肝移植手术后非吻合口胆管狭窄的相关危险因素及防治
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摘要
自1963年Starzl施行首例人体原位肝移植术以来,经过将近50年的发展,随着相关手术操作技术日益完善、新型免疫抑制剂的临床应用、不断进步的围手术期处理措施、手术适应证及手术时机的恰当选择,肝移植受体术后的生存率、生存质量均得到不断的提高。目前肝移植已经成为终末期肝病的有效治疗措施。
然后,肝移植术后术后胆道并发症一直是影响肝移植受体术后长期存活的重要原因之一,被称之为“阿喀琉斯之踵”。胆道并发症最常见的临床类型为胆漏、胆管狭窄,以及胆道感染、胆道结石、胆道出血等,其中胆管狭窄包括胆管吻合口狭窄和非吻合口胆管狭窄。随着外科手术技巧的不断提高、技术细节的不断改进,与手术操作联系更为紧密的胆漏、吻合口狭窄等并发症发生率不断下降,而非吻合口胆管狭窄所占比例随之升高,发生率在2-20%之间,有“阿喀琉斯之踵再现”之称。
而据不同文献分析,有多种原因可能导致肝移植术后非吻合口胆管狭窄,包括冷热缺血、二次热缺血、无肝期的延长、肝动脉血栓与狭窄、急性排斥反应、慢性排斥反应、ABO血型不相容、巨细胞病毒感染、丙肝病毒感染等等,而各文献统计分析结果均有不一致之处。
有鉴于此,我们对2004年8月-2010年10月我院施行的219例原位肝脏移植手术的临床资料进行回顾性分析,使用单因素分析与多因素分析等统计学手段,寻找与术后非吻合口胆管狭窄相关的危险因素,同时回顾典型病例及相关诊断方法、治疗措施,从而为临床上更有效的预防和治疗肝移植术后非吻合口胆管狭窄提供理论依据。
[目的]
肝移植术后胆道并发症是影响手术成功率和术后生存率的重要并发症,而其中非吻合口胆管狭窄近年来所占比重逐渐上升,越来越引起人们的重视。引起非吻合口胆管狭窄的原因错综复杂,不同研究发现的危险因素也各不一致。因此,我们对2004年8月-2010年10月我院施行的219例原位肝脏移植手术的临床资料进行回顾性分析,探讨肝移植术后非吻合口胆管狭窄的危险因素及防治要点。
[方法]
1、研究资料
收集南方医科大学附属南方医院肝胆外科2004年8月-2010年10月施行的219例次原位肝脏移植手术的临床资料,排除术后3天内死亡和病历资料不完整者。
2、诊断标准：
肝移植术后非吻合口胆管狭窄早期的表现通常为黄疸或者肝功能检查异常,胆道造影或MRCP是诊断非吻合口胆管狭窄的重要手段,直接的胆道造影是诊断的影像学金标准,临床上常用的诊断方法有：
(1)内镜逆行胰胆管造影发现胆管狭窄,狭窄处不位于吻合口；
(2)经皮肝穿刺胆道引流发现胆管狭窄,狭窄处不位于吻合口；
(3)磁共振胰胆管成像发现胆管狭窄,狭窄处不位于吻合口；
(4)留置T管者经T管行胆道造影发现胆管狭窄,狭窄处不位于吻合口；
(5)再次手术者术中发现胆管狭窄,狭窄处不位于吻合口。
3、相关因素选择
查阅相关文献,选择21项可能与非胆管吻合口狭窄相关的因素进行统计分析。
术前资料：年龄、性别、丙肝抗体。
手术资料：供受体血型是否相同、供受体血型是否相容、无肝期时间、热缺血时间、冷缺血时间、二次热缺血时间、是否复杂肝动脉重建、胆道缝合方式、是否留置T管。
术后资料：有无急性排斥反应、肝动脉并发症、巨细胞病毒感染,以及术后1天、1周、1月的肝动脉收缩期最大流速(Vmax)与阻力指数(RI)。
4、统计学处理
将符合诊断标准的病例归为NABS组,其余病例归为对照组。先对21项变量进行单因素分析,比较胆道并发症组和对照组之间的差异,初步找出与非吻合口胆管狭窄相关的危险因素,其中计数资料比较采用X2检验,不满足X2检验条件者用Fisher精确概率计算,计量资料先进行Kolmogorov-Smirnov正态性检验,正态分布资料比较采用两独立样本t检验,非正态分布资料采用两独立样本Wilcoxon秩和检验。
以P<0.05作为初筛标准将有统计学意义的危险因素纳入Logistic逐步回归分析,找出主要的危险因素。采用SPSS13.0统计软件,按a=0.05检验水准,P<0.05为差异有统计学意义。
[结果]
1、一般情况
南方医科大学南方医院自2004年8月-2010年10月共施行219例次原位肝脏移植手术,其中2例为再次肝移植。男189例,女30例,平均年龄48.21±11.14(16-75)岁。原发病包括原发性肝癌144例,单纯肝硬化43例,重症肝炎30例,布加综合征1例,肝豆状核变性1例。37例供受体血型不相同,其中12例供受体血型不相容。
2、手术情况
全部供肝均来自心脏停搏供体,采用原位双重灌注肝肾联合获取法。219次肝移植手术中包括161例经典原位肝移植、58例改良背驮式肝移植,均未采用静脉转流。中位手术时间7小时(4-15.5小时),中位无肝期60分钟(35-150分钟),中位热缺血时间5分钟(2-7分钟),中位冷缺血时间6小时(4-12小时),中位二次热缺血时间22分钟(15-50分钟)。
