Do We Need to Use a Stent in Biliary Reconstruction to Decrease the Incidence of Biliary Complications in Liver Transplantation? A Systematic Review and Meta-Analysis

Background and Aim Biliary complications are a significant cause of morbidity post-transplantation, and the routine use of biliary stents in liver transplantation to reduce these complications remains controversial. This study aimed to compare the incidence of biliary complications with and without the use of trans anastomotic biliary stent in liver transplantation. Method PubMed, Scopes, Web of Science, and Cochrane library were searched for eligible studies from inception to February 2022, and a systematic review and meta-analysis were done to compare the incidence of biliary complications in the two groups. Results Seventeen studies with a total of 2623 patients were included. The pooled results from the included studies showed an equal rate of biliary complications (i.e., strictures, leaks and cholangitis) in stented and non-stented patients after liver transplantation. However, the cost and biliary intervention rates are higher in stented patients. In addition to that, our sub-group analysis showed no significant decrease in the incidence of biliary complications after using trans anastomotic biliary stent in living donor liver transplant (LDLT), deceased donor liver transplant (DDLT), Roux-en-Y hepaticojejunostomy (RYHJ), and duct-to-duct anastomosis, pediatric, and adult liver transplantation. Conclusion No added benefit on the routine use of endobiliary stent in liver transplantation. However, stented patients are at higher risk of needing multiple ERCPs.

Liver transplantation (LT) has become a standard of care for acute liver cell failure, end-stage liver disease, and primary liver cancer with liver cirrhosis. 1 Biliary complications remain the leading cause of mortality and morbidity after liver transplantation. Their overall rate ranges from 15 to 25%. With associated mortality of 10%. 2 These complications include strictures, bile leakage, and cholangitis. 3 Bile duct complications often depend on the type of transplant graft, either a living donor or deceased donor liver transplant, the number of bile ducts involved in the anastomosis, and the anastomosis itself used by the surgeon (choledochocholedochotomy or hepaticojejunostomy). 4 Despite using biliary stent by most transplant centers as a way to decrease the incidence of biliary complications, there is limited evidence in the literature for its necessity in biliary anastomosis. On the one hand, some studies reported that the use of biliary stents appeared to dramatically decrease the rate of biliary complications. 5,6 On the other hand, other studies found that trans-anastomotic biliary stent was not required in liver transplantation to decrease the incidence of biliary complications and biliary reconstruction without stenting was a safe and efficient technique. 7,8 In addition to that, as reported by some studies, the routine use of endobiliary stents is associated with a remarkable increase in the biliary complications and increases the rate of biliary intervention. This study aimed to compare the rate of biliary complication with and without the use of trans anastomotic biliary stent (internal and external) in liver transplantation. Moreover, we aimed to detect the outcome of using stent in different modalities of liver transplantation (LDLT and DDLT), different age groups (adult and pediatric liver transplantation), and various types of reconstructions (duct to duct anastomosis and hepaticojejunostomy).

Search Strategy
The search was directed through PubMed/MEDLINE, Scopus, Web of science, and the Cochrane Library for information from inception to February 2022 with a combination of the following terms: Liver transplantation, stent, and biliary tract. All studies were reviewed and evaluated by two authors (Elkomos, B. E. and Abdelaal A. A.). according to the eligibility process. Abstract-based eligibility studies were obtained, and the manuscripts were fully reviewed.

Inclusion and Exclusion Criteria
The eligible studies included the following: (1) randomized controlled trials and prospective or retrospective cohort studies; (2) target populations were all patients underwent liver transplantation; (3) studies designed to compare the outcomes of biliary anastomosis using stent versus no stent; (4) studies providing a sufficient description of the methods and baseline characteristics; and (5) the primary outcome was postoperative complications including cholangitis, stricture, and leakage for the two groups. The following types of studies were not included in our study: (1) unrelated or in vitro studies; (2) reviews, case reports, and case series; and (3) studies missing a comparison group.

