Variability of fasting and post-methionine plasma homocysteine levels in normo- and hyperhomocysteinaemic individuals.

To assess the variability of plasma homocysteine levels, fasting and post-methionine homocysteine levels were measured twice, at baseline and after follow-up of 1-4 months, in 16 individuals with normal and 26 with elevated homocysteine levels after methionine loading. The intra-individual coefficients of variation varied from 15 to 23% for fasting and post-methionine homocysteine levels, whether these levels were within the normal range or not. As a result, test-retest agreement was poor when subjects were dichotomized as having 'normal' or 'abnormal' homocysteine levels (itself a questionable concept). There was a relation between the average post-methionine homocysteine levels (at the first and second measurement) and the difference between both measurements (r = 0.37, P = 0.016). In normohomocysteinaemic individuals, delta (i.e., the difference between baseline and follow-up) fasting homocysteine and delta post-methionine homocysteine were correlated negatively with delta folate serum levels: r = -0.64, P = 0.007 and r = -0.50, P = 0.05, respectively. Individuals homozygous for the 677 C-->T mutation in the 5,10-methylenetetrahydrofolate reductase gene showed a greater variation of fasting homocysteine levels than those homozygous for the wild type (P = 0.017). In summary, we suggest that there is a substantial intra-individual variability in plasma homocysteine levels over time and that this variability is significantly related to the variability in serum folate levels, especially in normohomocysteinaemic individuals.     

Influence of age,sex and vitamin status on fasting and post-methionine load plasma homocysteine levels

BACKGROUND AND OBJECTIVES: To investigate the effects of age, sex and vitamin status on total plasma homocysteine (tHCy), both after fasting (FtHCy) and two hours post-methionine load (PML-tHCy). The secondary aim was to determine the reference values for FtHCy and PML-tHCy. DESIGN AND METHODS: A cohort of apparently healthy volunteers underwent blood sampling for FtHCy, PML-tHCy, creatinine, serum folate, vitamin B12 and vitamin B6 (pyridoxal-5-phosphate, PLP). RESULTS: In 147 subjects (M/F= 82/65, age range: 14-94 years), FtHCy was significantly higher in men than in women. In men, age and folate levels explained 20.5% and 19.0% of FtHCy variance, respectively. In women, age and vitamin B12 accounted for 22.6% and 17.8% of FtHCy variance, respectively. PML-tHCy was similar in men and women. PML-tHCy was negatively correlated with folate in both sexes, and with vitamin B12 and age in women only. Folate accounted for 20% of the variance of PML-tHCy in men, while in women vitamin B12 and PLP explained 40% and 20% of variance of PML-tHCy, respectively. The reference values of FtHCy and PML-tHCy were: 19.63 and 40.18 mol/L, respectively, for men under 45 years, 14.26 and 28.31 mol/L, respectively, for women under 45 years, 28.38 and 36.48 mol/L for men above 45 years, and 22.49 and 44.06 mol/L for women above 45 years. INTERPRETATION AND CONCLUSIONS: Age, gender and vitamin status influence both FtHCy and PML-tHCy in normal subjects. Reference values should be calculated according to age and sex.     

Fasting and post-methionine homocysteine levels in a healthy Australian population

Abstract Background: Plasma homocysteine (H[e]) is frequently measured in patients with occlusive vascular disease, but levels vary between populations and between laboratories.
Aims: We sought to derive reference values for an Australian population over a wide age range.
Methods: We measured plasma H(e) in the fasting state and after methionine loading in 116 volunteers selected at random from the Hunter districts of the New South Wales electoral roll and in 49 apparently healthy, active subjects recruited from the region's lawn bowling clubs. Reference ranges were derived for born sexes, in three age strata. We collaborated with two international laboratories in standardising our results.
Results: Mean fasting H(e) levels were approximately 2.7 μ.mol/L higher in men than women, at all ages (95% CI for the difference, 1.2 to 4.1 μmol/L). Levels increased with age (approximately 1.0 μmol/L/decade, 95% CI 0.5 to 1.5) and were correlated with serum creatine (r=0.48), serum folate (r=−0.30), red cell folate (r=−0.25) and serum B₁₂ (r=−0.31) (all p <0.001). These results are similar to those reported in other populations.
Conclusions: We have defined reference ranges for a typical Australian population, following careful laboratory standardisation. H(e) levels must be interpreted with regard to age, sex, renal function and vitamin B₁₂ and folate status.     

