Methylenetetrahydrofolate reductase 677 T allele protects against persistent HBV infection in West Africa

BACKGROUND/AIMS: Homocysteine metabolism is linked to DNA methylation, a mechanism potentially involved in the course of hepatitis B virus (HBV) infection. We evaluated the association of determinants of homocysteine metabolism with the outcome of HBV infection. METHODS: Four hundred and fifty-five healthy adults from Togo and Benin were tested for HBV serologic markers, HLA DR alleles, folate, vitamin B12, methylenetetrahydrofolate reductase (MTHFR) 677 C-->T, 1298 A-->C and methionine synthase 2756 A-->G polymorphisms. RESULTS: Seventy-eight percent of the study population was anti-HBc positive. Among them, 202 (56.9%) were anti-HBs positive and 58 (16.3%) were HBsAg positive. After stepwise logistic regression, the MTHFR 677 T allele was independently associated with persistence of detectable anti-HBs antibodies (OR: 2.47; 95% CI: 1.29-4.71; p=0.006). The mean HBV DNA level was significantly lower in HBsAg positive subjects carrying the 677 T allele than in those with the 677 CC genotype (1000+/-1406 vs. 2,400,000+/-214,000 copies/ml, p=0.005). Beninese origin and HLA-DRB1*09 allele were the other determinants independently associated with favorable outcome of HBV infection. CONCLUSIONS: The methylenetetrahydrofolate reductase 677 T allele seems to protect against chronic HBV infection in young African adults.     

Homocysteine Levels in Chronic Gastritis and Other Conditions: Relations to Incident Cardiovascular Disease and Dementia

Background Homocysteine levels in circulation are determined by several factors and hyperhomocysteinemia is reportedly associated with cardiovascular diseases and dementia. The aim of this study is to determine the relation of chronic gastritis and other conditions to homocysteine levels and their relation to incident cardiovascular diseases and dementia. Methods An adult population-based cohort (N = 488) was screened for H. pylori infection, gastro-duodenitis (endoscopic biopsies), disease history, and lifestyle factors. Blood samples were analyzed for pepsinogen I and II (gastric function), vitamin B12, folate, homocysteine, and cystatin C (renal function). The methylenetetrahydrofolate reductase C677T polymorphism reportedly associated with hyperhomocysteinemia was analyzed by pyrosequencing. Incident cardiovascular diseases and dementia were monitored during a median follow-up interval of 10 years. Results At baseline, there was a positive relation of S-homocysteine to male gender, age, S-cystatin C, methylenetetrahydrofolate reductase 677TT genotype and atrophic gastritis. During follow-up, cardiovascular diseases occurred in 101/438 and dementia in 25/488 participants, respectively. Logistic regression analysis (adjusting for gender, age at baseline, follow-up interval, BMI, smoking, alcohol consumption, NSAID use, P-cholesterol, and P-triglycerides) showed an association of S-homocysteine higher than 14.5 μmol/l to cardiovascular diseases (OR 2.05 [95% c.i. 1.14–3.70]), but not to dementia overall. Conclusions Gender, age, vitamin B12, folate, renal function, atrophic gastritis and the methylenetetrahydrofolate 677TT genotype were significant determinants of homocysteine levels, which were positively related to incident cardiovascular diseases.     

Plasma homocysteine and lipoprotein profile in patients with peripheral arterial occlusive disease

