Endoscopic management of biliary strictures after living donor liver transplantation
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Living donor liver transplantation (LDLT) is an effective alternative to deceased liver transplantation (DDLT) for end-stage liver disease. Although advances in surgical techniques, immunosuppressive management, and post-transplant care have improved the overall outcomes of LDLT, biliary strictures remain the major unsolved problem. Endoscopic retrograde cholangiopancreatography (ERCP) is currently considered the first-line therapy for biliary strictures following LDLT with duct-to-duct reconstruction, with percutaneous and surgical interventions reserved for patients with unsuccessful management via ERCP. Endoscopic management of biliary strictures is technically more challenging in LDLT than in DDLT because of the complexity of the biliary anastomosis, in addition to the tortuous and angulated biliary system. Placement of one or more plastic stents after balloon dilation has been the standard strategy for post-LDLT stricture, but this requires multiple stent exchange to prevent stent occlusion until stricture resolution. Inside stents might prevent duodenobiliary reflux and thus have longer stent patency, obviating the need for multiple ERCPs. Newly developed covered self-expandable metallic stents with anti-migration systems are alternatives to the placement of multiple plastic stents. With the advent of deep enteroscopy, biliary strictures in LDLT patients with Roux-en-Y hepaticojejunostomy are now treatable endoscopically. In this review, we discuss the short- and long-term outcomes of endoscopic management of post-LDLT strictures as well as recent advances in this field.
KeywordsLiving donor liver transplantation Biliary complication Biliary stricture Endoscopic retrograde cholangiopancreatography Biliary stent
Living donor liver transplantation
Deceased donor liver transplantation
Endoscopic retrograde cholangiopancreatography
Biliary anastomotic stricture
Randomized controlled trial
Magnetic resonance cholangiopancreatography
Drip-infusion cholangiography with CT
Percutaneous transhepatic biliary drainage
Self-expandable metallic stent
Liver transplantation is the treatment of choice for selected patients with end-stage liver disease and hepatocellular carcinoma, and can offer the hope of survival to patients in danger of imminent death. Because of the scarcity of deceased-donor organs as well as the increasing number of patients on the waiting list, living donor liver transplantation (LDLT) is performed as an alternative to deceased donor liver transplantation (DDLT) . Compared to DDLT using a whole liver, LDLT is technically more complex and challenging. Although refinements in surgical techniques, immunosuppressive management, and post-operative care have led to improved outcomes for LDLT [2, 3, 4], biliary complications, particularly biliary strictures, still develop in a substantial proportion of LDLT patients [5, 6, 7, 8, 9, 10, 11, 12]. Biliary strictures affect long-term LDLT recipient outcomes and quality of life and can cause graft loss and even mortality [12, 13].
Roux-en-Y hepaticojejunostomy (RYHJ) was previously the standard biliary reconstruction technique used in LDLT patients. However, in recent years, duct-to-duct (DD) biliary reconstruction has been the preferred method over RYHJ [6, 14, 15, 16] because of its simplicity, rapid gastrointestinal recovery, lower risk of bacterial colonization of the biliary tract, and preservation of physiological bilioenteric and bowel continuity [4, 15]. In addition, DD biliary reconstruction allows easier endoscopic access to the biliary system for the evaluation and management of biliary strictures following liver transplantation. Thus, endoscopic retrograde cholangiopancreatography (ERCP) is currently performed as the first-line treatment modality for post-LDLT biliary strictures . Nevertheless, endoscopic management of biliary strictures is technically more difficult in LDLT than in DDLT, principally because of the difference in the type of graft used (partial vs whole size) and the method of biliary reconstruction. Compared to DDLT, the DD biliary anastomosis is more peripheral, smaller, and more complex in LDLT [5, 16, 18], and the reconstructed bile duct in LDLT is sometimes tortuous and angulated due to hypertrophy of the transplanted liver . Therefore, the strategies and outcomes of endoscopic management of biliary strictures after DDLT cannot be applied to LDLT patients [13, 19].
In this review, we focus on the status of endoscopic management of biliary strictures after LDLT. We also summarize recent advances in endoscopic techniques for management of this complication.
Incidence and risk factors of biliary strictures after LDLT
Incidence of biliary complications after LDLT
Overall biliary complications
Gondolesi et al. 
Hwang et al. 
Morioka et al. 
Shah et al. 
Kyoden et al. 
Chang et al. 
Zimmerman et al. 
