Abstract
To understand if the risk of biliary complications is higher with living donor liver transplantation (LDLT) compared to deceased donor liver transplantation (DDLT), the present meta-analysis was conducted to analyze the differences between these two types of liver transplantations. Three databases were searched from inception to September 2023 for comparative studies reporting biliary complications with LDLT and DDLT. Odds ratios (OR) with 95% confidence intervals were calculated for all the dichotomous outcomes. Twenty-eight studies were included in the final analysis. LDLT was associated with a significantly higher incidence of biliary complications than DDLT (OR 1.96, 95% CI: 1.56-2.47). However, on subgroup analysis, only studies published in or before 2014 reported a higher incidence of biliary complications with LDLT, but not with studies published after 2014. An analysis of individual adverse events showed that LDLT was associated with a higher incidence of both bile leak (OR 3.38, 95% CI: 2.52-4.53) and biliary stricture (OR 1.75, 95% CI: 1.20-2.55). LDLT was associated with a higher incidence of overall biliary complications, including bile leak and biliary stricture. With advances in surgical techniques, there has been a reduction in the risk of biliary complications.
Keywords: bile leak, deceased donor liver transplantation, liver transplantation, living donor liver transplantation, post-transplant biliary stricture
Introduction and background
Liver transplantation (LT) is often regarded as the definite treatment option for the management of end-stage liver disease (ESLD), acute liver failure (ALF), and primary liver cancers. With advances in surgical techniques and immunosuppression regimens, there has been a remarkable improvement in the survival rates of these patients. At present, the reported five-year survival following a successful LT stands at 70-75% [1,2].
Following LT, biliary complications are common and constitute a significant cause of morbidity and mortality. Up to 25% of patients may develop biliary complications after undergoing LT, out of which 10% may ultimately die of these complications. Common biliary complications after LT include biliary stricture (both non-anastomotic and anastomotic) and bile leak. Rare complications include bile stones, clots, bile cast syndrome, and hemobilia [3]. Timely diagnosis and management are necessary to salvage the graft and improve long-term outcomes [4]. In India and most Southeast Asian countries, live donor liver transplant (LDLT) constitutes the major bulk of LT in contrast to Western countries due to the lower rate of cadaveric organ donation [5].
Traditionally, biliary complications were thought to be higher in LDLT than in DDLT. The reported biliary complications following LDLT are about two to three times higher than those with cadaveric LT. Multiple factors related to surgical techniques are major reasons for increased biliary complications. Extensive hilar dissection in LDLT leads to disturbed blood supply to bile ducts and ultimately causes various biliary complications in these patients [6]. However, a better understanding of vascular anatomy and improved surgical techniques have significantly reduced these complications, even in LDLT settings. However, an updated systematic review and meta-analysis are lacking in this regard. The primary aim of this systematic review and meta-analysis is to provide updated data regarding the incidence of various biliary complications in the setting of LDLT in contrast to cadaveric LT.
Review
Methods
Information Sources and Search Strategy
A comprehensive search was conducted using the databases of MEDLINE, EMBASE, and Scopus from inception to September 2023. The keywords used were: (Liver OR Hepat* OR HCC OR Cirrhosis) AND (LDLT OR Live donor OR Living donor) AND (DDLT OR Deceased donor OR Cadaveric) AND (Biliary OR Bile OR Bile duct AND (Complication OR Adverse events OR Leak OR Stricture). The manual searching of reference lists of the included studies was also undertaken to ensure that all potentially relevant studies were included. The systematic review and meta-analysis were conducted per the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines [7].
Study Selection
All prospective and retrospective studies fulfilling the following PICO criteria were included: (a) Patients - patients with cirrhosis of the liver undergoing LT; (b) Intervention - LDLT; (c) Comparison - DDLT; (d) Outcomes - biliary complications. The biliary complications included both bile leak and stricture. In accordance with the selection criteria above, the titles and abstracts of all studies were independently reviewed by two authors. A third reviewer resolved any disagreements. The exclusion criteria used were non-comparative studies, conference abstracts, case series, and non-English studies.
