Homocysteinemia Levels Research Articles

Hyperhomocysteinemia and High Doses of Nilotinib Favour Cardio-Vascular Events in Chronic Phase Chronic Myelogenous Leukemia (CML) Patients

Despite its high efficacy on CML, long-term exposure to nilotinib, a second generation tyrosine kinase inhibitor (TKI2), has been reported to increase the onset of arterial cardiovascular events (CVE) in chronic phase (CP) CML patients (pts), especially in pts with cardiovascular risk factors. However, some pts without any cardiovascular risk factors may experience arterial thrombotic events and the pathogenesis of this phenomenon remains obscure. Homocystein (HC) is a key sulphured amino-acid derived from methionin, independently associated with increased frequencies of thrombo-embolic events, early arteriosclerosis and increased cardiovascular mortality (Nygard NEJM 1997). In addition, in vitro, this amino-acid induces the proliferation of smooth muscle cells, endothelial cell dysfunction, increased collagen synthesis and exerts pro-inflammatory rearrangements within the arterial wall.In the present study, we wanted to determine if hyperhomocysteinemia might influence the onset of cardio-vascular events in a series of 114 CP CML pts on nilotinib. We have prospectively analysed in a multicentric study, on-nilotinib cohorts of CP CML pts between September 2011 and July 2014 with standard clinical assessments [height, weight, body mass index (BMI)], onset of any CV events, and basic routine blood metabolic laboratory assessments (fasting glucose, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, glycosylated haemoglobin, homocysteinemia (Biorad kit on HLPC on Summit Dionex system, Thermo Fischer scientific, France), vitamines B9 and B12. All the 114 pts were in CP-CML on nilotinib [43 as first-line, 71 as second-line or more, since a median of 51.5 (3-164) months], 49 were males, with a median age of 51.7 (18-81) at CML diagnosis and 58 (82-20) at nilotinib initiation. Twenty-eight (24.5%) pts presented some CV risk factors prior to nilotinib initiation, and 24 (21%) had an active tobacco abuse at assessment (4 patients unknown). Median weight was 69 (44-149) kg and median BMI was 24.5 (16.5-46) kg/m2 (8 patients >30). Overall, 21 (18.5) pts presented new or worsened pre-existing CVE on nilotinib after a median follow-up of 51.5 months since TKI2 initiation. These CVE occurred after a median of 47 (7.5-82.3) months with a regular increase along the years (Cumulative incidence (CI) 3% at 1 year, 4.12% at 2, 5.15% at 3, 9.30 at 5 and 20.62% at 8.3 years). In total, 3 pts died, 2 from brain stroke, 1 from sudden death in a pt with a history of myocardial infarction. In an univariate analysis we compared our cohort of nilotinib pts to a similar cohort of 17 pts on imatinib as control [median age 56 years since CML diagnosis (p=ns), median duration of imatinib 39 months (p=ns), median weight 70.5 kg (p=ns), BMI 25.9 kg/m2 (p=ns)]. None of these imatinib pts had shown any CVE during follow-up. HC was significantly lower in imatinib-treated pts (p=0.029), in female pts (p=0.018) and increased with age (p<0.001), fasting glucose (p=0.001), glycosylated haemoglobin (p=0.027) were significantly lower too. There was no correlation between HC and cholesterol (total, HDL, LDL). We constructed in the nilotinib cohort a ROC curve to determine the HC cut-off threshold for CVE which was 13.75 mmol/l [AUC=0.68 (95% CI: 0.54-0.82), sensitivity 65%, specificity 71%]. We looked at the CI of CVE according to the HC levels, segregating the pts according to the HC threshold. There was a significant difference (p=0.003) in the incidence of CVE in patients on nilotinib according to the HC level, as shown on figure 1. [Display omitted] The CI of CVE was significantly higher in pts on nilotinib 800 mg daily (38% at latest follow-up) versus pts on ≤600 mg daily, (10%, p=0.005, Gray test). Finally multivariate analysis identified age [p<0.001, HR 1.05 (95% CI 1.02-1.09)], 800 mg daily nilotinib dose [p=0.0049, HR 7.08 (95% CI 1.81-27.6)], and HC [p=0.043, HR 1.11 (95% CI 1.03-1.19)], with an increased risk of CVE on nilotinib.In conclusion, nilotinib seems to favour CVE in the long-term in CP CML pts, especially in patients with CV risk factors, and these CVE are specifically linked to higher doses of nilotinib and high levels of homocysteinemia. This marker could represent a useful tool to detect pts at risk of arterial CVE on nilotinib. Whether hyperhomocysteinemia is one of the causes of CVE of a consequence of nilotinib treatment remains to be determined. DisclosuresMichallet:Genzyme: Consultancy; Oseus: Consultancy; BMS: lectures, lectures Other; Novartis: lectures, lectures Other; MSD: lectures Other. Etienne:Novartis: Consultancy; BMS: lectures, lectures Other. Nicolini:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria.

