Biliary complications following orthotopic liver transplantation: a 10-year audit

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ORIGINAL ARTICLE

Biliary complications following orthotopic liver transplantation:

a 10-year audit

Nalaka Gunawansa1, John L. McCall2, Andrew Holden3, Lindsay Plank4& Stephen R. Munn4,5

1National Hospital of Sri Lanka and New Zealand Liver Transplant Unit, National Hospital of Sri Lanka, Colombo, Sri Lanka,2Department of Surgery, Faculty of Medicine, University of Otago, Dunedin, New Zealand,3Department of Radiology, Auckland City Hospital, Auckland, New Zealand,4Department of Surgery, Faculty of Medicine, University of Auckland, Auckland, New Zealand and5Department of Surgery, Auckland District Health Board, Auckland, New Zealand

Abstracthpb_300391..399

Background: Biliary complications following liver transplantation result in major morbidity. We under-took a 10-year audit of the incidence, management and outcomes of post-transplant biliary complications at the New Zealand Liver Transplant Unit.

Methods: Prospectively collected data on 348 consecutive liver transplants performed between February 1998 and October 2008 were reviewed. The minimum follow-up was 6 months.

Results: A total of 309 adult and 39 paediatric transplants were performed over the study period. Of these, 296 (85%) were whole liver grafts and 52 (15%) were partial liver grafts (24 split-liver, eight reduced-size and 20 live-donor grafts). There were 80 biliary complications, which included 63 (18%) strictures and 17 (5%) bile leaks. Partial graft, a paediatric recipient and a Roux-en-Y biliary anastomosis were independent predictors of biliary strictures. Twenty-five (40%) strictures were successfully managed non-operatively and 38 (60%) required surgery (31 biliary reconstructions, three segmental resections and four retransplants). Seven (41%) bile leaks required surgical revision and 10 (59%) were managed non-operatively. There was no mortality related directly to biliary complications.

Conclusions: Biliary complications affected one in five transplant recipients. Paediatric status, partial graft and Roux-en-Y anastomosis were independently associated with the occurrence of biliary strictures. Over half of the affected patients required surgical revision, but no mortality resulted from biliary complications.

Keywords

liver,transplant,outcomes

Received 23 September 2010; accepted 24 January 2011

Correspondence

Nalaka Gunawansa, National Hospital of Sri Lanka and New Zealand Liver Transplant Unit, National Hospital of Sri Lanka, Colombo 0110, Sri Lanka. Tel:+ 94 773 737644. Fax: + 94 112 698 443. E-mail: nalakagunawansa@yahoo.co.uk

Introduction

Biliary complications following orthotopic liver transplantation (OLT) remain a common problem despite advances in organ procurement, preservation and surgical technique. Reported inci-dences of post-transplant biliary complications are around 10–25%1–3 and such complications result in significant patient

morbidity and occasional graft loss. The incidence of biliary com-plications has also been influenced by the increased use of partial liver (PL) grafts, which include reduced-size grafts, split-liver grafts and live-donor grafts.

The New Zealand Liver Transplant Unit (NZLTU) was initiated in February 1998 with adult recipients, using only whole liver (WL) grafts. The first paediatric recipient was transplanted in 2002, since when paediatric transplants have represented an average of six to eight of the 36–40 OLTs carried out per annum. Until May 2009, all WL grafts are sourced from donors after brain death and do not include any organs donated after cardiac death.

This paper was presented at the 2009 Annual Meeting of the Transplant Society of Australia and New Zealand, 17–19 June 2009, Canberra, Australia.

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The first PL transplant was performed in 2002, as was the first transplant from a live donor. There has since been a steady increase in the use of PL grafts in both paediatric and adult recipi-ents. The protocol for allograft preservation has also changed twice during this 10-year period.

The purpose of this study was to review the first 10 years of OLT at the NZLTU to identify the incidence, associated risk factors, management and outcomes of post-OLT biliary complications.

Materials and methods

A prospective database of all patients undergoing transplantation at the NZLTU has been maintained. The current study is based on an analysis of these prospectively collected data, supplemented by inpatient and outpatient clinical records and subsidiary databases of radiological and endoscopic interventions performed in OLT recipients.

