【作者】 李晓；

【导师】 李玉亮；

【作者基本信息】 山东大学 ， 外科学（专业学位）， 2020， 硕士

【摘要】 研究背景胆囊结石(Gallbladderstone,GS)是消化系统的常见病和多发病,其发病率呈逐年上升趋势,在我国,GS的发病率已达10%。大部分GS患者终生不会表现出相应的临床症状,不需要过多的干预措施;少部分GS可以引起胆绞痛、恶心和/或呕吐、发烧以及黄疸等症状,因此对于症状性GS,建议积极治疗。目前GS有多种治疗方法,常见的治疗手段包括胆囊切除术、药物溶石治疗、体外冲击波碎石(extracorporeal shock wave lithotripsy,ESWL)、胆囊引流术、内镜微创保胆手术、激光碎石术等。其中胆囊切除术是公认的首选治疗方式。近年来,腹腔镜胆囊切除术(laparoscopic cholecystectomy,LC)逐渐代替了传统的开腹胆囊切除手术,它具有花费较、创伤小、患者术后恢复快、住院时间短等优点,深受患者和医生的青睐。但是,胆囊切除术后人体会失去正常的胆囊生理功能,因此会产生一些诸如脂肪泻、厌油腻等相关的并发症,这给患者术后的生活造成了一定程度的影响;同时,与开放手术相同,LC仍需要在静脉全麻下进行,部分心、肺功能不全的患者存在手术禁忌,且LC也会造成诸如胆管损伤、出血、胆瘘、伤口感染、其他器官损伤、胆总管结石症、胆道狭窄、十二指肠胃返流、皮下气肿、腹泻等并发症。口服胆汁酸制剂药物溶石和ESWL治疗GS安全性好,溶石和碎石效率高,但有关随访调查发现两种方法治疗后结石复发率较高。一些临床研究表明,如果将ESWL联合药物溶石治疗,对有症状的GS患者可达到较高的结石完全清除率。对于存在手术禁忌症,保守治疗欠佳,合并急性胆囊炎的患者,胆囊引流术是暂时缓解病情的有效手段,也可为后续手术治疗做准备。随着科学技术的发展、人们生活水平的提高以及对于保胆需求的增加,GS新的治疗方法层出不穷,而其中创伤小且简便易行、安全可靠的微创介入手术逐渐显现出其独特的优势。在上世纪60年代的一篇报道中,Mondet等人首先应用经皮经肝入路途径治疗胆总管结石,开创了经皮经肝入路术式的先河,以此为基础,经皮经肝入路下利用液电碎石术(electrohydraulic lithotripsy EHL)、激光碎石术、球囊扩张术等治疗胆结石在临床上逐渐得到开展。尤其是对于内窥镜术式不适用的体积较大且伴感染的胆总管结石(common bile duct stone,CBDS)患者,经皮经肝入路与各种辅助取石方法相结合是一种有效的替代治疗手段。而双频双脉冲掺钕钇铝石榴石(frequency-doubled double-pulse neodymium YAG,FREDDY)激光碎石术采用双频双脉冲技术,形成高能机械冲击波,从结石内部瓦解和粉碎结石,其碎石能量大,碎石效率高,对于很多传统手术较难处理的胆囊大结石有着明显的优势;此外,人体组织对于FREDDY激光基本不吸收,在碎石过程中不产生热效应,改善了以往钬激光碎石术治疗结石造成穿孔、出血及临近组织器官损伤等情况。目前关于经皮经肝下应用FREDDY激光碎石术治疗GS的研究相对较少。基于近年来我科开展在经皮经肝下扩张十二指肠乳头肌顺行排石术(percutaneous transhepatic papillary balloon dilation,PTPBD)治疗胆总管结石的技术基础,我们提出经皮经肝入路下应用FREDDY激光治疗GS的设想。研究目的本研究旨在评估经皮经肝FREDDY激光碎石术治疗GS的安全性、可行性及有效性。重点关注经皮经肝FREDDY激光碎石术的碎石成功率,术中有无胆囊出血穿孔、胆道及其他器官的损伤,术后有无腹膜炎、胰腺炎、胆瘘、胆系感染,以及随访过程中的结石复发率、有无胆囊癌的发生等指标,为该技术应用于GS的治疗提供依据。研究对象与方法选取自2017年3月至2019年11月山东大学第二医院介入医学科收治的10例GS患者进行回顾性分析,均接受经皮经肝FREDDY激光碎石术治疗。本研究入组标准:(1)影像学检查显示存在GS,且结石直径≥2.0cm;(2)伴有胆囊炎的症状,如疼痛、发热;(3)不能耐受或拒绝外科手术、腹腔镜手术、内镜手术,或者有保留胆囊意愿的患者;(4)KPS评分>70分。排除标准:(1)严重的心功能不全(根据纽约心脏病协会心功能分级标准:Ⅲ-Ⅳ级),严重的肺病(通过咨询呼吸疾病专家确定),肝功能不全(肝功能Child-Pugh分级:C级)或肾病(3级慢性肾病);(2)严重凝血功能障碍(凝血酶原时间>17s和/或血小板计数<60×1012/L)、营养不良(白蛋白<30g/L)、中重度贫血(血红蛋白<90g/L);(3)胆囊收缩试验显示胆囊收缩功能差(胆囊收缩率<40%);(4)孕妇及哺乳期女性。收集并记录患者的一般资料、术前及术后1周的影像资料与白细胞(white blood cell,WBC)、谷丙转氨酶(Alanine aminotransferase,ALT)、谷草转氨酶(aspartate aminotransferase,AST)、直接胆红素(direct bilirubin,DBIL)、总胆红素(total bilirubin,TBIL)、白蛋白(albumin,ALB)、血清脂肪酶、淀粉酶(amylase,AMY)和肿瘤标志物糖类抗原 19-9(carbohydrate antigen 199,CA19-9)等实验室检查结果、患者手术情况(手术次数、是否碎石成功、手术失败原因、有无手术相关并发症等)以及患者术后随访情况(术后定期复查腹部CT、B超或MRCP,以及上述血常规、血清淀粉酶和肝脏功能等检查指标,观察有无慢性胆囊炎、胆囊癌及结石复发等远期并发症)。所有的数据均采用GraphPad Prism 7.05统计软件进行统计学处理。对于正态分布的计量数据,以平均值土标准差(x±s)表示,采用配对样本t检验对同一个患者的术前术后同一个变量进行比较;计数资料用数值及百分比表示。检验水准为α=0.05,P<0.05表明差异有统计学意义。研究结果本次研究共收治10例GS患者,其中男4例,女6例;平均年龄60.2±17.0 岁(23-80 岁);GS 平均直径为 26.3±3.0mm(22-31mm);单纯 GS 患者4例,GS合并胆总管结石患者6例。所有患者均完成碎石,碎石成功率为100%(10/10)。见表 1。术后 1 周复查 WBC、ALT、AST、TBIL、DBIL、ALB、AMY、脂肪酶、CA199等实验室指标以及B超下行胆囊收缩功能试验测定胆囊收缩功能,其中AST、淀粉酶、脂肪酶、TBIL、DBIL、WBC较术前有所下降,且差异具有统计学意义;ALT、CA19-9、ALB较术前下降,差异无统计学意义;胆囊收缩功能较术前有所升高,差异无统计学意义(见表2)。术后1例患者出现发热、腹痛等不适,考虑术后发生腹膜炎,给予抗感染、止痛等对症处理后好转;1例患者术后引流管引流出较多血性液体,伴血压下降,考虑手术所致胆囊出血,给予输血、补液等治疗后好转。术后无胰腺炎、胆道穿孔、感染等其他不良事件发生,并发症发生率:20.0%(2/10)。术后随访2年,在10例患者术后随访复查的超声图像中,发现泥沙样结石1例,直径约3.0mm小结石1例,结石复发率为20.0%(2/10)。研究结论本研究初步证明,对于手术适应症范围内的GS患者,应用经皮经肝FREDDY激光碎石术治疗,比较好地体现了介入微创技术的优越性,保证了胆道系统的完整性以及术后胆囊正常生理功能,满足了人们的保胆需求;同时解除胆道梗阻,改善了患者的临床症状,减少了患者的身心痛苦。FREDDY激光采用双频双脉冲技术,碎石成功率高,对体积较大碎石效果显著,有效性较好;FREDDY激光不易被人体组织吸收,碎石过程不产生热效应,并发症发生率低,且经皮经肝入路术后患者恢复较快,术后并发症发生率低,该技术具有较高的安全性。因此经皮经肝FREDDY激光碎石术有望成为胆囊结石患者的一种安全有效的替代治疗方法,尤其是对于体积较大、其他保胆治疗方法欠佳的胆囊结石患者,该技术具有较好地优势。但是本研究样本量小,随访时间较短,缺乏与外科手术及其他保胆手术的前瞻性随机对照研究,需要更多的临床数据来检验这一观点。更多还原

