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PubMed1983

Folate malabsorption in aged rats related to low levels of pancreatic folyl conjugase.

Folate absorption and transport were studied in young (2 to 3 months) and aged (28 to 30 months) rats. From studies of the rise in serum folate levels after ingestion and transport across everted intestinal segments it was concluded that the absorption of dietary polyglutamyl folates was impaired in aged animals. Simple folates (monoglutamyl pteroates) were utilized equally well in both age groups. Decreased hydrolysis of polyglutamylfolates to simple forms have been observed in the aged group. High folyl conjugase (pteroyl gamma-glutamyl hydrolase) levels are induced in pancreas as a response to dietary folate intake; the conjugase is secreted into the gut lumen where enzyme levels rise sequentially reaching maximum in the midgut region within 30 to 60 min after folate ingestion. The rise in serum folate after folate ingestion parallels the rise in luminal folyl conjugase. Pancreatic and luminal conjugases (but not mucosal conjugase) have similar pH optima. It is suggested that dietary folates are preferentially hydrolyzed to absorbable forms by a luminal folyl conjugase which is of pancreatic origin. The overall enzyme levels are much lower in pancreas of the aged rats, leading to reduced availability of absorbable dietary folates and resulting in folate malabsorption in these animals. It is suggested that the intestinal mucosal conjugase does not play a significant role in the physiological absorption of dietary folates.

Adenosine Triphosphatases↗
PubMed1986

Folate and vitamin B12 levels in an urban elderly population with chronic diseases. Assessment of two laboratory folate assays: microbiologic and radioassay.

Folate levels of serum and red blood cells (RBC) and vitamin B12 serum levels were investigated in 326 urban chronically ill elderly ambulatory patients and 41 healthy young control subjects. Two laboratory methods were used for investigating the folate levels, the microbiologic assay (MBA) with Lactobacillus casei and radioassay (RA). Serum and RBC samples of 326 patients were tested by the folate MBA and 270 of the same samples by the RIA methods. In the MBA 6.8% of the patients and 12.2% of controls had low levels of folate RBC (less than 200 ng/mL) and 1.8% of patients and 4.8% of controls had low serum folate levels (less than 5 ng/mL). All of the patients with the low folate levels had normal hematologic findings and no clinical symptoms of folate deficiency. In the RIA method, all of the patients and almost all of the control subjects (except one) had normal folate levels. Ten of the patients (3%) had low levels of serum vitamin B12 (less than 200 pg/mL). They were hematologically normal. They had normal Schilling tests and normal vitamin B12 dietary intake. Their RBC folate levels were normal and even somewhat higher. Forty percent of these patients had macular degeneration of the eyes. The data indicate the superiority of the RA method over the MBA and bring into question the accuracy of previous studies. The data furnish further evidence that a low vitamin B12 level in the elderly is not necessarily a true vitamin B12 deficiency and raise the possibility of an association between low B12 serum levels and macular degeneration of the eyes.

Adult↗
PubMed1999

Hyperhomocyst(e)inaemia in children with chronic renal failure.

BACKGROUND: Hyperhomocyst(e)inaemia has been identified as a significant risk factor for the occurrence of atherosclerosis in adults with chronic renal failure. Because of its presumed direct toxic effect on the vascular wall, long-standing hyperhomocyst(e)inaemia in children with chronic renal failure might have an important influence on their risk of future development of atherosclerosis. Hitherto no data on hyperhomocyst(e)inaemia in children with renal failure have been published. METHODS: We investigated 16 children with chronic renal failure on conservative management, 12 children on haemodialysis and 17 children with a renal transplant. Age-matched controls were used for comparison. Plasma homocyst(e)ine levels after an overnight fast were determined by HPLC. Glomerular filtration rate was estimated by the Schwartz formula. RESULTS: Mean plasma homocyst(e)ine levels were 12.6 +/- 5.2 micromol/l in the conservatively managed group, 22.2 +/- 13.5 micromol/l in the haemodialysed group, 14.2 +/- 2.1 micromol/l in transplanted children with an estimated GFR > 60 ml/min/1.73 m2 and 17.5 +/- 5.1 micromol/l in transplanted children with a lower estimated GFR. In all groups homocyst(e)ine levels were significantly elevated as compared to controls. Homocyst(e)ine levels were significantly correlated with age and negatively correlated with estimated GFR and serum folate levels. CONCLUSIONS: Hyperhomocyst(e)inaemia is a feature of chronic renal failure in children as well as in adults. Elevated homocyst(e)ine levels can already be demonstrated in children with renal failure before end-stage renal disease has developed and persist after renal transplantation. Whether treatment of hyperhomocyst(e)inaemia in children with renal failure decreases the risk for future atherosclerosis remains to be proven.

