- Email: [email protected]
Primary Sclerosing Cholangitis: Role of Extrahepatic Biliary Resection
Primary Sclerosing Cholangitis: Role of Extrahepatic Biliary Resection Timothy M Pawlik, MD, MPH, FACS, Vanessa A Olbrecht, MD, Henry A Pitt, MD, FACS, Ana L Gleisner, MD, Michael A Choti, MD, MBA, FACS, Richard D Schulick, MD, FACS, John L Cameron, MD, FACS Most centers advocate orthotopic liver transplantation (OLT) for patients with primary sclerosing cholangitis (PSC) and cirrhosis. Management of PSC patients without cirrhosis remains controversial. We examined the results of extrahepatic biliary resection (EHBR) for PSC. STUDY DESIGN: Between 1981 and 2006, 126 patients with PSC underwent EHBR (n ⫽ 77) or OLT (n ⫽ 49). Data on biliary drainage procedures, perioperative morbidity, and longterm survival were collected and analyzed. RESULTS: Of 77 patients undergoing EHBR, mean preoperative bilirubin level was 5.6 mg/dL. Nine (11.7%) patients had cirrhosis. Most patients had preoperative biliary drainage (ERCP, 61.0%; PTC, 67.5%). At operation, 73 (94.8%) patients underwent EHBR, including hepatic duct bifurcation. Most patients also had insertion of bilateral transhepatic silicone elastomer biliary stents; 4 (5.2%) underwent EHBR with stent insertion plus hepatectomy. For EHBR patients, perioperative complication rate was 38.7% and 30-day mortality was 3.9%. Bilirubin levels significantly decreased postoperatively (mean drop 3.8 mg/dL; p ⬍ 0.01). At 3 years, 57.1% of patients had no PSC-related readmissions, and 16.2% had more than 3. At a median followup of 10.5 years, 5- and 10-year survival was 76.4% and 52.7%, respectively. Cholangiocarcinoma did not develop in any patients, and only seven required OLT. Factors associated with worse survival included postoperative bilirubin ⱖ 2 mg/dL and history of cirrhosis (both p ⬍ 0.001). In patients undergoing EHBR, noncirrhotic patients had significantly better longterm outcomes versus cirrhotic patients (10-year survival, 60.2% versus 12.0%; p ⬍ 0.001). In contrast, 10-year survival of OLT patients with cirrhosis was 57.0%. CONCLUSIONS: Noncirrhotic patients with PSC can be successfully managed with EHBR. EHBR for noncirrhotic patients is associated with low perioperative morbidity, few readmissions, no new cholangiocarcinomas, and 10-year survival ⬎ 60%. OLT should be reserved for patients with PSC and associated hepatic cirrhosis. (J Am Coll Surg 2008;206:822–832. © 2008 by the American College of Surgeons) BACKGROUND:
women and is strongly associated with inflammatory bowel disease, particularly ulcerative colitis.2-5 PSC is also associated with increased risk of cholangiocarcinoma, with series showing cancer developing in 8% to 30% of patients with time.2,6,7 Although orthotopic liver transplantation (OLT) remains the only effective therapy for patients with PSC after development of end-stage liver disease, treatment ear-
Primary sclerosing cholangitis (PSC) is an idiopathic chronic cholestatic disease of the liver characterized by inflammation that leads to fibrosis and stricturing of the intra- and extrahepatic biliary tree. In most patients, PSC is progressive and eventually results in end-stage liver disease and cirrhosis.1 PSC occurs twice as often in men as in Competing Interests Declared: None. Dr Pawlik is supported by grant number 1KL2RR025006-01 from the National Center for Research Resources, a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Ana Gleisner is supported by an International Union Against Cancer/American Cancer Society Beginning Investigators Fellowship funded by the American Cancer Society and by a grant from CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior). This article represents the personal viewpoints of the authors and cannot be construed as a statement of official National Center for Research Resources or National Institutes of Health policy.
© 2008 by the American College of Surgeons Published by Elsevier Inc.