Data Extraction and Quality Assessment
Two reviewers independently extracted the data, while a third reviewer arbitrated any conflicts. Each study's title, first author, year of publication, country, number of patients, age and sex distribution, indication for TIPS, outcome metrics, and follow-up time were all listed on the form. Using a Newcastle-Ottawa scale for cohort studies [8], two independent reviewers evaluated the quality of the included studies. In the event of a disagreement, a third reviewer was contacted.
Statistical Analysis
Odds ratios (OR) with 95% confidence intervals (CI) were calculated for all the dichotomous outcomes. Regardless of heterogeneity, the Mantel-Haenszel test for random effects was used. Cochran's Q test and I2 statistics were used to determine the heterogeneity between the studies. A P-value of Q test < 0.1 or the I2 value > 30% was significant. Publication bias was assessed by visual inspection of the funnel plot. Subgroup analysis and leave-one-out meta-analysis were conducted for sensitivity analysis. RevMan software (version 5.4.1, Cochrane Collaboration) and STATA software (version 17, StataCorp., College Station, TX) were used for statistical analysis.
Results
Baseline Characteristics and Quality Assessment of Included Studies
The above search strategy yielded 1889 records, out of which 28 studies were included in the final analysis [9-36]. Figure 1 shows the flowchart for the study selection and inclusion process. Tables 1, 2 summarize the baseline characteristics and outcomes of individual studies included in the meta-analysis. All the studies were retrospective in nature except for the one by Liu et al. [10]. Fourteen studies were from Asian countries [10,11,16,17,19,20,23,24,26,29-31,34,36], 11 were from North America [12-14,18,21,22,25,27,28,32,33], and one each from Europe [9] and South America [15]. Two studies included some pediatric patients [11,17], while the rest included adult patients exclusively. Three studies included patients with hepatocellular carcinoma (HCC) exclusively [20,24,26]. Eleven studies were of good quality [9,10,16,19-21,24,25,27,29,36], 13 studies were of fair quality, [11-14,17,22,23,26,28,30,32,33,35], and four were of poor quality [15,18,31,34].
Table 1. Baseline characteristics of the studies included in the meta-analysis.
DDLT: Deceased donor liver transplantation; HCC: Hepatocellular carcinoma; LDLT: Living donor liver transplantation; MELD: Model for End-Stage Liver Disease
| Author, year | Country, No. of centers | Design | Arm | No. of patients | Age, in years | Male sex | MELD score | Patients with HCC | Study quality |