Adolescent↗
PubMed1995

Every-other-week methotrexate in patients with rheumatoid arthritis. A double-blind, placebo-controlled prospective study.

OBJECTIVE: To determine if patients with rheumatoid arthritis (RA) that is stable with weekly methotrexate (MTX) therapy could be switched to an every-other-week regimen of MTX. METHODS: Forty-seven patients with classic or definite RA who had received MTX for at least 8 months were studied. Clinical measurements consisted of the number of tender and swollen joints, physician and patient global evaluation of disease activity on a 5-point scale, grip strength, patient evaluation of pain, morning stiffness, and the interval to onset of fatigue from time of awakening. Laboratory measures included the erythrocyte sedimentation rate (ESR), rheumatoid factor, C-reactive protein (CRP), and baseline serum folate levels. Uptake of MTX was measured with tritiated thymidine from peripheral blood mononuclear cells (PBMC) from patients ex vivo. Serum measures of interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor alpha (TNF alpha) were performed in sera, and TNF alpha was also measured on PBMC supernatants. RESULTS: Twelve of the 23 patients receiving every-other-week MTX (52%) were able to complete 6 months of this treatment without experiencing a disease flare. Eleven of the 23 patients receiving every-other-week MTX (48%) withdrew from the study before completing 6 months of treatment, because of a flare. No significant differences in clinical or laboratory parameters were seen when the 24 patients receiving weekly MTX were compared with the 12 patients in the every-other-week MTX group who successfully completed 6 months of the study. None of the changes in serum cytokine levels were significantly different between the patients receiving MTX weekly versus those receiving it every other week, and changes in ESR and CRP did not differ between groups. Age, sex, RA disease duration, MTX weekly dose or duration, baseline joint counts, or serum folate status did not predict a flare. Tritiated MTX uptake did not differ between groups. CONCLUSION: Some patients with RA that is stable on weekly dosing are able to change to every-other-week dosing without experiencing a flare in their disease activity.

Aged↗
PubMed1999

Do dialysis patients need extra folate supplementation?

To assess folate status and to evaluate the need for conventional folate supplementation in patients on dialysis, we measured serum folate, vitamin B12, and red cell folate concentrations by radioimmunoassay. Thirty-four continuous ambulatory peritoneal dialysis (CAPD) patients and 60 hemodialysis (HD) patients who had not been supplemented with folate were enrolled. Serum folate levels (5.8 +/- 3.6 ng/mL vs 2.0 +/- 1.1 ng/mL, p < 0.001) and vitamin B12 levels (831.4 +/- 416.9 pg/mL vs 513.9 +/- 213.3 pg/mL, p < 0.001) were significantly higher in CAPD patients than HD patients. The red cell folate levels (849.7 +/- 489.4 ng/mL vs 491.0 +/- 253.2 ng/mL, p < 0.001) were also significantly higher in CAPD patients. The incidences of folate deficiency in CAPD and HD patients were overestimated using the cut-off value for serum folate concentration (3.0% vs 71.7%, respectively), but the incidence of true folate deficiency was lower using the cut-off value for red cell folate level (0.0% vs 10.0%, respectively). In conclusion, the true incidence of folate deficiency in stable CAPD and HD patients is surprisingly low, even in patients who may not be taking folate supplements. The need for conventional folate supplementation in patients with end-stage renal disease on dialysis must therefore be re-evaluated. Before the decision is made to use folate supplementation, measurement of red cell folate is essential to assess of folate reserves of the patients on dialysis.

Adult↗
PubMed1999

[Left branch portal vein thrombosis associated with hyperhomocysteinemia].

