Decreased renal expressions of heat shock protein-72 and -25 are associated with renal dysfunction in biliary cirrhotic rats.

During the course of liver cirrhosis, severe renal complications frequently occur. However, the pathogenesis of renal dysfunction in liver cirrhosis has not been completely understood. In this study, we investigated the association between renal function and expressions of renal heat shock proteins (HSPs) in biliary cirrhotic rats. Following bile duct ligation (BDL), renal function and expressions of HSPs were compared in control and BDL cirrhotic rats. Serum BUN and creatinine levels were significantly higher in cirrhotic rats compared with control rats at 4 weeks post-BDL operation. Renal expressions of HSP72 and HSP25 were decreased with progression of liver cirrhosis in BDL rats by Western blotting. Immunohistochemistry revealed that expression of renal HSP72 was suppressed in tubular epithelial cells, and expression of renal HSP25 was suppressed not only in tubular epithelial cells but also in blood vessels in rats with liver cirrhosis. Renal expressions of HSP90 and HSP60 did not differ between control and BDL rats. Renal function was impaired in biliary cirrhotic rats with decreased expressions of renal HSP72 and HSP25. These findings suggest that decreased expressions of renal HSP72 and HSP25 may be a part of the pathogenesis of renal dysfunction in liver cirrhosis.     

Patients with elevated baseline liver enzymes do not have higher frequency of hepatotoxicity from lovastatin than those with normal baseline liver enzymes

BACKGROUND: It is recommended that lovastatin be avoided in patients with unexplained elevation in transaminase levels. However, there are no studies that evaluated the risk of lovastatin hepatotoxicity in subjects with elevated liver enzymes. Our study tested the hypothesis that patients with elevated liver enzymes are not at higher risk for hepatotoxicity from lovastatin. METHODS: Our study consisted of the following three cohorts of patients seen between December 1987 and December 1998: cohort 1: 135 patients with elevated baseline enzymes (aspartate transaminase [AST] >40 IU/L or alanine transaminase [ALT] >35 IU/L) who received lovastatin; cohort 2: 620 patients without elevated liver enzymes who received lovastatin; and cohort 3: 2644 patients with elevated liver enzymes but not prescribed lovastatin. Elevations in liver biochemistries over a 12-month period after lovastatin was prescribed were categorized into mild-moderate or severe elevations and into "Hy's Rule" based on published criteria. RESULTS: The incidence of mild-moderate elevations and severe elevations in liver biochemistries in cohort 1 were 6.6% and 0%, respectively. Compared with cohort 2, individuals in cohort 1 had higher incidence of mild-moderate elevations (6.6% versus 3%; P = 0.03) but not severe elevations (0% versus 0.3%; P = 0.9). Compared with cohort 3, patients in cohort 1 had similar mild-moderate elevations (6.6% versus 11%; P = 0.2) but lower severe elevations (0% versus 5.5%; P < 0.01). No one in cohorts 1 or 2 developed elevations meeting Hy's Rule, whereas 3.5% of the patients in cohort 3 exhibited such elevations (P < 0.05 versus cohort 1 or cohort 2). CONCLUSIONS: Significant hepatotoxicity from lovastatin was very infrequent in this study, and individuals with elevated baseline liver enzyme levels did not have higher frequency of lovastatin hepatotoxicity than those with normal liver enzyme levels.     

Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review

Non-alcoholic fatty liver disease is a serious and growing clinical problem. Despite lifestyle modification, i.e. diet and physical activity, being the recommended therapy, there are currently no systematic evaluations of its efficacy. This review applies a systematic approach to evaluating lifestyle modifications studied to date. Medline (Pubmed), Scopus, and the Cochrane Controlled Trials Register were searched for studies and study groups assessing the effect of diet, physical activity, and/or exercise modification in adult populations with non-alcoholic fatty liver disease. The outcome markers of interest were indicators of steatosis, histological evidence of inflammation and fibrosis, and glucose control/insulin sensitivity. We identified 23 studies for inclusion; seven had control groups, but only six were randomised. Eleven groups received diet-only interventions, two exercise-only, and 19 diet and physical activity/exercise. Studies consistently showed reductions in liver fat and/or liver aminotransferase concentration, with the strongest correlation being with weight reduction. Of the 5 studies reporting changes in histopathology, all showed a trend towards reduction in inflammation, in 2 this was statistically significant. Changes in fibrosis were less consistent with only one study showing a significant reduction. The majority of studies also reported improvements in glucose control/insulin sensitivity following intervention. However, study design, definition of disease, assessment methods, and interventions varied considerably across studies. Lifestyle modifications leading to weight reduction and/or increased physical activity consistently reduced liver fat and improved glucose control/insulin sensitivity. Limited data also suggest that lifestyle interventions may hold benefits for histopathology.     