Hyperhomocysteinemia independently causes and promotes atherosclerosis in LDL receptor-deficient mice.

BackgroundHyperhomocysteine is an independent risk factor of coronary heart disease (CHD). However, whether hyperhomocysteine affects the progression of atherosclerosis is unclear. In the present study, we examined the effect of hyperhomocysteine on the formation of atherosclerosis in low-density lipoprotein receptor-deficient (LDLr−/−) mice.MethodsForty-eight 7-week-old LDLr−/− mice were assigned to the following groups: mice fed a standard rodent diet (control group), mice fed a high-methionine diet (high-methionine group), mice fed a high-fat diet (high-fat group), and mice fed a diet high in both methionine and fat (high-methionine and high-fat group). At the age of 19, 23, and 27 weeks, four mice at each interval in every group were sacrificed.ResultsAt the end of the study, mice did not show atherosclerotic lesions in the aortic sinus and aortic surface until 27 weeks old in the control group. However, atherosclerotic lesions developed in the other three groups at 19 weeks. The amount of atherosclerotic lesions on the aortic surface was lower in the high-methionine group than in the high-fat group (P < 0.001). Atherosclerotic lesions on the aortic surface in the high-methionine and high-fat group were the most severe. The mean area of atherosclerotic lesions in the aortic sinus compared with atherosclerotic lesions on the aortic surface was lower in the high-methionine group than in the high-fat group (P < 0.001). Atherosclerotic lesions in the aortic sinus in the high-methionine and high-fat group were the most severe.ConclusionsHomocysteinemia accelerates atherosclerotic lesions and induces early atherosclerosis independently in LDLr−/− mice. Reducing the level of homocysteinemia may be beneficial for prevention and treatment of CHD.

337 NON ALCOHOLIC FATTY LIVER DISEASE AND AGING. PREVALENCE AND ASSOCIATED FACTORS

B12 vitamine, folic acid, homocysteinemia and C677T MTHFR polymorphisms. We also analyzed the relationship between hyperhomocysteinemia and MTHFR polymorphisms with the grade of steatosis, NAS score and fibrosis in NAFLD patients. Results: Hyperhomocysteinemia and homocygotic mutation of C677T MTHFR gene were found to be signficantly more frequent in NAFLD patients than in healthy controls (36% vs. 7% and 31% vs. 9%, respectively; p < 0.01). We did not observe any statistical relation between hyperhomocysteinemia and MTHFR mutations with metabolic or epidemiological factors for NAFLD. The degree of liver injury of NAFLD, determined by liver biopsy, was not associated with homocysteinemia levels nor with MTHFR C677T polymorphism. Conclusions: 1. Hyperhomocysteinemia and homocygotic mutation of C677T MTHFR gene are more prevalent in spanish patients with NAFLD comparing with healthy subjects; 2. In our study, hyperhomocysteinemia and homocygotic mutation of C677T MTHFR gene could be useful biomarkers for NAFLD, regardless of the presence of metabolic risk factors or the degree of liver injury.

