Treatment with high-dose folic acid effectively lowers plasma homocysteine concentration in cyclosporine-treated renal transplant recipients.
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Cyclosporine↗
Biomedical subjects
B Hultberg
Publications and source records attributed to B Hultberg.
The effects of homocysteine and copper ions on the concentration and redox status of thiols in cell line cultures.
Different fractions (reduced and total) of thiols (homocysteine, cysteine and glutathione) were determined in HeLa cell cultures with and without addition of copper ions and/or homocysteine. In cell cultures without any addition the concentration of all intracellular thiols increased between 1 and 24 h of culture. Glutathione had the highest, whereas homocysteine showed the lowest, proportion of the reduced form. In the medium, there was a decrease of total cysteine during the incubation, but the amount of extracellular reduced cysteine increased. Both homocysteine and glutathione were released into the medium. The amount of exported homocysteine during the incubation exceeded several-fold the intracellular amount. There were no signs of cell toxicity induced by the high amounts of extracellularly added homocysteine (2000 mumol/l) in HeLa cell cultures, except a slight decrease in the concentration of intracellular glutathione. After the addition of copper ions (500 mumol/l) there was a retarded cell growth, decreased intracellular concentration of glutathione, increased release of glutathione into the medium and a lower proportion of all intra- and extracellular reduced thiols. After the addition of both copper ions and homocysteine to HeLa cell cultures, similar changes as with the addition of copper ions were noted except that the cell growth was still more retarded and that a very high level of intracellular homocysteine was noted at 1 h of incubation. N-acetylcysteine lowered, in these experiments, the intracellular accumulation of homocysteine and restored, to some extent, the cell growth. In an endothelial cell line even the presence of 500 mumol/l of homocysteine and 50 mumol/l of copper ions inhibited the cell growth and decreased the cellular level of glutathione. Whilst the levels of homocysteine in our short-time cell culture experiments are higher than the mild hyperhomocysteinemia thought to be atherogenic in humans (20-30 mumol/l), it is conceivable that over a longer time-course (several decades) these lower levels of homocysteine in the presence of copper ions could be sufficient to induce cellular effects similar to those found in the present study, eventually leading to atherosclerosis.
Acetylcysteine↗
Copper ions differ from other thiol reactive metal ions in their effects on the concentration and redox status of thiols in HeLa cell cultures.
Ions of metals such as copper, mercury, silver and cadmium are known to exhibit a high affinity for thiol groups and may therefore severely disturb many metabolic functions in the cell. Copper ions are also known to catalyse the formation of toxic oxygen species through a series of redox reactions. In the present study, we have determined the concentration of reduced and total glutathione, cysteine and homocysteine in a cell culture system (HeLa cell line) after addition of these metal ions. The main findings of the metal ion effect on the total thiol concentrations are that all metal ions increased the release of glutathione into the medium. Since the intracellular concentration of glutathione did not decrease under these conditions, the synthesis of glutathione must have been increased. In contrast to the other metal ions, copper ions also increased the release of homocysteine into the medium, possibly through interaction with S-adenosylhomocysteine hydrolase. The main findings of metal ion effects on reduced thiol are that, at concentrations not interfering with cell growth, mercury, silver and cadmium ions increased the concentration of extracellular reduced glutathione, possibly reflecting the increase of total glutathione in the medium. In contrast to the other metal ions, the addition of even very low amounts of copper ions (1 mumol/l) decreased the concentration of intra- and extracellular reduced thiols indicating oxidative stress.
Animals↗
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.
Aged↗
Marginal folate deficiency as a possible cause of hyperhomocystinaemia in stroke patients.
It has been reported that patients with vascular disease seem to increase their concentration of plasma homocysteine after the acute episode, whereas reexamined control subjects do not change their concentration of plasma homocysteine over time. Since the main determinants of plasma homocysteine are serum cobalamin, blood folate and serum creatinine we measured these quantities in 20 control subjects and 49 stroke patients in the acute phase and at reexamination 1.5-2 years after acute stroke onset. There were no significant differences between the levels of blood folate, serum cobalamin and serum creatinine in the acute and convalescent phase of all 49 stroke patients. However, we noted a significant decrease of blood folate concentrations in a subgroup of patients (n = 25) who had increased plasma homocysteine concentrations. Thus the increase in plasma homocysteine concentrations in this group of patients may partly be caused by a marginal folate deficiency.