门静脉重建上均为端端吻合,以5-0Prolene线行2定点连续吻合,吻合完毕后即开放门静脉,结束无肝期。1例患者门静脉系统广泛血栓形成,遂行腔门静脉半转位术。
肝动脉重建大多采用分支袖片技术,在辅助放大镜下使用6-0prolene缝线进行,缝合方式上大多使用2定点连续缝合,12例使用了复杂的动脉重建方式,包括双口吻合、腹主动脉搭桥、腹主动脉袖片整形等。
胆道重建上均使用6-0 prolene线进行供受体肝总管端端吻合,无使用胆肠吻合者。192例使用后壁连续+前壁间断缝合,27例使用间断缝合。184例未放置T管,35例放置T管,其中2例T管经胆囊管放置。
3、术后处理
术后3天内每日行床旁彩色超声多普勒检查供肝血流情况,之后间断定期复查B超,观察是否有肝动脉狭窄或血栓形成,记录收缩期最大流速及阻力指数。术后常规采用他克莫司(FK506)+吗替麦考酚酯+激素三联抗排斥治疗；FK506的血药浓度维持在10-12ng/mL。抗感染治疗上常规使用三代头孢菌素或加用β-内酰胺酶抑制剂,合用奥硝唑等药物抗厌氧菌。乙肝患者或携带者术后早期常规给予乙肝免疫球蛋白,并长期服用抗乙肝病毒药物,可选用拉米夫定、阿德福韦酯、博路定之一
4、术后并发症
术后共14例发生非吻合口胆管狭窄,患病率为6.39%,发生的中位时间为43天(5-570天)。发生的部位上9例位于供体侧,4例位于受体侧,1例为全胆道的狭窄。
肝动脉并发症共7例,其中2例肝动脉栓塞,5例无症状肝动脉狭窄。急性排斥反应27例。移植物抗宿主病2例。巨细胞病毒感染5例。腹腔内出血4例。5、治疗与转归
所有14例NABS中,1例经T管置管引流后治愈；1例经胆肠吻合术后死于呼吸衰竭；1例合并肝动脉栓塞者,因移植肝功能不良行再次肝移植后仍死于肝功能衰竭；6例予ERCP治疗后治愈(2例放置胆道内支架,4例仅放置鼻胆管引流)；5例予PTCD治疗(1例放置胆道内支架,3例放置内外引流管,1例因无法通过胆总管下段进入十二指肠,仅放置外引流管),其中3例治愈,1例死于上消化道出血、肝性脑病,1例死于脑血管意外。
所有14例(?)NABS中有4例死亡,病死率28.57%,2例接受再次手术治疗,再手术率14.29%,其中1例为再次肝移植,再移植率7.14%。
6、单因素分析
首先对11个计量资料进行Kolmogorov-Smirnov正态性检验,发现除年龄以外的其他计量资料均不符合正态分布。对符合正态分布的计量资料(年龄)使用两独立样本t检验进行比较,未能发现两组数据间存在显著差异。对不符合正态分布的计量资料使用两独立样本Wilcoxon秩和检验,可发现胆道并发症组与对照组间的RI(术后1月)存在显著差异(P=0.014)。
对10个计数资料比较采用X2检验,不满足X2检验条件者用Fisher精确概率计算,可发现肝动脉并发症(P=0.006)、急性排斥反应(P=0.018)的发生率存在显著差异。
因此,由单因素分析可发现急性排斥反应、肝动脉并发症、术后1月肝动脉阻力指数降低可能是非吻合口胆管狭窄的危险因素。
7、多因素分析
将上述3个变量引入Logistic逐步回归分析,最终结果显示结果显示急性排斥反应(P=0.011)、肝动脉并发症(P=0.012)、术后1月的肝动脉阻力指数(RI)≤0.64(P=0.012)是术后非吻合口胆管狭窄的独立危险因素。
[结论]
多种因素可以导致肝移植术后非吻合口胆管狭窄,急性排斥反应、肝动脉并发症、术后1月肝动脉阻力指数≤0.64是术后非吻合口胆管狭窄的独立危险因素,应针对上述危险因素采取切实有效的预防措施。肝动脉血流动力学的严密监测、必要的预防性抗凝治疗、规范的抗排斥治疗可能有助于降低其发生率。对于非吻合口胆管狭窄的治疗上首选ERCP及PTCD治疗,无效者应积极再次手术治疗,甚至行再次肝移植。
Since Starzl successfully performed the first human liver transplantation in the world in 1963,50 years had passed. Due to the development of surgery technics, new immunosuppressants, improved perioperative management, and appropriate choice of recipients and surgery time, the survival rate and the quality of life has been improved gradually. Liver transplantation has become the most effective treatment for patients of last stage liver diseases.