Hyperhomocysteinemia in patients with pulmonary embolism

Investigation of hyperhomocysteinemia (HHcy) as an important risk factor for pulmonary thromboembolism (PTE), which represents a most dangerous consequence of a unique phenomenon of venous thromboembolism which still suffers from sometimes conflicting or inadequately clarified results. The role of homocysteine in the clinical manifestation of this life-threatening disease and its treatment (in which any further information may be decisive) requires detailed examination. The purpose of this study is to determine the differences in HHcy incidence and homocysteinemia levels between patients with PTE and healthy persons. The study enrolled 70 patients with PTE and 50 healthy persons. Homocysteine was measured using the HPLC method with fluorescent detection and HHcy was defined as homocysteinemia above 12 ?mol/L. Statistical analyses included chi-square and Mann Whitney U tests. The median homocysteinemia value was significantly higher (p=0.017) in the patients (12.10 ?mol/L) than in the controls (10.35 ?mol/L). The comparison of HHcy incidence between the patients (51.5%) and controls (30%) revealed a significant difference (p=0.021). In patients, homocysteinemia was significantly higher (p=0.002) in men (14.05?mol/L) than in women (10.01 ?mol/L). HHcy was present in 67.6% of men with PTE, which was significantly higher (p=0.006) than the incidence in women with PTE (33.3%). Healthy males had significantly higher (p=0.001) homocysteinemia (12.54 ?mol/L) than healthy females (9.4 ?mol/L). A significant difference (p=0.031) was observed between the incidences of HHcy in healthy males (44.0%) and healthy females (16.0%). We conclude that the incidence of hyperhomocysteinemia and homocysteinemia are significantly higher in all the patients compared with the healthy persons, as well as in both healthy males and males with PTE compared with healthy females and female patients. This indicates that HHcy findings in PE are likely to have a clinical importance.

Association of hyperhomocysteinemia and folate deficiency with colon tumors in patients with inflammatory bowel disease

Folate deficiency associated with hyperhomocysteinemia might increase the risk of developing colorectal cancer. The aim of this study was to evaluate factors associated with colonic carcinogenesis, in particular, folate and homocysteinemia levels, in a cross-sectional study of patients with inflammatory bowel disease (IBD). IBD patients with carcinogenic lesions discovered during colonoscopy [dysplasia-associated lesion or masses (DALM), colorectal cancer] were included and compared with the whole population of IBD patients with a normal colonoscopy performed during the same period. The following parameters were collected at the time of colonoscopy: age, sex, type, duration, activity, and extent of the disease, treatment, smoking status, and vitamin B12, folate, and homocysteinemia levels. Univariate and multivariate analyses were performed after adjusting for the main parameters. One hundred and fourteen patients [41 with ulcerative colitis (UC), 73 with Crohn's disease (CD)] were included. Twenty-six carcinogenic lesions were isolated: 18 DALM (7 high-grade and 11 low-grade dysplasia) and 8 colorectal cancers. In univariate analysis, the factors associated with carcinogenesis were: active smoking (P = 0.03), folate level < 145 pmol/L (P = 0.02), hyperhomocysteinemia > 15 micromol/L (P = 0.003), duration of disease > 10 years (P = 0.006), and UC (P = 0.02). In multivariate analysis, patients with hyperhomocysteinemia associated with folate deficiency had 17 times as many carcinogenic lesions as patients with normal homocysteinemia whatever the folate status and duration of the disease (P = 0.01). Patients with hyperhomocysteinemia without folate deficiency had 2.5 times as many carcinogenic lesions as patients with normal homocysteinemia (P = 0.08). Our data suggest that in IBD patients with normal homocysteinemia, the increase in carcinogenic risk is negligible. Conversely, in patients with hyperhomocysteinemia, folate deficiency may be associated with increased colorectal carcinogenesis in IBD patients.

Phenotypic and genotypic risk factors for cardiovascular events in an incident dialysis cohort

Cardiovascular disease (CVD) remains the major cause of death in patients with end-stage renal disease (ESRD). Traditional risk factors do not explain the high prevalence of CVD in this population, and other non-traditional cardiovascular (CV) risk markers have now been described. Therefore, the potential relationship between CVD and phenotypic and genotypic risk markers was investigated prospectively in incident dialysis patients cohort. The 279 patients (244 on hemodialysis, 35 on peritoneal dialysis) within the Diamant Alpin Dialysis Cohort Study were investigated. Phenotypic and genotypic parameters were determined at dialysis initiation, patients monitored over a 2-year period, and CV events (morbidity and mortality) recorded. Globally, 82 CV events occurred and 26 patients (9.3%) died from CVD, whereas 28 (10%) died from non-CV causes. Previous CV events were strongly predictive of CV events occurrence, whatever patients had had one (hazard ratio (HR) 2, 95% confidence intervals (CI) 1.1-3.5) or more (HR 3.9, 95% CI 2.1-7.1) CV accidents before starting dialysis. Both lipoprotein(a) (HR 1.67, 95% CI 1-2.5) and total plasma homocysteine at cutoff 30 micromol/l (HR 1.7, 95% CI 1.1-2.8) were independent predictors of CV events outcome. In the subgroup of patients with homocysteine < 30 micromol/l, methylenetetrahydrofolate reductase (MTHFR) TT was the sole biological parameter predictive of CV event outcome (HR 2.5, 95% CI 1.1-10, P = 0.03). ESRD patients who enter chronic dialysis with a previous CV event, high total homocysteinemia levels, or MTHFR 677TT genotype must be considered at high risk of incident CV events.

