Long-term follow-up of endoscopic therapy for stenosis of the biliobiliary anastomosis associated with orthotopic liver transplantation

Authors


  • The study protocol was approved by the institutional review board.

Address reprint requests to Jörg G. Albert, M.D., Department of Medicine I, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Telephone: +49-69-6301-5297; FAX: +49-69-6301-6247; E-mail: j.albert@med.uni-frankfurt.de

Abstract

Endoscopic treatment for stenosis of an anastomotic biliary stricture (ABS) after orthotopic liver transplantation (OLT) has been proven to be effective and safe, but the long-term outcomes and the risk factors for recurrence are unknown. All 374 patients who underwent OLT at Frankfurt University Hospital were screened for the occurrence of ABSs. ABSs were treated via the endoscopic insertion of a plastic endoprosthesis (29.8%), balloon dilation (12.8%), or a combination of the two (57.4%). The mean follow-up time was 151 weeks, and the mean survival time was 3.4 years. ABSs were observed in 47 patients (12.6%). The mean time from OLT to an ABS was 16.25 months (median = 3.25 months). The cumulative incidence rates for ABSs were 0.09 after 12 months, 0.10/24 m. and 0.11/36 m. In 12 cases (25.5%), ABSs were observed more than 12 months after OLT. ABSs recurred in 16 of the 47 patients (34%). The occurrence of an ABS 6 weeks or more after OLT was a significant predictor of ABS recurrence [P = 0.04, hazard ratio (HR) = 0.235]. There was a trend of hepatitis C virus (HCV) infections being predominant in patients experiencing ABS recurrence (30% for HCV etiology versus 4% for non-HCV etiology) in comparison with patients not experiencing recurrence (36% for HCV etiology versus 30% for non-HCV etiology, P > 0.05). The severity of the initial stricture predicted ABS recurrence (P = 0.046, HR = 2.78), but it did not influence overall survival. The long-term resolution of ABSs was observed in 45 of the 47 patients (95.7%), and ABS recurrence was treated with another attempt (n = 16 or 34%) or 2 more attempts (n = 1) at endoscopic treatment. In conclusion, the long-term success of the endoscopic treatment of ABSs is highly probable if recurrent strictures are again treated endoscopically. ABSs might occur late (>36 months) after OLT, and lifelong follow-up is essential for identifying OLT patients with ABSs. Liver Transpl 19:586–593, 2013. © 2013 AASLD.

Abbreviations
ABS

anastomotic biliary stricture

ERC

endoscopic retrograde cholangiography

ERCP

endoscopic retrograde cholangiopancreatography

HCC

hepatocellular carcinoma

HCV

hepatitis C virus

HR

hazard ratio

ITBL

ischemic-type biliary lesion

LT

liver transplantation

NS

not significant

OLT

orthotopic liver transplantation

PTCD

percutaneous transhepatic cholangiodrainage

Anastomotic biliary strictures (ABSs; ie, strictures of biliobiliary anastomoses) are a major cause of morbidity in patients undergoing orthotopic liver transplantation (OLT), with an incidence ranging from 8% to approximately 20%.[1-3] Many strictures are symptomatic within the first year after OLT, but they may occur later. Risk factors include biliary leakage and issues of surgical technique, but the development of stenosis is incompletely understood. Nonoperative ABS management has become the treatment of first choice, and endoscopic retrograde cholangiography (ERC) and percutaneous transhepatic cholangiography are now the gold standards for diagnosis and treatment.[4, 5] Therapy includes endoscopic plastic stent placement, balloon dilation, or a combination of the 2 techniques. Success rates as high as 90% have been reported, but strictures may recur in more than 20% of patients.[6]

It is essential to distinguish ABSs from ischemic-type biliary lesions (ITBLs), which most often occur apart from the biliobiliary anastomosis in proximal and intrahepatic biliary vessels. The treatment and the prognosis differ significantly between ITBLs and ABSs, and ITBLs are associated with a less favorable prognosis.[7] Long-term outcomes for ABSs are supposed to be better than those for ITBLs, but limited data are available for the long-term follow-up of the endoscopic treatment of ABSs. Risk factors for stricture recurrence after endoscopic therapy are not well established.[3, 8]

Thus, we investigated the long-term outcomes of endoscopic therapy for ABSs in OLT patients, and we identified risk factors for stricture recurrence.