Nevertheless, biliary complication (BC), which is called "Achilles heel", is still one of the most important causes of death following the postoperative period in the liver transplantation. BCs include biliary leakage, biliary stricture, biliary infection, biliary calculi, and hemobilia. Biliary stricture consists of anastomotic biliary stricture (ABS) and nonanastomotic biliary stricture (NABS). With the operative techniques developing in these days, decrease can be observed in biliary leakage and ABS which are more concerned with techniques, and NABS relatively increased, of which the incidence rate is between 2 and 20%. So it is called "Reappearance of Achilles heel",
There are various causes of NABS according to different literatures, such as warm ischemic time (WIT), cold ischemic time (CIT), second warm ischemic time (WIT2), long anhepatic phase, hepatic artery complications, acute rejection (AR), chronic rejection(CR), ABO incompatibility, cytomegalovirus (CMV) infection, hepatitis C virus (HCV) infection. Many difference can be found out between these literatures.
Accordingly, we retrospectively analysed 219 patients who underwent liver transplantation in Hepatobiliary Surgery Department of Nanfang Hospital from August 2004 to October 2010, using univariate and multivariate analysis to find the risk factors associated with NABS. Typical cases, diagnosis and management were also reviewed. These findings can be used to guide the prevention and treatment of NABS in clinical.
[Objective]
BC is one of the most important complications affecting the success rate and postoperative survival rate after liver transplantation, and the proportion of NABS increased gradually this years, which were drawing an increasing attention.The causes of NABS are intricate and complexed, and there are diverse risk factors according to defferent researches. We retrospectively analysed 219 patients, who underwent liver transplantation in Nanfang Hospital from August 2004 to October 2010, to investigate the risk factors associated with NABS and the prevention and management of NABS.
[Methods]
l.Materials
219 cases of liver transplantation admitted in Nanfang Hospital from August 2004 to October 2010 were studied retrospectively, excluding the patients died within 3 days after transplantation or cases without a complete record.
2. Diagnostic Criteria
(1) Diagnosed by ERCP.
(2) Diagnosed by PTC.
(3) Diagnosed by MRCP.
(4) Diagnosed by T-tube cholangiography.
(5) Found during reoperation.
3. The choice of relevant factors
Twenty-one independent variables were selected according to the experience in our center and reference literature.
(1)Preoperative factors:gender, age, HCV antigen.
(2)Intraoperative factors:ABO identity, ABO compatibility, anhepatic phase time, warm ischemic time (WIT), cold ischemic time (CIT), second warm ischemic time (WIT2), complicated hepatic artery reconstruction, bile duct anastomotic method, the use of T-tube.
(3) postoperative factors:acute rejection, hepatic artery complications, cytomegalovirus (CMV) infection, maximum blood flow velocity during systole (Vmax) and resistive index (RI) of hepatic artery at 1 day,1 week and 1 month after transplantation.
4. Statistical analysis
Cases consistent with the above-mentioned diagnostic criteria were classified as NABS group, the remainder were classified as the control group. First, the Twenty-one variables were analyzed in univariate analysis to screen out the possible risk factors associated with NABS. Count data were compared byχ2 test when meet the condition, otherwise by Fisher's Exact Test. Measurement data were screened by Kolmogorov-Smirnov normality test. The normal data were compared by independent samples t test, others by independent samples Wilcoxon rank sum test. In view of the existence of certain factors can interact, there will be statistically significant risk factors included in Logistic regression analysis to identify major risk factors. All data were analyzed by SPSS13.0, A P value of<0.05 was regarded as statistically significant.
