胆道闭锁胆管细胞破坏与修复的研究进展

摘要：胆道闭锁（BA）是一种由肝内外胆管系统堵塞引发的小儿肝胆外科疾病，如不及时治疗将引起胆汁性肝硬 化，最终发展为肝衰竭而导致患儿死亡。胆管上皮细胞破坏，胆管管腔逐渐狭窄，最终形成纤维条索是BA主要病理 改变。胆管上皮细胞不仅是被动受害者，也被认为是胆管病理学中潜在的效应物。目前，随着国内外对于BA胆管 上皮细胞的研究越来越深入，胆管上皮细胞破坏与修复方面取得了一些进展，本文就胆管结构改变、胆管上皮细胞 破坏、胆管增生与修复、上皮间质转化与肝纤维化的关系等方面作一综述。     

Cefmetazole excretion into the bile after hepatic portojejunostomy in congenital bile duct atresia

Antibiotics excretion into the bile was studied using CMZ which was administered by drip infusion in 12 postoperative cases of congenital bile duct atresia patients who had hepatic portojejunostomy with SURUGA II type enterostomy with the following results. Group I (correctable type children, with good bile flow, no jaundice): Excellent excretion was almost the same as that seen in adult patients. Group IIa (uncorrectable type children, with good bile flow, no jaundice): Excretion was poor but good depending on the amount of bile flow and liver function. Group IIb (uncorrectable type children, with poor bile flow, jaundice): Excretion was very poor. Group III (uncorrectable type infants, with good flow, no jaundice): Excretion was good depending on the amount of bile flow and liver function. Our study indicates that antibiotics excretion into the bile in children is closely related to the condition of the hepatic function and biliary passage.     

胆囊切除术致胆管损伤的原因分析及处理

目的探讨胆囊切除术致胆管损伤的原因以及处理措施和时机。方法回顾性分析我院外科收治的24例胆管损伤患者的病因以及采取的再手术方式和时间,预后情况。结果11例胆囊切除术中发现胆管损伤的患者,立刻行胆管修复等手术,预后情况满意;13例术后发现胆管损伤的患者,采取胆管手术处理,只有1例因胆汁性肝硬化,胆管感染死亡,其他患者未出现胆管狭窄和胆管炎等并发症。结论在胆囊切除术中,要注意可能发生胆管损伤的危险因素,加以避免,如存在胆管损伤,力争早发现,早治疗,可有效的减少胆管狭窄,胆管炎等并发症,提高患者的生存质量。     

胆管癌46例CT诊断分析

目的 探讨胆管癌患者的CT诊断.方法 回顾性分析46例经手术、经皮穿刺活检并病理证实的胆管癌患者的资料,总结其CT平扫及动态增强表现.结果 12例肝内胆管癌CT平扫表现为类圆形、不规则形的低密度肿块,肝内胆管扩张66.7%(8/12),肝叶萎缩41.7%(5/12),增强扫描动脉期肿瘤周边轻度强化;延迟扫描随时间延长,病灶逐步强化,尤其9min后,所有病灶均高于正常肝实质密度.肝门部胆管癌24例均显示肝内胆管扩张,形态呈"软藤样",21例显示肝门区软组织肿块,另3例仅显示胆管壁增厚、狭窄或中断,可合并肝门淋巴结、后腹膜淋巴结、网膜转移及腹水.肝外胆管癌10例肝内外胆管扩张、胆囊增大、胆总管突然截断或胆总管不规则狭窄.结论 CT可较清晰的显示胆管癌病变、胆管扩张程度及对周围浸润范围,对早期发现胆管癌价值较大.     

腹腔镜胆囊切除术中胆管损伤的诊治体会

目的 探讨腹腔镜胆囊切除术中胆管损伤的原因、预防和治疗原则.方法 回顾性分析我院10多年来8000例LC中发生胆管损伤病例的临床资料.结果 全组15例发生胆管损伤,发生率为0.18%,其中肝,总管横断2例,胆总管横断2例,胆管节段性缺损2例,肝外胆管裂伤穿孔3例,胆总管部分钳夹6例.除1例为术后胆漏、胆汁性腹膜炎再次手术时发现,其余均为术中发现.全组均治愈.结论 LC术中胆管损伤,将胆总管误认为胆囊管是最常见的原因,若能术中发现及时处理,预后较好,熟悉肝外胆道系统的生理及病理解剖变异,强化操作训练,正确掌握手术适应症,把握中转开腹的时机可减少胆管损伤的发生,治疗原则是及早发现和及时处理胆道损伤,解除梗阻,重建胆道-空肠通路,防止胆管狭窄.     

