Frequency of Biliary Complications
Primary type of biliary complication according to biliary reconstruction type is summarized in Table 5. In addition to 110 primary biliary complications, we identified concurrent, later developing, or recurrent biliary complications consisting of: 16 cases of AS, 18 cases of NAS, 4 cases of SS, and 5 cases of MC, the total number of cases of biliary complications adding up to 153. The incidence of AS and NAS, including strictures that occurred as secondary biliary complications, but excluding recurrent biliary complications, were 65 (10.9%) of 596 cases and 36 (6%) of 596 cases, respectively. The total number of transplants developing any kind of biliary stricture was 99 (16.6%) of 596 cases. The incidence of BL was 24 (4%) of 596. Median time from LTx to development of AS, NAS, BL, SS, and MC was 209 days (IQR, 56–615 days), 331 days (IQR, 123–767 days), 34 days (IQR, 25–47 days), 434 days (IQR, 182–488 days), and 105 days (IQR, 40–1190 days), respectively.
In Table 6, data are presented on treatments used and the results obtained. ERCP and/or PTC were successful in 47 (90.4%) of 52 AS cases, 24 (72.7%) of 33 NAS cases, 23 (100%) of 23 BL cases, 9 (81.8%) of 11 SS cases, and 4 (80%) of 5 MC cases, adjusting for patients who did not finish treatment and patients with ongoing treatment. In 3 patients with AS and 1 with MC where ERCP treatment was unsuccessful to reach or pass the stricture, PTC was used with success. A mixed approach of ERCP and PTC treatment was successful in 7 cases of AS, 5 cases of NAS, 1 case of BL and 2 cases of MC. Two patients with AS, 4 patients with NAS, 2 patients with SS and 1 patient with MC needed a retransplant, and 2 patients with complete anastomotic stenosis was re-anastomosed surgically. One AS patient with failed ERCP, and 1 NAS patient with failed PTC, had spontaneous resolution of symptoms. In 3 patients with NAS, ERCP and/or PTC were not able to reach the stricture, and decision was made to await further treatment. All patients who did not finish treatment died from non–treatment-related causes. The recurrence rate after successful AS and NAS treatment was 3/47 (6.4%) and 7/24 (29.2%) respectively.
There were no major procedure-related complications reported in 418 ERCP and 182 PTC procedures. After ERCP, 7 patients developed moderate, and 7 patients mild pancreatitis, according to the Cotton criteria.14 In addition, 7 cases of hemorrhage, 6 cases of cholangitis and 5 cases of sepsis were reported, adding up to a complication rate of 7.7% in the ERCP group. In the PTC group, complications were limited to 6 cases of sepsis and 1 case of cholangitis, with a total complication rate of 3.8%.
Graft and Patient Survivals
Graft survival was impaired in patients with biliary complications compared with the graft survival in patients without biliary complications (Figure 1). The 1-, 3-, 5-, and 10-year graft survival rates for patients with biliary complications were 90%, 73.8%, 67.4% and 44%, respectively. The corresponding graft survival rates for patients without complications were 91.6%, 86.1%, 82.9%, and 71.8%, respectively (P < 0.0001).
Figure 2 displays patient survival rate in 109 patients developing biliary complications, and a control group of 476 patients without biliary complications. The 1-, 3-, 5-, and 10-year patient survivals for patients with biliary complications were 92.7%, 80%, 74.7%, and 54.1%, respectively. The corresponding survival rates for patients without complications were 92%, 86.6%, 83.7%, and 72.8%, respectively (P < 0.01).
In our study, we show that the overall frequency of biliary complications (18.5%) after LTx and the frequency of the most common biliary complication, ASs (44.4%), are in the ranges of previously reported complication rates of 6% to 34% and 47%, respectively.3-5,15,16 Although the range of BLs has been large historically, between 2% and 21%,8,15-20 such complications are becoming less frequent.21 Possible etiologies for developing a BL include biliary ischemia, downstream obstruction, or leak caused by T-tube removal. The use of T-tubes in CC anastomosis was considered standard procedure in the past. Advantages included the possibilities of direct measurement of bile output in the early postsurgical period, easy access in the need of radiological examination, and the ability to rapidly decompress the biliary tree if needed.9 It was also believed to decrease AS formation. Disadvantages mainly include BL upon its removal and higher overall complication rates.22 T-tubes are known to be one of the major risk factors associated with BLs,9,21 which is supported by the findings of increased rate of BLs in the group with T-tubes (P < 0.02) in our study. Few patients after the year of 2008 had a CC anastomosis with a T-tube, reflecting the shift away from its use at our department. Our low incidence of BLs (4%) may partly be due to our current restrictive use of T-tubes. However, some studies challenge the current opinion against use of T-tubes in LTx, reporting low rates of leak after removal and biliary complications overall.23,24
We know of no literature reviews concluding intraoperative blood loss to be a significant risk factor for biliary complications after LTx. However, our findings of increased intraoperative blood loss in patients developing biliary complications (P < 0.001) has been reported in a few other studies.25,26 A recent study on a large cohort of liver transplanted children did not see a correlation between intraoperative blood units transfused and the development of biliary complications,27 suggesting adults might be more sensitive to intraoperative blood loss and development of such complications.