A biliary stricture was defined as any narrowing in the bile ducts identified on post-transplant imaging that was associated with graft dysfunction and required intervention by radiological, endoscopic or surgical means. The indications for imaging were graft dysfunction detected by elevated serum transaminases, clinical evidence of sepsis or features of biliary stasis on allograft biopsy. Routine cholangiography was not performed. Imaging of the biliary tree was performed using either magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP). Percutaneous transhepatic cholangiography (PTC) was performed if ERCP either failed or was not possible as a result of a Roux-en-Y (ReY) biliary anastomosis.

Three different organ preservation techniques were used during the 10-year study period. From February 1998 to June 2002, Uni-versity of Wisconsin perfusion fluid (UWS) was infused in situ under gravitational pressure. From July 2002 to August 2007, an additional 500 mL of UWS was infused under arterial pressure perfusion (APP) on the back-table (UWS + APP). From Septem-ber 2007 to OctoSeptem-ber 2008, a low-viscosity perfusion fluid, histi-dine tryptophan ketaglutarate (HTK), was infused in situ under gravitational pressure without the addition of back-table APP.

The preferred technique for bile duct reconstruction was duct-to-duct choledocho-choledochostomy (D–D) below the donor cystic duct, using interrupted sutures. A stent or T-tube was not used. In most paediatric recipients, in retransplants and in recipi-ents with primary sclerosing cholangitis (PSC), an ReY was per-formed using the same anastomotic technique. Post-transplant immunosuppression was standardized with prednisone and tac-rolimus combination in the majority of patients, while those with pre-OLT renal dysfunction were managed with prednisone and i.v. dacluzimab or basiliximab induction along with mycophe-nalate mofetil and delayed introduction of low-dose tacrolimus.

Patient and donor variables included in the analysis were: recipient age (paediatric<14 years, adult ⱖ14 years); donor age (<50 years, ⱖ50 years); type of graft (WL, PL); cold ischaemia

time (CIT;<10 h, ⱖ10 h); warm ischaemia time (WIT; <45 min, ⱖ45 min); graft preservation solution and technique (UWS, UWS + APP, HTK); type of biliary anastomosis (D–D, ReY), and asso-ciated presence or absence of hepatic artery stenosis (HAS) or thrombosis (HAT).

Initially, biliary strictures were managed with endoscopic or radiological dilatation and stenting. Endoscopic therapy was always used as the preferred mode of non-operative treatment, with balloon cholangioplasty and stenting. Covered stents and, more recently, multiple stenting were used for anastomotic strictures (AS), whereas uncovered stents were used in non-anastomotic strictures (NAS) involving the intrahepatic biliary tree. Percutaneous radiological therapy using standard pigtail stents was reserved for those with an ReY, failure of endoscopic therapy or for isolated intrahepatic NAS. A combination of endoscopic and radiological techniques was used for inserting internal–external stents in complex strictures. Choledochoscopy was not used routinely in the management of these strictures. Repeat imaging, dilatation and stenting were undertaken at inter-vals of approximately 6 weeks or earlier if there was clinical or biochemical evidence of stent blockage. This process was contin-ued until the stricture had either resolved completely or the treat-ment was deemed to have failed (generally after 4–6 months of non-operative therapy), at which point surgical revision of the biliary anastomosis was offered. In the presence of severe NAS limited to one area of the allograft, segmental liver resection was performed when non-operative approaches were unsuccessful. Retransplantation was considered when all non-operative and operative treatment options had been exhausted.

The data were entered into an electronic database and statistical analysis carried out using sas Version 9.1 (SAS Institute, Inc., Cary, NC, USA). Descriptive statistics have been used to characterize the study population. Variables such as WIT and CIT have been categorized and used as categorical variables in order to facilitate a comparison between our findings and results reported in the literature. Univariate and multivariate logistic regression analyses were performed to identify factors associated with the presence of biliary strictures. For these analyses, recipient age, donor age and ischaemic times were dichotomized.

