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Terminal ileum resection is associated with higher plasma homocysteine levels in Crohn's disease.

BACKGROUND: Elevated plasma total homocysteine (tHcy) is associated with a higher risk of thrombosis. Crohn's disease (CD) is associated with hypercoagulability of undefined etiology. We investigated tHcy in patients with CD and its relationship with vitamin status, disease activity, location, duration, and history of terminal ileum (TI) resection. STUDY: We examined fasting plasma tHcy, folate, serum vitamin B12 levels, and sedimentation rate in consecutive adult patients with CD. Harvey-Bradshaw index of CD activity and history of TI resection and thromboembolism were recorded. RESULTS: Median plasma tHcy was 10.2 micromol/L in 125 patients with CD. Men (n = 60) had higher plasma tHcy than women (n = 65) (11.2 vs. 9.1 micromol/L; p = 0.004). Patients with a history of TI resection showed lower serum B12 levels (293 vs. 503 pg/mL; p < 0.001) and higher plasma tHcy levels (11.0 vs. 9.35 micromol/L; p = 0.027) than patients without such history. Multivariate analysis showed history of TI resection, serum B12, and creatinine levels to be significant predictors of elevated plasma tHcy. Fourteen patients with CD with a history of thrombosis had an elevated median plasma tHcy of 11.6 micromol/L. CONCLUSIONS: Terminal ileum resection contributes to elevated plasma tHcy levels in CD cases. We recommend tHcy screening in patients with CD, especially in those with prior history of TI resection, and the initiation of vitamin supplementation when appropriate.

Adult↗

[Iron or combined iron-folic acid-vitamin B12 therapy during pregnancy? (author's transl)].

128 women with mild anemias below 12 g% Hb received 100 mg iron or 100 mg iron, 0.44 mg folic acid and 0.66 mg vitamin B12 daily from the 20th to the 24th weeks of pregnancy until confinement. With pure iron therapy the maternal hemoglobin, erythrocyte, hematocrit and serum levels rose significantly, whereas in the placebo group (37 pregnant women) they fell markedly. Iron-folic acid-vitamin B12 administration led to no improvement in the hemoglobin regeneration or in the serum iron. After 60 days' treatment with the combined iron preparation, a rise in the serum and erythrocyte folate levels had already been achieved in the pregnancy women.

Anemia, Hypochromic↗

The relationship between maternal dietary intake and infant birthweight.

BACKGROUND: Zinc and folate are important for fetal growth. However, the relationship between the dietary intake of these nutrients and pregnancy outcome is not settled. METHODS: A prospective study was conducted to ascertain the relationship between maternal dietary zinc and folate intake (n = 1398), serum zinc and folate levels (n = 289), and infant birthweight. Twenty-four hour recalls were used to measure energy, zinc, folate and other nutrient intakes at 18 and 30 weeks of gestation. Subjects in the study were offered daily folic acid (1.0 mg) and iron (60 mg as ferrous sulfate) at enrollment. RESULTS: Maternal zinc nutriture as assessed by serum and dietary intake was not associated with birthweight or length of gestation. There was a small but significant positive association between maternal folate intake and adjusted infant birthweight (beta = 0.05, p = 0.03). The indirect measures of maternal nutritional status including maternal pre-pregnancy weight (beta = 8.0, p = 0.0001) and weight gain during pregnancy (beta = 18.1, p = 0.0001) were stronger predictors of adjusted infant birthweight as compared to energy intake and intake of zinc and folate. An increase of 320, 290, and 48 g in infant birthweight was associated with the 90th-10th percentile difference for pre-pregnancy weight, weight gain during pregnancy, and folate intake respectively. CONCLUSION: These results indicate that pre-pregnancy weight and weight gain during pregnancy are both strong predictors of infant birthweight. Folate intake, although significantly associated with birthweight, was a weak predictor while maternal intake of zinc and other nutrients was not associated with birthweight.