【Abstract】 Background Gallbladder stone(GS)is a familiar disease in digestive system.The incidence of the disease is increasing with age year by year.In China,the frequencie of GS has reached 10%in adults.Most of the stones do not cause symptoms,which called asymptomatic GS.A small group of GS is responsible for symptoms such as biliary colic,nausea and/or vomiting,fever and jaundice,etc.Treatment is needed for symptomatic GS as suggested.At present,there are many kinds of treatments for GS,include cholecystectomy,drug litholysis,extracorporeal shock wave lithotripsy(ESWL),gallbladder drainage,,choledochoscopic gallbladder-preserving surgery,laser lithotripsy,among which cholecystectomy is recognized as the first choice.In the past few years,laparoscopic cholecystectomy(laparoscopic cholecystectomy,LC)with the advantages of less cost,less trauma,shorter hospital stay,quicker recovery and so on,has gradually supplanted the traditional open surgery and wins good comments from patients and doctors;however,patients who lose physiological function of gallbladder after cholecystectomy,will develope some related complications,like steatorrhea,aversion to greasy food,and so on,which affects the quality of life to some extent.Meanwhile,as with open surgery,LC still needs to be performed under intravenous general anesthesia,cardiac and pulmonary insufficiency are considered to be contraindications for the disease.Drug litholysis by taking bile acid preparations and ESWL have the advantages of better safety and efficiency in treating GS,however,the follow-up investigation found that the recurrence rate of stones after the two methods was quite high.Related studies show that the combination of ESWL and drug dissolution can achieve a higher complete clearance for symptomatic patients with GS.For patients who develop acute cholecystitis,but have contraindications to surgery,gallbladder drainage is an effective method when conservative treatments are not satisfactory,and it can also prepare patients for follow-up operation.As the improvement of people’s living standards,development of technology and increase of the demands for gallbladder preservation,new treatment methods emerge in an endless stream for GS,and the minimal invasive surgery with less trauma,simple and safe operation,gradually shows its unique advantages..In a report of the 1960s,Mondet et al.first applied the percutaneous transhepatic approach to handle common bile duct stone(CBDS),and opened the door to the operation for choledocholithiasis.On this basis,under the guide of the percutaneous transhepatic avenues,we can use laser lithotripsy,electrohydraulic lithotripsy(EHL),balloon dilation and other remedies to treat choledocholithiasis.Especially for patients with large and infectious choledocholithiasis who are not suitable for endoscopic procedures,percutaneous transhepatic approach combining with various auxiliary methods is an effective alternative technique.Frequency-doubled double-pulse neodymium YAG(FREDDY)laser lithotripsy adopts short-pulse and double frequency technology to form high-energy mechanical shock wave,which can disintegrate