Role of homocysteine in the development of the cerebral and cardiovascular pathology in young persons

Cerebral and cardiovascular pathology is the leading cause of the death and invalidity in industrially developed countries. During recent years new data allowed to increase significantly the presentations of the pathogenesis of these diseases. They revealed that hyperhomocysteinemia increases the risk of early development of atherosclerosis and thrombosis of the coronary, cerebral and peripheral arteries independently of the traditional risk factors and it is the prognostic marker of the lethal outcome. The objective of this study was to appreciate the role of homocysteine in the development of the cerebral and cardiovascular pathology (ischemic stroke, myocardial infarction) in young persons. We examined 28 patients during an acute period of the ischemic stroke (IS) and 10 patients with acute myocardial infarction (AMI) (mean age 45.1 ± 1.15 and 40.9 ± 2.34 years). Clinical evaluation of the neurological status of the patients with IS was conducted traditionally and according to the international clinical scales determining neurological deficiency (Bartela, NIH-NINDS, Orgogoso, Scandinavian, Index of the Disorders of Adoptive Activity) at patient's admission. The control group consisted of 15 healthy subjects (mean age 44.7 ± 1.02 years). The homocysteine concentration in the blood was analyzed in all fasting patients on the immunochemoluminescent analyzer 'IMMULITE One' (USA) using the assay kit of 'DPC' production (USA). We revealed the presence of the moderate hyperhomocysteinemia in the patients with IS and AMI. The mean concentration of the serum homocysteine exceeded the mean concentration of this metabolite in healthy subjects by 57% and 48%, respectively. The patients with IS had dependence of the clinical course of the disease on the homocysteinemia level. In mild (n = 7) and moderate (n = 9) neurological deficiency, the mean concentration of homocysteine was 8.1 ± 0.65 and 10.8 ± 1.44 μmol/l respectively. In expressed and gross (n = 11) neurological deficiency, the mean concentration of homocysteine was 16.0 ± 2.44 μmol/l, which exceeded the control value by 85%. In two patients with gross neurological deficiency and the highest values of homocysteine, the disease finished by fatal outcome. All patients with increased homocysteine concentration had atherosclerotic changes of the vessels that were uncharacteristic for their age. All patients had the atherothrombotic subtype of IS. The development of AMI and the severe degree of the atherothrombotic subtype of IS in young persons may thus be conditioned by increased homocysteine concentration provoking early formation of the atherosclerotic changes of the vessels and thrombosis. The obtained data may be useful in the composition of programs of the prophylactic measures.

Prognostic value of homocysteinemia in patients with congestive heart failure

Elevated plasma homocysteine levels are associated with increased risk of vascular disease and of congestive heart failure (CHF), with a relationship between homocysteine values and disease severity. Hyperhomocysteinemia is a risk factor for cardiac dysfunction. In this study, the predictive value of elevated homocysteine levels was investigated in the prognosis of ischemic and non-ischemic CHF. A total of 159 patients with CHF, 89 with non-ischemic and 70 with ischemic CHF (83% males, mean age 62 years, mean ejection fraction 27%), and 119 controls (79% males, mean age 59.8 years) had fasting blood samples taken to measure plasma homocysteine, vitamin B(12) and folate levels. Coronary angiography was performed for all patients. The mean duration of follow-up was 49.6+/-36.7 months. As in other studies, the mean level of homocysteinemia was significantly higher in the CHF group (15.80 micromol/L) than in the control group (10.90 micromol/L) (p=0.001) whatever the etiology (non-ischemic, 16.11+/-6.84 micromol/L; ischemic, 15.41+/-6.45 micromol/L). This result was observed without vitamin deficiency, but in patients, the mean creatinine value was moderately higher than in controls. We found a positive correlation between plasma homocysteine levels and New York Heart Association (NYHA) classification, creatinine and age. Moreover, hyperhomocysteinemia appears to be a powerful predictive factor of mortality in CHF patients (relative risk of death, 4.23; p=0.0003). In the follow-up of this study, 41.5% of patients with homocysteinemia >17 micromol/L died vs. 21.3% of patients with levels <17 micromol/L. In multivariate analysis, when homocysteine levels were adjusted for a second parameter (age, NYHA, creatinine, diabetes), the risk of death remained significant after each adjustment. Elevated homocysteine levels observed in CHF patients, whatever the etiology of their heart disease (ischemic or non-ischemic), were correlated with the severity of the disease. Hyperhomocysteinemia appears to be a predictive factor of mortality in CHF patients.

