【作者】 陈洁；

【导师】 陈世耀；

【作者基本信息】 复旦大学 ， 内科学， 2013， 博士

【摘要】 目的：1.以回顾性队列研究比较在同时存在食管及胃静脉曲张的患者中两种内镜治疗方案(连续套扎+组织黏合剂注射vs套扎序贯硬化剂+组织黏合剂注射)对预防再出血的疗效,进一步建立随机对照临床试验来验证结论。2.研究内镜治疗肝癌患者合并食管胃静脉曲张破裂出血的疗效及安全性,并且了解这部分患者的生存情况,进一步分析影响预后的因素。方法：1.回顾性分析2004年4月1日—2012年3月27日因肝硬化食管胃静脉曲张破裂出血收住入院,经胃镜确诊同时存在食管及胃静脉曲张,并行连续套扎+组织黏合剂注射或套扎序贯硬化剂+组织黏合剂注射治疗的76例患者。2.随机对照试验中纳入2012年3月28日—2012年10月26日收住入院,既往经胃镜确诊同时存在食管及胃静脉曲张,曾接受套扎+组织黏合剂注射的50例肝硬化患者。3.回顾性研究2004年4月1日—2012年10月31日确诊原发性肝癌,并且因食管胃静脉曲张破裂出血而行内镜治疗的117例患者。4.登记入选时患者临床特征、实验室和辅助检查结果作为基线特征,进一步随访再出血、生存和并发症等情况。统计学分析采用SPSS16.0软件。生存分析采用Kaplan-Meier法,运用Log-Rank检验进行生存曲线的比较。预后因素的多因素分析采用Cox逐步回归模型的方法。结果：1.回顾性队列研究中,76例患者的中位随访时间为13.1个月,套扎组与序贯组的累积再出血率(P=0.867)、病死率(P=O.756)的差异无统计学意义。两组患者曲张静脉根除率(OR=1.53,95%CI0.39-6.03, P=0.803)的差异无统计学意义。序贯组中患者发生胸骨后疼痛(OR=4.00,95%CI1.10-15.84, P=0.038)的风险显著高于套扎组。两组患者门脉高压性胃病的发生率(OR=1.67,95%CI0.57-4.84, P=0.345)的差异无统计学意义。2.随机对照试验中,50例患者的中位随访时间为6.0个月,其中13例(26.0%)发生再出血,套扎组和序贯组患者的再出血率的差异没有统计学意义(16.0%vs36.0%,P=0.102)。分层分析发现,同时口服心得安治疗的患者中,套扎组的再出血率显著低于序贯组(0%vs50%,P=0.039)；不合并糖尿病的患者中,套扎组的再出血率亦显著低于序贯组(11.1%vs45.0%,P=0.023)。两组患者曲张静脉的根除率的差异无统计学意义。随访中有2例患者(4.0%)死亡,两组患者病死率的差异没有统计学意义(0.0%vs8.0%,P=0.153)。两组患者并发症的发生率、门脉高压性胃病的发生率均无显著差异。3.117例肝癌患者的中位随访时间为9.6个月,60例患者(48.7%)发生再出血,患者1年、2年和5年的累积再出血率分别为46.6%、65.6%和73.2%。65例患者(55.6%)发生死亡,患者1年、2年和5年的累积生存率分别为59.8%、46.2%和24.1%。,不同的内镜治疗措施对患者术后发生再出血或死亡的风险没有显著差异,而低钠血症(P=0.028, HR=6.660,95%CI1.225-36.197)和彩超测得门脉主干内径>12mm (P=0.001, HR=12.340,95%CI2.692-56.558)是预测患者发生再出血的独立预后因素；AFP>20ng/ml (P=0.004, HR=3.851,95%CI1.522-9.743)和凝血酶时间>21秒(P=0.001, HR=38.207,95%CI6.196-235.620)是预测肝癌患者发生死亡的独立预后因素。结论：1.回顾性队列研究表明,对于同时存在食管及胃静脉曲张的肝硬化患者,连续套扎+组织黏合剂注射和套扎序贯硬化剂+组织黏合剂注射在再出血率、曲张静脉根除率、病死率、门脉高压性胃病的发生率方面的差异无统计学意义,但序贯组发生胸骨后疼痛的风险显著高于套扎组。2.随机对照试验的初步观察结果表明,对于同时存在食管及胃静脉曲张的肝硬化患者,连续套扎+组织黏合剂注射和套扎序贯硬化剂+组织黏合剂注射在再出血率方面的差异无统计学意义。同时口服心得安治疗或不合并糖尿病的患者中,套扎组的再出血率显著低于序贯组。两组患者的曲张静脉根除率、胃静脉曲张的复发率、总体病死率、并发症发生率和门脉高压性胃病发生率亦的差异无统计学意义。因此连续套扎+组织黏合剂注射可能更适合作为预防再出血的治疗方案。3.合并食管胃静脉曲张破裂出血的肝癌患者总体预后较差。不同的内镜治疗措施对患者术后发生再出血的风险没有显著差异。低钠血症和彩超测得门脉主干内径>12mm是预测患者内镜治疗后发生再出血的独立预后因素；AFP>20ng/ml、凝血酶时间>21秒是预测肝癌患者内镜治疗后发生死亡的独立预后因素。更多还原