Adult↗

Hyperhomocysteinemia but not the C677T mutation of methylenetetrahydrofolate reductase is an independent risk determinant of carotid wall thickening. The Perth Carotid Ultrasound Disease Assessment Study (CUDAS)

BACKGROUND: Hyperhomocysteinemia has been identified as a potential risk factor for atherosclerosis. This study examined whether a modest elevation of plasma total homocysteine (tHcy) was an independent risk factor for increased carotid artery intimal-medial wall thickness (IMT) and focal plaque formation in a large, randomly selected community population. We also examined whether vitamin cofactors and the C677T genetic mutation of the methylenetetrahydrofolate reductase (MTHFR) enzyme were major contributors to elevated plasma tHcy and carotid vascular disease. METHODS AND RESULTS: In 1111 subjects (558 men, 553 women) 52+/-13 years old (mean+/-SD; range, 27 to 77 years) recruited from a random electoral roll survey, we measured fasting tHcy and performed bilateral carotid B-mode ultrasound. For the total population, mean tHcy was 12.1+/-4.0 micromol/L. Plasma tHcy levels were correlated with IMT (Spearman rank rs=0.31, P=0.0001). After adjustment for age, sex, and other conventional risk factors, subjects in the highest versus the lowest quartile of tHcy had an odds ratio of 2.60 (95% CI, 1.51 to 4.45) for increased IMT and 1.76 (95% CI, 1.10 to 2.82) for plaque. Serum and dietary folate levels and the C677T mutation in MTHFR were independent determinants of tHcy (all P=0.0001). The mutant homozygotes (10% of the population) had higher mean tHcy than heterozygotes or those without the mutation (14.2 versus 12.3 versus 11.6 micromol/L, respectively, P=0.0001). The inverse association of folate levels with tHcy was steeper in the mutant homozygotes. Despite this, the C677T MTHFR mutation was not independently predictive of increased carotid IMT or plaque formation. CONCLUSIONS: Mild hyperhomocysteinemia is an independent risk factor for increased carotid artery wall thickness and plaque formation in a general population. Lower levels of dietary folate intake and the C677T mutation in MTHFR are important causes of mild hyperhomocysteinemia and may therefore contribute to vascular disease in the community.

Adult↗

Methylenetetrahydrofolate reductase gene polymorphism in Indian stroke patients.

BACKGROUND AND AIMS: In view of the prevailing controversy about the role of Methylenetetrahydrofolate reductase (MTHFR) C677T mutation in stroke and paucity of studies from India, this study has been undertaken to evaluate MTHFR C677T gene polymorphism in consecutive ischemic stroke patients and correlate these with folic acid, homocysteine (Hcy) and conventional risk factors. SETTINGS AND DESIGN: Ischemic stroke patients prospectively evaluated in a tertiary care teaching hospital. MATERIALS AND METHODS: Computerized tomography proven ischemic stroke patients were prospectively evaluated including clinical, family history of stroke, dietary habits and addictions. Their fasting and postprandial blood sugar, lipid profile, vitamin B12, folic acid and MTHFR gene analysis were done. STATISTICAL ANALYSIS: MTHFR gene polymorphism was correlated with serum folic acid, Vitamin B12 and Hcy levels; family history of stroke in first-degree relatives; and dietary habits; employing Chi-square test. RESULTS: There were 58 patients with ischemic stroke, whose mean age was 50 (4-79) years; among them, 10 were females. MTHFR gene polymorphism was present in 19 (32.8%) patients, 3 were homozygous and 16 were heterozygous. Both serum folate and B12 levels were low in 29 (50%) patients and Hcy in 48 (83%). Hypertension was present in 28 (48%) patients, diabetes in 12 (21%), hyperlipidemia in 52 (90%), smoking in 17 (29%), obesity in 1 (1.7%) and family history of stroke in first-degree relatives in 13 (22.4%). There was no significant relationship of MTHFR gene polymorphism with folic acid, B12, Hcy levels, dietary habits and number of risk factors. Vitamin B12 level was low in vegetarians (P<0.003). In 3 patients with MTHFR TT alleles, Hcy was elevated in all 3, low folic acid in 2 and family history of stroke in 1 patient. CONCLUSION: MTHFR gene polymorphism was found in one-third of patients with ischemic stroke and was insignificantly associated with higher frequency of elevated Hcy.

Adolescent↗

Comparison of folate levels in convulsing and non-convulsing febrile children.

