Significant allograft dysfunction after liver transplantation is suggested by persistently raised serum liver enzymes, with elevated transaminases being indicative of acute and progressive processes such as acute cellular rejection, hepatitis, or hepatic artery thrombosis. Elevated alkaline phosphatase and gamma-glutamyl transferase are commonly seen, but are often less specific and more difficult to interpret.1, 2 A proportion of patients with cholangitic symptoms, bile duct dilatation on ultrasound, or features of bile duct obstruction on liver biopsy, will have a radiologically significant bile duct stricture on endoscopic retrograde cholangiopancreatography,3–5 and where endoscopic therapy (either balloon dilatation or stenting) fails,6 these patients usually undergo biliary reconstructive surgery (HJ).7–11 However, the role of surgery in the management of bile duct strictures after liver transplantation has not been established. The aims of this study were to analyze liver biopsy findings in patients with bile duct strictures, with particular reference to the presence of coexisting pathologies, and to determine the functional significance of strictures indirectly by examining the effect of biliary reconstruction on allograft function.
There is no accurate method to determine the functional significance of bile duct strictures after liver transplantation, and although biliary reconstructive surgery (Roux-en-Y hepaticojejunostomy, HJ) is the second-line treatment in patients with persistent allograft dysfunction following failed endoscopic therapy, there is no evidence to support this approach. Liver transplant recipients with allograft dysfunction and demonstrable bile duct strictures who had undergone hepaticojejunostomy were identified from a prospective database. Preoperative and follow-up clinical, biochemical, and radiological data were collected. Perioperative liver biopsies were evaluated prospectively by two histopathologists blinded to clinical information. The biopsies were scored according to presence and severity of biliary features, fibrosis, and coexisting diseases. The effects of preoperative factors on postoperative allograft function were analyzed using SPSS statistical software. After hepatico-jejunostomy, graft function returned to normal in 8/44 patients (18%), improved in 16/44 (36%), but remained abnormal in 20/44 (45%), including 4 patients who subsequently underwent retransplantation. Hepaticojejunostomy was more likely to yield a favorable outcome (improved or normal graft function) when performed within 2 years of transplantation. Prolonged duration of biliary obstruction was associated with development of advanced graft fibrosis at the time of surgery, but neither factor significantly influenced postoperative graft function. In conclusion, biliary reconstruction successfully restores graft function in the majority of patients who present with anastomotic strictures within the first 2 years after liver transplantation. In patients presenting with bile duct strictures late after transplantation, surgery should be reserved for selected patients without histological evidence of graft fibrosis (moderate–severe) or significant nonbiliary pathology. (Liver Transpl 2004;10:928–.934)
Patients and Methods
Over a 14-year period (42 whole organ liver allografts), 44 patients (24 male, 20 female, mean age 50 ± 13 years) underwent HJ because of isolated extrahepatic biliary strictures (Table 1). Preoperatively, all patients were evaluated by ultrasound and either endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography. In cases in which hepatic artery thrombosis could not be excluded by ultrasound, patients also underwent hepatic angiography. All patients underwent liver biopsy at the time of surgery. Patients were followed (median of 51 months; range 2–117) by routine clinical evaluation and liver function tests, and underwent liver biopsy when clinically indicated. Perioperative liver biopsy specimens were reviewed at the time of compilation of this report by two histopathologists who were blinded to clinical outcome. Biopsies were scored according to presence/severity of biliary features (edema and neutrophilic/eosinophilic infiltration of portal tracts, cholestasis, ductular proliferation, biliary interface activity, and deposition of copper-associated orcein-positive granules), severity of fibrosis, and presence of other pathologies. Fibrosis was scored on scale from 0–4 according to Scheuer.12 Mean immunosuppressant drug levels (tacrolimus, cyclosporine A, or mycophenolate mofetil) were determined for each patient, but as assay methodology has changed during the study period (cyclosporine A assay changed from Fluorescent Polarization Immunoassay for the Abbott TDx analyzers (TDx FPIA) to Fluorescent Polarization Immunoassay for the Abbott AxSYM analyzers (AxSYM FPIA) on 20 January 1998; tacrolimus assay changed from IMx1 to Imx2 on 11 February 1997), for purposes of comparison, old levels were converted to current assay equivalents using derived formulas (cyclosporine A: (N – 6.8)/1.33; tacrolimus: (N × 1.05) – 1.81).13, 14 Patients were grouped according to postoperative allograft function, and preoperative variables, including histology, were compared between groups.
