Hyperhomocysteinemia in inflammatory bowel disease patients without past intestinal resections: correlations with cobalamin, pyridoxine, folate concentrations, acute phase reactants, disease activity, and prior thromboembolic complications

OBJECTIVE: Homocysteine is a sulfur-containing amino acid formed during the demethylation of methionine and high levels of this amino acid is a known risk factor for both arterial and also venous thromboembolic complications. Deficiencies of cobalamin, folate, and pyridoxine may predispose subjects to hyperhomocysteinemia, a common phenomenon in inflammatory bowel disease (IBD) patients. The aim of this study was to identify the prevalence, risk factors of hyperhomocysteinemia and its correlation with prior thromboembolic events in an IBD cohort without past intestinal resections. METHODS: In this prospective study, we studied the concentrations of homocysteine, cobalamin, folate, and pyridoxine in 105 consecutive patients with IBD, of whom 11 had a prior history of thromboembolic complications. Data regarding smoking habits, medication use, disease location, and severity were gathered and patients with past intestinal resections were excluded. Age-matched and sex-matched 85 healthy volunteers served as controls and multivariate regression analysis was performed to find out independent predictors of hyperhomocysteinemia. RESULTS: The mean age (+/-SD) in the IBD cohort was 38.69+/-12.13 years, and 51% were male. The mean age in the control group was 37.61+/-10.05 years, and 52% were male. Homocysteine concentrations in patients were higher [16.35 micromol/L (range 6.82 to 48.15) vs. 9.60 micromol/L (range 4.97 to 17.39), P=0.000] and hyperhomocysteinemia had a higher prevalence in patients than in the controls (56.2% vs. 4.7%, chi2=56.179, P=0.000), thus IBD significantly increased the risk of hyperhomocysteinemia [odds ratio=25.973 (95% confidence interval: 8.861-76.128)]. Homocysteine concentrations in patients with a history of thrombosis were not higher than those without a history of thrombosis [16.29 micromol/L (range 8.45 to 34.75) vs. 16.36 micromol/L (range 6.82 to 48.15), not significant]. Hyperhomocysteinemia was found in 54.5% of patients with thrombosis and 56.4% of patients without thrombosis (not significant). On stepwise regression analysis, plasma cobalamin level, albumin concentration, erythrocyte sedimentation rate, and platelet count were found to be independent predictors of elevated homocysteine levels. CONCLUSIONS: IBD patients have a higher prevalence of hyperhomocysteinemia than do healthy controls and elevated homocysteine levels are independently associated with lower serum cobalamin, albumin levels and elevated erythrocyte sedimentation rate, and platelet count. There is no correlation between hyperhomocysteinemia and a history of prior thromboembolic events.     

Hyperhomocysteinemia and inflammatory bowel disease: prevalence and predictors in a cross-sectional study

OBJECTIVE: Homocysteine is a sulfur-containing amino acid formed during the demethylation of methionine. Vitamin B12 and folate deficiency and therapy with antifolate drugs may predispose patients with inflammatory bowel disease (IBD) to hyperhomocysteinemia. The known associations between hyperhomocysteinemia and smoking, osteoporosis, and thrombosis make it an interesting candidate as a pathogenetic link in IBD. The aim of this study was to identify the prevalence and risk factors of hyperhomocysteinemia in patients with IBD. METHODS: Sixty-five consecutive IBD patients were recruited from a tertiary outpatient gastroenterology practice. Fasting plasma homocysteine levels were measured, along with vitamin B12 and folate. Data regarding medication use, multivitamin use, disease location and severity, and extraintestinal manifestations of IBD were gathered. Homocysteine levels in 138 healthy control subjects were compared with the IBD cohort, and adjustments for age and sex were made using logistic regression. Multivariate analysis was performed to seek predictors of homocysteine levels. RESULTS: The mean age in the IBD cohort was 42+/-13.4 yr (+/-SD), and 43% were male. The mean disease duration was 13.8+/-9.4 yr, and 32% had used steroids within the last 3 months. Immunomodulator therapy had been used in 32%, and 75% had had an intestinal resection. Osteoporosis was present in 33% of patients. Five patients had experienced venous thrombosis or stroke, but only one of these had hyperhomocysteinemia. Of the 10 IBD patients (15.4%) with hyperhomocysteinemia, only two had vitamin B12 deficiency. The homocysteine levels in the IBD cohort cases and controls were 8.7 and 6.6 micromol/L, respectively (p < 0.05). IBD significantly increased the risk of hyperhomocysteinemia (adjusted odds ratio = 5.9 [95% CI: 1.5-24]). Advanced age, male sex, vitamin B12 deficiency or lower vitamin B12 serum levels, and multivitamin therapy were independently associated with higher homocysteine levels in the multivariate analysis (R2 = 0.55; p = 0.001). CONCLUSIONS: Hyperhomocysteinemia is significantly more common in patients with IBD compared with healthy controls, and is associated with lower (but not necessarily deficient) vitamin B12 levels.     