Biliary strictures usually occur at the anastomosis (biliary anastomotic stricture; BAS), and non-BAS after LDLT is relatively rare. At Kyoto University, non-BAS occurred in 5 of 273 right-liver LDLT patients (2%), accounting for 6% of all biliary strictures . Chang et al. reported that among 339 patients undergoing right-liver LDLT, all of the biliary strictures and non-BAS developed in 121 (36%) and 11 (10%), respectively . At the Mayo Clinic Hospital in Arizona, ischemic-type strictures were observed in 3 of 110 LDLT patients (3%) .
Etiologies and risk factors for biliary strictures after LDLT
Biliary strictures occur more frequently after LDLT than after DDLT [12, 27, 28, 29]. Compared to DDLT, a partial graft has a smaller bile duct diameter and sometimes multiple biliary openings, rendering biliary reconstruction in LDLT complex and technically demanding. In a systematic review by Akamatsu et al., while there were no significant differences in the incidence of bile leakage between LDLT and DDLT (9.5 vs 7.8%), the incidence of BAS was significantly higher in LDLT patients than in DDLT patients (19 vs 12%) .
Various factors may be associated with the development of post-LDLT biliary strictures. These include recipient, graft, technical, inflammatory, ischemic, and immunological factors, which may act independently or synergistically in stricture development. Because bile duct epithelial cells (cholangiocytes) are vulnerable to ischemic and reperfusion injury , local ischemic change around the biliary anastomosis, particularly due to devascularization of the bile duct at the hilar dissection of the graft, is believed to be a major contributor to BAS. Another important risk factor for BAS is bile leakage [11, 23, 31, 32], which causes peribiliary inflammation and subsequent fibrosis, leading to stricture formation at the anastomosis.
Other risk factors for BAS identified in multivariate analyses include donor age >50 years , preoperative MELD score ≥35 , urgency of the surgery , bile duct diameter , a graft with multiple bile ducts , graft cold ischemia time [24, 34], hepatic artery stenosis , and acute cellular rejection . Whether the biliary reconstruction technique affects the development of BAS is controversial. A retrospective study of 310 adult LDLTs at the University of Tokyo identified DD biliary reconstruction as the only significant risk factor for biliary strictures by univariate analyses . The Kyoto group also reported that the biliary stricture rate was significantly higher in DD biliary reconstruction . Both Seoul University  and Hong Kong University  studies, however, found no significant difference between DD biliary reconstruction and RYHJ in terms of the incidence of biliary strictures by multivariate analyses. A prospective randomized control trial (RCT) is needed to clarify this issue.
Hepatic artery thrombosis or stenosis is considered an important risk factor for non-BAS . Immunological factors (e.g., ABO blood type incompatibility [37, 38] and cytomegalovirus infection ) are also associated with non-BAS formation. Because cholangiocytes play an important role in mucosal immunity in the biliary system [40, 41], they are the primary targets of immune attack, which leads to stricture formation.
The surgeon’s experience might affect biliary strictures after LDLT. The Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL), a multicenter study conducted in the United States , found that liver transplant recipients at centers with higher volumes of LDLT were less likely to develop biliary strictures. Kim et al. at Samsung Medical Center, however, found no significant differences in the incidence of biliary stricture with experience, while they showed that bile leakage occurred more frequently in the LDLT patients of the junior surgeon than those of the senior surgeon .
Diagnosis of biliary strictures after LDLT
The majority of biliary strictures develop within the first year after transplantation, but their onset can be delayed for many years after LDLT . The clinical presentation of biliary strictures is highly variable; patients may remain asymptomatic despite the presence of biliary strictures , or present with anorexia, pruritus, fever, abdominal pain, or jaundice. In asymptomatic LDLT patients, abnormal liver function tests, such as elevated bilirubin and alkaline phosphatase, should raise suspicion of biliary strictures. In LDLT patients with cholestasis, the priority is to differentiate biliary obstruction from liver parenchymal causes including acute or chronic rejection, recurrence of the primary disease, and drug-induced liver injury.
Endoscopic management of biliary strictures after LDLT
ERCP has become the first-line modality for the management of biliary strictures after LDLT; percutaneous transhepatic biliary drainage (PTBD) and surgery are reserved for cases in which an endoscopic approach is unsuccessful or the biliary reconstruction is RYHJ . With the recent advent of balloon-assisted enteroscopy, biliary complications in LDLT patients with RY anastomosis are now endoscopically treatable. Before performing ERCP, it is mandatory for endoscopists to review the details of the biliary reconstruction record as well as MRCP and/or CT performed prior to ERCP . In addition, endoscopists must understand the normal anatomy and potential variation in the biliary system . Such knowledge will decrease the procedure time and increase the success rate of complex endoscopic procedures.