| Garcia-Retortillo 2004 [9] | Spain, Single | Retrospective | LDLT | 22 | 59 (24–68) | 13 (59.1%) | 11 (5–24) | 13 (59.1%) | Good |
| DDLT | 95 | 59 (38–66) | 58 (61.1%) | 11 (2–28) | 45 (47.4%) | ||||
| Liu et al. 2006 [10] | Hong Kong, Single | Prospective | LDLT | 124 | 47.5 (18–68) | 97 (78.2%) | 21 (7–46) | 36 (29%) | Good |
| DDLT | 56 | 48 (27–66) | 44 (78.6%) | 19 (6–49) | 11 (19.6%) | ||||
| Al-Sebayel et al. 2007 [11] | Saudi Arabia, Single | Retrospective | LDLT | 45 | 47 (1.5–63) | 29 (64.4%) | - | 21 (17%) | Fair |
| DDLT | 77 | 44 (11–63) | 38 (49.3%) | - | |||||
| Freise et al. 2008 [12] | USA, Multicentric | Retrospective | LDLT | 384 | 49.6 ± 10.7 | 222 (58%) | 15 ± 6 | 63 (16%) | Fair |
| DDLT | 216 | 51.4 ± 9.7 | 128 (59%) | 21 ± 9 | 39 (18%) | ||||
| Lai et al. 2009 [13] | USA, Single | Retrospective | LDLT | 86 | 50.6 ± 12.2 | 42 (49%) | 20.5 ± 5.1 | 31 (36%) | Fair |
| DDLT | 403 | 53.6 ± 10.8 | 289 (72%) | 23.0 ± 9.8 | 126 (31%) | ||||
| Fisher et al. 2009 [14] | USA, Single | Retrospective | LDLT | 107 | 48.5 ± 12.0 | 66 (61.7%) | 14.1 ± 0.6 | 8 (7.4%) | Fair |
| DDLT | 465 | 51.5 ± 8.6 | 366 (78.7%) | 18.7 ± 0.4 | 134 (28.9%) | ||||
| Gómez et al. 2009 [15] | Argentina, Single | Retrospective | LDLT | 30 | - | - | - | - | Poor |
| DDLT | 357 | - | - | - | - | ||||
| Li et al. 2011 [16] | China, Single | Retrospective | LDLT | 128 | 42.96 ± 8.57 | 108 | 19.5 ± 10.7 | 0 | Good |
| DDLT | 221 | 44.55 ± 9.71 | 179 | 18.2 ± 9.6 | 0 | ||||
| Saha et al. 2012 [17] | India, Single | Retrospective | LDLT | 18 | 21.6 (0.5–61) | - | - | 0 | Fair |
| DDLT | 35 | 35.2 (1.2–63) | - | - | 0 | ||||
| Chan et al. 2013 [18] | Canada, Single | Retrospective | LDLT | 29 | - | - | - | - | Poor |
| DDLT | 333 | - | - | - | - | ||||
| Jiang et al. 2013 [19] | China, Single | Retrospective | LDLT | 70 | 40.2 ± 8.1 | 62 (88.6%) | 23.9 ± 5.6 | 0 | Good |
| DDLT | 191 | 44.1 ± 9.3 | 162 (84.8%) | 21.7 ± 5.7 | 0 | ||||
| Lei et al. 2013 [20] | China, Single | Retrospective | LDLT | 31 | 44.4 ± 9.7 | 18 (58.1%) | 9.3 ± 6.1 | 31 (100%) | Good |
| DDLT | 52 | 44.0 ± 8.2 | 31 (59.6%) | 9.1 ± 5.8 | 52 (100%) | ||||
| Reichman et al. 2013 [21] | Canada, Single | Retrospective | LDLT | 145 | 54.2 ± 7.5 | 117 (80.7%) | 14.4 (6–29) | 55 (37.9%) | Good |
| DDLT | 145 | 53.9 ± 7.7 | 117 (80.7%) | 14 (6–33) | 80 (55%) | ||||
| Zimmerman et al. 2013 [22] | USA, Multicentric | Retrospective | LDLT | 356 | - | - | - | - | Fair |
| DDLT | 189 | - | - | - | - | ||||
