Clinical trial: B vitamins improve health in patients with coeliac disease living on a gluten-free diet.

BACKGROUND: Patients with coeliac disease living on a gluten-free diet show vitamin deficiency and reduced subjective health status. AIM: To study the biochemical and clinical effects of B vitamin supplementation in adults with longstanding coeliac disease. METHODS: In a double blind placebo controlled multicentre trial, 65 coeliac patients (61% women) aged 45-64 years on a strict gluten-free diet for several years were randomized to a daily dose of 0.8 mg folic acid,0.5 mg cyanocobalamin and 3 mg pyridoxine or placebo for 6 months. The outcome measures were psychological general well-being (PGWB) and the plasma total homocysteine (tHcy) level, marker of B vitamin status. RESULTS: Fifty-seven patients (88%) completed the trial. The tHcy level was baseline median 11.7 micromol/L (7.4-23.0), significantly higher than in matched population controls [10.2 micromol/L (6.7-22.6) (P < 0.01)]. Following vitamin supplementation, tHcy dropped a median of 34% (P < 0.001), accompanied by significant improvement in well-being (P < 0.01), notably Anxiety (P < 0.05) and Depressed Mood (P < 0.05) for patients with poor well-being. CONCLUSIONS: Adults with longstanding coeliac disease taking extra B vitamins for 6 months showed normalized tHcy and significant improvement in general well-being, suggesting that B vitamins should be considered in people advised to follow a gluten-free diet.

Hyperhomocysteinaemia is not associated with increased levels of asymmetric dimethylarginine in patients with ischaemic heart disease.

BACKGROUND: Elevated plasma total homocysteine appears to be related to endothelial dysfunction and impaired nitric oxide production. We aimed to investigate [1] whether elevated levels of plasma total homocysteine are associated with high plasma levels of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, and [2] whether reduction of plasma total homocysteine levels by folate and vitamin B supplementation lowers plasma concentration of asymmetric dimethylarginine. MATERIALS AND METHODS: Sixty patients with ischaemic heart disease and with plasma total homocysteine levels of 15.0 micromol L-1 were randomized to open therapy with folic acid, pyridoxine and cyancobalamin for 3 months (n = 30) or to no treatment (n = 30). Samples were also obtained from 34 patients with plasma total homocysteine levels of 8.0 micromol L-1 on admission. RESULTS: Plasma asymmetric dimethylarginine concentrations in patients with elevated total homocysteine levels were not significantly higher (0.68 +/- 0.19 micromol L-1) than in patients with low total homocysteine levels (0.61 +/- 0.10 micromol L-1; P = 0.08). Plasma asymmetric dimethylarginine level in the vitamin supplemented group was 0.65 +/- 0.12 micromol L-1 before, and 0.64 +/- 0.12 micromol L-1 after 3 months of vitamin supplementation (NS). Plasma asymmetric dimethylarginine levels were correlated with serum cystatin C levels (P < 0.001). CONCLUSION: A nonsignificant trend to increased plasma levels of asymmetric dimethylarginine in patients with high plasma total homocysteine levels may be explained by concomitant subtle renal dysfunction. Substantial reduction of plasma total homocysteine did not affect the level of plasma asymmetric dimethylarginine.

Improvement of cognitive functions after cobalamin/folate supplementation in elderly patients with dementia and elevated plasma homocysteine.

OBJECTIVES: To investigate the effect of cobalamin/folate supplementation on cognitive function in elderly patients with dementia. METHOD: The cobalamin/folate status of the patients was evaluated by measuring plasma homocysteine, serum methylmalonic acid, serum cobalamin and blood folate. Thirty-three patients were studied and repeatedly assessed with the Mini-Mental State Examination (MMSE) and 'A short cognitive performance test for assessing memory and attention' (SKT) during vitamin substitution. RESULTS: Patients with mild-moderate dementia and elevated plasma homocysteine levels improved clinically with increased test scores after vitamin substitution, while severely demented patients and patients with normal plasma homocysteine levels did not improve clinically. CONCLUSIONS: Plasma homocysteine may be the best marker for detecting treatable cobalamin/folate deficiency in patients with dementia.

Treatment of cobalamin deficiency in dementia, evaluated clinically and with cerebral blood flow measurements.

We investigated the relation between cobalamin deficiency, clinical changes and brain function in dementia patients. On admittance to the clinic, 24 patients had cobalamin deficiency, and dementia with additional symptoms of delirium. During cobalamin supplementation, the patients underwent repeated regional cerebral blood flow (rCBF) studies, psychiatric evaluations, and in some cases assessment with MMSE and the Organic Brain Syndrome scale. Fifteen patients who showed mild to moderate dementia improved clinically, and also showed a concomitant increase in their general CBF after treatment. In contrast, 9 patients who were severely demented showed no obvious clinical improvement, and no general blood flow change, although some regional flow increases were seen in sensory motor areas. We conclude that symptoms which probably indicated superimposed delirium such as clouding of consciousness, disorientation and clinical fluctuation, responded to the vitamin B12 supplementation, while the underlying dementia condition remained basically unchanged. The clinical improvement was also mirrored in general and focal rCBF changes.