Aged↗
Poor metabolic control, early age at onset, and marginal folate deficiency are associated with increasing levels of plasma homocysteine in insulin-dependent diabetes mellitus. A five-year follow-up study.
In a previous study, we showed that diabetic patients exhibited significantly increased concentrations of total plasma homocysteine (tHcy), but not until the onset of nephropathy. It was suggested that the hyperhomocysteinaemia might contribute to the accelerated atherosclerotic process in diabetic patients. In the present study, we have analysed the main determinants of plasma homocysteine (i.e. serum cobalamin, blood folate and serum creatinine), and also some other parameters related to diabetes mellitus, such as medical history, metabolic and renal quantities, on two occasions with a 5-year interval in 50 patients with insulin-dependent diabetes mellitus, in order to further elucidate the relation between plasma tHcy and diabetes mellitus. The result of the present study shows that diabetic patients with the lowest age at onset and with the poorest metabolic control are those most prone to a rapid increase in plasma tHcy concentration. The increment in plasma tHcy concentration in this group of patients may at least partly be explained by a marginal deficiency of blood folate concentrations.
Adult↗
Serum levels of IgG antibodies against Tamm-Horsfall protein and urinary excretion of NAG and alpha-1-microglobulin as possible markers for tubular damage in patients with a continent ileal reservoir for urinary diversion.
Serum IgG antibodies against Tamm-Horsfall protein and urinary excretion of NAG and alpha-1-microglobulin were measured in 26 patients with a Kock reservoir for continent urinary diversion or orthotopic bladder reconstruction in order to detect any signs of tubular damage. None of these markers for tubular damage was correlated to the postoperative observation time ranging between 2 and 16 years. No correlation was found between these markers and signs of renal scarring or upper urinary tract dilatation as judged from urographies. A positive correlation was demonstrated between NAG excretion and antibodies against Tamm-Horsfall protein. The annual reduction in GFR was increased in patients with elevated alpha-1-microglobulin excretion but not in patients with elevated titres of antibodies against Tamm-Horsfall protein or increased NAG excretion. Patients with previous or present reflux nipple problems had elevated excretion of alpha-1-microglobulin. Regular determinations of alpha-1-microglobulin excretion appear to be of value in the follow-up of these patients.
Acetylglucosaminidase↗
Hyperhomocysteinemia in cyclosporine-treated renal transplant recipients.
Moderate hyperhomocysteinemia, an independent cardiovascular risk factor, has been reported in renal transplant recipients. In the present study, plasma concentrations of total homocysteine were significantly increased in 120 renal transplant recipients as compared with 60 healthy controls (19.0 +/- 6.9 vs. 11.6 +/- 2.8 mumol/L, P < 0.0001) and as compared with 53 patients without a transplant but with a comparable degree of renal failure (19.0 +/- 6.9 vs. 16.0 4.9 mumol/L, P < 0.01). There was a significant inverse correlation between glomerular filtration rates and plasma homocysteine concentrations in the renal transplant recipients (r = -0.52, P < 0.0001). Groups of renal transplant recipients, with and without cyclosporine, and renal patients without a transplant were studied; these groups were comparable regarding age, sex distribution, glomerular filtration rate, and folate and vitamin B12 concentrations. Renal transplant recipients on cyclosporine had significantly higher plasma homocysteine concentrations than those not on cyclosporine (19.5 +/- 7.6 vs. 16.2 +/- 4.8 mumol/L, P < 0.05), and the patients without a transplant (19.5 +/- 7.6 vs. 16.0 +/- 4.9 mumol/L, P < 0.01). Thus, the hyperhomocysteinemia of renal transplant recipients not treated with cyclosporine, and that of renal patients without a transplant probably is explained by the same mechanism: renal insufficiency. An additional mechanism seems to operate in renal transplant recipients treated with cyclosporine. The lack of correlation between the concentrations of plasma homocysteine and red cell folate in these patients suggests that cyclosporine interferes with folate-assisted remethylation of homocysteine. Plasma homocysteine concentrations were significantly increased in 24 patients with a history of atherosclerotic complications as compared with the remaining 96 renal transplant recipients (20.8 +/- 4.4 vs. 18.5 +/- 7.3 mumol/L, P < 0.01).