Methylene dianiline: acute toxicity and effects on biliary function.

4,4'-Methylene dianiline (4,4'-diaminodiphenylmethane, DAPM), which is used in the polymer industry, causes hepatobiliary damage in exposed humans. Our objectives were to characterize the acute toxicity of DAPM in liver, particularly on secretion of biliary constituents and on biliary epithelial cell gamma-glutamyl transpeptidase (GGT) activity. Biliary cannulas were positioned in Sprague-Dawley male rats under pentobarbital anesthesia. After 1 hr of control bile collection, each rat was given 250 mg DAPM/kg (50 mg/ml) po in 35% ethanol or 35% ethanol only; bile was collected for a further 4 hr. Groups of rats were also examined for liver injury and biliary function at 8 and 24 hr after DAPM. Four hours after DAPM administration, main bile duct cells were severely damaged with minimal damage to peripheral bile ductule cells. Focal periportal hepatocellular necrosis and extensive cytolysis of cortical thymocytes occurred by 24 hr. Serum indicators of liver injury were elevated by 4 hr and continued to rise through 24 hr. By 4 hr, biliary protein concentration was increased 4-fold while concentrations of biliary bile salt, bilirubin, and glutathione were decreased by approximately 80, 50, and 200%, respectively. DAPM also induced a striking effect on biliary glucose with an approximately 20-fold increase. Histochemical staining of main bile duct GGT was absent by 8 hr after DAPM. Bile flow was diminished by 40% at 4 hr; three of five rats had no bile flow by 8 hr and none had any bile flow by 24 hr. These results indicate that DAPM rapidly diminishes bile flow and alters the secretion of biliary constituents and is highly injurious to biliary epithelial cells.     

逆行胰胆管造影在肝外胆管结石中的治疗价值

目的探讨肝外胆管结石的内镜下治疗价值。方法内镜下行十二指肠乳头插管,选择性胆道插管成功造影后,视情况行乳头切开,在X-线透视下用碎石器碎石,网篮、气囊取石或放置胆道内支架引流。结果共治疗21例,其中肝外胆管结石取净17例,放置内支架4例。结论内镜下治疗肝外胆管结石安全、有效、并发症少,是目前治疗肝外胆管结石理想方法 。     

医源性胆管损伤临床研究

目的 研究医源性胆管损伤的原因、预防和处理方法.方法 对1980年1月-2005年8月我院诊治的55例医源性胆管损伤的临床资料进行回顾性分析.结果 对术中及术后不同时期发现的胆管损伤分别进行胆道修复、引流及胆肠吻合等方法处理,经1～25年随访,临床治愈率达96.4%(53/55).结论 胆囊切除术时Calot三角区解剖不清是发生医源性胆管损伤的主要原因.胆管损伤应早发现,及时处理.根据损伤的情况和术后时间选择不同的处理方法.     

可视化仿真手术在肝内外胆管结石治疗中的应用

目的研究胆总管切开取石、左半肝切除可视化仿真手术技术在肝内外胆管结石治疗中的临床意义。方法利用肝内外胆管结石患者的腹部64排螺旋CT扫描数据,用程序和人工相结合方法对图像进行分割,采用自主研发的医学图象处理软件进行三维重建,重建出的腹部脏器及其管道模型分别以STL格式输出,然后导入到FreeForm Modeling System进行修饰、平滑和可视化仿真手术。结果当肝脏设置为半透明时,可以清晰显示肝内、外胆管结石的大致位置、个数及肝内、外胆管的扩张及狭窄情况。仿真手术接近实际操作。本患者仿真手术结果显示结石无残留,达到理想的手术效果。结论胆总管切开取石、左半肝切除可视化仿真手术在肝内外胆管结石治疗中在手术方案的制定,术中取净结石,对胆道狭窄和扩张进行恰当的处理,对减少术后结石的残留和复发有重要意义。     

