Author Affiliations: Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery (Shin MH, Moon DB, Lee SG, Hwang S, Kim KH, Ahn CS, Ha TY, Song GW, Jung DH, Park GC, Yun YI, Kim WJ, Kang WH and Kim SH) and Department of Radiology and Research Institute of Radiology (Ko GY), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43 gil, Songpa-gu, Seoul 05505, Korea

Corresponding Author: Deok-Bog Moon, MD, Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olimpic-ro 43 gil, Songpa-gu, Seoul 05505, Korea (Tel: +82-2-30105971; Fax: +82-2- 30106701; Email: mdb1@amc.seoul.kr)

 

© 2016, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(16)60126-1

Published online August 25, 2016.

 

 

Contributors: SMH, MDB, LSG, HS and SGW designed the study. SMH, HS, KKH, ACS, HTY, SGW, JDH, PGC, YYI, KWJ, KWH, KSH and KGY performed the study, collected and analyzed the data. SMH and MDB performed the study and wrote the first draft. All the authors contributed to the design and interpretation of the study and to further drafts. MDB is the guarantor.

Funding: None.

Ethical approval: The study was approved by the Institutional Review Board.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: Although perioperative portal vein (PV) stent implantation is an effective treatment for steno-occlusive disease in adult living donor liver transplantation (LDLT) recipients, we experienced high incidence of biliary anastomotic strictures (BAS) after PV stenting. In this study, we sought to clarify the relation between BAS and PV stenting and to suggest the possible mechanism of BAS and measures to reduce its incidence.

 

METHODS: We retrospectively analyzed 44 LDLT recipients who underwent PV stent implantation across the line of PV anastomosis regardless of the location of steno-occlusion (stent group) and their matched controls (non-stented LDLT recipients, n=131).

 

RESULTS: The incidence of BAS was higher in patients in the stent group than that in the control group (43.2% vs 17.6%, P=0.001). Cumulative 6-month and 1-, 2- and 5-year BAS rates were 31.8%, 34.1%, 41.4% and 43.2%, respectively, in the stent group and 13.0%, 13.8%, 16.1% and 17.8%, respectively, in the control group (P=0.001). Multivariate analysis revealed that PV stenting was an independent risk factor for BAS.

 

CONCLUSIONS: Although PV stent implantation is a reliable treatment modality for steno-occlusive PV in adult LDLT recipients, innovative methods to prevent the PV stent from crossing the line of PV anastomosis may be necessary to reduce the incidence of postoperative BAS.

 

(Hepatobiliary Pancreat Dis Int 2016;15:480-486)

 

KEY WORDS: portal vein stenting; biliary stricture; living donor liver transplantation

 

 

Although outcomes of adult living donor liver transplantation (LDLT) have steadily improved, biliary complications are a major contributor to poor quality of life, graft loss and mortality. The number and size of reconstructed bile ducts (BDs), history of biliary leakage, type of graft, reconstruction technique and methodology, and other recipient- and donor-associated variables have been shown to be associated with biliary complications.^[1-6] Several efforts have been made to minimize the occurrence of biliary anastomotic strictures (BAS), including alterations in operative strategy in donors and biliary reconstruction.^{[4, 7-10]} However, a recent meta-analysis revealed a 19% overall incidence of BAS after LDLT.^[1]

 

Stent placement into the portal vein (PV) during or after LDLT in recipients with steno-occlusive PV has shown acceptable success rates.^[11-15] Most common complications of PV stent implantation include technical failure, anastomotic rupture, thrombosis and bleeding.^[11-13] Despite the relatively high incidence of BAS after PV stenting, its long-term effects on the biliary system have not been reported. In this study, we sought to assess the association between BAS and PV stenting and identify the mechanism by which PV stenting contributes to BAS. Furthermore, methods to reduce BAS in these patients were briefly discussed.

