta-analysis of randomised controlled trials … <h3>Abstract</h3> <b>Objective:</b> To determine the size of reduction in homocysteine concentrations produced by dietary supplementation with folic acid and with vitamins B-12 or B-6. <b>Design:</b> Meta-analysis of randomised controlled trials that assessed the effects of folic acid based supplements on blood homocysteine concentrations. Multivariate regression analysis was used to determine the effects on homocysteine concentrations of different doses of folic acid and of the addition of vitamin B-12 or B-6. <b>Subjects:</b> Individual data on 1114 people included in 12 trials. <b>Findings:</b> The proportional and absolute reductions in blood homocysteine produced by folic acid supplements were greater at higher pretreatment blood homocysteine concentrations (P<0.001) and at lower pretreatment blood folate concentrations (P<0.001). After standardisation to pretreatment blood concentrations of homocysteine of 12 μmol/l and of folate of 12 nmol/l (approximate average concentrations for Western populations), dietary folic acid reduced blood homocysteine concentrations by 25% (95% confidence interval 23% to 28%; P<0.001), with similar effects in the range of 0.5-5 mg folic acid daily. Vitamin B-12 (mean 0.5 mg daily) produced an additional 7% (3% to 10%) reduction in blood homocysteine. Vitamin B-6 (mean 16.5 mg daily) did not have a significant additional effect. <b>Conclusions:</b> Typically in Western populations, daily supplementation with both 0.5-5 mg folic acid and about 0.5 mg vitamin B-12 would be expected to reduce blood homocysteine concentrations by about a quarter to a third (for example, from about 12 μmol/l to 8-9 μmol/l). Large scale randomised trials of such regimens in high risk populations are now needed to determine whether lowering blood homocysteine concentrations reduces the risk of vascular disease. <h3>Key messages</h3> Higher blood homocysteine concentrations seem to be associated with higher risks of occlusive vascular disease and with lower blood concentrations of folate and vitamins B-12 and B-6 Proportional and absolute reductions in blood homocysteine concentrations with folic acid supplements are greater at higher pretreatment blood homocysteine concentrations and at lower pretreatment blood folate concentrations In typical Western populations, supplementation with both 0.5-5 mg daily folic acid and about 0.5 mg daily vitamin B-12 should reduce blood homocysteine concentrations by about a quarter to a third Large scale randomised trials of such regimens in people at high risk are now needed to determine whether lowering blood homocysteine concentrations reduces the risk of vascular disease

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5, 10-Methylenetetrahydrofolate Reductase Gene Variants and Congenital Anomalies: A HuGE Review

2000-05-01

Lorenzo D. Botto , Quanhe Yang

The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism. The MTHFR gene is located on chromosome 1 (1p36.3), and two common alleles, the C677T (thermolabile) allele and the A1298C … The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism. The MTHFR gene is located on chromosome 1 (1p36.3), and two common alleles, the C677T (thermolabile) allele and the A1298C allele, have been described. The population frequency of C677T homozygosity ranges from 1% or less among Blacks from Africa and the United States to 20% or more among Italians and US Hispanics. C677T homozygosity in infants is associated with a moderately increased risk for spina bifida (pooled odds ratio = 1.8; 95% confidence interval: 1.4, 2.2). Maternal C677T homozygosity also appears to be a moderate risk factor (pooled odds ratio = 2.0; 95% confidence interval: 1.5, 2.8). The A 1298C allele combined with the C677T allele also could be associated with an increased risk for spina bifida. Some data suggest that the risk for spina bifida associated with C677T homozygosity may depend on nutritional status (e.g., blood folate levels, intake of vitamins) or on the genotype of other folate-related genes (e.g., cystathionine-beta-synthase and methionine synthase reductase). Studies of the C677T allele in relation to oral clefts, Down syndrome, and fetal anticonvulsant syndrome either have yielded conflicting results or have not been yet replicated.

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Total homocysteine in plasma or serum: methods and clinical applications

1993-09-01

Per Magne Ueland , Helga Refsum , Sally P. Stabler +3 more

Total homocysteine is defined as the sum of all homocysteine species in plasma/serum, including free and protein-bound forms. In the present review, we compare and evaluate several techniques for the … Total homocysteine is defined as the sum of all homocysteine species in plasma/serum, including free and protein-bound forms. In the present review, we compare and evaluate several techniques for the determination of total homocysteine. Because these assays include the conversion of all forms into a single species by reduction, the redistribution between free and protein-bound homocysteine through disulfide interchange does not affect the results, and total homocysteine can be measured in stored samples. Total homocysteine in whole blood increases at room temperature because of a continuous production and release of homocysteine from blood cells, but artificial increase is low if the blood sample is centrifuged within 1 h of collection or placed on ice. Different methods correlate well, and values between 5 and 15 mumol/L in fasting subjects are considered normal. Total homocysteine in serum/plasma is increased markedly in patients with cobalamin or folate deficiency, and decreases only when they are treated with the deficient vitamin. Total homocysteine is therefore of value for the diagnosis and follow-up of these deficiency states and may compensate for weaknesses of the traditional laboratory tests. In addition, total homocysteine is an independent risk factor for premature cardiovascular diseases. These disorders justify introduction of the total homocysteine assay in the routine clinical chemistry laboratory.

The Sulfur-Containing Amino Acids: An Overview

2006-06-01

John T. Brosnan , Margaret E. Brosnan

Biomarkers of Nutrition for Development—Folate Review

2015-06-04

Lynn B. Bailey , Patrick J. Stover , Helene McNulty +7 more

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Facts and Recommendations about Total Homocysteine Determinations: An Expert Opinion

2004-01-01

Helga Refsum , A. David Smith , Per Magne Ueland +7 more

Abstract Background: Measurement of plasma total homocysteine has become common as new methods have been introduced. A wide range of disorders are associated with increased concentrations of total homocysteine. The … Abstract Background: Measurement of plasma total homocysteine has become common as new methods have been introduced. A wide range of disorders are associated with increased concentrations of total homocysteine. The purpose of this review is to provide an international expert opinion on the practical aspects of total homocysteine determinations in clinical practice and in the research setting and on the relevance of total homocysteine measurements as diagnostic or screening tests in several target populations. Methods: Published data available on Medline were used as the basis for the recommendations. Drafts of the recommendations were critically discussed at meetings over a period of 3 years. Outcome: This review is divided into two sections: (a) determination of homocysteine (methods and their performance, sample collection and handling, biological determinants, reference intervals, within-person variability, and methionine loading test); and (b) risk assessment and disease diagnosis (homocystinuria, folate and cobalamin deficiencies, cardiovascular disease, renal failure, psychiatric disorders and cognitive impairment, pregnancy complications and birth defects, and screening of elderly and newborns). Each of these subsections concludes with a separate series of recommendations to assist the clinician and the research scientist in making informed decisions. The review concludes with a list of unresolved questions.