In the literature, the incidence of biliary strictures after LTx ranges from 5% to 15%.2,15-17,28 In our study, the stricture incidence (16.6%) seems to be high. However, when subgrouping the incidence in relation to the model for end-stage liver disease (MELD), our results are in line with those described by Sundaram and colleagues,21 showing a significantly higher biliary stricture incidence in the post-MELD era (15.4% vs. 6.4%, P < 0.001). The increased use of extended criteria for donor livers, and the acceptance of organs from marginal donors, has led to an increased rate of biliary stricture formation.29 Other potential factors contributing to the increased stricture incidence are the access to more advanced diagnostic methods, the tendency of more actively treating borderline cases of biliary complications, and the growing ERCP competence available. Additionally, we have a relatively high proportion of patients transplanted for primary sclerosing cholangitis in our material. These patients are known to develop more often biliary strictures in the new liver.30
Anastomotic strictures are most of the times believed to be the result of technical issues at the anastomosis which, when combined with biliary ischemia, initiate a localized fibrotic response. Other possible contributing factors are prolonged ICU stay, sex mismatch transplants, and postoperative BLs.6,31 The optimal endoscopic treatment of ASs have been suggested to be a combination of large diameter balloon dilatation and prolonged biliary stenting over 12 months.32-34 Strictures often respond well even to shorter treatment duration, but recurrence rates have been reported to be higher.6,35,36 The recurrence rate of ASs in our study (6.4%) is lower than the reported rate in a meta-analysis (9%).37 One factor contributing to our low stricture recurrence rate might be the fact that all except 4 of the patients successfully treated with ERCP received stent treatment. A treatment approach using stents is known to lead to less recurrent strictures, as opposed to dilatation treatment only.38 The overall success rate for endoscopic and/or percutaneous treatment of anastomotic (90.4%) and nonanastomotic (72.8%) strictures is in the upper range of the results of several other authors evaluating endoscopic and/or percutaneous treatments.2,6,15,18,32-36,39-44 The lower treatment success rate (72.8%) and higher recurrence rate of NASs (29.2%) suggest that it is, generally, a more challenging complication to handle, and the optimal way approach these strictures remains uncertain. We found NASs to be the dominating primary complication type (45%) among patients with a choledochojejunostomy. Seven of the 9 patients in this group were transplanted because of primary sclerosing cholangitis. This may be 1 factor that contribute to the lower treatment success rates among patients with NASs. The high success rates in treating biliary leaks (100%) and SS (81.8%) are in line with the results of other studies.15,18,43,45
The PTC technique proved to be of important value in patients where an endoscopic approach was unsatisfactory or failed. Several patients also benefitted from rendezvous procedures combining ERCP and PTC. However, a primary PTC approach frequently requires more treatment procedures until resolution of the biliary complication. Additionally, the percutaneous drainage carry higher risk of infection and bring discomfort to the patient, as compared to ERCP stenting. We did find ERCP to have a doubled procedure-related complication rate (7.7% vs. 3.8%). However, no complication was severe. Our current regimen is that ERCP is the first line of treatment for this patient group, with complementing PTC therapy in case of ERCP failure.