The relationship between folic acid levels and occurrence of convulsion in febrile subjects was studied in thirty-two children aged 8 months to 5 years. Both the serum and red cell folate levels were significantly higher in the febrile children who convulsed than in those who did not convulse. When the period of convulsion was more than thirty minutes, there was a significant rise in the red cell folate. These results suggest that the accumulation of folate in the serum and red cell may be causally related to the development of the convulsing state in febrile children.

Body Temperature↗

Cystatin C as a determinant of fasting plasma total homocysteine levels in coronary artery disease patients with normal serum creatinine.

Serum creatinine, a surrogate for both renal function and homocysteine generation, is a determinant of fasting plasma total homocysteine levels in coronary artery disease (CAD) patients. We hypothesized that among stable-CAD patients with normal creatinine levels (ie, </=1.4 mg/dL), serum cystatin C, a more sensitive indicator of glomerular filtration rate, would better predict fasting total homocysteine levels in comparison with serum creatinine. Fasting plasma total homocysteine, folate, vitamin B(12), and pyridoxal 5'-phosphate levels, along with serum cystatin C, creatinine, and albumin levels, were determined in 164 consecutive stable-CAD patients (mean+/-SD age, 61+/-9 years; 78.7% men) whose serum creatinine level was </=1.4 mg/dL. All subjects were examined at least 3 to 4 months after the widespread availability of cereal grain flour products fortified with folic acid. General linear modeling with ANCOVA revealed that serum cystatin C (P<0.001), B(12) (P<0.001), age (P=0.002), albumin (P=0.008), and sex (P=0.024) were independent determinants of fasting total homocysteine levels. Cystatin C alone determined over half of the variability (ie, R(2)) in total homocysteine levels accounted for by these 5 independent regressors. In contrast, creatinine, folate, and pyridoxal 5'-phosphate were not independently predictive of fasting total homocysteine levels (P>0.2). Consistent with the impact of folic acid fortification of cereal grain flour in the general population, only 1 of the CAD subjects (0.6%) had a plasma folate level <3 ng/mL. We conclude that serum cystatin C levels may reflect subtle decreases in renal function that independently predict fasting total homocysteine levels among stable-CAD patients with normal serum creatinine.

Adult↗

Evaluation of genetic variants in the reduced folate carrier and in glutamate carboxypeptidase II for spina bifida risk.

Genetic variants in folate metabolism have been reported to increase risk for neural tube defects (NTD). The first such sequence change was the 677C-->T substitution in methylenetetrahydrofolate reductase (MTHFR), but additional sequence changes have been identified in enzymes or transporters for folates. Two recently identified variants are the 1561C-->T (H475Y) mutation in glutamate carboxypeptidase II (GCPII) and the 80A-->G (H27R) change in the reduced folate carrier RFC-1. We examined a group of mothers of spina bifida offspring, and a group of control women, for the above polymorphisms to assess their impact on NTD risk as well as on homocysteine and nutrient (RBC folate, serum folate, and serum cobalamin) levels. The GCPII variant (in the heterozygous state) did not influence NTD risk or metabolite levels; homozygous mutant (YY) women were not observed in our study group. The homozygous mutant (RR) genotype for the RFC-1 gene was not associated with a significant difference in NTD risk (OR=1.39, 95% CI=0.55-3.54), but there was a borderline significant (p=0.065) decrease in RBC folate levels, compared with the HH genotype. However, the combination of the RR genotype for RFC-1 and low RBC folate was associated with a significant 4.6-fold increase in NTD risk (OR=4.6, 95% CI=1.47-14.37). Since this small study is the first to demonstrate increased risk for women with the RFC-1 variant for having a child with a NTD, additional larger studies are required to confirm this change as another potential genetic modifier for spina bifida risk.

Alleles↗

Hematologic manifestations and impaired liver synthetic function during valproate monotherapy.