PATIENTS AND METHODS

All patients who underwent deceased donor OLT for end-stage liver disease or acute liver failure between 1996 and 2009 were retrospectively included in this single-center study if they had undergone biliary reconstruction with a biliobiliary anastomosis. Generally, when a sufficient length of the donor's common bile duct was available, anastomoses were fashioned in the following way. Side-to-side anastomoses often included hepatic duct portions from both the donor and the recipient to make maximum use of the bile duct length. For duct-to-duct anastomoses, both donor and recipient ducts were shortened to allow bile duct stumps that were well vascularized at both ends and, at the same time, allow tension-free reconstruction.

An ABS was suspected if signs of cholangitis, pruritus, or progressive jaundice were observed during scheduled clinical investigations or by abdominal ultrasonography. The patients were regularly supervised postoperatively by our transplantation clinic. Clinical parameters (pruritus), elevations of cholestatic enzymes, or the dilation of intrahepatic bile ducts during abdominal ultrasonography suggested the presence of an anastomotic stricture. Magnetic resonance cholangiopancreatography was not routinely performed but was conducted for patients with doubtful clinical, laboratory, or ultrasonography findings. Endoscopic retrograde cholangiopancreatography (ERCP) was considered the gold standard for establishing the diagnosis of an ABS. An ABS was defined as a stricture occurring at or directly adjacent to the biliobiliary (hepatocholedochal or choledochocholedochal) anastomosis. Nonanastomotic strictures were defined as strictures involving the donor hepatic duct proximal to the anastomosis and the right and/or left hepatic ducts and/or intrahepatic branches. All patients with nonanastomotic strictures and ITBLs and patients with biliodigestive anastomoses were excluded from this study.

Hepatic artery thrombosis or stenosis was excluded for all patients with cross-sectional imaging techniques (computed tomography angiography, magnetic resonance tomography, or conventional angiography). Hepatitis C virus (HCV) recurrence and chronic rejection were excluded by liver biopsy for all patients with clinical suspicion of rejection.

Endoscopic Treatment

ERC was performed with a therapeutic duodenoscope (TJF-160R and TJF-160VR, Olympus Corp., Tokyo, Japan) under conscious sedation (midazolam, propofol, and/or short-acting opiates) by an experienced endoscopist. After the confirmation of a stricture by fluoroscopic imaging, endoscopic sphincterotomy was performed. The bile duct was cannulated with a hydrophilic guide wire (eg, Terumo, United States). Each ABS was classified as a high-, medium-, or low-grade stricture as follows: a stricture was considered high-grade if there was luminal narrowing of 90% or more of the diameter of the common bile duct and/or there were severe difficulties in passing the stricture with a guide wire, and the stricture was considered medium- or low-grade if there was luminal narrowing of less than 90%. Endoscopic therapy consisted of (1) inserting plastic endoprostheses of an appropriate diameter (7, 10, or 11.5 Fr; OptiMed Medizinische Instrumente GmbH, Ettlingen, Germany) and increasing the diameter size and number of stents when it was possible, (2) using balloon dilatation (6- and 8-mm MaxForce balloon catheters, Boston Scientific, Ratingen, Germany), or (3) doing both. A combination of balloon dilation and stent insertion was performed in some patients according to the judgment of the investigator. Endoscopic therapy was judged to be successful when the serum bilirubin level decreased to a value of 1.5 mg/dL or less and/or there was radiomorphological resolution of the stricture after completion of endoscopic therapy with stenosis of less than 30% of the diameter of the common bile duct. During follow-up, patients presented routinely every 2 months at our interdisciplinary transplantation clinic, at which abdominal ultrasound examinations and liver function tests were performed.