Adult↗
Plasma beta-hexosaminidase isoenzymes A and B in patients with cerebral infarction.
We determined plasma activity of the isoenzymes of beta-hexosaminidase (Hex) in 151 patients with cerebral infarction, since earlier findings have shown a relation between Hex isoenzymes and risk factors for vascular disease in normal subjects. Compared with 206 control subjects, an elevated level of plasma Hex isoenzymes was found in patients with cerebral infarction, particularly females. However, there was no relation to the clinical subtypes of diagnosis or to the presence of any risk factors for vascular disease, such as carotid artery stenosis, major potential cardio-embolic risk factors on echocardiography, hypertension, heart disease, diabetes mellitus or tobacco smoking. Instead, our findings indicate that Hex isoenzymes in patients with cerebral infarction are more influenced by the level of serum aspartate aminotransferase and blood glucose. The main conclusion is that the liver function as reflected by the level of liver enzymes and glucose metabolism are the major determinants of Hex isoenzymes in plasma.
Aged↗
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.
Acetylcysteine↗
Hyperhomocysteinaemia--a common finding in a psychogeriatric population.
Plasma homocysteine concentration is a sensitive marker for cobalamin and folate deficiency. The previously reported high incidence of increased plasma homocysteine in psychogeriatric patients and the association between reduced concentrations of cobalamin, folate and neuropsychiatric symptoms led to the present study on 741 consecutive psychogeriatric patients. The concentrations of plasma homocysteine correlated significantly with blood folate, serum cobalamin and serum creatinine both in demented (n = 295) and in non-demented patients with other psychiatric disorders (n = 215). Plasma homocysteine concentrations were significantly increased in both the demented and the non-demented patients, whereas only the demented patients had lower blood folate and serum creatinine concentrations than 163 control subjects. Almost all of the different diagnostic groups of demented and non-demented patients exhibited significantly increased plasma homocysteine concentrations compared with control subjects. Significantly decreased blood folate concentrations were mainly found in the different diagnosis groups of demented patients. Plasma homocysteine concentrations in both demented and non-demented patients with serum cobalamin and blood folate above the lower 20th percentile of these vitamins in the control subjects were also studied. Despite these vitamin concentrations, both groups of patients still exhibited significantly higher plasma homocysteine concentrations than the control subjects, which may indicate an increased frequency of impaired genetic capacity to metabolize homocysteine in these patients. Patients with either dementia of vascular cause or a history of other occlusive arterial disease had a significantly higher plasma homocysteine concentration than those without a history of vascular disease.
Aged↗
beta-Hexosaminidase isoenzymes A and B in middle-aged and elderly subjects: determinants of plasma levels and relation to vascular disease.
Plasma/serum beta-hexosaminidase (Hex) activity is known to be increased in chronic alcoholism, liver disorders, pregnancy and diabetes mellitus. Hex activity also shows an association with risk factors for vascular disease and heredity for arteriosclerosis. There are several isoenzymes of Hex. Using an enzyme immunoassay for Hex isoenzymes (Hex A and Hex B) we studied possible determinants of Hex isoenzymes and their relation to vascular disease in randomly invited (n = 244) 35-95-year-old men and women. In both sexes there were significant age-related increases in Hex activities and men exhibited higher activity of both isoenzymes. Both Hex isoenzymes correlated with age, systolic blood pressure, serum triglycerides and liver enzymes, whereas Hex A was distinguished from Hex B by its stronger correlation with blood glucose. In multiple linear regression analysis Hex A was explained to 20.7% by blood glucose, age, serum aspartate aminotransferase and glutamyl transpeptidase. Hex B was explained to 14% by age, serum glutamyl transpeptidase and serum triglycerides. There was no significant increase in Hex isoenzymes in subjects with hypertension, diabetes mellitus or myocardial disease, nor did current smokers exhibit any increase of these enzymes compared to non-smokers. The main conclusion in that liver function, as reflected by the level of liver enzymes and glucose metabolism, is the major determinant for Hex isoenzymes in plasma.