Blood levels of homocysteine and atherosclerotic vascular disease

In contrast to cross-sectional and case-control studies, which tend to report strong positive associations between plasma homocysteine and vascular risk, many prospective epidemiologic studies indicate modest associations at most, whereas other prospective studies report no evidence of association. Thus, while homocysteine may represent a causal factor in atherothrombosis, it is also possible that homocysteine is a marker of preclinical disease, or a consequence of other factors more closely linked to risk. Randomized trials are necessary to test reliably whether lowering homocysteine levels will decrease risks of atherosclerotic vascular disease. Current guidelines from the American College of Cardiology and the American Heart Association do not support population-based homocysteine screening to determine cardiovascular risk.     

Racial variation in fasting and random homocysteine levels

Homocysteine (Hcy) levels have been shown to be a predeterminant of thrombotic diseases. We measured the Hcy levels of 50 blacks and 50 whites equally divided by gender to determine if there is a significant racial difference in either fasting or random Hcy levels. Dietary, medication, smoking, alcohol, past medical, educational, and occupational histories were obtained, and the body mass index calculated. Total serum fasting and random Hcy levels, B12, folate, BUN, creatinine, and lipid profiles were drawn from each participant. Analysis of the results showed that white males have the highest fasting Hcy levels, 10.5 microM/l, whereas random Hcy levels were not significantly different. Correlation between fasting and random Hcy levels was poor (R = 0.61). B12 levels in black subjects were significantly higher, 490.8 pg/ml, compared to whites, 382.8 pg/ml, P = 0.001, but contributed little to total Hcy levels (R(2) = 0.08). Folic acid levels, all within normal range, were not significantly different between the two racial groups and also did not appear to greatly affect Hcy levels (R(2) = 0.06). Our study demonstrates that, despite the genetic diversity of these two racial groups in the U.S., white males in this age group have higher fasting Hcy levels than black males, and white males, but not black males, have higher fasting homocysteine levels than females. This discrepancy in Hcy levels may reflect methylene-tetrahydrofolate reductase (MTHFR) enzyme polymorphisms, known to be higher in whites, rather than socioeconomic influences.     

Relationship between cardio-ankle vascular index and homocysteine in hypertension subjects with hyperhomocysteinemia

Background: Arteriosclerosis evaluated by arterial stiffness is the basic pathophysiological change during the development of hypertension. Cardio-ankle vascular index (CAVI) is an index of arterial stiffness. Hyperhomocysteinemia (HHcy) is an independent risk factor for vascular diseases. However, there was little research about the relationship between CAVI and homocysteine (Hcy) in hypertension subjects with HHcy. Methods: A total of 330 subjects (M/F 133/197) from Vascular Medicine of Peking University Shougang Hospital were divided into four groups: control group (group 1, normotensive with normal Hcy, n = 149), hypertension group (group 2, n = 113), HHcy group (group 3, n = 30), and hypertension with HHcy group (group 4, n = 38). CAVI was measured by VS-1000 apparatus. Results: Our results showed that CAVI was significantly higher in group 4 than in group 1 and group 2 (8.41 ± 1.08 vs. 7.79 ± 1.14; 8.41 ± 1.08 vs. 7.87 ± 1.02, both p < 0.05, respectively). Positive correlation between CAVI and Hcy was found in the entire study group (r = 0.109, p = 0.049) and hypertension subjects (group 2 + group 4; r = 0.202, p = 0.014). Multivariate analysis showed that Hcy was an independent associating factor of CAVI in all subjects (β = 0.251, p = 0.034). Conclusions: The present study showed that CAVI was significantly higher in hypertension subjects with HHcy compared to hypertension group. There was significant correlation between CAVI and Hcy, indicating the relationship between arterial stiffness and biomarkers in vascular-related diseases.     

Altered platelet reactivity in peripheral vascular disease complicated with elevated plasma homocysteine levels

