Epidemiology of Homocysteine Levels and Relation to Vitamins

In the present study, we assessed the relationship between serum folate, vitamin B12, and homocysteine levels and clinical response in patients with major depressive disorder (MDD) who had previously failed to respond to open treatment with fluoxetine 20 mg/day and were enrolled in a 4-week, double-blind trial of either (1) fluoxetine dose increase, (2) lithium augmentation of fluoxetine, or (3) desipramine augmentation of fluoxetine. Fifty-five outpatients (mean +/- SD age = 41.7 +/- 10.6 years; 50.9% women) with MDD as assessed with the Structured Clinical Interview for DSM-III-R who were enrolled in the double-blind trial had serum folate, vitamin B12, and homocysteine measurements completed at baseline (prior to fluoxetine treatment initiation). Folate levels were classified as either low (< or = 2.5 ng/mL) or normal. Vitamin B12 levels were classified as either low (< or = 200 pg/mL) or normal. Homocysteine levels were classified as either elevated (> or = 13.2 micromol/L) or normal. With the use of a logistic regression, we then assessed the relationship between (1) low or normal folate levels, (2) normal or low B12 levels, and (3) elevated or normal homocysteine levels and clinical response to double-blind treatment. The study was conducted from November 1992 to January 1999. Low serum folate levels (chi2=3.626, p =.04), but not elevated homocysteine (p >.05) or low vitamin B12 levels (p >.05), were associated with poorer response to treatment. The response rates for patients with (N = 14) and without (N = 38) low folate levels were 7.1% versus 44.7%, respectively. Low serum folate levels were found to be associated with further treatment resistance among patients with fluoxetine-resistant MDD.

Folate and Vitamin B6 Intake and Risk of Colon Cancer in Relation to p53 Expression

The homocysteine level is considered to be a product of genetic and lifestyle interactions, mainly mutated methylenetetrahydrofolate reductase (MTHFR) and the intake of folate, vitamin B12 and pyridoxine, and their blood levels. Physical activity has been associated with lower homocysteine levels in some population studies, especially among elderly subjects. To further elucidate the observed association between homocysteine and physical activity, while accounting for the effect of the MTHFR C677T genotype, and of plasma levels of folate and B12 vitamins, a cross-sectional study of 620 males and females, aged 70.5 +/- 6.8 years, was carried out. Information on lifestyle habits was collected and laboratory examinations of 12-h fasting total plasma homocysteine, folate, and vitamin B12, as well as DNA analysis for MTHFR C677T variant, were performed. Median total homocysteine values were 11.4 micromol/l for males and 9.4 for females; p < 0.001. Smoking and ethnic origin were not found to be associated with homocysteine levels. Physically active subjects had significantly lower total homocysteine levels when adjusted for sex (p = 0.01). Significant inverse correlations were found between body mass index, plasma folate, B12 and homocysteine levels. Homocysteine levels of the CC, CT and TT genotypes were 9.7, 10.6 and 10.2 mumol/l, respectively (p = 0.002, controlling for sex). In a multiple linear regression model, a sedentary lifestyle increased homocysteine levels by 7% as compared to an active one (p = 0.03) controlling for sex, age, body mass index, folate, vitamin B12, and C677T genotype, all of which were also found to be significantly associated with homocysteine levels. Any level of physical activity was found to be independently associated with lower homocysteine levels in an elderly population, controlling for MTHFR genotype, plasma B-vitamins, age, sex, smoking and BMI. This study emphasizes the importance of maintaining a physically active lifestyle in the elderly.

