Presence of multiple bile ducts in the liver graft increases the incidence of biliary complications in pediatric liver transplantation

Authors

  • Paolo R.O. Salvalaggio,

    1. Department of Surgery, Children's Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL
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  • Peter F. Whitington,

    1. Department of Pediatrics, Children's Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL
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  • Estella M. Alonso,

    1. Department of Pediatrics, Children's Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL
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  • Riccardo A. Superina

    Corresponding author
    1. Department of Surgery, Children's Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL
    • Department of Pediatric Surgery, Northwestern University Feinberg School of Medicine, 700 W Fullerton St., Suite N745, Chicago, IL 60614
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    • Telephone: 773-975-8821; FAX: 773-975-8534


Abstract

We studied the impact of multiple bile duct anastomosis on the development of biliary complications after liver transplantation in children. A total of 101 patients received a primary liver transplant and were divided into 2 groups: those with a single bile duct (n = 77) and those with multiple bile ducts (n = 24). Mean follow-up was 39.8 ± 20.8 months. A total of 27 patients presented with biliary complications (26.7%), 18 patients (18.7%) presented with early complications (12 leaks and 6 strictures), and 9 patients (8.9%) had late strictures. Hepatic artery thrombosis (HAT) and multiple bile ducts were significant risk factors for the development of biliary complications, and the presence of multiple bile ducts was an independent risk factor. Patients with multiple bile ducts had a significantly greater incidence of total biliary complications compared to those with single ducts. Patients with multiple ducts had a higher incidence of leaks when compared to those in the single duct group, but the incidence of strictures, both early and late, was similar in both groups. One-year patient and graft survivals were not statistically different in the 2 groups. In conclusion, the presence of more than one bile duct in the graft is an independent risk factor for the development of biliary complications after pediatric liver transplantation. (Liver Transpl 2005;11:161-166.)

Liver transplantation is the definitive treatment for end-stage liver disease in children.1 Posttransplantation biliary complications occur in 15 to 35% of pediatric liver transplant recipients and are associated with a high rate of morbidity and mortality. Bile duct complications delay recovery from the transplant, reduce the quality of life of children, and may reduce the function and long-term survival of the allograft.2–9

Reduced size, split, and living related liver transplant techniques have decreased the amount of time spent waiting for a transplant as well as the death rate of children on the waiting list.10–12 However, some series have suggested that the incidence of biliary complications has increased with the use of these techniques.6, 13–15 In contrast, others have shown that the incidence of biliary complications is not affected by the use of these techniques and that the initial high rate of biliary complications decreases after the initial learning experience.2, 16, 17

Prolonged cold-ischemia, hepatic artery thrombosis (HAT), cytomegalovirus infection, and chronic rejection have also been linked to an increased incidence of biliary complications.2, 3, 9, 18, 19 However, the presence of multiple bile ducts in the graft has rarely been studied as a risk factor for biliary complication after liver transplantation in children.3

Our study retrospectively analyzed our results to identify risk factors for the development of biliary complications and to determine the importance of the presence of multiple ducts in the incidence of biliary complications after liver transplantation.

Abbreviations:

HAT, hepatic artery thrombosis.

Materials and Methods

Collection of Data, Inclusion Criteria, and Follow-up

Between August 1997 and September 2003, 122 pediatric patients underwent 160 liver transplants at Children's Memorial Hospital. Medical records and the transplant database were reviewed to identify patients who developed biliary complications. This study includes the 101 patients who underwent primary liver transplantation at our institution and have at least 1 year of follow-up. A patient that received a graft from an ABO blood group incompatible donor was excluded from this analysis. Mean follow-up was 39.8 ± 20.8 (range 17-73) months. The Institutional Review Board of Children's Memorial Institute approved this study for education and research.

Demographics

Demographics and main indications for transplantation of the patients included in the study are shown in Table 1.