Elevated plasma concentrations of the sulphur-containing amino acid homocysteine (Hcy) is associated with increased risk of atherosclerosis and arterial thrombosis. The mechanism by which Hcy exerts these effects has yet to be fully elucidated, although a variety of possible mechanisms have been proposed, including endothelial dysfunction or haemostatic abnormalities. However, the influence of Hcy on platelets, cells central to the atherothrombotic process, has never been addressed directly in patient studies. Here, the influence of mild hyperhomocysteinaemia (hHcy) on platelet function was explored in patients with peripheral occlusive arterial disease as evidence by intermittent claudication. Claudicants (n = 39) were assigned to one of two subgroups depending on their plasma Hcy concentrations. hHcy claudicants had plasma Hcy concentrations of 18.9 +/- 1.0 microM (n = 24), compared to 11.3 +/- 0.5 microM for normohomocysteinemic (nHcy) claudicants (n = 15) and 12.6 +/- 0.7 microM for age-matched controls (n=15). Platelet function was evaluated ex vivo in both groups and compared to age-matched controls. Platelet activation and sensitivity to nitric oxide-mediated inhibition was assessed by platelet fibrinogen binding and P-selectin expression. At low concentrations of adenosine diphosphate (ADP; 0.1 microM) and thrombin (0.02 U/ml), platelets from hHcy claudicants were more reactive than those from age-matched controls, but not nHcy claudicants. Agonist-induced P-selectin expression was significantly raised in hHcy claudicants compared to all other groups. Interestingly no differences were observed between nHcy claudicants and age-matched controls, indicating that claudication per se did not affect platelet function. Since platelet activity in vivo is determined by the exposure to both agonists and antagonists, we subsequently tested the sensitivity of platelets to inhibition by nitric oxide (NO), using the same platelet markers. Platelets from hHcy claudicants were significantly less sensitive to GSNO (1-100 microM)-mediated inhibition than all other groups. GSNO (1microM) induced 42.6 +/- 10 and 39 +/- 11.5% inhibition of ADP-induced fibrinogen binding for the nHcy claudicants and age-matched controls, respectively. However, in hHcy claudicants only 16.4 +/- 9.7% inhibition was observed, significantly less than the other groups (P < 0.01). Again no differences between nHCy claudicants and controls were observed. These results suggest the presence of claudication alone does not influence platelet function but if complicated with mild hyperhomocysteinemia, the sensitivity to agonists is increased, and more importantly, their sensitivity to inhibition is greatly reduced. The overall effect would be an increased propensity for platelet activation. The presence of even mildly elevated plasma Hcy could dramatically increase thrombotic risk.     

血管性痴呆患者与其血浆同型半胱氨酸水平的关系

目的 探讨血管性痴呆(VD)患者与其血浆同型半胱氨酸水平的关系.方法 用高效液相色谱仪和电化学检测法测定1998年2月至2000年2月收治的37例VD患者的血浆总同型半胱氨酸水平,并与40名正常同龄对照组及40例非痴呆脑梗死组比较.运用多聚酶链反应-限制性内切酶片段长度多态性技术(PCR-RFLP)检测N5,N10-亚甲基四氢叶酸还原酶(MTHFR)基因多态性,同时测定血浆叶酸及维生素B12水平.结果 VD患者血浆总同型半胱氨酸水平显著高于正常同龄对照组和非痴呆脑梗死组;MTHFR基因型有3种,即纯合子(T/T)型、杂合子(T/C)型和纯合子(C/C)型.3组基因型和等位基因频率相比,差异均无显著性;VD组血浆叶酸及维生素B12水平明显低于正常同龄对照组和非痴呆脑梗死组(P＜0.05).结论 高同型半胱氨酸血症可能是VD发病的一个新的危险因素.     

Determinants of fasting and postprandial serum bile acid levels in healthy man

The relationship between serum levels of conjugates of cholic acid measured by radioimmunoassay, bile acid absorption, and hepatic clearance was studied in order to define the determinants of fasting and postprandial serum bile acids in healthy man. Acute or chronic interruption of the enterohepatic circulation caused a significant decrease in basal serum levels of cholyl conjugates, while liquid or solid meals caused a marked and reproducible increase in serum cholyl conjugates. A temporal correlation was demonstrated postprandially or after intravenous cholecystokinin between intestinal transit of bile acids and simultaneous changes in levels of serum cholyl conjugates. Finally, the plasma disappearance of intravenously injected cholylglycine was shown to be unaffected by serum levels of endogenous cholyl conjugates. These data are consistent with the interpretation that, in the presence of normal hepatic function, the major determinant of serum bile acids is their rate of intestinal absorption.This work was supported by Mayo Foundation and USPHS Grant AM 16770.A part of this work was presented at the 1975 meeting of the American Association for the Study of Liver Disease and published in abstract form (1). Dr. Hoffman's present address is: Division of Gastroenterology, Department of Medicine, University of Texas, Houston, Texas. Dr. Korman's present address is: Department of Medicine, Monash University, Prince Henry's Hospital, Melbourne, Australia. Dr. Cowen's present address is: Department of Medicine, Royal Brisbane Hospital, Queensland, Australia.     

Cystatin C as a determinant of fasting plasma total homocysteine levels in coronary artery disease patients with normal serum creatinine.

Serum creatinine, a surrogate for both renal function and homocysteine generation, is a determinant of fasting plasma total homocysteine levels in coronary artery disease (CAD) patients. We hypothesized that among stable-CAD patients with normal creatinine levels (ie, 0.2). Consistent with the impact of folic acid fortification of cereal grain flour in the general population, only 1 of the CAD subjects (0.6%) had a plasma folate level <3 ng/mL. We conclude that serum cystatin C levels may reflect subtle decreases in renal function that independently predict fasting total homocysteine levels among stable-CAD patients with normal serum creatinine.     

