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收稿日期:2018年10月12日
接受日期:2018年11月20日
发布日期:2018年11月23日
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活体供肝移植(LDLT)术后肝移植衰竭、发病率和死亡率的危险因素:综述文章。临床试验4:DOI: 10.15761/CRT.1000242
亚历山大大学普通外科学系,亚历山大,埃及
DOI: 10.15761 / CRT.1000242
背景:肝移植是现代生活的一个突破.随着肝移植需求的增加,LDLT应运而生。随着需求的进一步增加,捐助者的范围开始扩大,开始使用边缘捐助者。影响移植物衰竭的因素越来越广泛,包括多种因素。
宗旨和目标:本文综述了LDLT术后肝移植衰竭的危险因素。并分析这些因素的影响及其对患者发病率和死亡率的影响。
结论:研究了多种因素作为LDLT术后移植物衰竭和患者死亡的危险因素.早期移植失败率很低。这是应该的来根据年龄、性别、体重指数(BMI)和abo -相容性选择最佳供体;供肝节段切除术的计算机辅助规划与决策及最佳GRWR冷缺血时间短;中心拥有高水平的专业知识;及时发现导致早期移植失败的血管、胆道和免疫并发症,并进行早期有效的处理。晚期移植物衰竭的潜在危险因素包括对治疗无效的CR患者和不可避免的疾病复发患者。因此,这两种并发症构成了肝移植的真正问题。
肝移植失败的危险因素,发病率和死亡率,LDLT
肝移植(LT)是终末期肝病患者唯一有效的治疗方法。随着手术技术的进步和免疫抑制治疗的进展,在过去的几十年里,肝移植已经成为常规手术[1]。随着原位肝移植适应症的扩大[2,3],对移植器官的需求也在增加。不幸的是,死者捐献器官的供应不能满足日益增长的需求。因此,扩大供体池和降低等待名单死亡率是当今肝移植界面临的主要挑战之一[4]。增加活体供肝移植(LDLT)的频率满足了这两个挑战[5,6]。由于死亡供体稀缺,LDLT已成为主要的肝移植形式,尤其是在亚洲国家[7,8]。LDLT在儿科人群中的成功导致了该技术在成人人群中的改进[9]。对于LDLT供体和受体的充分选择是预防死亡率和发病率的重要因素,包括移植物失败和再次移植的需要[10,11]。很少有研究调查导致移植物衰竭的因素,尤其是LDLT[12,13]。 Several risk factors for graft loss after LDLT were identified by researchers as donor age [14], MELD score [15-19], intraoperative blood loss [19-21], warm ischemic time [21], and small for size syndrome [22-25]. Other studies investigated the factors responsible for graft loss and retransplantation namely hepatic artery thrombosis [26,27] primary non-function [26] and hyperacute rejection [28]. Although improving outcomes and survival after LDLT with meticulous selection criteria [9,29], still no definite criteria can predict graft dysfunction or failure.
在LDLT中,移植物类型和大小的选择是手术中最重要的方面之一。
虽然供体肝脏剩余体积的安全界限尚未得到精确估计,但一般认为正常肝脏可以耐受右肝切除术,因为左肝残余占肝总体积的30.0% -40.0%,对供体来说是安全的[30]。基于这一概念,1998年2月京都大学引入了右脑叶移植项目[31]。在右叶第5段和第8段主要在肝中静脉(MHV)引流的情况下,采用包括MHV(扩展右叶移植物)在内的右叶移植物,以防止这些节段充血,保持右叶移植物的功能体积,防止受体发生小尺寸综合征[32]。越来越多地使用扩展的右叶移植物是由于认识到在移植物中包含这条静脉的重要性,只要它不影响供体剩余肝脏体积的静脉引流。
成人LDLT适应症扩大后,出现了“移植物体积小”的问题。这个问题在尸体肝移植和儿童LDLT中都没有发现。右脑叶移植的引入部分解决了这一问题[31]。然而,尽管移植物容量足够,一些右叶移植物仍出现胆汁分泌不良、合成功能延迟、胆汁淤积时间延长和顽固性腹水。由于这些症状表明在最佳移植物体积存在的情况下移植物功能较差,因此被称为“小尺寸综合征”[33]。因此,“小体积综合征”不仅存在于“小体积移植物”中,也存在于最佳移植物甚至大体积移植物中。一些解释被引入来澄清这一综合征,并进行了一些研究来解决这一致命问题[23]。目前正在探索和创新几种技术,试图减轻“小体型综合症”的影响。其中一种方法是通过添加移植物获得更大的肝块,如辅助部分原位LDLT (APOLT)[34],但它有很多并发症和双肝移植[35,36],这并不常见,因为它需要两个可用的供体存在,这并不总是可行的。其他手术包括MHV至右叶移植物,这可能不会增加肝脏体积,但可以通过防止前段充血来改善移植物功能[37]。 Injury of the graft may be produced by persistent portal hypertension and portal over perfusion of the graft [38]. Control of portal pressure and graft perfusion may be adopted to prevent graft injury in such cases. This was achieved by innovative techniques such as splenic artery ligation (SPL) [39,40], or permanent portacaval (PC) shunt [41,42].