Plasma homocysteine is a sensitive marker for tissue deficiency of both cobalamines and folates in a psychogeriatric population.

The concentration of blood folates was decreased and the concentration of plasma homocysteine was increased in a psychogeriatric population, whereas the concentrations of methylmalonic acid or serum cobalamins were not changed compared with healthy subjects. The highest frequency of abnormal values was shown by plasma homocysteine concentration, which was increased in 88 of 168 patients. In 29 of these 88 patients increased concentration of plasma homocysteine could possibly be attributed to tissue cobalamin deficiency. One patient had only a lowered concentration of blood folate. Thirteen patients had elevated concentrations of serum creatinine which could explain increased plasma homocysteine concentration. Even if the remaining patients (n = 45) had normal vitamin levels in circulation, the increased plasma homocysteine concentration in most cases must be attributed to tissue deficiency of cobalamins and/or folates. Thus, many patients with increased plasma homocysteine concentrations need further vitamin supplementation despite their normal vitamin levels in serum and blood. Copyrightz1999S.KargerAG,Basel

Plasma methylmalonic acid in relation to serum cobalamin and plasma homocysteine in a psychogeriatric population and the effect of cobalamin treatment.

Cobalamin deficiency seems to be a relatively common condition in psychogeriatric patients. To elucidate the diagnostic possibility of cobalamin deficiency we have in this study analysed three markers for cobalamin deficiency, plasma methylmalonic acid, plasma homocysteine and serum cobalamin, in 96 psychogeriatric patients. Patients were divided into four groups according to serum cobalamins above or below 150 pmol/l and normal (< 19.9 mumol/l) or increased plasma homocysteine. The upper reference limit (95th percentile) for plasma methylmalonic acid in 100 healthy subjects was established to 0.42 mumol/l. The mean value of methylmalonic acid was increased only in the group of patients with serum cobalamin below 150 pmol/l and increased plasma homocysteine compared to the other groups. In this group six (46%) out of 13 patients exhibited increased plasma methylmalonic acid, whereas in the other groups the frequency of increased plasma methylmalonic acid only varied from 10 to 13%. During cobalamin supplementation the most pronounced decrease of plasma methylmalonic acid also occurred in the group of patients with low serum cobalamin levels and increased plasma homocysteine. Only 39% of the initial mean value for plasma methylmalonic acid was noted after 7-10 days of cobalamin administration.

N-acetylcysteine treatment lowers plasma homocysteine but not serum lipoprotein(a) levels.

High levels of lipoprotein(a) (Lp(a)) or homocysteine in plasma have both been associated with an increased risk for premature cardiovascular disease. For both components, the plasma levels are primarily genetically determined, and they have been very restintant to therapeutic approaches. It has been suggested that N-acetylcysteine (NAC) breaks disulphide bonds in Lp(a) as well as between homocysteine and plasma proteins. In the present study we analyze if this mechanism, in vivo, could be used to lower plasma concentrations of Lp(a) and homocysteine. Treatment with NAC and placebo was performed in a double blind cross over design with 2 weeks wash-out between treatments. Eleven subjects with high plasma Lp(a) (> 0.3 milligram) were recruited from the Lipid Clinic at Sahlgren's Hospital, Göteborg, Sweden. Main outcome measures were treatment effects on plasma Lp(a) and plasma amino thiols (homocysteine, cysteine and cysteinyl glycine). There was no significant effect on plasma Lp(a) levels. Plasma thiols were significantly reduced during treatment with NAC: homocysteine by 45% (P < 0.0001), cysteinyl glycine by 24% (P < 0.0001) and cysteine by 11% (P = 0.0002). The high dose of NAC was well tolerated. In conclusion NAC has no effect on plasma Lp(a) levels while the reduction in homocysteine is considerable and might be of clinical significance in cases with high plasma homocysteine levels.

Plasma homocysteine in relation to serum cobalamin and blood folate in a psychogeriatric population.

Plasma homocysteine, serum cobalamin and blood folate were analysed in 296 consecutive patients referred to a psychogeriatric department for diagnosis of mental disease. Plasma homocysteine correlated with positive significance with age and serum creatinine, and with negative significance with serum cobalamin and blood folate. Approximately 35-40% of the patients with low serum cobalamin (< 150 pmol l-1) or low blood folates (< 150 nmol l-1) exhibited normal values of plasma homocysteine (< 19.9 mumol l-1). Possibly, these patients do not have a deficiency of the vitamins in the tissue. At least 7.5% of the patients with serum cobalamin levels (> 150 pmol l-1) showed an inexplicably increased level of plasma homocysteine. These patients might have a deficiency of tissue cobalamin despite the normal serum cobalamin levels. The effect of cobalamin supplementation for 7-10 days on plasma homocysteine was tested in 62 patients with different levels of serum cobalamins. We found the most pronounced decrease of plasma homocysteine in the patients with lowest serum cobalamin levels and in the patients with highest plasma homocysteine, indicating that the percentage decrease of the initial concentration of plasma homocysteine could reflect the degree of cobalamin deficiency. Folate supplementation for 7-10 days reduced plasma homocysteine not only in patients with folate deficiency but also in those with a normal folate status, and even in patients with cobalamin deficiency. The latter patients further reduced their plasma homocysteine after additional cobalamin treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of high-dose pyridoxine and folic acid supplementation on serum lipid and plasma homocysteine concentrations in dialysis patients.