Prevalence and associated metabolic factors of fatty liver disease in the elderly

Objective

The aim of this study was to investigate the metabolic risk factors for fatty liver disease in the elderly, and determine the prevalence of fatty liver disease in the elderly in Wuhan, central China.

Methods

The study was a case–control study based on all 4226 adults above 60 years of age from a cohort investigated in 2010–11 at the medical examination center of Zhongnan hospital, using 3145 randomly selected adults under 60 years of age from the same cohort as controls. Fatty liver disease (FLD) was identified with ultrasound imaging. The risk factors measured were body mass index (BMI), and plasma concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low density lipoprotein (LDL) and serum uric acid (SUA). The probability of steatohepatitis with advanced fibrosis was predicted using a score based on BMI, age, ALT, and TG (BAAT),and using AST/ALT ratio (AAR).

Results

FLD was higher in the elderly (26.7%) than in the non-elderly (22.8%) and similar in the elderly between men and women (26.6% vs 27.0%, p > 0.05). BMI, TC, TG, LDL, SUA, AST and ALT were all significantly higher in FLD, whereas the level of HDL was markedly lower. Multiple regression analyses showed that obesity, high TC, TG, SUA, low HDL, and elevated ALT, AAR < 1 were closely related to the elderly FLD, while male sex, obesity, high TC, TG, low HDL, elevated ALT, AST and AAR < 1 were closely related to the non-elderly FLD. The prevalence of steatohepatitis with advanced fibrosis estimated as BAAT index ≥ 3 was 2.4% in all subjects, and was higher in the elderly FLD patients than in the non-elderly FLD patients.

Conclusion

The prevalence of FLD is higher in the elderly, and is broadly related to the same metabolic risk factors as in the non-elderly. However, female-sex is no longer protective with increasing age, and the prevalence of steatohepatitis with advanced fibrosis is estimated to be considerably higher in the elderly FLD patients than in the non-elderly FLD controls.     

Prediction of coronary atherosclerotic disease with liver transaminase level.

BACKGROUND/AIMS: Recent studies have shown that liver transaminases are associated with components of the metabolic syndrome including central obesity, type 2 diabetes, dyslipidaemia and high blood pressure, but their direct influence on coronary atherosclerosis has not been investigated before. We conducted this study to evaluate the predictive value of liver transaminases for angiography-documented coronary atherosclerosis in patients with coronary heart disease. METHODS: Six hundred and thirty consecutive patients with suspicious coronary artery disease (CAD) who were candidates for coronary angiography were enrolled. In addition to coronary angiography, measurements of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations, C-reactive protein (CRP) level and assessment of the traits of the metabolic syndrome were performed in all patients. RESULTS: ALT and ALT/AST ratios were significantly correlated with angiographic atherosclerosis score in women (r=0.17 and 0.24 respectively). Logistic regression analysis showed that the ALT/AST ratio in women could predict severe CAD [odds ratio (OR) 3.93, 95% confidence interval (CI) 1.76-8.76]. After adjustment for components of the metabolic syndrome and CRP concentration, the OR remained significant (4.00 [1.76-9.14]). Although significant in univariate analysis, neither ALT (OR 0.98, 95% CI 0.77-1.15) nor AST (OR 0.99, 95% CI 0.72-1.22) could predict severe CAD in men. CONCLUSION: An elevated ALT/AST ratio in women predicts coronary atherosclerosis independently of the metabolic syndrome and serum CRP concentration, and should warrant further diagnostic and therapeutic interventions.     

Increased liver markers are associated with higher risk of type 2 diabetes

AIM: To investigate the association between liver markers and the risk of type 2 diabetes (T2DM) and impaired fasting glucose (IFG).METHODS: A total of 8863 participants (3408 men and 5455 women) over 30 years of age were analyzed from the fifth Korean National Health and Nutrition Examination Survey (2010-2011). The associations of serum liver markers such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), AST/ALT, and gamma-glutamyltransferase (GGT) with T2DM and IFG were analyzed using logistic regression models. Participants were divided into sex-specific quartiles on the basis of liver markers.RESULTS: The prevalence of T2DM and IFG were 11.3% and 18.3%. Increasing quartiles of ALT and GGT were positively and AST/ALT were negatively correlated with T2DM and IFG. Analysis of the liver marker combinations showed that if any two or more markers were in the highest risk quartile, the risks of both T2DM and IFG increased significantly. The risk was greatest when the highest ALT and GGT and lowest AST/ALT quartile were combined, with the risk of T2DM at 3.21 (95%CI: 1.829-5.622, P < 0.001) in men and 4.60 (95%CI: 3.217-6.582, P < 0.001) in women. Men and women with the highest AST and ALT and lowest AST/ALT quartile had a 1.99 and 2.40 times increased risk of IFG.CONCLUSION: Higher levels of GGT and ALT and lower AST/ALT within the physiological range are independent, additive risk factors of T2DM and IFG.     