肝脂肪变性是LDLT的一个危险因素。有共识认为,大脂肪变性比小脂肪变性更能影响移植物功能和存活,因为它可能发展为非酒精性脂肪性肝炎(NASH)和最终肝硬化伴移植物衰竭[43-46]。在体重指数(BMI)≥25 kg/m的超重或肥胖供体中怀疑存在2[47]。在这类供体中,CT和超声可用于评估肝脏脂肪[48]。脂肪变性供者肝脏功能肿块减少。有研究认为,供体肝脏脂肪变性每增加1%,功能性移植物质量就会减少1%[49]。这一点必须考虑到GRWR的计算中。在尸体肝移植中,脂肪变性与原发性无功能(PNF)和可恢复的初始功能不良有关[43,44,46]。多达80%的严重脂肪变性患者会发生PNF,因此脂肪变性超过60%的移植物是移植的禁忌症[43,50,51]。大约30%接受肝脏中度脂肪变性手术的患者出现初始功能不良[51]。几组研究表明,脂肪变性小于30%的肝脏移植与非脂肪变性肝脏移植的结果相似[45,52-54]。在LDLT中,Hayashi评估了脂肪变性对移植物预后的影响,发现轻度至中度脂肪变性的移植物在早期移植物功能方面表现出轻微的干扰,但与对照组相似[55]。 Grafts with severe steatosis were associated with poor function and outcome [55]. Similarly, Soejima evaluated the impact of the degree of steatosis in 60 consecutive donors and recipients. One-year graft survival in none, mild and moderate steatosis groups was comparable (85.9%, 80.7%, and 80.0%). He concluded that grafts with moderate steatosis (<50%) can be used if the residual volume in the donor is at least 40% to avoid additional risk related to steatosis [56]. Cho reported similar regeneration ability and early outcome between recipients receiving mild steatotic (≤ 30% macrosteatosis) vs. normal (≤ 5% macrosteatosis) liver grafts. Using biopsies performed 10 days after surgery, he noted that the degree of steatosis decreased to less than 10% in all grafts suggesting that mild steatosis is rapidly reversible after LDLT [57]. Although the use of grafts with mild to moderate steatosis yields comparable results with those without steatosis, it appears risky to use such grafts on a routine basis. Their use are justified when they are not associated with other risk factors. It is recommended that donors with BMI ≥25 should undergo diet control and exercise which permit reduction of liver steatosis allowing a delayed but safer transplantation for both donors and recipients. Liver biopsy is recommended in countries where there is lack of expertise in the evaluation and diagnosis of hepatic steatosis by radiological means. It also serves to detect other pathological conditions in the donor such as hepatitis, fibrosis or cirrhosis, which may be prevalent in these countries. PNF, which is common in cadaveric liver transplantation, did not occur in the present series most likely due to the short cold ischemic time (CIT) in LDLT.