Homocysteine in inflammatory bowel disease: a risk factor for thromboembolic complications?

OBJECTIVE: Patients with inflammatory bowel disease (IBD) are at increased risk for thromboembolic events. Hyperhomocysteinemia, which is an established risk factor for arterial as well as venous thrombosis, may be more prevalent in IBD because of vitamin deficiencies. METHODS: In this retrospective study, we studied the concentrations of total homocysteine (tHcy), cobalamin, folate, and pyridoxine in 231 consecutive patients with IBD, of whom 16 patients had a history of venous thrombosis, and nine a history of arterial thrombosis. Age- and gender-matched healthy volunteers served as controls (n = 102). RESULTS: Homocysteine concentrations in patients were higher (12.3 micromol/L [range 4.6-51.3] vs 11.1 micromol/L [range 3.9-27.6], p = 0.001) and hyperhomocysteinemia tended to be more prevalent in patients than in the controls (11.1% vs 5%, p = 0.07). Folate, cobalamin, creatinine, and pyridoxine concentrations were correlated with tHcy. Folate deficiency was infrequently encountered in IBD patients (4.3%). The tHcy concentration in patients with a history of venous or arterial thrombosis was not higher than in patients without a history of thrombosis (12.7 micromol/L [range 4.6-40.1] and 15.2 micromol/L (range 10.5-26.8) vs 12.3 micromol/L [range 10.5-26.8], not significant). Hyperhomocysteinemia was found in 18.8% of the patients with venous thrombosis, 11.1% of the patients with arterial thrombosis, and 10.5% of the patients without thrombosis (not significant). CONCLUSIONS: Hyperhomocysteinemia is a common phenomenon in IBD and correlates with serum folate, cobalamin, creatinine, and pyridoxine concentrations. No correlation between tHcy and a history of venous or arterial thromboembolic complications is found. Hyperhomocysteinemia does not seem to be a major contributory factor in the development of venous or arterial thrombosis in IBD patients.     

Hyperhomocysteinemia in Greek Patients with Inflammatory Bowel Disease

In recent years hyperhomocysteinemia has been established as a new risk factor for arterial and venous thrombosis. Since patients with inflammatory bowel disease (IBD) frequently suffer from thromboembolic events, we studied the prevalence and clinical significance of hyperhomocysteinemia in Greek patients with ulcerative colitis (UC) and Crohn's disease (CD). In 108 consecutive fasting IBD patients (53 UC and 55 CD) and 74 healthy controls (HC), a standard record of various clinical thrombotic risk factors was completed by interview, and fasting serum concentrations of total homocysteine (tHcy), folate, cobalamin, creatinine, cholesterol, HDL, LDL, and triglycerides were measured. The concentration (mean ± sd) of serum tHcy was significantly higher in UC (15.9 ± 10.3 mol/liter) and CD patients (13.6 ± 6.5) than in controls (9.6 ± 3.4, P < 0.05). Both UC and CD patients had lower levels of folate than HC (P < 0.05). Covariance analysis of age, gender, and all clinical variables indicated that the differences in homocysteine levels between IBD patients and HC remain significant even after adjustment for these covariates. In conclusion, mild hyperhomocysteinemia is common in Greek IBD patients and may account for the increased thrombotic risk of these patients.     

