Evaluation of metformin therapy using controlled attenuation parameter and transient elastography in patients with non-alcoholic fatty liver disease

Background

Non-alcoholic fatty liver disease (NAFLD) is among the most common causes of liver disease worldwide. There is growing evidence on pathogenesis and pathophysiology of NAFLD. However, there is still no universally accepted pharmacotherapy protocol.

超声判别肝纤维化改变的实验研究

目的通过观察肝纤维化兔的超声表现,了解超声判别兔肝纤维化的诊断指标,避免创伤性定性诊断对实验动物实验价值的影响。方法新西兰兔30只,采用四氯化碳对肝脏的毒性建立肝纤维化动物模型,应用彩色超声观察兔肝不同时期(从正常肝到肝硬化)的回声改变、兔门静脉血流动力学的变化,包括平均速度(Vm)和速度随呼吸变化的阻力指数(V⊿=V呼-V吸/V呼),每一变化均由活检病理诊断证实。结果兔肝纤维化时肝实质回声增强、光点粗大、呈非均质性改变,门静脉三级以下分支显示不清、V⊿增大(P<0.05)、Vm减低(P<0.05)。结论超声技术可作为兔肝纤维化的无创性定性检查方法。     

Impact of inhibitors of the Renin-Angiotensin-aldosterone system on liver fibrosis and portal hypertension

Morbidity and mortality of chronic liver disease are primarily caused by liver cirrhosis and portal hypertension, both of them secondary disorders of progressive liver fibrosis. The main fibrogenic cell type in the liver, the hepatic stellate cell (HSC), is activated and stimulated by several factors, among which the renin-angiotensin-aldosterone system (RAAS) plays a major role. Angiotensin II induces various profibrotic pathways via the angiotensin II receptor type 1 (AT(1) receptor) not only in heart and kidney, but also in liver tissue. Stimulation of the AT(1) receptor promotes the transformation of the quiescent HSC into the myofibroblast like activated HSC and the synthesis of transforming growth factor-beta1 (TGF-beta), the major profibrotic cytokine in the liver. In addition, aldosterone has been suggested to induce profibrotic effects in chronic heart and liver disease. This review focuses on the concept that inhibitors of the RAAS retard or even reverse liver fibrosis and reduce portal hypertension. Angiotensin converting enzyme (ACE) inhibitors, AT(1) receptor antagonists, and aldosterone antagonists have been demonstrated to reduce the proliferation of HSC, to decrease the synthesis of profibrotic molecules, and to have the potential to improve liver fibrosis. However, side-effects such as systemic hypotension may impair the clinical application of RAAS inhibitors in patients with liver cirrhosis and portal hypertension. Also, efficacy may be limited by the downregulation of AT(1) receptors in advanced fibrosis, which has been observed in animal and human studies. Randomized clinical studies are essential to evaluate, whether this approach is beneficial in patients with chronic liver disease and progressive fibrosis.     

Reliability of liver stiffness measurement in non-alcoholic fatty liver disease: the effects of body mass index

Background Liver stiffness measurement (LSM) using transient elastography (TE) is used to stage fibrosis in patients with liver disease, diagnostic reliability and the factors affecting its performance in patients with non‐alcoholic fatty liver disease (NAFLD) are incompletely understood. Aim To assess LSM. Methods Consecutive NAFLD patients (n = 169), assessed by liver biopsy (Kleiner score), anthropometrical, biochemical and metabolic features, underwent LSM using TE with standard M probe. Results Liver stiffness measurement was not reliable in 23 patients (14%) due to obesity. Among patients with a reliable TE, a LSM value >7.25 kPa was the best cut‐off for predicting significant fibrosis at biopsy (AUC 0.794); however, this cut‐off still failed to rule out F2‐F4 fibrosis in 31% (false‐negative rate) or rule in F3‐F4 in 29% (false‐positive rate). Similarly a LSM value >8.75 kPa was the best cut‐off for severe fibrosis (F3‐F4) (AUC 0.870), with a rate of false‐negatives 24% and of false‐positives 2%. Body mass index was the major determinant of these diagnostic errors in predicting significant and severe fibrosis both by overestimating or underestimating the stage of fibrosis. Conclusions In NAFLD patients, even when liver stiffness measurement is feasible, high BMI values negatively affect the diagnostic reliability. Improved performance of transient elastography could be obtained using specifically designed probes.     

