Thalidomide decreases intrahepatic resistance in cirrhotic rats

Increased intrahepatic resistance (IHR) within cirrhotic liver is caused by increased endotoxemia, cytokines tumor necrosis factor-α (TNF-α), vasoconstrictor thromboxane A₂ (TXA₂), and disrupted microvasculatures. We evaluated the effects of thalidomide-related inhibition of TNF-α upon the hepatic microcirculation of cirrhosis in rats. Portal venous pressure (PVP), hepatic TNF-α, expression of thromboxane synthase (TXS), and leukocyte common antigen (LCA) were measured in bile-duct-ligated (BDL) rats receiving 1 month of thalidomide (BDL-thalido rats). Portal perfusion pressure (PPP), IHR, and hepatic TXA₂ production were measured in the isolated liver perfusion system. Intravital microscopy was used to examine hepatic microvascular disruptions. In BDL-thalido rats, PVP, PPP, IHR, hepatic TXA₂ and TNF-α, hydroxyproline content, expression of TXS and LCA, and LPS-induced leukocyte recruitment were significantly decreased. Conversely, hepatic microvascular density and perfused sinusoids were significantly increased. Thalidomide decreased PVP and IHR by reducing hepatic TXA₂ and improving hepatic microvascular disruptions in rats with biliary cirrhosis.     

肝硬化患者内毒素、T N F -α和N O 水平与 高动力循环状态的相关性研究

目的：观察肝硬化患者血流动力学变化情况及血浆内毒素（LPS）、肿瘤坏死因子-α（TNF-α）和NO的水平并探讨之间相关关系。方法：试验检测血浆内毒素,双抗体夹心ELISA检测TNF-α,NO2^-／NO3^-测定采用硝酸还原法。并对CO、MAP、SVRI行同步观察。结果：健康组与肝硬化患者比较。失代偿组高动力循环状态特征明显。失代偿组、代偿组、健康组LPS、TNF-α、NO依次明显升高（P〈0．01）。血浆LPS与TNF-α和N0之间呈直线正相关。血浆NO水平与CO呈显著性正相关;与MAP、SVRI呈显著性负相关。结论：肝硬化患者血浆LPS、TNF-α、NO生成增多,NO在肝硬化血液动力学紊乱中起重要作用。     

肝硬化合并肝肾综合征的临床特点分析

目的探讨肝硬化合并肝肾综合征的临床特点。方法分析患者的病因,Child-Pugh肝功能分级及肝肾综合征的诱因,比较Ⅰ型、Ⅱ型肝肾综合征发病前后的血肌酐、血钠和尿量变化。结果肝肾综合征的发病率为8.46%;全部为肝硬化患者;其中大量腹水者14例,自发性腹膜炎或其他部位感染者11例,上消化道出血者9例,大量放腹水(2 000 ml/次)而未采取补充有效血容量5例,中等量以下腹水且无上述诱因者14例,肝移植失败后诱发肝肾综合征1例。Child-Pugh B级5例,Child-Pugh C级49例。结论肝功能储备状态差;大多数患者发病前有诱因,血肌酐值明显升高,尿量减少明显,血钠减少。     

肝炎肝硬化和酒精性肝硬化的B超表现比较

目的比较肝炎肝硬化和酒精性肝硬化的B超表现,为临床工作提供参考。方法收集2007年1月1日至2008年12月31日入住温州医学院附属第三医院肝硬化患者的B超资料,回顾性分析比较其B超表现特点。结果酒精性肝硬化患者肝脏肿大的比例高于肝炎肝硬化患者,差异有统计学意义(P0.001),但二者肝脏缩小比例差异无统计学意义。酒精性肝硬化患者肝脏表面光滑的比例较高而呈锯齿状的比例较低,与肝炎肝硬化患者比较差异均有统计学意义(P=0.015和P=0.027)。酒精性肝硬化患者肝内明显可见结节的比例低于肝炎肝硬化患者,二者差异有统计学意义(P=0.009)。门静脉宽度比较2组均数差异无统计学意义(P=0.581)。结论与肝炎肝硬化患者比较,酒精性肝硬化患者肝右叶斜径增大的比例较高,表面较光滑而较少出现锯齿状,发现粗大不规则结节的比例较低,而门静脉内径二者无差异。     

Circulating microRNAs associated with liver fibrosis in chronic hepatitis C patients

A major challenge in hepatitis C research is the detection of early potential for progressive liver disease. MicroRNAs (miRNAs) are small RNAs that regulate gene expression and can be biomarkers of pathological processes. In this study, we compared circulating miRNAs identified in hepatitis C virus (HCV)-infected patients presenting two extremes of liver disease: mild/moderate fibrosis and cirrhosis. The patients in the cirrhosis group subsequently developed hepatocellular carcinoma (HCC). We identified 163 mature miRNAs in the mild/moderate fibrosis group and 171 in the cirrhosis group, with 144 in common to both groups. Differential expression analysis revealed 5 upregulated miRNAs and 2 downregulated miRNAs in the cirrhosis group relative to the mild/moderate fibrosis group. Functional analyses of regulatory networks (target gene and miRNA) identified gene categories involved in cell cycle biological processes and metabolic pathways related to cell cycle, cancer, and apoptosis. These results suggest that the differentially expressed circulating miRNAs observed in this work (miR-215-5p, miR-483-5p, miR-193b-3p, miR-34a-5p, miR-885-5p, miR-26b-5p and miR -197-3p) may be candidates for biomarkers in the prognosis of liver disease.     

