|Year : 2015 | Volume
| Issue : 5 | Page : 201-207
Differences in risk factors for early-onset and late-onset biliary complications in liver transplant patients
Hsiu-Lung Fan1, An-Chieh Feng1, Meng-Hsing Ho1, Shih-Ming Kuo2, Wei-Chou Chang3, Teng-Wei Chen1
1 Department of Surgery, Division of General Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
2 Department of Surgery, Division of Pediatric Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
3 Department of Radiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
|Date of Submission||08-May-2015|
|Date of Decision||28-Jul-2015|
|Date of Acceptance||06-Aug-2015|
|Date of Web Publication||22-Oct-2015|
Department of Surgery, Division of General Surgery, Tri-Service General Hospital, National Defense Medical Center, 325, Section 2, Chen-Kung Road, Neihu 114, Taipei, Taiwan
Source of Support: None, Conflict of Interest: None
Context: Despite the use of advanced surgical techniques, the incidence of biliary complications (BCs) after liver transplantation (LT) is high. Hence, there may be additional unidentified causes of BC. Aims: To identify the risk factors for BCs occurring within 6 months or beyond 6 months after LT. Materials and Methods : We enrolled 237 patients who underwent LT from August 2001 to December 2012. Of the 237 patients, 173 did not have BCs (no BC group), 42 had BCs within 6 months after LT (early-onset BC group), and 22 had BCs beyond 6 months after LT (late-onset BC group). Statistical Analysis Used: Patients' demographic, clinical, and biochemical data were analyzed using the Mann-Whitney U-test, Chi-square test, Fisher's exact test, and multiple logistic regression analysis. Results: Multivariate analysis indicated that only partial liver graft (odds ratio [OR], 2.741; 95% confidence interval [CI], 1.236-6.077; P=0.013) was an independent risk factor for early-onset BC after LT, whereas acute rejection (OR, 6.556; 95% CI, 2.380-18.056; P < 0.001), multiple bile ducts (OR, 4.227; 95% CI, 1.212-14.740; P = 0.024), and pre-LT serum albumin level (OR, 2.234; 95% CI, 1.178-4.238; P = 0.014) were the independent risk factors for late-onset BC after LT. Conclusion: Early-onset and late-onset BCs after LT are associated with different risk factors. Partial liver graft is a risk factor for early-onset BC, whereas pre-LT serum albumin level, multiple bile ducts, and acute rejection are the risk factors for late-onset BC. As it is easily controllable, prevention of acute rejection may help to reduce the incidence of BCs.
Keywords: Acute rejection, biliary complication, liver transplantation
|How to cite this article:|
Fan HL, Feng AC, Ho MH, Kuo SM, Chang WC, Chen TW. Differences in risk factors for early-onset and late-onset biliary complications in liver transplant patients. J Med Sci 2015;35:201-7
|How to cite this URL:|
Fan HL, Feng AC, Ho MH, Kuo SM, Chang WC, Chen TW. Differences in risk factors for early-onset and late-onset biliary complications in liver transplant patients. J Med Sci [serial online] 2015 [cited 2021 Apr 23];35:201-7. Available from: https://www.jmedscindmc.com/text.asp?2015/35/5/201/167743
| Introduction|| |
Biliary complications (BCs) remain the Achilles' heel of liver transplantation (LT), with an incidence of 5.3-40.6%. ,,,,,,,,,,, Despite the efforts made to preserve the blood supply of the bile duct in the recipient and donor,  the incidence of BCs remains at 5.3-12.8%, ,,,,, implying the presence of some BC etiologies that are unrelated to the surgical technique.
The duration between the transplantation and the development of BC has not received much attention. Several studies have supported the hypothesis that early-onset and late-onset BCs may have different etiologies. , In the present study, we aimed to identify the risk factors for BCs occurring within 6 months or beyond 6 months after LT.
| Materials and Methods|| |
Two hundred thirty-seven consecutive patients underwent LT at our institution from August 2001 to December 2012. The immunosuppressive protocol consisted of corticosteroid, tacrolimus, and mycophenolate mofetil in all the transplanted patients. The biliary tracts were reconstructed using duct-to-duct anastomosis with either 5-0 or 6-0 prolene sutures or polydioxanone sutures in all the transplanted patients. A stricture was considered to be present when the serum total bilirubin levels were elevated, or dilatation of the intrahepatic bile duct was noted on ultrasonography or computed tomography. The presence of the stricture was subsequently confirmed by endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance imaging (MRI). In the present study, leakage was defined as the presence of biloma formation on ERCP or MRI. In this study, we retrospectively reviewed these ERCP and MRI findings and enrolled the patients with BCs for further analyses.