stones from the inside.FREDDY has large output energy and high efficiency for crushing stones,especially suitable for large GS that are difficult to be treated by traditional treatments.In addition,FREDDY laser can not be absorbed by human tissues basically,so there is no thermal effect causing tissue damage in the process.Therefore,FREDDY laser lithotripsy can improve the complications caused by holmium laser lithotripsy previously,such as gallbladder bleeding,perforation and nearby tissue and organ damage.At the moment,there are few studies on the treatment of GS with percutaneous transhepatic FREDDY laser lithotripsy.Nowadays,our department has put forward the idea of percutaneous transhepatic FREDDY laser lithotripsy for the treatment of GS on the basis of clinical developments of percutaneous transhepatic papillary balloon dilation(PTPBD)in the treatment of common duct stone.Objectives To investigate the safety,feasibility and effectiveness of percutaneous transhepatic FREDDY laser lithotripsy in the treatment of GS.Focus on the success rate,bleeding and perforation of gallbladder,damage of bile duct and other organs,peritonitis,pancreatitis,bile leakage,infection of biliary system,as well as the recurrence of stones and occurrence of gallbladder cancer during the follow-up,etc.,so as to provide some basis for the application of this technology in the treatment of GS.Materials and Method Ten patients with GS admitted to the Second Hospital of Shandong University from March 2017 to November 2019 were selected as the research subjects.Enrollment criteria:(1)diameter of GS≥2.0 cm confirmed by imaging examination,;(2)symptoms associated with cholecystitis,such as pain and fever;(3)can not tolerate or refuse surgery,laparoscopic surgery,endoscopic surgery,or want to preserve the gallbladder;(4)KPS score>70.Exclusion criteria:(1)Severe cardiac dysfunction(New York Heart Association class:Grade Ⅲ-Ⅳ),severe lung diseases(determined by consulting respiratory specialists),liver dysfunction(Child-Pugh liver function grade:C)or kidney diseases(Grade 3 chronic kidney disease);(2)Severe coagulopathy(prothrombin time>17s and/or platelet count<60 ×1012/L),malnutrition(albumin<30g/L),anemia(hemoglobin<90g/L);(3)Poor gallbladder contraction function showed by gallbladder contraction test(gallbladder contraction rate<40%);(4)pregnant and lactating women.Collect and record patients’ general information,imaging data,white blood cell(WBC),alanine aminotransferase(ALT),aspartate aminotransferase(AST),direct bilirubin(DBIL),total bilirubin(TBIL),albumin(ALB),serum lipase and amylase(AMY),and tumor marker carbohydrate antigen 199(CA199)1 week before and after operation,as well as operation condition(numbers of operations,whether lithotripsy is successful,causes of surgical failure,intraoperative complications,etc.)and postoperative follow-up(periodical review of transabdominal ultrasound,CT or MRCP,and the above-mentioned laboratory tests such as blood routine and liver function,to observe whether there were any long-term complications such as chronic cholecystitis,gallbladder cancer,and recurrence of stones).All statistical analyses were finished using GraphPad Prism 7.05 Categorical variables were presented as number and percentage.Continuous data were presented as