【作者】 蒋铁民；

【导师】 温浩； 吐尔干艾力·阿吉；

【作者基本信息】 新疆医科大学 ， 外科学（普外）， 2023， 博士

【摘要】 目的:离体肝切除自体肝移植(Ex Vivo Liver Resection and Auto-Transplantation,ELRA)术后移植肝的流出道并发症和移植肝的体积再生不足是导致术后移植肝功能障碍,甚至死亡的重要原因之一。本研究主要关注ELRA流出道重建的关键技术和肝交感神经对肝脏再生(肝纤维化)的影响,旨在为降低ELRA术后肝功能不全并发症的发生率,为提高ELRA的治疗效果提供理论指导。(1)提出肝静脉流出道血管侵犯的分型及与其相对应的血管重建方式,阐述了其在术前评估和术中重建策略中的重要作用;总结了ELRA术后流出道梗阻的临床特点及处理方式和治疗结果。(2)探讨肝圆韧带作为ELRA肝流出道血管重建中血管替代物的有效性和安全性(3)总结终末期肝泡型棘球蚴病(Alveolar Echinococcosis,AE)引起的门静脉、肝静脉、下腔静脉和肝动脉的侧支循环及其在ELRA术中血管重建的作用。(4)观察肝硬化患者中肝脏交感神经和肝再生(肝纤维化)程度的相关性;借助大鼠去交感神经和脊髓横断模型,探索交感神经对肝再生(肝纤维化)的影响;方法:第一部分,(1)收集114例接受ELRA治疗的肝泡型棘球蚴病(AE)患者的病历资料、术前CT、术中照片、病理学检查及血管造影等资料,对拟保留侧肝脏的肝静脉和下腔静脉的受侵犯的特点(部位、角度和长度)进行分型。并在此基础上,总结了与分型相对应的血管重建方式。(2)对在随访过程中出现流出道梗阻(Hepatic venous outflow obstruction,HVOO)患者的介入治疗的结果进行描述,利用Kaplan-Meier法进行生存分析,并绘制生存曲线。第二部分,(1)收集24例ELRA术中使用肝圆韧带修复健侧肝脏流出道患者的临床资料,对肝圆韧带修复流出道的方式进行详细描述,并评估手术的结果;(2)回顾利用肝圆韧带修复血管的外文文献,对其手术修复细节和结果做一总结和综述。第三部分,收集51例终末期肝AE伴有侧枝血管形成患者的增强CT和血管造影的影像学资料,通过分别对门静脉(PV)、肝静脉、下腔静脉(IVC)和肝动脉的侵犯及侧支血管建立的情况进行观察总结,并探讨侧支血管在ELRA术中血管重建起到的作用。第四部分,(1)收集肝硬化患者的病理标本,检测病理变化,纤维化及交感神经在病灶中的分布情况(2)建立大鼠药物去交感神经和脊髓损伤兴奋交感神经模型,检测肝再生(肝纤维化)和相关指标。结果:第一部分,(1)将肝静脉和下腔静脉分别归类为H0-H5型和I0-I3型,其侧支循环分别分型为A型、B型。根据血管侵犯的具体分型,有必要对手术重建的方式作出初步的决策。114例ELRA患者中,30天内的死亡率为7.0%(8/114),另有7例患者在90天内死亡。术后最常见的并发症为胸腔积液21例(25%)。(2)发生HVOO共11例,其中1例死于肝功能衰竭,另10例患者行介入治疗,效果良好。HVOO介入血运重建成功的患者与无HVOO患者的生存率无统计学差异(P>0.05)。第二部分,(1)纳入24例患者(男性10例,女性14例)。无肝期中位时间为450(290-672)分钟。残余肝体积与标准肝体积的比值四分位数为0.71(0.43-0.97)。中位失血量1000(500-5000)毫升。术后平均住院时间为23(1-85)天。24例患者中,3例患者术后死亡,但与血管并发症无关。(2)回顾相关文献6篇,共报告了31例病例,只有1例使用LTH修复门静脉,术后血管狭窄导致门静脉高压症,其余患者均未出现血管相关并发症。第三部分,门静脉、肝静脉、下腔静脉和肝动脉侧支循环形成分别有33例、5例、12例和1例。PV侧支血管按通路不同分两型:Ⅰ型:门静脉-门静脉通路(13例)。II型:I型合并门静脉-体循环通路(20例);肝静脉的主要侧支血管为短肝静脉,2例患者出现了肝内静脉丛交通支;IVC侧支血管表现为椎静脉丛和腰静脉丛扩张;1例患者肝动脉主干受侵,健侧肝脏由非正常解剖位置的动脉提供血供,此供血动脉的来源是侧支血管形成还是血管变异仍值得探讨,但其在终末期肝AE中确实起到了代偿维持健康侧肝脏的血液供应的作用。第四部分,(1)对肝硬化患者的病理切片进行观察,发现肝脏内的交感神经纤维分布在肝脏的纤维化间隔中(2)通过化学6-OHDA去除了大鼠肝脏的交感神经,化学去交感神经的大鼠模型的肝再生能力减弱,肝脏纤维化程度减轻;脊髓损伤后,大鼠的肝脏交感神经呈现亢进状态,肝再生能力增强,肝脏纤维化加重。结论:第一部分,流出道血管侵犯分型及相应的血管重建方式的提出,有助于手术决策和规范入路,利于减少HVOO的发生。当发生HVOO后,应在肝功能衰竭前立即处理。血管介入是一种有效的方法。第二部分,肝圆韧带可作为离体肝切除和自体移植的血管移植替代物。它具有取材方便、无供区损伤、无免疫排斥反应等优点,具有良好的临床应用前景。第三部分,由于HAE特殊的生物学性质,HAE患者的肝脏血管表现出独特的侧支血管。对其进行深入研究,有助于我们更好地了解肝内病变及其合并症导致的侧支血管形成的发生发展过程,也为终末期HAE的外科治疗提供了新的思路。第四部分,对肝硬化患者中交感神经的分布的观察,以及调控肝脏交感神经对肝再生(肝纤维化)的影响,表示交感神经可能在肝脏疾病发生发展中起到了重要作用。更多还原

【Abstract】 Objective: Outflow tract complications and insufficient volume regeneration of the transplanted liver after ex vivo liver resection and auto-transplantation(ELRA)are one of the important causes of early postoperative liver dysfunction and even death.This study focuses on the key techniques of ELRA outflow tract reconstruction and the influence of liver sympathetic nerve on liver regeneration(liver fibrosis),aiming at reducing the incidence of early complications of liver insufficiency after ELRA surgery and providing theoretical guidance for improving the therapeutic effect of ELRA.(1)The classification of hepatic venous outflow tract vascular invasion and its corresponding vascular reconstruction mode were proposed,and its important role in preoperative evaluation and intraoperative reconstruction strategy was expounded.The clinical characteristics,treatment methods and results of outflow tract obstruction after ELRA operation were summarized.(2)To explore the effectiveness and safety of ligamenta teres hepatis as a vascular substitute for ELRA hepatic outflow tract vascular reconstruction.