When an identified stricture could not be passed by the guide wire on the transpapillary approach, a combined percutaneous/endoscopic rendezvous procedure was performed via the percutaneous introduction of the guide wire (percutaneous transhepatic cholangiography) through the anastomosis so that it could be received by a duodenoscope for stent placement. All further stent exchange sessions were performed via the endoscopic route with a duodenoscope.

We evaluated the long-term success of endoscopic treatment in all patients with ABSs in terms of influencing factors, and we identified risk factors for stricture recurrence.

Statistical Analysis

The statistical analysis was performed with IBM SPSS Statistics 19 (IBM Corp., Armonk, NY) and R 2.14 (R Foundation for Statistical Computing, Vienna, Austria).

The time to an ABS and risk factors for developing an ABS were analyzed with a competing risk analysis to account for the competing risks of death and retransplantation. Observing either an ABS or death during follow-up, we had to consider the competing risks of the endpoints stenosis and death. The occurrence of one of the two events significantly changed the probability of the other event or even made it impossible. To analyze concurrent events, we performed a competing risk analysis with dedicated software (R 2.14). Overall survival was analyzed via Cox regression. The Kaplan-Meier method was used to calculate the actuarial relapse-free survival probabilities after the first session of endoscopic therapy.

The time to ABS recurrence and risk factors for restenosis were analyzed with a competing risk analysis to account for the competing risk of death, and overall survival after stenosis was analyzed via Cox regression. The significance level was a P value of 0.05 or less. We categorized the patients into groups A {early occurrence of stenosis [less than 6 weeks after liver transplantation (LT)]} and B [late occurrence of stenosis (6 weeks or more after LT)] for comparisons of the risks of stenosis recurrence.

To analyze the influence of etiology on the occurrence of ABSs and on overall survival after LT, we considered the following groups: viral or toxic etiology with hepatocellular carcinoma (HCC), viral or toxic etiology without HCC, other etiology with HCC, and other etiology without HCC. Here, other etiology comprises nonviral and nontoxic causes of liver diseases such as nonalcoholic steatohepatitis and autoimmune disease.

RESULTS

Between 1996 and 2009, 405 OLT procedures were performed in 374 patients at our center (Table 1). The mean follow-up time was 151 weeks (median = 146 weeks, standard error = 21 weeks, standard deviation = 144 weeks), and the mean survival time was 3.4 years. A stricture of the biliobiliary anastomosis occurred in 47 patients (12.6%). Each biliobiliary anastomosis was established as an end-to-end anastomosis (n = 12), an end-to-side anastomosis (n = 11), or a side-to-side anastomosis (n = 24); for 10 cases, the type of anastomosis was unknown. Patients with an ABS were referred for endoscopic therapy; 6 patients were treated with balloon dilation (12.8%), 14 were treated via the insertion of plastic endoprostheses (29.8%), and 27 were treated with a combination of balloon dilation and stent insertion (57.4%). Stenosis of the anastomosis was accompanied by biliary leakage in 13 patients (28%). The mean and median durations of endoscopic therapy were 28 and 36 weeks, respectively, with a mean of 4.2 ERC sessions per patient. ABSs were classified as high-grade (n = 24) or medium- or low-grade (n = 23).

Table 1. Clinical Data for the Patients
Patients (n)374
Mean age (years)49.8
Sex [n (%)] 
Male254 (67.9)
Female120 (32.1)
Indication for LT [n (%)] 
Viral103 (28)
HCC105 (28)
Toxic69 (18)
Nonalcoholic steatohepatitis19 (5)
Autoimmune hepatitis30 (8)
Other48 (13)
Deaths during follow-up (n)127
Mean survival (years)3.4
Re-OLT during follow-up [n (%)]28 (7.8)