[Results]
1. General results
219 cases of liver transplantation were performed in Nanfang Hospital from August 2004 to October 2010, which including 2 cases of replantation.189 cases of male, and 30 female. The average age was 48.21±11.14(16～75). In respect of protopathy, these cases are consists of 144 cases primary liver cancer,43 cases simple cirrhosis,30 cases serious hepatitis,1 case Budd-Chiari syndrome,1 case Wilson's disease. There are 37 cases of ABO difference between donor and recipient, including 12 cases of ABO incompatibility.
2. Surgery
All the donor livers came from non-heart-beating donors (NHBD),by means of liver-kidney harvesting method with in situ double infusion.219 cases include 161 cases of orthotopic liver transplantation and 58 cases of piggyback liver transplantation. None used venous bypass. The median operation time is 7h (4-15h). The median anhepatic phase time is 60 min (35-150min). The median WIT is 5 min (2-7 min). The median CIT is 6h (4-12h). The median WIT2 is 22 min (15-20 min).
End to end two fixed-point continuous anastomosis by 5-0 Prolene line was used to reconstruct the portal vein, which was opened immediately after anastomosis to end the anhepatic phase. One case with extensive portal vein thrombosis underwent cavoportal hemitransposition.
Two fixed-point continuous anastomosis by 6-0 prolene line with a loupe, as well as branch patch techniques was used to reconstructe hepatic artery in most of the cases. Complicated reconstruction was performed in 12 cases, including double anastomosis, abdominal aorta bypass, and abdominal aorta patches reforming.
End to end anastomosis by 6-0 prolene line was used to reconstruct the bile duct, without case of cholangioenterostomy.192 cases used continuous suture in posterior wall with interrupted suture in anterior wall, and 27 cases total continuous suture. T-tube was used in 35 cases, and in two cases it was placed through cystic duct. The other 184 cases didn't use T-tube.
3. Postoperative management
Color Doppler ultrasound was used per day within 3 days after transplantation and at intervals beyond 3 days to evaluate the liver blood flow and detect hepatic artery stenosis or thrombosis, with Vmax and RI recorded. Tacrolimus, Mycophenolate Mofetil, and glucocorticoid were used as routine immunosuppressants. The concentration of FK506 was maintained between 10 to 12 ng/mL. In terms of antibiotics, third generation cephalosporin with or without Beta-lactamase inhibitors were used, as well as ornidazole against anaerobe. HBV patients or carriers were given anti-hepatic B immunoglobulin in the early period after transplantation, and anti-hepatic B virus medicine in long term, such as Lamivudine, adefovir and entecavir.
4. Postoperative complications
NABS occurred in 14 cases (6.39%). The median occurrence time was 43d (5-570d).9 cases occurred at the donor side,4 at the recipient side, and one at whole bile duct.
Hepatic artery complications occurred in 7 cases, including 2 cases of thrombosis and 5 cases of stenosis. Graft versus host disease occurred in 2 cases, CMV infection in 5 cases, and Intraabdominal hemorrhage in 4 cases.
5. Treatment and prognosis
One case was cured by intubation through T-tube. One case died of respiratory failure after choledochojejunostomy. One case with hepatic artery thrombosis died of liver failure after retransplantation.6 cases were cured by ERCP (2 with and 4 without biliary stent).5 cases underwent PTCD (one case with biliary stent,3 with internal and external catheter, one with only external catheter), with 3 cases cured, one died of upper gastrointestinal bleeding and hepatic encephalopathy, and one died of cerebrovascular accident.
Among the 14 cases,4 cases died (28.57%), two cases underwent reoperation (14.29%) with one case retransplantation (7.14%).
6. Univariate analysis
Kolmogorov-Smirnov normality test of 11 measurement variates showed only one obeyed normal distribution (age), which showed no significant difference between NABS group and control group by means of independent samples t test. Wilcoxon rank sum test of the other nonnormal ones showed significant difference between two groups in RI one month after transplantation (P=0.014).
Among the 10 count variates,χ2 test was performed for the ones meet its condition, and Fisher's Exact Test for the others. It showed significant difference in incidence of hepatic artery complications (P=0.006) and acute rejection (P=0.018) between the two groups.
After univariate analysis of 21 perioperative factors, three were considered to be risk factors associated with NABS:a decreased hepatic arterial resistive index (RI) one month after transplantation, acute rejection, and hepatic artery complications.
7. Multivariate analysis
Logistic regression analysis showed the same three independent risk factors associated with biliary complications:acute rejection(P=0.011), hepatic artery complications(P=0.012), and the hepatic arterial resistive index (RI) one month after transplantation lower than 0.64(P=0.012).
[Conclusion]
Nonanastomotic biliary stricture after liver transplantation can be caused by diverse risk factors, with three most important:acute rejection, hepatic artery complications, and the hepatic arterial resistive index (RI) one month after transplantation lower than 0.64. Rigorous monitoring of hepatic arterial flow, preventative anticoagulant therapy, normative antirejection therapy are the keys to reducing the incidence. The preferred treatment should be ERCP or PTCD. Reoperation could be taken into account for ineffective ones, as far as to retransplantation.