Endoscopic management of biliary strictures consists of passing the stricture with a guide wire, balloon dilation, and placement of one or more stents. Passing the stricture with a guide wire is a fundamental prerequisite for technical success of endoscopic stricture management. In LDLT patients, the strictures are often very tight and twisted due to the presence of dense fibrotic tissue and the hypertrophic transplanted liver, rendering this procedure challenging. At the University of Okayama, a guide wire could not be traversed across the stricture in 7 (17%) of 41 patients with biliary stricture . The Seoul National University  and Mayo Clinic Hospital in Arizona  reported that the incidence of failed guide wire passage through the stricture was 38% (10/26 patients) and 16% (6/38 patients), respectively. At the University of Tokyo, it was impossible to pass various guide wires through the stricture in 3 (18%) of 17 patients with BAS and non-BAS . Combination use of a bendable ERCP catheter (SwingTip cannula; Olympus EndoTherapy, Tokyo, Japan) and an angle-tip hydrophilic guide wire with high torque control (e.g., Radifocus Guidewire; Terumo, Tokyo, Japan) can assist negotiation of difficult strictures. In LDLT patients with difficult-to-pass strictures by conventional methods, a single-operator peroral cholangioscopy (SpyGlass System; Boston Scientific, Natick, MA, USA) may enable passage of a guide wire through the stricture under direct visualization [55, 56]. Woo et al. reported that the SpyGlass was helpful in passage of a guide wire in 9 (60%) of 15 LDLT patients with unsuccessful conventional methods . Interestingly, a recent report suggests that cholangioscopic findings help predict the response to endoscopic management of post-DDLT BAS .
After successful passage of a guide wire, a balloon catheter is advanced and positioned across the stricture. The balloon size should be determined based on the diameter of the bile duct just proximal and distal to the stricture. Because both donor and recipient ducts are not generally very dilated in LDLT patients, a 4–8 mm diameter balloon is employed. When a severe stricture does not allow passage of a balloon catheter, a Soehendra Biliary Dilation Catheter (Cook Medical, Winston-Salem, NC, USA) or a Soehendra stent retriever (Cook Medical) is effective for traversing the stricture .
Plastic stent placement
For the endoscopic management of BAS, temporary placement of single or multiple 7–11.5 Fr plastic stents (PSs) is generally recommended after balloon dilation based on the results of DDLT studies, which indicate that balloon dilation alone is less effective for BAS than balloon dilation followed by PS placement [59, 60, 61]. Endoscopic sphincterotomy (EST) is performed at many institutions to prevent post-ERCP pancreatitis, particularly when multiple PSs are placed across the papilla. Similar to the protocols for benign biliary strictures in non-transplanted patients, PSs are usually exchanged every 3 months to prevent stent occlusion and subsequent acute cholangitis. In the majority of patients with BAS, PSs are placed for at least 1 year. All of the PSs are removed after a cholangiogram shows that the BAS has resolved.
The results of balloon dilation followed by PS placement for BAS have been variable, with technical endoscopic and final endoscopic success rates ranging from 40−84% and from 20−100%, respectively [26, 28, 31, 33, 54, 62, 63, 64]. Technical endoscopic success is defined as successful placement of biliary stents without the aid of a percutaneous procedure (i.e., rendezvous technique), and final endoscopic success is resolution of BAS after stent removal. To achieve final success, an average of 2.2–6.3 ERCPs was required during an average period of 4.1–14.5 months [26, 31, 54, 62, 63, 64]. At Okayama University, an institution dedicated to endoscopic management of complex malignant hilar obstruction [65, 66], technical endoscopic success and final endoscopic success were achieved in 31 (76%) and 21 (51%) of 41 LDLT patients with BAS, respectively . Their management strategy appeared to be relatively conservative; among 35 patients with eventual endoscopic success, they placed a single PS in 26 patients and two PSs in the remaining 9 because of technical difficulty as well as concern over the risk of stent-induced cholangitis/abscess. Hsieh et al. recently reported that a more aggressive strategy with PSs after EST and balloon dilation had an 84% (32/38 LDLT patients with strictures) technical endoscopic success rate and a 100% final endoscopic success rate . In their study, the interval between LDLT and BAS development was relatively short (median 2.1 months), which might be related to the outcome [64, 67]. Their impressive result has not been reproduced, likely because the small donor bile duct and angulated biliary system in LDLT patients often preclude the deployment of multiple PSs [19, 54].