abo血型不相容供者肝移植:被认为是LDLT的一个危险因素,因为预先形成的抗abo抗体介导了超急性排斥反应的风险[58-60]。abo血型不相容的供体可能是危及生命的情况下(如暴发性肝衰竭(FHF))唯一可用的移植物来源。在获得尸体供体有限的国家,使用abo血型不匹配的活体供体移植更为常见,特别是当供体来源仅限于直系亲属时[61,62]。血浆置换术对降低移植前抗体滴度有效,但对维持移植后低抗体滴度无效,且不能防止肝坏死患者死亡。Yandza证实,与成人相比,2岁以下儿童的抗abo抗体滴度和发病率较低[63]。古根海姆认为,abo血型不相容的肝移植仅适用于成人受体作为紧急情况[58]。相反,Hanto在成人中报告了令人鼓舞的结果[64]。据报道,在abo血型不相容的尸体供体肝移植中,术前死亡率、动脉血栓形成和不可逆排斥反应的发生率以及再移植率均高于abo血型相容或相同的移植,无论患者是成人还是儿童,是急诊移植还是择期移植,也无论移植指征如何[58,65-67]。Gordon发现尸体供体的abo血型不相容肝移植的存活率降低。因此,由于缺乏合适的供体移植,abo血型不匹配的尸体供体肝移植一直被认为只有在紧急情况下才有理由,特别是在儿童中[68]。 Farges has reported that hyperacute rejection is a complication in adult patients undergoing ABO-incompatible cadaveric liver transplantation [61]. Renard and Andrews also reported hepatic necrosis with hemorrhagic and perivascular parenchymal collapse in pediatric cases [69]. A difference in outcome between adult and pediatric cadaveric liver transplantation has been reported, with pediatric transplants being more successful [70,71]. The reasons for more favorable outcome in children are not totally clear [72,73], but they may be related to lower anti-ABO antibodies levels, [63], or to an immature complement system [74] thus, the factors that initiate hyperacute rejection are absent during early infancy. In contrast, adults undergoing splenectomy in ABO-incompatible liver transplantation to decrease the incidence of hyperacute rejection together with the addition of other immunosuppressive agents in such cases also might contribute to poor outcome in these patients [68,71]. Some centers showed insignificant difference in the results of ABO-incompatible and ABO-compatible grafts as regards the graft failure in LDLT which can be attributed to the ABO-incompatibility protocol adopted in these centers [75-78]. Although ABO incompatible LDLT may be carried out with relative safety in infants <1 year old using standard immunosuppression, yet, it carries increased risk of graft failure in older patients and should be used only in urgent cases and/or when they are the only available donors.
捐赠者的年龄和性别:肝移植的危险因素在国际文献中得到了广泛的研究。匹兹堡组研究了供体年龄和性别对尸体肝移植移植结果的影响。他们发现,捐赠者年龄的影响只有在他们超过45岁时才变得明显。他们还发现,女性供者的肝脏移植效果明显较差,女性供者对男性受体的2年移植存活率为55%(范围为45%至67%);女性供者对女性受者,64%(范围54%至77%);男性供体对男性受体,72%(范围66%至78%);男性供体对女性受体的比例为78%(70% ~ 88%)[79]。Ikegami研究了供体年龄对LDLT的影响。他发现,中年人(30-50岁)和老年供者(>50岁)的肝移植在1个月时恢复的体积可达标准肝体积(SLV)的80%,而年轻供者(<30岁)的肝移植在移植后仅1周内恢复的体积也可达标准肝体积的80.0%。这些结果表明,在年轻的肝脏中,肝脏再生比在年老的肝脏中发生得更早,进行得更快。 He also found significant prolongation of prothrombin time values in POD 3 in the grafts obtained from aged donors than those from younger ones [80]. Kimura also reported reduced capacity in protein synthesis in hepatic grafts obtained from aged donors [81]. Old age and female gender should be considered as risk factors in LDLT. They are considered more risky if they are additive such as in old female donors. However, they should not be discarded from donation in the face of shortage of liver donors.
受者在移植时的状态:器官共享联合网络(UNOS)现状:被认为是移植物和患者生存的危险因素。FHF属于器官共享联合网络(UNOS)状态1,据报道,根据疾病原因和患者年龄,儿童死亡率在70-95%之间[82]。由于FHF患儿在等待尸体同种异体移植时可能会出现器官衰竭和不可逆神经损伤的进展,因此在等待尸体移植时,尽早进行LDLT手术是至关重要的。1994年Tanaka首次尝试将LDLT作为儿童FHF的一种治疗模式[83],他报道了3例儿童FHF患者,所有患者均接受左叶肝移植,估计为体重的0.8-1.0%,并成功出院。1998年,同一组报告了11例儿童的随访结果,平均随访28个月(13-67个月),生存率为73.0%[84]。在东部[85]和西部[86]的儿科患者中也报道了类似的结果。Mack在2001年报道了一项回顾性研究,对19例FHF合并多器官衰竭(MOF)的儿童患者进行了LDLT和接受尸体同种异体移植(CAD)的相似组患者的结果进行了比较。与CAD组相比,LDLT组患者的生存率明显提高。LDLT组的30天和6个月生存率分别为88.0%和63.0%,而CAD组分别为45.0%和27.0%。他认为,生存结果的差异与LDLT受体比CAD受体等待移植的时间和冷缺血时间更短有关[87]。 The application of LDLT in FHF in adults was first addressed by Lo in 1999 who reported that when cadaveric organ donation is scarce, emergency LDLT can be applied to high urgency adult patients [88]. Nishizaki suggested that a high success rate of LDLT and low donor risk could be achieved in adult patients with FHF using a left lobe graft. He reported 15 adult patients with FHF treated with a left lobe graft which corresponded to 23.0-54.0% of recipients’ standard liver volume. The overall survival rate was 80.0% with a follow-up period from 3-43 months. He also reported no significant differences in survival outcomes comparing the patients with a liver graft to a standard liver volume ratio of <30.0% and those with a ratio of ≥ 30.0% [89]. In the lights of these studies, it appears that, the results of LDLT in adult patients with FHF were superior to those in pediatric patients. The difference may be related to the cause of the disease, incidence of rejection and the rate of postoperative complications. Testa reported the results of 7 patients who had acute-on-chronic liver failure and underwent urgent LDLT using right lobe grafts. Patient and graft survival rates were only 43.0% at a mean follow-up of 15.1 months [90].