阿德福韦酯联合拉米夫定治疗乙型肝炎DNA 阳性肝硬化疗效观察

目的:探讨阿德福韦酯联合拉米夫定治疗HBV DNA阳性乙型肝炎肝硬化的疗效。方法:46例HBV DNA阳性乙肝肝硬化患者随机分为对照组及观察组。在保肝等对症治疗基础上,观察组22例患者联用阿德福韦酯与拉米夫定,对照组24例患者予阿德福韦酯,总疗程均为48周。结果:在治疗12周后,观察组与对照组HBV DNA转阴率分别为54.5%、20.8%(P<0.05),ALT复常率分别为63.6%、33.3%(P<0.05)。治疗24周、48周后上述指标无统计学差异。两组患者未见明显药物不良反应。结论:阿德福韦酯联合拉米夫定治疗HBV DNA阳性乙型肝炎肝硬化起效快,降低病毒载量疗效佳,安全性好。     

视黄醇结合蛋白4在非酒精性脂肪肝病大鼠组织中的表达

目的:视黄醇结合蛋白4(RBP4)在非酒精性肝脂肪变模型大鼠中的表达情况,以探求其在疾病发生、发展中的意义。方法:40只wistar大鼠随机分为对照组和造模组,分析各组在2、4、6、8周4个时间点血清ALT、AST、TG、TC的变化及肝组织RBP4的表达情况。结果:随着造模时间延长,造模组大鼠肝脏脂肪变越来越明显,血清ALT、AST、TG、TC逐渐升高(p<0.05)。造模组肝组织RBP4的mRNA的表达随造模时间逐渐增强;造模组免疫组化结果发现,RBP4的表达随造模时间逐渐增强(p<0.05)。结论:在大鼠非酒精性脂肪肝模型中,RBP4的表达随造模时间延长而增加,与同期对照组相比有统计学差异,因此RBP4可能作为一个敏感的指标反映非酒精性脂肪肝的发生及发展情况。     

肝纤维化的实验动物模型

本文讨论了建立肝纤维化动物模型的技术与存在的问题,以大鼠为主要动物讨论了目前常用的几种造模方法、每种造模方法的致病机理、造模途径、效果,同时比较了不同造模方法的优缺点及各自的用途,提出了肝纤维化动物模型领域的研究方向。     

Androgen metabolism and biotransformation in nontumoral and malignant human liver tissues and cells

There is indirect multiple evidence that hints at a potential role of sex steroids in development and progression of human hepatocellular carcinoma (HCC). In the present study, we have investigated androgen metabolism in a panel of human liver cancer cell lines (HA22T, Huh7, HepG2) and in normal, cirrhotic and malignant human liver tissues aiming to dissect the potential impact of individual enzyme activities and their products in normal and diseased human liver, both in vivo and in vitro. Using our intact cell analysis we were able to assess rates and pathways of androgen metabolism in living conditions. Overall, incubation of cultured cells or tissue minces with either testosterone (T) or androstenedione (Ad) used as precursor resulted in a large extent of 17βoxidation of T to Ad (cells: 28–77%; tissues: 35–50%). In malignant liver cell lines, both HA22T and Huh7 cells showed consistent amounts of the 5α-reductase enzyme products (18% and 15%, respectively), while 5β-reductase activity was more pronounced in Huh7 cells (18%) than in HA22T cells (1.8%). Interestingly, a significant extent of estrogen formation could be observed in Huh7 cells (5.4–11.5%), while no aromatase activity could be detected in HA22T cells. In HepG2 cells, along with a relatively high proportion of Ad, estrogens represented the most prominent (50–55%) end product of androgen metabolism, regardless of the precursor used. In liver tissues, equivalent results could be obtained, with a consistent proportion of 17βoxidation of T to Ad (35–50%) being observed in the majority of samples. However, while normal liver tissue samples exhibited a minor proportion of bioactive androgens (3.4%) with no aromatase products, HCC tissues showed a significant extent of aromatase activity (nearly 20%) with estrogen representing the most prominent metabolic product after 24 h incubation with either T or Ad. HCV and alcoholic cirrhotic tissues displayed different patterns of androgen metabolism. The former produced limited amounts of bioactive androgens (5.3%) and considerable levels of the intermediate aromatase product 19OH-Ad (up to 28%), the latter exhibited a prevalence of androgen degradation through the 5β-reductase pathway (9.8%) and a significant extent of aromatase activity (16% as a whole). In conclusion, three major metabolic states could be depicted, depending on prevalent pathways of androgen metabolism and steroid receptor status: estrogenic, androgenic, and mixed. This model supports the idea that local estrogen biosynthesis may be implicated in human HCC and provides a basis for the exploitation of aromatase inhibitors and/or ER antagonists or selective estrogen receptor modulators (SERMs) as a new therapeutic strategy in HCC patients.     

不同分化程度的原发性肝癌MRI初步临床研究

目的:探讨原发性肝癌不同分化程度、细胞类型的MRI图像特征、参数。方法:回顾性分析肝硬化再生结节27例、肝细胞癌75例81处病灶(高度分化15例,中度分化40例,低度分化26例)、肝内胆管癌20例的病理结果及MRI影像学数据,比较再生结节、肝细胞癌和肝内胆管癌之间,以及肝细胞癌各种组织分化程度之间的ADC值、强化程度差异。结果:常规MRI平扫结合LAVA可准确诊断大部分原发性肝癌病例。再生结节、肝细胞癌及肝内胆管癌ADC值均值的具有显著统计学差异(P0.01);肝细胞癌高分化组、中分化组及低分化组ADC值均值均具有显著统计学差异(P0.01),但中、低分化肝细胞癌ADC值均值的差异无实际临床意义;高分化肝细胞癌与肝内胆管癌ADC值均值的差异无统计学意义(P=0.27)。结论:常规MRI结合DWI、多期动态增强扫描有助于区分原发性肝癌各种组织分化程度及细胞类型。