In a prospective study 50 children with new onset epilepsy were investigated. Routine screening for complete blood count, serum protein, albumin, gamma-glutamyltransferase (gamma-GT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and coagulation studies before, 3, 6 and 9 weeks after commencement of antiepileptic therapy with valproate were carried out. Serum B12 and folate levels were also determined in 29 patients. The aim of the study was to evaluate the effect of VPA on these laboratory findings. We found a significant reduction of red blood count and platelet count, whereas MCV showed a significant upward trend. Vitamin B12 levels were elevated after starting VPA therapy. We found no elevations of liver enzymes, but a significant transient reduction of ALT after 3 and 6 weeks and significantly reduced serum protein and albumin after 3, 6 and 9 weeks. Coagulation studies revealed a significant downward trend in serum fibrinogen and upward trend in thrombin time. The other parameters showed no significant changes after onset of VPA treatment. We think that reduced red blood cell and platelet counts, and elevated MCV indicate a direct toxic effect on a hematopoietic precursor or stem cell in patients treated with VPA. Furthermore, reduced protein, albumin and fibrinogen indicate an impaired liver synthetic function in asymptomatic children treated with VPA monotherapy.

Adolescent↗

Folate supplements and phenytoin-salicylate interaction.

We found biphasic fluctuations of serum phenytoin level when aspirin was added to chronic phenytoin therapy for an epileptic patient. The total serum phenytoin level was lowered initially by addition of aspirin. However, after 4 months on phenytoin-aspirin combination therapy, he showed elevated serum phenytoin levels, mild nystagmus, and serum folate deficiency.

Adult↗

Relationship of phytohaemagglutinin-induced lymphocyte transformation to disease activity in systemic lupus erythematosus.

Phytohaemagglutinin-induced lymphocyte transformation was studied in 19 patients with systemic lupus erythematosus (SLE) in relation to disease activity, peripheral blood lymphocyte count, serum iron and folate levels, and corticosteroid treatment. Similar studies were performed on a group of 28 age- and sex-matched controls and on 10 patients with facial palsy who were examined before and after 7 days of high-dose corticosteroid treatment. The patients with SLE were found to have an impairment of lymphocyte transformation which was most marked in active stages of the disease and associated with a lymphopenia. This depressed transformation, which improved with the development of a remission, could not be attributed to the effects of corticosteroid treatment, inhibitory serum factors, iron deficiency, or any numerical reduction in blood lymphocytes, thus indicating along with evidence from other sources that SLE patients have a defect of cell-mediated immunity. The aetiological implications of these findings are discussed.

Adolescent↗

Hematological parameters and cobalamin status in infants born to smoking mothers.

Hematological parameters, serum cobalamin and folate levels, and the concentrations of the functional markers plasma methylmalonic acid and total homocysteine were determined in 173 newborns and 46 infants at 6 weeks to see whether maternal smoking influences the hematological parameters and the vitamin status of the newborn. At birth, there was a strong inverse correlation between the number of cigarettes smoked per day during pregnancy and red blood cell count (r = -0.56, p = 0.001) and hemoglobin level (r = -0.52, p = 0.003) in the newborns. Neonates born to smoking mothers had lower red blood cell counts and lower hemoglobin and serum cobalamin levels as compared with infants born to nonsmoking mothers. At 6 weeks, maternal smoking significantly predicted the methylmalonic acid and total homocysteine levels, suggesting an influence from smoking on the cobalamin function in these infants.

Adult↗

Homocysteinemia due to folate deficiency.

We examined the relationship between serum folate and total homocyst(e)ine levels by determining protein-bound homocyst(e)ine in stored serum from 19 subjects with subnormal serum folate (less than 2 ng/mL), 137 subjects with low normal serum folate (between 2.0 and 3.9 ng/mL), 44 subjects with normal serum folate (between 4.0 and 17.9 ng/mL), and 38 subjects with high serum folate (above 18 ng/mL). Eighty-four percent of the subjects with subnormal serum folate and 56% of the subjects with low normal serum folate had more than 7.05 nmol/mL serum total homocyst(e)ine (ie, more than two standard deviations above the normal mean). Thirty-two percent of these subjects had more than a three-fold increase in serum total homocyst(e)ine. These observations support the hypothesis that depletion of tissue folate causes homocysteinemia in nonhomocystinuric subjects. Subnormal as well as low normal concentrations of serum folate appear to produce an accumulation of homocyst(e)ine. In addition, relatively normal levels of serum total homocyst(e)ine were observed in four pregnant women with low serum folate, supporting previous suggestions of an influence of female sex hormone(s) in homocysteine metabolism.