Results

During the study period, 348 consecutive OLTs were performed in 338 recipients. A total of 38 (11%) recipients died during follow-up, including three inpatients (inpatient mortality 0.8%). The causes of the three inpatient deaths were massive stroke (post-OLT day 16), pneumonia-induced septicaemia (post-(post-OLT day 5) and HAT (post-OLT day 4). Of the remaining 35 deaths, none were a direct result of biliary complications and follow-up was complete until the time of death. Follow-up of all remaining 310 recipients was complete to February 2009; the median length of follow-up was 69 months (range: 6–132 months).

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Recipients included 309 (89%) adult and 39 (11%) paediatric patients. Of the transplant recipients, 296 (85%) recipients, including seven paediatric patients, received WL grafts and the remaining 52 (15%) received PL grafts. The PL grafts comprised 24 split-liver grafts, eight reduced-size grafts and 20 live-donor grafts. Demographic details of the recipient population, donor population and transplant procedures are shown in Table 1.

There were 80 biliary complications in 70 recipients (overall biliary complication rate 20%). These included 17 (5%) bile leaks and 63 (18%) biliary strictures (ten patients had both leak and stricture). Breakdowns and outcomes of the bile leaks and biliary strictures are shown in Figs 1 and 2, respectively. Bile leaks were diagnosed at a median of 17 days (range: 1–31 days) post-transplant. Eight of the 11 (73%) anastomotic leaks progressed to strictures despite treatment and were managed according to the protocol for biliary strictures. Two such AS following bile leaks progressed despite endoscopic stenting and were managed by biliary reconstruction. The remaining six strictures were successfully managed by endoscopic stenting.

Of the 63 patients who developed bile duct strictures, 46 (73%) had AS, nine (14%) had NAS and eight (13%) had mixed stric-tures (AS + NAS). The median time to presentation was 121 days (range: 5–1296 days) after OLT. On univariate analysis the factors significantly associated with biliary strictures were PL graft, HTK preservation solution, ReY biliary anastomosis and HAS or HAT. On multivariate analysis, the only factors independently associ-ated with biliary stricture were PL graft, ReY anastomosis and paediatric status (Table 2).

A subgroup analysis was carried out for all adult recipients of WL grafts (n = 289) to further minimize any bias created by strong predictors such as paediatric status and PL graft. This demonstrated HTK preservation solution and an ReY biliary anastomosis to be independent risk factors for the occurrence of biliary strictures (Table 3).

Twenty-five (40%) patients with biliary strictures were success-fully managed by endoscopic or radiological dilatation and stent-ing. Thirteen of these were managed by endoscopy and stenting alone, with a median of three (range: 1–8) endoscopic stent insertion/exchange procedures. The median time to stricture resolution was 61 days (range: 36–118 days). The remaining 12 patients underwent radiology-guided percutaneous stent insertion or combined ERCP and percutaneous treatment. In one patient, the stricture was associated with late HAS and required concomitant hepatic artery stenting. The median time to complete resolution with percutaneous stenting was 109 days (range: 74–236 days), during which a median of four (range: 2–9) interventions were carried out.

Thirty-eight (60%) patients in whom strictures did not respond to non-surgical treatment underwent surgical revision. Of these, 31 underwent biliary reconstruction with an ReY hepati-cojejunostomy. The overall success rate of post-stricture ReY biliary reconstruction was 87% (27/31). The four patients who developed recurrent strictures after biliary reconstruction were

treated with PTC dilatation and stenting (n = 2), surgical re-revision (n = 1) and retransplantation (n = 1). Four patients with severe ischaemic cholangiopathy secondary to HAS or HAT were not suitable for reconstruction. Three were successfully retransplanted, but the fourth exhibited an unrelated malignancy

Table 1Demographic information

Variable/characteristics n %

Patient characteristics

Age (median= 43 years; range: 5 months to 69 years)

Paediatric,<14 years 39 11

Adult,ⱖ14 years 309 89

Gender

Male 190 55

Female 158 45

Aetiology of liver disease

Fulminant 26 7

Primary sclerosing cholangitis 24 7

Primary biliary cirrhosis 13 4

Hepatitis B 67 19 Hepatitis C 76 22 Cryptogenic 31 9 Alcohol-related 29 8 Autoimmune 8 2 Budd–Chiari syndrome 11 3