Moreover, in the present study, early-onset BC (the early-onset BC group) was defined as the diagnosis of BC within 6 months after LT, late-onset BC (the late-onset BC group) was defined as the diagnosis of BC beyond 6 months after LT, and no BC (no BC group) was defined as the lack of evidence of BCs during the follow-up period after LT.
The patients' characteristics were retrospectively recorded, including age, gender, underlying liver disease (hepatitis B virus infection, hepatitis C virus infection, alcohol abuse, or hepatocellular carcinoma), medical history before LT (diabetes mellitus, hypertension, uremia, ascites, hepatic encephalopathy, and bleeding from esophageal varices), blood test results before LT (albumin, creatinine, international normalized ratio [INR], total bilirubin, platelet count, and ammonia levels), and model for end-stage liver disease (MELD) scores. MELD scores were calculated according to the following formula: MELD score = (3.78 × log e [bilirubin level in mg/dL]) + (11.2 × log e [INR]) + (9.6 × log e [creatinine level in mg/dL]) + (6.4 × [etiology: 0 if cholestatic or alcoholic, 1 otherwise]).  The surgery-related factors were also recorded, including surgery type (deceased-donor LT or living-donor LT), graft type (whole graft or partial graft), ABO-incompatible LT, number of bile ducts (single or multiple), implementation of splenectomy, implementation of ductoplasty, amount of intraoperative blood loss, operative time, and graft weight. Postoperative complications were recorded and included acute rejection, posttransplant hemodialysis, posttransplant diabetes mellitus, or cytomegalovirus infection.
The risk factors for early-onset BCs were analyzed by comparing the variables in the no BC group and the early-onset BC group. The risk factors for late-onset BCs were analyzed by comparing the variables in the no BC group and late-onset BC group. The study was approved by the institutional review board of our hospital.
Unless otherwise stated, continuous variables are presented as the median (interquartile range), and categorical variables are expressed as the number (percentage) of events. To detect the differences between the groups, the Mann-Whitney U-test was used for continuous variables, and the Chi-square test was used for categorical variables. If 20% of the expected numbers were <5, Fisher's exact test was used instead of the Chi-square test. Patients' characteristic variables with a P value of <0.10 were entered into a binary logistic regression model for the univariate analysis. Statistically significant variables with a P value of <0.05 in the univariate analysis were entered into a backward multivariate analysis. All the statistical calculations were performed using SPSS version 15.0 (IBM-SPSS, Inc., Chicago, IL, USA). Significance was defined as P < 0.05.
| Results|| |
The study included 237 patients (183 men and 54 women), with a mean age of 52.4 years. Of 237 patients, 173 did not have BCs (the no BC group), 42 had BCs within 6 months after LT (the early-onset BC group), and 22 had BCs beyond 6 months after LT (the late-onset BC group). The characteristics of the early-onset BC group and the late-onset BC group are summarized in [Table 1]. In the early-onset BC group, 9.5% had leakage, 64.3% had stricture, and 26.2% had both leakage and stricture. In the late-onset BC group, 4.5% had leakage, 86.4% had stricture, and 9.1% had both stricture and leakage. The mean diagnostic time was 2.38 ± 0.28 months and 20.7 ± 3.68 months in the early-onset BC group and late-onset BC group, respectively. There were no significant differences in stricture site, stricture number, dilatation of intrahepatic duct (IHD), tortuous IHD, dilatation of the common bile duct (CBD), and tortuous CBD between the early-onset BC group and late-onset BC group.