Table 1. Demographics of Pediatric Patients at Children's Memorial Hospital
  1. Abbreviations: LL, left lobe of the liver; LLS, left lateral segment of the liver; RL, right lobe of the liver.

Age<1 year old52 (51%)
 >1 year old49 (49%)
GenderBoys53 (52%)
 Girls48 (48%)
Weight<10 kg52 (51%)
 >10 kg49 (49%)
DiagnosisBiliary atresia39 (39%)
 Non-biliary atresia62 (61%)
GraftWhole36 (36%)
 Split16 (16%)
 Reduction14 (14%)
 Living donor35 (35%)
Anatomical unityWhole36 (36%)
 LL14 (14%)
 LLS50 (50%)
 RL1 (1%)

Surgical Technique and Protocols

The technique of whole organ pediatric orthotopic liver transplantation and reduced-size techniques have been previously described in detail.10–12, 20–23 Grafts were implanted by the means of the “piggyback” technique whenever possible without the use of venous-venous bypass. A total of 94 patients underwent Roux-en-Y choledochojejunostomy (92%) and 8 children underwent choledochocholedochostomy (8%). For both types of reconstruction, the biliary anastomosis was performed with a single layer of polydioxanone-interrupted sutures. Ducts smaller than 2 mm were stented internally with short polyethylene catheters. Bile ducts found along the liver plate were ligated if they were not judged to be important (usually smaller than 1 mm). In borderline circumstances when the importance of a very small duct was questionable, an anastomosis was performed. External drains were kept in the right subphrenic space and below the biliary anastomosis for at least 7 days. Immunosuppression consisted of a calcineurin inhibitor (usually cyclosporine), azathioprine, and steroids for all patients. Doppler ultrasound was used to confirm flow in the portal vein and hepatic artery during the first 3 days after transplantation in all patients in this study.

Assessment of Biliary Complications

Biliary complication was defined as any deviation from the expected postoperative course caused by a problem in the biliary anastomosis. A biliary complication was diagnosed using clinical and biochemical criteria and confirmed radiologically. Ultrasonography was usually the initial radiological investigation, followed by transhepatic cholangiography. Computed tomography (CT) or biliary scintigraphy was utilized as indicated. For analysis, biliary complications were divided into leaks and strictures. Leaks were confirmed by the presence of bile staining in the external drains, by radiological methods or at laparotomy. Strictures were diagnosed 1st by ultrasound and confirmed by percutaneous transhepatic cholangiogram. Strictures diagnosed before the 1st year after transplant were defined as early strictures, and those after 1 year as late strictures. All leaks were defined as early complications. Early biliary complications include leaks and early biliary strictures.

Risk Factors for Biliary Complications

Potential risk factors for biliary complications that were reviewed in our analysis included: recipient gender, age, and type of disease; length of surgery; cold ischemia time; donor source (deceased vs. living donor); type of graft used (whole organ vs. reduced size technical variants); type of biliary reconstruction (Roux-en-Y choledochojejunostomy vs. choledochocholedochostomy); relative amount of intraoperative transfused blood; presence of HAT; presence of cytomegalovirus infection; presence of acute rejection; and number of bile ducts.

Number of Bile Ducts

The number of bile ducts was defined as the number of biliary anastomosis that were performed for biliary reconstruction. According to the reconstruction described in the operating note, patients were subsequently divided into 2 groups: those with single bile duct grafts (single bile duct group; n = 77) and those with multiple bile duct grafts (multiple bile duct group; n = 24). Small bile ducts that were sutured closed during surgery were not counted.

Statistical Analysis

Continuous data are expressed as the mean ± standard deviation. Actuarial curves of patient and graft survival were compared by the log-rank test according to the Kaplan-Meier survival analysis. For univariate analysis, the significance of differences between groups was determined by Student's t-test for unpaired populations or Mann-Whitney test for continuous data and by chi-square statistic and Fisher's exact test for categorical data. For multivariate analysis, analysis of variance was utilized for comparison between the variables. Statistical analysis was performed with the use of In Stat version 3.0 (Graph Pad Software, San Diego, CA) and StatView JMP version 5 (SAS Institute, Cary, NC) statistical software. For all comparisons, P < .05 was considered to be statistically significant.