 

 

This retrospective analysis utilized prospectively collected data from all adult patients who underwent adult LDLT at our institution between January 2000 and August 2008. Of the 1560 adult LDLT recipients, 77 underwent PV stent implantation during or within 1 month of LDLT. To eliminate the effect of confounding factors and to reduce the complexity of analysis, the following categories of patients were excluded: (1) LDLT performed for primary or secondary biliary cirrhosis; (2) dual LDLT transplantation or re-transplantation; (3) BAS associated with diffuse ischemic-type cholangiopathy; (4) history of biliary leakage or hepatic arterial complications prior to BAS; (5) follow-up duration of <3 months. One patient who had PV stenosis caused by direct invasion of recurrent cancer was excluded because of the direct effect of the tumor on the BD. None of the included patients had undergone ABO-incompatible LDLT. The study was approved by the Institutional Review Board.

 

On medical record review, 44 LDLT recipients who underwent stent implantation across the line of PV anastomosis (stent group) were identified. This group was matched (1:3 ratio) with a control group of 131 patients who did not undergo PV stenting. The matching criteria were: (1) Model for End-stage Liver Disease (MELD) score (±5 points), (2) recipient age (±5 years), (3) size (smallest, ±1.5 mm) and multiplicity of BD, and (4) duration of follow-up (±12 months).

 

The diameter and anatomy of the BDs in the graft were assessed by intraoperative cholangiography (IOC) during donor operation. All IOCs were performed with the patient in the same position and with the same distances between the detector, patient and X-ray source. Although the surgical methods for BD anastomosis practiced at our institution were modified over time, the between-group difference in this respect was negligible as the LDLT procedures were performed during the same time periods. Details about the preparation of the graft BD, reconstruction method, and anastomosis technique have been described elsewhere.^{[3, 16]} All grafts were perfused with histidine-tryptophan-ketoglutarate solution on the back table only through the PV. All recipients with external biliary stents were examined by IOC after completion of BD anastomosis.

 

PV stenting in all 44 patients was performed to relieve the steno-occlusive site of the recipient’s native PV. However, PV stent was positioned across the line of PV anastomosis even in the absence of anastomotic stenosis. In 33 out of the 44 (75.0%) patients, the PV stent was implanted during the LDLT procedure through the inferior mesenteric vein or branches of the superior mesenteric vein. In the remaining 11 (25.0%) patients, PV stent was implanted after LDLT either by laparotomy (8/11, 72.7%) or via percutaneous route (3/11, 27.3%). The mean and median duration between LDLT and stent placement in these 11 patients were 7.0±1.3 days and 6.5 days (range 2-17), respectively. This discrepancy between timing of LDLT and PV stenting was not taken into account because it was thought to have a negligible influence on the long-term occurrence of BAS. The detailed methods of intraoperative or percutaneous PV stent placement have been described elsewhere.^{[12, 13]}

 

During routine surveillance, BAS was primarily suspected in patients with elevated levels of liver enzymes, dilation of intrahepatic ducts on computed tomography, or delayed biliary excretion on hepatobiliary scintigraphy. BAS was confirmed by cholangiography through an external biliary drainage tube or during biliary intervention, such as endoscopic retrograde biliary drainage or percutaneous transhepatic biliary drainage to treat biliary strictures. Magnetic resonance imaging with cholangiography was not used frequently to diagnose BAS because of its innate deficiency in delineating distorted biliary anatomy.

 

All statistical analyses were performed using the SPSS 21 statistical package (IBM, Chicago, IL, USA). The results are expressed as mean±SD, median (range), or as number (percentage). Normally distributed continuous variables were compared using Student’s t test; non-normally distributed continuous variables were compared using Mann-Whitney U test. Categorical variables were compared using the Chi-squared test or Fisher’s exact test, as applicable. BAS-free survival and overall survival rates were determined using the Kaplan-Meier method and compared with the log-rank test. Multivariate analyses were performed using a Cox regression model to assess factors affecting the incidence of BAS. A P value <0.05 was regarded as statistically significant; all P values were two-tailed.

 

 

Clinical characteristics by study group are presented in Table 1. Patients in both groups were followed up until December 2013; the mean follow-up duration in the stent and control groups was 94.9±39.9 and 94.3±37.8 months, respectively. In case of liver grafts that had multiple duct openings, the size and anastomotic method for the smallest opening was assessed. After unification ductoplasty, the size of the opening was measured as a single duct. The graft parameters are presented in Table 2. All variables related to BD were comparable between the two groups. Overall 1-, 3- and 5-year recipient survival rates were 95.5%, 90.9% and 90.9% in the stent group, and 97.7%, 92.4% and 90.1% in the control group, respectively (P=0.63, Fig. 1).