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A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase

1995-05-01

Phyllis Frosst , Henk J. Blom , Renate Milos +7 more

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Homocysteine and Risk of Ischemic Heart Disease and Stroke

2002-10-23

Homocysteine Studies Collaboration

It has been suggested that total blood homocysteine concentrations are associated with the risk of ischemic heart disease (IHD) and stroke.To assess the relationship of homocysteine concentrations with vascular disease … It has been suggested that total blood homocysteine concentrations are associated with the risk of ischemic heart disease (IHD) and stroke.To assess the relationship of homocysteine concentrations with vascular disease risk.MEDLINE was searched for articles published from January 1966 to January 1999. Relevant studies were identified by systematic searches of the literature for all reported observational studies of associations between IHD or stroke risk and homocysteine concentrations. Additional studies were identified by a hand search of references of original articles or review articles and by personal communication with relevant investigators.Studies were included if they had data available by January 1999 on total blood homocysteine concentrations, sex, and age at event. Studies were excluded if they measured only blood concentrations of free homocysteine or of homocysteine after a methionine-loading test or if relevant clinical data were unavailable or incomplete.Data from 30 prospective or retrospective studies involving a total of 5073 IHD events and 1113 stroke events were included in a meta-analysis of individual participant data, with allowance made for differences between studies, for confounding by known cardiovascular risk factors, and for regression dilution bias. Combined odds ratios (ORs) for the association of IHD and stroke with blood homocysteine concentrations were obtained by using conditional logistic regression.Stronger associations were observed in retrospective studies of homocysteine measured in blood collected after the onset of disease than in prospective studies among individuals who had no history of cardiovascular disease when blood was collected. After adjustment for known cardiovascular risk factors and regression dilution bias in the prospective studies, a 25% lower usual (corrected for regression dilution bias) homocysteine level (about 3 micromol/L [0.41 mg/L]) was associated with an 11% (OR, 0.89; 95% confidence interval [CI], 0.83-0.96) lower IHD risk and 19% (OR, 0.81; 95% CI, 0.69-0.95) lower stroke risk.This meta-analysis of observational studies suggests that elevated homocysteine is at most a modest independent predictor of IHD and stroke risk in healthy populations. Studies of the impact on disease risk of genetic variants that affect blood homocysteine concentrations will help determine whether homocysteine is causally related to vascular disease, as may large randomized trials of the effects on IHD and stroke of vitamin supplementation to lower blood homocysteine concentrations.

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Plasma Homocysteine Levels and Mortality in Patients with Coronary Artery Disease

1997-07-24

Ottar Nygård , Jan Erik Nordrehaug , Helga Refsum +3 more

Elevated plasma homocysteine levels are a risk factor for coronary heart disease, but the prognostic value of homocysteine levels in patients with established coronary artery disease has not been defined. Elevated plasma homocysteine levels are a risk factor for coronary heart disease, but the prognostic value of homocysteine levels in patients with established coronary artery disease has not been defined.

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Homocysteine and Atherothrombosis

1998-04-09

George N. Welch , Joseph Loscalzo

In 1969, McCully made the clinical observation linking elevated plasma homocyst(e)ine concentrations with vascular disease.1 He reported autopsy evidence of extensive arterial thrombosis and atherosclerosis in two children with elevated … In 1969, McCully made the clinical observation linking elevated plasma homocyst(e)ine concentrations with vascular disease.1 He reported autopsy evidence of extensive arterial thrombosis and atherosclerosis in two children with elevated plasma homocyst(e)ine concentrations and homocystinuria. On the basis of this observation, he proposed that elevated plasma homocyst(e)ine (hyperhomocyst(e)inemia) can cause atherosclerotic vascular disease. The term "homocyst(e)ine" is used to define the combined pool of homocysteine, homocystine, mixed disulfides involving homocysteine, and homocysteine thiolactone found in the plasma of patients with hyperhomocyst(e)inemia.Subsequent investigations have confirmed McCully's hypothesis, and it has recently become clear that hyperhomocyst(e)inemia is an independent risk factor . . .

Prevention of the First Occurrence of Neural-Tube Defects by Periconceptional Vitamin Supplementation

1992-12-24

Andrew E. Czeizel , István Dudás

The risk of recurrent neural-tube defects is decreased in women who take folic acid or multivitamins containing folic acid during the periconceptional period. The extent to which such supplementation can … The risk of recurrent neural-tube defects is decreased in women who take folic acid or multivitamins containing folic acid during the periconceptional period. The extent to which such supplementation can reduce the first occurrence of defects is not known.

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Neuropsychiatric Disorders Caused by Cobalamin Deficiency in the Absence of Anemia or Macrocytosis

1988-06-30

John Lindenbaum , Edward B. Healton , David G. Savage +6 more

Among 141 consecutive patients with neuropsychiatric abnormalities due to cobalamin deficiency, we found that 40 (28 percent) had no anemia or macrocytosis. The hematocrit was normal in 34, the mean … Among 141 consecutive patients with neuropsychiatric abnormalities due to cobalamin deficiency, we found that 40 (28 percent) had no anemia or macrocytosis. The hematocrit was normal in 34, the mean cell volume was normal in 25, and both tests were normal in 19. Characteristic features in such patients included paresthesia, sensory loss, ataxia, dementia, and psychiatric disorders; long-standing neurologic symptoms without anemia; normal white-cell and platelet counts and serum bilirubin and lactate dehydrogenase levels; and markedly elevated serum concentrations of methylmalonic acid and total homocysteine. Serum cobalamin levels were above 150 pmol per liter (200 pg per milliliter) in 2 patients, between 75 and 150 pmol per liter (100 and 200 pg per milliliter) in 16, and below 75 pmol per liter (100 pg per milliliter) in only 22. Except for one patient who died during the first week of treatment, every patient in this group benefited from cobalamin therapy. Responses included improvement in neuropsychiatric abnormalities (39 of 39), improvement (often within the normal range) in one or more hematologic findings (36 of 39), and a decrease of more than 50 percent in levels of serum methylmalonic acid, total homocysteine, or both (31 of 31). We conclude that neuropsychiatric disorders due to cobalamin deficiency occur commonly in the absence of anemia or an elevated mean cell volume and that measurements of serum methylmalonic acid and total homocysteine both before and after treatment are useful in the diagnosis of these patients. (N Engl J Med 1988; 318:1720–8.)

Hyperhomocysteinemia: An Independent Risk Factor for Vascular Disease

1991-04-25

Robert Clarke , Leslie Daly , Killian Robinson +4 more

Hyperhomocysteinemia arising from impaired methionine metabolism, probably usually due to a deficiency of cystathionine β-synthase, is associated with premature cerebral, peripheral, and possibly coronary vascular disease. Both the strength of … Hyperhomocysteinemia arising from impaired methionine metabolism, probably usually due to a deficiency of cystathionine β-synthase, is associated with premature cerebral, peripheral, and possibly coronary vascular disease. Both the strength of this association and its independence of other risk factors for cardiovascular disease are uncertain. We studied the extent to which the association could be explained by heterozygous cystathionine β-synthase deficiency.

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One-Carbon Metabolism in Health and Disease

2016-09-16

Gregory S. Ducker , Joshua D. Rabinowitz

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Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group.

1991-07-20

Jean Sneddon , J. W. Densem , N J Wald +3 more

Vitamin B<sub>12</sub>Deficiency

2013-01-10

Sally P. Stabler

Vitamin B12 deficiency causes reversible megaloblastic anemia, demyelinating disease, or both. Current assays have insufficient sensitivity and specificity; methylmalonic acid levels are useful to confirm diagnosis. Parenteral or high-dose oral … Vitamin B12 deficiency causes reversible megaloblastic anemia, demyelinating disease, or both. Current assays have insufficient sensitivity and specificity; methylmalonic acid levels are useful to confirm diagnosis. Parenteral or high-dose oral vitamin B12 is effective therapy.

Escherichia coli and Salmonella typhimurium: Cellular and molecular biology

1988-06-01

Philippe Lejeune

Prevention of Neural-Tube Defects with Folic Acid in China

1999-12-09

Caren Contact , Yolanda Masterson , David W. H. Riches +1 more

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HOMOCYSTEINE METABOLISM

1999-07-01

Jacob Selhub

▪ Abstract Homocysteine is a sulfur amino acid whose metabolism stands at the intersection of two pathways: remethylation to methionine, which requires folate and vitamin B 12 (or betaine in … ▪ Abstract Homocysteine is a sulfur amino acid whose metabolism stands at the intersection of two pathways: remethylation to methionine, which requires folate and vitamin B 12 (or betaine in an alternative reaction); and transsulfuration to cystathionine, which requires pyridoxal-5′-phosphate. The two pathways are coordinated by S-adenosylmethionine, which acts as an allosteric inhibitor of the methylenetetrahydrofolate reductase reaction and as an activator of cystathionine β-synthase. Hyperhomocysteinemia, a condition that recent epidemiological studies have shown to be associated with increased risk of vascular disease, arises from disrupted homocysteine metabolism. Severe hyperhomocysteinemia is due to rare genetic defects resulting in deficiencies in cystathionine beta synthase, methylenetetrahydrofolate reductase, or in enzymes involved in methyl-B 12 synthesis and homocysteine methylation. Mild hyperhomocysteinemia seen in fasting conditions is due to mild impairment in the methylation pathway (i.e. folate or B 12 deficiencies or methylenetetrahydrofolate reductase thermolability). Post–methionine-load hyperhomocysteinemia may be due to heterozygous cystathionine β-synthase defect or B 6 deficiency. Early studies with nonphysiological high homocysteine levels showed a variety of deleterious effects on endothelial or smooth muscle cells in culture. More recent studies with human beings and animals with mild hyperhomocysteinemia provided encouraging results in the attempt to understand the mechanism that underlies this relationship between mild elevations of plasma homocysteine and vascular disease. The studies with animal models indicated the possibility that the effect of elevated homocysteine is multifactorial, affecting both the vascular wall structure and the blood coagulation system.

Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study

1991-07-01

Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis.

1969-07-01

McCully Ks

Estimation of Homocysteine and Its Relationship with Vitamin B12 and Folic Acid Levels in Patients with Cardiovascular Disease

2025-06-24

Ahmed Zaelan , Hanadi Abdulqader Jasim , Huda Farhan | University of Thi-Qar Journal of Science

Globally, one of the leading causes of death is cardiovascular disease (CVD). The plasma levels of homocysteine rise after myocardial ischemia and are involved in numerous methylation processes. This study … Globally, one of the leading causes of death is cardiovascular disease (CVD). The plasma levels of homocysteine rise after myocardial ischemia and are involved in numerous methylation processes. This study aimed to evaluate homocysteine levels and their relationship with vitamin B12 and folic acid (vitamin B9) in patients with cardiovascular disease and early-stage heart disease due to hypertension, lipidemia, etc. The present study included 120 participants aged between 30 to 70 years and was divided into three groups. Forty patients with acute myocardial infarction (G1), forty patients with early-stage heart disease (G2), and forty healthy participants (G3). Quantitative determination of homocysteine, vitamin B12, and vitamin B9 is measured based on the competitive enzyme-linked immunosorbent assay (ELISA) technology. Acute myocardial infarction and early-stage heart disease patients also had their total cholesterol, triglyceride, HDL, and LDL levels examined. The study showed that raised homocysteine levels are linked with deficiencies in vitamin B9 and vitamin B12 (P ≤0.0001). A highly significant positive correlation between homocysteine and lipid profile between G1 and G3, and G2 and G3 (P-value≤0.0001). Also, a significant positive correlation exists between homocysteine and triglyceride between G2 and G3 (P-value=0.012). A negative correlation between homocysteine, vitamin B9, and vitamin B12 at G1, G2, and G3 groups (P-value≤0.0001). The study's findings indicated that increased homocysteine levels, which are caused by deficiencies in vitamin B12 and vitamin B9, raise the risk of cardiovascular disease.

TRATAMENTO DA DOENÇA HEPÁTICA GORDUROSA NÃO ALCOÓLICA

2025-06-24

ARTHUR SOARES PASSOS , KARINY DIAS DA SILVA , LUIZ EDUARDO FERREIRA MAZZANTI +2 more | Editora Pasteur eBooks

Probable Commonality of Cleft Palate: Placental Arginine Metabolic dysregulation and Oxidative Stress

2025-06-24

Xiao Luo , Chaodong Zhang , Qiang Zheng +2 more | International Journal of Oral and Maxillofacial Surgery

Clinical Profile and utility of biomarkers in children with Cobalamin (Vitamin B12) deficiency: A Cross-sectional Study

2025-06-23

Sruthi Sankar , Ranjini Srinivasan , Vandana Bharadwaj +1 more | Annals of Clinical Biochemistry International Journal of Laboratory Medicine

Background To assess utility of novel biomarkers in diagnosing children with clinical cobalamin deficiency. Current practice uses total vitamin B12 levels to confirm diagnosis, which lacks sensitivity when used in … Background To assess utility of novel biomarkers in diagnosing children with clinical cobalamin deficiency. Current practice uses total vitamin B12 levels to confirm diagnosis, which lacks sensitivity when used in isolation. Methods Between November 2020 and September 2022, a prospective cross-sectional study was carried out in a tertiary teaching hospital. Children between 1 month-18 years with clinical symptoms/at-risk of developing B12 deficiency were included. Relevant clinical and laboratory information (including total B12 and biomarker levels) were documented. Sensitivity and specificity of individual biomarkers was assessed using 4cB12, an indicator of functional B12 status. Version 4.2.1 of R language was used for statistical analysis. Results Analysis was done on sixty-seven children. Anorexia, fatigue and behavioural abnormalities were among the leading clinical characteristics. 49% children had peripheral smear(PS) suggestive of cobalamin deficiency, 43% had low total B12 levels. Among biomarkers, 85% children had low Holotranscobalamin(HoloTC), 73% and 55% had high Methylmalonic acid(MMA) and elevated Homocysteine(Hcy) levels respectively. Sensitivity of total B12 was 51%, HoloTC 87%, MMA 83% and Hcy 64%. Combination of low HoloTC, macrocytosis and abnormal PS had 94% sensitivity while HoloTC with mean corpuscular volume(MCV) alone was 88% sensitive in detecting cobalamin deficiency. Conclusion Low total B12 levels lack sensitivity to diagnose cobalamin deficiency. Although combination of low HoloTC with abnormal smear and macrocytosis was found to have better sensitivity, reporting an abnormal smear is time consuming, requires skilled personnel. Combination of low HoloTC with macrocytosis has good sensitivity, can be considered a better screening tool for detecting B12 deficiency.

Cobalamin E Disease: An Ultrarare Treatable Cause of Hemolytic Anemia in Infancy

2025-06-23

Pankaj Prasun , Jose Ricardo Suarez , Katelyn J Watkin | Journal of Pediatric Hematology/Oncology

Concerning the debate about homocysteine, B vitamins, and dementia

2025-06-23

Joshua W. Miller , Andrew McCaddon , Jin‐Tai Yu +3 more | Journal of Alzheimer s Disease

It is important to identify modifiable risk factors for dementia and to introduce policies to implement their modification. The Lancet Commission on Dementia Prevention, Intervention and Care failed to identify … It is important to identify modifiable risk factors for dementia and to introduce policies to implement their modification. The Lancet Commission on Dementia Prevention, Intervention and Care failed to identify raised plasma homocysteine as a risk factor, despite considerable evidence; hence there is a need for a debate on this matter.

The Influence of Micronutrients and Environmental Factors on Thyroid DNA Integrity

2025-06-21

Katarzyna D. Arczewska , Agnieszka Piekiełko‐Witkowska | Nutrients

Micronutrients and environmental factors are key exogenous agents influencing thyroid DNA integrity. Micronutrients act as cofactors in DNA replication, repair, and antioxidant defence, while environmental exposure, such as radiation, heavy … Micronutrients and environmental factors are key exogenous agents influencing thyroid DNA integrity. Micronutrients act as cofactors in DNA replication, repair, and antioxidant defence, while environmental exposure, such as radiation, heavy metals, and endocrine-disrupting chemicals, can directly damage DNA, leading to genomic instability. Although many studies have confirmed the link between micronutrient status and thyroid health, the effects of nutrient imbalances and environmental stressors on thyroid DNA remain underexplored. This narrative review examines how these factors may compromise thyroid genome stability and contribute to disease development. The analysis focused on the roles of iodine, selenium, iron, zinc, copper and vitamins D, B9, and B12 as well as environmental exposures such as radiation, heavy metals, and endocrine-disrupting chemicals. The findings suggest that both micronutrient imbalance and environmental stress can impair DNA integrity in thyroid cells. Understanding these complex relationships is critical for developing effective strategies to maintain thyroid health and mitigate the risk of thyroid diseases associated with compromised genomic integrity. Methodology: This narrative review was based on 254 articles retrieved through a manual search of the PubMed and Google Scholar databases, covering the years 2000–2025 and focusing on the influence of micronutrients and environmental factors on thyroid DNA integrity and repair. Several seminal earlier publications, fundamental to a comprehensive understanding of the topic, were also included.