The characteristics of the no BC group and the early-onset BC group are summarized in [Table 2], whereas the characteristics of the no BC group and the late-onset BC group are summarized in [Table 3]. The average follow-up duration was 38.3 months (range: 0-136 months).
|Table 2: Characteristics of patients without BCs and with early-onset BCs|
Click here to view
|Table 3: Characteristics of patients without BCs and with late-onset BCs|
Click here to view
Univariate and multivariate analyses of the early-onset biliary complication group with the no biliary complication group
Univariate analysis showed that the surgery type (P = 0.033) and graft type (P = 0.013) were significantly differed between the groups [Table 4]. These factors were included into the multivariate analysis, which indicated that only graft type (odds ratio [OR], 2.741; 95% confidence interval [CI], 1.236-6.077; P = 0.013) was an independent risk factor for early-onset BCs after LT [Table 4].
|Table 4: Univariate and multivariate analysis of early-onset BCs after liver transplantation|
Click here to view
Univariate and multivariate analyses of the late-onset biliary complication group with the no biliary complication group
Univariate analysis showed that postoperative rejection (P < 0.001), graft type (whole vs. partial; P = 0.034), serum albumin level (P = 0.016), and graft weight (P = 0.038) were significantly differed between the groups [Table 5]. However, the surgery type (P = 0.051), number of bile ducts (single vs. multiple; P = 0.050), preoperative ascites (P = 0.084), and preoperative uremia (P = 0.071) were not the significant risk factors for late-onset BCs, based on the results of univariate analysis. The significant factors in the univariate analysis (P > 0.05 and <1.00) were included in the multivariate analysis. Multivariate analysis showed that acute rejection (OR, 6.556; 95% CI, 2.380-18.056; P < 0.001), number of bile ducts (OR, 4.227; 95% CI, 1.212-14.740; P = 0.024), and serum albumin level (OR, 2.234; 95% CI, 1.178-4.238; P = 0.014) were the independent risk factors for late-onset BCs after LT [Table 5].
|Table 5: Univariate and multivariate analysis of late-onset BCs after liver transplantation|
Click here to view
| Discussion|| |
In the present study, we analyzed the risk factors for early-onset and late-onset BCs in the patients who underwent LT. In our cohort, the risk factors for BCs were dependent on the time interval after LT. A partial liver graft was the only identified independent risk factor for BC occurring within the first 6 months after LT. In contrast, acute rejection, multiple bile ducts, and pretransplant serum albumin level were identified as the independent risk factors for BCs occurring beyond 6 months after LT.
The risk factors for BCs have been investigated in several studies. These risk factors include hepatic artery complications,  cytomegalovirus infections,  female donor/male recipient,  different era of LT,  intensive care unit stay,  donor age of >50 years,  number of bile ducts,  cold ischemia time,  placement of the T-tube,  and bile duct diameter.  In contrast, other studies determined that MELD score,  donor age,  blood type incompatibility,  graft/recipient weight ratio,  cold ischemia time,  and warm ischemia time  were not associated with BCs. Thus, the actual risk factors for BC after LT are unclear. Hence, it will be necessary to analyze additional large series studies to better identify the actual risk factors.
In the present study, a partial liver graft was the only identified independent risk factor for BCs occurring within the first 6 months after LT. This result can be logically explained by the proven risk factors themselves, including the number of bile ducts  and bile duct diameter.  The diameter of the bile ducts in partial liver grafts is smaller than that in whole grafts; moreover, there may be several bile ducts in partial liver grafts, which makes bile duct anastomoses more difficult. In addition, acute rejection, multiple bile ducts, and pretransplant serum albumin level were the independent risk factors for BCs occurring beyond 6 months after LT. However, the number of bile ducts cannot be accurately predicted in some cases because of the anatomic variation. The pretransplant serum albumin level may also vary, as this level is occasionally dependent on commercial albumin supplementation before transplantation.
Acute rejection has received an increasing amount of attention as a risk factor for BCs. The first study to consider this parameter as a risk factor for BCs - By the Hong Kong research group of Chok - Determined that acute cellular rejection was a significant risk factor for anastomotic stricture.  Gámán et al. also determined that BCs are associated with acute rejection.  This association may be explained by the fact that biliary epithelial cells are one of the targets of certain liver diseases such as acute allograft rejection.  The relationship between rejection and BCs was also explained by the findings of pathological examination, which indicated that the bile duct damage was greater in the patients with acute rejection than in those with the recurrent liver disease.  However, some studies have stated contrasting findings. Verdonk et al. showed that anastomotic biliary stricture was not related to acute rejection,  whereas Park et al. also presented the same opinion.  In this study, acute rejection was significantly associated with late-onset BCs but was not related to early-onset BCs. These findings suggest that understanding the difference in early- or late-onset BCs may help to explain the discrepant results obtained in the previous studies.