|Postoperative Allograft Function|
|Improved or Resolved||Progressive|
|Age (yrs)||48 ± 13||53 ± 13|
|Gender (female : male)||5:7||1:1|
|Median follow-up (months)||58||42|
|Indication for OLT (n)|
|Acute liver failure||4||3|
|Primary biliary cirrhosis||5||6|
|Primary sclerosing cholangitis||2||0|
|Alcoholic liver disease||3||5|
|Alpha-1 antitrypsin deficiency||0||1|
|Biliary anastomosis (n)|
|T-tube (n, %)||4 (17%)||6 (30%)|
|Cold ischaemia time (hours)||8.9 ± 3.3||8.4 ± 4.1|
|Hepatic artery thrombosis (n, %)||1||2|
|Anastomotic stricture||17 (71%)||10 (50%)|
|Preoperative Bilirubin (1–20 μmol/l)||50 ± 33||49 ± 41|
|Preoperative AST (10–50 U/L)||101 ± 64||90 ± 86|
|Preoperative ALP (30–130 U/L)||324 ± 183||299 ± 185|
|Preoperative γGT (1–55 U/L)||536 ± 364||407 ± 371|
|Duct dilatation on ultrasonography (n, %)||14 (58%)||11 (55%)|
|Radiological intervention (stent or balloon dilation) (n, %)||5 (21%)||6 (30%)|
|Time from OLT to Biliary reconstruction (months) (mean ± SD)||34 ± 33||47 ± 37|
|>24 months from OLT to biliary reconstruction (n, %)*||8 (33%)||13 (65%)|
Continuous variables are expressed as means ± standard deviation. Differences between groups were analyzed using one-way analysis of variance (continuous data) and independent t test (categorical data). Statistical analysis was done using SPSS statistical software (SPSS, Chicago, IL).
Clinical and Laboratory
All patients underwent orthotopic liver transplantation with ABO compatible allografts. Primary indications for orthotopic liver transplantation are presented in Table 1. Bile duct anastomoses were direct (end-to-end) in 30 cases, gallbladder conduit in 9, and HJ in 5. Mean cold ischemia time was 8.7 ± 3.6 hours. Post-transplant, all 44 patients developed allograft dysfunction with an obstructive pattern of liver enzyme derangement. Mean bilirubin, aspartate transaminase, alkaline phosphatase, and gamma-glutamyl transferase levels prior to HJ were 50 ± 36 μmol/L, 96 ± 74 IU/L, 312 ± 182 IU/L, and 478 ± 368 IU/L, respectively.
Mean bilirubin, aspartate transaminase, alkaline phosphatase, and gamma-glutamyl transferase in patients with normal/improved and abnormal allograft function were 50 ± 33 vs. 49 ± 41μmol/L, 35 ± 18 vs. 85 ± 118 IU/L, 132 ± 78 vs. 367 ± 228 IU/L, and 107 ± 98 vs. 476 ± 489 IU/L, respectively. There was no significant difference in age, gender, median follow-up, or indication for orthotopic liver transplantation between patients with abnormal allograft function and patients with normal or improved allograft function (Table 1).
Duct dilation was evident on ultrasonographic examination in 25 patients, and endoscopic retrograde cholangiopancreatography, which was possible in 43 patients, demonstrated 27 anastomotic and 8 nonanastomotic strictures. Other diagnoses were duct dilatation (4), stones (3), and cholangiopathy (1). Hepatic artery thrombosis was diagnosed preoperatively in 3 patients. All patients (including 11 who had balloon dilatation or stent placement) underwent HJ at a median of 23 months (range 2–126) after liver transplantation.