The Role of GST Gene Polymorphic Variants in Antipsychotic-Induced Metabolic Disorders in Schizophrenia: A Pilot Study

2025-06-21

Irina A. Mednova , Ekaterina V. Mikhalitskaya , N. Vyalova +6 more | Pharmaceuticals

The life expectancy of patients with psychotic disorders is significantly shorter than that of the general population; antipsychotic-induced metabolic disorders play a significant role in reducing life expectancy. Both metabolic … The life expectancy of patients with psychotic disorders is significantly shorter than that of the general population; antipsychotic-induced metabolic disorders play a significant role in reducing life expectancy. Both metabolic syndrome (MetS) and schizophrenia are multifactorial conditions. One area where the two conditions overlap is oxidative stress, which is present in both diseases. The glutathione-S-transferase (GST) system is a major line of defense against exogenous toxicants and oxidative damage to cells. The aim of our study was to perform an association analysis of gene polymorphisms with metabolic disorders in patients with schizophrenia treated with antipsychotic therapy. Methods: A total of 639 white patients with schizophrenia (ICD-10) from Siberia (Russia) were included in the study. Genotyping was carried out using real-time polymerase chain reaction for two single-nucleotide polymorphisms (SNPs) in the GSTP1 (rs614080 and rs1695) and one SNP in the GSTO1 (rs49252). Results: We found that rs1695*GG genotype of GSTP1 is a risk factor for the development of overweight (OR 2.36; 95% CI: 1.3–4.29; p = 0.0054). In the subgroup of patients receiving first-generation antipsychotics as basic therapy, the risk of overweight was associated with carriage of the rs1695*GG (OR 5.43; 95% CI: 2.24–13.16; p < 0.001) genotype of GSTP1 in a recessive model of inheritance. In contrast, an association of rs1695*G GSTP1 with obesity (OR: 0.42; 95% CI: 0.20–0.87; p = 0.018) was shown in the dominant model of inheritance in patients receiving second-generation antipsychotics. Conclusions: The pilot results obtained confirm the hypothesis of a violation of the antioxidant status, in particular the involvement of GSTP1, in the development of antipsychotic-induced metabolic disorders in schizophrenia. Further studies with larger samples and different ethnic groups are needed to confirm the obtained results.

173-OR: Eligibility, Impact, and Costs for Tirzepatide for the Primary Prevention of Diabetes Mellitus

2025-06-21

Jay B. Lusk , Shannon Aymes , E T O'Brien +1 more | Diabetes

Introduction and Objective: A recent trial of tirzepatide (SURMOUNT) found a 92% reduction of diabetes incidence among patients with overweight or obesity over three years. Our objective was to estimate … Introduction and Objective: A recent trial of tirzepatide (SURMOUNT) found a 92% reduction of diabetes incidence among patients with overweight or obesity over three years. Our objective was to estimate the potential population, outcomes, and cost associated with use of tirzepatide for the primary prevention of DM. Methods: Data from the 2021-2023 cycle of the National Health and Nutrition Examination Survey (NHANES) were used to estimate risk reductions for the incidence of DM extrapolated from SURMOUNT results. Costs and savings (from saved diabetes care costs) of tirzepatide were estimated under current U.S. list prices, direct to patient prices, and UK list prices. Results: In total, 2,022 NHANES participants were eligible for tirzepatide therapy (51% female, 49% male, median age 53, IQR 37-66) translating to a weighted U.S. population estimate of 83,454,492 (95% CI 74,423,832 - 92,485,151). Across the lifespan, 30,522,710 cases of diabetes could be prevented if risk reduction was persistent. Projected costs/savings are shown in Table 1. Conclusion: Nearly one in three Americans are potentially eligible for tirzepatide for the primary prevention of DM. At current list price, treating the entire population could cost nearly 20 trillion dollars, offset by only 3.4 trillion dollars of savings, yielding a net cost of approximately 16 trillion dollars, or 60% of 2023 US gross domestic product; treatment at the UK list price would result in nearly 500 billion in net savings. Disclosure J.B. Lusk: None. S. Aymes: None. E. OBrien: Research Support; Pfizer Inc. F. Li: None.

Cobalamin

2025-06-21

| Reactions Weekly

PREVALENCE, PATTERNS AND ASSOCIATED FACTORS FOR NEURAL TUBE DEFECT AMONG YOUNG INFANTS ADMITTED AT BUGANDO MEDICAL CENTRE IN NORTHWESTERN TANZANIA: A CROSS SECTION HOSPITAL BASED OBSERVATIONAL STUDY

2025-06-20

Caster Gigwa Justine , Rose Laisser , Florentina Mashuda +7 more | medRxiv (Cold Spring Harbor Laboratory)

ABSTRACT Background In Africa, including Tanzania, the trend for neural tube defects (NTDs) has been increasing, and has been shown to increase morbidity and mortality in young infants. At Bugando … ABSTRACT Background In Africa, including Tanzania, the trend for neural tube defects (NTDs) has been increasing, and has been shown to increase morbidity and mortality in young infants. At Bugando Medical Centre (BMC)-a tertiary hospital serving the population of Northwestern Tanzania, the cases of NTD are commonly reported, but its exact prevalence, patterns and associated factors in young infants admitted at BMC remain unknown. Therefore, this study determined the prevalence, patterns and associated factors for NTD among young infants admitted at BMC. Methodology It is a cross-sectional observational study involving young infants aged 0-3 months admitted at BMC. Ethical approval and clearance to conduct the study was obtained from relevant authority before beginning the study. Since the total number of young infant admitted at the respective BMC premises (E4, neonatal Unit, C5, E5, C6, neonatal intensive care unit, and C2 wards) per month is small, therefore, a census sampling technique to ensure all eligible subjects are included during the study period was chosen. To supplement information on the young infants, a questionnaire-administered questionnaire was used to collect information from the infants’ mothers. Data were managed using Microsoft Excel database, and were cleaned and imported to STATA version 13 for analysis. Multivariate logistic regression analysis done, significant levels was set at p-value less than 0.05. Results A total of 525 young infants were enrolled in the study from February to May 2021, of which 298 (56.8 percent) were male. NTDs was found in 73 (13.9%) of the 525 infants hospitalized at BMC during the study period, and the most common pattern was myelomeningocele 50(68.5%). Failure to use folic acid supplementation during preconception and early first trimester, living in rural residence, lower education and overweight during pre-conception period are the key factors associated with NTD among young infants Conclusion This study demonstrated that NTD is one of the prevalent condition contributing to admission among young infants at BMC. Recommendation BMC should provide regular health education on NTD prevention to all women of reproductive age in the community. The use of folic acid supplement in preconception should be emphasized to all women of reproductive age since folic acid use have been reported to reduce NTD in various studies including the present study.