雌激素对纤维化疾病的影响

雌激素(Estrogen)通过核结合模式作用于其受体,雌激素受体(ER)除了在女性生殖系统表达外,还在乳腺、心血管、骨骼系统、前列腺、皮肤及结缔组织等多种组织、器官的多种细胞内表达,并与相应的生理及病理变化相关。大量文献表明,雌激素对纤维化疾病的形成与发展起到明显的促进作用。1雌激素影响纤维化疾病的生物学机制1.1雌激素对成纤维细胞生长增殖的影响雌激素中的主要活性成分为雌二醇,尤其是17-β雌二醇(17-βE2)。正常皮肤成纤维细胞表达ER,雌激素可直接调控该细胞的增殖。通过台盼蓝排斥实验发现,生理浓度的17-βE2(1pM～1mM)可明显…     

FibroScan受控衰减参数及瞬时弹性测定值在慢性肝病中的应用价值

目的:探讨FibroScan受控衰减参数(CAP)及瞬时弹性测定值在慢性肝病不同阶段中的应用价值。方法:收集2014年12月—2016年12月就诊于山西大医院消化科的慢性肝病患者131例,按照病因分为慢性乙型肝炎(CHB)组(n=50),慢性丙型肝炎(CHC)组(n=20),原发性胆汁性肝硬化(PBC)组(n=15),肝硬化组(n=31)及肝癌组(n=15)。比较各组间CAP值及瞬时弹性测定值(E)。结果:各组CAP值比较,差异有统计学意义(P<0.05),其中CHB组、PBC组、肝硬化组、肝癌组均低于CHC组,肝硬化组低于CHB组,差异均有统计学意义(P<0.05)。各组E值比较,CHB组、CHC组、PBC组均低于肝硬化组及肝癌组,肝硬化组低于肝癌组,CHC组低于PBC组,差异均有统计学意义(P<0.05)。结论:FibroScan受控衰减参数及瞬时弹性测定值联合应用有助于区分肝病的不同阶段,有助于在不同阶段尽早进行干预性治疗。     

Diagnosis of liver fibrosis

Hepatic fibrosis and cirrhosis represent the main consequence of chronic liver diseases of different origin. Therefore, the clinical assessment of disease severity is a must in the management of patients with chronic liver damage. Although liver biopsy may be associated with sampling error, interobserver variability and potential complications, it still remains the gold standard for establishing the severity of hepatic necroinflammation and fibrosis. In the last years, several non-invasive tests for the assessment of disease activity and stage have been proposed. However, at present all these tests are not totally accurate and reliable and need further evaluation.     

曼性乙型肝炎患者红细胞参数和血小板参数检测的临床意义

目的探讨慢性乙型肝炎患者红细胞参数和血小板参数检测的临床意义。方法对89例慢性乙型肝炎患者的临床资料进行回顾性分析．选择50例健康体检者为对照组,比较两组红细胞参数和血小板参数。结果慢性乙型肝炎中度患者红细胞参数和血小板参数与对照组比较,差异有统计学意义（P〈0．05）;慢性乙型肝炎重度患者与对照组比较,差异也有统计学意义（P〈0．01）。慢性乙型肝炎重度患者红细胞参数和血小板参数异常检出率〉中度患者〉轻度患者。结论红细胞参数和血小板参数的改变可反映慢性乙型肝炎病情轻重和肝脏损害程度。     

Impact of dose selection on parameter estimation using a rapid binding approximation model of target-mediated drug disposition