Biliary atresia/Alagille syndrome 27 8

Retransplants 10 3

Hepatic artery thrombosis/primary non-function 6 2

Other 20 6

Donor characteristics

Age (median= 40 years; range: 5–79 years)

Age<50 years 235 68 Ageⱖ50 years 113 32 Gender Male 184 53 Female 164 47 Transplant characteristics

Warm ischaemia (median= 8 min; range: 28–69 min)

<45 min 239 69

ⱖ45 min 109 31

Cold ischaemia (median= 439 min; range: 106–916 min)

<10 h 226 65 ⱖ10 h 112 35 Graft size Whole liver 296 85 Split-liver graft 24 7 Reduced-size graft 8 2 Live-donor graft 20 6

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and was not considered for retransplantation. Three patients with segmental NAS were managed with segmental liver resections.

Discussion

This study represents a complete audit of biliary complications in 348 consecutive OLTs performed at the NZLTU over a 10-year period. The overall rate of biliary complications was 20% and rates of occurrence of strictures and bile leaks were 18% and 5%, respectively. Most patients with anastomotic bile leaks went on to develop subsequent AS (Fig. 3). Overall, 40% of the strictures were successfully managed by non-operative interventions and 60% eventually required surgical correction. Four patients under-went retransplantation, but no mortality directly related to biliary complications occurred.

The reported incidence of post-transplant biliary strictures varies widely among different study groups depending on the extent of follow-up and the nature of the study population. In deceased-donor transplants, the reported incidence is 5–15%,2,4

whereas in living-donor transplants it may be as high as 32%.5–7

The incidence in the present study, which included all transplant types, falls within this range. Similarly, the incidence of bile l eaks is within the reported range of 2–15%.2,8,9

Many factors have been reported to be associated with the occurrence of post-transplant biliary strictures. These include paediatric status,10 recurrent PSC,11 advanced donor age,12,13

donation after cardiac death,14,15 prolonged WIT and CIT,16,17

ABO incompatibility,18,19type of biliary reconstruction,20,21HAS

or HAT,22,23 postoperative bile leak,24,25 severe rejection,26 and

cytomegalovirus (CMV) infection.27 Interestingly, donor age,

WIT and CIT were not found to be independently associated with biliary strictures in our study. The allograft bile ducts are perfused exclusively from the hepatic arterial blood supply. Therefore, any compromise in the hepatic artery will result in bile duct ischaemia, leading to stricture formation. Six of 16 (38%) recipients of transplants that were complicated by HAS or HAT in our series went on to develop bile duct strictures. Although HAS/HAT was not found to be an independent risk factor for biliary strictures in the statistical analysis, three of the four patients who required retransplantation had concomitant arterial problems.

The higher incidence of biliary problems among recipients of PL grafts is related to the small calibre of the ducts and the poten-tial for the compromise of the periductal vascular supply during the preparation of such grafts.28,29Leaks from small unrecognized

tributaries or the cut surface may also contribute. An ReY biliary

Bile leaks (n = 17)

Anastomotic leaks (n = 11)

Cut surface leaks (n = 4)

Cystic duct stump leaks (n = 2) ERCP + stenting Percutaneous drainage (n = 2) Surgical repair (n = 2) Surgical repair (n = 5) ERCP + stenting (n = 6) Progression to AS (n = 10) (n = 6) (n = 4) Treated as AS

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anastomosis was found to be an independent risk factor for stricture formation, even when paediatric recipients and PL grafts were excluded (Table 2). Bacterial colonization of the biliary tree originating from the choledochojejunal anastomosis may account for the increased risk associated with an ReY.

The ischaemic-type biliary lesion (ITBL) (Fig. 4) refers to cho-langiopathy that occurs in the absence of a recognized cause, such as HAS/HAT, recurrent PSC or chronic ductopaenic rejection.30,31

Reported incidences of ITBL vary widely among transplant centres and range from as little as 1.4% to as much as 26.0%.13,32–34

This inconsistency probably reflects a lack of consensus on the

definition of ITBL as the term is sometimes used to describe all NAS. Although the aetiology of ITBL is multifactorial, one of the mechanisms strongly implicated is ischaemic injury to the biliary tree during organ procurement and preservation.16,35 In this

study, we attempted to identify any possible association of organ preservation method with the incidence of ITBL.