Plasma Homocysteine Levels and Intracerebral Hemorrhage: A Mendelian Randomization Analysis

2025-06-20

Shu‐Heng Chen , Xiangli Guo , Yingchao He +1 more | Cureus

Dietary choline and betaine intake in relation to psychological disorders in adults

2025-06-20

Shervin Kazeminejad , Zahra Moradmand , Farnaz Shahdadian +3 more | British Journal Of Nutrition

Abstract Dietary choline and betaine, suggested as neuroprotective nutrients, have not been sufficiently studied in relation to psychological disorders. This study aimed to investigate the association between dietary choline and … Abstract Dietary choline and betaine, suggested as neuroprotective nutrients, have not been sufficiently studied in relation to psychological disorders. This study aimed to investigate the association between dietary choline and betaine and common psychological disorders (depression, anxiety, and psychological distress) among Iranian adults. Using a multistage cluster random sampling method, 533 middle-aged adults were included in this cross-sectional study. Dietary intakes were assessed using a validated semi-quantitative 168-item food frequency questionnaire. Depression, anxiety, and psychological distress were evaluated using the Hospital Anxiety and Depression Scale and the General Health Questionnaire, both validated for the Iranian population. Binary logistic regression was applied to explore the associations. Mean age of participants was 42.6±11.14 y; of whom 18.9, 5.1, and 33.4% had depression, anxiety, and psychological distress, respectively. In crude model, the highest intake of choline was negatively associated with depression (OR=0.52; 95%CI: 0.30, 0.91), anxiety (OR=0.38; 95%CI: 0.14, 0.99), and distress (OR=0.60; 95%CI: 0.38, 0.94) compared to the lowest intake. After considering all confounders, such associations remained significant in case of depression (OR=0.51; 95% CI: 0.26, 0.98), but not for anxiety and distress. Additionally, there was no significant association between betaine intake and odds of depression, anxiety, or distress in both crude and adjusted models. This study suggests a protective association between choline intake and depression, while no significant relation was found in case of anxiety and distress. Betaine intake was not related to psychological disorders. Further prospective studies are crucial to replicate these findings.

Genome and transcriptome wide association study identify candidate genes regulating folate levels in maize

2025-06-19

Chenglin Zou , Meng Yang , Aihua Huang +3 more | Frontiers in Plant Science

Background Maize ( Zea mays L.) serves as a crucial dietary source of folate for humans. However, the genetic regulatory mechanisms underlying the natural variation of folate in maize remain … Background Maize ( Zea mays L.) serves as a crucial dietary source of folate for humans. However, the genetic regulatory mechanisms underlying the natural variation of folate in maize remain poorly understood. Here, we integrated multi-omics approaches to elucidate the molecular mechanisms governing folate accumulation in maize. Methods A total of 380 maize kernels representing 190 maize inbred lines from China, Thailand, Mexico, and Peru were collected. RNA-seq was conducted on 380 maize kernel samples, and folate content was quantified using high-performance liquid chromatography (HPLC). The samples were stratified into high and low folate groups based on median folate values. Differentially expressed genes (DEGs) were identified between the two groups identified. Candidate genes associated with folate accumulation were further located by integrating transcriptome-wide association studies (TWAS) and genome-wide association studies (GWAS) analyses. Finally, quantitative real-time PCR (qRT-PCR) was employed to validate the expression patterns of these candidate genes. Results A total of 137 DEGs that exhibited significant differences between the high-folate and low-folate groups were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that these genes were significantly enriched in pathways related to phenylpropanoid biosynthesis, oxidoreductase activity, and stress response. GWAS identified 2,153 candidate genes associated with folate traits ( P ≤ 1.00E-05). Through the integration of DEGs and the intersection of genes identified by GWAS, seven candidate genes were further identified. In addition, TWAS analysis further identified 13 causal genes associated with the candidate genes, which are involved in folate biosynthesis. In addition, the expression levels of these candidate genes were validated by qRT-PCR experiments, suggesting significantly higher expressions in the high folate group compared to the low-folate group. Conclusion This study identifies key regulatory genes potentially influencing folate accumulation in maize and provides critical insights for the development of biofortified maize varieties with enhanced nutritional value.

Association between red blood cell folate and accelerated aging in American adults: a cross-sectional study from the national health and nutrition examination survey

2025-06-19

Jiani Wang , Zhen Song , Cheng Xu +1 more | Frontiers in Nutrition

Objective The study aims to explore the relationship between red blood cell (RBC) folate concentrations and accelerated aging. Methods Data were derived from the National Health and Nutrition Examination Survey … Objective The study aims to explore the relationship between red blood cell (RBC) folate concentrations and accelerated aging. Methods Data were derived from the National Health and Nutrition Examination Survey (NHANES) cycles of 2007–2010, including 8,944 participants aged ≥ 20 years. Phenotypic age acceleration (PhenoAgeAccel) was calculated using chronological age and 9 aging-related biomarkers. Multivariate linear regression and generalized additive models were used to analyze the relationship between RBC folate levels and PhenoAgeAccel. Smooth curve fitting was used to explore the potential non-linear relationship and threshold effect analysis was applied to examine inflection point. Results The analysis revealed a U-shaped relationship between RBC folate levels and PhenoAgeAccel, with the inflection point at 732.9 ng/mL. The PhenoAgeAccel decreased by 0.0027 years per 1 ng/mL increase in RBC folate when RBC folate ≤ 732.9 ng/mL (β: −0.0027, 95% CI: −0.0051, −0.0002), and increased by 0.0058 years per 1 ng/mL increase in RBC folate when RBC folate &gt; 732.9 ng/mL (β: 0.0058, 95% CI: 0.0026, 0.0090). Subgroup analysis indicated consistent associations across most demographic and health categories, except for a positive correlation in participants with cardiovascular diseases. Conclusion There was a U-shaped association between RBC folate and accelerated aging among US adults.

Beyond Folate: The Emerging Role of Maternal Vitamin B12 in Neural Tube Development

2025-06-19

Lirong Nie , Xinru Liu , Xiaoxue Li +5 more | Nutrients

Background/Objectives: Folic acid (FA) supplementation can effectively reduce the occurrence of neural tube defects (NTDs). Vitamin B12 is involved in folate metabolism; however, studies have not reached a definitive conclusion … Background/Objectives: Folic acid (FA) supplementation can effectively reduce the occurrence of neural tube defects (NTDs). Vitamin B12 is involved in folate metabolism; however, studies have not reached a definitive conclusion on the association between vitamin B12 and NTDs independent of folate levels. A systematic review and meta-analysis were performed to summarize existing research and investigate the effect of vitamin B12 on NTDs. Methods: Studies were systematically searched in PubMed, Web of Science, Embase, and Cochrane, published before 1 March 2024. Standardized mean difference (SMD) with 95% confidence interval (CI) was employed to assess the association between maternal vitamin B12 in blood and NTDs. Results: A total of 38 studies were included, with a total of 2316 NTDs and 4298 controls, covering 14 countries worldwide. Compared with the non-NTD group, the NTD group exhibited a lower vitamin B12 level [SMD = -0.23, 95% CI (-0.32, -0.14), p < 0.001, I2 = 58.3%] with a statistically significant difference. Additionally, there was a significant association between maternal vitamin B12 concentration and NTDs when there was no significant difference in folate between the NTD and control groups [SMD: -0.19, 95% CI (-0.28, -0.10)]. Conclusions: Vitamin B12 supplement is also essential for the prevention of NTDs besides folic acid. Monitoring vitamin B12 concentration among pregnant women and considering appropriate supplementation with a combination of vitamin B12 and folic acid could be explored.

Lower dietary folate intake increases the risk of autoimmune thyroiditis

2025-06-19

Lijun Chen , Changjian Yan , Yan Lin +7 more | Frontiers in Nutrition

Background Autoimmune thyroid diseases (AITDs) are a group of organ-specific autoimmune disorders resulting from the loss of immune tolerance, with autoimmune thyroiditis (AIT) being the most common phenotype. In recent … Background Autoimmune thyroid diseases (AITDs) are a group of organ-specific autoimmune disorders resulting from the loss of immune tolerance, with autoimmune thyroiditis (AIT) being the most common phenotype. In recent years, folate, an essential nutrient, has been associated with the onset of various autoimmune diseases. However, the relationship between dietary folate intake and AIT remains unclear. Objective This study seeks to explore the possible link between folate consumption and AIT. Methods This study is based on the 2009–2010 National Health and Nutrition Examination Survey (NHANES) data to analyze the connection between folate consumption and the risk of AIT. A total of 2037 participants were included in the study. Based on TPOAb or TgAb levels, participants were classified into the AIT group ( n = 144) and the non-AIT group ( n = 1893), and clinical variables were compared between these two groups. Univariate and multivariate logistic regression models were employed to examine the relationship between AIT risk and various factors, including demographics, complete blood count, blood biochemistry parameters, thyroid function test, urinary iodine concentration, as well as intakes of vitamin B12 and folate. A diagnostic model for AIT was constructed using dietary folate intake, TSH, age, sex, urinary iodine concentration, and vitamin B12 intake. Results The analysis results indicate that the dietary folate intake of AIT patients was significantly lower than that of the non-AIT group (356.7 ± 172.4 vs. 396.1 ± 200.3mcg/day, p &lt; 0.05). Participants in the high dietary folate intake group showed a 52% lower risk of AIT compared to the low-intake group (OR = 0.48, 95%CI: 0.33–0.71, p &lt; 0.001) in the univariate analysis. This association remained significant after multivariable adjustment (OR = 0.53, 95%CI: 0.35–0.80, p = 0.003). Conclusion This cross-sectional study is the first to explore the association between dietary folate consumption and the likelihood of developing AIT. The results suggest that lower dietary folate intake may be an independent factor contributing to AIT. It may provide new insights for the development of future dietary prevention strategies for AIT.