Several studies have identified moderate hyperhomocysteinemia (HCy) as an independent risk factor for atherosclerosis. The purpose of this case control study was to determine lipoprotein profile and homocysteine concentration in serum of 85 male patients with peripheral arterial occlusive disease (PAOD) and in 51 normolipidemic age-matched male controls. Cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol as well as subfractions HDL2 and HDL3 cholesterol, low-density lipoprotein (LDL) cholesterol, apo B, apo A-I, and lipoprotein particles LpA-I and LpA-I:A-II were measured in serum. Homocysteine, folic acid, and vitamins B6 and B12 were determined with the help of high-pressure liquid chromatography. The 677 C --> T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene was analyzed in PAOD patients. Patients with peripheral arterial occlusive disease showed a significantly higher mean concentration of homocysteine than control subjects (p<0.001). There was a negative correlation between the levels of homocysteine and vitamin B12 as well as folic acid (for vitamin B12: r=-0.40 and for folic acid: r=-0.38). The prevalence of hyperhomocysteinemia (Hcy >16 micromol/L) in the patients was 45% in contrast to 8% in controls. HDL cholesterol, HDL3 cholesterol, Apo A-I, and Lp A-I were significantly reduced in patients and triglycerides were elevated. The elevated plasma homocysteine concentration is frequently seen in homozygous carriers of a point mutation (677 C --> T) in the methylenetetrahydrofolate reductase gene, as the product of this gene is an enzyme, participating in homocysteine remethylation. The homozygous state for the 677 C --> T mutation was found in 13.3% of PAOD patients.     

Fasting, postprandial, and post-methionine-load homocysteinaemia and methylenetetrahydrofolate reductase polymorphism in vascular disease

Hyperhomocysteinaemia is an independent risk factor for cardiovascular disease. The C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) is a common genetic cause of increased homocysteine (HCY) levels. Post-methionine-load HCY concentrations allow identification of certain cases of hyperhomocysteinaemia not demonstrated by fasting levels. This study investigated the relationship between MTHFR polymorphism and (1) fasting HCY levels (77 patients); (2) post-methionine HCY levels (54 patients); and (3) postprandial HCY concentrations (36 patients) in cardiovascular disease. As expected, mean fasting HCY value was higher in the +/+ patients. Moreover, patients who were homozygous for the mutation exhibited significantly increased mean post-methionine-load HCY; in contrast, literature results are conflicting. Mean postprandial HCY, which is not known to be increased in controls, was also increased in the (+/+) patients, although the difference did not reach statistical significance, probably owing to the small size of the sample. MTFHR polymorphism is known to be aggravated by a drop in circulating folate. Additional risk factors may be more prevalent in patients with cardiovascular disease.     

Prevalence of anti-HCV among Chinese patients with acute and chronic liver disease

To assess whether the hepatitis C virus plays an important role in Chinese patients with acute and chronic liver disease, antibodies to HCV (anti-HCV) were measured by enzyme immunoassay in 67 patients with type A and B acute viral hepatitis, 165 patients with non-A, non-B (NANB) hepatitis, 438 patients with chronic hepatitis, 200 patients with postnecrotic liver cirrhosis, 72 patients with alcoholic liver disease, 55 patients with non-alcoholic fatty liver, 24 patients with toxic and drug-induced hepatitis, and 20 patients with other chronic liver diseases. Anti-HCV was not detected in sera from patients with type A and B acute viral hepatitis, toxic and drug-induced hepatitis, primary biliary cirrhosis, Wilson's disease, or lupoid hepatitis. The anti-HCV prevalence was found to be highest in patients with NANB hepatitis (59% in sporadic and 73.2% in transfusion-associated), 16.4% in non-alcoholic fatty liver, 5.6% in alcoholic liver disease, 6.8% in chronic hepatitis, and 16% in postnecrotic liver cirrhosis. In patients with chronic hepatitis, the anti-HCV prevalence was significantly higher in HBsAg-negative (15/34, 44.1%) than in HBsAg-positive cases (15/404, 3.7%; P less than 0.0001). The results indicate that HCV is a major agent of NANB hepatitis and plays an important role in HBsAg-negative chronic liver disease in Taiwan.     

