Björn Hultberg

Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease Effects of pyridoxine and folic acid treatment☆

Severe homocysteinemia due to genetic defects either of pyridoxal 5-phosphate (PLP)-dependent cystathionine beta-synthase (CBS) or of enzymes in vitamin B12 and folate metabolism is associated with very early-onset vascular disease. Therefore, we studied homocysteine metabolism in 72 patients presenting before the age of 55 years with occlusive arterial disease of cerebral, carotid, or aorto-iliac vessels. Twenty patients (28%) had basal homocysteinemia; and 26 patients (36%) had abnormal increases of plasma homocysteine after peroral methionine loading, which exceeded the highest value for 46 comparable controls and was within the range for 20 obligate heterozygotes for homocystinuria due to CBS deficiency. Basal plasma homocysteine content was strongly and negatively correlated to vitamin B12 and folate concentrations. Plasma PLP was depressed in most patients but there was no correlation between PLP and homocysteine values. In 20 patients, treatment with pyridoxine hydrochloride (240 mg/day) and folic acid (10 mg/day) reduced fasting homocysteine after 4 weeks by a mean of 53%, and methionine response by a mean of 39%. These data show that a substantial proportion of patients with early-onset vascular disease have impaired homocysteine metabolism, which may contribute to vascular disease, and that the impaired metabolism can be improved easily and without side effects.

Folic acid-an innocuous means to reduce plasma homocysteine

With an improved highly reproducible method, we measured total plasma homocysteine (free plus protein-bound) and related amino acids in the fasting state in healthy subjects, before and after treatment with co-factors for homocysteine metabolism: 1 mg cyanocobalamin (n = 14), 5 mg folic acid (n = 13) or 40 mg pyridoxine hydrochloride (n = 15) daily for 14 days. Cyanocobalamin and pyridoxine hydrochloride had no effects on plasma levels of amino acids, but folic acid had a considerable homocysteine-lowering effect. Total plasma homocysteine was reduced in all but two subjects, from 19.9 +/- 4.4 (mean +/- SEM) to 9.5 +/- 1.0 mumol/l (-52%, p less than 0.01). We propose that folic acid in excess acts by enhancing the remethylation of homocysteine to methionine. The finding confirms a previous report by us. Since homocysteine is considered to be an atherogenic amino acid and recent reports suggest that mild to moderate homocysteinaemia is also associated with premature vascular disease, treatment with folic acid might be of use as prophylaxis.

Plasma homocysteine before and after methionine loading with regard to age, gender, and menopausal status

Abstract. Homocysteine is a probably atherogenic amino acid, the fasting and post‐methionine load serum concentrations of which have been reported to be much lower in premenopausal women than in men and postmenopausal women. This difference has been proposed to explain the reduced proneness of premenopausal women to vascular disease. We measured both free and total plasma homocysteine concentrations both fasting and postmethionine load, in 169 healthy subjects. Twelve subjects (7%) had distinctly abnormal plasma homocysteine values. Among the remaining 157 subjects, neither fasting nor post‐load values of free or total homocysteine were lower in premenopausal women (n= 46) than in men of similar age (n= 41) or postmenopausal women (n= 37). Fasting but not post‐load values were lower in postmenopausal women than in men of similar age (n= 33), and lower among the women as a whole (n= 83) than among the men (n= 74). In men, fasting values increased with age, and paralleled age‐related decreases in the concentrations of homocysteine metabolism cofactors (serum vitamin B12, blood folate, and plasma pyridoxal 5‐phosphate). Both in men and in women, fasting total plasma homocysteine values were significantly and negatively correlated to serum vitamin B12 and blood folate concentrations. Whether the small differences in plasma homocysteine values between the present men and women may be a contributory factor vis‐à‐vis their different proneness to vascular disease has yet to be settled.

Moderate homocysteinemia--a possible risk factor for arteriosclerotic cerebrovascular disease.

Highly elevated concentrations of homocysteine measured as homocysteine or cysteine- homocysteine mixed disulfide (MDS) are found in plasma and urine in subjects with inherited abnormalities of the methionine metabolism. These subjects have a high incidence of arteriosclerotic vascular complica- tions during childhood. Homocysteine causes endothelial cell injury and cell detachment that initiates the development of arteriosclerosis. The present study demonstrates a significantly elevated mean plasma MDS concentration in 19 patients with arteriosclerotic cerebrovascular disease compared to 17 controls. Our findings suggest that moderate homocysteinemia might be a risk factor for arteriosclerotic cerebrovascular disease. Stroke Vol 15, No 6, 1984

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.