胆道术后肝外胆管结石的手术体会

目的总结胆道外科手术后肝外胆管结石的可能原因,及再次手术处理的体会。方法回顾性分析2003年1月至2013年1月我科收治的69例胆道术后肝外胆管结石的临床资料,并结合国内外相关文献进行探讨。结果 69例均顺利完成手术;发生副损伤1例,切口感染或脂肪液化6例,1例自动出院后死亡;7例胆总管残留结石。结论胆道术后肝外胆管结石的原因有术后残留结石、胆囊结石或肝内胆管结石脱落、再发结石等;其治疗主要为以胆总管切开取石+T管引流及胆肠吻合为主的手术治疗;术前充分准备,选择合适的手术方式,术中正确寻找胆总管、避免误伤是治疗胆道术后肝外胆管结石的关键。     

肝内胆管结石的外科手术治疗进展

肝内胆管结石是我国的常见病和难治病。目前外科治疗的主要治疗手段有经肝外胆管切开取石术、肝部分切除术、胆肠吻合术、肝移植术以及术中辅助措施如纤维胆道镜、B超和介入手段等。其中，肝部分切除术和胆肠吻合术是治疗本病最常用的术式，但任何一种手术方法和治疗措施不可能解决各种不同类型的结石，因此给予针对性的个体化手术，以尽可能提高结石清除率、降低术后并发症，是目前外科手术治疗的共识。     

Undifferentiated spindle and giant cell carcinoma of the common bile duct

Undifferentiated spindle and giant cell carcinoma of the common bile duct has not been reported previously. We present here a case of 71-year-old man with the undifferentiated spindle and giant cell carcinoma of the common bile duct, including immunohistochemical findings. A nodular infiltrating tumor was located at the lower portion of the extrahepatic bile duct, and measured 1.2 x 0.6 cm in size. Histologically, the tumor was composed of proliferated sarcomatoid spindle tumor cells. Numerous multinucleated giant cells were intermingled with the sarcomatoid spindle tumor cells. Immunohistochemically, the tumor cells were positive for both cytokeratin and vimentin. We speculated that the tumor originated from epithelial cells, and showed sarcomatoid neplastic changes.     

腹腔镜胆囊切除术患者手术前后肝外胆管直径变化及与胆囊收缩素CCK关系的临床研究

目的研究腹腔镜胆囊切除术患者手术前后肝外胆管直径变化及与胆囊收缩素CCK关系。方法选取2011年12月至2012年12月进行腹腔镜胆囊切除术治疗的68例胆囊结石患者为观察组,68例常规体检示健康的人员为对照组,然后将观察组术前、术后3个月、6个月及对照组的肝外胆管直径、血清CCK水平进行比较,并分析二者之间的相关性。结果观察组术前、术后3个月及6个月的肝外胆管直径、血清CCK水平呈现先升后降的趋势,且均高于对照组,P均<0.05,均有显著性差异,经Pearson相关性分析显示肝外胆管直径与血清CCK水平呈正相关。结论腹腔镜胆囊切除术患者手术前后肝外胆管直径变化呈现先升后降,且与CCK呈现正相关。     

TGF-β1、 Smad2在胆道闭锁肝纤维化中的作用

目的 研究转化生长因子（TGF）-β1与Smad2蛋白在胆道闭锁（BA）肝组织中表达情况及在肝纤维化进程中的作用。方法 选取2010年1月—2014年7月尸检（患儿死于非肝胆疾病,正常对照组）5例,胆管扩张症肝活检（胆扩组）10例,BA肝活检（早期肝纤维化组）19例,BA晚期进行肝移植患者自体肝活检（晚期肝硬化组）11例,采用HE染色观察肝标本纤维化评价其纤维化程度,免疫组化染色检测TGF-β1与Smad2蛋白在肝组织中的表达,实时荧光定量聚合酶链式反应（qRT-PCR）方法检测肝组织中TGF-β1与Smad2基因表达情况。结果 HE：正常对照组肝组织无胶原纤维增生,胆扩组有轻度纤维细胞增生,早期肝纤维化组胶原纤维增生、桥接纤维化现象显著,而晚期肝纤维化组假小叶显著。免疫组化：TGF-β1蛋白平均光密度值在早期肝纤维化组表达最高（P<0.05）;Smad2蛋白在4组间表达差异无统计学意义。qRT-PCR：胆扩组、早期肝纤维化组和晚期肝纤维化组三组肝内TGF-β1、Smad2 mRNA含量均为早期组最高（P<0.017）。结论 BA 肝纤维化早期TGF-β1、 Smad2促进纤维化至P-P、P-C型桥样结构形成;随着纤维化程度加重,TGF-β1、 Smad2表达促纤维化作用逐渐减弱。     

胆囊切除术中肝外胆管损伤的类型及对策

目的:探讨胆囊切除术中肝外胆管损伤的类型及对策.方法:总结我院20例肝外胆管损伤类型,包括胆总管横断、肝总管横断、左右肝管汇合部损伤、右肝管损伤、副肝管损伤、胆总管灼伤,分别采用部分损伤修复、胆管端端吻合、胆管空肠Roux-Y吻合等手术,或加T管支撑引流术.结果:全部病例随访6个月至10年,3例因胆管狭窄行2次及以上手...     