MTHFR C677T Polymorphism and Risk of HCC in Patients With Liver Cirrhosis: Role of Male Gender and Alcohol Consumption

Background:  A single nucleotide polymorphism (SNP) C677T in the methylenetetrahydrofolate reductase (MTHFR) gene has been identified. The TT or CT genotypes show a marked reduction of the enzyme activity; this causes higher homocysteine levels and alterations of folate metabolism. Folate metabolism is essential for DNA synthesis and methylation, crucial steps in carcinogenesis. In this paper, we investigated whether the MTHFR C677T SNP could influence the occurrence of hepatocellular carcinoma (HCC) in a cohort of patients transplanted for end stage liver disease of different etiologies.
Methods:  Two hundred and twelve consecutive patients who underwent liver transplantation for end stage liver disease due to hepatitis B or C, alcoholic liver disease, and other causes were studied. Two hundred and thirty-six blood donors served as controls. Focal hepatic lesions were searched in the sectioned explanted livers. The presence of the MTHFR C677T SNP was determined via polymerase chain reaction amplification.
Results:  Among the 65 patients with HCC, 22 had the CC genotype, 30 the CT, and 13 the TT genotype. Only in patients with alcoholic liver disease was a significant association detected between the TT genotype and the presence of liver cancer (6/17 vs. 5/46, p  < 0.05). At stepwise logistic regression analysis the independent selected predictors of HCC were found: age at transplantation >55 years ( p  < 0.001) and the association among male gender, alcoholic liver disease, and MTHFR TT genotype ( p  = 0.002).
Conclusions:  The present study suggests that male TT carriers with alcoholic cirrhosis bear an increased risk of developing HCC.     

The influence of age, sex, vitamin B(12), folate levels and methylenetetrahydrofolate reductase C677T genetic mutations on plasma homocysteine in the Chinese population

BACKGROUND AND OBJECTIVES. Thromboembolic diseases remain a major cause of morbidity and mortality in most countries. The present study was thus conducted to determine the influences of age, sex, the methylenetetrahydrofolate reductase (MTHFR) gene mutation and the B vitamins on the plasma homocysteine (Hcy) levels in the Chinese. Our previous study found that Chinese carry the same mutation of the methylenetetrahydrofolate reductase (MTHFR) gene described in Western populations, with a 677CAET substitution being another possible cause of thrombosis. DESIGN AND METHODS. The study population comprised 445 consecutively enrolled Chinese subjects of different ages and sex. Overall 69 subjects were found to have homozygous 677CAET mutation of the MTHFR gene, and were classified as Group I; 164 subjects were found to have heterozygous mutation and classified as Group II; 212 had no such mutation and were classified as Group III. RESULTS. The mean plasma Hcy did not differ significantly between these 3 groups. When each group was divided again by gender, we found that both age and plasma Hcy levels were significantly higher in the males than in the females. In addition to Hcy levels, we also measured plasma vitamin B(12) and folate levels in 258 randomized subjects. Univariate and multivariate analysis showed MTHFR mutation could affect Hcy level, and univariate and multivariate analysis showed that age, MTHFR mutation and vitamin B(12) could affect the log(Hcy) levels. INTERPRETATION AND CONCLUSIONS. We demonstrate that some Chinese carry the 677CAET mutation of the methylenetetrahydrofolate reductase gene. This could affect their homocysteine levels and thus be a risk factor for thromboembolic disease.     

Prevalence and clinical associations of posttransplant fatty liver disease.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) could recur after liver transplant in patients with preexisting NAFLD, and has recently been reported to occur after transplant in patients transplanted without preexisting NAFLD. The literature on posttransplant NAFLD is limited. We aimed to study the prevalence of posttransplant NAFLD in patients transplanted for non-NAFLD-related liver diseases. METHODS: Thirty liver transplant recipients: 18 with chronic hepatitis B (CHB), seven with chronic hepatitis C (CHC), five others, were recruited. Liver biopsies were performed in all CHB and CHC patients annually as per protocol, or when clinically indicated. All biopsies were reviewed by one hepato-histopathologist blindly to assess and stage for steatosis and steatohepatitis. RESULTS: After a mean follow-up of 44+/-4 months, 12 (40%) and four (13%) developed posttransplant steatosis and steatohepatitis, respectively. None developed steatosis-related fibrosis or cirrhosis. Posttransplant steatohepatitis was associated with higher pretransplant body mass index (BMI) (32.3+/-3.9 vs 23.1+/-0.8, P=0.02) and higher BMI at last biopsy (32.5+/-4.3 vs 22.9+/-0.7, P=0.01). CONCLUSION: Posttransplant steatosis is common after liver transplant even in patients transplanted for non-NAFLD-related liver diseases. However, it is mostly benign during our follow-up, with only 13% developing steatohepatitis and none with fibrosis or cirrhosis.     