ObjectiveThis study was conducted to confirm the results of the authors' previous research on schizophrenia manifesting high serum homocysteine and low folate levels. This study is anchored on a theory that a high serum homocysteine concentration affects schizophrenia by virtue of a neurotoxic mechanism, and on a report that some schizophrenia patients with high homocysteine levels benefited from high folate ingestion.MethodsThe serum homocysteine, folate, and vitamin B12 levels of 236 normal-control-group subjects and 234 schizophrenia subjects who met the diagnostic criteria based on DSM-IV-TR were compared. The homocysteine levels were measured via fluorescence polarization immunoassay, and the folate and vitamin B12 levels were determined via radioimmunoassay.ResultsThe homocysteine levels of the patient group were significantly higher than those of the normal control group. The homocysteine level was more negatively correlated with the folate level in the schizophrenia group than in the control group. The percentages of female and male schizophrenia subjects manifesting high homocysteine levels were 33.8 and 51.5%, respectively. The percentage of schizophrenia subjects with low folate levels was 66.2%. In the low- and normal-folate-level groups, the patient group showed significantly higher homocysteine levels than the normal control group. The low-folate-level patient group particularly showed significantly higher homocysteine levels than the low-folate-level normal control group.ConclusionSome schizophrenia patients with high serum homocysteine levels may have the genetic defect of having low folate serum levels. In such cases, folate ingestion may be a good management modality for clinical improvement.

Methylenetetrahydrofolate reductase genotype, vitamin B12, and folate influence plasma homocysteine in hemodialysis patients.

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Hyperhomocysteinemia is an independent predictor of the risk for cognitive decline and may be a result of low levels of vitamins B12 , B6 , and folate. Previous findings suggest that adequate intake of these vitamins may reduce homocysteine levels. This review aimed to assess the effects of treatment with vitamins B6, B12 , and/or folic acid in the homocysteine levels in patients with mild cognitive impairment (MCI). A systematic literature review was conducted in EMBASE, MEDLINE®, PsycINFO, and Cochrane Central Register of Controlled Trials. The research question was formulated using the Population, Intervention, Comparison, and Outcome (PICO) framework: in patients with MCI (P); what is the efficacy of vitamins B6 , B12 , and/or folic acid intake (I); compared with baseline values, and/or compared with controls (C); in reducing homocysteine levels from baseline (O). A total of eight primary studies with a total of 1,140 participants were included in the review. Four were randomized controlled trials, one was a quasi-controlled trial, and three were observational studies. All studies included folic acid in their intervention, seven vitamin B12 , and four vitamin B6 . Mean (SD) length of the intervention period was 18.8 (19.3) months, ranging from 1 to 60 months. All studies showed a statistically significant decrease in homocysteine levels in groups treated with vitamins B6, B12 , and/or folic acid compared to controls, with a mean decline of homocysteine concentration of 31.9% in the intervention arms whereas it increased by 0.7% in the control arm. This review identified evidence of a reduction of plasma homocysteine levels in MCI patients taking vitamins B6, B12 , and/or folic acid supplements, with statistically significant declines being observed after 1 month of supplementation. Findings support that supplementation with these vitamins might be an option to reduce homocysteine levels in people with MCI and elevated plasma homocysteine.

BackgroundVitamin B12, vitamin B6 and folic acid are homocysteine-reducing agents. People with schizophrenia have been found to have increased homocysteine levels. Elevated homocysteine has been associated with impaired cognition. Previous research in chronic schizophrenia has shown that supplementation with folate plus vitamin B12 can improve cognition and clinical symptoms. Whether homocysteine lowering agents are effective in first-episode psychosis is unknown. The aim of this study was to investigate if adjunctive vitamin B12, B6 and folic acid can lower homocysteine and improve symptomatology and cognition in people with first-episode psychosis.MethodsThis was a randomised, double-blind, placebo-controlled trial conducted at the Early Psychosis Prevention and Intervention Centre (EPPIC) in Melbourne, Australia. One hundred and twenty patients aged 15–26 years with first-episode psychosis consented and were randomised to receive folic acid 5mg, vitamin B12 0.4mg, and vitamin B6 50mg or placebo, each taken once-daily for 12 weeks as an adjunct to antipsychotic medication. Co-primary measures were change in cognition as measured by a composite score from a battery of 11 tests and total symptomatology (PANSS) over 12 weeks. Secondary outcomes included additional cognitive, symptom, functioning, tolerability and safety measures.ResultsOf the 120 participants randomised in the study, 20 dropped out with no follow-up assessments and were excluded from analysis. Of the remaining 100 participants, 52 were in the vitamins group and 48 the placebo group. At baseline, the two treatment groups had lower levels of folate and vitamin B12 intake than healthy controls, but did not differ from each other. Vitamin B12, B6 and folic acid reduced homocysteine levels in the vitamin group over 12 weeks. The homocysteine lowering effects of the vitamins did not confer a major advantage over placebo therapy in improving the co-primary PANSS (p=.75) or composite cognition (p=0.79) outcomes over 12 weeks. There was a significant difference between groups among females in the cognitive domain of speed of processing (p=.049) and attention/vigilance (p=0.002), in which the mean performance of the placebo group declined over 12 weeks, whereas performance in the vitamin group remained showed improvement.DiscussionFolic acid, B12 and B6 supplementation appears well tolerated and safe in first-episode psychosis and lowers homocysteine levels in this population. However, supplementation may not offer extra benefits to all patients with first-episode psychosis, with the possible exception of speed of processing and attention/vigilance. Although previous research suggests that males preferentially benefit, our findings suggest that there may be a specific beneficial effect on cognition for females with first-episode psychosis.