The male proportion of patients developing biliary complications was significantly larger than the female proportion, comparing to the sex distribution in the group not developing biliary complications. This tendency was reported in another study, but the numbers were not significant.43 The proportion of males have previously been reported to be dominant among patients developing biliary complications.37
To our knowledge, this study is the first to show that, despite a high success rate in treating biliary complications after LTx, both graft and patient survivals were significantly impaired. This correlation has previously been reported only in retransplanted patients,46 and other studies have reported graft but not patient survival to be impaired in patients developing nonanastomotic biliary strictures.2,47 In contrast to the present study, biliary strictures overall are not known to affect graft and patient survival,2,6 and a recent study found biliary complications to not affect graft and patient survival in liver transplanted patients.43
In summary, we conclude that both endoscopic and percutaneous therapies are safe and efficient for treating biliary complications after LTx, and that surgery should be saved as a last resort. Our findings also indicate that by improvement in prevention of biliary complications one could improve patient and graft survivals after LTx.
The authors thank Marie E. Larsson (research engineer, Division of Transplantation Surgery, Karolinska University Hospital) for contribution to the statistical analysis.
1. Duffy JP, Kao K, Ko CY, et al. Long-term patient outcome and quality of life after liver transplantation: analysis of 20-year survivors. Ann Surg
2. Graziadei IW, Schwaighofer H, Koch R, et al. Long-term outcome of endoscopic treatment of biliary strictures after liver transplantation. Liver Transpl
3. Gholson CF, Zibari G, McDonald JC. Endoscopic diagnosis and management of biliary complications following orthotopic liver transplantation. Dig Dis Sci
4. Tung BY, Kimmey MB. Biliary complications of orthotopic liver transplantation. Dig Dis
5. Akamatsu N, Sugawara Y, Hashimoto D. Biliary reconstruction, its complications and management of biliary complications after adult liver transplantation: a systematic review of the incidence, risk factors and outcome. Transpl Int
6. Verdonk RC, Buis CI, Porte RJ, et al. Anastomotic biliary strictures after liver transplantation: causes and consequences. Liver Transpl
7. Buis CI, Hoekstra H, Verdonk RC, et al. Causes and consequences of ischemic-type biliary lesions after liver transplantation. J Hepato-Biliary-Pancreat Surg
8. Pfau PR, Kochman ML, Lewis JD, et al. Endoscopic management of postoperative biliary complications in orthotopic liver transplantation. Gastrointest Endosc
9. Kochhar G, Parungao JM, Hanouneh IA, et al. Biliary complications following liver transplantation. World J Gastroenterol
10. Macias-Gomez C, Dumonceau JM. Endoscopic management of biliary complications after liver transplantation: an evidence-based review. World J Gastrointest Endosc
11. Mangiavillano B, Pagano N, Baron TH, et al. Outcome of stenting in biliary and pancreatic benign and malignant diseases: a comprehensive review. World J Gastroenterol
12. Ring EJ, Oleaga JA, Freiman DB, et al. Therapeutic applications of catheter cholangiography. Radiology
13. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg
14. Cotton PB, Lehman G, Vennes J, et al. Endoscopic sphincterotomy complications and their management: an attempt at consensus. Gastrointest Endosc
15. Park JS, Kim MH, Lee SK, et al. Efficacy of endoscopic and percutaneous treatments for biliary complications after cadaveric and living donor liver transplantation. Gastrointest Endosc
16. Rerknimitr R, Sherman S, Fogel EL, et al. Biliary tract complications after orthotopic liver transplantation with choledochocholedochostomy anastomosis: endoscopic findings and results of therapy. Gastrointest Endosc
17. Greif F, Bronsther OL, Van Thiel DH, et al. The incidence, timing, and management of biliary tract complications after orthotopic liver transplantation. Ann Surg
18. Thuluvath PJ, Atassi T, Lee J. An endoscopic approach to biliary complications following orthotopic liver transplantation. Liver Int
19. Thethy S, Thomson BNj, Pleass H, et al. Management of biliary tract complications after orthotopic liver transplantation. Clin Transpl
20. O'Connor TP, Lewis WD, Jenkins RL. Biliary tract complications after liver transplantation. Arch Surg
21. Sundaram V, Jones DT, Shah NH, et al. Posttransplant biliary complications in the pre- and post-model for end-stage liver disease era. Liver Transpl
