HBV相关慢加急性肝衰竭患者肝组织和血清中基质细胞衍生因子-1α的变化及其意义

发布时间：2018-04-21 04:30

  本文选题：基质细胞衍生因子-1α + CXCR4　； 参考：《河北医科大学》2013年硕士论文

【摘要】：目的：乙型肝炎病毒（hepatitis B virus, HBV）相关慢加急性肝衰竭（acute-on-chronic liver failure,ACLF）是在慢性乙型肝病基础上发生的严重肝功能损害，出现以黄疸、肝性脑病和腹水等为主要表现的临床综合征，其发病急，病情凶险，，病死率高且治疗方法有限。来自骨髓的干细胞可迁移到损伤肝脏，通过分化为肝细胞修复损伤肝组织。本研究通过观察HBV相关ACLF患者肝组织及血清中基质细胞衍生因子-1α (stromal cellderived factor-1α，SDF-lα)的水平及肝组织Ki-67的表达，同时比较不同预后ACLF患者血清SDF-1α水平，初步探讨SDF-1α在ACLF患者肝干细胞归巢中的作用。 方法：收集2011年3月至2012年11月于河北医科大学第三医院和石家庄市第五医院住院患者，共57例，其中HBV相关ACLF患者30例，慢性乙型肝炎(chronic hepatitis B CHB)患者27例，另外选取同期河北医科大学第三医院健康体检者20例作为健康对照组。另外收集接受肝移植的ACLF患者及肝组织活检的CHB患者肝组织各10例，正常供体肝组织8例。HBV相关ACLF和CHB的诊断分别符合中华医学会感染病学分会及肝病学分会联合制定的2006年版《肝衰竭诊疗指南》和2010年版《慢性乙型肝炎防治指南》中的诊断标准。检测患者血清生化指标、凝血功能及HBV DNA载量，应用实时荧光定量PCR检测肝组织SDF-1α mRNA的表达，免疫组织化学检测肝组织内SDF-1α及Ki-67蛋白的表达，酶联免疫吸附法检测血清SDF-1α的水平。比较血清SDF-1α水平在ACLF患者存活组和死亡组间的差异，并与HBV DNA载量及终末期肝病模型（model of end-stage liver disease, MELD）评分进行相关性分析。 结果： 1ACLF组、CHB组及健康对照组人口学及临床特点 各组患者的年龄和性别比例具有可比性。ACLF组患者血清丙氨酸氨基转移酶（alanine aminotransferase,ALT）、天冬氨酸氨基转移酶（aspartateaminotransferase, AST）、总胆红素（total bilirubin, TBIL）、直接胆红素（direct bilirubin, DBIL）、国际标准化比值（international normalized ratio,INR）水平明显高于CHB组及健康对照组（P均0.01），ACLF组和CHB组HBV DNA载量无明显差异（P0.05）。 2ACLF患者肝组织SDF-1α mRNA表达增多 共8例HBV相关ACLF患者、10例CHB患者和8例健康对照者接受SDF-1α mRNA表达检测。ACLF组肝组织SDF-1α mRNA表达（3.4±1.02）显著高于CHB组（2.16±1.19）和健康对照组（1.00），差异均具有统计学意义（P0.05或P0.01）。同样，CHB组与健康对照组比较，差异也具有统计学意义（P0.05）。 3ACLF患者肝组织SDF-1α及Ki-67蛋白表达增多 共10例HBV相关ACLF患者、10例CHB患者和6例健康对照者接受肝组织SDF-1α及Ki67表达检测。ACLF患者汇管区胆管上皮细胞和肝脏干细胞高表达SDF-1α，且伴明显的小管样反应，而健康对照者仅在胆管上皮细胞表达SDF-1α，其阳性染色平均吸光度值分别为（0.345±0.095）、（0.178±0.116）、（0.051±0.022）。ACLF患者汇管区内可见大量的Ki-67+细胞，肝实质内亦可见散在分布的阳性细胞，其阳性细胞数依次为（171.2±52.8）、（42.4±17.8）和（4.7±1.9）/高倍视野，各组间比较差异均有统计学意义（P均0.01），其中以ACLF组为最高，健康对照组最低。 4ACLF患者血清SDF-1α水平降低 共30例HBV相关ACLF患者、27例CHB患者和20例健康对照者接受血清SDF-1α水平检测。ACLF组血清SDF-1α水平（1717.33±458.07pg/ml）显著低于CHB组（2638.96±574.04pg/ml）及健康对照组（2378.20±660.09pg/ml）（P均0.01）。而CHB组与健康对照组相比，差别无统计学意义(P0.05)。 5不同预后ACLF患者血清SDF-1α水平变化 共30例不同预后的HBV相关ACLF患者接受血清SDF-1α水平检测。根据患者第28天的生存状况，分为存活组（11例）和死亡组（19例）。存活组患者入院时血清SDF-1α水平（1497.69±408.55pg/ml）低于死亡组患者（1844.50±445.84pg/ml），两组间比较差异具有统计学意义(P0.05)。 6ACLF患者血清SDF-1α水平与HBV DNA及MELD评分的相关性 ACLF患者血清SDF-1α水平与HBV DNA载量（r=0.21, P=0.27）及MELD评分（r=0.17, P=0.38）无相关性。 结论： 1HBV相关ACLF患者肝组织内存在肝干细胞再生。 2HBV相关ACLF患者肝组织内SDF-1α表达较CHB患者及正常对照组明显增多，但外周血中SDF-1α水平却明显降低，肝组织与外周血之间SDF-1α由高到低的浓度梯度可能是促进干细胞归巢至损伤肝脏的机制之一。 3外周血中低水平SDF-1α可能更有利于干细胞的归巢，因此其水平较低可能预示患者短期预后较好。