 

The incidence of BAS was significantly higher in the stent group than that in the control group (43.2% vs 17.6%, P=0.001). The median duration from LDLT to occurrence of BAS in the stent and control groups was 4.0 months (range 0.7-45.6) and 4.2 months (range 0.5-55.0), respectively (P=0.70). The cumulative 6-month and 1-, 2- and 5-year BAS rates were 31.8%, 34.1%, 41.4% and 43.2%, respectively, in the stent group and 13.0%, 13.8%, 16.1% and 17.8%, respectively, in the control group (P=0.001) (Fig. 2). Many patients experienced BAS within 6 months in both groups and the very early onset rate (<1 month post-LDLT) was also comparable between the stent (1/44, 2.3%) and control (3/131, 2.3%) groups. Management methods and treatment outcomes were similar in the two groups (Table 3). Two patients in the control group died of PTBD: one from traumatic injury (74 months post-LDLT and 18 months after detection of BAS) and one from graft failure with gastrointestinal bleeding (8 months post-LDLT and 6 months after detection of BAS). In the stent group, one patient had been treated for repetitive stenosis, with several attempts made to remove the tube at short intervals; one patient died of graft failure with brain hemorrhage (17 months after LDLT and 4 months after BAS); and one patient died from recurrent HCC (19 months after LDLT and 18 months after BAS).

 

On univariate analysis, warm and cold ischemic time of the graft, BD opening size <5 mm, multiplicity of BD, PV stenting, and acute cellular rejection (ACR) were significantly associated with BAS (all P<0.05) (Table 4). On multivariate analysis using these significant risk factors, BD opening size <5 mm, PV stenting, and ACR were independent risk factors for BAS (Table 5).

 

When PV stenosis was found during LDLT, surgical revision was primarily considered. However, radiological intervention was preferred when PV had no room for revision. The PV stents were 10-14 mm in diameter and 4-8 cm in length. The diameter of the PV stent was finally determined by the diameter of the recipient’s PV on intraoperative cine-portography (IOCP), although the minimum diameter was set at 10 mm to secure adequate portal flow and to avoid portal flow steal.^[15]

 

The indications for PV stenting during or after LDLT were anastomotic stenosis of PV (10/44, 22.7%; 5 during LDLT and 5 after LDLT) and PV thrombosis or stenosis even after thrombectomy (33/44, 75.0%; 27 during LDLT and 6 after LDLT), and size discrepancy between donor and recipient portal vein (1/44, 2.3%; during LDLT). In patients who had undergone PV stenting, univariate analysis showed that warm ischemic time of the graft and BD opening size <5 mm were significant risk factors for BAS (Table 6). Multivariate analysis, however, failed to identify any independent risk factors associated with BAS in these patients.

 

 

All partial liver grafts in adult LDLT require adequate portal inflow for immediate graft regeneration in order to meet the metabolic demands. Insufficient portal flow during the early postoperative period can result in graft failure.^[17] Steno-occlusion of the PV faced during surgery is due primarily to preoperative steno-occlusion of the recipient’s PV,^[18] whereas postoperative steno-occlusion is associated primarily with technical factors, such as a tight suture line, tension or twisting of the PV in the area of the anastomosis, or extrinsic compression of the PV caused by hematoma and reactive edema.^{[13, 19-21]}

 

Fourteen percent of adult recipients who underwent LDLT at our institution had steno-occlusive PV and 76.7% of them were associated with large portosystemic shunts. Eversion thrombectomy is the most frequent primary method used to restore adequate portal inflow,^[22,23] but it may be ineffective in patients with severe steno-occlusion because complete surgical correction of an intrapancreatic PV stenosis or thrombus is not feasible during the LDLT procedure. Patients with this condition are routinely monitored by IOCP, not only to evaluate the anatomical abnormality in the PV and coexisting portal flow steal through the portosystemic collaterals but also to simultaneously correct this condition. If necessary, we performed PV stenting and/or interruption of portosystemic collaterals under IOCP guidance.^{[11, 15, 22]}

 

Traditionally, postoperative PV complications have been treated surgically, including thrombectomy, anastomotic revision, or re-transplantation. However, interventional procedures such as PV stenting performed under radiological guidance have been shown to be acceptable, safe, and effective in cases where surgery is considered technically challenging or is contraindicated due to complications.^{[11-15, 24]} As a result, many PV complications after LDLT have been treated by percutaneous or intraoperative PV stenting or balloon angioplasty.