(3)To summarize the collateral circulation of portal vein,hepatic vein,inferior vena cava and hepatic artery caused by end-stage hepatic AE and its role in vascular reconstruction during ELRA surgery.(4)To observe the correlation between the degree of liver sympathetic nerve and liver regeneration(liver fibrosis)in patients with cirrhosis;To explore the effect of sympathetic nerve on liver regeneration(liver fibrosis)by using the model of de sympathetic nerve and spinal cord injury in rats.Methods: In the first part,(1)The medical records,preoperative CT,intraoperative photographs,pathological examination and angiography of 114 patients with hepatic alveolar echinococcosis disease(AE)who received ELRA treatment were collected.The invaded features(location,Angle and length)of hepatic vein and inferior vena cava in the intended reserved side liver were classified.On this basis,the vascular reconstruction methods corresponding to its classification were summarized.(2)The results of interventional therapy in patients with outflow tract obstruction(HVOO)during follow-up were described.Kaplan-Meier method was used for survival analysis and survival curve was drawn.In the second part,(1)The clinical data of 24 patients with ELRA who used ligamenta teres hepatis to repair the outflow tract on the healthy side were collected,the method of repairing the outflow tract with round hepatic ligament was described in detail,and the results of the operation were evaluated.(2)Review the foreign literatures on the use of ligamenta teres hepatis for vascular repair,and make a summary and review of the details and results of surgical repair.In the third part,enhanced CT and angiography imaging data of 51 patients with end-stage hepatic AE accompanied by collateral angiogenesis were collected,and the invasion of portal vein(PV),hepatic vein,inferior vena cava(IVC)and hepatic artery and the establishment of collateral vessels were observed and summarized,and the role of collateral vessels in vascular reconstruction during ELRA operation was discussed.In the fourth part,(1)Pathological specimens of patients with cirrhosis were collected to detect pathological changes,fibrosis and sympathetic nerve distribution in the lesion.(2)Rat models of drug de sympathetic nerve and sympathetic nerve excitation from spinal cord injury were established to detect liver regeneration(liver fibrosis)and related indicators.Results: In the first part,(1)hepatic veins were divided into H0-H5 and I0-I3 types,and their collateral circulation was divided into A and B types respectively.Based on the specific type of vascular invasion,it is necessary to make an initial decision about the mode of surgical reconstruction.Among 114 patients with ELRA,the mortality rate within 30 days was 7.0%(8/114),and seven patients died within 90 days.The most common postoperative complication was pleural effusion in 21 cases(25%).(2)A total of 11 cases of HVOO occurred,of which 1died of liver failure,and the other 10 patients received interventional therapy,and the effect was good.There was no significant difference in survival rate between patients with successful HVOO interventional revascularization and those without HVOO(P>0.05).In the second part,(1)Twenty-four patients(10 males and 14 females)were included.The median hepaticis-free period was 450(290,672)minutes.The ratio of residual liver volume to standard liver volume quartile was 0.71(0.43,0.97).Median blood loss was 1000(500,5000)ml.The mean postoperative hospital stay was 23(1-85)days.Of the 24 patients,3 died after surgery,but were not related to vascular complications.