然后,肝移植术后术后胆道并发症一直是影响肝移植受体术后长期存活的重要原因之一,被称之为“阿喀琉斯之踵”。胆道并发症最常见的临床类型为胆漏、胆管狭窄,以及胆道感染、胆道结石、胆道出血等,其中胆管狭窄包括胆管吻合口狭窄和非吻合口胆管狭窄。随着外科手术技巧的不断提高、技术细节的不断改进,与手术操作联系更为紧密的胆漏、吻合口狭窄等并发症发生率不断下降,而非吻合口胆管狭窄所占比例随之升高,发生率在2-20%之间,有“阿喀琉斯之踵再现”之称。
而据不同文献分析,有多种原因可能导致肝移植术后非吻合口胆管狭窄,包括冷热缺血、二次热缺血、无肝期的延长、肝动脉血栓与狭窄、急性排斥反应、慢性排斥反应、ABO血型不相容、巨细胞病毒感染、丙肝病毒感染等等,而各文献统计分析结果均有不一致之处。
有鉴于此,我们对2004年8月-2010年10月我院施行的219例原位肝脏移植手术的临床资料进行回顾性分析,使用单因素分析与多因素分析等统计学手段,寻找与术后非吻合口胆管狭窄相关的危险因素,同时回顾典型病例及相关诊断方法、治疗措施,从而为临床上更有效的预防和治疗肝移植术后非吻合口胆管狭窄提供理论依据。
[目的]
肝移植术后胆道并发症是影响手术成功率和术后生存率的重要并发症,而其中非吻合口胆管狭窄近年来所占比重逐渐上升,越来越引起人们的重视。引起非吻合口胆管狭窄的原因错综复杂,不同研究发现的危险因素也各不一致。因此,我们对2004年8月-2010年10月我院施行的219例原位肝脏移植手术的临床资料进行回顾性分析,探讨肝移植术后非吻合口胆管狭窄的危险因素及防治要点。
[方法]
1、研究资料
收集南方医科大学附属南方医院肝胆外科2004年8月-2010年10月施行的219例次原位肝脏移植手术的临床资料,排除术后3天内死亡和病历资料不完整者。
2、诊断标准：
肝移植术后非吻合口胆管狭窄早期的表现通常为黄疸或者肝功能检查异常,胆道造影或MRCP是诊断非吻合口胆管狭窄的重要手段,直接的胆道造影是诊断的影像学金标准,临床上常用的诊断方法有：
(1)内镜逆行胰胆管造影发现胆管狭窄,狭窄处不位于吻合口；
(2)经皮肝穿刺胆道引流发现胆管狭窄,狭窄处不位于吻合口；
(3)磁共振胰胆管成像发现胆管狭窄,狭窄处不位于吻合口；
(4)留置T管者经T管行胆道造影发现胆管狭窄,狭窄处不位于吻合口；
(5)再次手术者术中发现胆管狭窄,狭窄处不位于吻合口。
3、相关因素选择
查阅相关文献,选择21项可能与非胆管吻合口狭窄相关的因素进行统计分析。
术前资料：年龄、性别、丙肝抗体。
手术资料：供受体血型是否相同、供受体血型是否相容、无肝期时间、热缺血时间、冷缺血时间、二次热缺血时间、是否复杂肝动脉重建、胆道缝合方式、是否留置T管。
术后资料：有无急性排斥反应、肝动脉并发症、巨细胞病毒感染,以及术后1天、1周、1月的肝动脉收缩期最大流速(Vmax)与阻力指数(RI)。
4、统计学处理
将符合诊断标准的病例归为NABS组,其余病例归为对照组。先对21项变量进行单因素分析,比较胆道并发症组和对照组之间的差异,初步找出与非吻合口胆管狭窄相关的危险因素,其中计数资料比较采用X2检验,不满足X2检验条件者用Fisher精确概率计算,计量资料先进行Kolmogorov-Smirnov正态性检验,正态分布资料比较采用两独立样本t检验,非正态分布资料采用两独立样本Wilcoxon秩和检验。
以P<0.05作为初筛标准将有统计学意义的危险因素纳入Logistic逐步回归分析,找出主要的危险因素。采用SPSS13.0统计软件,按a=0.05检验水准,P<0.05为差异有统计学意义。
[结果]
1、一般情况
南方医科大学南方医院自2004年8月-2010年10月共施行219例次原位肝脏移植手术,其中2例为再次肝移植。男189例,女30例,平均年龄48.21±11.14(16-75)岁。原发病包括原发性肝癌144例,单纯肝硬化43例,重症肝炎30例,布加综合征1例,肝豆状核变性1例。37例供受体血型不相同,其中12例供受体血型不相容。
2、手术情况
全部供肝均来自心脏停搏供体,采用原位双重灌注肝肾联合获取法。219次肝移植手术中包括161例经典原位肝移植、58例改良背驮式肝移植,均未采用静脉转流。中位手术时间7小时(4-15.5小时),中位无肝期60分钟(35-150分钟),中位热缺血时间5分钟(2-7分钟),中位冷缺血时间6小时(4-12小时),中位二次热缺血时间22分钟(15-50分钟)。
门静脉重建上均为端端吻合,以5-0Prolene线行2定点连续吻合,吻合完毕后即开放门静脉,结束无肝期。1例患者门静脉系统广泛血栓形成,遂行腔门静脉半转位术。