Inside stent placement
In general, PSs are placed across the papilla, with their distal end exposed into the duodenum. This provokes free reflux of duodenal contents through the stent, which is considered the main cause of stent occlusion [68, 69]. Therefore, PSs usually require prophylactic exchange every 2–4 months, particularly in immunocompromised LDLT patients, causing increased cost and patient burden. In addition, EST is generally performed prior to placement of a large-bore PS or multiple PSs to prevent obstruction of pancreatic outflow with resultant acute pancreatitis. EST results in permanent loss of sphincter of Oddi function [70, 71], leading to subsequent duodenobiliary reflux and bacterial colonization of the biliary system . Consequently, EST can diminish one of the advantages of DD biliary reconstruction in LDLT patients.
Balloon dilation and nasobiliary catheter placement
Balloon dilation followed by NBC placement also preserves the function of the sphincter of Oddi. At the University of Tokyo, strictures are dilated with a 4–8 mm balloon, followed by placement of a 7 Fr NBC across the stricture to maintain patency . Repeat balloon is performed 5–7 days later and an NBC is left in situ for 1–5 days. We used this protocol as the first-line therapy in 36 (39%) of 93 LDLT patients with biliary strictures [unpublished data]. The cumulative recurrence rate after balloon dilation and NBC placement was high (38.9% at 6 months, 44.4% at 1 year, and 59.9% at 3 years). However, a small number of patients with post-LDLT biliary stricture (15/93; 16% patients) experienced stricture resolution without recurrence using this strategy, which could prevent unnecessary additional ERCPs. Therefore, the patients with post-LDLT strictures that will benefit from balloon dilation and NBC placement should be identified. Disadvantages of NBC placement include patient discomfort, risk of tube withdrawal, prolonged hospitalization, and fluid/electrolyte imbalance.
Self-expandable metallic sent placement
Self-expandable metallic stents (SEMS) were initially developed to overcome the disadvantage of PSs (short stent patency due to small caliber). SEMS with a larger diameter (30 Fr or 10 mm), equivalent to three 10 Fr PSs, have significantly longer patency than PSs for palliation of malignant biliary obstruction. The small pre-deployment diameter of the delivery system facilitates insertion of SEMS. These advantages of SEMS over PSs have resulted in their use for benign biliary strictures. Initial experience of uncovered SEMS for this indication, however, yielded disappointing results because of stent-induced complications such as hyperplastic tissue ingrowth and overgrowth resulting in stent occlusion [81, 82, 83]. Once uncovered SEMS become embedded into the tissue, their endoscopic removal is technically very difficult or impossible . Occluded SEMS further result in biliary stone/sludge formation and recurrent cholangitis . In addition, SEMS present for years in the biliary system might cause serious vascular complications in liver transplant patients . Consequently, uncovered SEMS placement is contraindicated for benign biliary strictures .
Fully covered SEMS are designed to prevent tissue ingrowth through the mesh and have shown efficacy for malignant distal biliary obstruction [88, 89]. Because they are readily removed from the bile duct during ERCP , covered SEMS are more appropriate for benign biliary strictures. In two recent RCTs of covered SESM versus multiple PSs for biliary strictures after DDLT, stricture resolution rates were similar, but covered SEMS required significantly fewer ERCPs to resolve the strictures [91, 92].
A disadvantage of covered SEMS is stent migration . A German RCT demonstrated a 33% incidence of covered SEMS migration in post-DDLT strictures . According to a recent systematic review by Kao et al., the overall SEMS migration rate was 16% . Interestingly, liver transplant patients are more likely to have stent migration than biliary strictures due to other benign causes . Other factors likely to be associated with stent migration include a stricture close to the hilum, a large bile duct below the stricture, and a short stricture . While stent migration occurred spontaneously without the need for further interventions in some cases , it could result in severe consequences . Stent migration might have a negative impact on stricture resolution . Another problem is duodenobiliary reflux when placing a large-diameter covered SEMS across the papilla, which disturbs the physiological status of the biliary system. In addition, EST is required to prevent post-ERCP pancreatitis prior to covered SEMS placement , resulting in loss of sphincter of Oddi function [70, 71].
Endoscopic management of biliary strictures after RYHJ
Risk factors or failed endoscopic management of post-LDLT biliary strictures
Identification of risk factors for failure of endoscopic management is not only helpful for patient risk stratification but also enables use of other treatment modalities (i.e., PTBD or surgery) after unsuccessful management via ERCP. There is general agreement that non-BASs are intractable to endoscopic management [10, 18]. Endoscopic therapy may be more likely to fail in LDLT patients with a history of hepatic artery stenosis  and surgery for bleeding during the first month after liver transplantation , which are potentially related to ischemia, leading to non-BAS formation.