The biliary epithelium is supplied solely from the hepatic artery via small end-arteries and is therefore vulnerable to incomplete perfusion during flushing with preservation fluid. University of Wisconsin perfusion fluid has high viscosity at the low temperatures used for organ preservation, and is

theoreti-Successful resolution (n = 25) (15 AS, 7 AS+NAS, 3 NAS)

Recurrent stricture

(n = 38) (31 AS, 6 NAS, 1 AS+NAS)

Segmental liver resection (n = 3) (NAS)

Considered for re-transplant (n = 4) (3 NAS, 1 AS+NAS)

Successfully re-transplanted (n = 3) (NAS)

Palliative care (n = 1) (AS+NAS) Surgical biliary reconstruction

(n = 31) (AS) Successful resolution (n = 27) Recurrent stricture (n = 4) Successfully re-transplanted (n = 1)

Second round of PTC dilatation and stenting (n = 2) ERCP/PTC balloon dilatation /stenting (n = 62) Open surgical access tube insertion (n = 1) Biliary strictures

(n = 63) (46 AS, 8 AS+NAS, 9 NAS)

Second surgical reconstruction (n = 1)

Figure 2Outcome of post-transplant biliary strictures. AS, anastomotic stricture; NAS, non-anastomotic stricture; ERCP, endoscopic retrograde cholangiopancreatography; PTC, percutaneous transhepatic cholangiography

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cally disadvantageous in this regard. Others have reported that hepatic APP with UWS reduces the risk for ITBL.13An

alterna-tive strategy is to use low-viscosity perfusion solutions such as HTK.32We used both of these methods during the study period

and, interestingly, found that HTK was associated with an increased rate of biliary strictures among adult recipients with WL grafts. We conducted separate comparisons for AS and NAS, but found no clear association of perfusion technique or solu-tion with purely NAS. When the patient with concomitant HAS and NAS was excluded, only eight cases of ITBL were identified in total; these included three of 128 (2%) patients in whom UWS standard perfusion had been performed, five of 174 (3%) patients who received UWS + APP, and no HTK patients. Hence, the small number of ITBLs encountered may limit our ability to draw any conclusions regarding the effect of preservation tech-nique on ITBL. Nevertheless, a recent large study using registry data found that HTK was associated with worse graft and patient survival in liver transplantation, including live donor

transplan-tation.36Based on these findings, as well as our own experience,

we have changed our practice again and returned to using UWS as the preferred preservation solution.

One of the limitations of the present study is the retrospective nature of its data analysis despite our access to a comprehensive prospective database. In addition, as discussed earlier, changes in graft type and perfusion technique occurred over the study period. Further, the aetiology of the liver disease leading to OLT was not considered in the analysis. Additional donor characteris-tics (other than age), such as extended criteria donation, were not considered separately because of the difficulties of retrieving such data in a retrospective manner. The small sample size of ITBL and HAT cases probably limits our ability to make definite recommen-dations based on this study. However, as the NZLTU is the only liver transplant unit in New Zealand, our study population was all-inclusive and longterm follow-up data were available for all patients. We also included all biliary problems regardless of other factors such as vascular pathology. The findings are therefore

Table 2Univariate and multivariate analysis for the presence of biliary strictures in all transplant recipients (n= 348)

Variables Total

transplants, n

Biliary strictures,

n (%)

Univariate analysis Multivariate analysis

OR (95% CI) P-value OR (95% CI) P-value

Recipient age 0.79 (0.37–1.85) 0.57 5.10 (1.40–18.56) 0.014 <14 years 39 9 (23) ⱖ14 years 309 54 (17.5) Donor age 1.08 (0.61–1.91) 0.79 1.24 (0.68–2.29) 0.48 ⱖ50 years 113 22 (19.5) <50 years 235 41 (17.4) Graft 2.59 (1.34–5.01) 0.0046 3.10 (1.11–8.69) 0.031 Partial liver 52 16 (30.8) Whole liver 296 47 (15.9)