关于MELD分数:作为肝移植失败的危险因素。Freeman在2003年[91]表明,当MELD得分低于10甚至可能低于14分时,接受者几乎无法获得终身受益。移植时MELD评分大于25分的候选人,移植后死亡率的相对风险开始增加。因此,MELD得分在14-25之间的候选人似乎获得了最多的终身受益。这些似乎是成人LDLT的理想候选者。
乙肝相关肝病患者进行肝移植后,复发性移植物感染和移植物衰竭的发生率很高[92]。因此,许多移植中心不愿意考虑乙肝病毒相关肝病患者进行移植。在Markowitz引入高剂量HBIG和拉米夫定联合预防HBV复发的方案后,结果开始改善。他报道了移植前HBV-DNA阳性的10例患者中有4例,在中位随访近1年时HBsAg和HBV-DNA均为阴性[93]。为了减轻高剂量终身HBIG的经济负担,移植后连续2年使用HBIG治疗,再加上拉米夫定单药治疗,可有效预防移植前病毒复制水平低的患者再次感染[94]。
据报道,在尸体肝移植中,慢性hcv相关性肝硬化引起的慢性终末期肝病患者的肝移植后会出现严重的移植物损伤,在LDLT中甚至更多[95,96]。提示移植物损伤的原因是移植物中HCV感染的复发。通过ALT升高、HCV-RNA检测和肝活检诊断疾病复发[97]。对UNOS数据库的分析显示,初次移植后hcv阳性患者的5年生存率显著降低[98]。加州大学洛杉矶分校(UCLA)的移植组观察到86.0%的hcv感染的LDLT受体复发肝炎,而尸体移植受体只有30.0%。HCV平均复发时间为4.75个月[95]。哥伦比亚大学组报告了类似的结果,平均随访19个月,80.0%的LDLT受体复发HCV,而尸体受体为58.0% (p值<0.05)[96]。众所周知,在急性排斥反应治疗中使用大剂量甲基强的松龙可增加HCV复发和纤维化进展[99]。为了降低HCV的复发率和进展率,京都组开始了对HCV终末期肝衰竭患者进行无类固醇免疫抑制的方案。使用他克莫司单药治疗而不使用霉酚酸酯,因为已证明使用霉酚酸酯可导致更严重的复发[100]。 The key point in the management of transplanted patients affected with HCV infection is the regular follow up of transplanted patients to detect early recurrence by PCR and the application of the treatment protocol to guard against the development of liver cirrhosis in the graft and subsequent failure. It is suggested that treatment of LDLT recipients before transplantation may prevent HCV recurrence after transplantation [101]. In a study involving 21 patients receiving a prophylactic treatment by interferon (IFN) and ribavirin (RBV), liver histology was normal in 81.0% of patients one year after transplantation, and virological clearance was observed in 41.0% of patients [102]. Leucopenia and thrombopenia were noted in all studies and resulted in dose reduction in some patients. Moreover, in the early report of Feray, chronic rejection may occur in patients under treatment [103].