Quantitative testing of liver function in relation to fibrosis in patients with chronic hepatitis B and C

Abstract: Background/Aim: Quantitative tests of liver function may be superior to conventional tests to assess the prognosis of patients with liver diseases. There are insufficient data from quantitative testing of liver function (QTLF) for patients with chronic hepatitis B and C, particularly with regard to fibrosis. Therefore, we applied a broad panel of QTLF to these patients. Methods: Three hundred and sixty‐seven consecutive patients with chronic hepatitis B or C underwent liver biopsy and QTLF, which included tests for hepatic metabolism (aminopyrine breath test, galactose elimination capacity) and for hepatic perfusion (sorbitol clearance, indocyanine green clearance). QTLF values were correlated with liver histology (grading and staging for inflammation and fibrosis) and Child–Pugh classification for liver cirrhosis. Results: In patients with no and moderate fibrosis, metabolic liver function was significantly decreased, whereas hepatic perfusion remained normal. Severe fibrosis and cirrhosis showed a significant decline in all QTLFs. Hepatic inflammation only reduced metabolic liver function, irrespective of the inflammatory grade. Viral etiology and HCV genotypes did not change QTLF. Conclusions: In summary, viral damage compromises hepatic metabolism before perfusion. Therefore, tests of metabolic liver function (aminopyrine breath test, galactose elimination capacity) should be useful to search for drugs that restore liver function in viral hepatitis irrespective of the fibrosis stage.     

A common mutation C677T in the 5,10-methyltetrahydrofolate reductase gene is associated to idiopathic deep venous thrombosis

PURPOSE: Moderate hyperhomocysteinemia is a risk factor for deep venous thrombosis. The homozygous C677T methylenetetrahydrofolate reductase (MTHFR) mutation is associated with increased level of total plasma homocysteine. The association between homozygous C677T mutation and deep venous thrombosis is still controversial. METHOD: In order to evaluate this association, we studied the prevalence of C677T mutation in 168 patients with confirmed deep venous thrombosis; 31 with an idiopathic deep venous thrombosis (group A) and 137 with thromboembolic event explained by one or more clinical and/or biological risk factors (group B). RESULTS: The distribution of genotypes was different between group A and B [++/+ -/- -(n(%))] : 9(29)/10(32)/12(39) vs 16(12)/57(42)/64(46) (chi(2) : 6.03; P: 0.049). The comparison between homozygotes and the two other genotypes showed significant statistical relationship between homozygous genotype and idiopathic character of deep venous thrombosis (chi(2) : 6.01; P : 0.014; OR : 3.09 [IC 95% : 1.06-8.53]). CONCLUSION: These results suggest that homozygous C677T methylenetetrahydrofolate reductase mutation could be considered as a genetic risk factor for venous thrombosis.     

Measurement of serum branched-chain amino acids to tyrosine ratio level is useful in a prediction of a change of serum albumin level in chronic liver disease.