Plasma homocysteine in the acute and convalescent phases after stroke

BACKGROUND AND PURPOSE Stroke patients frequently manifest moderate hyperhomocysteinemia. In most published studies, plasma homocysteine was measured at least 1 month after stroke (or the interval was not reported). To determine whether plasma homocysteine concentrations change in the acute phase, we compared acute-phase values with both convalescent-phase and control values. METHODS Plasma homocysteine concentrations were measured in the acute phase (mean, 2 days after stroke onset) in 162 first-ever stroke patients aged 50 years or more (median, 75 years) and again at a median interval of 583 days (range, 460 to 645 days) after stroke onset in a subgroup of 17 patients, with values for 60 age-matched subjects serving as controls. Twenty of the control subjects were reexamined 2 to 3 years after their initial examination. RESULTS The median plasma homocysteine concentration was 13.4 mumol/L in the patient group compared with 13.8 mumol/L for control subjects (NS, Mann-Whitney U test) and increased from 11.4 mumol/L in the acute phase to 14.5 mumol/L in the convalescent phase in the subgroup of patients examined twice (P < .01, Wilcoxon signed rank test). In the 20 reexamined control subjects, no significant change over time in plasma homocysteine concentration was found. CONCLUSIONS The post-acute-phase increase in plasma homocysteine may explain why higher values were obtained for stroke patients than for control subjects in previous studies. Possible reasons for the variation in plasma homocysteine concentrations over time are (1) an acute-phase reduction secondary to a decrease in plasma albumin and (2) an increase in plasma homocysteine during the convalescent phase due to modified vitamin intake and/or lifestyle. The timing of plasma homocysteine measurements relative to stroke onset is a factor to be considered in the interpretation of results.

Higher total plasma homocysteine in vitamin B12 deficiency than in heterozygosity for homocystinuria due to cystathionine β-synthase deficiency☆

Homocysteine is an amino acid considered to cause vascular injury, arteriosclerosis, and thromboembolism. Total plasma homocysteine (free and protein-bound) was found to be twice as high in asymptomatic vitamin B12-deficient subjects (23.8 +/- 3.8 mumol/L, means +/- SEM, n = 20) as in controls (11.5 +/- 0.9 mumol/L, P less than .0001, n = 21), and higher than in heterozygotes for homocystinuria due to cystathionine beta-synthase deficiency (13.8 +/- 1.6 mumol/L, P less than .01, n = 14), who were recently shown to be much more common among patients with premature vascular disease than expected. Eight (40%) vitamin B12-deficient and two (14%) heterozygote subjects had significant homocysteinemia (greater than mean +2 SD for controls). After administration of hydroxycobalamin to vitamin B12-deficient subjects, homocysteine levels decreased to normal (-49%, 12.2 +/- 1.5 mumol/L, P less than .0001, n = 20). Thus, if homocysteine does cause vascular injury, theoretically vitamin B12-deficiency might be associated with an increased frequency of vascular disease.

Plasma homocysteine in acute myocardial infarction: homocysteine-lowering effect of folic acid

Abstract. 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.

Homocysteine and myocardial infarction.

Five (24%) subjects out of a group of 21 men, 48-58 years old (mean 54), who had suffered their first myocardial infarction (MI) before the age of 55 and with a low risk profile vis-à-vis conventional risk factors in a health screening preceding the MI, had abnormally high total plasma homocysteine values in the fasting state when investigated within 1-7 years (mean 3) after their MI. The patient group was exactly matched with 36 control subjects for sex, age, diastolic blood pressure, smoking, and serum concentrations of cholesterol and triglycerides. Total plasma homocysteine was negatively correlated to both erythrocyte folate and serum vitamin B12, and vitamin concentrations below the median of the normal distribution were found in the five with high plasma homocysteine content, indicating a possible involvement of reduced remethylation of plasma homocysteine to methionine. After methionine loading, in 3 of the patient group (14%) homocysteine levels exceeded mean +2 SD for controls, which may indicate heterozygosity for homocystinuria. Results are consistent with the hypothesis that a high plasma homocysteine content may be a risk factor for MI.

The increase of plasma homocysteine concentrations with age is partly due to the deterioration of renal function as determined by plasma cystatin C.

Abstract One of the main determinants of plasma homocysteine in healthy subjects is serum creatinine. In the present study, we therefore investigated the relation between plasma homocysteine concentration, serum creatinine and a new marker for glomerular filtration rate, plasma cystatin C concentration. Cystatin C reflects the glomerular filtration better than serum creatinine and is not related to the muscle mass and formation of creatinine. The study group consisted of 255 healthy subjects from a well-defined area in the southern part of Sweden. The concentration of plasma homocysteine was increased in men compared to women. This difference disappeared when men and women were stratified by serum creatinine values. Statistically significant correlations were noted between plasma homocysteine and age, plasma cystatin C and serum creatinine. It is shown that plasma homocysteine is not only correlated to serum creatinine as a result of renal function but also as a result of the relationship between homocysteine production and creatine-creatinine synthesis. Using linear regression we were able to show that plasma cystatin C had a higher explanatory value than age. Serum creatinine showed a lower explanatory power than age. The findings in the present study might suggest that the increase of plasma homocysteine concentration with age could be partly due to the deterioration of renal function. Study