22. Scatton O, Meunier B, Cherqui D, et al. Randomized trial of choledochocholedochostomy with or without a T tube in orthotopic liver transplantation. Ann Surg
23. Gastaca M, Matarranz A, Munoz F, et al. Biliary complications in orthotopic liver transplantation using choledochocholedochostomy with a T-tube. Transplant Proc
24. Lopez-Andujar R, Oron EM, Carregnato AF, et al. T-tube or no T-tube in cadaveric orthotopic liver transplantation: the eternal dilemma: results of a prospective and randomized clinical trial. Ann Surg
25. Selvakumar N, Saha BA, Naidu SC. Is duct to duct biliary anastomosis the rule in orthotopic liver transplantation? Indian J Surg
26. Gastaca M, Matarranz A, Martinez L, et al. Risk factors for biliary complications after orthotopic liver transplantation with T-tube: a single-center cohort of 743 transplants. Transplant Proc
27. Feier FH, Seda-Neto J, da Fonseca EA, et al. Analysis of factors associated with biliary complications in children after liver transplantation. Transplantation
28. Colonna JO II, Shaked A, Gomes AS, et al. Biliary strictures complicating liver transplantation. Incidence, pathogenesis, management, and outcome. Ann Surg
29. Nemes B, Gaman G, Doros A. Biliary complications after liver transplantation. Expert Rev Gastroenterol Hepatol
30. Hildebrand T, Pannicke N, Dechene A, et al. Biliary strictures and recurrence after liver transplantation for primary sclerosing cholangitis: a retrospective multicenter analysis. Liver Transpl
31. Moser MA, Wall WJ. Management of biliary problems after liver transplantation. Liver Transpl
32. Tabibian JH, Asham EH, Han S, et al. Endoscopic treatment of postorthotopic liver transplantation anastomotic biliary strictures with maximal stent therapy (with video). Gastrointest Endosc
33. Tringali A, Barbaro F, Pizzicannella M, et al. Endoscopic management with multiple plastic stents of anastomotic biliary stricture following liver transplantation: long-term results. Endoscopy
34. Holt AP, Thorburn D, Mirza D, et al. A prospective study of standardized nonsurgical therapy in the management of biliary anastomotic strictures complicating liver transplantation. Transplantation
35. Zoepf T, Maldonado-Lopez EJ, Hilgard P, et al. Balloon dilatation vs. balloon dilatation plus bile duct endoprostheses for treatment of anastomotic biliary strictures after liver transplantation. Liver Transpl
36. Pasha SF, Harrison ME, Das A, et al. Endoscopic treatment of anastomotic biliary strictures after deceased donor liver transplantation: outcomes after maximal stent therapy. Gastrointest Endosc
37. Peng C, Ma C, Xu G, et al. The efficacy and safety of endoscopic balloon dilation combined with stenting in patients with biliary anastomotic strictures after orthotopic liver transplantation. Cell Biochem Biophys
38. Schwartz DA, Petersen BT, Poterucha JJ, et al. Endoscopic therapy of anastomotic bile duct strictures occurring after liver transplantation. Gastrointest Endosc
39. Weber A, Prinz C, Gerngross C, et al. Long-term outcome of endoscopic and/or percutaneous transhepatic therapy in patients with biliary stricture after orthotopic liver transplantation. J Gastroenterol
40. Rizk RS, McVicar JP, Emond MJ, et al. Endoscopic management of biliary strictures in liver transplant recipients: effect on patient and graft survival. Gastrointest Endosc
41. Morelli J, Mulcahy HE, Willner IR, et al. Long-term outcomes for patients with post-liver transplant anastomotic biliary strictures treated by endoscopic stent placement. Gastrointest Endosc
42. Poley JW, Lekkerkerker MN, Metselaar HJ, et al. Clinical outcome of progressive stenting in patients with anastomotic strictures after orthotopic liver transplantation. Endoscopy
43. Mejia GA, Olarte-Parra C, Pedraza A, et al. Biliary complications after liver transplantation: incidence, risk factors and impact on patient and graft survival. Transplant Proc
44. Faleschini G, Vadala di Prampero SF, Bulajic M, et al. Predictors of endoscopic treatment outcome in the management of biliary complications after orthotopic liver transplantation. Eur J Gastroenterol Hepatol
45. Saab S, Martin P, Soliman GY, et al. Endoscopic management of biliary leaks after T-tube removal in liver transplant recipients: nasobiliary drainage versus biliary stenting. Liver Transpl
46. Enestvedt CK, Malik S, Reese PP, et al. Biliary complications adversely affect patient and graft survival after liver retransplantation. Liver Transpl
© 2019 The Authors. Published by Wolters Kluwer Health, Inc.
47. Guichelaar MM, Benson JT, Malinchoc M, et al. Risk factors for and clinical course of non-anastomotic biliary strictures after liver transplantation. Am J Transplant