Results

A total of 36 children received a whole organ and 65 received a reduced-size technical variant graft (1 right lobe, 14 left lobes, and 50 left lateral segments). Technical variant allografts included 16 split livers, 35 organs from live donors, and 14 livers that were reduced from cadaveric organs in which only 1 portion of the liver was used for transplantation.

Rate of Biliary Complications

A total of 27 patients presented with biliary complications (26.7%); 18 patients (17.8%) presented with early complications (12 leaks and 6 strictures) and 9 patients (8.9%) had late strictures.

Risk Factors for Biliary Complications

By univariate analysis (Table 2), only HAT (P = .03) and the presence of multiple bile ducts (P = .04) were significant risk factors for the development of biliary complications.

Table 2. Results of Univariate Analysis of the Risk Factors for the Overall Number of Biliary Complications
VariablesIncidenceP Value
  • *

    P < .05.

  • Abbreviations: HAT, hepatic artery thrombosis; LL, left lobe of the liver; LLS, left lateral segment of the liver; CJ, choledochojejunostomy; CC, choledochocholedochostomy; CMV, cytomegalovirus.

HAT (yes vs. no)53.8% vs. 22.7%.03*
Cold ischemia time (<12 hours vs. >12 hours)25% vs. 28.4%.83
CMV infection or disease (yes vs. no)34% vs. 28.5%.88
Episodes of acute rejection (yes vs. no)28.8% vs. 23.8%.65
Age (<1 year old vs. >1 year old)32.4% vs. 28.8%.79
Gender (boys vs. girls)32.6% vs. 20.8%.18
Weight (<10 kg vs. >10 kg)29.7% vs. 26%.67
Blood transfusion (<2 units of blood vs. >2 units of blood)20% vs. 30%.37
Type of biliary reconstruction (CJ vs. CC)26.8% vs. 25%.90
Length of surgery (<6 hours vs. >6 hours)28.5% vs. 30.4%.88
Diagnosis (biliary atresia vs. nonbiliary atresia)25.6% vs. 23.5%.20
Anatomical unity (LL vs. LLS)28.5% vs. 30%.26
Performance of technical variant (yes vs. no)30.7% vs. 19.4% 
Type of technical variant  
 Split vs.18.7% vs..44
 Reduction vs.35.7% vs. 
 Living-donor graft34.2% 
Graft source (decreased donor vs. living-donor graft)25.4% vs. 34.2%.44
Number of bile ducts (single vs. multiple)22% vs. 42%.04*

Effect of Multiple Ducts on Biliary Complications

Of 101 patients, 24 (23.7%) had more than 1 bile duct anastomosis. Of the 24 grafts with multiple bile ducts, 20 (83%) were segment 2-3 (left lateral segments) grafts, 3 (12%) were segment 2-3-4 (left lobes) grafts, and 1 was a segment 5-6-7-8 (right lobe) graft. A total of 19 (79%) of the grafts with multiple ducts originated from live donors. Table 3A demonstrates that there was no difference in age, size of recipients, cold ischemia time, or incidence of HAT between those with single and those with multiple bile duct grafts. In fact, the cold ischemia time for recipients in the multiple bile ducts group ranged from 2 to 12 hours (average 5.6 ± 3.1 hours) and for patients in the single bile duct group it ranged from 2 to 14 hours (average 7.4 ± 2.7 hours), P > .05. Therefore, the presence of multiple bile ducts was an independent risk factor for the development of biliary complications. Patients with multiple bile ducts had a significantly greater incidence of total biliary complications compared to those with single bile ducts (10 / 24 [42%] vs. 17 / 77 [22%]; P < .05). This difference was observed primarily in the incidence of biliary leaks. Patients with multiple bile ducts tended to have a higher incidence of leaks when compared to those in the single bile duct group (21 vs. 9%), but the incidence of strictures, both early and late, was similar in both groups (Table 3B).