Aim: In patients with hepatitis C virus (HCV)-associated chronic liver diseases, especially in those with liver cirrhosis, accurate evaluation of their protein nutrition status is very important to improve their quality of life. Whereas the serum albumin level is commonly used to evaluate patients' protein nutrition status, in the present study, the serum amino acid levels were measured, as they also provide valuable information. Methods: Serum albumin levels and branched-chain amino acids (BCAA) to tyrosine ratio (BTR) were determined in 447 patients with HCV-associated chronic liver diseases (313 with chronic hepatitis and 134 with liver cirrhosis). Results: Chronic hepatitis progressed to liver cirrhosis, serum albumin and serum BTR levels decreased significantlyas chronic hepatitis progressed to liver cirrhosis. Hypoalbuminemia was significantly more common in patients with liver cirrhosis than in those with chronic hepatitis; however, the incidence of an amino acid imbalance was significantly higher than that of hypoalbuminemia in patients with liver cirrhosis. The presence of an amino acid imbalance was associated with a reduction in the serum albumin level 1 year later. Conclusions: It is important to evaluate serum albumin levels and the BTR in patients with HCV-associated chronic liver diseases.     

Increased prevalence of methylenetetrahydrofolate reductase C677T variant in patients with inflammatory bowel disease, and its clinical implications

BACKGROUND: Inflammatory bowel disease (IBD) is associated with an increased incidence of thromboembolic disease. Hyperhomocysteinaemia (hyper-tHcy), a condition associated with the C677T variant of 5, 10-methylenetetrahydrofolate reductase (MTHFR), is linked with an increased incidence of thromboembolic disease. Hyper-tHcy has been reported in patients with IBD. AIMS: To assess the prevalence of the C677T MTHFR genotype and the contribution of this genotype to hyper-tHcy in patients with IBD. METHODS: Patients with established IBD (n=174) and healthy controls (n=273) were studied. DNA samples were genotyped for the MTHFR (C677T) mutation. Subjects were categorised as homozygous for the thermolabile variant (TT), heterozygous for wild type and variant (CT), or homozygous for the wild type (CC). RESULTS: Plasma homocysteine concentrations were significantly higher in patients with IBD than in healthy controls. A total of 17.5% of ulcerative colitis and 16.8% of Crohn's disease patients were homozygous for the C677T variant compared with 7.3% of controls. Homozygosity (TT) for the variant was associated with higher plasma tHcy levels in patients with IBD and in healthy controls. When all subjects who were TT for the variant were excluded, median plasma tHcy was still significantly higher in IBD than controls. Plasma vitamin B(12) levels were lower in patients with IBD irrespective of MTHFR genotype. CONCLUSIONS: There is an association between the thermolabile MTHFR C677T variant and IBD. This accounts in part for the raised plasma tHcy found in patients with IBD and may contribute to the increased incidence of thromboembolic complications. All patients with IBD should receive low dose folic acid and vitamin B(12) therapy to protect against the thromboembolic complications of raised tHcy.     

Severe methylenetetrahydrofolate reductase deficiency revealed by a pulmonary embolism in a young adult

Deficiency in methylenetetrahydrofolate reductase (MTHFR), the enzyme involved in the remethylation of homocysteine to methionine using methyltetrahydrofolate as cofactor, induces hyperhomocysteinaemia, homocysteinuria, hypomethioninaemia and low methylfolate levels. Diagnosis usually occurs during infancy because of various neurological abnormalities. We report MTHFR deficiency diagnosed in an adult woman after a pulmonary embolism. Her adult sister, intellectually retarded, suffered from the same disease. Molecular analysis of the MTHFR gene exhibited four different mutations (two missense mutations, one exon skipping and C677T). The impact of these mutations was analysed through the biological abnormalities in the parents and children.     

Relation between homocysteinaemia and diabetic neuropathy in patients with Type 2 diabetes mellitus.