Presented at the Southern Surgical Association 119th Annual Meeting, Hot Springs, VA, December 2007. Received November 29, 2007; Accepted December 1, 2007. From the Departments of Surgery, Johns Hopkins University Hospital, Baltimore, MD (Pawlik, Olbrecht, Gleisner, Choti, Schulick, Cameron) and Indiana University School of Medicine, Indianapolis, IN (Pitt). Correspondence address: Timothy M Pawlik, MD, MPH, FACS, Department of Surgery, Johns Hopkins University Hospital, Halsted 614, 600 N Wolfe St, Baltimore, MD, 21287. email: [email protected]
822
ISSN 1072-7515/08/$34.00 doi:10.1016/j.jamcollsurg.2007.12.015
Vol. 206, No. 5, May 2008
Pawlik et al
Surgical Resection for Primary Sclerosing Cholangitis
823
Abbreviations and Acronyms
EHBR INR OLT PSC
⫽ ⫽ ⫽ ⫽
extrahepatic biliary resection international normalized ratio orthotopic liver transplantation primary sclerosing cholangitis
lier in the course of the disease remains controversial. Currently, early treatment options include medical therapy, endoscopic or percutaneous dilation or stenting,8,9 and various surgical procedures. Beginning in the early 1980s, several studies examined the use of surgical resection of the extrahepatic biliary tree for treatment of PSC.10-14 It was noted that even though PSC usually involved the entire intra- and extrahepatic biliary tree, the most severe stricturing was at the hepatic duct bifurcation. Most of these series involved resecting the bifurcation and the entire extrahepatic biliary tree. These studies were limited because of their small sample size and inadequate longterm followup. As such, many surgeons continue to consider OLT as the only definitive form of therapy for patients with PSC and dominant strictures.15,16 Other investigators10,12-14,17 have advocated for extrahepatic biliary resection (EHBR) in carefully selected noncirrhotic patients with PSC. The role of surgical treatment and general management of noncirrhotic patients with PSC remains unclear. The purpose of this study was to investigate the role of EHBR and determine perioperative morbidity and longterm survival in the largest cohort of patients with the longest followup of any series published to date.
METHODS Between 1981 and 2006, 126 patients with PSC underwent EHBR at the Johns Hopkins University Hospital (n ⫽ 65), Indiana University (n ⫽ 5), and the Medical College of Wisconsin (n ⫽ 7), or OLT at Johns Hopkins University Hospital (n ⫽ 49). The study was approved by the institutional review boards at the respective institutions. Only patients with a diagnosis of PSC at the time of operation were included in the current study. Specifically, all patients had cholangiographic findings consistent with a diagnosis of PSC, including stricturing of the bile ducts.18 Often, the most severe stricturing was at the hepatic duct bifurcation. Cholangiographic findings were supported by a clinical history and histologic specimens consistent with PSC. Operations were usually performed because of persistent hyperbilirubinemia and a dominant stricture, usually at the bifurcation (Fig. 1). Operations were occasionally performed to rule out cholangiocarcinoma. Nine patients with PSC and cholangiocarcinoma based on pathology results were included in the current study. Patients with scle-
Figure 1. (A) Preoperative cholangiogram with right transhepatic stent across right hepatic duct stricture. (B) Postoperative cholangiogram after resection of hepatic duct bifurcation, bilateral cholangiojejunostomies, and transhepatic stents.