The preservation of the blood supply of the bile duct is known to play an important role in preventing BCs. Hashimoto et al. determined that the hepatic artery buffer response, which is calculated based on the hepatic artery flow and portal vein flow, was associated with early-onset BCs.  However, in the present study, factors such as blood loss or ductoplasty were not related to early-onset BCs. This discrepancy may be explained by the inconsistent definition of early-onset or late-onset BCs. Moreover, it is possible that factors such as blood loss or ductoplasty may not reflect the actual blood supply of the bile duct.
The time interval to the development of BCs after LT has been considered in a small number of studies. Greif et al. determined that two-third of BCs developed within the first 3 months after LT.  Mosca et al. defined late BCs as those occurring after the removal of the T-tube drain, that is, after a period of 3 months.  Hwang et al. used BC-free survival rates at 1, 3, and 5 years to determine the incidence of BCs over time.  In brief, these findings indicated that the time interval may play a role in the development of BCs.  Hence, it is necessary to adopt different strategies to prevent BCs during different time periods.
The current study has certain limitations. One limitation is the retrospective nature of the study. Moreover, the cut-off time interval of early or late-onset BCs has not been clearly defined in the literature. Lin et al. defined perioperative BCs as those occurring within 90 days after LT and early operative BCs as those occurring within 12 months after LT.  Chang et al. showed that 78.5% of liver transplant patients developed BCs within 1-year of transplantation and 94.2% of patients had BCs within 2 years of transplantation. Chang also defined the early period as within 1-year after transplantation.  Hashimoto et al. chose 60 days as the cut-off to define early or late BCs.  In the present study, we chose 6 months as the cut-off time interval. Future studies should identify the risk factors for early- or late-onset BCs by using various time intervals in order to determine the optimal cut-off times.
| Conclusion|| |
There were different risk factors associated with early-onset or late-onset BCs after LT. Moreover, we noted that acute rejection was a risk factor of late-onset BCs. As this condition is potentially controllable, we believe that the optimal prevention of acute rejection may help to lower the incidence of BCs.
| References|| |
Kling K, Lau H, Colombani P. Biliary complications of living related pediatric liver transplant patients. Pediatr Transplant 2004;8:178-84.
Soin AS, Kumaran V, Rastogi AN, Mohanka R, Mehta N, Saigal S, et al.
Evolution of a reliable biliary reconstructive technique in 400 consecutive living donor liver transplants. J Am Coll Surg 2010;211:24-32.
Lin TS, Concejero AM, Chen CL, Chiang YC, Wang CC, Wang SH, et al.
Routine microsurgical biliary reconstruction decreases early anastomotic complications in living donor liver transplantation. Liver Transpl 2009;15:1766-75.
Marubashi S, Dono K, Nagano H, Kobayashi S, Takeda Y, Umeshita K, et al.
Biliary reconstruction in living donor liver transplantation: Technical invention and risk factor analysis for anastomotic stricture. Transplantation 2009;88:1123-30.
Shah SA, Grant DR, McGilvray ID, Greig PD, Selzner M, Lilly LB, et al.
Biliary strictures in 130 consecutive right lobe living donor liver transplant recipients: Results of a Western Center. Am J Transplant 2007;7:161-7.
Kim SH, Lee KW, Kim YK, Cho SY, Han SS, Park SJ. Tailored telescopic reconstruction of the bile duct in living donor liver transplantation. Liver Transpl 2010;16:1069-74.
Soejima Y, Fukuhara T, Morita K, Yoshizumi T, IkegamiT, Yamashita Y, et al.
A simple hilar dissection technique preserving maximum blood supply to the bile duct in living donor liver transplantation. Transplantation 2008;86:1468-9.
Mita A, Hashikura Y, Masuda Y, Ohno Y, Urata K, Nakazawa Y, et al.