[Abstract]:Objective: the hepatitis B virus (hepatitis B virus, HBV) associated acute liver failure (acute-on-chronic liver failure, ACLF) is a severe liver function damage based on chronic hepatitis B, which is characterized by jaundice, hepatic encephalopathy and ascites, which are characterized by acute, acute, dangerous, high mortality and treatment. The stem cells from the bone marrow can migrate to the injured liver and repair the liver tissue by differentiating into hepatocytes. This study observed the level of the matrix derived factor -1 alpha (stromal cellderived factor-1 alpha, SDF-l a) in the liver tissue and serum of the HBV related ACLF patients and the expression of Ki-67 in the liver tissue, and compared the different preconditioning. The level of serum SDF-1 alpha in post ACLF patients was preliminarily explored to investigate the role of SDF-1 alpha in the homing of hepatic stem cells in ACLF patients.
Methods: 57 cases were collected from March 2011 to November 2012 in Third Hospital of Hebei Medical University and fifth hospital in Shijiazhuang. Among them, 30 cases of HBV related ACLF patients, 27 cases of chronic hepatitis B (chronic hepatitis B CHB), and 20 healthy controls in Third Hospital of Hebei Medical University in the same period were selected as the healthy control group. In addition, 10 patients with ACLF and CHB patients with liver biopsy were collected, and 8 cases of.HBV related ACLF and CHB in normal donor liver tissues were diagnosed respectively in accordance with the 2006 edition of the association of infectious diseases and Hepatology branch of the Chinese Medical Association, the guide for the diagnosis and treatment of liver failure, and the 2010 edition of the guide for the prevention and treatment of chronic hepatitis B, respectively. The serum biochemical indexes, blood coagulation function and HBV DNA load were detected, the expression of SDF-1 alpha mRNA in liver tissue was detected by real-time fluorescence quantitative PCR, the expression of SDF-1 alpha and Ki-67 protein in liver tissue was detected by immunohistochemistry, and the level of serum SDF-1 a was detected by enzyme linked immunosorbent assay. The level of serum SDF-1 alpha was compared with those of ACLF patients. The difference between the survival group and the death group was correlated with the HBV DNA load and the model of end-stage liver disease (MELD) score.
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