Perioperative Liver Biopsies
Out of 39 available biopsy specimens, 29 (74%) displayed predominantly biliary features, alone in 20 cases and in combination with other pathological features in 9 (chronic rejection, 3; viral-like hepatitis, 1; recurrent primary biliary cirrhosis, 2; and recurrent hepatitis C, 3). Features of either rejection or disease recurrence were the most frequently observed nonbiliary pathology (32 and 37%, respectively) in patients without biliary features preoperatively (n = 10; Table 2).
|Patient||Primary diagnosis||Preoperative pathology||Preoperative advanced fibrosis||Postoperative graft function||Postoperative pathology|
|4||Alcoholic cirrhosis||Biliary||No||Abnormal||Cholestasis + rejection|
|5||Primary biliary cirrhosis||Biliary||No||Abnormal||Cholangiopathy|
|6||Seronegative hepatitis||Biliary||No||Abnormal||Rejection + HCV|
|7||Acute hepatitis B||Biliary + Hepatitis||No||Abnormal||HBV|
|8||Primary biliary cirrhosis||Biliary + Rejection||No||Abnormal||Rejection|
|10||Seronegative hepatitis||Biliary||Yes||Abnormal||Cholestasis + rejection|
|11||α1 antitrypsin deficiency||—||No||Abnormal||—|
|12||Primary biliary cirrhosis||Biliary + Rejection||No||Abnormal||Rejection|
|13||Autoimmune hepatitis||Biliary||No||Abnormal||Recurrent A1 hepatitis|
|14||Primary biliary cirrhosis||Hepatitis||Yes||Abnormal||NRH|
|19||Primary biliary cirrhosis||Ischaemia||No||Abnormal||Fibrosis|
|20||Primary biliary cirrhosis||Cirrhosis||No||Abnormal||—|
|21||Budd-Chiari syndrome||Biliary + Rejection||No||Improved||Cholangiopathy|
|22||Primary biliary cirrhosis||Biliary||No||Improved||—|
|24||Primary biliary cirrhosis||Biliary||No||Improved||Steatohepatitis|
|25||Primary biliary cirrhosis||Biliary + PBC||No||Improved||—|
|28||Primary biliary cirrhosis||Biliary + PBC||Yes||Improved||Cholangiopathy + NRH|
|29||PSC||Hepatitis||No||Improved||Biliary + fibrosis|
|30||HCV Cirrhosis||Biliary||Yes||Improved||Cholangiopathy + HCV|
|31||HCV Cirrhosis||Biliary + HCV||Yes||Improved||Biliary + HCV|
|32||Acute liver failure||Rejection||No||Improved||Rejection|
|37||Primary biliary cirrhosis||Biliary||No||Normal||NRH|
|42||HCV Cirrhosis||Biliary + HCV||No||Normal||—|
|44||HCV Cirrhosis||Biliary + HCV||Yes||Normal||—|
Advanced fibrosis (grade 3 or 4) was present in 12/39% of biopsies taken at the time of HJ (31%), including biopsies taken in two patients with normal allograft function at follow-up. There was significant correlation between the duration of biliary features prior to biliary reconstruction (defined as the time between the earliest available biopsy showing biliary features and biliary reconstruction) and the presence of advanced fibrosis at the time of reconstruction (OR 1.05; 95% CI 1.00–1.10; P = .04, see Figs. 1 and 2). The median duration of biliary features in patients with and without advanced fibrosis at the time of surgery was 21 (range 1–108) and 4 months (range 1–84), respectively. Correlation between duration of biliary features and presence of advanced fibrosis was also evident on multivariate analysis, although it was not of statistical significance (P = .06).
Clinical and Laboratory
After a median follow-up of 51 months (range 3–117) after HJ, allograft function returned to normal in 8 patients (18%), improved in 16 (36%), and remained abnormal in 20 (45%) (Table 2). Postoperative complications occurred in 8 patients (18%) and there were no perioperative deaths. In the group of 20 patients with abnormal allograft function, 2 patients underwent unsuccessful HJ revision at 4 months and 7 years. Four patients required retransplantation, 2 for chronic rejection and 2 for recurrent viral hepatitis (B and C).
Postoperative Liver Biopsies
Follow-up biopsies were available for comparison in 23 out of 44 patients (including 13 out of 20 patients with persistently abnormal allograft function; Table 2). Of 20 cases with isolated biliary features at the time of reconstruction, postoperative allograft function returned to normal in 4 (20%), improved in 6 (30%), and remained abnormal in 10 (50%). Follow-up biopsies were obtained in 9 (including 5/10 patients with abnormal postoperative allograft function) and showed persistence of biliary features in 4 (isolated in 2 and associated with rejection in 2) and presence of other pathologies in the remainder (rejection, 2; recurrent autoimmune hepatitis, 1; steatohepatitis, 1; nodular regenerative hyperplasia, 1).