Nonsurgical policy for treatment of bilioenteric anastomotic stricture after living donor liver transplantation. Transpl Int 2008;21:320-7.
Soejima Y, Taketomi A, Yoshizumi T, Uchiyama H, Harada N, Ijichi H, et al.
Biliary strictures in living donor liver transplantation: Incidence, management, and technical evolution. Liver Transpl 2006;12:979-86.
Gondolesi GE, Varotti G, Florman SS, Muñoz L, Fishbein TM, Emre SH, et al.
Biliary complications in 96 consecutive right lobe living donor transplant recipients. Transplantation 2004;77:1842-8.
Liu CL, Lo CM, Chan SC, Fan ST. Safety of duct-to-duct biliary reconstruction in right-lobe live-donor liver transplantation without biliary drainage. Transplantation 2004;77:726-32.
Giacomoni A, Lauterio A, Slim AO, Vanzulli A, Calcagno A, Mangoni I, et al.
Biliary complications after living donor adult liver transplantation. Transpl Int 2006;19:466-73.
Greif F, Bronsther OL, Van Thiel DH, Casavilla A, Iwatsuki S, Tzakis A, et al.
The incidence, timing, and management of biliary tract complications after orthotopic liver transplantation. Ann Surg 1994;219:40-5.
Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 2000;31:864-71.
Kasahara M, Egawa H, Takada Y, Oike F, Sakamoto S, Kiuchi T, et al.
Biliary reconstruction in right lobe living-donor liver transplantation: Comparison of different techniques in 321 recipients. Ann Surg 2006;243:559-66.
Verdonk RC, Buis CI, Porte RJ, van der Jagt EJ, Limburg AJ, van den Berg AP, et al.
Anastomotic biliary strictures after liver transplantation: Causes and consequences. Liver Transpl 2006;12:726-35.
Park JB, Kwon CH, Choi GS, Chun JM, Jung GO, Kim SJ, et al.
Prolonged cold ischemic time is a risk factor for biliary strictures in duct-to-duct biliary reconstruction in living donor liver transplantation. Transplantation 2008;86:1536-42.
López-Andújar R, Orón EM, Carregnato AF, Suárez FV, Herraiz AM, Rodríguez FS, 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 2013;258:21-9.
Chok KS, Chan SC, Cheung TT, Sharr WW, Chan AC, Lo CM, et al.
Bile duct anastomotic stricture after adult-to-adult right lobe living donor liver transplantation. Liver Transpl 2011;17:47-52.
Gámán G, Gelley F, Doros A, Zádori G, Görög D, Fehérvári I, et al.
Biliary complications after orthotopic liver transplantation: The Hungarian experience. Transplant Proc 2013;45:3695-7.
Brain JG, Robertson H, Thompson E, Humphreys EH, Gardner A, Booth TA, et al.
Biliary epithelial senescence and plasticity in acute cellular rejection. Am J Transplant 2013;13:1688-702.
Shin E, Kim JH, Yu E. Histopathological causes of late liver allograft dysfunction: Analysis at a single institution. Korean J Pathol 2013;47:21-7.
Hashimoto K, Miller CM, Quintini C, Aucejo FN, Hirose K, Uso TD, et al.
Is impaired hepatic arterial buffer response a risk factor for biliary anastomotic stricture in liver transplant recipients? Surgery 2010;148:582-8.
Mosca S, Militerno G, Guardascione MA, Amitrano L, Picciotto FP, Cuomo O. Late biliary tract complications after orthotopic liver transplantation: Diagnostic and therapeutic role of endoscopic retrograde cholangiopancreatography. J Gastroenterol Hepatol 2000;15:654-60.
Hwang S, Lee SG, Sung KB, Park KM, Kim KH, Ahn CS, et al.
Long-term incidence, risk factors, and management of biliary complications after adult living donor liver transplantation. Liver Transpl 2006;12: 831-8.
Chang JH, Lee IS, Choi JY, Yoon SK, Kim DG, You YK, et al.
Biliary stricture after adult right-lobe living-donor liver transplantation with duct-to-duct anastomosis: Long-term outcome and its related factors after endoscopic treatment. Gut Liver 2010;4:226-33.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]