| Kim et al. 2014 [23] | South Korea, Single | Retrospective | LDLT | 21 | 53.1 ± 10.3 | 14 | 13.1 ± 5.4 | 17 (80.9%) | Fair |
| DDLT | 29 | 51.3 ± 9.2 | 15 | 24.9 ± 11.6 | 11 (37.9%) | ||||
| Wan et al. 2014 [24] | China, Single | Retrospective | LDLT | 40 | 48.6 ± 9.7 | 34 (85%) | 6-19: 87.5% | 40 (100%) | Good |
| DDLT | 80 | 49.5 ± 8.9 | 68 (85%) | 6-19: 88.7% | 80 (100%) | ||||
| Sandal et al. 2015 [25] | USA, Single | Retrospective | LDLT | 62 | 52.9 ± 9.4 | 36 (58.1%) | 13.9 ± 4.2 | 2 (3.2%) | Good |
| DDLT | 108 | 52.0 ± 10.6 | 76 (70.4%) | 20.1 ± 8.8 | 0 | ||||
| Hu et al. 2016 [26] | China, Multicenter | Retrospective | LDLT | 389 | 48.0 ± 8.6 | 360 (92.5%) | - | 389 (100%) | Fair |
| DDLT | 6471 | 50.1 ± 9.4 | 5817 (89.9%) | - | 6471 (100%) | ||||
| Samstein et al. 2016 [27] | USA, Multicentric | Retrospective | LDLT | 565 | 51.0 ± 10.9 | 311 (55%) | 6-15: 57% | 70 (12%) | Good |
| DDLT | 471 | 52.2 ± 10.4 | 285 (61%) | 6-15: 34% | 103 (22%) | ||||
| Barbas et al. 2017 [28] | Canada, Multicenter | Retrospective | LDLT | 48 | 54.7 ± 9.4 | 35 (72.9%) | 17.8 ± 8.7 | 8 (16.7%) | Fair |
| DDLT | 128 | 56.7 ± 9.3 | 87 (68.0%) | 21.8 ± 10.3 | 42 (32.8%) | ||||
| Chok et al. 2017 [29] | China, Single | Retrospective | LDLT | 54 | 51 (19–67) | 42 (77.8%) | 40 (35–40) | 3 (5.5%) | Good |
| DDLT | 40 | 51 (23–66) | 34 (85%) | 39 (35–40) | 1 (2.5%) | ||||
| Kim et al. 2017 [30] | South Korea, Single | Retrospective | LDLT | 109 | 52.0 ± 8.5 | 81 (74.3%) | 12.5 ± 8.3 | 68 (62.4%) | Fair |
| DDLT | 76 | 53.1 ± 11.0 | 50 (65.8%) | 24.9 ± 11.7 | 16 (21.1%) | ||||
| Miyagi et al. 2017 [31] | Japan, Single | Retrospective | LDLT | 168 | - | - | - | - | Poor |
| DDLT | 441 | - | - | - | - | ||||
| Humar et al. 2019 [32] | USA, Single | Retrospective | LDLT | 245 | 56 | 144 (59%) | 16 | 54 (22%) | Fair |
| DDLT | 592 | 56 | 414 (70%) | 22 | 213 (36%) | ||||
| Amara et al. 2022 [33] | USA, Multicenter | Retrospective | LDLT | 109 | - | 57 (52.3%) | - | 17 (15.6%) | Fair |
| DDLT | 1684 | - | 1135 (67.4%) | - | 561 (33.3%) | ||||
| Karakaya et al. 2022 [34] | Turkey, Single | Retrospective | LDLT | 151 | - | - | - | - | Poor |
| DDLT | 23 | - | - | - | - | ||||
| Meier et al. 2022 [35] | UNOS database | Retrospective | LDLT | 318 | 53.9 ± 11.1 | 158 (49.7%) | 35.6 ± 7.0 | 50 (15.7%) | Fair |
| DDLT | 3165 | 53.5 ± 10.6 | 2045 (64.6%) | 19.0 ± 9.7 | 626 (19.8%) | ||||
| Lapisatepun et al. 2023 [36] | Thailand, Multicenter | Retrospective | LDLT | 20 | 54.7 ± 11.7 | 14 (70%) | 14.5 (12−23.5) | 11 (55.0%) | Good |
| DDLT | 20 | 48.8 ± 14.3 | 14 (70%) | 14.5 (7.5−22.5) | 14 (70.0%) |
Table 2. Outcome of individual studies.