The mean time to an ABS was 16.25 months (mean = 3.25 months). The cumulative ABS incidence rates were 0.09 after 12 months, 0.10 after 24 months, and 0.11 after 36 months, and in 12 cases (25.5%), an ABS was observed more than 12 months after OLT (Fig. 1). A competing risk analysis revealed that patients who manifested HCC with viral or toxic hepatopathy had an increased risk of developing ABSs (P = 0.003; Table 2 and Fig. 2A). In contrast, sex, age, cold ischemia time, and chronic HCV were not found to be significant risk factors for ABS occurrence. Cold ischemia time, HCV infection, sex, age, and time of ABS occurrence (a time-dependent risk factor) did not influence overall survival (Table 2 and Fig. 2B). In 32 of 198 cases (16%), endoscopic therapy was accompanied by complications, which included cholangitis (19 or 9.5%), pancreatitis (6 or 3%), bleeding (5 or 2.5%), and perforation (2 or 1%). All complications were conservatively handled, and there were no deaths associated with endoscopic interventions.

Figure 1.

Time to the occurrence of a stricture of the biliobiliary anastomosis after LT.

Table 2. Indications for OLT and Occurrences of Strictures at Biliobiliary Anastomoses and Death
 TotalABSDeath
nCompeting Risk: P Value or HRnCox Regression: P Value or HR
Viral or toxic etiology with HCC (n)6415P = 0.003 (reference group)13HR = 0.4
Viral or toxic etiology without HCC (n)17023HR = 0.553HR = 0.5
Other etiology with HCC (n)41024P = 0.005 (reference group)
Other etiology without HCC (n)959HR = 0.327HR = 0.4
Age (n)     
>50 years19826NS61NS
≤50 years1722156
Sex (n)     
Male25129NS78NS
Female1191839
HCV (n)10914NS34NS
Mean cold ischemia time (minutes)579624NS563NS
Figure 2.

(A) Competing risk analysis of the appearance of a stricture of the biliobiliary anastomosis (ie, an ABS) after OLT and (B) Kaplan-Meier analysis of death. Cancer indicates HCC. HCC is accompanied by an increased risk of stricture development in patients with prevalent viral or toxic hepatitis as the reason for liver cirrhosis instead of autoimmune hepatitis, nonalcoholic steatohepatitis, or another etiology.

ABS Relapse and Risk Factors

In 16 of the 47 patients (34%) who completed endoscopic treatment for ABSs, we observed ABS relapse during follow-up (Table 3). These patients were again assigned to endoscopic treatment. Endoscopic therapy for recurrent ABSs succeeded in 13 patients (81.2%), but endoscopic therapy failed in 2 patients: a biliodigestive anastomosis was established in one patient, and liver retransplantation was performed in another patient. One patient suffered a second relapse, and a second round of endoscopic treatment was successfully completed. Therefore, 45 of 47 patients (95.7%) were effectively treated for ABSs endoscopically at the completion of long-term follow-up. The mean time to restenosis was 14.5 months (median = 12.3 months). The cumulative incidence rates of recurrent strictures were 0.16 after 12 months, 0.27 after 24 months, and 0.36 after 36 months.

Table 3. Follow-Up After the Termination of Endoscopic Therapy for Strictures at Biliobiliary Anastomoses: A Comparison of Patients With ABS Recurrence at the Biliobiliary Stricture and Patients Without Recurrence
 ABS RecurrenceNo RecurrenceHR/P Value
Etiology of liver cirrhosis (n)  NS
HCV1417 
Non-HCV214
Mean age (years)4950NS
Sex (n)  NS
Male1217 
Female414
Time from OLT to first ERC (weeks)  NS
Mean/standard error56/24.973/33 
Range4-4101-998 
Bile leakage (n)  NS
Yes211 
No1420
Mean cold ischemia time (minutes)575651NS
Mean duration of endoscopic therapy (weeks)31.528NS
Type of endoscopic therapy (n)   
Plastic endoprosthesis alone212Reference group
Balloon dilation alone15HR = 1.01/P = 0.99
Combination1314HR = 4.61/P = 0.055
Severity of the stricture (n)   
High grade1113HR = 2.78/P = 0.046
Medium/low grade518

We categorized the patients into groups A [early occurrence of stenosis (less than 6 weeks after LT)] and B [late occurrence of stenosis (6 weeks or more after LT)], and we found a significant difference (P = 0.04), with late stenosis leading to a higher risk of recurrence. In group A, 2 of the 17 patients experienced recurrence of the anastomotic stenosis, whereas 14 of the 30 patients in group B did [P = 0.04, hazard ratio (HR) = 0.235].