Predictive Factors of Hyperhomocysteinemia in HIV-Positive Patients

In the present study, we assessed the relationship between serum folate, vitamin B12, and homocysteine levels on the rate of relapse in outpatients with remitted major depressive disorder (MDD) during a 28-week continuation phase of treatment with fluoxetine. Seventy-one outpatients (mean +/- SD age = 40.2 +/- 11.1 years; 56.3% women) with MDD (as assessed with the Structured Clinical Interview for DSM-III-R) who had remitted and who were enrolled in the continuation phase of treatment with fluoxetine had serum folate, vitamin B12, and homocysteine measurements completed at baseline (prior to acute-phase treatment). Patients were followed for 28 weeks of continued treatment with fluoxetine 40 mg/day to monitor for depressive relapse. Folate levels were classified as either low (< or = 2.5 ng/mL) or normal. Vitamin B12 levels were classified as either low (< or = 200 pg/mL) or normal. Homocysteine levels were classified as either elevated (> or = 13.2 micromol/L) or normal. With the use of separate logistic regressions, we then assessed the relationship between folate, vitamin B12, and homocysteine level status and relapse. The study was conducted from November 1992 to January 1999. The presence of low serum folate levels (p =.004), but not low B12 (p >.05) or elevated homocysteine levels (p >.05), was associated with relapse during continuation treatment with fluoxetine. The relapse rates for patients with (N = 7) and without (N = 64) low folate levels were 42.9% versus 3.2%, respectively. Low serum folate levels were found to place patients with remitted MDD at risk for depressive relapse during the continuation phase of treatment with fluoxetine.

Disorders in the metabolism of homocysteine and B vitamins, which are involved in a one-carbon transfer reaction and important for DNA synthesis and methylation, have been hypothesized to be associated with carcinogenesis. The purpose of this study is to evalu-ate the levels of homocysteine, vitamin B12 and folic acid in patients with newly diagnosed lung cancer and determines whether they might be used as an accurate tumor marker for monitoring the patients if they are found to be elevated in lung cancer. Forty male patients with lung cancer were included in this study. Age-matched forty healthy males who had not malignant disease or had not received any drug affecting plasma homocysteine levels were selected as control group. Homocysteine, vitamin B12 and folate levels were measured in the samples obtained from the patients and controls. Mean age of the patients with lung cancer was 58.7 ± 9.9 years. All the patients were cigarettes smokers. Mean daily consumption of cigarettes was 2.0±0.7 packs and mean duration of smoking was 30 ± 11 years. Histologic type of carcinoma was found to be squamous cell carcinoma in 55%, adenocarcinoma - in 35%, and small cell carcinoma - in 10% of the cases. Clinical stage was stage IA in 20%, stage IB - in 20%, stage IIA - in 2.5%, stage IIB - in 10%, stage IIIA - in 12.5%, stage IIIB - in 20%, and stage IV - in 15% of the cases. Mean homocysteine level was 15.3 ± 7.3 µmol/l in the patients with lung cancer while 9.8 ± 2.6 µmol/l in controls. Homocysteine level was significantly higher in the patients with lung cancer compared to control group (p < 0.001). Mean folate level was 4.3 ± 1.8 pg/ml in cancer cases while 6.1 ± 2.3 pg/ml in controls. That is to say, plasma folate levels were significantly lower in cases of lung cancer compared to controls (p < 0.001). There was no significantly difference between groups with regard to B12 levels (mean B12 level was 234 ± 99 and 240 ± 104 ng/ml in the patients with lung cancer and controls, respectively, p = 0.78). Plasma homocysteine, vitamin B12 and folate levels did not show significant difference with respect to histologic type of carcinoma. No significant correlation was found between plasma homocysteine, vitamin B12, folate levels and number of cigarettes smoked per day, duration of smoking, age of the patient, and clinical stage of carcinoma. There was also no correlation between number of cigarettes smoked per day, duration of smoking, age of the patient and clinical stage of carcinoma. A possible inverse correlation between plasma homocysteine, vitamin B12 and folate levels was not observed. In conclusion, high plasma homocysteine and low folate levels could be associated with lung cancer. However, further studies performed on large patient population are needed.