DDLT: Deceased donor liver transplantation; LDLT: Living donor liver transplantation
| Author, year | Arm | No. of patients | Biliary complications | Bile leak | Biliary stricture | Anastomotic leak | Anastomotic stricture |
| Garcia-Retortillo 2004 [9] | LDLT | 22 | 16 (72.7%) | - | - | - | - |
| DDLT | 95 | 21 (22.1%) | - | - | - | - | |
| Liu et al. 2006 [10] | LDLT | 124 | 32 (25.8%) | 5 (4.0%) | 31 (25.0%) | - | - |
| DDLT | 56 | 4 (7.1%) | 2 (3.6%) | 3 (5.4%) | - | - | |
| Al-Sebayel et al. 2007 [11] | LDLT | 45 | 11 (24.4%) | - | - | - | - |
| DDLT | 77 | 2 (2.5%) | - | - | - | - | |
| Freise et al. 2008 [12] | LDLT | 384 | 161 (41.9%) | 122 (31.7%) | 75 (19.5% | - | - |
| DDLT | 216 | 53 (17.9%) | 22 (10.1%) | 35 (16.2%) | - | - | |
| Lai et al. 2009 [13] | LDLT | 86 | 15 (17%) | - | - | - | - |
| DDLT | 403 | 34 (8%) | - | - | - | - | |
| Fisher et al. 2009 [14] | LDLT | 107 | 29 (27.1%) | - | - | - | - |
| DDLT | 465 | 82 (17.6%) | - | - | - | - | |
| Gómez et al. 2009 [15] | LDLT | 30 | 10 (33.3%) | 4 (13.3%) | 10 (33.3%) | 1 (33.3%) | 10 (33.3%) |
| DDLT | 357 | 34 (9.5%) | 6 (1.6%) | 27 (7.5%) | 4 (1.12%) | 27 (7.5%) | |
| Li et al. 2011 [16] | LDLT | 128 | 19 (14.8%) | 12 (9.3%) | 7 (5.4%) | - | - |
| DDLT | 221 | 24 (10.8%) | 3 (1.35%) | 15 (6.7%) | - | - | |
| Saha et al. 2012 [17] | LDLT | 18 | 5 (27.7%) | 3 (16.6%) | 2 (11,1%) | - | - |
| DDLT | 35 | 3 (8.5%) | 1 (2.8%) | 2 (5.7%) | - | - | |
| Chan et al. 2013 [18] | LDLT | 29 | - | 2 (6.8%) | 8 (27.5% | - | 8 (27.5%) |
| DDLT | 333 | - | 24 (7.2%) | 39 (11.7%) | - | 33 (9.9%) | |
| Jiang et al. 2013 [19] | LDLT | 70 | 16 (22.8%) | 7 (10%) | 9 (12.8%) | - | - |
| DDLT | 191 | 25 (13%) | 12 (6.2%) | 13 (6.8%) | - | - | |
| Lei et al. 2013 [20] | LDLT | 31 | - | 1 (3.2%) | 0 | - | - |
| DDLT | 52 | - | 1 (1.9%) | 1 (1.9%) | - | - | |
| Reichman et al. 2013 [21] | LDLT | 145 | 50 (34.4%) | 26 (17.9%) | 30 (20.6%) | - | - |
| DDLT | 145 | 25 (17.2%) | 7 (4.82%) | 18 (12.4%) | - | - | |
| Zimmerman et al. 2013 [22] | LDLT | 356 | 141 (25%) | 95 (26.6%) | 50 (14.0%) | - | - |
| DDLT | 189 | 47 (40%) | 19 (10.0%) | 29 (15.3%) | - | - | |
| Kim et al. 2014 [23] | LDLT | 21 | 2 (9.5%) | - | - | - | - |
| DDLT | 29 | 2 (6.8%) | - | - | - | - | |
| Wan et al. 2014 [24] | LDLT | 40 | - | 4 (10%) | 7 (17.5%) | - | - |
| DDLT | 80 | - | 1 (1.2%) | 5 (6.25%) | - | - | |
| Sandal et al. 2015 [25] | LDLT | 62 | 20 (32.3%) | - | - | - | - |
| DDLT | 108 | 42 (38.9%) | - | - | - | - | |
| Hu et al. 2016 [26] | LDLT | 389 | 81 (20.8%) | - | - | - | - |
| DDLT | 6471 | 721 (11.1%) | - | - | - | - | |
| Samstein et al. 2016 [27] | LDLT | 565 | - | 147 (26%) | 181 (32%) | - | - |
| DDLT | 471 | - | 42 (9%) | 99 (21%) | - | - | |
| Barbas et al. 2017 [28] | LDLT | 48 | 7 (14.5%) | 4 (8.3%) | 3 (6.25%) | - | - |
| DDLT | 128 | 6 (4.6%) | 2 (1.5%) | 4 (3.12%) | - | - | |
| Chok et al. 2017 [29] | LDLT | 54 | 2 (3.7%) | - | 2 (3.7%) | - | - |
| DDLT | 40 | 1 (2.5%) | - | 1 (2.5%) | - | - | |