A case of MTHFR deficiency

2025-06-19

Nv Sunsarachari , J Bindhu Madhavi | International Journal of Contemporary Medicine

IntroductionThis case highlights a rare, potentially treatable cause of adult-onset spastic paraparesis—methylenetetrahydrofolate reductase (MTHFR) deficiency. Early diagnosis of this metabolic disorder is essential to prevent disease progression and irreversible neurological … IntroductionThis case highlights a rare, potentially treatable cause of adult-onset spastic paraparesis—methylenetetrahydrofolate reductase (MTHFR) deficiency. Early diagnosis of this metabolic disorder is essential to prevent disease progression and irreversible neurological damage. This report adds to the limited literature on late-onset MTHFR deficiency, emphasizing the importance of metabolic evaluation in unexplained spastic paraparesis.Patient Concerns and Clinical FindingsChief Complaints:Progressive stiffness in both lower limbs for 1 yearWeakness in both lower limbs for 5 monthsHistory of Present Illness:Difficulty wearing footwear and foot draggingPseudobulbar affectDifficulty walking, climbing stairs, and rising from a squatting positionGeneral Examination:Tall, well-built malePresence of gynecomastiaNeurological Examination:No cranial nerve deficits or sensory lossSpastic gait with Grade 3 spasticityExaggerated deep tendon reflexesBilateral extensor plantar responsesDiagnosis, Interventions, and OutcomeDiagnosis:Adult-onset MTHFR deficiency presenting as spastic paraparesis with hyperhomocysteinemiaInterventions:Anhydrous betaine (targeting homocysteine metabolism)Baclofen (for symptomatic spasticity relief)Outcome:The patient was discharged with improved lower limb strength (power +4/5 bilaterally) and is under regular follow-up for monitoring and ongoing management.Conclusion and Key Take awaysInborn errors of metabolism, including MTHFR deficiency, can manifest in adulthood.MTHFR deficiency, though rare, is a treatable cause of progressive neurological decline.Routine measurement of plasma homocysteine levels in cases of unexplained spastic paraparesis can facilitate early diagnosis and intervention, potentially preventing irreversible neurological damage.

Association between cerebral small vessel disease and malnutrition risk: a retrospective cross-sectional study

2025-06-18

Junyi Liu , Jie Lin , Junling Zhuang +5 more | Frontiers in Neurology

Introduction Malnutrition is associated with increased morbidity and mortality from multiple diseases. However, the relationship between cerebral small vessel disease (CSVD) and malnutrition or malnutrition risk remains underexplored. This retrospective … Introduction Malnutrition is associated with increased morbidity and mortality from multiple diseases. However, the relationship between cerebral small vessel disease (CSVD) and malnutrition or malnutrition risk remains underexplored. This retrospective study investigated the association between malnutrition risk and CSVD, along with its common imaging markers. Methods A total of 806 participants from a neurology department underwent cranial MRI scans and nutritional assessments. The presence of imaging markers of CSVD, including white matter hyperintensities, lacune, perivascular spaces, and cerebral microbleeds, was evaluated by expert neurologists. Malnutrition risk was assessed using the Geriatric Nutritional Risk Index (GNRI) and Controlling Nutritional Status (CONUT) scores. Logistic regression, subgroup, and interaction analyses were performed to evaluate the associations between malnutrition risk, CSVD, and its common imaging markers. Results and discussion After adjusting for potential confounders, patients at risk of malnutrition, as identified by both the GNRI and CONUT scores, exhibited more severe CSVD and its common imaging markers. Further analyses revealed interactions between GNRI score and smoking, highlighting potential modifying effects on the relationship between malnutrition risk and CSVD. Collectively, malnutrition risk, as assessed by objective nutritional indices, is independently associated with CSVD and its common imaging markers. These results emphasize the importance of addressing malnutrition in the prevention and management of CSVD.

Exploring the association of vitamin B12 deficiency and dental health in older adults

2025-06-18

Man Hung , Amir Mohajeri , Jerry Marx +2 more | Frontiers in Nutrition

Background Vitamin B12 plays a crucial role in overall health, yet its impact on dental health, particularly dental caries, remains underexplored. Older adults are at an increased risk of vitamin … Background Vitamin B12 plays a crucial role in overall health, yet its impact on dental health, particularly dental caries, remains underexplored. Older adults are at an increased risk of vitamin B12 deficiency and dental disease, but the relationship between these two factors is not well understood. This study examines the association between serum vitamin B12 levels and dental health in older adults using data from the NHANES 2011–2014 cycles. Methods A cross-sectional analysis was conducted using NHANES data from 1,907 participants aged 65 and older. Serum vitamin B12 levels were categorized as normal (&gt;221 pmol/L), marginal (148–221 pmol/L), and deficient (&lt;148 pmol/L). Dental status was assessed using the Decayed, Missing, and Filled Teeth (DMFT) index based on NHANES dental health examinations. Poisson regression models evaluated associations between vitamin B12 levels and DMFT scores, adjusting for age, sex, race/ethnicity, education, and income. Results Lower vitamin B12 levels were significantly associated with higher DMFT scores ( p &lt; 0.05). Participants with marginal and deficient vitamin B12 levels exhibited increased DMFT scores compared to those with normal vitamin B12 levels, and these differences persisted after adjusting for demographic and socioeconomic factors. The findings suggest that inadequate vitamin B12 status may contribute to a greater cumulative burden of dental disease in older adults. Conclusion These findings suggest that vitamin B12 deficiency may contribute to a greater lifetime burden of dental disease in older adults. Further research is needed to explore causal mechanisms and assess whether vitamin B12 supplementation could be a preventive measure for maintaining dental health in aging populations.

[Association between maternal periconceptional supplementation of folic acid or multiple micronutrients containing folic acid and perinatal mortality rate].

2025-06-18

Chen Liu , Li Z , Lei Jin +2 more | PubMed

To describe the prevalence of perinatal death in Tongzhou District of Beijing, and to estimate the association between maternal periconceptional supplementation of folic acid or multiple micronutrients containing folic acid … To describe the prevalence of perinatal death in Tongzhou District of Beijing, and to estimate the association between maternal periconceptional supplementation of folic acid or multiple micronutrients containing folic acid and perinatal mortality rate. A retrospective cohort study was conducted based on the maternal and child care system in Tongzhou District of Beijing. The subjects were 94 490 perinatal who were born during January 2013 to December 2018. The information on perinatal outcomes and maternal periconceptional supplementation of folic acid or multiple micronutrients containing folic acid were collected. The Poisson log-linear model was used to estimate the association between maternal periconceptional folic acid or multiple micronutrients supplementation and perinatal mortality rate. The overall perinatal mortality rate was 2.71‰. The perinatal mortality rates for maternal nutrients supplementation containing folic acid and no supplementation during periconceptional period were 2.63‰ and 3.43‰, respectively, and the difference in rates was not statistically significant [crude risk ratio (cRR) = 0.77, 95%CI: 0.54-1.14]. After adjusting for potential confounding factors including ethnicity, age, education level, occupation, household registration, parity, numbers of fetuses, gestational age, pregnant with assisted reproductive technology, delivery year and pre-pregnancy body mass index, the rates remained not statistically significant [adjusted risk ratio (aRR) = 0.93, 95%CI: 0.77-1.13]. The perinatal mortality rates were 2.23‰ and 2.99‰ for pure folic acid and multi-nutrients supplements containing folic acid, respectively, and the difference in rates was statistically significant (cRR = 1.34, 95% CI: 1.02-1.76). The rates difference remained statistically significant after adjusting for potential confounders (aRR = 1.31, 95% CI: 1.06-1.62). Additionally, the perinatal mortality rates differences among the non-supplementation group and the supplementation group with variate timing of initiation (pre-conception or post-conception) or frequency of supplementation (low-frequency or high-frequency) were not statistically significant, regardless of adjusting for confounders. The overall perinatal mortality rate was lower than the national average level in Tongzhou District of Beijing. Maternal periconceptional supplementation of pure folic acid or micronutrients containing folic acid had no impact on perinatal mortality. The association between maternal periconceptional supplementation of multiple micronutrients containing folic acid and perinatal mortality rate need further research.