胆道镜在治疗术后肝内外胆管残余结石中的应用

目的 探讨胆道镜在治疗术后肝内外胆管残余结石的临床治疗效果。方法 回顾分析南京医科大学第一附属医院胆道外科2003年2月至2014年12月施行胆道镜检查的4 092例患者的临床资料。结果 在所有4 092例行胆道镜检查的患者中,1 399例术后发现有胆道残余结石,残余结石率为34.18%。1 399例有残余结石的患者共经窦道取石2 672次,手术时间(24.19±13.42)min,并发症发生率为5.18%,残石率为0.37%。结论 胆道镜用于治疗术后肝内外胆管残余结石是安全有效的,值得大力推广。     

肝脏CD4、CD8及CD68表达与Kasai术后胆管炎的关系研究

目的　探讨T淋巴细胞表面抗原CD4、CD8、巨噬细胞特异性抗原CD68表达与胆道闭锁肝门-空肠吻合术（Kasai术）后胆管炎的关系。方法　选取Kasai术后行肝移植手术的27例胆道闭锁患儿,根据既往胆管炎发作情况将其分为频发胆管炎组（10例）、早期胆管炎组（7例）和无胆管炎组（10例）,比较各组患儿的一般临床资料。取患儿肝移植时病肝的肝门部肝组织,行HE染色观察肝纤维化、胆管增生、肝组织炎性细胞浸润程度及胆栓情况,免疫组织化学染色检测CD4、CD8及CD68蛋白表达情况。结果　3组患儿性别、年龄、Kasai手术年龄、自体肝生存时间、肝移植时白细胞计数、C反应蛋白及肝功能指标差异均无统计学意义;HE染色示3组患儿肝纤维化、胆管增生及胆栓分级差异均无统计学意义,而频发胆管炎组汇管区炎性细胞浸润程度较无胆管炎组和早期胆管炎组严重;免疫组化染色显示3组患儿CD4蛋白表达差异无统计学意义;频发胆管炎组CD8、CD68蛋白表达水平均高于无胆管炎组和早期胆管炎组（P＜0.05）。结论　Kasai术后胆管炎肝脏病理改变主要为CD8＋T细胞及CD68＋巨噬细胞参与的炎症反应,CD8及CD68表达增高可能是胆管炎反复发作的危险因素。     

MMP-7在胆道闭锁肝纤维化患者中的表达及临床意义

目的 研究基质金属蛋白酶7（MMP-7）与胆道闭锁（BA）患者肝纤维化分级、胆管反应程度之间的关系, 探索其在肝纤维化进程中的作用及临床意义。方法 选取2017年6月—2018年4月我院收治的15例胆道闭锁患儿 行Kasai手术时的肝活检组织（G1组）,另选取2015年1月—2016年1月因行Kasai术后肝脏功能衰竭而行肝移植术 的病肝组织41例（移植组）,将移植组按Kasai手术与肝移植的间隔时间分为2组：G2组（28例,间隔时间＜2年）和G3 组（13例,间隔时间≥2年）。采用HE染色观察3组患者肝脏纤维化程度,免疫组化染色检测MMP-7和CK-19蛋白在 肝脏中的表达情况并进行半定量分析。结果 （1）免疫组化结果显示,MMP-7主要表达于胆管上皮细胞、增生的胆 管、汇管区周围肝细胞,随着肝纤维化程度进展,胆管细胞及肝细胞MMP-7表达强度增加,且胆管细胞比肝细胞表达 更为强烈。MMP-7在G1~G3组中的表达水平分别为（0.068±0.017）vs（. 0.093±0.017）vs（. 0.084±0.016）,差异有统计学 意义（F=10.541,P＜0.001）,CK-19在3组的表达水平分别为（0.119±0.036）vs（. 0.157±0.040）vs（. 0.110±0.044）,差异有 统计学意义（F=7.296,P＜0.001）,G2组MMP-7、CK-19蛋白表达水平明显高于其余2组（P＜0.05）,G1组与G3组之 间差异无统计学意义（P＞0.05）。（2）3组的肝纤维化程度分别为2（2,3）vs. 4（3,4）vs. 4（2,4）（H=17.785,P＜0.001）, G2组纤维化程度明显高于其余2组,差异具有统计学意义（P＜0.017）。（3）相关性检验示：MMP-7蛋白表达量与肝纤 维化程度呈弱正相关（rs=0.609,P＜0.001）,但与胆管反应程度（CK-19）无明显线性相关性（r=0.007,P=0.962）。结 论 MMP-7在BA患儿Kasai术后肝组织中高表达,并且随肝纤维化程度加重而表达升高,其可能参与并促进了BA 肝纤维化进程,提示自体肝生存不佳。     