Effects of intermittent fasting on serum lipid levels, coagulation status and plasma homocysteine levels

BACKGROUND: During Ramadan, Muslims fast during the daylight hours for a month. The duration of restricted food and beverage intake is approximately 12 h/day which makes Ramadan a unique model of intermittent fasting. Many physiological and psychological changes are observed during Ramadan that are probably due to the changes in eating and sleeping patterns. METHODS: Serum total cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), prothrombin time, activated partial thromboplastin time (aPTT), plasma fibrinogen, D-dimer and homocysteine levels were measured in 24 healthy fasting volunteers (12 females, 12 males) aged 21-35 years. Venous blood samples were taken 1 week before Ramadan, on the 21st day of Ramadan and 20 days after Ramadan. RESULTS: No significant changes were observed on serum total cholesterol, triglycerides and LDL levels. HDL levels were significantly elevated during Ramadan (p < 0.001) and 20 days after Ramadan (p < 0.05). Prothrombin time, aPTT, fibrinogen and D-dimer levels were in the physiologic limits in all samples but D-dimer levels were significantly low at the end of Ramadan in comparison to pre- and post-fasting levels (p < 0.001). Homocysteine levels, being still in reference ranges, were low during Ramadan (p < 0.05) and reached the pre-fasting levels after Ramadan. CONCLUSION: Our results demonstrate that intermittent fasting led to some beneficial changes in serum HDL and plasma homocysteine levels, and the coagulation status. These changes may be due to omitting at least one meal when the body was particularly metabolically active and possibly had a low blood viscosity level at the same time. We conclude that intermittent fasting may have beneficial effects on hemostatic risk markers for cardiovascular diseases.     

Fibrinogen and homocysteine levels in coronary artery disease

Conventional risk factors like high serum cholesterol, smoking and hypertension do not explain all the mortality and morbidity due to coronary artery disease in Indian population. Novel factors like plasma fibrinogen and homocysteine have been currently recognised as independent risk factors for coronary artery disease. A case-control study was carried out to examine the role of plasma fibrinogen, homocysteine, lipid profile and anthropometric parameters in angiographically established coronary artery disease patients. The relationship between the biochemical and anthropometric parameters was also examined. Fifty-eight male patients in the age range of 35-60 years with angiographically established coronary artery disease and equal number of matched-controls were the subjects of this study. Cases with coronary artery disease had significantly higher waist-to-hip ratio, waist-to-thigh ratio, plasma fibrinogen and total cholesterol. Mean plasma total homocysteine levels were not significantly different between cases and controls. In Indian population, elevated plasma fibrinogen and abdominal obesity appear to be significantly associated with coronary artery disease.     

Glucose levels in the normal range predict incident diabetes in families with premature coronary heart disease

PURPOSE: Little is known about excess risk of incident diabetes conferred by fasting plasma glucose (FPG) within the normal range (<5.6 mmol/l) for high risk families. METHODS: Healthy 30-59 year old non-diabetic siblings (N = 542) of index cases with documented premature coronary disease were followed prospectively for type 2 diabetes. RESULTS: During 8.7+/-3 years of follow-up, incident diabetes was identified in 7.8%. Rates were incremental with baseline non-diabetes FPG thresholds of 5.0, 5.6, 6.1, and 6.7 mmol/l (p for trend < 0.0001). FPG was the strongest predictor of incident diabetes even across levels within the normal range. The multivariable adjusted relative risk was 14.9 (95% CI = 3.4-65.2) at FPG thresholds > or =5.0 mmol/l versus FPG <5.0 mmol/l. The maximal diagnostic efficiency for FPG was 5.50 mmol/l; with sensitivity and specificity 0.782. All FPG thresholds in the normal range between 5.0 and 5.6 mmol/l showed efficiency levels >0.74. The overall area under the ROC curve predicting incident diabetes for normal and prediabetes ranges of FPG was 0.867. CONCLUSION: Higher FPG levels within the designated "normal" range in high risk families are a potent independent risk factor for type 2 diabetes and may serve as a sentinel to trigger primary preventive interventions.     