Where biliary features coexisted with features of other pathologies (n = 9), allograft function remained abnormal in 33%, improved in 44%, and returned to normal in 22%. Follow-up biopsies, which were available in 6, showed resolution of biliary features in 3 (all with abnormal allograft function, due to hepatitis B recurrence in 1 and rejection in 2), and residual biliary features in the remaining 3 (all with an improvement in allograft function). In 3 patients who had biliary features coexisting with features of hepatitis C recurrence preoperatively, allograft function returned to normal after surgery in 2 patients, and improved in a patient who had advanced fibrosis preoperatively and persistent biliary features postoperatively.
Allograft function failed to return to normal in 90% of patients (9/10), with preoperative biopsies lacking biliary features; follow-up biopsies available in 7 showed features of rejection (3), fibrosis (2), hepatitis (1), or nodular regenerative hyperplasia (1). In the 6 patients with features of rejection on preoperative biopsy (isolated in 3 and associated with biliary features in 3), follow-up biopsies showed ongoing rejection in 4 (3 of whom had progressive allograft dysfunction) and cholangiopathy in 1. Of patients with follow-up biopsies that showed chronic rejection, 70% were classified perioperatively as “biliary,” and 36% of all biopsies that showed rejection also had biliary features. In the 4 patients with hepatitis on preoperative biopsies, postoperative biopsies showed nodular regenerative hyperplasia, biliary features with fibrosis, chronic rejection, and autoimmune-like hepatitis.
Effect of Preoperative Parameters on Postoperative Allograft Function
Timing of HJ after orthotopic liver transplantation was the only factor that significantly influenced postoperative allograft function on univariate analysis. Of 23 patients, 16 (70%) who underwent early HJ (within 2 years of transplantation) had normal or improved allograft function at follow-up, in contrast to only 8 of 21 (38%) patients who had delayed HJ (OR, 3.71; 95% CI 1.06–12.97; P = .04; Fig. 1). Of patients who underwent early HJ, 67% had anastomotic strictures, compared to only 29% of those who had delayed HJ (chi-squared, P = .02), and allograft function improved in 63% of cases with anastomotic strictures vs. 41% of cases without (P = .14). Of patients who underwent early HJ, 21% had previous endoscopic therapy, compared to 50% of patients who had delayed HJ (P = .19; Fisher's exact test). Using logistic regression analysis of allograft outcome, and considering the following categorical variables: time from orthotopic liver transplantation to HJ greater than 2 years; presence of advanced fibrosis; type of stricture (anastomotic or other); and previous endoscopic therapy, there remained a strong association between timing of HJ and outcome after surgery, although it was not statistically significant (OR, 4.58; 95% CI 0.94–22.45; P = .06). Age, gender, primary diagnosis, type of biliary anastomosis, preoperative endoscopic therapy, presence of an anastomotic stricture, hepatic artery thrombosis, preoperative allograft function, or year of surgery had no significant effect on outcome after HJ (Table 1). There was no significant association between either duration of biliary features or presence of advanced fibrosis and postoperative allograft function (P = .13 and .24, respectively). Timing of HJ (less than 2 years post-transplant) had a positive predictive value for normal/improved postoperative allograft function of 68%. Corresponding values for the remaining preoperative variables are shown in Table 3. There was no difference in exposure to immunosuppression between patients with abnormal and normal/improved allograft function at follow-up. All patients with hepatic artery thrombosis (n = 3) presented with late biliary strictures. Of these, postoperative allograft function remained abnormal in 2 patients with nonanastomotic strictures, but improved in 1 patient who had an anastomotic stricture. Based on our findings, we have suggested an algorithm that may be useful in identifying which patients with bile duct strictures should be offered biliary reconstructive surgery (Fig. 3).