AIMS: Limited data are available on determinants of diabetic neuropathy as its pathogenesis is multifactorial. Since homocysteine exhibits toxic effects on vascular endothelial cells, the association between homocysteine and the prevalence of neuropathy in Type 2 diabetes mellitus was investigated. METHODS: A total of 65 Type 2 diabetic patients were consecutively enrolled into the study. Neuropathy was diagnosed according to clinical symptoms, clinical examination, electrophysiological sensory testing and autonomic function testing. With regard to homocysteine-related parameters, plasma homocysteine, folate, vitamin B12, vitamin B6 and renal function (creatinine, ceratinine clearance, cystatin C) were measured, and the C677T polymorphism of the methylenetetrahydrofolate reductase gene was determined. RESULTS: Forty-three of the Type 2 diabetic patients were classified as suffering from neuropathy. Both patient groups were comparable with regard to demographic data, blood pressure, glucose metabolism, renal function and homocysteine-related vitamins. In contrast, homocysteine levels (P = 0.04) and the frequency of hyperhomocysteinemia (>or= 15 micromol/l) (P = 0.01) were significantly increased in neuropathic patients. In a logistic regression model with neuropathy as dependent variable, homocysteine (adjusted for creatinine, homocysteine-related vitamins, HbA1c and duration of diabetes) was the only significant variable associated with the prevalence of neuropathy (odds ratio for homocysteine per 5 micromol/l increase: 2.60 (95% confidence interval 1.07-6.33)). CONCLUSION: The data indicate that homocysteine is independently associated with the prevalence of diabetic neuropathy in a collective of Type 2 diabetic patients. A larger, prospective study would be desirable to clarify the role of homocysteine in the pathogenesis of diabetic neuropathy.     

Relationships between blood levels of fat soluble vitamins and disease etiology and severity in adults awaiting liver transplantation

Background and Aims: Although malnutrition is common in liver disease, there are limited data on fat soluble vitamins in various diseases. The aims of this study were to: (i) determine fat soluble vitamin levels in patients assessed for liver transplantation; (ii) compare levels between different disease etiologies (hepatocellular and cholestatic) and between subgroups of hepatocellular disease; and (iii) assess the multivariate contribution to vitamin levels of etiology and various indicators of disease severity. Methods: This was a cross‐sectional study of 107 inpatients awaiting liver transplantation, mean age 47 years. Biochemical parameters included plasma retinol, 25‐hydroxycholecalciferol, and vitamin E. Biochemical (albumin, bilirubin and zinc) and clinical indicators (Child‐Pugh and Model of End Stage Liver Disease [MELD] scores) of disease severity were determined. Results: Deficiencies of retinol (< 1.0 µmol/L), 25‐hydroxycholecalciferol (< 50 nmol/L) and vitamin E (< 11 µmol/L) were present in 75%, 66% and 3%, respectively, of patients. Concentrations of retinol and vitamin E were lower in hepatocellular than cholestatic disease but 25‐hydroxycholecalciferol concentrations were similar. Child–Pugh score was higher in hepatocellular than cholestatic disease. Concentrations of retinol were lower in alcoholic liver disease (ALD) than hepatitis and Child–Pugh score was higher in ALD. For the whole group, levels of retinol, 25‐hydroxycholecalciferol and vitamin E were negatively related to Child–Pugh score, MELD score and bilirubin, and positively related to albumin. When Child–Pugh scores were controlled for, retinol was lower in the hepatocellular group. Conclusions: There was a high prevalence of fat soluble vitamin deficiencies with vitamin levels being related to disease severity. Retinol was lower in the hepatocellular group.     

Methylenetetrahydrofolate reductase 677 C-->T mutation and coronary heart disease risk in UK Indian Asians