Outcomes of Interest
We assessed the postoperative complications for using stent in biliary anastomosis versus biliary reconstruction without using stent in liver transplantation, including biliary stricture, cholangitis, and leakage. In addition to that, our aims were to detect the effect of using various types of stents (internal and external stent). Our sub-group analysis aimed to detect the outcome of using stent in different modalities of liver transplantation (LDLT and DDLT), different age groups (adult and pediatric liver transplantation), and various types of reconstructions (duct to duct anastomosis and hepaticojejunostomy).

Data Extraction
We extracted data on study characteristics (author, year of publication, country of transplant, study design and study period), patient characteristics (sample size, follow-up period, causes of transplantation, and Child score), operative details (type of graft, type of biliary anastomosis, and type of stent used), and study outcomes (incidence of postoperative cholangitis, stricture, and leakage for stented and nonstented group). The data were extracted by 2 investigators (Elkomos, B. E. and Abdelaal A. A.) independently.

Statistical Analysis
The meta-analysis was conducted according to Cochrane Handbook for Systematic Reviews of Interventions, 9 which is recommended by the Cochrane Collaboration. Regarding postoperative complications (stricture, cholangitis and leakage), the pooled risk ratios (RRs) and their corresponding 95% confidence intervals (CIs) were calculated with fixed effects models. However, if there was moderate or considerable heterogeneity (I 2 > 40), random-effects models were used to solve the heterogeneity between studies. All calculations for the current meta-analysis were performed with Review Manager 5.4 for Windows (Cochrane Collaboration, Oxford, UK).

Assessment of Publication Bias and Heterogeneity
Funnel plots were generated so that we could visually inspect for publication bias. The statistical methods for detecting funnel plot asymmetry were the Begg Mazumdar rank correlation test and the Egger regression asymmetry test. Statistical heterogeneity was assessed with forest plots and the inconsistency statistic (I2). An I 2 value of 40% or less corresponded to low heterogeneity. Statistical significance was considered at P < 0.05.

External Stent
On the other hand, external stent was used in six of the included studies. While the incidence of stricture was reported in the 9 studies (1074 participants) and leakage reported by 7 studies (877 participants), only two of the included studies (151 participants) calculated the rate of post-operative cholangitis. Similar to internal stent, no decrease in the incidence of post-operative complications     (Fig. 4).

Subgroup Analysis
To investigate the effect of using stents versus no stent in different modalities of liver transplantation (LDLT and DDLT), different age groups (adult and pediatric liver transplantation) and various types of reconstructions (duct to duct anastomosis and hepaticojejunostomy).

Type of the Graft
Turning to the type of the graft, 3 of the included studies used grafts from living donors, 10 studies used grafts from deceased donors, and only one study used both types.

Age of the Recipient
Regarding the age of the recipient, the transplantation in 13 (2031 participants) of the included studies was for adult recipient and in four studies, only (586 patients) transplantation was for pediatrics.

Type of Biliary Anastomosis
Turing to the type of biliary anastomosis, 6 studies (886 patients) used duct to duct anastomosis, 3 studies (643 patients) used Roux-en-Y hepaticojejunostomy, 5 studies used both modalities, and 3 of the included studies did not specify the type of anastomosis.  (Fig. 9).

Publication Bias Assessment
There was no evidence of publication bias. The funnel plot analysis demonstrated a symmetrical appearance, and the P values were greater than 0.05 for all comparisons according to the Begg-Mazumdar test and eggers test.