Adult↗
The effect of reduced glomerular filtration rate on plasma total homocysteine concentration.
The concentration of homocysteine in plasma has been shown to be increased in renal failure, possibly contributing to the accelerated atherosclerosis observed in uraemic patients. The aim of the present study was to document the relationship between plasma total homocysteine (tHcy) concentrations and glomerular filtration rates (GFR) in highly selected patients, with renal function ranging from normal to dialysis dependency. GFR was defined as the plasma clearance of iohexol; a more accurate method than the creatinine-based estimations applied in previous studies. Plasma tHcy concentrations were highly correlated to GFR (r = -0.70, p < 0.0001) and were significantly increased already in moderate renal failure. According to a multiple regression analysis, GFR and red cell folate concentrations independently predicted plasma tHcy concentrations, whereas those of serum creatinine, plasma pyridoxal-5-phosphate, urine albumin and urine alpha-1-microglobulin (a marker of tubular damage) did not. Thus, GFR seems to be a better determinant of plasma tHcy concentration than serum creatinine concentration. Plasma total cysteine and total cysteinylglycine concentrations followed the same pattern as those of tHcy.
Adult↗
Iohexol clearance for GFR-determination in renal failure--single or multiple plasma sampling?
The present study examined the agreement between single and multiple sample plasma clearance of iohexol, a non-ionic contrast agent, in renal failure. Sixty-five patients with varying degree of renal insufficiency received 10 ml iohexol (300 mg I/ml) i.v. and plasma samples were collected four times during the following 3-24 h. Plasma-iodine concentrations were determined by X-ray fluorescence. Predicted creatinine clearance was used to choose one of the samples for determination of single sample clearance. A single plasma specimen collected at 4 h for GFR above 50 ml/min, at 7 h for GFR between 20 and 50 ml/min, and at 24 h for GFR below 20 ml/min gave values in good agreement with those based on a four sample slope clearance. No sign of nephrotoxicity was noted after administration of the contrast agent. It is concluded that single sample plasma clearance after single injection of iohexol gives a good estimate of GFR in renal failure and is advantageous in clinical practice.
Adult↗
Metabolism of homocysteine, its relation to the other cellular thiols and its mechanism of cell damage in a cell culture line (human histiocytic cell line U-937).
This study shows that the intracellular concentration of homocysteine in cultured cells is kept low due to an accumulation in the medium. The intracellular level of homocysteine was decreased when its precursor, methionine, was omitted from the culture medium. Intracellular glutathione and cysteine were lowered in cystine-deficient medium. Intracellular glutathione was also lowered when copper ions were added to the culture medium. It is evident from this study that the intracellular concentration of homocysteine was not influenced by the lowered level of glutathione and/or cysteine. High amounts of homocysteine added to the medium give rise to an increase of intracellular reduced homocysteine, which participates in the transsulfuration pathway and can replace cysteine in the synthesis of glutathione. The addition of relatively high amounts of reduced homocysteine (500 mumol/l) in the presence of copper ions (100 mumol/l) to the culture medium can be directly toxic to the cells, possibly due to oxygen radicals formed by thiol auto-oxidation. Whilst the level of homocysteine in this study using short-time cell culture experiment is much higher than the mild hyperhomocysteinemia thought to be atherogenic in humans, it is conceivable that over a longer time course these levels of homocysteine could be sufficient to induce endothelial dysfunction, eventually leading to atherosclerosis.
Arteriosclerosis↗
Plasma homocysteine in acute myocardial infarction: homocysteine-lowering effect of folic acid.