There was a trend of HCV infections being predominant in patients experiencing ABS recurrence (30% for HCV etiology versus 4% for non-HCV etiology) in comparison with patients not experiencing recurrence (36% for HCV etiology versus 30% for non-HCV etiology, P > 0.05). The combination of balloon dilation with the insertion of plastic stents showed a tendency for recurrent strictures during follow-up (P = 0.055, HR = 4.61; Table 3). In contrast, balloon dilation and stent insertion were associated with similar incidence rates of ABS relapse (P = 0.99, HR = 1.01). A severe initial stricture (ie, a high-grade stricture versus a medium- or low-grade stricture) was associated with an increased incidence of ABS recurrence (P = 0.046, HR = 2.78).

A competing risk analysis did not identify HCV as a risk factor for restenosis, but it was a factor for an increased incidence of death (P = 0.02, HR = 5.4). Sex, age, biliary leakage at the site of the anastomosis, cold ischemia time, duration of stent therapy, and time from OLT to the occurrence of stenosis were not identified as predictive for restenosis or overall survival.

DISCUSSION

The endoscopic treatment of ABSs associated with OLT has excellent outcomes. During a long-term follow-up of approximately 3 years, we observed a success rate of 95.7% with scheduled stent exchange sessions in which multiple plastic endoprostheses were inserted over biliobiliary anastomoses. ABS relapse was successfully treated by the resumption of endoscopic treatment. The surgical revision of ABSs became necessary in only 2 of 47 patients (4%). The overall survival of patients with ABSs was not different from the overall survival of OLT patients who did not manifest a biliary stricture (this confirmed previous experience[8]), and the care of OLT patients, who suffered much from biliary complications in the early era of LT, was significantly improved. The overall survival of our patients at 3 years was 71%, which corresponds to the survival rate of 70% found by the European Liver Transplant Registry.[9] However, it is important to be aware of this study's finding that ABSs can occur even years after OLT: we observed ABSs in approximately one-quarter of our patients more than 1 year after OLT, and ABSs were even diagnosed not before 3 years after OLT in a few patients. It may well be that the surveillance of OLT patients must, therefore, include consideration of ABSs during lifelong follow-up. Success rates of more than 90% for the endoscopic therapy of ABSs have been reported by other studies excluding nonanastomotic strictures and ITBLs,[10] but long-term results have not been provided until now. Moreover, the late occurrence of ABSs (more than 1 year after OLT) has hardly been recognized in adults, and follow-up of endoscopic treatment more than 2 years after OLT has not been taken into account in an adult population until now.[11, 12] Our finding that 25.5% of ABSs became evident more than 12 months after OLT is novel.[13, 14] In pediatric patients, however, long-term follow-up studies have reported stricture formation up to 10 years after transplantationem.[15-17]

The late occurrence of ABSs was associated with a viral etiology of liver cirrhosis (data not presented), and we found a tendency of higher ABS recurrence rates in HCV patients. Moreover, the late occurrence of ABSs (more than 6 weeks after LT) was found to be a significant predictor of ABS recurrence: 2 of 17 patients with early ABSs experienced recurrence of the anastomotic stenosis, whereas 14 of 30 patients with late ABSs did (P = 0.04, HR = 0.235). Others have found ABS recurrence to be a common complication after OLT,[18] and in nearly 1 of 5 patients, these strictures recurred after initially successful endoscopic therapy. There were no clinical or endoscopic parameters identified in this study that predicted recurrence, however. The relationship of HCV infection with the occurrence of late ABSs has been noted before: those patients who experienced early HCV recurrence in the transplanted liver had an exceedingly high ABS rate of 16% in 1 study.[19] The authors hypothesized an HCV-specific immune response in patients with early HCV recurrence that could exaggerate inflammation around the biliary anastomosis and result in ABSs. Our findings confirm a clear trend of HCV infection for the late occurrence of ABSs and the recurrence of strictures during long-term follow-up. Moreover, HCC patients had a significantly increased risk of developing an ABS in our study. The latter might be associated with transarterial chemoembolization, which is used in most of our patients as a bridge to transplantation and might provoke alterations in the blood supply of the liver.

