新生儿引起肝内胆汁淤积是由感染、遗传代谢性疾病、胃肠外营养、基因突变等各种不同病因导致胆汁形成、分泌和排泄障碍。胆汁在体内淤积会影响新生儿的生长发育,严重者出现肝纤维化、肝功能衰竭等不可逆的改变,其发病的机制涉及参与肝脏胆汁酸分泌的各种转运体、肝细胞膜转运蛋白转录和和转录后的调控等。本文归纳总结近年来国内外关于胆汁酸转运体及其转录和转录后的调控,从而为此疾病的防治提供理论依据,为将来降低其发生率和改善预后。

Neonatal intrahepatic cholestasis is caused by infection,genetic metabolic diseases,parenteral nutrition,gene mutation and other different causes leading to bile formation,secretion and excretion disorders．Bile stasis in the body will affect the growth and development of the newborn,and in severe cases,irreversible changes such as liver fibrosis and liver failure will occur．The pathogenesis of bile stasis involves various transporters involved in the secretion of bile acids in the liver,transcription and post transcription regulation of liver cell membrane transporters．In this paper,we summarized the recent studies on bile acid transporters and their transcriptional and post transcriptional regulation at home and abroad,so as to provide a theoretical basis for the prevention and treatment of this disease,and to reduce its incidence and improve its prognosis in the future.

目的 分析妊娠期肝内胆汁淤积症(ICP)孕妇与正常孕妇围产结局及ICP孕妇不同总胆汁酸水平对围产结局及新生儿的影响,为做好ICP孕妇的妊娠期管理及其新生儿预后评估提供参考依据。方法 以2010年3月—2020年3月在我院分娩的ICP孕妇 249例为观察组,同期分娩的249例正常孕妇为对照组,比较2组围产结局相关指标。结果 观察组羊水污染、新生儿黄疸、新生儿呼吸窘迫综合征发生率均高于对照组,根据总胆汁酸水平分组,重度组早产、羊水污染发生率高于轻度组,以上差异均有统计学意义(P＜0.05)。总胆汁酸水平是ICP孕妇发生早产的危险因素(P＜0.05)。结论 ICP孕妇总胆汁酸水平可用于发生早产的预测,及时干预有利于提高其围产期质量。

Objective To analyze the perinatal outcome of women with intrahepatic cholestasis of pregnancy (ICP) and normal pregnant women and the effects of different levels of total bile acid in ICP women on perinatal outcome and newborn. To provide a reference for the management of pregnancy and prognosis of ICP women. Methods From March 2010 to March 2020, 249 women with ICP delivered in our hospital were included as the observation group, 249 normal pregnant women delivered in the same period as the control group, the perinatal outcomes of the two groups were analyzed and compared. Results The incidences of amniotic fluid contamination, neonatal jaundice and neonatal respiratory distress syndrome in the observation group were higher than that in the control group. Grouping by the total bile acid level, the incidences of premature delivery and amniotic fluid contamination in the severe group were higher than that in the mild group, with statistical significance (P<0.05). Total bile acid level was a risk factor for premature delivery in women with ICP (P<0.05). Conclusions The level of total bile acid in women with ICP can be used to predict the occurrence of premature delivery, and timely intervention is beneficial to improve the perinatal quality of ICP women.

目的 初步探究胆管结扎诱导的梗阻性胆汁淤积对大鼠肝细胞的影响。方法 10只Lewis大鼠随机分为对照组和胆汁淤积组,每组各5只,胆汁淤积组采用胆管结扎2周诱导梗阻性胆汁淤积大鼠模型。苏木精-伊红染色和苯胺蓝染色比较组织病理变化,使用生化分析比较两组小鼠肝功能情况。采用改良的两步胶原酶灌注分离原代肝细胞,通过RT-qPCR检测两组小鼠肝细胞标志基因、细胞增殖标志基因以及胆管细胞标志基因的表达情况。结果 与对照组相比,胆汁淤积组肝脏表现为明显的肝组织紊乱和纤维胶原蛋白沉积以及肝功能的损害。胆汁淤积组较对照组的原代肝细胞更高表达细胞增殖标志基因：细胞增殖标志物（Ki67）基因,叉头盒M1蛋白（Foxm1）基因,增殖细胞核抗原（Pcna）基因和肝细胞生长因子（HGF）基因（P<0.05）;胆汁淤积组的原代肝细胞表达更低水平的肝细胞标志基因：白蛋白（Alb）基因,多药耐药相关蛋白2（Mrp2）基因,胆盐输出泵（Bsep）基因和肝细胞连环蛋白1（Catenin1）基因（P<0.05）,同时表达更高水平的胆管细胞标志基因：细胞角蛋白7（Ck7）基因,细胞角蛋白 19（Ck19）基因,胆管细胞多药耐药性蛋白1（Mdr1）基因和胆管细胞囊性纤维化跨膜传导调节因子（Cftr）基因（P<0.05）以及肝祖细胞标志基因：上皮细胞黏附分子（Epcam）基因和Y染色体性别决定区-盒转录因子9（Sox9）基因（P<0.05）。结论 胆汁淤积可诱导肝细胞向胆管细胞特性转化的可塑性。

Objective To explore the effect of bile duct ligation induced obstructive cholestasis on rat hepatocytes. Methods Ten Lewis rats were randomly divided into control group and cholestasis group, and the cholestasis was induced by bile duct ligation for 2 weeks. The histopathological changes were compared by H&E and aniline blue staining and the liver function was compared by biochemical analysis. Primary hepatocytes were isolated by modified two-step collagenase perfusion, and the expressions of hepatocyte marker genes, cell proliferation marker genes and cholangiocyte marker genes were detected by RT-qPCR. Results Compared with the control group,the liver of the cholestatic group showed obvious disordered histopathology, deposition of fibrous collagen and impaired liver function. Compared with the control group, the primary hepatocytes in the cholestasis group expressed higher cell proliferation-related genes（Ki67,Foxm1,Pcna and HGF）（P<0. 05）. Primary hepatocytes in the cholestasis group expressed lower levels of hepatocyte marker genes（Alb,Mrp2,Bsep and Catenin1）（P<0. 05）,and higher levels of cholangiocyte marker genes（Ck7,Ck19,Mdr1 and Cftr）（P<0. 05）and higher levels of the hepatic progenitor cell marker genes（Epcam and Sox9）（P<0. 05）. Conclusions Cholestasis induces rat hepatocyte plasticity in the transformation into bile duct properties.