Risk Factors for Thromboembolic Complications in Inflammatory Bowel Disease: The Role of Hyperhomocysteinaemia

Inflammatory bowel disease (IBD) is associated with an increased risk for thromboembolic events. Aim of this study was to examine the relationship of hyperhomocysteinemia and thrombosis in IBD patients and to assess the role of this factor in addition to other known prothrombotic abnormalities. IBD patients with a history of thrombosis (n = 22) and sex-, age-, and diagnosis-matched IBD controls (n = 23) were studied. Homocysteine (tHcy) was assessed before and after methionine loading. Plasma levels of protein C, protein S, antithrombin III, and fibrinogen and the presence of anticardiolipin and antiphospholipid antibodies were determined and genetic testing for factor V Leiden and the prothrombin gene mutation was performed. Results showed that fasting homocysteine levels in IBD patients with a history of arterial or venous thrombosis tended to be higher than in IBD controls, although not significantly. The increase in homocysteine levels after methionine loading was significantly higher in IBD patients in the arterial thrombosis group than in IBD controls (40.9 ± 17.7 vs. 27.2 ± 9.9 M; P < 0.05). Among the other prothrombotic factors, only factor V Leiden was significantly associated with a history of venous thrombosis (20 vs. 0%). At least one risk factor was found in 64% of the IBD patients with previous thromboembolic complications. We conclude that there is an association between hyperhomocysteinemia and a history of arterial thrombosis in IBD patients. We confirm the high prevalence of factor V Leiden in IBD patients with a history of venous thrombosis. In the majority of IBD patients with previous thromboembolic complications, at least one prothrombotic risk factor is detected.     

Hyperhomocysteinemia in patients with mild chronic renal failure

BACKGROUND: The aim of this study was to evaluate the prevalence of high plasma levels of homocysteine in patients with mild renal failure. METHODS: Forty-six chronic renal failure patients (25 males and 21 females, mean age 55.6+/-14.4 years) were recruited for the study. Mean plasma creatinine was 2.1+/-1.0 mg/dl and mean creatinine clearance was 50.6+/-26.3 ml/min. Patients with severe renal failure were excluded. Patients were compared with a control group with normal renal function (n=35, 22 men and 13 women, mean age 50.0+/-11.5 years). Plasma homocysteine values were measured in both groups at baseline and after an oral overload of methionine. RESULTS: Baseline homocysteine levels of patients were higher than those of controls (16.5+/-7.3 vs. 10.4+/-4.2 micromol/l, p<0.0001). Some 34 patients and 4 controls had increased plasma homocysteine levels at baseline. After the oral overload, 4 more patients had abnormally increased homocysteine levels, meaning that 83% of the patients with chronic renal failure had hyperhomocysteinemia. CONCLUSIONS: Hyperhomocysteinemia is a very common finding among patients with mild renal failure. The need for vitamin supplementation should be evaluated in the first stage of chronic renal failure.     

Plasma homocysteine levels in acute coronary syndromes

Hyperhomocysteinemia is currently regarded as an independent and modifiable risk factor for ischemic vascular diseases and thrombosis. We measured fasting plasma total homocysteine levels by HPLC with fluorescence detection in 30 patients presenting with acute coronary syndromes and 30 age and sex-matched control subjects. Demographic data, classical risk factors (systolic blood pressure, diabetes mellitus, smoking, ethanol intake, family history of ischaemic heart disease) and life-style habits were recorded. Lipid fractions including total cholesterol, triglycerides, HDL-cholesterol, total cholesterol/HDL-cholesterol ratio, serum creatinine, LDL-cholesterol and vitamins involved in the metabolism of homocysteine, folic acid and vitamin B12 were also assessed. Total fasting homocysteine concentrations were significantly higher in the patient group (12.2 +/- 1.01 micromol/l) than in the control subjects (7.05 +/- 0.36 micromol/l; p < 0.0001). Homocysteine correlated positively with age (r = 0.617; p < 0.01) and serum creatinine (r = 0.457; p < 0.01) in the patient group. Hyperhomocysteinemia was not associated with vitamin B12 or folate deficiency states. Vitamin B12 concentration was 273 +/- 16.4 ng/l in the control group and 284.3 +/- 32.2 ng/l in the patient group (p = NS). Serum folate concentration also was not significantly different between controls and patients; 7.57 +/- 0.58 microg/l and 8.05 +/- 0.72 microg/l, respectively. Since no significant difference was observed in the lipid parameters between patients and controls, the hyperhomocysteinemia in the patient group supports the view that homocysteine is an independent risk factor for cardiovascular diseases. Our results strongly suggest that elevated homocysteine levels are among the interacting factors in the complex, multifactorial pathophysiology of ischemic heart disease.     