| Kim et al. 2017 [30] | LDLT | 109 | 10 (9.1%) | - | - | - | - |
| DDLT | 76 | 5 (6.5%) | - | - | - | - | |
| Miyagi et al. 2017 [31] | LDLT | 168 | 29 (17.2%) | - | - | - | - |
| DDLT | 441 | 82 (18.5%) | - | - | - | - | |
| Humar et al. 2019 [32] | LDLT | 245 | 36 (14.6%) | 29 (11.8%) | 12 (4.89%) | - | - |
| DDLT | 592 | 110 (18.5%) | 42 (7.09%) | 75 (12.6%) | - | - | |
| Amara et al. 2022 [33] | LDLT | 109 | 34 (31.1%) | - | - | - | - |
| DDLT | 1684 | 314 (18.6%) | - | - | - | - | |
| Karakaya et al. 2022 [34] | LDLT | 151 | 46 (30.4%) | - | - | - | - |
| DDLT | 23 | 8 (34.7%) | - | - | - | - | |
| Meier et al. 2022 [35] | LDLT | 138 | - | 50 (36.2%) | 66 (47.8%) | - | 60 (43.4%) |
| DDLT | 276 | - | 24 (8.6%) | 87 (31.5%) | - | 64 (23.1%) | |
| Lapisatepun et al. 2023 [36] | LDLT | 20 | 8 (40%) | - | - | - | - |
| DDLT | 20 | 2 (10%) | - | - | - | - |
Figure 1. PRISMA flowchart showing the study identification, selection, and inclusion process.
PRISMA: Preferred Reporting Items for Systematic Review and Meta-Analyses
Biliary Complications
A total of 25 studies with 15,158 patients reported the incidence of post-LT biliary complications [9-17,19,21-23,15,26,28-34,36]. The pooled incidence of biliary complications with LDLT and DDLT were 24.4 (95% CI: 19.2-29.7; I2 = 92.0%) and 13.1% (95% CI: 10.6-15.5; I2 = 90.8%), respectively. LDLT was associated with significantly higher odds of biliary complications after LT with OR 2.00 (95% CI: 1.57-2.54; p < 0.000; I2 = 66%) with significant heterogeneity. On subgroup analysis of the studies based on the year of publication, with studies published on or before 2014 showing significantly higher odds of biliary complications after LT with OR 2.53 (95% CI: 1.97-3.25; p < 0.000; I2 = 39%) but comparable pooled odds in studies published after 2014 (OR 1.36, 95% CI: 0.92-2.02; p = 0.07; I2 = 74%) (Figure 2).
Figure 2. Forest plot comparing the risk of overall biliary complications between the living donor and deceased donor liver transplantation with subgroup analysis based on the year of publication.
DDLT: Deceased donor liver transplantation; LDLT: Living donor liver transplantation
Bile Leak
Overall, 15 studies with 5693 patients analyzed the risk of bile leak between LDLT and DDLT [10,12,15-22,24,27,28,32,35]. The pooled incidence of bile leak with LDLT and DDLT were 15.5 (95% CI: 9.9 - 21.3; I2 = 93.1%) and 5.0% (95% CI: 3.3-6.8; I2 = 84.1%), respectively. LDLT was associated with significantly higher odds of biliary leak after LT with OR 3.45 (95% CI: 2.58-4.61; p < 0.000; I2 = 40%) without significant heterogeneity. On subgroup analysis of the studies based on the year of publication, the odds of biliary complications were higher with LDLT in both subgroups (studies published on or before 2014 and after 2014) (Figure 3).
Figure 3. Forest plot comparing the risk of bile leak between the living donor and deceased donor liver transplantation with subgroup analysis based on the year of publication.