肝动脉重建大多采用分支袖片技术,在辅助放大镜下使用6-0prolene缝线进行,缝合方式上大多使用2定点连续缝合,12例使用了复杂的动脉重建方式,包括双口吻合、腹主动脉搭桥、腹主动脉袖片整形等。
胆道重建上均使用6-0 prolene线进行供受体肝总管端端吻合,无使用胆肠吻合者。192例使用后壁连续+前壁间断缝合,27例使用间断缝合。184例未放置T管,35例放置T管,其中2例T管经胆囊管放置。
3、术后处理
术后3天内每日行床旁彩色超声多普勒检查供肝血流情况,之后间断定期复查B超,观察是否有肝动脉狭窄或血栓形成,记录收缩期最大流速及阻力指数。术后常规采用他克莫司(FK506)+吗替麦考酚酯+激素三联抗排斥治疗；FK506的血药浓度维持在10-12ng/mL。抗感染治疗上常规使用三代头孢菌素或加用β-内酰胺酶抑制剂,合用奥硝唑等药物抗厌氧菌。乙肝患者或携带者术后早期常规给予乙肝免疫球蛋白,并长期服用抗乙肝病毒药物,可选用拉米夫定、阿德福韦酯、博路定之一
4、术后并发症
术后共14例发生非吻合口胆管狭窄,患病率为6.39%,发生的中位时间为43天(5-570天)。发生的部位上9例位于供体侧,4例位于受体侧,1例为全胆道的狭窄。
肝动脉并发症共7例,其中2例肝动脉栓塞,5例无症状肝动脉狭窄。急性排斥反应27例。移植物抗宿主病2例。巨细胞病毒感染5例。腹腔内出血4例。5、治疗与转归
所有14例NABS中,1例经T管置管引流后治愈；1例经胆肠吻合术后死于呼吸衰竭；1例合并肝动脉栓塞者,因移植肝功能不良行再次肝移植后仍死于肝功能衰竭；6例予ERCP治疗后治愈(2例放置胆道内支架,4例仅放置鼻胆管引流)；5例予PTCD治疗(1例放置胆道内支架,3例放置内外引流管,1例因无法通过胆总管下段进入十二指肠,仅放置外引流管),其中3例治愈,1例死于上消化道出血、肝性脑病,1例死于脑血管意外。
所有14例(?)NABS中有4例死亡,病死率28.57%,2例接受再次手术治疗,再手术率14.29%,其中1例为再次肝移植,再移植率7.14%。
6、单因素分析
首先对11个计量资料进行Kolmogorov-Smirnov正态性检验,发现除年龄以外的其他计量资料均不符合正态分布。对符合正态分布的计量资料(年龄)使用两独立样本t检验进行比较,未能发现两组数据间存在显著差异。对不符合正态分布的计量资料使用两独立样本Wilcoxon秩和检验,可发现胆道并发症组与对照组间的RI(术后1月)存在显著差异(P=0.014)。
对10个计数资料比较采用X2检验,不满足X2检验条件者用Fisher精确概率计算,可发现肝动脉并发症(P=0.006)、急性排斥反应(P=0.018)的发生率存在显著差异。
因此,由单因素分析可发现急性排斥反应、肝动脉并发症、术后1月肝动脉阻力指数降低可能是非吻合口胆管狭窄的危险因素。
7、多因素分析
将上述3个变量引入Logistic逐步回归分析,最终结果显示结果显示急性排斥反应(P=0.011)、肝动脉并发症(P=0.012)、术后1月的肝动脉阻力指数(RI)≤0.64(P=0.012)是术后非吻合口胆管狭窄的独立危险因素。
[结论]
多种因素可以导致肝移植术后非吻合口胆管狭窄,急性排斥反应、肝动脉并发症、术后1月肝动脉阻力指数≤0.64是术后非吻合口胆管狭窄的独立危险因素,应针对上述危险因素采取切实有效的预防措施。肝动脉血流动力学的严密监测、必要的预防性抗凝治疗、规范的抗排斥治疗可能有助于降低其发生率。对于非吻合口胆管狭窄的治疗上首选ERCP及PTCD治疗,无效者应积极再次手术治疗,甚至行再次肝移植。
Since Starzl successfully performed the first human liver transplantation in the world in 1963,50 years had passed. Due to the development of surgery technics, new immunosuppressants, improved perioperative management, and appropriate choice of recipients and surgery time, the survival rate and the quality of life has been improved gradually. Liver transplantation has become the most effective treatment for patients of last stage liver diseases.