Discussion
Biliary complications post-transplantation can cause a remarkable decline in the incidence of patient and graft survival. 26 Forty percent of these complications are from bile duct strictures. Anastomotic biliary stricture account for 80% of all strictures, and non-anastomotic stricture account for 20%. 27 The majority of these patients will need an average of one sessions of ERCP every 3 months, with stenting and dilation for 1-2 years 2 . Moreover, the incidence of bile leaks that occur mainly from the anastomotic site range from 2 to 25% post-transplant; 2,28 and they usually require on average two ERCP sessions. 29 It is noteworthy to mention that bile leak is a risk factor for strictures and vice versa. 30 Biliary reconstruction remains the Achilles' heel of liver transplantation. 31 According to Ikegami et al., to avoid these complications, the anastomosis should be tension-free, not too long or short, with good blood supply, accurate understanding, and planning of biliary anatomic variation. 32 In addition to that, many centers have used trans anastomotic biliary stent (internal or external stent) as a way to reduce the incidence of biliary complications. Moreover, the T-tube was previously used to provide an easy access to the biliary system for cholangiography, to allow monitoring of the quality and output of bile and for decompression of biliary system. However, on the one hand, a recent metaanalysis consisting of 1027 patients illustrated that those without a T tube had a decreased incidence of cholangitis and peritonitis with overall decreased rate of biliary complications. 33 In addition to that, according to Zhoa et al., the recent studies failed to support the routine use of T-tube in adult liver transplantation. 34 On the other hand, the routine use of biliary stents as a way to decrease the incidence of biliary complications is still controversial. According to a pilot study conducted by Barkun et al., the use of trans-anastomotic biliary stents for duct-to-duct anastomosis significantly decrease the rate of biliary complications when compared to biliary anastomosis without stenting. 5 Moreover, as reported by Welling et al., the use of biliary stent appeared to be protective against bile leak. 6 Bawa et al. demonstrated a high rate of biliary complications particularly associated with the use of endobiliary stents and they argued that choledochocholedochostomy without stenting was an efficient and a safe technique for biliary reconstruction. 12 Mathur et al. also demonstrated that stenting using internal feeding tubes was associated with greater morbidity. 10 Moreover, Stented patients had a higher risk of needing multiple ERCPs and endoscopic procedures in the first 90 days after transplantation. Verran et al. and Alsharabi et al. also found that internal biliary drainage was not required in liver transplantation. 7,35 In this meta-analysis, A wide variety of trans anastomotic biliary stents have been used since Terrier reported the use of an internal stent for the first time in 1890. 36 As previously mentioned, the T-tube that was introduced in 1912 by Kehr as a method for stenting the common bile duct after choledochotomy and providing external drainage, is associated with an increase in the incidence of biliary complications. 37 On the one hand, according to Jung et al., 20 the use of plastic internal stent in biliary reconstructions is associated with a significant decrease in the incidence of biliary complications and Janousek et al. reported that using bio-absorbable stent could also decrease the complication rate. However, according to our study, no added benefit on using internal biliary stent in LDLT is an excellent alternative to DDLT especially in the areas with low deceased organ availability. 39 However, Stricture Leakage Cholangitis Fig. 7 Biliary complication for stent (internal or external) vs. stentless in adult recipient the incidence of biliary complications in LDLT is 2-3 times higher than that in DDLT and as reported by Sharma et al., the rate of biliary complication ranges from 5-15% after deceased donor liver transplantation and 28-32% after living donor liver transplantation. 40 This could be attributed to the fact that LDLT anastomoses are made between multiple small peripheral bile ducts. 41 According to some studies, the surgical experience is associated with a dramatic decrease in the incidence of these complications after LDLT. 42,43 Other studies reported that the use of trans-anastomotic biliary stent in LDLT can decrease the incidence of post-transplant biliary complications 22 and according to Croome KP et al., there is a role of leaving a stent for early diagnosis of ischemic cholangiopathy in donation after circulatory death (DCD) livers. 44 However, according to the pooled results of the included studies, no significant decrease in the biliary complications after the routine use of stent in either LDLT or DDLT.