rosing cholangitis because of any known secondary causes were excluded. All patients undergoing EHBR underwent excision of the hepatic duct bifurcation and the extrahepatic biliary tree. Generally, reconstruction through bilateral hepatic jejunostomies also included insertion of bilateral transhepatic silicone elastomer stents, which were left in longterm. After operation, all patients were followed regularly and monitored prospectively. Standard demographic, clinico-
824
Pawlik et al
Surgical Resection for Primary Sclerosing Cholangitis
J Am Coll Surg
Table 1. Clinical Characteristics of Study Patients Stratified by Operation Type (n ⫽ 126) Variable
Demographics Age (y), mean ⫾ SD Male gender Race, n (%) Caucasian African American Other Presenting symptoms, n (%) Jaundice Pruritus Pain History of cholangitis Associated diseases, n (%) Inflammatory bowel disease Ulcerative colitis Crohn’s disease NOS None Cirrhosis Portal hypertension Splenomegaly Diabetes Preoperative laboratory values, mean ⫾ SD Bilirubin (mg/dL) Creatinine (mg/dL) Prothrombin time (INR) Albumin (g/dL) MELD Previous biliary drainage, n (%) Percutaneous approach Endoscopic approach Previous hospitalization(s)
EHBR (n ⴝ 77)
Transplantation (n ⴝ 49)
50.1 ⫾ 13.7 47 (61.0)
46.2 ⫾ 11.5 33 (67.3)
0.101 0.473
63 (81.8) 13 (16.9) 1 (1.3)
39 (79.6) 8 (16.3) 2 (4.1)
0.756
62 (80.5) 37 (48.1) 30 (39.0) 30 (39.0)
44 (89.8) 28 (57.1) 23 (46.9) 22 (44.9)
0.165 0.320 0.377 0.509
20 (20.6) 9 (11.7) 1 (1.3) 47 (61.0) 9 (11.7) 5 (6.5) 4 (5.2) 11 (14.3)
22 (44.9) 14 (28.6) 3 (6.1) 10 (20.4) 39 (79.6) 30 (61.2) 30 (61.2) 4 (8.2)
0.028 0.017 0.132 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 0.301
5.6 ⫾ 6.9 1.0 ⫾ 0.4 1.1 ⫾ 0.1 3.7 ⫾ 0.6 13.0 ⫾ 4.0
9.2 ⫾ 10.6 0.9 ⫾ 0.4 1.3 ⫾ 0.5 3.2 ⫾ 0.8 15.7 ⫾ 7.4
52 (67.5) 47 (61.0) 59 (76.6)
9 (18.4) 35 (71.4) 41 (83.7)
p Value
0.006 0.198 0.008 0.001 0.03 ⬍ 0.001 0.233 0.340
EHBR, extrahepatic biliary resection; INR, international normalized ratio; MELD, Model of End-Stage Liver Disease; NOS, not otherwise specified.
pathologic, and procedure-specific data were collected for each patient. Specifically, data on presenting symptoms, history of biliary procedures, underlying liver disease and cirrhosis, and surgical details were recorded. Additional information on perioperative bilirubin levels, morbidity, number of readmissions, subsequent need for biliary intervention or drainage, and incidence of cholangiocarcinoma was also determined. Longterm data on need for salvage OLT and survival were recorded. Summary statistics were obtained using established methods and presented as percentages, mean or median values, as appropriate; variance was reported as ⫾ SD. Longterm survival was estimated using the nonparametric product limit method (Kaplan and Meier).19 Differences in survival were examined using the log-rank test. Factors associated with recurrence and survival were examined using
univariate and multivariate analyses. Univariate analyses were performed using chi-square test for categorical data or t-test for continuous data. Multivariate analyses were done using Cox regression models. Hazards ratio and 95% confidence intervals were estimated and a p value ⬍ 0.05 was considered significant. All statistical analyses were performed using SPSS version 11.5 (SPSS, Inc).