Central obesity and smoking are key modifiable risk factors for elevated C-reactive protein in Asian individuals who are not eligible for statin therapy

Objective:

Statin therapy reduces coronary heart disease (CHD) and mortality in individuals with elevated C-reactive protein (CRP) but low-density lipoprotein cholesterol below the threshold at which statin therapy is recommended. We determined the proportion of individuals with elevated CRP in whom statin therapy was not indicated, and examined predictors for elevated CRP in a multi-ethnic Asian population.

Design:

We studied 3404 participants (Chinese, Malays and Asian-Indians) without a history of hypercholesterolemia living in Singapore (mean age±s.d.: 48.9±11.2 years). Eligibility for statin therapy was determined based on the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III (ATPIII)) guideline. CRP was measured by high-sensitivity enzyme-linked immunosorbent assay method. CRP level greater than 2 mg l⁻¹ was considered as elevated.

Results:

Elevated CRP was found in 29.3% participants who were not eligible for statin therapy (n=2974). Elevated CRP was more common in females and amongst those of Malay or Asian-Indian ethnicity. Compared with participants with low CRP, those with elevated CRP were shown to have higher levels of obesity, blood pressure, triglyceride and insulin resistance (IR), but lower high-density lipoprotein cholesterol levels (all Ps<0.001). After multivariate analysis, gender (odds ratio (OR) 3.34 for females), ethnicity (Malay OR 1.57, 95% confidence interval (CI) 1.25–1.96; Asian-Indian OR 1.97, 95% CI 1.55–2.50), waist circumference (OR 1.06, 95% CI 1.05–1.07), smoking (OR 1.49, 95% CI 1.08–2.05) and IR (OR 1.14, 95% CI 1.07–1.22) were significant predictors of CRP (all Ps--values<0.05).

Conclusion:

Routine measurement of CRP identifies a substantial number of Asian individuals at risk of CHD in whom statin therapy is not currently indicated, particularly in women and certain ethnic groups (Malays and Asian Indians). Weight loss and smoking cessation are important measures to reduce the proportion of individuals with elevated CRP.     

急性胆道梗阻大鼠肝脏iNOS的表达及意义

目的 探讨大鼠阻塞性黄疸时诱导型一氧化氮合酶（iNOS）在肝脏中的变化及其意义.方法 选择成年SD大鼠60只,随机分为假手术对照组（S组）30只和阻塞性黄疸组（OJ组）30只.各组分别于术后1、3、7、10、14 d时点处死大鼠6只,检测血清丙氨酸氨基转移酶（ALT）、谷草转氨酶（AST）、血清总胆红素（TB）;观察肝组织普通病理改变以及iNOS蛋白、iNOS mRNA的表达情况.结果 S组肝细胞无肿胀、坏死,肝细胞索排列整齐.OJ组大鼠肝组织可见炎性细胞浸润,细小胆管和无管腔的小胆管增生,纤维组织细胞增生,肝细胞出现变性坏死.OJ组术后ALT、AST、TB迅速增高,与S组比较差异有统计学意义（P均＜0.05）.OJ组术后iNOS基因和蛋白水平表达升高,于第14天达到峰值,与S组比较差异有统计学意义（P均＜0.05）.结论 NO在阻塞性黄疸肝损害中具有双重作用.OJ早期NO可扩张血管,改善肝脏功能;随着iNOS增加,过量的NO产生细胞毒性可损伤肝脏.     

Circulating irisin,omentin-1, and lipoprotein subparticles in adults at higher cardiovascular risk

Objective

Muscle and fat are now recognized as metabolism-regulating endocrine organs. However, muscle and adipocyte-derived novel cytokines such as irisin and omentin-1 remain understudied in relation to metabolic biomarkers that are associated with cardiovascular risk.