Nevertheless, biliary complication (BC), which is called "Achilles heel", is still one of the most important causes of death following the postoperative period in the liver transplantation. BCs include biliary leakage, biliary stricture, biliary infection, biliary calculi, and hemobilia. Biliary stricture consists of anastomotic biliary stricture (ABS) and nonanastomotic biliary stricture (NABS). With the operative techniques developing in these days, decrease can be observed in biliary leakage and ABS which are more concerned with techniques, and NABS relatively increased, of which the incidence rate is between 2 and 20%. So it is called "Reappearance of Achilles heel",
There are various causes of NABS according to different literatures, such as warm ischemic time (WIT), cold ischemic time (CIT), second warm ischemic time (WIT2), long anhepatic phase, hepatic artery complications, acute rejection (AR), chronic rejection(CR), ABO incompatibility, cytomegalovirus (CMV) infection, hepatitis C virus (HCV) infection. Many difference can be found out between these literatures.
Accordingly, we retrospectively analysed 219 patients who underwent liver transplantation in Hepatobiliary Surgery Department of Nanfang Hospital from August 2004 to October 2010, using univariate and multivariate analysis to find the risk factors associated with NABS. Typical cases, diagnosis and management were also reviewed. These findings can be used to guide the prevention and treatment of NABS in clinical.
[Objective]
BC is one of the most important complications affecting the success rate and postoperative survival rate after liver transplantation, and the proportion of NABS increased gradually this years, which were drawing an increasing attention.The causes of NABS are intricate and complexed, and there are diverse risk factors according to defferent researches. We retrospectively analysed 219 patients, who underwent liver transplantation in Nanfang Hospital from August 2004 to October 2010, to investigate the risk factors associated with NABS and the prevention and management of NABS.
[Methods]
l.Materials
219 cases of liver transplantation admitted in Nanfang Hospital from August 2004 to October 2010 were studied retrospectively, excluding the patients died within 3 days after transplantation or cases without a complete record.
2. Diagnostic Criteria
(1) Diagnosed by ERCP.
(2) Diagnosed by PTC.
(3) Diagnosed by MRCP.
(4) Diagnosed by T-tube cholangiography.
(5) Found during reoperation.
3. The choice of relevant factors
Twenty-one independent variables were selected according to the experience in our center and reference literature.
(1)Preoperative factors:gender, age, HCV antigen.
(2)Intraoperative factors:ABO identity, ABO compatibility, anhepatic phase time, warm ischemic time (WIT), cold ischemic time (CIT), second warm ischemic time (WIT2), complicated hepatic artery reconstruction, bile duct anastomotic method, the use of T-tube.
(3) postoperative factors:acute rejection, hepatic artery complications, cytomegalovirus (CMV) infection, maximum blood flow velocity during systole (Vmax) and resistive index (RI) of hepatic artery at 1 day,1 week and 1 month after transplantation.
4. Statistical analysis
Cases consistent with the above-mentioned diagnostic criteria were classified as NABS group, the remainder were classified as the control group. First, the Twenty-one variables were analyzed in univariate analysis to screen out the possible risk factors associated with NABS. Count data were compared byχ2 test when meet the condition, otherwise by Fisher's Exact Test. Measurement data were screened by Kolmogorov-Smirnov normality test. The normal data were compared by independent samples t test, others by independent samples Wilcoxon rank sum test. In view of the existence of certain factors can interact, there will be statistically significant risk factors included in Logistic regression analysis to identify major risk factors. All data were analyzed by SPSS13.0, A P value of<0.05 was regarded as statistically significant.
[Results]
1. General results
219 cases of liver transplantation were performed in Nanfang Hospital from August 2004 to October 2010, which including 2 cases of replantation.189 cases of male, and 30 female. The average age was 48.21±11.14(16～75). In respect of protopathy, these cases are consists of 144 cases primary liver cancer,43 cases simple cirrhosis,30 cases serious hepatitis,1 case Budd-Chiari syndrome,1 case Wilson's disease. There are 37 cases of ABO difference between donor and recipient, including 12 cases of ABO incompatibility.