A 34 year-old man, who was a smoker, was hospitalised because of severe epigastric and right upper quadrant pain. An isolated left branch portal vein thrombosis was diagnosed using ultrasonography and arteriography. Two thrombogenic pathologies were found: i) a latent myeloproliferative syndrome with spontaneous presence of erythroid colony forming unit (CFU-E) in bone marrow culture, normal blood cell count, platelet count and medullogram; ii) a hyperhomocysteinemia associated with low serum folate levels and a methyl tetrahydrofolate reductase mutation. The association of these two factors probably resulted in portal vein thrombosis. This is the first adult case of a portal vein thrombosis associated with hyperhomocysteinemia. Increased homocysteine serum levels could be a previously unrecognized factor for portal vein thrombosis. Homocysteinemia should be systematically investigated in patients with idiopathic portal vein thrombosis since folate supplements could prevent deleterious vascular effects of hyperhomocysteinemia.

Adult↗
PubMed1975

Evaluation of a radioassay for serum folate and the effects of ascorbate and methotrexate.

In this study a competitive binding assay for serum folate is evaluated with special attention to storage conditions of the serum samples and the effect of methotrexate on the assay results. Average serum folate levels were 31 nmol/1 +/- 8 (S.D.) in 59 nromal sera and 19 nmol/1 +/- 12 (S.D.) in 354 sera from hospitalized patients of which 43 values were lower than 9 nmol/1. Serum folate appeared to be stable at - 20 degrees C for at least 5 weeks. The addition of ascorbate, which is said to stabilize serum folate, caused a non-specific increase of the measured folate. Methotrexate acted competitively with the tracer folate in the assay sytem when added in vitro and elevated the folate readings. The same occurred in the serum of a patient after intravenous methotrexate.

Ascorbic Acid↗
PubMed1984

Congenital pernicious anemia: report of seven patients, with studies of the extended family.

Seven children ages 1 1/2 to 12 years with congenital pernicious anemia were detected in an extended Mexican family. All affected children had megaloblastic anemia accompanied by low serum B12 and normal serum folate levels. Gastric fluid analysis in six patients revealed normal gastric acidity and absent intrinsic factor. Serum antibodies to intrinsic factor or parietal cells were also absent. Schilling tests performed in six of the seven patients yielded abnormal results. Of the three patients in whom gastric biopsy was done, two had normal histologic findings (including examination by electron microscopy) and one had mild atrophy. All patients responded rapidly to parenterally administered vitamin B12 therapy. In addition, 170 family members were screened for the defect with complete blood counts and serum B12 levels. Such screening detected pernicious anemia in two of the children, but no other abnormalities that could be attributed to pernicious anemia were found in other family members. Based on the family pedigree, autosomal recessive inheritance is likely. The variability of age of presentation in this family is noteworthy and suggests that expression may be modified by still undefined factors.

Anemia, Pernicious↗
PubMedDate not supplied

Stillbirth rates and folic acid and zinc status in low-socioeconomic pregnant women of Brazilian Amazon.

Twenty-five women in their first trimester and 25 women in their third trimester of pregnancy were randomly chosen from the slum areas of eight towns in the Brazilian Amazon (Manaus, Sao Luis, Boa Vista, Porto Velho, Sao Gabriel, Santarem, Tefe, and Benjamin Constant). Blood samples were removed from the subjects for folic acid and zinc analyses, and the women were asked questions about whether they had suffered from complications during previous pregnancies. It was found that the stillbirth rates reported ranged from 0 to 20/1000 pregnancies. The town that had the highest stillbirth rate (Santarem) also had the highest percentage of women with deficient erythrocyte (red blood cell, RBC) folate status. All of the women in Santarem also had deficient serum folate levels in both trimesters of pregnancy, as well as the lowest average RBC folate value in the third trimester of pregnancy. The same town was also one of two in which the pregnant women had the lowest mean serum zinc levels in the third trimester.

Brazil↗
PubMed1983

Psychological disturbances and folic acid in chronic epileptic outpatients.

The relationship between serum folate level and psychological disturbances was studied in a series of 95 chronic epileptic outpatients. All were nondrinkers. Serum folic acid in all cases and vitamin B12 in 83 cases were determined by radioimmunoassay. Only three factors were significantly related with psychological disturbances: serum levels of folic acid were significantly lower and the mean corpuscular volume of the erythrocytes was significantly higher in disturbed patients, particularly in those with the most severe psychiatric syndromes, and the incidence of disturbances was significantly higher in patients treated with three or more drugs. Conversely, variables such as number or type of seizures, duration of epilepsy, duration of treatment, presence of structural neurological lesions, previous mental retardation, or focal temporal lobe disturbances in the EEG did not show any statistical relationship to the presence of psychological disturbances. No relevant relationship was found between serum vitamin B12 and psychological disturbances.