Patients with psoriasis are at increased risk for cardiovascular comorbidities. Previous studies examined the possible contribution of serum homocysteine, folate and vitamin B12 to cardiovascular risks in patients with psoriasis but had conflicting conclusions. To perform a systematic review and meta-analysis of studies on serum homocysteine, folate and vitamin B12 levels in patients with psoriasis. Online databases were searched on 15 February 2018 to include studies comparing serum homocysteine, folate and vitamin B12 levels between patients with psoriasis and controls. A random effects model was adopted to estimate odds ratios for dichotomous data and standardized mean differences (SMDs) for continuous data. A comprehensive literature search identified 24 studies eligible for inclusion. Compared with controls, patients with psoriasis had a significantly higher serum homocysteine level [SMD 0·41, 95% confidence interval (CI) 0·21-0·61; I2 = 76·7%, 18 studies], a higher prevalence of hyperhomocysteinaemia (odds ratio 3·48, 95% CI 2·08-5·83; I2 = 41·1%, seven studies) and a lower serum folate level (SMD -0·94, 95% CI -1·49 to -0·40; I2 = 95·6%, 14 studies). However, there was no difference in serum vitamin B12 levels between patients with psoriasis and the control group (SMD 0·004, 95% CI -0·49 to 0·50; I2 = 92%, 11 studies). Metaregression analysis revealed a significant inverse correlation between the SMD of homocysteine levels and folate levels. Patients with psoriasis might have higher serum homocysteine and lower folate levels than control patients without psoriasis. However, due to significant heterogeneity and other limitations, the associations require further examinations in more studies.

Patients with psoriasis have an increased risk of coronary heart disease and stroke. It has been suggested that psoriasis causes raised blood levels of homocysteine. High levels of homocysteine are linked to atherosclerosis (“furring up” of the arteries). The breakdown of homocysteine is dependent on folic acid and vitamin B12. Low blood levels of folic acid have been reported in psoriasis, partly due to its consumption by increased cell turnover in the skin and partly due to reduced absorption in the gut. The authors, based in Taiwan, reviewed the published studies and confirmed that patients with psoriasis indeed had high levels of homocysteine and low levels of folic acid in their blood compared with controls (people without psoriasis). There was no difference in the blood levels of vitamin B12 between psoriasis patients and controls. The authors express a note of caution, since many other confounding factors may affect the results. However, they recommend testing homocysteine blood levels in psoriatic patients to identify those at risk of cardiovascular disease. Further studies are recommended, particularly to investigate whether giving folic acid or vitamin B12 reduces the risk of these complications.