肝细胞癌中肝移植被认为是比切除更好的治疗方法。这种想法是基于这样一个事实,即超过90.0%的病例在潜在肝硬化的情况下发生HCC,最常见的原因是慢性乙型或丙型肝炎[104,105]。由于肿瘤的多中心性,这些病例切除后几年内继发病变的发生率很高[106]。在这种情况下,移植是一种合乎逻辑的方法,因为它可能同时治愈肝硬化和HCC[107,108]。尸体肝移植治疗HCC的主要缺点之一是患者必须等待肝脏移植[109,110]。这种等待时间会影响移植的结果,因为在等待时间内疾病可能会发生进展。成人LDLT的最新发展为移植提供了另一种供肝来源,这与等待时间或UNOS标准无关。对于有活体供体的患者,供体器官不是稀缺资源[111,112]。目前尸体供体计划的选择标准是基于肿瘤特征的回顾性分析,并且只将移植分配给满足米兰标准的患者[113]。这些标准提供的移植结果与非HCC患者的移植结果相似。 These criteria are based on tumor size and number. Single tumors must be <5cm in diameter, if more than one lesion is present, the maximum number of tumors must be 3 or less and none of them is >3cm in diameter. The rationale behind the use of these criteria is to preserve the outcome in HCC as compared with non-HCC patients so that organ use is optimized [114]. Because LDLT has been a successful and fully accepted treatment for adult patients with end-stage liver disease, interest in this modality as the treatment for HCC has risen. More liberal criteria has been suggested based on the premise that the outcomes of these expanded criteria are similar to those of the more conservative criteria in terms of post-transplantation survival [115-117]. Based on these studies, LDLT was proposed for expanded criteria with little adverse effect on outcome. The pilot study on LDLT for HCC was started in February 1999 in Kyoto University with an approval from the institutional ethical committee with inclusion criteria consisting of otherwise untreatable HCC with complete exclusion of extra-hepatic lesion or macroscopic vascular invasion, irrespective of tumor size and number [13,118]. Some studies demonstrated favorable results in the patients fulfilling these selection criteria and concluded that Milan criteria do not seem to be suitable for selecting HCC patients for LDLT [118,119]. Similar results were reported by Yao, who concluded that the Milan criteria may be expanded with excellent survival in LDLT [120]. From these studies, it is clearly demonstrated that patients with HCC outside the Milan criteria and excluded from cadaveric donor transplantation could survive nearly the same as patients with HCC within Milan criteria in LDLT programs. Therefore, the application of the Milan criteria for all patients with HCC would have denied many patients who can survive after transplantation. Therefore, transplantation is by far the best treatment option for patients with HCC, if a careful search reveals no extra-hepatic disease. In LDLT programs, where the patient has his special living donor, the UNOS and Milan criteria are not necessarily relevant.
就技术而言,LDLT与尸体lt相比是一项复杂的手术。全面了解肝脏、肝动脉、肝静脉、门静脉和胆管系统的节段解剖结构,并能够识别这种解剖结构中的变异,对于成功和安全地进行LDLT至关重要。通过对尸体肝脏的仔细解剖和肝脏腐蚀铸型的检查,详细描述了这一过程中遇到的各种解剖变异[121-123]。尽管如此,在不同的中心仍然报告了许多技术并发症,这些并发症可能严重到足以导致移植物衰竭和死亡。肝动脉血栓形成(HAT)是最常见也是最关键的血管并发症[124-126]。12.0%的成人和超过40.0%的儿科受体发生此病[126,127]。HAT可导致肝坏死、胆道渗漏或狭窄,最终导致脓毒症复发[128]。早期诊断和及时干预是必要的,因为在大多数情况下需要紧急再移植。11.0%的肝受体存在肝动脉狭窄(HAS)。它通常局限于吻合部位。在大多数情况下,它是由技术故障引起的,导致血管内膜损伤,随后出现坏死和瘢痕形成。 Tight anastomosis can reduce blood flow, which favors arterial thrombosis. In some cases arterial stenosis per se represent an indication of retransplantation [129]. Portal vein thrombosis (PVT) is one of the life threatening complications of liver transplantation, especially when occurs in the immediate postoperative period [130,131]. Acute PVT may lead to portal hypertension or hepatic ischemia with catastrophic sequelae. Late-onset PVT, on the other hand, is generally well tolerated, although it may eventually lead to graft compromise requiring aggressive intervention [132]. Portal vein stenosis (PVS) usually develops slowly after transplantation, and it is suggested by the presence of gastrointestinal varices, ascites and splenomegaly. It is diagnosed by Doppler ultrasonography in asymptomatic cases [133]. Thrombosis or stenosis of the portal venous trunk may be observed in 1.0% to 12.5% liver recipients [126,133,134]. Abnormal blood flow through the portal vein may be caused by technical error, coagulation disorders, previous surgical interventions (splenectomy) or damage of the endothelium of the portal vein during cannulation [126,127,134]. Hepatic venous outflow obstruction may occur due to stenosis and/or thrombosis mainly at the anastomotic site or sites. Several potential mechanisms could be implicated as the cause of anastomotic hepatic vein stenosis. Technical failure is the most likely cause such as tight anastomosis causing purse-string phenomenon, stitches catching the back wall or additional stitches for hemostasis. Twisting of the outflow vessel of the left lobe graft secondary to its displacement to the empty right liver fossa occurring upon closure of the abdominal wall may be another cause of hepatic venous outflow obstruction [135]. A third cause may be the structural stenosis of the hepatic vein secondary to enlargement of the graft during the process of regeneration. Hepatic venous outflow obstruction may lead to cirrhosis of the graft if such obstruction continues to be present for a long time. The recent introduction of microsurgical techniques for arterial anastomosis in LDLT has greatly reduced the incidence of HAT compared with previous reports [60,135]. From these studies it was concluded that vascular thrombosis occurs mostly during hospital stay and may be responsible for early graft failure, while vascular stenosis appeared late in increasing frequency as the period of follow up increases and may be responsible for of late graft failure [136].