2. Surgery
All the donor livers came from non-heart-beating donors (NHBD),by means of liver-kidney harvesting method with in situ double infusion.219 cases include 161 cases of orthotopic liver transplantation and 58 cases of piggyback liver transplantation. None used venous bypass. The median operation time is 7h (4-15h). The median anhepatic phase time is 60 min (35-150min). The median WIT is 5 min (2-7 min). The median CIT is 6h (4-12h). The median WIT2 is 22 min (15-20 min).
End to end two fixed-point continuous anastomosis by 5-0 Prolene line was used to reconstruct the portal vein, which was opened immediately after anastomosis to end the anhepatic phase. One case with extensive portal vein thrombosis underwent cavoportal hemitransposition.
Two fixed-point continuous anastomosis by 6-0 prolene line with a loupe, as well as branch patch techniques was used to reconstructe hepatic artery in most of the cases. Complicated reconstruction was performed in 12 cases, including double anastomosis, abdominal aorta bypass, and abdominal aorta patches reforming.
End to end anastomosis by 6-0 prolene line was used to reconstruct the bile duct, without case of cholangioenterostomy.192 cases used continuous suture in posterior wall with interrupted suture in anterior wall, and 27 cases total continuous suture. T-tube was used in 35 cases, and in two cases it was placed through cystic duct. The other 184 cases didn't use T-tube.
3. Postoperative management
Color Doppler ultrasound was used per day within 3 days after transplantation and at intervals beyond 3 days to evaluate the liver blood flow and detect hepatic artery stenosis or thrombosis, with Vmax and RI recorded. Tacrolimus, Mycophenolate Mofetil, and glucocorticoid were used as routine immunosuppressants. The concentration of FK506 was maintained between 10 to 12 ng/mL. In terms of antibiotics, third generation cephalosporin with or without Beta-lactamase inhibitors were used, as well as ornidazole against anaerobe. HBV patients or carriers were given anti-hepatic B immunoglobulin in the early period after transplantation, and anti-hepatic B virus medicine in long term, such as Lamivudine, adefovir and entecavir.
4. Postoperative complications
NABS occurred in 14 cases (6.39%). The median occurrence time was 43d (5-570d).9 cases occurred at the donor side,4 at the recipient side, and one at whole bile duct.
Hepatic artery complications occurred in 7 cases, including 2 cases of thrombosis and 5 cases of stenosis. Graft versus host disease occurred in 2 cases, CMV infection in 5 cases, and Intraabdominal hemorrhage in 4 cases.
5. Treatment and prognosis
One case was cured by intubation through T-tube. One case died of respiratory failure after choledochojejunostomy. One case with hepatic artery thrombosis died of liver failure after retransplantation.6 cases were cured by ERCP (2 with and 4 without biliary stent).5 cases underwent PTCD (one case with biliary stent,3 with internal and external catheter, one with only external catheter), with 3 cases cured, one died of upper gastrointestinal bleeding and hepatic encephalopathy, and one died of cerebrovascular accident.
Among the 14 cases,4 cases died (28.57%), two cases underwent reoperation (14.29%) with one case retransplantation (7.14%).
6. Univariate analysis
Kolmogorov-Smirnov normality test of 11 measurement variates showed only one obeyed normal distribution (age), which showed no significant difference between NABS group and control group by means of independent samples t test. Wilcoxon rank sum test of the other nonnormal ones showed significant difference between two groups in RI one month after transplantation (P=0.014).
Among the 10 count variates,χ2 test was performed for the ones meet its condition, and Fisher's Exact Test for the others. It showed significant difference in incidence of hepatic artery complications (P=0.006) and acute rejection (P=0.018) between the two groups.
After univariate analysis of 21 perioperative factors, three were considered to be risk factors associated with NABS:a decreased hepatic arterial resistive index (RI) one month after transplantation, acute rejection, and hepatic artery complications.
7. Multivariate analysis
Logistic regression analysis showed the same three independent risk factors associated with biliary complications:acute rejection(P=0.011), hepatic artery complications(P=0.012), and the hepatic arterial resistive index (RI) one month after transplantation lower than 0.64(P=0.012).
[Conclusion]
Nonanastomotic biliary stricture after liver transplantation can be caused by diverse risk factors, with three most important:acute rejection, hepatic artery complications, and the hepatic arterial resistive index (RI) one month after transplantation lower than 0.64. Rigorous monitoring of hepatic arterial flow, preventative anticoagulant therapy, normative antirejection therapy are the keys to reducing the incidence. The preferred treatment should be ERCP or PTCD. Reoperation could be taken into account for ineffective ones, as far as to retransplantation.
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