Since the first report of liver transplantation in 1963, the rate of biliary complications has not changed a lot, with the overall incidence in pediatric LT still ranging from 10 to 35%. 11,43 Despite the routine use of biliary stent in pediatric liver transplantation in some centers to decrease the biliary complication, no enough studies could be found to support that. In addition to that, according to a survey including surgeons from the highest performing pediatric liver transplantation centers in north America, the routine use of t-tubes in biliary reconstruction should be avoided. 45 However, according to Sakamoto S. et al., a trans-anastomotic biliary stent should be used in D2D biliary reconstruction in pediatric LDLT to decrease the incidence of biliary complication. 17 The pooled results of the included studies showed that no added benefit in the routine use of biliary stent in pediatric or adult liver transplantation.
Since 1870 when the first attempt of cholecystoenterostomy was done by Alexandervon Winiwarter, a wide variety of techniques for biliary reconstruction have been described. 46 However, the two most common forms of biliary reconstruction in liver transplantation are choledochocholedochostomy (CC, duct-to-duct anastomosis) and Roux-en-Y Hepaticojejunostomy (RYHJ, connection of the bile duct to a portion of jejunum). The choice of the type biliary reconstruction depends on surgeon decision as no clear-cut guideline on the best type of biliary reconstruction. It is determined by numerous factors, including the size of recipient and donor bile ducts, underlying liver pathology, and previous transplantation or previous biliary surgery. According to some studies, the incidence of strictures of all types are more prevalent with Roux-en-Y than choledochojejunostomy. 47 However, according to a meta-analysis comparing duct-to-duct versus Roux-en-Y biliary reconstruction following liver transplantation for primary sclerosing cholangitis, both techniques have similar rate of biliary stricture but RYHJ has a higher risk of cholangitis. 48 Duct-to-duct anastomosis is the most common biliary reconstruction procedure performed during OLT. This is because, firstly, duct-to-duct anastomosis is faster and easier than RYHJ. Secondly, duct-to-duct anastomosis does not require intestinal manipulation and entero-enteric anastomosis. Thirdly, this type of anastomosis enables easier endoscopic access postoperatively. Lastly, it decreases the incidence of ascending cholangitis theoretically by preservation of the sphincter of Oddi and no reflux of enteric content in the biliary tree. 14,49,50 Regarding the use of biliary stent, according to Girard E. et al. 24 and Sakamoto S et al., 17 the use of trans-anastomotic biliary stent in duct-toduct anastomosis is associated with a remarkable decrease in the incidence of biliary complication. In addition to that, Egawa H. et al. 13 reported that the use of biliary stent can decrease the rate of postoperative leakage and stricture in RYHJ. However, according to our study, no added benefit on the routine use of biliary stent in both modalities as regard biliary complication.
Best of our knowledge, it is the first meta-analysis to compare biliary complications after using trans-anastomotic biliary stent versus no stent in liver transplantation and subgroup analysis was done to detect the effect of using stent in different modalities of liver transplantation (LDLT and DDLT), different age groups (adult and pediatric liver transplantation), and various types of reconstructions (duct to duct anastomosis and hepaticojejunostomy). In addition to that, all the studies comparing between the two groups were included in our study. However, we have to acknowledge some limitations in our study. Firstly, not all the included studies were randomized controlled trials. Secondly, the existence of significant heterogeneity in some outcomes could not be explained well enough by subgroup analysis. Moreover, none of the included studies compared the acute rejection or the graft loss secondary to biliary complications between the two groups. In addition to that, most of the studies were conducted in Asia and only few of them were conducted in North America and Europe. Lastly, more studies are needed to compare the use of stent versus stentless in pediatric liver transplantation and RYHJ. Moreover, only one study was found comparing the use bio-absorbable stent vs. stent less in biliary reconstruction.

Conclusion
No added benefit on the routine use of endobiliary stent in liver transplantation including living donor liver transplant (LDLT), deceased donor liver transplant (DDLT), Roux-en-Y hepaticojejunostomy (RYHJ) and duct-to-duct anastomosis, pediatric and adult liver transplantation. However, stented patients are at higher risk of needing multiple ERCPs. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Fig. 10 Biliary complication for stent (internal or external) vs. stentless in RYHJ anastomosis