Hyperhomocysteinemia and related factors in 600 hospitalized elderly subjects

Hyperhomocysteinemia (HHcy) is a metabolic disorder frequently occurring in the elderly population. Recently several reports have suggested abnormalities in homocysteine (tHcy) metabolism implicating HHcy as a metabolic link in the multifactorial processes characterizing many geriatric illnesses-with special emphasis on atherosclerotic vascular diseases and cognitive impairment. The present study was undertaken in a large sample of elderly hospitalized subjects to determine (1) the prevalence of HHcy, (2) the association of HHcy with vascular and cognitive disorders, and (3) the factors independently predicting Hhcy. Six hundred elderly subjects (264 men and 336 women; mean age, 79 +/- 9 years) were randomly chosen from those admitted as inpatients over a period of 3 years. In all patients, body mass index (BMI), mid-upper arm muscle area (MUAMA), plasma cholesterol, triglycerides, total proteins, albumin, lymphocyte count, creatinine, homocysteine (fasting and 4 hours after methionine oral load), serum vitamin B(6), vitamin B(12), and folate concentrations were measured. The presence of disease or use of medications known to affect homocysteine plasma levels were also recorded. The mean fasting tHcy level was 16.8 +/- 12 micromol/L in the whole sample, 18.18 +/- 13.25 micromol/L in men, and 15.86 +/- 12.14 micromol/L in women (P =.005 men v women). The mean Hcy level 4 hours after methionine load was 37.95 +/- 20.9 in the whole sample. Prevalence of hyperhomocysteinemia (fasting Hcy > or = 15 micromol/L or 4 hours after methionine load > or = 35 micromol/L) was 61% (365/600) (67% in men and 56% in women, P <.05). HHcy was rarely (8%) an isolated disorder; in addition to diabetes (20%), renal failure (48.2%), and malnutrition (20.2%), it was often associated with heart failure (30%), malignancies (20.5%), and the use of diuretics (56%) and anticonvulsant drugs (13%). Plasma homocysteine progressively increases across subjects from those with no diabetes, malnutrition, renal failure, obesity, inflammatory bowel disease, heart failure to those with 1, 2, or more concurrent diseases. Multiple stepwise regression analysis showed that 72% of plasma total fasting tHcy variability was explained by age, serum folate, plasma albumin, use of diuretics, and renal function (measured as plasma creatinine clearance). In conclusion, the present study documents that hyperhomocysteinemia, in elderly hospitalized patients is (1) a common finding, (2) frequently associated with vascular and cognitive disorders, and (3) probably a secondary phenomenon in most cases. The major predictor of high plasma homocysteine levels were age, serum folate, plasma albumin, plasma creatinine clearance, and use of diuretic drugs. These variables explain a large proportion of plasma Hcy variability.     

Hyperhomocysteinemia in patients with heart failure referred for cardiac transplantation: preliminary observations

BACKGROUND: Hyperhomocysteinemia is becoming recognized as a risk factor for cardiovascular disease, yet there are limited data on the prevalence of hyperhomocysteinemia in patients with heart failure. HYPOTHESIS: The purpose of this study was to examine the prevalence of hyperhomocysteinemia in patients with severe heart failure and to correlate serum homocysteine levels with factors that may affect homocysteine metabolism. METHODS: Serum homocysteine levels were measured at the time of cardiac transplant evaluation in 89 consecutive patients with severe heart failure. Homocysteine levels for patients with ischemic cardiomyopathy (ICM) were compared with levels obtained in patients with nonischemic cardiomyopathy (NICM), and homocysteine levels were correlated with demographic and hemodynamic parameters as well as functional status. RESULTS: The mean plasma homocysteine level was increased (14.3 +/- 5.3 micromol/l, normal <9.0 micromol/l) and was equivalent between patients with ICM versus NICM (14.7 +/- 5.8 micromol/l vs. 13.8 +/- 4.5 micromol/l, p = 0.44). Elevated homocysteine levels were seen in a large proportion (89%) of patients and were equally common to patients with NICM (94%) and ICM (85%). Serum homocysteine levels correlated with serum creatinine (r = 0.51, p < 0.001), with a history of diabetes (p = 0.028), and with a history of peripheral vascular disease (p = 0.045). Only 6% of patients were receiving folic acid therapy at the time of transplant referral. CONCLUSION: Hyperhomocysteinemia is common in patients with severe heart failure, and plasma homocysteine levels are uniformly elevated regardless of the etiology of heart failure. Elevated plasma homocysteine levels are likely a consequence of heart failure-related renal insufficiency.     