DDLT: Deceased donor liver transplantation; LDLT: Living donor liver transplantation
Biliary Stricture
A total of 16 studies with 5869 patients compared the risk of biliary stricture between LDLT and DDLT [10,12,15-22,24,27-29,32,35]. The pooled incidence of the biliary stricture with LDLT and DDLT were 17.2 (95% CI: 11.1-23.3; I2 = 94.8%) and 10.3% (95% CI: 6.9-13.6; I2 = 91.6%), respectively. LDLT was associated with significantly higher odds of biliary stricture after LT with OR 1.68 (95% CI: 1.19-2.39; p = 0.003; I2 = 71%) with significant heterogeneity. On subgroup analysis of the studies based on the year of publication, with studies published on or before 2014 showing significantly higher odds of biliary stricture after LT with OR 1.97 (95% CI: 1.27-3.05; p = 0.002; I2 = 63%) but comparable pooled odds in studies published after 2014 (OR 1.30, 95% CI: 0.66-2.57; p = 0.44; I2 = 83%) (Figure 4).
Figure 4. Forest plot comparing the risk of biliary stricture between the living donor and deceased donor liver transplantation with subgroup analysis based on the year of publication.
DDLT: Deceased donor liver transplantation; LDLT: Living donor liver transplantation
Publication Bias and Sensitivity Analysis
Visual inspection of the funnel plot for each of the individual outcomes showed a fairly symmetrical distribution, with the majority of the dots located at the top of the plot. This indicates a higher number of studies with greater precision without any evidence of significant publication bias for any of the outcomes (Figure 5).
Figure 5. Funnel plot for assessment of publication bias with respect to (A) biliary complications, (B) bile leak, and (C) biliary stricture.
Meta-regression analysis showed that publication year was a significant covariate contributing to heterogeneity concerning biliary complication (p = 0.0098) (Figure 6). This indicates that with progressing years, there was a significant reduction in the incidence of biliary complications with LT.
Figure 6. Bubble plot showing publication year as a significant covariate contributing to heterogeneity concerning biliary complication on meta-regression analysis.
Leave-one-out analysis and analysis after the exclusion of poor-quality studies did not show a significant difference in the overall effect size for biliary complications or bile leaks. On the exclusion of poor-quality studies, the odds of developing a biliary stricture with LDLT reduced from 1.68 (95% CI: 1.19-2.39; I2 = 71%) to 1.43 (95% CI: 1.02-2.01; I2 = 65%).
Discussion
Traditionally, the incidence of biliary complications was thought to be higher in cases of LDLT as compared to cadaveric LT. Apart from hilar dissection in LDLT contributing to de-vascularization of the bile duct and subsequent bile leak, the need to dissect the left or right hepatic duct of the recipient increases the complexities of surgery, prolongs ischemic time, and increases the risk of biliary complications. Similarly, mobilization of the recipient hepatic duct to achieve a tension-free anastomosis may lead to disturbances in blood supply to the bile duct and consequent biliary complications [3]. Ziogas et al. compared the outcome of LDLT with donation after brain death (DBD) and donation after circulatory death (DCD) in patients with cholestatic liver disease [37]. The authors reported that the risk of graft failure was comparable between LDLT and DBD but higher with DCD, which was likely due to a high rate of biliary complications with DCD. Thus, multiple factors can predispose to a higher risk of biliary complications in LDLT.
However, with advancements in surgical techniques and immunosuppression, these complications have significantly reduced in recent times in the LDLT setting, though an updated meta-analysis is lacking at present. The primary aim of this meta-analysis was to compare incidences of various biliary complications in LDLT and DDLT settings. The present meta-analysis of 28 studies showed that around one-fourth of patients with LDLT and one-seventh of patients with DDLT develop biliary complications. LDLT was associated with a significantly higher incidence of overall biliary complications, bile leak, and biliary stricture with OR of 1.96 (1.56-2.47), 3.38 (2.52-4.53), and 1.75 (1.20-2.55), respectively. On subgroup analysis, only studies published in or before 2014 had a higher incidence of biliary complications and biliary stricture with LDLT, but not with studies published after 2014. This suggests that with improvement in surgical techniques and immunosuppression, there has been a significant reduction in the rate of biliary complications.