(2)Review of 6 relevant literatures,a total of 31 cases were reported,of which only 1 case was repaired with LTH portal vein,and postoperative vessel stenosis led to portal hypertension,and the other patients did not have vascular related complications.In the third part,there were 33 cases of portal vein,5 cases of hepatic vein,12 cases of inferior vena cava and 1 case of hepatic artery collateral circulation.PV collateral vessels were divided into two types according to different access: Type I:portal-portal vein access(13 cases).Type II: Type I combined with portal-systemic circulation(20 cases);The collateral vessels of hepatic veins were short hepatic veins,and 2 patients had communication branches of intrahepatic venous plexus.The lateral vessels of IVC showed dilatation of the vertebral venous plexus and lumbar venous plexus.In one patient,the main hepatic artery was invaded,and the healthy liver was supplied by arteries in abnormal anatomical position.Whether the source of this supplying artery was collateral vascularization or vascular variation is still worth discussing,but it does play a compensatory role in maintaining the blood supply of the healthy liver in the end-stage liver AE.In the fourth part,(1)Pathological sections of patients with cirrhosis were observed,and it was found that sympathetic nerve fibers in the liver were distributed in the fibrosis septa of the liver.(2)The sympathetic nerve in the rat liver was removed by chemical 6-OHDA,and the degree of liver fibrosis in the rat model with chemical sympathetic nerve removal was reduced,and the ability of liver regeneration was weakened and the degree of liver fibrosis was reduced in the rat model with chemical desympathetic nerves.After spinal cord injury,the liver sympathetic nerve of rats showed hyperactivity,liver regeneration ability was enhanced,liver fibrosis was aggravated.Conclusion: In the first part,the classification of outflow tract vascular invasion and corresponding vascular reconstruction methods are proposed,which is helpful for surgical decision-making and standardized approach,and conducive to reducing the occurrence of HVOO.When HVOO occurs,it should be treated immediately before liver failure.Vascular intervention is an effective method.In the second part,the ligamenta teres hepatis can be used as a vascular replacement graft for in vitro hepatectomy and autotransplantation.It has the advantages of convenient sampling,no donor damage and no immune rejection,and has a good clinical application prospect.In the third part,due to the special biological properties of HAE,liver vessels of HAE patients exhibit unique collateral vessels.In-depth study of HAE will help us to better understand the occurrence and development of collateral angiogenesis caused by intrahepatic lesions and their complications,and also provide a new idea for surgical treatment of end-stage HAE.The fourth part is the observation of the distribution of sympathetic nerve in patients with cirrhosis,and the influence of regulating liver sympathetic nerve on liver regeneration(liver fibrosis),indicating the importance of sympathetic nerve in the occurrence and development of liver diseases.更多还原