Acute hyperhomocysteinemia decreases NO bioavailability in healthy adults

Hyperhomocysteinemia is associated with decreased vascular reactivity and increased cardiovascular morbidity. Oxidative stress and reduced NO bioavailability have been proposed as a mechanism for the adverse effects of chronically elevated plasma homocysteine levels. Recent studies suggest that acute elevations of plasma homocysteine may also impair endothelial function and vasodilation, however, the mechanism is not clear. In the present study, we investigated whether moderate hyperhomocysteinemia after methionine loading decreases NO bioavailability, increases oxidative stress, and impairs receptor-mediated NO-dependent venodilation in healthy adults. After oral methionine loading (0.1g/kg), mean homocysteine concentrations increased 3.2-fold, from 6.9 +/- 0.5 to 27.8 +/- 1.9 micromol/l (n = 16), whereas plasma NO(x) concentrations, an indicator of NO release, were decreased by 12% compared to placebo treatment (P = 0.005). Vitamin E levels in freshly isolated low density lipoprotein (LDL), a sensitive marker of LDL oxidation, and LDL lipid (hydro)peroxide levels were unchanged after methionine loading. Endothelium-dependent venodilation induced by bradykinin was reduced by 18% during hyperhomocysteinemia (P = 0.06). Taken together our data suggest that the reduced NO bioavailability was likely due to decreased NO synthesis and release rather than to NO destruction by oxidative stress.     

Hyperhomocysteinemia and methylenetetrahydrofolate reductase 677C-->T and 1298A-->C mutations in patients with inflammatory bowel disease.

BACKGROUND: Hyperhomocysteinemia has been recently described in patients with inflammatory bowel disease (IBD), that could be related to the increased risk for thrombosis that exists in this disease. The aim of this study was the assessment of hyperhomocysteinemia in patients with IBD and its relation among vitamin B12 and folate levels, and methylenetetrahydrofolate reductase (MTHFR) 677C-->T and 1298A-->C mutations. PATIENTS AND METHODS: Fifty two consecutive patients with IBD were studied (29 women and 23 men); age: mean (standard deviation 41.7 [11.9] years) and 186 controls with no difference in age and gender. Hyperhomocysteinemia was considered as homocysteine levels higher than mean plus two standard deviations of the control group (> or = 13 micromol/l). RESULTS: patients had an elevated prevalence of hyperhomocysteinemia (17.3 vs. 3.7%; p = 0.002) and lower folate (7.6 [4.1] vs. 8.9 [3.7] ng/ml; p = 0.01) and B12 vitamin levels (499 [287] vs. 603 [231] pg/ml; p = 0.003). Homocysteinemia was higher (14.3 [5.8] vs. 9.1 [3.9] micromol/l; p = 0.006) in 6 patients (11.5%) that had suffered thromboembolism. Frequency of MTHFR 677C-->T (13.5 vs. 11.3%; p = 0.66) and 1298A-->C (7.8 vs. 7.0%; p = 0.76) mutations was not increased in patients. Odds ratio (OR) for IBD in hyperhomocysteinemic patient was 5.51, 95% confidence interval (CI), 1.81-16.76; p = 0.002). Hyperhomocysteinemia was negatively associated with feminine gender (OR 0.08, 95% CI 0.01-0.49; p = 0.006) and folate levels (OR 0.04, 95%CI: 0.007-0.20; p < 0.001). CONCLUSIONS: hyperhomocysteinemia is associated with IBD and low folate levels, and could be involved in development of thromboembolism. MTHFR 677C-->T and 1298A-->C mutations are not related with the disease.     