Adolescent↗
PubMed2005

Study on circadian variation in folate pharmacokinetics.

BACKGROUND: In a new preparation of prenatal multivitamins, PregVit, two tablets a day (a.m. and p.m.) are given. Folic acid is separated from iron and zinc and is given in the p.m. tablet to overcome problems due to folic acid interactions with iron or zinc, and frequent presence of nausea and vomiting of pregnancy in the morning. The circadian variation of folate in humans has not been investigated. This is the first study attempting to determine whether circadian variation of folate pharmacokinetics exists in humans. OBJECTIVES: To determine whether circadian rhythm of folate pharmacokinetics exists in humans. METHODS: In a crossover design, six healthy, non-pregnant women were randomized to receive 1 tablet of PregVit p.m., containing 1.1 mg of folic acid, in the morning or evening. Serum folate levels were measured over 10 hours. The area under the concentration-time curve (AUC) was used to compare the extent of absorption between the two time periods. RESULTS: The mean AUC values for serum folate after administration of PregVit p.m. were 334.5+/-119.6 nM*h and 283.1+/-64.3 nM*h for morning and evening, respectively (P = 0.17). The morning and evening peak serum folate concentrations were also similar (135.3+/-41.7 nM and 130.3+/-14.2 nM, respectively) (P = 0.75). Similarly, the time to peak for the morning arm (1 0.5 hour) was similar to evening administration (1+/-0.4 hour). CONCLUSIONS: There is no evidence of circadian variation in folate pharmacokinetics. Thus, the introduction of folate in PregVit p.m. will not affect its effectiveness as compared to its routine administration in the morning.

Adolescent↗
PubMed1986

Assay of methylmalonic acid in the serum of patients with cobalamin deficiency using capillary gas chromatography-mass spectrometry.

To determine the incidence of elevated levels of serum methylmalonic acid in patients with cobalamin deficiency, we utilized a new capillary gas chromatographic-mass spectrometric technique to measure methylmalonic acid in the serum of 73 patients with clinically confirmed cobalamin deficiency. Values ranged from 55 to 22,300 ng/ml, and 69 of the 73 patients had values above the normal range of 19-76 ng/ml as determined for 50 normal blood donors. In the cobalamin-deficient patients, serum methylmalonic acid was significantly correlated with the serum folate level and the degree of neurologic involvement. Some patients with pernicious anemia who were intermittently treated with cyanocobalamin were found to have elevated serum levels of methylmalonic acid while free of hematologic and neurologic abnormalities. A cobalamin-deficient patient is described with a normal serum cobalamin and an elevated serum methylmalonic acid. We conclude that the ability to measure methylmalonic acid in human serum will be useful in studies designed to determine the incidence of cobalamin deficiency in various patient populations.

Adolescent↗
PubMed2002

Does oral folic acid lower total homocysteine levels and improve endothelial function in children with chronic renal failure?

BACKGROUND: Accelerated vascular disease is common in chronic renal failure (CRF) and accounts for significant mortality and morbidity. Elevated homocysteine levels may contribute by an effect on endothelial function. METHODS AND RESULTS: We performed a double-blind placebo-controlled randomized crossover trial of folic acid at 5 mg/m2 in 25 normotensive children 12+/-3 (7 to 17) years of age with CRF (glomerular filtration rate 26.8+/-13.2 mL/min per 1.73 m2) of noninflammatory etiology. Each subject underwent two 8-week periods of folic acid and placebo separated by an 8-week washout period. The effect of folic acid on homocysteine levels, LDL oxidation, and both endothelial-dependent and -independent vascular function were measured. After oral folic acid, serum folate levels rose from 11.7+/-4.25 to 635+/-519 microg/L (P=0.001), red cell folate levels rose from 364+/-195 to 2891+/-2623 microg/L (P<0.001), and total homocysteine levels fell from 10.28+/-4.16 to 8.62+/-2.32 micromol/L (P=0.03). In addition, there was a significant improvement in flow-mediated dilatation (FMD) (endothelial-dependent dilatation) from 7.21+/-2.8% to 8.47+/-3.01% (P=0.036) with no change in response to glyceryl trinitrate (endothelial-independent dilatation). There was no significant change in FMD or glyceryl trinitrate during the placebo phase. There was, however, no significant difference in final FMD after placebo or folic acid. Lag times for LDL oxidation were prolonged during the treatment phase (58.4+/-18.7 to 68.1+/-25.9 minutes, P=0.01). CONCLUSION: Folic acid supplementation in children with CRF may improve endothelial function with an increased resistance of LDL to oxidation.