Plasma homocysteine concentrations are elevated in UK Indian Asians and may contribute to twice as many coronary heart disease (CHD) deaths in this group compared with European whites. The mechanisms underlying elevated homocysteine concentrations among Indian Asians are not well understood. In this study, we have investigated the extent to which the methylenetetrahydrofolate reductase (MTHFR) 677 C-->T mutation accounts for elevated plasma homocysteine and increased CHD risk in Indian Asians compared with European whites. We investigated 454 male cases (with myocardial infarction or angiographically proven CHD: 224 Indian Asians, 230 European whites) and 805 healthy male controls (381 Indian Asians, 424 European whites). Fasting homocysteine concentrations, MTHFR 677 C-->T genotype, and conventional CHD risk factors were measured. The prevalence of homozygous MTHFR 677T in Indian Asian controls was less than one third that in European white controls (3.1% versus 9. 7%, P<0.001). In Indian Asians, the TT MTHFR genotype was not associated with homocysteine concentrations and was not present in any of the Asian controls with hyperhomocysteinemia (>15 micromol/L). In contrast, among European whites, the TT MTHFR genotype was strongly related to elevated plasma homocysteine concentrations and was found in 27% of the European controls with hyperhomocysteinemia. Elevated homocysteine in Indian Asian compared with European white controls was accounted for by their reduced levels of B vitamins but not by the MTHFR 677T genotype. However, neither the TT MTHFR genotype nor B vitamin levels explained the elevated homocysteine concentrations in CHD cases compared with controls. TT MTHFR was not a risk factor for early-onset CHD in Indian Asians (odds ratio, 0.5; 95% confidence interval, 0.1 to 2.4; P=0.39), unlike in European whites (odds ratio, 2.1; 95% confidence interval, 1.1 to 4. 1; P=0.02). We conclude that the MTHFR 677T: mutation does not contribute to elevated plasma homocysteine concentrations or increased CHD risk in Indian Asians compared with European whites. Our results suggest that novel genetic defects and/or environmental factors influence homocysteine metabolism in Indian Asians residing in the United Kingdom.     

慢性肾衰竭血透患者N5, N10-亚甲基四氢叶酸还原酶基因多态性和血浆同型半胱氨酸水平的研究

目的研究血透患者N5, N10-亚甲基四氢叶酸还原酶(MTHFR)基因多态性及血清叶酸、维生素B12 (Vit B12)水平与血浆总同型半胱氨酸(tHcy)的关系.方法运用聚合酶链反应-限制性内切酶片断长度多态性技术(PCR-RFLP),检测53例血透患者(HD组)及40例健康对照组(C组)的MTHFR基因多态性;用高效液相色谱法和荧光探测仪测定血浆tHcy水平;用免疫化学发光法测定血清叶酸、Vit B12水平.结果 (1)MTHFR基因型有3种,纯合子突变型(+/+)、杂合子突变型(+/-)、正常型(-/-).HD组中(+/+)型频率为30.2 %,(+/-)型频率为45.3%,(-/-)型频率为24.5%,T等位基因频率为52.8%,基因型分布和等位基因频率与C组比较差异无显著性.(2)HD组中98%的患者存在着高Hcy (＞15.0 μmol/L)血症,平均血浆 tHcy 水平显著高于C组(38.68 μmol/L 对15.47 μmol/L,P<0.01).(3)HD组中(+/+)型平均血浆tHcy水平高于(-/-)型(45.32 μmol/L 对28.44 μmol/L),两者差异具有显著性(P=0.038).(4)HD组血清叶酸、Vit B12均与血浆tHcy水平呈负相关(r=-0.377,P=0.005;r=-0.311,P=0.023).结论血透患者血浆tHcy水平升高不仅与患者尿毒症时对其清除及代谢障碍有关,还受到MTHFR基因多态性和叶酸、Vit B12水平的影响.     