 

Although radiological intervention is a promising therapeutic modality for patients with PV complications, these tend to cause biliary complications. To our knowledge, this study is the first to report a strong relationship between PV stenting and post-transplant biliary strictures. Early experience with PV stenting at our institution showed a high incidence of BAS during the follow-up period (Fig. 3). In this study, the incidence of BAS was about 2.5-fold higher in the stent group than that in the control group (43.2% vs 17.6%).

 

The BAS-free survival rate in the pair-matched control group was comparable to that reported previously from our institution,^{[3, 25]} but was slightly higher (3-year BAS rate of 16.8%) than that published recently (3-year BAS rate of 14.3%),^[25] because the former included the learning period of duct-to-duct anastomosis, which had a higher biliary complication rate (3-year BAS rate of 25.4%).^[3]

 

Multivariate analysis in this study showed that BD opening size <5 mm, PV stenting, and ACR were independent risk factors for BAS, indicating that PV stenting per se is closely associated with the development of BAS. However, in the stent group, we did not find any independent risk factors for BAS (Table 6). The results indicated a significant direct association of stenting with BAS.

 

At the outset of this study, we expected the direct compression of the BD by the PV stent to be the main cause for BAS. However, there was no demonstrable evidence of the pure extrinsic mechanical impact on the BD because IOC, which was performed after BD anastomosis following PV stenting, did not show any conformational change in the biliary tract (Fig. 3C). In addition, the patterns of BAS on cholangiography during endoscopic retrograde or percutaneous transhepatic biliary drainage did not differ markedly between the two groups (Fig. 3D). Although this study could not determine its underlying mechanism, we speculate the following possible mechanisms: PV stenting was definitely an independent risk factor for BAS and there was no conceivable reason except its physical effect on the BD. Therefore, the PV stent crossing the anastomosis, with its tip positioned above the anastomosis line, can place extrinsic pressure on the adjacent communicating arteries and peribiliary vascular plexus of the graft side, without necessarily affecting the shape of the biliary tract, thus exposing the BD to pressure-induced ischemic damage. Moreover, it can also induce periportal inflammation, which may result in cicatricial changes at the adjacent BD anastomosis site. The fact that the small-sized BD opening of the graft, i.e., the factor most associated with BAS development, was not an independent risk factor in the stent group (Table 6), indirectly supports our hypothesis of pressure-associated BD ischemia.

 

Securing the PV anastomosis with an adequate diameter is important to prevent the PV stent crossing the anastomosis line and thereby minimize chances of BAS associated with PV stenting. We recently introduced new surgical approaches to LDLT in recipients with steno-occlusive PV. Patch venoplasty of the stenotic main PV at the suprapancreatic portion can enlarge the PV segment used for anastomosis and alleviate the risk of PV stenosis at the anastomotic line. PV stenting can then be done without crossing the PV anastomotic line even though PV stenting is necessary to relieve intrapancreatic PV stenosis. Prospective evaluation of the suggested surgical approaches is necessary to clarify the cause of the high incidence of BAS and the success of surgery for steno-occlusive PV during adult LDLT.

 

In contrast to intraoperative PV stent implantation, postoperative PV stenting, mostly related to the problem of PV anastomosis itself, requires the PV stent to cross the line of PV anastomosis despite the high risk of BAS, because surgical revision of portal anastomosis is not feasible in most clinical settings following LDLT. Therefore, the importance of skilled and meticulous PV anastomosis during adult LDLT, even in uncomplicated cases, cannot be overemphasized.

 

In conclusion, in this study, we found PV stent implantation across the anastomosis line to be an independent risk factor for BAS following adult LDLT. In order to prevent the PV stent from crossing the anastomosis line, new surgical approaches for securing PV anastomosis with adequate diameter need to be validated prospectively.

 

 

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