LDLT后的胆道并发症仍然是最常见的发病原因,并可能导致受体死亡。据报道,胆漏、胆囊瘤和狭窄等并发症的发生率为10.0%至30.0%[137-140]。这些并发症主要归因于缺血和技术故障[141]。由于LDLT患者胆道并发症的普遍存在,建议采取预防措施以降低这些并发症的发生率。众所周知,吻合口周围的缺血性改变是吻合口狭窄的主要原因,因此应更加注意保存供体切除胆管周围的胆周神经丛。
尽管最近免疫抑制疗法有所改善,但肝移植排斥反应仍然是肝移植患者发病和移植物丢失的主要原因[142-145]。体液性排斥反应(HR)是移植后早期发生的罕见并发症,通常是致命的。对于HR没有特殊的治疗方法,拯救患者生命的唯一方法是紧急再移植。因此,预防这种疾病是必不可少的,如果可能的话,可以通过选择abo相同或abo相容的供体来实现。慢性排斥反应(CR)是一种惰性的,但进行性的同种异体移植损伤,通常是不可逆的,最终导致大多数带血管的实体器官移植失败。据报道,移植后5年,心脏、肺、胰腺和肾脏异体移植受者中有多达30-50%的人会发生这种情况,而肝移植受者中只有4-8%的人会发生这种情况[146]。同种异体肝脏移植与其他实体器官的不同之处在于,CR是潜在可逆的。这种特性通常归因于肝脏独特的免疫生物学特性和胆管的再生能力,胆管是CR的主要靶点之一[147-149]。CR可在肝移植后3周内发生,命名为急性胆管消失综合征[150]。但多发生在2个月后,通常在1年内[151152]。 Late onset (later than 1 year) CR is typically seen in inadequately immunosuppressed recipients, either as a result of non-compliance or intentionally attenuated immunosuppression [151]. If the findings indicate a late stage of CR, retransplantation is preferable to too-potent immunosuppression, which may cause fatal infectious complications [151]. CR of a liver allograft may be reversible to some extent. This result was reported in world literature [147,148,153,154]. This reversibility usually occurs before the duct loss or obliterative arteriopathy have become severe. Some patients with CR was found to have experienced one or more episodes of ACR. This may evolve directly from inadequately controlled ACR episodes as reported in some literatures [142,154,155]. The results also show a lower incidence of CR in liver allografts compared to other vascularized allografts. This has been explained by the immunological theories of the so called hepatic tolerogenesity [156]. Graft-versus-host disease (GVHD) is a rare complication that occurs after LT. Smith reported 12 cases of GVHD among 1082 LT done between 1991 and 1998 at Baylor University Medical Center [157]. GVHD is usually a fatal disease and future approaches should focus on its prevention. This can be achieved by HLA matching before LDLT because the donors of all cases of GVHD were of HLA homozygous. Additional risk factors were reported by other authors and include, recipients older than 65 years and recipients of donors more than 40 years younger than the recipients [157].