Cold ischaemia time 1.11 (0.63–1.93) 0.73 1.34 (0.72–2.50) 0.36

ⱖ10 h 122 23 (18.9)

<10 h 226 40 (17.7)

Warm ischaemia time 1.49 (0.81–2.02) 0.39 1.71 (0.96–2.37) 0.15

ⱖ45 min 109 21 (19.3) <45 min 239 42 (17.6) Preservation UWS 128 17 (13.3) UWS+ APP 174 33 (19.0) 1.53 (0.82–2.94) 0.19 1.65 (0.82–3.33) 0.17 HTK 46 13 (28.2) 3.16 (1.42–7.03) 0.0048 2.34 (0.93–5.88) 0.07 Biliary anastomosis 2.66 (1.48–4.79) 0.0011 3.28 (1.54–6.99) 0.002 Roux-en-Y 75 23 (30.7) D–D 273 40 (14.7)

Hepatic artery disease 3.50 (1.17–10.46) 0.025 2.76 (0.84–9.11) 0.095

HAS/HAT+ 16 06 (37.5)

HAS/HAT- 332 57 (17.2)

OR, odds ratio; 95% CI, 95% confidence interval; UWS, University of Wisconsin perfusion fluid; APP, arterial pressure perfusion; HTK, histidine tryptophan ketaglutarate infusion; D–D, duct-to-duct choledocho-choledochostomy; HAS, hepatic artery stenosis; HAT, hepatic artery thrombosis

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inclusive and representative of a real-world experience and are not subject to incomplete follow-up or selection bias.

In conclusion, post-transplant biliary complications remain a major cause of morbidity following OLT, affecting one in five patients. Initial endoscopic or percutaneous management

was successful in 40% of patients, whereas surgical treatment was required in 60%. Retransplantation was rarely required in the absence of concomitant arterial pathology and no mortality occurred as a direct result of biliary complications.

Table 3Univariate and multivariate analysis for the presence of biliary strictures in whole graft adult recipients (n= 289)

Variables Univariate analysis Multivariate analysis

Odds ratio 95% CI P-value Odds ratio 95% CI P-value

Donor age

ⱖ50 years, <50 years 0.95 0.50–1.82 0.89 0.94 0.48–1.85 0.87

Cold ischaemia time

ⱖ10 h, <10 h 1.14 0.60–2.15 0.69 1.35 0.68–2.71 0.40

Warm ischaemia time

ⱖ45 min, <45 min 1.55 0.87–2.12 0.30 1.67 0.88–2.30 0.11 Preservation UWS vs. APP 1.23 0.62–2.43 0.56 1.58 0.75–3.33 0.23 UWS vs. HTK 2.70 1.06–6.86 0.04 2.86 1.04–7.89 0.04 Biliary anastomosis ReY, D–D 3.89 1.79–8.47 0.0006 3.89 1.73–8.74 0.001

Hepatic artery disease

HAS/HAT+ 3.04 0.853–10.821 0.086 2.88 0.75–11.09 0.12

HAS/HAT-95% CI, HAS/HAT-95% confidence interval; UWS, University of Wisconsin perfusion fluid; APP, arterial pressure perfusion; HTK, histidine trypto-phan ketaglutarate infusion; ReY, Roux-en-Y; D–D, duct-to-duct choledocho-choledochostomy; HAS, hepatic artery stenosis; HAT, hepatic artery thrombosis

Figure 3Anastomotic biliary stricture (WL transplant presenting at post-operative day 37)

Figure 4Non-anastomotic biliary strictures complicating an anastomotic stricture (WL transplant presenting at post-operative day 51)

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Acknowledgements

The authors would like to acknowledge P. Johnston (transplant surgeon), Associate Professor E. Gane and Dr D. Orr (hepatologists), Drs D. Duncan and C. Kennedy (interventional radiologists), and Drs S. Chin, H. Evans and S. Mouat (paediatric hepatologists), all of whom contributed to the clinical management of the patients referred to in this study.

Conflicts of interest

None declared.

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