Hiper-homocisteinemia como fator de risco para doença aterosclerótica coronariana em idosos

To investigate whether hyperhomocysteinemia is an independent risk factor for atherosclerotic disease in elderly individuals. A case-control study with 172 elderly individuals, 88 belonging to control group and 84 to case group, who showed coronary angiography requested for clinical indications. Quantitative coronary angiography was performed in 91% of the patients. Homocysteinemia was assessed in a continuous and categorized way, through univariate and multivariate analysis. When analyzed continuously, in univariate analysis, it was verified that case group elderly individuals showed an average homocysteinemia levels significantly higher than the control group individuals' (14.33 +/- 4.59 micromol/l against 11.99 +/- 4.59 micromol/l, p = 0.015). In multivariate analysis, continuous homocysteinemia was associated to the risk rate for coronary artery disease of 1.07 for each 1 micromol/l increase of homocysteine level. Na increase of 5 micromol/l corresponded to the risk rate of 1.40. When analyzed in categorized way, the values found over percentile 75 of control group (14 micromol/l) were defined as hyperhomocysteinemia. Hyperhomocysteinemia was found in 34% of elderly individuals, being 37.3% in control group and 62.7% in case group (p = 0.009). In multivariate analysis, hyperhomocysteinemia constituted an independent risk factor for coronary atherosclerotic disease for elderly individuals, with a risk rate for coronary artery disease of 2.03, confidence interval 95%, 1.02-4.03. Hyperhomocysteinemia was an independent risk factor for coronary artery disease in elderly individuals.

T03-P-016 Relationship between levels of homocysteinemia, alpha-tocopherol of low density lipoproteins, blood pressure parameters in Siberian men population

T03-P-016 Relationship between levels of homocysteinemia, alpha-tocopherol of low density lipoproteins, blood pressure parameters in Siberian men population

HEPATOLOGY HIGHLIGHTS *

HEPATOLOGY HIGHLIGHTS *

Homocysteinemia, serum folate and vitamin B12 in very young patients with diabetes mellitus type 1.

Recently a link between hyperhomocysteinemia [HH(e)] and diabetic micro- and macrovascular complications has been reported. However, it is far from clear whether HH(e) is an epiphenomenon or a cause of angiopathic complications. To try to clarify this question we studied adolescents and young diabetic patients without or with only initial complications. Plasma levels of basal homocysteinemia [H(e)], folate and vitamin B12 were measured in 76 young diabetic patients (age range 13.6-32.2 yr) and 70 normal volunteers matched for sex and age. In 68 diabetic patients and 53 controls we evaluated the levels of homocysteinemia 2 h after a methionine-loading test. Total (free + protein bound) plasma H(e) level was measured by HPLC. Basal or post-load HH(e) occurred in 4.1% of diabetic patients and 12.4% of controls (frequencies not statistically different). In diabetic patients plasma homocysteine values were statistically lower than in controls, but this difference was present only in females. The females showed lower homocysteine values and higher folate levels than males only in the diabetic group. We did not find significant differences in H(e) levels between patients with early complications, late complications or without complications of any type. Considering very young diabetic patients, the risk of hyperhomocysteinemia does not appear to be greater than in normal controls. Furthermore, our data seem to demonstrate that HH(e) is not a preexisting condition in diabetic patients, even in those predisposed to early complications.