INTESTINAL HANDLING OF MERCURY IN THE RAT: IMPLICATIONS OF INTESTINAL SECRETION OF INORGANIC MERCURY FOLLOWING BILIARY LIGATION OR CANNULATION

Three sets of experiments were carried out to determine if there is an intestinal secretory component in the fecal excretion of administered inorganic mercury. In the first set of experiments the disposition of a nontoxic 0.5-mumol/kg intravenous dose of inorganic mercury was evaluated in control rats and rats whose bile duct had been ligated. Data collected 24 h after the administration of mercuric chloride indicated that some inorganic mercury had moved from the blood across the epithelium into the lumen of the stomach, small intestine, and large intestine. This secretory movement of mercury was most prominent in the small intestine. Interestingly, the renal uptake and accumulation of mercury were diminished significantly in the rats whose bile duct had been ligated. A time-course experiment showed that the maximum amount of secretory movement of mercury into the lumen of the small intestine occurred during the initial 12 h after the injection of mercuric chloride. By the end of 24 h after the injection of mercuric chloride, much of the inorganic mercury secreted in the small intestine appeared to have moved down into the large intestine. In a third experiment, the disposition of mercury was evaluated in control rats and rats who had their bile duct cannulated. The rationale for this third experiment was to study the disposition of mercury under conditions where obstruction of biliary outflow from the liver would not be as much of an issue as with ligation of the bile duct. Evidence for movement of mercury into the lumen of the intestines was also obtained from the rats whose bile duct had been ligated. Eighteen hours after the injection of mercuric chloride the amount of mercury in the luminal compartment of the small intestine was not statistically different between the two groups of rats. Approximately 1.7-2.1% of the administered dose was present in the luminal contents of the small intestine. Decreased renal uptake of mercury was also detected in the rats whose bile duct had been cannulated. The findings from the present study show that when bile flow is obstructed or diverted, clear evidence for secretory movement of mercury into the lumen of the gastrointestinal (GI) tract can be demonstrated. These findings also indicate that the secretory movement of mercury into the lumen of the GI tract is a mechanism that contributes significantly to the pool of mercury that is excreted in the feces.     

Xenobiotic-induced liver injury and fibrosis

INTRODUCTION: Many different drugs and xenobiotics (chemical compounds foreign to an organism) can injure the bile duct epithelium and cause inflammatory bile duct diseases (cholangiopathies) ranging from transient cholestasis to vanishing bile duct syndrome, sclerosing cholangitis with development of biliary fibrosis and cirrhosis. Animal models of xenobiotic-induced liver injury have provided major mechanistic insights into the molecular mechanisms of xenobiotic-induced cholangiopathies and biliary fibrosis including primary biliary cirrhosis and primary sclerosing cholangitis. AREAS COVERED: In this review, the authors discuss the basic principles of xenobiotic-induced liver and bile duct injury and biliary fibrosis with emphasis on animal models. A PubMed search was performed using the search terms "xenobiotic," "liver injury," "cholestasis," and "biliary fibrosis." Reference lists of retrieved articles were also searched for relevant literature. EXPERT OPINION: Xenobiotic-induced cholangiopathies are underestimated and frequently overlooked medical conditions due to their often transient nature. However, biliary disease may progress to vanishing bile duct syndrome, biliary fibrosis, and cirrhosis. Moreover, xenobiotics may prime the liver for subsequent liver disease by other agents and may also contribute to the development of hepatobiliary cancer though interaction with resident stem cells.