Factors associated with hyperhomocysteinemia in Crohn's disease

AIMS: The incidence of thromboembolic disease is increased in patients with inflammatory bowel disease. Hyperhomocysteinemia is one of the risk factors for thrombosis. The aims were: 1) to assess the prevalence of hyperhomocysteinemia in a large series of patients with Crohn's disease; 2) to search for clinical and biological factors associated with hyperhomocysteinemia.PATIENTS AND METHODS: One hundred seventy-one patients with Crohn's disease (64 males, 107 females), median age 31 years (range: 16-82), were studied. The median duration of the disease was 7 years. The concentrations of homocysteine, folate, cobalamin and C-reactive protein were measured in serum from blood sample of each patient.RESULTS: The mean concentration of seric homocysteine was 14.8 micromol/L (N: 4.4 - 12.4 micromol/L). Hyperhomocysteinemia was observed in 89 patients (52%). It was significantly associated with age, sex, smoking habit, serum cobalamin level and history of ileal surgical resection (P<0.05). In the group of operated patients, there was a statistically significant association between hyperhomocysteinemia and the length of small bowel resected. In multivariate analysis, sex and smoking were associated with hyperhomocysteinemia.CONCLUSION: More than half of the patients with Crohn's disease have hyperhomocysteinemia. This result stresses the need for preventing reversible factors associated with hyperhomocysteinemia, such as smoking and cobalamin deficiency, in order to lower the thrombotic risk of patients with Crohn's disease.     

Hyperhomocysteinemia is common in patients with antiphospholipid syndrome and may contribute to expression of major thrombotic events.

Homocysteine plasma levels were measured by high-performance liquid chromatography in 52 patients with primary antiphospholipid syndrome (APS). Elevated homocysteine concentrations (>or= 15 micromol/l) were found in 16/52 (30.8%) APS patients. Elevated homocysteine levels were found to be associated with an increased risk for a major thromboembolic event (50 versus 16.7%, P = 0.014). Hyperhomocysteinemia is a common finding in APS patients, and may contribute to severity of thrombotic tendency observed in this syndrome.     

Demonstration of rapid onset vascular endothelial dysfunction after hyperhomocysteinemia: an effect reversible with vitamin C therapy

BACKGROUND: Hyperhomocysteinemia is a major and independent risk factor for vascular disease. The mechanisms by which homocysteine promotes atherosclerosis are not well understood. We hypothesized that elevated homocysteine concentrations are associated with rapid onset endothelial dysfunction, which is mediated through oxidant stress mechanisms and can be inhibited by the antioxidant vitamin C. Methods and RESULTS: We studied 17 healthy volunteers (10 male and 7 female) aged 33 (range 21 to 59) years. Brachial artery diameter responses to hyperemic flow (endothelium dependent), and glyceryltrinitrate (GTN, endothelium independent) were measured with high resolution ultrasound at 0 hours (fasting), 2 hours, and 4 hours after (1) oral methionine (L-methionine 100 mg/kg), (2) oral methionine preceded by vitamin C (1g/day, for 1 week), and (3) placebo, on separate days and in random order. Plasma homocysteine increased (0 hours, 12.8+/-1.4; 2 hours, 25.4+/-2.5; and 4 hours, 31. 2+/-3.1 micromol/l, P<0.001), and flow-mediated dilatation fell (0 hours, 4.3+/-0.7; 2 hours, 1.1+/-0.9; and 4 hours, -0.7+/-0.8%) after oral L-methionine. There was an inverse linear relationship between homocysteine concentration and flow-mediated dilatation (P<0. 001). Pretreatment with vitamin C did not affect the rise in homocysteine concentrations after methionine (0 hours, 13.6+/-1.6; 2 hours, 28.3+/-2.9; and 4 hours, 33.8+/-3.7 micromol/l, P=0.27), but did ameliorate the reduction in flow-mediated dilatation (0 hours, 4. 0+/-1.0; 2 hours, 3.5+/-1.2 and 4 hours, 2.8+/-0.7%, P=0.02). GTN-induced endothelium independent brachial artery dilatation was not affected after methionine or methionine preceded by vitamin C. CONCLUSIONS: We conclude that an elevation in homocysteine concentration is associated with an acute impairment of vascular endothelial function that can be prevented by pretreatment with vitamin C in healthy subjects. Our results support the hypothesis that the adverse effects of homocysteine on vascular endothelial cells are mediated through oxidative stress mechanisms.     

Role of homocysteine for thromboembolic complication in patients with non-valvular atrial fibrilation.