Background: Folate and other nutrients in the one-carbon metabolism pathway play essential roles in DNA synthesis and methylation, and may be critically involved in carcinogenesis. Low folate intake has been linked to the development of breast, colorectal and pancreatic cancer, and the effect may be modulated by other factors such as alcohol drinking and smoking. Up to date, few cohort studies have investigated the intakes of folate and related nutrients in relation to gastric and esophageal cancer. Method: We examined the association between the intakes of folate, methionine, and vitamin B6 and B12 and gastric and esophageal cancer in the National Institutes of Health–AARP Diet and Health Study (492,293 men and women, aged 50 to 71 at baseline in 1995-1996). Dietary and supplemental intakes of such nutrients were assessed with a food frequency questionnaire at baseline. Total intake is a sum of dietary and supplemental intakes. Cancer cases were ascertained by linkage to state cancer registries. A multivariate Cox proportional hazard model was used to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results: During an average of 9 years of follow up, we identified 815 and 935 incident cases of esophageal and gastric cancer, respectively. The median intake of dietary folate in the lowest (Q1), the middle (Q3) and the highest quintile (Q5) were 275, 405, and 595 mcg/d, respectively. Compared to Q3, Q1 of dietary folate intake was associated with a significantly higher risk of esophageal cancer (RR =1.33, 95% CI, 1.08, 1.64), while no further risk reduction was observed in Q5 (RR =1.01, 95% CI, 0.79, 1.28). The elevated risk in Q1 in relation to Q3 was more pronounced in esophageal squamous cell carcinoma (RR =1.91, 95% CI, 1.17, 3.10) than in esophageal adenocarcinoma (RR =1.22, 95% CI, 0.96, 1.54), and was observed across subgroups of alcohol consumption and smoking (RR (95% CI): 1.49 (0.95, 2.33) in nondrinkers, 1.25 (0.91, 1.72) in drinkers of &amp;gt;0-15 g/d of alcohol consumption, and 1.33 (0.92, 1.91) in drinkers of &amp;gt;15 g/d; and 1.29 (0.76, 2.18) in never smokers and 1.29 (1.02, 1.63) in ever smokers). Among other nutrients, low dietary intake of vitamin B6 was also associated with increased risk of esophageal cancer (Q1 vs. Q3: RR =1.30, 95% CI, 1.05, 1.61), and gastric cancer (Q1 vs. Q3: RR =1.22, 95% CI, 0.99, 1.50). There was a similar L-shaped association between esophageal cancer and total intake of folate and vitamin B6. No association was observed with methionine or vitamin B12. Conclusion: Our findings suggest that low intake of folate and vitamin B6 was associated with increased risk of esophageal cancer while higher intake of these nutrients did not provide additional benefits. Citation Format: Qian Xiao, Jiansong Ren, Christian Abnet, Yikyung Park. Intakes of folate, methionine, and vitamin B6 and B12 and risk of esophageal and gastric cancer in a large cohort study. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A105.

Elevated plasma homocysteine level is associated with coronary artery disease (CAD). Homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is typically but inconsistently associated with hyperhomocysteinemia. We examined the impact of daily intake of folate, a co-factor in homocysteine metabolism, on plasma homocysteine and folate levels in CAD patients in relation with MTHFR genotypes. Daily folate intake was assessed from 3-day food records in 99 patients with CAD: 35 with the T/T (homozygous mutant) genotype and 64 with the C/C or C/T (non-T/T) genotypes. Patients with the T/T genotype had higher fasting plasma homocysteine levels (18.4±1.9 vs. 12.6±0.6 μmol/l, P=0.01) and lower plasma folate levels (17.8±1.7 vs. 20.8±1.0 nmol/l, P=0.02). There were no differences between the genotype groups in energy-adjusted folate intake. In patients with the non-T/T genotypes, higher folate intake was associated with higher plasma folate levels and lower plasma homocysteine levels. In T/T homozygotes this association was weaker. Linear regression analysis showed that folate intake, the MTHFR genotype, plasma vitamin B12 levels, and the interaction between plasma folate level and MTHFR genotype, predicted homocysteine elevation. (folate intake, P=0.04, MTHFR genotype, P=0.03, plasma folate, P=0.02, and plasma B12 level, P=0.004). The model explained only 29% of the variance in log-transformed plasma homocysteine levels. T/T homozygotes are more sensitive to the combination of low folate intake, low plasma folate and vitamin B12 level, than patients with non-T/T genotypes. The variability in plasma homocysteine in T/T homozygotes is only partly explained by these variables.