RESULTS Table 1 shows the clinicopathologic features of 126 patients with PSC included in the study. Overall, there were 80 (63.5%) men and 46 (36.5%) women; median patient age was 49 years old. The majority of patients presented clinically with pain, pruritus, and jaundice (Table 1). Of 126 patients with PSC, 77 patients were managed with
Vol. 206, No. 5, May 2008
Pawlik et al
EHBR, and 49 underwent liver transplantation. Patients who underwent EHBR were similar in age to those who underwent transplantation (median age EHBR, 50 years versus transplantation, 46 years; p ⫽ 0.10). The majority (n ⫽ 47; 61.0%) of EHBR patients did not have a history of inflammatory bowel disease, but most transplantation patients had a history of either ulcerative colitis (n ⫽ 22; 44.9%) or Crohn’s disease (n ⫽ 14; 28.6%) (p ⬍ 0.001). Underlying hepatic cirrhosis was more common among transplantation patients (n ⫽ 39; 79.6%) compared with EHBR patients (n ⫽ 9; 11.7%) (p ⬍ 0.001). As expected, portal hypertension and splenomegaly were also more frequent in patients undergoing transplantation versus EHBR (Table 1). Although mean creatinine level did not differ significantly between EHBR (1.0 ⫾ 0.4 mg/dL) and transplantation (0.9 ⫾ 0.4 mg/dL) cohorts (p ⫽ 0.198), there was a difference in mean prothrombin time/international normalized ratio (INR) and albumin levels. Specifically, EHBR patients had both a higher mean preoperative albumin (3.7 ⫾ 0.6 g/dL) and a lower INR (1.1 ⫾ 0.1) than transplantation patients (albumin, 3.2 ⫾ 0.8 g/dL; INR, 1.3 ⫾ 0.5; both p ⬍ 0.01). In addition, mean preoperative bilirubin was lower in patients undergoing EHBR (5.6 ⫾ 6.9 mg/dL) versus those managed with transplantation (9.2 ⫾ 10.6 mg/dL) (p ⫽ 0.006). EHBR patients who did not have cirrhosis had an even lower preoperative bilirubin level (4.5 ⫾ 5.0 mg/dL). As such, the mean preoperative Model of End-Stage Liver Disease score was lower in EHBR patients (all EHBR patients: 13.0 ⫾ 4.0; noncirrhotic EHBR patients: 12.6 ⫾ 3.8) compared with transplantation patients (15.7 ⫾ 7.4) (p ⫽ 0.03). Before operation, most patients had a history of preoperative biliary drainage. Preoperative biliary drainage involved both endoscopic (n ⫽ 82; 65.1%) and percutaneous (n ⫽ 61; 48.4%) management. Although the majority of patients in the EHBR group had undergone endoscopic (n ⫽ 47; 61.0%) and percutaneous (n ⫽ 52; 67.5%) procedures, transplantation patients were more likely to have undergone a preoperative endoscopic (n ⫽ 35; 71.4%) rather than percutaneous intervention (n ⫽ 9; 18.4%) (p ⬍ 0.001). At the time of operation, surgical treatment was OLT in 49 patients. Of those 77 patients who underwent resection, in 73 (94.8%) patients, the procedure consisted of EHBR, including resection of the hepatic duct bifurcation, and reconstruction—generally with the insertion of bilateral transhepatic silicone elastomer biliary stents—or EHBR with concomitant hepatic resection in 4 (5.2%) patients. On final surgical pathology, 4 (5.2%) patients treated with EHBR were noted to have cholangiocarcinoma, compared with 5 (10.2%) transplantation patients. There were 8 deaths (EHBR, n ⫽ 3; transplantation,
Surgical Resection for Primary Sclerosing Cholangitis
825
Table 2. Details of Perioperative Complications
Variable
Cholangitis Biliary leak/biloma GI bleeding Wound infection Nonbiliary sepsis Infectious complications Liver failure Respiratory complications Bleeding Abscess
EHBR (n ⴝ 77) n %
Transplantation (n ⴝ 49) n %
p Value
18 7 6 4 4
23.5 9.1 7.8 5.2 5.2
3 4 2 4 9
6.1 8.2 4.1 8.2 18.3
0.234 0.682 1.00 0.723 0.022
3 2
3.9 2.6
3 1
6.1 2.0
1.00 1.00
2 1 0
2.6 1.3 0
5 4 1
10.2 8.2 2.0
0.137 0.032 0.430
EHBR, extrahepatic biliary resection; GI, gastrointestinal.