Increased levels of homocysteine in patients with Crohn's disease are related to folate levels

OBJECTIVES: The risk for thrombotic events is increased in inflammatory bowel disease. The factors responsible for such a risk are poorly defined. Recently, an elevated homocysteine level is emerging as a risk factor for thrombosis. The aim of this study was to determine the levels of homocysteine in a well-characterized population of patients with Crohn's disease and to compare it to controls. METHODS: The levels of homocysteine were determined in 105 well-characterized patients with Crohn's disease and 106 controls. The levels of folate and B12, which are involved in the metabolism of homocysteine were determined as well. Patients were treated with steroid preparations only. RESULTS: Homocysteine levels were significantly elevated in the patient population. Elevated levels were correlated with both low B12 and folate levels, but folate deficiency turned out to be a more important factor. Low B12 levels were in correlation with the involvement of the terminal ileum. No correlation was found between homocysteine levels and either disease activity or involvement of the terminal ileum. CONCLUSIONS: Homocysteine levels are increased in patients with Crohn's disease and this finding is inversely correlated with folate levels. Supplementation of folate to patients with Crohn's disease may be warranted.     

高同型半胱氨酸血症与皮质下缺血性血管病患者认知功能障碍的关系

目的探讨高同型半胱氨酸血症(Hhcy)及叶酸、维生素B12缺乏与皮质下缺血性血管病(SIVD)不同程度认知功能障碍的相关性。方法将119例SIVD患者按照简易精神状态量表(MMSE)认知功能程度的不同分为痴呆组与非痴呆组。其中痴呆组54例,非痴呆组65例。对所有受试者检测其同型半胱氨酸(Hcy)及血清叶酸、维生素B12水平。结果痴呆组血浆Hcy水平为(43±9)μmol/L,显著高于非痴呆组的(20±6)μmol/L(P<0.01);血清叶酸和维生素B12水平分别为(8±4)nmol/L、(290±154)pmol/L,显著低于非痴呆组的(13±3)nmol/L、(504±141)pmol/L(均P<0.01)。采用Spearm an相关方法分析,显示不同性别的Hcy水平与MMSE分数均呈负相关(男:r=-0.685,女:r=-0.689,二者均P<0.01),与年龄均呈正相关(男:r=-0.592,女:r=0.576,二者均P<0.01);Hcy水平与糖尿病、血脂、高血压、吸烟、饮酒等其他危险因素无明显相关性(P>0.05)。结论伴随血浆Hcy水平增高SIVD认知功能障碍程度加重,Hhcy可能是SIVD认知功能障碍的独立危险因素,叶酸、维生素B12缺乏是间接引起Hhcy,而导致SIVD重要的营养因素。     

Creutzfeldt-Jakob disease and homocysteine levels in plasma and cerebrospinal fluid

BACKGROUND: There is evidence that homocysteine contributes to various neurodegenerative disorders. OBJECTIVE: To assess the values of homocysteine in patients with Creutzfeldt-Jakob disease (CJD) in both cerebrospinal fluid (CSF) and plasma. METHODS: Study design: Case control study. Total homocysteine was quantified in CSF and plasma samples of CJD patients (n=13) and healthy controls (n=13). RESULTS: Mean values in healthy controls: 0.15 micromol/l +/- 0.07 (CSF) and 9.10 micromol/l +/- 2.99 (plasma); mean values in CJD patients: 0.13 micromol/l +/- 0.03 (CSF) and 9.22 micromol/l +/- 1.81 (plasma). No significant differences between CJD patients and controls were observed (Mann-Whitney U, p >0.05). CONCLUSIONS: The results indicate that the CSF and plasma of CJD patients showed no higher endogenous levels of homocysteine as compared to normal healthy controls. These findings provide no evidence for an additional role of homocysteine in the pathogenetic mechanisms underlying CJD neurodegeneration.     

The effect of supraphysiologic doses of testosterone on fasting total homocysteine levels in normal men

Elevated total homocysteine (tHcy) levels are associated with increased risk for atherosclerotic cardiovascular disease. tHcy levels are higher in men than in women, and estrogen replacement therapy may reduce tHcy levels in postmenopausal women. The effect of androgenic hormones on tHcy levels in men has not been examined. The present study determined the effect of supraphysiologic doses of testosterone, with or without its aromatization to estradiol, on fasting tHcy levels in 14 normal male weightlifters aged 19–42 years. Subjects received testosterone enanthate (200 mg/week intramuscularly), the aromatase inhibitor, testolactone (1 g/day orally), or both drugs together in a crossover design. Each treatment lasted 3 weeks and each treatment was separated by a 4-week washout. Both testosterone regimens increased serum testosterone levels, whereas estradiol increased only during testosterone alone. Mean tHcy levels were not significantly altered when testosterone was given alone or together with testolactone. Testolactone did not significantly influence tHcy levels. We conclude that short-term, high-dose testosterone administration does not affect fasting tHcy levels in normal men.