Thromboembolism is the most important complication in patients with atrial fibrilation (AF). Homocysteine is a toxic amino acid that has been recently accepted as a risk factor for atherosclerosis and stroke. The aim of the present study is to show whether there is a relation between hyperhomocysteinemia and thromboembolic complications in patients with non-valvular AF. We admitted 38 patients with non-valvular AF. The patients were divided into two groups: group A (n = 20; mean age, 75.7 +/- 10.4 years; three males/17 females), and group B (n = 18; mean age, 68.0 +/- 10.6 years; 11 males/seven females). While group A consisted of the patients with AF and stroke, group B was composed of the patients with AF but without stroke. The patients having sinus rhythm (15 subjects) were used as the reference group to obtain the cut-off value. Homocysteine was measured by the immunoassay method. The means of the homocysteine levels were 12.4 +/- 3.3 micromol/l in group A, 8.3 +/- 2.3 micromol/l in group B and 9.3 +/- 1.8 micromol/l in the reference group. The cut-off value was 10.6 micromol/l. Group A had a statistically higher homocysteine level than not only group B, but also the reference group (P < 0.05). While 60% of group A (n = 12) had the elevated homocysteine level, the rate was only 22% for group B (n = 4). In conclusion, hyperhomocysteinemia may be one of the explanations for the increased rate of thromboembolic complications in older patients with AF.     

Hyperhomocysteinemia in women with advanced breast cancer

Patients with malignancy have an increased risk of venous thromboembolic disease but the pathophysiology of this association has not been precisely defined. Hyperhomocysteinemia has become established as one of the commonest conditions associated with venous and arterial thrombosis. We examined the prevalence of hyperhomocysteinemia in women with early (group A, n = 31), metastatic breast cancer (group B, n = 41) and in a group of healthy females (group C, n = 29). Blood samples were collected at diagnosis or prior to treatment. We measured both total plasma homocysteine (tHcy) and red cell folate (RCF). The Mean (SD) tHcy were group A - 9.43 micromol/l (5.6), group B - 11.34 micromol/l (5.1) and group C - 7.9 micromol/l (1.5). A total of 39% of patients with metastatic and 22.6% with early breast cancer had tHcy concentrations above the upper limit of normal. Women with metastatic disease had significantly higher tHcy compared with controls (P < 0.01) but not when compared with women with early breast cancer. Also, no difference was observed when women with early disease were compared with controls. We found no correlation between age and tHcy. Lower RCF levels were identified in group B compared with group A, but this does not fully explain the increased tHcy levels seen within the same group. We conclude that hyperhomocysteinemia is common in women with advanced breast cancer. This observation could explain the high rate of venous thrombosis in women with metastatic breast malignancy.     

Homocysteinemia and coronary artery disease: a case-control study in a Tunisian population

We have determined the prevalence of hyperhomocysteinemia and tested its relationship with coronary heart disease in Tunisian patients. The study included 70 angiogrphically proven coronary patients and 140 age- and sex-matched healthy subjects. Plasma homocysteine folate and vitamin B12 were analyzed by immunoenzymatic methods. Hyperhomocysteinemia was considered for plasma homocysteine concentration >17 micromol/L. Mean plasma homocysteine concentration and hyperhomocysteinemia prevalence were significantly (p<0.001) higher in patients (16.3 +/- 7.9 micromol/L and 29%) than controls (12.6 +/- 4.0 micromol/L and 10%). The association between hyperhomocysteinemia and coronary heart disease persisted after adjusting on main cardiovascular risk factors (multi adjusted odds ratio, 2.99; 95% CI, 1.18-7.59; p=0.02). No association was observed between hyperhomocysteinemia and coronary disease severity and extent. This study showed an independent association between hyperhomocysteinemia and coronary heart disease, suggesting a role of hyperhomocysteinemia in atherothrombogenesis. However, causal relationship is not yet established. Until results of homocysteine-lowering therapy trials become available, hyperhomocysteinemia should be researched and treated in coronary heart disease patients.     

High prevalence of hyperhomocysteinemia due to marginal deficiency of cobalamin or folate in chronic myeloproliferative disorders