The purpose of this study was to examine the role of dose selection on population pharmacokinetic (PK) parameter estimation using a rapid binding approximation of a target-mediated drug disposition (TMDD) model previously developed for interferon-β (IFN-β). A total of 50 replicate datasets each containing 100 subjects were created using NONMEM^®. The study design included IV injection of IFN-β followed by the SC route in a crossover manner, with each dose and route of administration separated by a 1,000 h washout period. Serial plasma PK samples were simulated up to 48 h for all subjects following each dose. Population mean PK parameters were re-estimated in NONMEM^® for each simulated dataset using the same TMDD model after including the following doses (MIU/kg): (A) 1, 3 and 10 (original study); (B) 1, 3 and 7; (C) 1, 3 and 5; (D) 1, 3 and 4; (E) 1 and 3; (F) 3 and 10; or (G) 10 MIU/kg only. Bias in the model fit was assessed by calculating the percent prediction error (PE%) for each of the population mean PK parameters relative to the estimates obtained from the fit to the 1, 3, and 10 MIU/kg doses (Case A). Relatively unbiased population mean PK parameter estimates (median PE% <8%) were obtained only when the study design included 1, 3 and a minimum higher dose of 7 MIU/kg. Bias increased for various parameters when the highest dose was less than 7 MIU/kg along with 1 and 3 MIU/kg being the low and intermediate dose levels. An increase in the bias for binding capacity, R_tot, and the equilibrium dissociation constant, K _D, was observed as the highest dose included in the dataset was reduced from 5 to 3 MIU/kg (median PE% ranged from ?4.71 to ?23.9% and ?4.76 to ?34.6%). Similar increases in the range of median PE% were also observed for other model parameters as the highest dose was reduced from 5 to 3 MIU/kg. Severely biased results were obtained from the study design that included only the 10 MIU/kg dose (Case G) suggesting that it is not sufficient to study just a high dose group. This bias was greatly reduced (median PE% <14%) for all parameters except K _D when the 3 and 10 MIU/kg doses were co-modeled (Case F). Plots of the PE% for R_tot and K _D versus the molar ratio of maximum dose to R_tot suggest that study designs should evaluate at least one IFN-β dose 3.5- to 4-fold higher than R_tot along with the 1 and 3 MIU/kg dose levels to obtain unbiased population PK parameter estimates. In summary, for the IFN-β model and study design, dose selection influences the ability to generate relatively unbiased population mean TMDD parameter estimates, which is based on maximum dose levels relative to R_tot. This simulation study highlights the role of dose selection in optimal study design strategies for drugs such as IFN-β that exhibit TMDD properties.     

NOXs在肝纤维化中的作用机制研究

还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶(nicotinamide adenine dinucleotide phosphate oxidase,NOXs)在肝纤维化中,有助于活性氧簇(reactive oxygen species,ROS)的产生,进而介导内质网应激(endoplasmic reticulum stress,ERS)的发生及IRE1α-XBP1(inositol-requiring enzyme 1 alpha,IRE1α;X-box binding protein 1,XBP1)信号通路的激活。ROS是指分子氧(O_2)单电子还原后生成的化学性质更为活跃的一类氧代谢产物及其衍生物,包括超氧阴离子(O_2~-)、羟自由基(·OH)、过氧化氢(H_2O_2)以及次氯酸根离子(OCl~-)等。它们可以与生物体内大量分子,包括无机分子、蛋白、脂质、碳水化合物和核酸广泛互作,介导氧化还原修饰,引起脂质过氧化,进而引起肝细胞损伤。另可作为第二信使影响包括肝星状细胞(hepatic stellate cells,HSC)在内的各种细胞的信号转导,导致HSC的异常活化和增殖,分泌大量胞外基质(extracellular matrix,ECM),进而促使肝细胞凋亡并诱发肝纤维化。该文将对近年来NOXs在肝纤维化中的作用机制研究作一综述,旨在为抗肝纤维化的研究提供新的视角和治疗靶标。     

生长抑素治疗肝纤维化研究进展

生长抑素是人体内广泛分布的环肽激素,近期有研究表明生长抑素能够减少星状细胞分泌细胞因子及细胞外基质,抑制其增殖及收缩,并促进其凋亡;同时调节枯否细胞分泌功能,介导肝干细胞归巢,对于各种病因肝纤维化尤其对于血吸虫性肝纤维化具有治疗作用。     

苦参碱对实验大鼠肝纤维化的影响

目的 :研究苦参碱对实验大鼠肝纤维化的防治作用 ,并探讨其可能的机制。方法 :应用四氯化碳诱导大鼠实验性肝纤维化 ,以苦参碱防治。观察3,6 ,12wk时溶剂对照组、四氯化碳组、苦参碱组血清丙氨酸转氨酶 (ALT)、透明质酸 (HA)、肝组织羟脯氨酸 (HyP)含量以及肝脏病理变化。结果 :苦参碱能显著减轻实验大鼠肝细胞变性、坏死及纤维组织的形成 ,同时能降低不同实验阶段血清ALT(P <0 .0 1) ,HA(P <0 .0 1)以及肝组织中HyP含量 (P <0 .0 5)。结论 :苦参碱有保护肝细胞 ,减轻肝细胞坏死 ,防治四氯化碳诱发的肝纤维化的作用。