Administration, Oral↗
PubMed1992

Factors influencing mutation at the hprt locus in T-lymphocytes: studies in normal women and women with benign and malignant breast masses.

A prospective, longitudinal study was performed to test the hypothesis that environmental factors (e.g., diet or cigarette smoking) modulate genetic damage caused by treatment for breast cancer and render these women more susceptible to developing second malignancies. A total of 107 women (49 with breast cancer, 52 with benign breast masses, and 6 normal women) were enrolled. This report describes initial studies at the time of enrollment and disease presentation. Mutant frequency at the hprt locus and cloning efficiency of peripheral blood lymphocytes did not differ significantly among the 3 groups. Mutant frequency increased with age, with a history of cigarette smoking, and with the number of years that current smokers used cigarettes. There was no correlation in women with benign masses between mutant frequency and the incidence of chromosome aberrations (28 women) or sister chromatid exchanges (23 women). A maternal history of breast cancer did not influence mutant frequency. There was no significant relationship between dietary intake of vitamins A, B12, C and E, folacin, selenium, calcium, caffeine, or multivitamin pills, and mutant frequency. Serum folate levels in the deficient range were associated (P = 0.02) with elevated mutant frequencies, whereas SCE rates inversely correlated with serum vitamin B12 levels. These results confirm the importance of age and, less so, cigarette smoking as factors that influence mutant frequency and suggest that a micronutrient, folic acid, may modify genetic damage at the hprt locus. To the extent that somatic mutation contributes to carcinogenesis, these environmental factors may enhance the risk of developing malignant transformation.

Adult↗
PubMed1975

The effect of diet and alcohol on the development of folate deficiency in the rat.

Studies of the rate of depletion of serum and tissue methylated and non-methylated folates were carried our in rats maintained for long periods on either a folate deficient (sucrose-water/sulphathiazole) diet or a deficient diet plus high alcohol intake. By means of implantation of a feeding gastrostomy tube, it was possible to sustain constant blood ethanol levels of between 50 and 300 mg/dl for 3-4 weeks with relatively normal calorie intake and without death of the animal. Using this animal model, which closely resembles severe alcoholism in man, a very rapid depression in serum 5-methyl tetrahydrofolate was observed similar to that reported in alcoholic man. At the same time, release of folates from liver stores was umimpaired by alcohol ingestion. Liver folate store depletion rates were identical for alcoholic and folate starved animals. The explanation for the sudden alcohol suppression of serum folate levels must, therefore, be sought at a point in the internal metabolic sequences of folate other than the delivery of folate stores to plasma.

Animals↗
PubMed1999

Supplementation with vitamin B12 decreases homocysteine and methylmalonic acid but also serum folate in patients with end-stage renal disease.

Hyperhomocysteinemia is frequently found in patients with end-stage renal disease (ESRD). Plasma total homocysteine (tHcy) concentrations may be reduced by supplementation with folic acid or combinations of folic acid, vitamin B12, and vitamin B6. Supplementation studies with vitamin B12 alone in patients with ESRD have not yet been published. In this study, we investigated the effects of intravenous injection of cyanocobalamin (1 mg/wk for 4 weeks) in ESRD patients (N = 14) with low serum cobalamin concentrations (<180 pmol/L). All patients had elevated levels of plasma tHcy, methylmalonic acid (MMA), and cystathionine before supplementation. After supplementation, plasma tHcy and MMA decreased 35% and 48%, respectively; however, cystathionine levels were unchanged. The extent of the plasma tHcy reduction tended to be influenced by the C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR). Serum cobalamin increased significantly upon supplementation, whereas serum folate levels were substantially reduced by 47%. In contrast, red blood cell (RBC) folate was unchanged. This study shows that vitamin B12 supplementation effectively decreases both MMA and plasma tHcy in ESRD patients with low B12 levels. Furthermore, it illustrates the close interrelation between vitamin B12 and folate metabolism.

Adult↗