|Preoperative Variable||Positive Predictive Value||P Value|
|HJ < 2 years post-OLT||68%||.04|
|Absence of viral etiology||51%||NS|
|Absence of PBC/PSC diagnosis||55%||NS|
|US: dilated ducts||56%||NS|
|ERCP: anastomotic stricture||63%||NS|
|Presence of biliary features||55%||NS|
|Absence of co-existing pathology||50%||NS|
|Presence of advanced fibrosis||53%||NS|
Of this cohort of patients with demonstrable bile duct obstruction, 49% had histological evidence of nonbiliary pathology, including 26% who had no biliary features, and 27% who had advanced allograft fibrosis at the time of biliary reconstructive surgery (Table 2). Postoperatively, liver function failed to returned to normal in 82% of patients, and biliary features, when present perioperatively, resolved in only 53%. Allograft loss was due to nonbiliary causes in all 4 cases (rejection and recurrent viral hepatitis). These data suggest that the presence of coexisting disease processes contributes significantly to allograft dysfunction in this group of patients, and that bile duct obstruction plays a role in only a minority. Morbidity and graft loss associated with post-transplant bile duct strictures in earlier reports are probably due to coexisting disease processes rather than obstruction to bile flow.3, 7–9
An adverse outcome following biliary reconstructive surgery (progressive deterioration in allograft dysfunction) was significantly more likely in patients with allograft dysfunction developing more than 2 years after liver transplantation (OR, 3.71; P = .04; Fig. 1). Only 1/3 of patients undergoing HJ after 2 years had anastomotic strictures, in contrast to 2/3 of patients undergoing surgery earlier (P = .02). Improved allograft function after surgery was more likely in patients who had anastomotic strictures (including 1 patient with concomitant hepatic artery thrombosis) than in those without, but this was not significant (63% vs. 41%, P = .14). Local factors, including injury to the vascular supply and size discrepancy between donor and recipient bile ducts, are likely to be responsible for the majority of anastomotic strictures,1 which present early after transplantation with allograft dysfunction that is responsive to biliary reconstructive surgery. The etiology of nonanastomotic strictures is poorly understood and probably multifactorial.7, 9, 15, 16 Disease processes such as rejection, recurrence of primary liver disease (including hepatitis C, primary biliary cirrhosis, and primary sclerosing cholangitis), and nodular regenerative hyperplasia, although sometimes evident early after transplantation, tend to become clinically manifest later, and in such patients, a stricture may be incidental and not contributing to allograft dysfunction. It may be secondary to another pathology, such as rejection, or it may coexist with another pathology and exacerbate allograft dysfunction. Of the patients in this series, 67% had histological evidence of nonbiliary pathology (including rejection in 28%) either perioperatively or at follow-up (Table 2).
Although liver biopsy plays an important role in the management of patients with allograft dysfunction, in this study the presence of either nonbiliary pathology or advanced fibrosis did not necessarily predict an adverse outcome after biliary reconstructive surgery in patients with bile duct strictures. This reflects difficulties associated with the interpretation of post-transplant liver biopsies and assessing the biological significance of anatomical strictures.2, 17, 18 Sampling errors may occur if a disease process such as ischemia or fibrosis is not distributed uniformly throughout the graft parenchyma. A similar pattern of ductopenia and duct loss can be seen in a variety of disease processes, including rejection and biliary obstruction,17, 18 and in the early stages it may not be possible to distinguish between the two. In our study, 70% of patients with follow-up biopsies that showed chronic rejection were classified perioperatively as “biliary,” and 36% of all biopsies that showed rejection also had biliary features (Table 2).
In patients with bile duct strictures after liver transplantation, allograft dysfunction is predominantly due to the presence of coexisting diseases (e.g., rejection), particularly in cases presenting more than 2 years after transplantation with nonanastomotic strictures. The presence of “biliary features” on liver biopsy does not predict a positive outcome after surgery, but the absence of such features argues against surgical reconstruction. Biliary reconstructive surgery is indicated for patients presenting with anastomotic strictures and early allograft dysfunction, while in patients presenting late, its role is less clear. In particular, patients with nonanastomotic strictures combined with unfavorable allograft histology (presence of severe fibrosis and lack of biliary features) are unlikely to benefit from surgery.
The decision to perform biliary reconstructive surgery in patients with anastomotic bile duct strictures should be based upon careful clinical and histological evaluation. Liver biopsy is particularly important in patients with delayed allograft dysfunction and a history of viral liver disease, primary biliary cirrhosis (PBC), or primary sclerosing cholangitis (PSC) following orthotopic liver transplantation.
A.M. was kindly supported by an ESOT-Novartis Scholarship.