Adolescent↗

Effect of ethynodiol diacetate and mestranol on serum folic acid and vitamin B12 levels and on tryptophan metabolism in baboons.

The effect of an oral contraceptive agent on serum folate and vitamin B12 levels and on some aspects of tryptophan metabolism in the baboon has been investigated. Folate levels were not affected by this treatment. Vitamin B12 levels were lowered during oral contraceptive treatment (P smaller than 0.1) and increased during a 30-day period of pyridoxine supplementation (P smaller than 0.01). Trends indicating deterioration of glucose tolerance and abnormal tryptophan metabolism were also observed. Definite conclusions concerning the effect of oral contraceptive agents on nutritive parameters could not be made. This is in keeping with the vast volume of literature published on the effects of oral contraceptive agents in humans and other species. It is concluded that perhaps, due to the biologically variable responses to oral contraceptive agents by individuals of any species, studies of serum levels of vitamins and other superficial biochemical parameters. Further, we conclude that the baboon could be a useful model for the study of endocrine influences on nutritive parameters, first because endocrine parameters resemble those of humans and second, because experimental protocols can be rigidly adhered to.

Animal Nutritional Physiological Phenomena↗

Microbially produced acetaldehyde from ethanol may increase the risk of colon cancer via folate deficiency.

High alcohol and low folate intake are independent risk factors for colorectal cancer. Acetaldehyde has been postulated to be a factor responsible for ethanol-associated carcinogenesis. High levels of acetaldehyde accumulate in the large intestine via the microbial oxidation of alcohol. Acetaldehyde degrades folate in vitro. Thus, it is possible that high intracolonic acetaldehyde levels break down folate in the colon. Our aim was to test the effect of high alcohol and acetaldehyde concentrations in the gut on systemic and local intestinal folate levels in rats. Twenty rats received 3 g/kg of ethanol twice a day for 2 weeks with or without concomitant ciprofloxacin administration. Twenty control rats received saline with or without ciprofloxacin. All rats were fed a diet with normal folate content. Alcohol treatment led to very high intracolonic acetaldehyde levels (387 +/- 185 microM), which were markedly decreased by concomitant ciprofloxacin treatment (21 +/- 4 microM). Erythrocyte, serum and small intestinal folate levels were unaffected by alcohol treatment. Alcohol administration decreased significantly colonic mucosal folate levels by 48%, and this effect was prevented by ciprofloxacin. We conclude that alcohol administration for 2 weeks leads to local folate deficiency of colonic mucosa in rats, most probably via the degradation of folate by the high levels of acetaldehyde microbially produced from ethanol. Our findings offer a unique explanation for the increased risk of colonic cancer associated with alcohol intake and folate deficiency.

Acetaldehyde↗

Polymorphisms of 5,10-methylenetetrahydrofolate reductase and risk of gastric cancer in a Chinese population: a case-control study.

Low dietary folate intake has been associated with increased risk of gastric cancer. The 5,10-methylenetetrahydrofolate reductase (MTHFR) involved in folate metabolism has 2 variants, C677T and A1298C, that result in decreased MTHFR activity and lower plasma folate levels. Therefore, we hypothesized that these 2 variants play a role in gastric carcinogenesis. We tested this hypothesis in a Chinese population-based case-control study of 187 histopathologically confirmed gastric cancer cases and 166 healthy controls frequency-matched by age (+/-5 years), gender and residential area. The 677TT genotype was associated with increased risk for gastric cancer [adjusted odds ratio (OR) = 1.87, 95% confidence interval (CI) = 1.00-3.48] compared to the 677CC genotype. This association was more pronounced for gastric cardia cancer (adjusted OR = 2.47, 95% CI = 1.14-5.32). However, no evidence was found for risk associated with the MTHFR A1298C polymorphism. Our findings support the hypothesis that MTHFR C677T variants contribute to gastric carcinogenesis, particularly in gastric cardia. Larger studies incorporating dietary folate intake and serum levels are needed to confirm our findings.

Adenocarcinoma↗

Hyperhomocysteinaemia and cardiovascular risk in female ovariectomized rats: role of folic acid and hormone replacement therapy.