The most common biliary complications after LT are biliary strictures, which constitute about 50% of all cases [3]. Post-LT biliary strictures may be anastomotic (AS) or non-anastomotic (NAS). Patients undergoing LDLT are at higher risk of developing AS due to small caliber bile duct and complex anastomotic techniques followed in an LDLT procedure. All but one study included in our meta-analysis had a higher incidence of biliary strictures in the LDLT setting. In the study by Humar et al., biliovascular complications between DDLT and LDLT were comparable [32]. However, in this study, patients in the LDLT group had low Model for End-Stage Liver Disease (MELD) scores. Moreover, more patients in DDLT groups had underlying HCC. Both high MELD scores and underlying HCC have been shown to be associated with a higher risk of biliary complications [38].
In line with biliary strictures, bile leaks were also found to be higher in LDLT in most of the included studies. Like biliary strictures, bile leaks can be anastomotic or non-anastomotic. The most common type of bile leak is anastomotic, with most of the cases occurring within four weeks of LT [3]. An older review reported that the incidence of biliary stricture ranges from 5% to 15% after DDLT and 28% to 32% after LDLT [39]. In agreement with this study, our meta-analysis also found that the incidence of bile leaks continues to be higher in LDLT settings. More importantly, in a recent study by Meier et al., the incidence of bile leak was as high as 36% in LDLT in contrast to 7%-10% in the DDLT setting [35]. With respect to the timing of the development of biliary stricture, Chan et al. reported that although there was a tendency for a more delayed onset of stricture with LDLT, the mean time to stricture onset was not significantly different between the two groups (98 ±17 vs. 172±65 days, P=0.11) [18]. Zimmerman et al. also did not show any difference in the median time from transplant to onset of a biliary leak or stricture [22].
The strength of the present meta-analysis remains in the fact that the present meta-analysis included the development of biliary complications as the primary outcome, while the previous meta-analyses included it as a secondary outcome, leading to the non-inclusion of many studies. Our study, though, is an updated meta-analysis including recent studies; nevertheless, it had a few limitations. Most of the included studies were retrospective. Some of the studies also included pediatric recipients who tend to have a higher risk of biliary complications after LT, although reanalysis after exclusion of the studies did not change the risk. More importantly, the type of LT (DDLT vs. LDLT) is only one of the many risk factors for having biliary complications after transplantation (e.g., ABO-incompatible liver transplantation, cytomegalovirus infection after LT, high MELD scores, presence of underlying HCC, ischemia times and type of biliary reconstruction) [3,39]. None of these factors have been separately analyzed in our study (because of the retrospective nature of most of the studies). We could not compare the risk of anastomotic and non-anastomotic strictures separately, as the data regarding the same were not available in the majority of the studies. None of the included studies in our meta-analysis looked separately into incidences of nonanastomotic strictures (NAS) in DDLT and LDLT settings. Similarly, rare biliary complications after LT, like choledocholithiasis, bile cast, hemobilia, and sphincter of Oddi dysfunction, have not been analyzed. Lastly, there was significant heterogeneity for all the outcomes reducing the strength of evidence.
Conclusions
To conclude, biliary complications, including biliary strictures and bile leaks, continue to be major causes of morbidity and mortality after LT. LDLT is associated with a higher incidence of biliary complications, including bile leak and biliary stricture, compared to DDLT. While improved surgical techniques and immunosuppression have reduced the incidence of biliary complications significantly, more is left to be desired. Further high-quality prospective studies are needed to provide a reliable database to compare the incidence of biliary complications between LDLT and DDLT.
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:
Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.
Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.
Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.
Author Contributions
Concept and design: Suprabhat Giri, Vedavyas Mohapatra, Manas Panigrahi, Preetam Nath, Bipadabhanjan Mallick, Dibya L. Praharaj
Acquisition, analysis, or interpretation of data: Suprabhat Giri, Saroj K. Sahu, Mansi Chaudhary
Drafting of the manuscript: Suprabhat Giri, Saroj K. Sahu, Dibya L. Praharaj
Critical review of the manuscript for important intellectual content: Suprabhat Giri, Saroj K. Sahu, Vedavyas Mohapatra, Mansi Chaudhary, Manas Panigrahi, Preetam Nath, Bipadabhanjan Mallick, Dibya L. Praharaj
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