Table 3. Characteristics of the Allografts (A) and Biliary Complications (B) According to the Number of Bile Ducts in the Grafts
A. Allografts
 Age (<1 year)Weight (<10 kg)TCI (>12 hours)HAT OccurrenceGraft Variant*Reduced Size Grafts
LLLLS
  • *

    P < .0001 between the groups.

  • P < .05 between the groups.

  • Abbreviations: SDG, single duct group; MDG, multiple duct group; TCI, time of cold ischemia; HAT, hepatic artery thrombosis; Graft Variant, splits, reductions, and living related transplants; LL, left lobe of the liver; LLS, left lateral segment of the liver.

SDG (n = 77)31 (40%)34 (44%)5 (7%)10 (13%)41 (54%)11 (14%)30 (40%)
MDG (n = 24)16 (66%)14 (58%)3 (12%)3 (12%)24 (100%)3 (12%)20 (88%)
B. Biliary Complications
CharacteristicsSingle Bile Duct Group (n = 77)Multiple Bile Duct Group (n = 24)P Value
Biliary complications17 (22%)10 (42%).04
Leaks7 (9%)5 (21%).02
Strictures10 (13%)5 (21%).44
Early strictures4 (5%)2 (8%).62
Late strictures6 (8%)3 (12%).44
Early complications11 (14%)7 (29%).09

Multiple Bile Ducts in the Absence of HAT

If patients with HAT were excluded from the analysis, the effect of multiple bile ducts on the incidence of biliary complications persisted. Patients with single bile ducts had only a 6% incidence of leaks compared to 14% in those with multiple ducts (P > .05). Table 4 shows that the overall incidence of biliary complications in patients with intact arterial flow was significantly less in those with single bile duct than in those with multiple bile ducts (18 vs. 38%; P = .04).

Table 4. Impact of the Presence of Multiple Bile Ducts in the Absence of Hepatic Artery Thrombosis
CharacteristicsSingle Bile Duct Group (n = 67)Multiple Bile Duct Group (n = 21)P Value
  • *

    P < .05 between the groups.

Biliary complications12 (18%)8 (38%).04*
Leaks4 (6%)3 (14%).21
Strictures8 (12%)5 (24%).28
Early strictures3 (4%)2 (9%).38
Late strictures5 (8%)3 (14%).38
Early complications7 (10%)6 (28%).11

Impact of Multiple Ducts on Patient and Graft Survival

Although patients with multiple bile ducts had a higher incidence of biliary complications, there was no statistical difference in early or late patient or graft survival between the 2 groups. Figure 1 illustrates that short- and long-term graft and patient survival are equivalent for patients with single or multiple bile ducts. One-year patient and graft survival was 89 and 81% for the single bile duct group compared to 76 and 73% for the multiple bile duct group (P = not significant). Three-year patient and graft survival was 86 and 80% for the single bile duct group compared to and 70 and 64% for the multiple bile ducts group (P = not significant). Even though the survival differences were not significant at 3 years after transplantation, there is a definite trend toward decreased survival in patients with more than 1 duct, which may become significant as more patients are added to the series.

Figure 1.

(A) Patient and (B) graft survival in patients according to the number of bile ducts.