Subjects and methods

Thirty-nine subjects with mean (± SD) BMI of 29.2 ± 5.4 kg/m² and either diabetes or two other cardiovascular risk factors were enrolled in a 6-month randomized trial of low-dose ethanol. We examined cross-sectional data at baseline, 3-month, and 6-month visits to assess (1) within-person stability of novel cytokines (irisin, omentin-1, visfatin, resistin, and soluble tumor necrosis factor receptor II) and (2) their associations with metabolic parameters, particularly lipoprotein subparticle profile.

Results

Repeated measures of irisin and omentin-1 were highly correlated, with intra-class correlations of 0.84 (95% CI: 0.74, 0.91; P < 0.001) and 0.81 (0.70, 0.89; P < 0.001), respectively. Irisin was negatively correlated with omentin-1 (7.4% irisin decrease per a 1-SD increment in omentin-1; 95% CI: 0.5%, 13.9%; P = 0.04). In models adjusted for age, sex, and race, irisin was negatively associated with HDL cholesterol (7.3% decrease per a 10 mg/dL increment; 1.0%, 13.3%; P = 0.02) and large HDL particles (15.5% decrease per a 1-SD or 3.5-μmol/L increment; 5.2%, 24.7%; P = 0.005). Omentin-1 was positively associated with mean VLDL size (3.8% increase per a 1-SD increment; 0.06%, 7.8%; P = 0.05). Adjustment for alcohol intervention, BMI, and other cytokines did not materially affect these associations.

Conclusions

Irisin and omentin-1 are stable within-person, inversely associated with each other, and closely related to lipoprotein profile. These molecules may be promising markers for cardiovascular risk.     

AAR和APRI对成年慢性丙型肝炎患者肝纤维化的诊断价值

目的探讨AST／ALT比值（AST／AL Tratio,AAR）和AST／PLT比值指数（AST／PLT ratio index。APRI）对成年慢性丙型肝炎（丙肝）患者肝纤维化的诊断价值。方法选择98例成年慢性丙肝患者进行回顾性分析。对所有患者进行肝脏穿刺活体组织检查以确定肝纤维化分期,比较分析AAR和APRI与肝纤维化分期的关系。结果AAR只在S0期与S1～S4期患者之间差异有统计学意义（P〈0．05）,在S0～S1期与S2～S4期、S0～S2期与S3～S4期、S0～S3期与S4期患者之间差异无统计学意义（P均〉0．05）;APRI在SO期与S1～S4期、S0—S1期与S2～S4期、S0～S2期与S3～S4期、S0～S3期与S4期患者之间差异均有统计学意义（P〈0．05）。受试者工作特征曲线分析显示,AAR诊断s1期、S2～S3期和S4期的曲线下面积均〈0．7,而APRI均〉0.7。APRI诊断S1期、S2～S3期和S4期的诊断界值分别为0．150、0．195和0．245。结论对于成年慢性丙肝患者肝纤维化分期的判定,APRI比AAR更具有参考价值,APRI可以用于S1期、S2～S3期和S4期的诊断。     

Placenta-derived CD95 ligand causes liver damage in hemolysis, elevated liver enzymes, and low platelet count syndrome

BACKGROUND & AIMS: The HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome is a life-threatening complication during pregnancy. The associated liver disease may be severe, and maternal hepatic complications may progress to the point that transplantation becomes necessary. CD95 (APO-1, Fas)-mediated apoptosis of liver cells is one of the major pathogenic mechanisms during liver disease. The interaction of CD95 with its ligand, CD95L(FasL), induces apoptosis and thus the source of the death-inducing ligand is critical for understanding the pathomechanism of liver damage involving the CD95-system. METHODS: Sera from HELLP patients were analyzed and used in cell culture experiments to study CD95-mediated apoptosis. We established a mouse model for placenta-induced liver damage and used a new therapeutical agent, LY498919, to block CD95 apoptosis. RESULTS: We describe apoptosis in the liver of HELLP patients and cytotoxic activity for primary human hepatocytes in HELLP serum. Blocking of CD95 signaling reduced the cytotoxic activity of HELLP serum. In addition, cytotoxic activity increased as HELLP syndrome developed. Furthermore, CD95L was found to be produced in the placenta and extracts of placenta were cytotoxic for human hepatocytes. Injection of mouse placenta extract in mice induces liver damage that could be prevented by blocking CD95L. CONCLUSIONS: Taken together, these data suggest that CD95L derived from the placenta acts systemically and is a primary cause of liver damage in HELLP syndrome. Our results also show that blocking of CD95L can reduce liver cell apoptosis, indicating that such a strategy may have therapeutic advantages.