Hyperhomocysteinaemia is an independent risk factor for arteriosclerosis, recurrent thromboembolic complications and osteoporosis. After menopause, a high level of total homocysteine seems to be secondary to the altered hormonal status. Hormone replacement therapy (HRT) limits the development of coronary artery disease through a variety of mechanisms. One such mechanism is through affecting homocysteine metabolism. Folate and vitamin B12 deficiencies are considered to be major risks for hyperhomocysteinaemia. This study, therefore, was undertaken to examine whether lowering homocysteine with HRT or folic acid in ovariectomized rats could attenuate cardiovascular complications. Sixty sexually mature female Wistar rats were ovariectomized. Three weeks later, they were treated with estradiol (15 microg kg(-1), every two weeks, i.m.) or folic acid (90 microg daily, orally), either alone or in a combined form for four weeks. In addition, groups of ovariectomized rats (positive control) and healthy rats (negative control) were given cottonseed oil. Blood samples were then collected for serum and plasma separation. Serum total homocysteine, folate, estradiol, plasma nitric oxide (NO), lipid profile, and susceptibility of non-high-density-lipoprotein cholesterol (non HDLC) content to oxidation were determined. In ovariectomized rats, hyperhomocysteinaemia was established and associated with significant increments of both atherogenic indexes (total cholesterol/HDLC, low-density-lipoprotein cholesterol (LDLC)/HDLC) and susceptibility of their non HDLC to oxidation. However, plasma NO, serum folate, and estradiol levels significantly decreased. HRT and folic acid significantly reduced total homocysteine and susceptibility of non HDLC to oxidation and increased plasma NO content. Moreover, a significant negative correlation was found between total homocysteine versus folate and estradiol (r = -0.5, P < 0.01; r = -0.25, P < 0.05, respectively). Meanwhile, a positive correlation with the susceptibility of lipoprotein to oxidation was observed (r = 0.85, P < 0.001). In conclusion, a low folate level is found to be associated with elevated total homocysteine. Folic acid supplementation, either individually or in a combined form with HRT, has a beneficial effect in low estrogen status subsequent to ovariectomy.

Animals↗

Hyperhomocystinemia and the prevalence of symptomatic atherosclerotic vascular disease in Taiwanese chronic hemodialysis patients: a retrospective study.

AIM: Hyperhomocystinemia is now recognized as an independent risk factor for atherosclerotic cardiovascular disease in patients with normal renal function. Hyperhomocystinemia is common in patients with chronic renal failure. This aim of this study was designed to look for associations between hyperhomocystinemia and clinically symptomatic atherosclerotic vascular disease (ASVD) in Taiwanese chronic hemodialysis patients. METHODS: Two hundred patients undergoing hemodialysis were enrolled in the study. They had predialysis blood work performed for total homocysteine, serum folate, and vitamin B12 levels. A history of clinically significant ASVD was elicited using information from the patients' questionnaires and verified by careful inpatient and outpatient chart review. RESULTS: Mean homocysteine concentration was 29.0 micromol/L overall. A total of 196 patients had hyperhomocystinemia and were enrolled in this study. ASVD was present in 24.5% of patients. The mean homocysteine concentration was 31.9 micromol/L and 28.7 micromol/L in patients with (n = 48) and without (n = 148) ASVD, respectively (P = 0.04). There was association hyperhomocystinemia between chronic hemodialysis patients with ASVD and without ASVD. There were significant differences including age, homocysteine level, vitamin B12 level and glucose intolerance in the two groups (P < 0.05). Plasma homocysteine concentrations showed significant positive correlations with serum folate or vitamin B12 in majority patients. No patient had serum folate or vitamin B12 deficiency. The adjusted odds ratio for atherosclerotic disease was 2.8 (95% CI, 1.109-7.467) for those subjects with a homocysteine level in the highest quartile compared with the lowest 3 quartiles. CONCLUSIONS: The prevalence of hyperhomocystinemia is 98% among hemodialysis patients. There is a significant association between hyperhomocystinemia and ASVD in Taiwanese chronic hemodialysis patients. There are also associations between homocysteine levels and serum folate/vitamin B12 levels in the majority of the patients. Clinical trials are needed to determine the optimal therapy of folic acid dose for hyperhomocystinemia in Taiwanese chronic hemodialysis patients in the future.

Aged↗