Morphological changes in the biliary tree as well as stricture are strongly associated with the outcome of endoscopic intervention [28, 67, 108, 109]. The Kyoto group found that the crane-neck deformity, sharp angulation of the anastomotic bile duct caused by a severely bent common bile duct, resulted in a poor outcome . In a study by Chok et al., stricture morphology was identified as a significant risk factor for failed endoscopic management of post-LDLT BAS in a multivariate analyses; pouched (round tip) BAS had a significantly lower success rate than other types of BAS (i.e., intermediately pouched and triangular types) . Gomez et al. found that none of the LDLT patients with pouched-type BAS (n = 2) or the crane-neck deformity (n = 3) achieved endoscopic stricture resolution . In addition, Lee et al.  and Kim et al.  showed that LDLT patients with a pouched stricture were at higher risk of endoscopic management failure. It is worth noting that Chok et al. reported a significant association between bile leakage and pouched BAS . Kato et al. identified bile leakage as a risk factor for endoscopic stent deployment failure . Although bile duct kinking rarely occurs in adult LDLT patients with DD biliary anastomosis, it might require surgical intervention (e.g., conversion to RYHJ) .
The timing of endoscopic management, the interval between LDLT and ERCP or between stricture and ERCP, also predicts endoscopic outcome [64, 67]. A delay in the onset or diagnosis of stricture after LDLT might cause a tight stricture, rendering endoscopic management difficult. In addition, experience in endoscopic management in LDLT patients has an impact on stricture resolution by ERCP [11, 33, 64].
Long-term outcomes of endoscopic management of post-LDLT biliary strictures
Because endoscopic management of post-LDLT biliary stricture is a relatively new topic, its long-term outcomes are not fully understood. Among LDLT patients undergoing balloon dilation and/or conventional PS placement, the rate of stricture recurrence has been reported to be 12–30% during a median follow-up period of 9.5–70 months [26, 31, 54, 63, 64]. The majority of recurrent strictures developed within the first year after stent removal. While most recurrent strictures were successfully retreated via ERCP, a small number of patients required PTBD or surgical revision. Hsieh et al., who adopted maximal PS therapy, reported that 79% of patients had no evidence of stricture recurrence during an average follow-up period of 70 months after initial management . In their study, recurrent stricture was observed in eight patients (21%), all of whom were successfully re-treated with the same endoscopic strategy. According to Seo et al., the duration of stent placement was significantly shorter in the recurrence than in the non-recurrence group (11.8 vs 29.0 weeks, p = 0.004) .
The Kyoto group evaluated the long-term outcome of inside stent placement. In their study, once stricture resolution was achieved with inside stents, 90% (73/81) of patients were free of recurrence during a median follow-up of 53.0 months . Strictures recurred in eight patients (10%). Management of recurrent stricture included repeat inside stent (n = 5), endoscopic balloon dilation (n = 1), PTBD (n = 1), and retransplantation (n = 1). At the University of Tokyo, we observed recurrent stricture in 1 (4%) of 25 patients with stricture resolution with inside stents over a median period after stent removal of 52 months [unpublished data].
If strictures are treated adequately, the development of BAS does not affect overall survival after LDLT [9, 24, 31, 33]. Chok et al. reported that there were no significant differences in 1-, 3-, and 5-year graft survival rates between patients with and without BAS . The University of Tokyo also showed that the 3- and 5-year overall survival rates in LDLT patients with biliary complications were not significantly different from those without biliary complications .
Biliary complications remain the Achilles’ heel of LDLT. Despite recent refinements in surgical techniques, immunosuppressive management, and post-LDLT care, biliary strictures still develop in a substantial number of LDLT patients. ERCP is the first-line modality for the management of biliary strictures in LDLT patients with DD biliary reconstruction. Multiple PS placement after balloon dilation is the procedure of choice for post-LDLT biliary strictures, and placement of inside stents is an alternative with longer stent patency. Covered SEMS may be useful particularly in LDLT patients with refractory biliary strictures. Unfortunately, the majority of the reported series in this topic is retrospective and includes small number of LDLT patients with strictures. In addition, there is considerable heterogeneity among centers regarding patient characteristics, biliary reconstruction methods, and endoscopic strategies, making it difficult to give standardized recommendations. RCTs are needed to determine the optimum endoscopic strategy for this challenging group of patients.
Compliance with ethical standards
Conflict of interest
Drs. Tsujino, Isayama, Kogure, Sato, Nakai, and Koike declare that they have no conflict of interest.
All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Informed consent was obtained from all patients for being included in the study.
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