Recipient age and operative criteria (bile duct size, biliary reconstruction surgeon, cold ischemia time, and biliary leakage) have been considered risk factors for the appearance of ABSs,[3, 20, 21] and smoking behavior has been suggested as a risk factor recently.[22] The late onset and delayed diagnosis of a stricture seem to be associated with a disadvantageous outcome. The failure rate of endoscopic treatment was found to be high in patients with a late onset and delayed diagnosis of the biliary stricture. Recurrence seems to occur frequently in patients with a short duration of stenting,[8] and the success of endoscopic treatment was improved by stent placement versus simple balloon dilation in another study[23] (Table 4). Modified endoscopic management approaches were suggested only recently: endoscopic dilation followed by maximal stent placement (up to 9 stents) was successful and dependent on the maximal number of inserted stents,[10] but the follow-up was less than 1 year in that study. Others have suggested minimizing the treatment duration to less than 4 months and reported a success rate of 87% with this algorithm.[26]

Table 4. Analysis of Studies of the Endoscopic Treatment of ABSs in LT Patients
StudyPatients (n)Study TypeInterventionERCP (n)aTotal Stenting Period (Months)bStricture Resolution
  1. a

    The data are presented as means or as means and ranges.

  2. b

    The data are presented as means.

Morelli et al.[24]25RetrospectiveERCP with dilation plus stents3 (1-6)80%
Zoepf et al.[23]72Retrospective, comparativeERCP and balloon dilation versus balloon dilation and plastic stent insertion4 (1-11)4Immediate: 88% Long-term: 38% (balloon dilation)/69% (balloon dilation and plastic stent insertion)
Alazmi et al.[18]143RetrospectiveERCP with dilation plus stents3.14.882%
Holt et al.[25]53ProspectiveERCP with dilation plus stents311Early: 92% Late: 69%
Lee et al.[5]79RetrospectiveERCP or PTCD2.964.6%
Seo et al.[8]68RetrospectiveERCP or PTCD with dilation plus stents2.36.965%
Pasha et al.[12]25RetrospectiveBalloon dilation plus multiple stents3.5 (1-9)4.6Early: 88% Late: 80%
Morelli et al.[26]38Prospective case seriesBalloon dilation plus multiple stents3.4 (2-6)3.587%
Tabibian et al.[10]69RetrospectiveBalloon dilation plus multiple stents3 (2-7)1594%
This study47RetrospectiveBalloon dilation plus multiple stents4.2795.7%

We had a high recurrence rate of 34% during long-term follow-up in this series, and high-grade strictures and strictures that were treated with a combination of balloon dilation and stent insertion (most likely indicating tight, high-risk strictures) most frequently relapsed. It is also possible that combining balloon dilation with stent insertion may have increased local trauma, and the effect of permanent dilation provided by the stents may be considered the main reason for successful endoscopic treatment. Our current endoscopic treatment approach to ABSs has, therefore, been changed predominantly to inserting plastic endoprostheses and applying an increasing number of stents of increasing size with every stent exchange up to the diameter of the native adjacent bile duct over a period of at least 6 months and up to 12 months. HCV patients and patients with high-grade strictures at the time of initial ERCP are at high risk for treatment relapse, and they are prone to treatment periods of not less than 12 months.

In conclusion, the long-term success rate of the endoscopic treatment of biliary anastomotic strictures is more than 90% if recurrent strictures are treated endoscopically again. We suggest extending endoscopic treatment to 1 year in high-risk patients (eg, patients with viral hepatitis and high-grade strictures) to ensure long-term success. Lifelong follow-up to screen for the occurrence of ABSs seems essential in LT patients because ABSs may occur late in a significant number of patients.

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