【Abstract】 Objective:1. To investigate the prophylactic effects of different endoscopic treatments (ligation+cyanoacrylate vs ligation plus sclerotherapy+cyanoacrylate) for esophagogastric varices in patients with liver cirrhosis. A randomized controlled trial was established to further confirm the results.2. To evaluate the efficacy of endoscopic therapy for esophagogastric varices in patients with hepatic carcinoma, long term survival in such patients and to identify prognostic factors for rebleeding and survival.Methods:1. A retrospective cohort was conducted with76patients with liver cirrhosis who were admitted to Zhongshan Hospital during1st April,2004and27th March,2012because of variceal bleeding. Each patient was diagnosed through gastroscopy both esophageal and gastric varices, who received either ligation+cyanoacrylate injection or combined ligation and sclerotherapy+cyanoacrylate injection.2. Cirrhotic patients who received treatment of ligation for esophageal yarices and cyanoacrylate injection for gastric varices from28th,May,2012to26th,Oct,2012were included in the randomized controlled trail.3. A retrospective study of117patients who underwent endoscopic therapy for esophagogastric varices complicated by hepatic carcinoma during1st April,2004and31th October,2012.4. Clinical information and laboratory or imaging results were investigated and recorded as baseline characteristics. All patients were followed up until endpoints. Primary and secondary outcomes were recurrence rate of bleeding, mortality rate, incidence rate of complications, etc. All analysis were performed using the SPSS16.0. Kaplan-Meier survival analysis was conducted and log-rank test was used to compare the curves. Prognostic factors were compared by Cox’s proportional hazard model.Results:1. The median follow-up period of76patients was13.1months. There was no significant difference of rebleeding rate (P=0.867), mortality rate (P=0.756) and eradication rate(P=0.803) between the two groups. The incidence of retrosternal pain (OR=4.00,95%CI1.10-15.84, P=0.038) was significantly higher in combination treatment group. No significant differences were found in the incidence rate of portal hypertensive gastropathy (OR=1.67,95%CI0.57-4.84, P=0.345) between the two groups.2. In the randomized controlled trial,50patients were followed up for a median duration of6.0months.13patients(26.0%) have recurrence of upper gastrointestinal bleeding. The rebleeding rate between the two groups were not significantly different16.0%vs36.0%, P=0.102). In stratified analysis, compared with combination treatment group, the rebleeding rate was significantly lower in ligation group(0.0%vs50.0%, P=0.039) among the patients who received propranolol concomitantly. Combination treatment group was also associated with significantly higher rebleeding risk(11.1%vs45.0%, P=0.023) among the patients without diabetes. However, different endoscopic treatments were not related with significantly different mortality rate(0.0%vs8.0%,P=0.153) or eradication rate between the two groups. The incidence rate of complications or portal hypertensive gastropathy was not significantly different.3. Median follow-up period of117patients was9.6months.60patients(48.7%) were presented with relapse of bleeding. The cumulative1-year,2-year and5-year rebleeding rate was46.6%,65.6%and59.8%.65patients(55.6%) were dead during the follow-up, with overall1-year,2-year and5-year cumulative mortality of59.8%,46.2%and24.1%. Different endoscopic procedures did not influence the risk of rebleeding or death. Hyponatremia(P=0.028, HR=6.660,95%CI1.225-36.197) and diameter of portal vein>12mm(P=0.001, HR=12.340,95%CI2.692-56.558) were independent predictor for relapse of bleeding, while AFP>20ng/ml(P=0.004, HR=3.851,95%CI1.522-9.743) and thrombin time>21s(P=0.001, HR=38.207,95%CI6.196-235.620) predicted shorter survival time.Conclusion:1. The results of the retrospective study suggested that there was no significant difference in terms of rebleeding, mortality, or eradication rate between ligation+cyanoacrylate group and combined ligation and sclerotherapy+cyanoacrylate group among cirrhotic patients with both esophageal and gastric varices. But the latter group was associated with higher risks of complications.2. The primary results of the randomized controlled trial demonstrated that among cirrhotic patients with both esophageal and gastric patients, there was no significant difference observed in relation to risk of rebleeding, mortality, incidence rate of complications or portal hypertensive gastropathy between ligation+cyanoacrylate group and combined ligation and sclerotherapy+cyanoacrylate group. However, the results of the stratified analysis suggested a superiority of ligation+cyanoacrylate injection for the prevention of rebleeding among such patients with concomitant use of propranodol or without diabetes.2. Patients who had esophagogastric variceal bleeding complicated by hepatic carcinoma had poor overall prognosis. Different endoscopic procedures were not related with increased risks of rebleeding or mortality. Hyponatremia and diameter of portal vein>12mm were independent predictor for relapse of bleeding, while AFP>20ng/ml and thrombin time>21s predicted shorter survival time in such patients.更多还原