Vitamina B12 como coadjuvante no tratamento de distúrbios depressivos: revisão integrativa

2025-06-18

Mauro de Meló Júnior , Pedro Sousa , Irineu da Silva +7 more | OBSERVATÓRIO DE LA ECONOMÍA LATINOAMERICANA

A deficiência de vitamina B12 tem sido associada ao desenvolvimento e à piora de sintomas depressivos, devido às suas funções essenciais no sistema nervoso central, como a síntese de neurotransmissores … A deficiência de vitamina B12 tem sido associada ao desenvolvimento e à piora de sintomas depressivos, devido às suas funções essenciais no sistema nervoso central, como a síntese de neurotransmissores e a regulação dos níveis de homocisteína. Diante disso, este estudo teve como objetivo compreender a influência da vitamina B12 no controle e tratamento da depressão, analisando sua relevância como fator complementar. Foi realizada uma revisão integrativa da literatura, com análise de artigos publicados em português e inglês nos últimos dez anos, incluindo estudos pré-clínicos e clínicos. Os resultados demonstraram que uma alimentação equilibrada, com níveis adequados de folato e vitamina B12, está relacionada à redução dos sintomas depressivos. Em contrapartida, dietas pobres nesses nutrientes agravam o quadro. Estudos com modelos animais mostraram que a suplementação de B12 pode reverter efeitos do estresse, e investigações clínicas identificaram baixos níveis da vitamina em mulheres com depressão. Além disso, a ingestão adequada de B6, B12 e selênio apresentou associação com menor incidência de depressão. Conclui-se que a vitamina B12 possui papel relevante na saúde mental e pode atuar como coadjuvante no tratamento da depressão, embora mais estudos sejam necessários para confirmar essa associação.

Perinatal palliative care in an infant with exencephaly: Supporting life beyond 3 years of age

2025-06-17

G. Bayo Varão , Elvira Parravicini , Aleha Aziz +1 more | Journal of Neonatal-Perinatal Medicine

Neural tube defects are the second most common type of fetal malformation in humans. Encephalocele, a type of neural tube defect, can be defined as a sack-like protrusion of brain … Neural tube defects are the second most common type of fetal malformation in humans. Encephalocele, a type of neural tube defect, can be defined as a sack-like protrusion of brain tissue herniating through an opening hole in the skull. Its prognosis depends on the location, size, the amount of brain tissue involved, and the presence of other intracranial anomalies. Exencephaly, another type of neural tube defect, is characterized by an incomplete covering of the skull, resulting in an exposed fetal brain. It is described in the literature as incompatible with extrauterine life and, in most cases, evolves into anencephaly before birth. We present the case of a newborn that was diagnosed at 13 weeks of gestational age with encephalocele, which later in pregnancy converted into exencephaly. The parents chose an approach of comfort/palliative care; the child is still alive at 3 years of age. This case highlights how perinatal palliative care can help manage patients with neural tube defects and optimize family outcomes.

Association of MTHFR Gene Variants (rs1801133 and rs1801131) with Serum Trace Elements Copper and Zinc and Biochemical Parameters (Homocysteine, Folic Acid, and Vitamin B12) in Individuals with Short Stature

2025-06-17

Abhay Kumar Yadav , Ankur Singh , Ashish Ashish +7 more | Research Square (Research Square)

<title>Abstract</title> <bold>Background:</bold> Human height generally follows a normal distribution; thus, short stature is defined as height below the 3rd percentile or 2 standard deviations (SD) from the mean. Homocysteine metabolism, … <title>Abstract</title> <bold>Background:</bold> Human height generally follows a normal distribution; thus, short stature is defined as height below the 3rd percentile or 2 standard deviations (SD) from the mean. Homocysteine metabolism, which involves folate and vitamin B12, is regulated by the methylenetetrahydrofolate reductase (MTHFR) enzyme. This study aimed to investigate the association of MTHFR polymorphisms with trace elements (copper and zinc), homocysteine, folic acid, and vitamin B12 in children with short stature. <bold>Methods:</bold> A total of 280 participants (130 short stature cases and 150 healthy controls), aged 4–12 years, were included. Serum homocysteine, folic acid, and vitamin B12 were measured using ELISA. MTHFR polymorphisms (rs1801133 and rs1801131) were genotyped using TaqMan® SNP Genotyping Assay via RT-PCR. Copper and zinc levels were measured by atomic absorption spectrophotometry. <bold>Results:</bold> The MTHFR rs1801133 polymorphism showed a significant association with short stature, with individuals carrying the TT genotype exhibiting higher homocysteine levels (26.3 ± 9.6 µmol/L), and lower folic acid (22.4 ± 4.3 ng/mL) and B12 levels (194.4 ± 27.9 pg/mL) compared to controls (p < 0.001). The TT genotype was also associated with higher copper (110.4 ± 14.94 µg/dL) and lower zinc levels (65.88 ± 16.69 µg/dL) in cases versus controls (p < 0.001). No significant association was observed for rs1801131. <bold>Conclusion:</bold> The MTHFR rs1801133 (TT genotype) is associated with elevated homocysteine, altered trace elements, and increased risk of short stature. These findings highlight the role of genetic and nutritional factors in growth regulation.

Recurrent Venous Thrombosis in an Adolescent Male with CBS Mutation and Persistent Antiphospholipid Antibody Positivity: A Case Report

2025-06-16

Yuebing Wang , Ru Li , Chun Li | Research Square (Research Square)

<title>Abstract</title> Homocysteine (Hcy) contributes to endothelial dysfunction and impaired thrombolysis, and genetic polymorphisms that elevate plasma Hcy concentrations have been linked to an increased risk of thrombosis. Notably, mutations in … <title>Abstract</title> Homocysteine (Hcy) contributes to endothelial dysfunction and impaired thrombolysis, and genetic polymorphisms that elevate plasma Hcy concentrations have been linked to an increased risk of thrombosis. Notably, mutations in the cystathionine β-synthase (CBS) gene, which reduce enzymatic activity, are a well-established cause of hyperhomocysteinemia (HHcy). This case report presents a 15-year-old male with recurrent, severe deep vein thrombosis (DVT) of the lower extremities, accompanied by persistent positivity for antiphospholipid antibodies. Laboratory evaluation revealed elevated homocysteine levels and mutations in the CBS gene, highlighting an underlying genetic predisposition. The persistent presence of antiphospholipid antibodies further underscores the multifactorial nature of his thrombophilic condition, involving genetic, metabolic, and autoimmune mechanisms.