Prevalence of metabolic syndrome, obesity and diabetes type 2 in cryptogenic cirrhosis

AIM： To evaluate the prevalence of metabolic syndrome （MS）, obesity and type 2 diabetes mellitus （T2DM） in a group of Mexican Mestizo patients with cryptogenic cirrhosis （CC） and to compare this group with patients with cirrhosis secondary to other causes （disease controls）. METHODS： Patients with CC, diagnosed between January, 1990 and April, 2005, were included in a retrospective study. Patients with cirrhosis caused by chronic hepatitis C, alcohol abuse or autoimmune hepatitis （AIH） served as disease controls. RESULTS： A total of 134 patients with CC were analyzed. Disease controls consisted of 81 patients with chronic hepatitis C, 33 with alcohol abuse and 20 with AIH. The median age of patients with CC was 57 years （range, 16-87）; 83 （61.9%） patients were female; 53 （39.6%） were Child A, 65 （48.5%） Child B, and 16 （11.9%） were Child C cirrhosis. The prevalence of MS （29.1% vs 6%; P 〈 0.001）, obesity （16.4% vs 8.2%; P = 0.04） and T2DM （40% vs 22.4%; P = 0.013） was higher in CC patients than in disease controls. There were no differences in sex, age or liver function tests between the two groups. CONCLUSION： The prevalence of MS, obesity and T2DM were higher in patients with CC than in patients with cirrhosis secondary to others causes. Our findings support the hypothesis that non-alcoholic steatohepatitis （NASH） plays an under-recognized role in CC.     

C677T methylene-tetrahydrofolate reductase mutation in type 2 diabetic patients with and without hyperhomocysteinaemia

OBJECTIVE: The aim of the study was to determine the prevalence of the C677T mutation in a cohort of type 2 diabetic patients with and without elevated total plasma homocysteine (tHcy). METHODS: 80 type 2 diabetic patients with hyperhomocysteinaemia (group 1, tHcy: 21.3 +/- 6.7 micromol/L) and 50 subjects with normal levels (group 2, tHcy 11.2 +/- 2.3 micromol/L) were studied. C677T mutation was assessed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Homozygosity was present in 23% of patients in group 1 and 8% in group 2 (P<0.02). No significant difference in heterozygosity frequency was observed between patients with and without hyperhomocysteinaemia. T allele frequency was 0.43 in group 1 and 0.35 in group 2. CONCLUSION: C677T mutation is frequent in diabetic patients with hyperhomocysteinaemia and could contribute, besides non genetic factors, to increased levels of tHcy.     

Total plasma homocysteine is associated with hypertension in Type I diabetic patients

AIMS/HYPOTHESIS: Although hyperhomocysteinaemia and methylenetetrahydrofolate reductase gene polymorphism are accepted risk factors for cardiovascular disease, their association with micro angiopathy or blood pressure in diabetic patients is still being debated. This study explores the relation between plasma homocysteine concentrations, methylenetetrahydrofolate reductase gene polymorphism, hypertension, diabetic microvascular and macrovascular complications associated with kidney function. METHODS: Vascular complications, hypertension, methylenetetrahydrofolate reductase genotype (RFLP with Hinf I digestion), and total plasma homocysteine (HPLC) were investigated in 389 well-characterized Type I (insulin-dependent) diabetic patients with normal (GFR> or=75 ml x min(-1) x (1.73 m(2))(-1); n=273), or impaired renal function (GFR <75 ml x min(-1) x (1.73 m(2))(-1); n=116). RESULTS: Patients with microvascular and macrovascular complications showed higher total plasma homocysteine concentrations than those without complications. However, after the data for GFR (main determinant for plasma homocysteine) was adjusted we observed that plasma homocysteine concentrations greater than 8.6 micro mol/l in patients with normal GFR are not related to vascular complications, but to hypertension (8.6-11.3 micro mol/l: OR 1.9; >11.3 micro mol/l: OR 3.7). The risk for coronary heart disease (CHD) was also enhanced by a plasma homocysteine concentration greater than 11.3 micro mol/l (OR 5.9). Although the T allele was an independent determinant of plasma homocysteine, the methylenetetrahydrofolate reductase gene polymorphism was neither associated with diabetic vascular complications nor with hypertension. CONCLUSION/INTERPRETATION: Increased plasma homocysteine concentrations but not the T allele per se, enhance the risk of hypertension and of CHD in Danish Type I diabetic patients with normal renal function.