肝移植后的感染问题是技术上成功肝移植后最严重和最困难的并发症之一。目前,感染是肝移植后死亡的主要原因[158]。受者容易受到感染,而感染通常是由身体的内在防御机制控制的。预防和治疗排斥反应所需的特异性免疫抑制治疗是这些患者的主要危险因素,并为机会性细菌、病毒或真菌在这些患者中引起感染铺平了道路。移植中心间肝移植后细菌感染的发生率差异很大,在35.0% - 68.0%之间[159-163]。细菌感染发生的时间显示,大多数细菌感染发生在术后即刻和住院期间。据报道,不同中心的LD术后早期细菌感染发生率较高[161163]。这可能是由于在此期间给予了强烈的免疫抑制治疗,以防止气管内管、导尿管和静脉导管引起的排斥反应和菌血症的存在。此外,在此期间,移植物的缺血性和胆道并发症发生率更高。肝移植细菌感染的危险在于诊断困难。由于患者的免疫抑制状态,感染的通常体征和症状可能被掩盖或不存在[164]。 In addition, clinical manifestations of graft ischemia or graft rejection can mimic those of infection. Bacterial infections can be severe enough to result in septic shock, multiple organ failure (MOF) and death. The incidence of invasive fungal infection was reported to be lower than in other centers which reported a range between 4.0% - 48.0% [165-167]. Mortality rate was reported to be 50.0% to 80.0% in the presence of fungal infection [163,165,168]. They stated that prolonged operative time, increased intra-operative transfusion requirements, choledochojejunostomy, prolonged hospitalization, graft failure and retransplantation, vascular and gastrointestinal complications, recurrent bacterial infections and extended use of antibiotics beyond the first week after transplantation were risk factors for the development of fungal infection. They recommended the prophylactic use of intravenous amphotericin B to prevent postoperative fungal infection in these patients. Cytomegalovirus (CMV) infection was reported to be 18.0% to 40.0% of patients [169,170]. Most of CMV infection occurs early usually between 3 and 8 weeks after LT [171-173]. The early occurrence of CMV infection may be related to the intense immunosuppressive therapy during this period to prevent or treat episodes of rejection. Epstein bar virus (EBV) infection came next in frequency to CMV infection. More cases of EBV infection occur late after patient discharge. The real problem in EBV infection is that it is a B cell lymphotropic virus capable of inducing proliferative changes leading to post-transplantation lymphoproliferative disorder (PTLD) and frank lymphoma. Over-immunosuppressive therapy was considered as a risk factor in the development of PTLD. Therefore, these patients responded well to cessation of immunosuppression together with large doses of intravenous acyclovir. Accurate diagnosis and early treatment of EBV infection remain elusive to guard against development of EBV-associated PTLD. Sometimes this management is not sufficient and the disease may result in patient death [174].
随着LD后患者生存率的提高,疾病复发率已成为主要关注的领域。复发率因原发性肝病而有很大差异。由于许多终末期肝脏疾病是由宿主或环境因素引起的[175-177],大多数接受移植的患者都会在某个时间点复发。另一方面,大多数代谢性肝病在移植后不会复发,因为它们主要局限于肝脏,可以说是真正治愈了。一些研究发现,慢性肝移植后复发疾病的发生率为10.0%[157,178]。疾病复发率随随访时间的延长而增加。据报道,某些因素会导致HCV复发率增加,如病毒载量高、供者年龄增加以及在LDLT而非尸体肝移植的情况下[179]。PEG-IFN和利巴韦林联合治疗在肝移植患者复发性HCV感染期间可能具有良好的耐受性和益处[180]。据报道,40.0%的肝移植患者出现HBV复发,并且病毒对拉米夫定治疗产生耐药性[157]。现在有越来越多的证据表明,通过适当的治疗,可以显著降低HBV复发的复发率。另有研究显示复发率为12.7%[181]。 HCC recurrence was detected by continuing elevation of the level of alpha-fetoprotein in the regular follow-up of the patient, confirmed by US detection of the recurrence in the graft. Additional investigations, including chest X-ray and brain scan, proved the presence of metastases. HCC recurrence represents a major risk factor in both graft failure and patient survival. The rate of recurrence of HCC after LT was dependent on the preoperative stage of the disease. Recurrent primary sclerosing cholangitis (PSC) was reported to be 20.0% [182,183] The clinical significance of recurrent PSC is that patients develop biliary strictures and it can mimic ductopenic rejection in presentation. Diagnosis relied on ERCP and liver biopsy. Single, dominant strictures in recurrent PSC are frequently amenable to dilatation. More extensive stricturing may require extensive surgical biliary reconstruction. Recurrent primary biliary cirrhosis (PBC) was reported to occur in 12.0% [184]. The detection was prompted by abnormal liver function tests on routine monitoring. Longer follow-up may be required to determine the clinical significance of recurrent PBC. Recurrent autoimmune hepatitis (AIH) was reported to occur between 25.0-33.0% [185]. The clinical presentation of recurrence is characterized by increased transaminases (particularly AST) coupled with an increase in the serum IgG level and the presence of anti-liver specific proteins or smooth muscle antibodies. Recurrence of AIH can be precipitated by the withdrawal of prednisolone from the immunosuppressive regimen and long-term corticosteroids are usually required in these situations [186].