means±standard deviations.We used paired t-tests for the identical indexes before and after the procedure in the same patient.A P-value of less than 0.05 was considered statistically significant.Results In this study,10 patients with GS were admitted,including 4 male and 6 female.The patients were all middle-aged and elderly with the average age of 60.2 ±17.0 years old(23-80 years old).The average diameter of GS was 26.3±3.0mm(22.0-31.0mm).There were 4 cases with simple GS and 6 cases with common bile duct stones.All stones were smashed completly,and the success rate of lithotripsy was 100%(10/10).See Table 1.WBC,ALT,AST,TBIL,DBIL,ALB,AMY,,CA199 and other indicators were reviewed 1 week after surgery.Among them,AST,AMY,lipase,TBIL,DBIL and WBC decreased when compared with preoperative values,and the difference was statistically significant.ALT,CA19-9,ALB reduced after surgery,but we found no statistic difference in the mean values.The contraction function of the gallbladder was improved to some extent after operation without statistic difference(See Table 2).One patient suffered from abdominal pain,fever and other discomfort after operation.Considering the occurrence of peritonitis after operation,it was improved after the symptomatic treatment such as anti-infection and pain relief;one had much blood drainage after surgery,accompanied by a drop in blood pressure.Healing gallbladder hemorrhage due to surgery,it was improved after giving blood transfusion and fluid supplement.No adverse events such as pancreatitis,biliary tract perforation,and infection occurred,the incidence of complications was 20.0%(2/10).After 2 years of follow-up,we found 1 Sediment-like stone and 1 microstone with the diameter of 3.0mm in the ultrasound images of the GS patients,the stone recurrence rate was 20.0%(2/10).Conclusion This study has initially proved that the application of percutaneous transhepatic FREDDY laser lithotripsy for GS patients consistent with indications better reflects the superiority of interventional minimally invasive surgery,which ensures the integrity of the biliary system and the normal physiological function of the gallbladder after surgery,and satisfies patients’ demand for preservation of cholecyst,At the same time,the bile duct obstruction is relieved,the clinical symptoms of the patient are improved,and the physical and mental afflictions of the patient is reduced.FREDDY laser adopts frequency-doubled double-pulse technology,with high successful rate of lithotripsy and significant effect on larger stones.The FREDDY laser can not be easily absorbed by the human soft tissue,and there is no thermal effect in the lithotripsy process,which is associated with low morbidity,and patients recover quickly after percutaneous transhepatic approach with low incidence of postoperative complications.Therefore,percutaneous transhepatic FREDDY laser lithotripsy is expected to become a safe and effective alternative method for GS with larger size or that can not be treated by other gallbladder-preserving instruments.However,because of the small sample size of this study,the short follow-up time,and the lack of prospective randomized controlled studies compared with surgery and other gallbladder-preserving procedures,more data is needed to explain this standpoint.更多还原