Discussion

Sir Roy Calne24 characterized biliary reconstruction as the Achilles heel of liver transplantation. Even with the recent advances in immunosuppression, organ preservation, patient management, expansion of the donor pool, and surgical techniques, biliary complications are still a cause of significant morbidity after liver transplantation. For children, biliary complications may be particularly problematic since their treatment may involve additional surgery, repeated radiological procedures, and placement of external drains that interfere with the quality of life, growth, and development and may compromise the function and the survival of the allograft.2–9

The main causes of early posttransplant biliary complications are technical errors and HAT.3 As expected, HAT was associated with a very high incidence of biliary complications in our patients, for which retransplantation was usually necessary because of bile duct necrosis or intrahepatic biliary strictures not amenable to dilatation. Microvascular techniques to decrease the incidence of HAT and salvage operations to revascularize grafts acutely after HAT has occurred may result in a decline in the incidence of bile duct complications related to ischemic duct damage.22, 25

However, the technical challenges of reconstructing separate small segmental ducts are considerable. With the increasing utilization of split and live donor segment 2-3 grafts for transplantation of small children, separate segmental ducts are frequently encountered. Over one-half (57%) of live donor grafts and 40% of segment 2-3 grafts in our series required at least 2 biliary anastomosis, 4 required 3 anastomoses, and 1 graft required 4 anastomoses. Broelsch et al.12 emphasized the importance of separate reimplantation of these very small ducts.

As discussed above, the presence of HAT was associated with biliary complications. However, other potential risk factors that have previously been associated with an increased likelihood of biliary complications, such as prolonged cold ischemia, number of episodes of acute rejection, development of chronic rejection, utilization of technical variant grafts, type of biliary reconstruction, age below 1 year or weight below 10 kg, and presence of cytomegalovirus infection were not found to be risk factors in our series.6, 26 Other risk factors that have been linked to the development of biliary complications, such as intrapulmonary shunting, warm ischemia time, and the use of stents for biliary reconstruction were not investigated in this series.3

The association of multiple bile ducts and a higher incidence of biliary complication may appear intuitively obvious, but the association has not been extensively studied. This is the first report that links the presence of multiple bile ducts in the liver allograft to the development of biliary complications. These complications are problematic, but they do not appear to change patient and graft survival, although our data does demonstrate that there is a tendency toward decreased survival in those with more than 1 duct, presumably because of the higher incidence of complications.

The Kyoto Group has reported their experience in the management of biliary complications with living related liver transplantation. Although they have observed a higher rate of biliary complication with the presence of stents for biliary reconstruction, no difference was observed with the presence of single or multiple biliary anastomosis.3

Early leaks and strictures remain among the most common complications after liver transplantation. Unlike late strictures, which may be related to chronic rejection, cholangitis, and other nontechnical issues, early complications not accompanied by HAT are likely related to surgical technique. Small multiple bile ducts offer a greater likelihood of leaking or being stenosed. Our operative methods have been refined with time. Currently, ducts that are less than 2 mm in diameter are stented internally to prevent postoperative edema from obstructing bile flow, and to prevent surgeons from inadvertently stitching the posterior bile duct wall during the performance of the anterior bile duct wall anastomosis. It has not been proven that this technique actually decreases leaks or stenosis, but it remains in use.

In this study, we have not correlated the presence of multiple ducts with the presence of aberrant arterial anatomy. It is possible that ligation of aberrant arterial branches may lead to the development of biliary complications.3 Egawa et al.3 described no relationship between lateral or medial side accessory artery ligation and biliary complications in living related liver transplantation. Whether this explains the higher incidence of biliary complications in the multiple bile ducts group still needs to be reviewed.

Our single-center study was performed retrospectively and is therefore subject to the usual limitations. In addition, it is possible that with a larger study population, we might have been able to demonstrate statistical significance where we found only trends or a numerical difference. Multicenter reviews of the effect of the number of bile ducts on outcome after transplantation may be useful in reinforcing our findings.

In summary, we have reviewed a number of risk factors for the development of biliary complications after pediatric liver transplantation. We found that HAT and the presence of multiple bile ducts were associated with a higher rate of biliary complications. The presence of multiple bile ducts also increases the relative risk of the occurrence of bile leaks. The risk of biliary complications is not associated with the cold ischemic time, size, anatomical segment, or source of the graft, but with the number of bile ducts and the complexity of the biliary reconstruction.

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