移植失败仍然是一个重要的问题,因为它会导致患者死亡或再次移植。世界文献报道的移植物失败率在9.0%-27.0%之间[187-190]。移植失败分为早期(1个月内发生)和晚期(1个月后发生)。据报道,原发性无功能(PNF)是尸体肝移植早期移植物衰竭最常见的原因[190],但由于冷缺血时间短,在LDLT中未发生。导致LDLT患者早期移植物失败率低的因素根据年龄、性别、体重指数(BMI)和abo -相容性选择最佳供体;供肝节段切除术的计算机辅助规划与决策及最佳GRWR冷缺血时间短;中心拥有高水平的专业知识;及时发现导致早期移植失败的血管、胆道和免疫并发症,并进行早期有效的处理。 Late graft failure cause were reported in many studies [150,191-193]. Most of the underlying causes of late graft failure include patients with CR which were not responding to treatment and patients with disease recurrence which is unavoidable. Therefore, both these complications constitute real problems in liver transplantation.
在肝移植领域,可能需要再移植来处理早期和晚期移植失败的患者。与初次移植相比,肝脏再移植被认为是移植物和患者生存的危险因素。2003年Rosen发现,年龄、血清胆红素、肌酐、初次移植后的时间间隔以及UNOS状态是再次移植患者预后的预测因素[178]。2004年,Postma研究了55例成人再移植患者[194]。他发现,移植前不良预后的重要危险因素包括HAT以外的移植指征(尤其是CR)、高肌酐水平、高胆红素水平和低凝血酶原水平(高INR)。他还发现,移植时代影响了存活率;1年和5年生存率分别由1996年前的56.0%和48.0%提高到1996年后的89.0%和81.0%。这显然与克服解剖失败的移植物及其血管的技术困难所获得的经验有关。他的结论是,再移植后的存活率逐年提高,目前已经相当接近于选择性初次移植的结果。进一步的改善可能是在实际再移植前改善肾功能。 The advances in surgical and medical care of recipients which were achieved in recent years have significantly improved patient and graft survival after the primary transplantation [195]. This situation may give a chance for the original disease to recur in the graft. Therefore, the real problem in the future will be the increase in the number of cases needing retransplantation. Efforts are needed to reduce the risk factors before retransplantation in order to obtain better patient and graft survival. However, this aim may be difficult to obtain because after primary LDLT, donor candidates among the recipient’s family will be limited, forcing the selection of marginal donors (older donors, ABO-incompatible donors, small-for-size or steatotic grafts). This situation is undoubtly will be responsible for the significant graft failure and patient mortality obtained in cases of retransplantation.
细菌感染是早期患者死亡的主要原因。移植物衰竭是第二大死亡原因。大多数死亡发生在住院期间。这种高住院死亡率可能与患者的术前状态、手术因素(手术时间、出血量、输血量、冷缺血时间、虫缺血时间)以及术后即刻进行强烈的免疫抑制治疗有关。接受者的年龄是死亡率的一个重要因素。与儿童患者相比,成人患者较差的结果可能与通常在成人患者中进行的右叶移植物相关的常见并发症以及小尺寸移植物的问题有关。UNOS状态2a是终末期肝病患者死亡率的重要因素。移植失败患者的再移植是患者死亡率的重要因素[196]。这可能与术前状态不佳、手术困难以及暴露于强免疫抑制治疗的并发症有关。右叶移植是导致患者死亡的重要因素。 This may be due to the high rate of vascular and biliary variations in the right lobe grafts, technical difficulties in the process of transplantation and the high incidence of postoperative complications.
研究了多种因素作为移植物衰竭的危险因素.导致LDLT早期移植物失败率低的因素包括:考虑年龄、性别、体重指数(BMI)和abo -相容性的最佳供体选择;供肝节段切除术的计算机辅助规划与决策及最佳GRWR冷缺血时间短;中心拥有高水平的专业知识;及时发现导致早期移植失败的血管、胆道和免疫并发症,并进行早期有效的处理。晚期移植物衰竭的潜在危险因素包括对治疗无效的CR患者和不可避免的疾病复发患者。因此,这两种并发症构成了肝移植的真正问题。
重要的是要记住,成功的肝移植并不能使患者恢复正常。而是一种新的疾病“肝移植”取代了以前的疾病。然而,与肝病晚期相比,这种新状态使患者有机会获得长期生存和更正常的生活方式。肝移植后,患者必须终生服用免疫抑制药物。停用处方药物可能导致排斥反应和患者病情迅速恶化。
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收稿日期:2018年10月12日
接受日期:2018年11月20日
发布日期:2018年11月23日
©2018 Azzam A.这是一篇根据知识共享署名许可条款发布的开放获取文章,允许在任何媒体上不受限制地使用、分发和复制,前提是注明原作者和来源。
活体供肝移植(LDLT)术后肝移植衰竭、发病率和死亡率的危险因素:综述文章。临床试验4:DOI: 10.15761/CRT.1000242
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