Hyperhomocysteinemia is an established risk factor for thrombosis. In patients with myeloproliferative disorders, thrombotic events are common. Our aim was to investigate whether the increased burden of proliferating cells present in these patients implies a risk of homocysteine (HCY) accumulation secondary to depletion of folate and/or cobalamin. Fifty patients (PV, 25; ET, 10; IMF, 15) and 163 healthy volunteers (HV) participated in the study. The prevalence of hyperhomocysteinemia was 56.0% in PV, 70.0% in ET, 60.0% in IMF, and 34.9% in HV. The mean P-homocysteine (P-HCY) was 13.88 +/- 4.24 micromol/L in PV, 12.78 +/- 3.70 in ET, 11.34 +/- 4.22 in IMF, and 9. 71 +/- 2.76 in HV. In PV and ET, but not in IMF, the mean P-HCY was significantly higher than in the HV group (P < 0.001, P = 0.028, and P = 0.163, respectively). Thirty-three percent of the patients with hyperhomocysteinemia displayed metabolic changes compatible with cobalamin deficiency (P-HCY and P-methylmalonic acid both elevated), while 67% were folate deficient (P-HCY elevated, P-methylmalonic acid normal). Supplementation therapy with the relevant vitamin was implemented in 11 vitamin-deficient patients and led to normalization of metabolite levels in all cases. No correlation between hyperhomocysteinemia and thrombosis was found. Our data indicate that patients with PV, ET, and IMF frequently develop hyperhomocysteinemia due to discrete depletion of cobalamin or folate. Vitamin therapy leads to normalization of P-HCY and should be considered, even though hyperhomocysteinemia does not seem to be of crucial importance for the thrombotic tendency in the myeloproliferative disorders.     

Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice

Hyperhomocysteinemia is an independent risk factor for atherothrombosis. However, causality is unproven, and it remains unknown whether hyperhomocysteinemia promotes atherosclerosis, plaque rupture, and/or thrombosis. We evaluated the short- and long-term effects of hyperhomocysteinemia on plaque size and structure in 99 atherosclerosis-prone apolipoprotein E-deficient mice. Hyperhomocysteinemia was induced by methionine (Met) or homocysteine (HcyH) supplementation: low Met (+11 g Met/kg food), high Met (+33 g Met/kg food), low HcyH (0.9 g HcyH/L drinking water), and high HcyH (1.8 g HcyH/L drinking water). Met and HcyH supplementation significantly raised plasma total homocysteine levels by 4- to 16-fold above those observed in mice fed a control diet (up to 146.1 micromol/L). Compared with controls, aortic root plaque size was significantly larger in supplemented groups after 3 months (56% and 173% larger in high-Met and high-HcyH, respectively) but not after 12 months. Hyperhomocysteinemia was associated with an increase in the amount of collagen in plaques after both 3 and 12 months. Mechanical testing of the tail tendons revealed no weakening of collagen after 12 months of hyperhomocysteinemia. Many plaques in both control and supplemented mice appeared rupture prone morphologically, but all aortic root plaques and all but 1 coronary plaque had an intact surface without rupture or thrombosis. Thus, diet-induced hyperhomocysteinemia promotes early atherosclerosis and plaque fibrosis but does not, even in the long term, weaken collagen or induce plaque rupture.     

Effects of folate supplementation in hyperhomocysteinemic pigs.

OBJECTIVES: The aim of this study was to evaluate the therapeutic effects of folic acid in the pig model of hyperhomocysteinemia. BACKGROUND: We have previously shown that pigs fed a methionine-rich diet develop hyperhomocysteinemia, arterial lesions and thrombotic events. Elevated homocysteine level is an independent risk factor for atherosclerosis that can be markedly lowered with daily folic acid administration. However, it is not known whether this treatment can prevent arterial lesions. METHODS: Three groups of pigs were studied: 8 control subjects received a standard diet; 8 received a methionine-rich diet for four months; 8 received a methionine-rich diet for 1 month and then the methionine-rich diet + 5 mg/day folic acid for 3 months. At month 4 after hemodynamic investigation, all the pigs were sacrificed. RESULTS: Control animals developed few usual vascular streaks. All the pigs fed a methionine-rich diet without folic acid treatment developed hyperhomocysteinemia (10.3+/-1.3 micromol/liter at basal state, 18.2+/-2.5 micromol/liter at one month and 14.6+/-3.8 micromol/liter at four months), hemodynamic abnormalities and diffuse arterial lesions with smooth muscle cell hyperplasia, endothelial alterations and elastic lamina dislocation. In this group, one pig died of venous thromboembolism and one of myocardial infarction. The pigs fed a methionine-rich diet + folic acid displayed similar arterial lesions and two had thrombotic events (one myocardial infarction and one pulmonary embolism), despite normalization of homocysteine levels (10.9+/-1.3 micromol/liter at basal state, 19.5+/-2.5 micromol/liter at one month and 11.4+/-3.8 micromol/liter at four months). CONCLUSIONS: In the pig model of hyperhomocysteinemia, 5 mg/day folic acid did not prevent arterial lesions or thrombotic events.