OBJECTIVES: Moderate hyperhomocysteinaemia is an independent risk factor for cardiovascular disease which may be causal. We investigated whether the concentration of plasma homocysteine changes between the acute phase of myocardial infarction and follow-up, and whether treatment with oral folic acid was effective in lowering homocysteine levels in patients with myocardial infarction. DESIGN AND SUBJECTS: Plasma total homocysteine levels 24-36 h (baseline) after onset of acute myocardial infarction were compared with the levels obtained at 6 weeks' follow-up and with the levels in the controls. In the same patients, we studied the effect on plasma homocysteine of 6 weeks' treatment with daily oral folic acid doses of 2.5 or 10 mg compared to no treatment. RESULTS: At baseline, 12 of 68 patients (18%) had moderate hyperhomocysteinaemia (> 17.3 mumol L-1; P < 0.05). Between baseline and follow-up, plasma homocysteine levels increased from 13.1 +/- 4.6 to 14.8 +/- 4.8 mumol L-1 (mean +/- SD; P < 0.001). Treatment with nitroglycerin, streptokinase, beta blockers, or acetylsalicylic acid seemed not to have caused this change. Folic acid lowered plasma homocysteine in all but two of 33 treated patients with a mean decrease of 4.4 mumol L-1 (-27%; P < 0.001). There was no difference between the effect of 2.5 and 10 mg of folic acid. In the untreated group (n = 20), plasma homocysteine increased with a mean increase of 0.6 mumol L-1 (+4%; P < 0.05). CONCLUSIONS: Plasma homocysteine seems to increase in the post myocardial infarction period, the cause of which warrants further study. Folic acid appears to be an effective treatment for the reduction of both normal and increased plasma homocysteine concentrations in patients with myocardial infarction. This suggests that folic acid should be used for intervention when studying the effect of homocysteine-lowering therapy on the risk on myocardial infarction.
Adult↗
Increases and time-course variations in beta-hexosaminidase isoenzyme B and carbohydrate-deficient transferrin in serum from alcoholics are similar.
beta-Hexosaminidase B-isoforms (beta-hexosaminidase B, P, and intermediate forms; abbreviated herein as "Hex B") and serum carbohydrate-deficient transferrin (CDT) are two markers of alcohol abuse. In the present study, we have compared "Hex B" with CDT as markers of alcohol abuse in a group of alcoholics hospitalized for detoxification after a period of heavy alcohol abuse. We have also followed the disappearance rate of these two markers from circulation. "Hex B" was elevated in 38 of 42 patients hospitalized for detoxication, whereas CDT was elevated in 35 of 42 patients. A highly significant correlation was noted between "Hex B" and CDT in these patients (p = 0.52, p < 0.001). Neither "Hex B" nor CDT correlated with gamma-glutamyltransferase or AST. The disappearance rates from serum of "Hex B" and CDT were determined in 21 hospitalized patients followed for up to 15 days. "Hex B" and CDT showed similar time-course variation and half-lives, 6.5 +/- 3.7 (mean +/- SD) and 8.6 +/- 4.1 days, respectively. The possible reasons for a relation between these two markers are discussed, and it is concluded that more experience of both "Hex B" and CDT in unselected populations is needed to establish the diagnostic potential of these tests as markers of alcohol abuse.
Adult↗
Liver disease and serum hexosaminidase levels. Studies in a human hepatoma cell-line (Hep G2 cells).
In various forms of liver disease, increased levels of the lysosomal enzyme beta-hexosaminidase (Hex) occur in serum. This may be caused by disturbances of the hepatocytic function, and we therefore studied the intracellular and extracellular isoenzyme pattern of Hex in a human hepatoma cell-line (Hep G2), using an immunoassay method, which separates Hex A and Hex B isoforms. This cell-line synthesizes and secretes Hex. The cumulative release of extracellular activity was about 3-10% of the intracellular activity. B-isoforms comprised one-third of intracellular activity but only 20% of extracellular activity. The proportion of extracellular B-isoforms increased with time, presumably due to instability of A-isoforms at 37 degrees C. Cycloheximide inhibited the release of Hex activity, whereas NH4Cl increased the extracellular fraction of Hex, even at a concentration of 1 mmol/l. We speculate that the increased concentration of NH4+ in patients with liver disease interferes with the distribution pathway of the lysosomal enzymes. This might be one reason for the increased serum Hex activity found in patients with liver disease.
Ammonium Chloride↗