Effect of Inorganic Components of Soy on Phosphatase and Transaminase Activity in Oral Fluid

2025-06-15

A.T. Mamaeva , Еshiev A.M. , Жоомарт Молдалиев | Bulletin of Science and Practice

This article deals with the influence of inorganic components of nasvay on phosphatase and transaminase activity in oral fluid. The aim of the study was to investigate different ways of … This article deals with the influence of inorganic components of nasvay on phosphatase and transaminase activity in oral fluid. The aim of the study was to investigate different ways of nasvay consumption and their influence on the mineral composition (Ca, P, F, Fe) of hard tissues of teeth, saliva and blood in persons consuming this product. In the course of the work, the trace element composition of dental cement was analyzed in 30 people who regularly consumed nasvay with a control group of 20 people who did not use this product. The results of the study confirmed the negative effect of nasvay on the composition and properties of oral fluid. A decrease in the content of inorganic trace elements such as calcium, phosphorus and iron was found, which is accompanied by a decrease in the rate of saliva secretion and a decrease in its pH. These changes negatively affect the processes of enamel remineralization, disturb the acid-alkaline balance and increase the risk of caries development. In addition, changes in the activity of oral fluid enzymes have been revealed: an increase in the activity of acid phosphatase and a decrease in enzyme activity under the influence of fluorides, oxalates and phosphates have been registered. The most probable reason for the increase in alkaline phosphatase activity is the change in calcium and phosphorus levels, which contributes to the formation of dental deposits and the development of pathological processes in the hard tissues of teeth.

1278-P: Comparison of Hepatic Steatosis and Fibrosis Indices between Patients with Werner Syndrome and Type 2 Diabetes

2025-06-13

Makoto Miyabayashi , MASAYA KOSHIZAKA , YOSHIRO MAEZAWA +1 more | Diabetes

Introduction and Objective: Werner syndrome (WS) is a rare genetic disease associated with insulin-resistant (IR) diabetes. Approximately 30% of patients with WS develop fatty liver. This study aimed to compare … Introduction and Objective: Werner syndrome (WS) is a rare genetic disease associated with insulin-resistant (IR) diabetes. Approximately 30% of patients with WS develop fatty liver. This study aimed to compare fatty liver in patients with WS and patients with type 2 diabetes (T2D). Methods: Data from 51 patients with WS in a registry were compared with 98 patients with T2D from another clinical trial. Hepatic steatosis indices included the Fatty Liver Index (FLI), Hepatic Steatosis Index (HSI), and non-alcoholic fatty liver disease-liver fat score (NAFLD-LFS). Fibrosis indices included the aspartate transferase to platelet ratio index (APRI) and fibrosis (FIB)-4 index. The Homeostatic Model Assessment of IR (HOMA-IR) score was analyzed for both groups, alongside its correlation with liver indices. Results: FLI, HSI, and FIB-4 indices were lower in patients with WS than in patients with T2D (P&lt;0.001; P&lt;0.001; P=0.003, respectively). NAFLD-LFS and APRI scores showed no significant difference. Liver steatosis and fibrosis were milder in patients with WS. HOMA-IR scores were similar between groups but highly correlated with LFS (WS: r=0.975; T2D: r=0.805). Conclusion: We found differences in the hepatic steatosis and FIB-4 indices between patients with WS and T2D, both of which were associated with IR. Despite having the same level of IR, steatosis was less in patients with WS, suggesting that they may still develop severe metabolic disorders. Some indices require age and body mass index (BMI) for calculation and, because liver damage occurs in patients with WS at a younger age and with a lower BMI, a different cutoff value may be necessary for accurately evaluating WS. Disclosure M. Miyabayashi: None. M. Koshizaka: None. Y. Maezawa: Research Support; NTT DOCOMO. K. Yokote: None.

1458-P: The Relationship between Insulin Resistance Indices and Hypothyroidism among 10 Million Chinese Adults

2025-06-13

Dan Shen , MAN SAILIMAI , Xiaochen Yang +4 more | Diabetes

Introduction and Objective: Metabolic score for insulin resistance (METS-IR) and triglyceride glucose (TyG) are convenient insulin resistance (IR) indices, however, evidence on their association with hypothyroidism is scarce. This study … Introduction and Objective: Metabolic score for insulin resistance (METS-IR) and triglyceride glucose (TyG) are convenient insulin resistance (IR) indices, however, evidence on their association with hypothyroidism is scarce. This study aimed to investigate the association between IR indices and hypothyroidism, as well as their discriminative abilities. Methods: This nationwide, cross-sectional study utilized data from the Meinian Health Check-up database. A total of 10,357,932 adults who had health check-ups between 2017 and 2023, including those with hypothyroidism and those with normal thyroid function were analyzed in this study. Overt hypothyroidism (OHypo) was defined as an elevated thyroid stimulating hormone (TSH) with reduced free thyroxine (FT4), whereas an elevated TSH with normal FT4 was considered subclinical hypothyroidism (SHypo). Results: Both METS-IR and TyG were statistically significant associated with an increased risk of OHypo and SHypo across quartiles and showed non-linear “J-shape” associations (Figure 1). The area under receiver operating characteristics curve of both IR indices were the same (0.75 for OHypo and 0.65 for SHypo). Similar associations and discriminative abilities were found in participants with or without prediabetes and diabetes. Conclusion: Hypothyroidism is linked to IR. METS-IR and TyG has a better discriminative performance for OHypo. Disclosure D. Shen: None. M. Sailimai: None. X. Yang: None. C. Yu: None. L. Li: None. B. Wang: None. J. Lv: None.

Mendelian randomization study of micronutrients and development of CKD in a Korean population

2025-06-13

Juyeon Lee , Sangjun Lee , Kook‐Hwan Oh +1 more | Nutrition Journal

Paternal Preconception Metformin Use and Offspring Risk of Congenital Malformations

2025-06-12

Krista F. Huybrechts , Loreen Straub , Ran S. Rotem +2 more | JAMA Network Open

This cohort study examines whether paternal exposure to metformin during spermatogenesis is associated with major congenital malformations in children. This cohort study examines whether paternal exposure to metformin during spermatogenesis is associated with major congenital malformations in children.

Dietary pattern and nutritional assessment in a cohort of mothers identified by neonatal screening for cobalamin deficiency in offspring: an Italian single center experience

2025-06-04

Martina Tosi , Veronica Maria Tagi , A. Colombo +7 more | Frontiers in Nutrition

During pregnancy, nutrient requirements increase while deficiencies can significantly affect pregnancy outcomes. Deficiencies may result from inadequate dietary intake, impaired absorption, or restrictive diets. This study aimed to retrospectively assess … During pregnancy, nutrient requirements increase while deficiencies can significantly affect pregnancy outcomes. Deficiencies may result from inadequate dietary intake, impaired absorption, or restrictive diets. This study aimed to retrospectively assess the nutritional status and dietary intakes in a cohort of mothers whose newborns were identified with vitamin B12 deficiency of maternal origin through Newborn Screening. Between 2021 and 2024, 107 newborn-mother dyads with altered biomarkers of cobalamin metabolism were identified and referred to the Metabolic Disease Unit for further evaluation and treatment. Mothers underwent biochemical assessments and nutritional interviews regarding pregnancy diet history, and dietary intakes were quantified using a dedicated software (MetadietaVR). Most of the cohort (47%) was from Asia, with an average age of 32.5 years. Plasma vitamin B12 levels averaged 240 pg/ml. Mothers who reported taking vitamin B12 supplements had higher plasma levels compared to those who did not supplement with B12 (255.5 ± 113 vs. 231.2 ± 104 pg/ml). Dietary habits during pregnancy revealed that 71% of mothers were omnivorous (O), 16% followed a lacto-vegetarian (LV) diet, 12% a lacto-ovo-vegetarian (LOV) diet, and 1% a vegan (V) diet. Most mothers (90%) were taking supplements during pregnancy, with 70.7% taking folic acid, 68.7% iron and 15% vitamin B12. Among women who achieved adequate vitamin B12 intake through both diet and supplementation, 95% were omnivores while 5% followed a LOV diet. This study emphasizes the importance of addressing maternal nutritional needs from the pre-conception period, as dietary patterns may not adequately reflect micronutrient intake. Even omnivorous diets, if unbalanced, can result in insufficient nutrient intake, underlying the necessity of targeted nutritional support during pregnancy.