Pyridoxine and folic acid supplementation in dialysis patients is a matter of debate. This study was performed to estimate the effects of pharmacologic doses of these vitamins on serum lipid and plasma homocysteine concentrations, which are known to be high in dialysis patients. Both hemodialysis and continuous ambulatory peritoneal dialysis patients were included in the study. Pyridoxine supplementation had a mild but significant cholesterol-lowering effect (7%). Folic acid supplementation significantly lowered plasma homocysteine concentrations by a mean of 30%. There was a strong, inverse correlation between blood folate and plasma homocysteine concentrations. These results indicate that daily supplementation with pyridoxine 300 mg and folic acid 5 mg has a beneficial effect on the cardiovascular risk profile in dialysis patients.

Plasma homocysteine in women on oral oestrogen-containing contraceptives and in men with oestrogen-treated prostatic carcinoma.

The mechanism by which oral oestrogen-containing contraceptives in women and oestrogen treatment of prostatic carcinoma in men increases the risk of vascular disease is unclear. These agents decrease serum concentrations of vitamin B12, pyridoxal 5-phosphate, and folate, all of which are essential for the metabolism of the atherogenic amino acid homocysteine. We found serum vitamin B12 concentrations to be lower in 17 women using oral contraceptives (219 +/- 84 pmol l-1) than in 13 age-matched female controls (385 +/- 129, p less than 0.001), but similar values were obtained in the two groups both for fasting plasma homocysteine concentrations (9.1 +/- 2.4 vs 9.2 +/- 3.6 mumol l-1) and for the increase in these concentrations after methionine loading (19.2 +/- 7.5 vs 17.8 +/- 5.2 mumol l-1). In five men with prostatic carcinoma, high-dose oestrogen treatment decreased serum vitamin B12 concentrations by a mean of 30% (p less than 0.05) within 4 weeks, during which fasting plasma homocysteine concentrations decreased (13.8 +/- 4.5 vs 10.5 +/- 2.8 mumol l-1) and response to methionine loading increased (12.4 +/- 3.4 vs 17.3 +/- 5.1 mumol l-1), though the latter changes were non-significant. Our findings do not support the hypothesis that hyperhomocysteinemia explains cardiovascular risk in women using oral oestrogen-containing contraceptives, or in oestrogen-treated men with prostatic carcinoma.

Early biochemical and histological changes in rats exposed to a single injection of thioacetamide.

Liver injury was induced by one subcutaneous administration of thioacetamide (200 mg/kg b.wt.) and studied 24 and 48 hrs later. Levels of aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) increased after 24 and 48 hrs. The lysosomal enzymes beta-hexosaminidase (beta-NAG) and beta-glucuronidase (beta-GLU) increased significantly after 24 hrs, while the level of beta-GLU returned to normal after 48 hrs, but the activity of beta-NAG remained significantly high even after 48 hrs. Histopathological examination showed necrotic hepatocytes around the central vein with infiltration of macrophages, neutrophils and eosinophils. The plasma zinc level decreased after 24 hrs and returned to normal after 48 hrs. Liver zinc content increased simultaneously at 24 hrs, returning to normal after 48 hrs. No alterations of plasma copper were observed after 24 and 48 hrs. Copper content of the liver increased significantly after 24 and 48 hrs. The present study thus shows that one dose of thioacetamide results in profound liver injury and supplementation of zinc prior to and simultaneously with thioacetamide normalized plasma zinc, increased liver zinc content and reduced the increase of beta-NAG, but did not influence the histological changes.

Total body hyperthermia induced by a computerized microwave technique: studies in normal rats and in rats with liver tumors.

A computerized system for inducing total body hyperthermia by microwave irradiation was tested in rats. The tolerance to hyperthermia at different temperatures and fractions was studied as well as its effect on the growth of transplanted adenocarcinomas in the liver. Survival results indicated that 41.5 degrees C was maximum tolerated temperature both after single and repeated one hour exposures. Besides the high mortality with a greater temperature (42 degrees C) there was a significant rise in S-aspartate-amino-transferase (S-ASAT) and S-beta-hexosaminidase (beta-nagas) indicating damage of normal cells. No significant reduction of tumor volume could be registered after treatment with total body hyperthermia (41.5 degrees C) for one hour three times during a 24 hour period.