n ⫽ 5) within 30 days of operation, for a perioperative mortality rate of 3.9% for EHBR and 10.2% for OLT. Overall complication rate was 33.9% (EHBR, 38.7% versus transplantation, 22.5%; p ⫽ 0.04). Common complications included cholangitis (n ⫽ 21; 16.7%), nonbiliary sepsis (n ⫽ 13; 10.3%), biliary leak/biloma (n ⫽ 11; 8.7%), bleeding (n ⫽ 8; 6.3%), and wound infection (n ⫽ 8; 6.3%) (Table 2). In those patients who experienced a complication, when postoperative morbidity was stratified by severity level, most complications were mild to moderate, requiring only symptomatic, noninvasive, or invasive management without residual dysfunction (EHBR, 70.1% versus transplantation, 75.5%; p ⫽ 0.33). In both cohorts, only a minority of patients experienced complications leading to residual dysfunction or death (EHBR, 3.9% versus transplantation, 10.2%; p ⫽ 0.14). After operation, bilirubin levels decreased substantially (Table 3). Specifically, patients treated with EHBR had a mean 3.8 mg/dL drop in bilirubin levels when preoperative versus postsurgery levels at 2 months were compared (p ⬍ 0.01). Although the initial mean bilirubin level was higher in transplantation patients compared with EHBR patients, mean bilirubin 2 months after operation was similar between the 2 groups (EHBR, 3.1 mg/dL versus transplantation, 2.9 mg/dL; p ⫽ 0.89). As such, transplantation patients on average experienced an overall greater drop in mean bilirubin levels after operation, although this difference was not statistically significant (p ⫽ 0.39). The majority of patients in both groups had a mean postoperative bilirubin ⬍ 2 mg/dL (EHBR, 73.3% versus transplantation, 75.0%; p ⫽ 0.60). Many patients treated with EHBR plus insertion of bilateral silicone elastomer stents had their stents left in longterm. These patients required stent ex-
826
Pawlik et al
Surgical Resection for Primary Sclerosing Cholangitis
Table 3. Pre- and Postoperative Bilirubin Levels Stratified by Type of Operation (n ⫽ 126) Variable
EHBR (n ⴝ 77)
Transplantation p (n ⴝ 49) Value
Preoperative bilirubin (mg/dL), n (%) ⬍2 26 (43.3) ⱖ2 34 (56.7) Mean 5.6 ⫾ 6.9 Postoperative* bilirubin (mg/dL), n (%) ⬍2 44 (73.3) ⱖ2 16 (26.7) Mean 3.1 ⫾ 6.0 Pre- to postoperative bilirubin change (mg/dL), mean ⫾ SD ⫺3.8 ⫾ 7.4
7 (21.9) 25 (78.1) 9.2 ⫾ 10.6
0.002 0.006
24 (75.0) 8 (25.0) 2.9 ⫾ 5.7
0.60 0.898
⫺5.8 ⫾ 11.1
0.39
*Bilirubin measured 2 months after operation. EHBR, extrahepatic biliary resection.
changes every several months at interventional radiology as an outpatient procedure. As some investigators do not consider EHBR a definitive form of therapy for patients with PSC, we were particularly interested in examining readmission and repeat biliary procedure rates in the EHBR cohort. The majority of patients treated with EHBR did not require any readmissions at either 1-year (81.3%) or 3-year (57.1%) followup. In fact, 3 years after EHBR, only 26.5% of patients had 1 to 3 PSC-related readmissions, and 16.2% of patients required more than 3 PSC-related readmissions. Overall, within 1 year of EHBR, 16 patients were readmitted, for a total of 19 hospitalizations (PSC-related, n ⫽ 17 versus non⫺PSC-related, n ⫽ 2). Reasons for readmission varied and included cholangitis after biliary stent change (n ⫽ 9), cholangitis (n ⫽ 4), and biliary leak/hemobilia (n ⫽ 2). Two patients with cirrhosis who
J Am Coll Surg
underwent EHBR were readmitted for liver failure and transplant evaluation. At 3 years, 21 patients had experienced readmission to the hospital, with the most common reason for readmission being biliary stent change (n ⫽ 12). At 3 years after EHBR, median number of PSC-related admissions was 0 (range 0 to 14). Median followup for the entire cohort of patients was ⬎ 10 years (EHBR, 10.2 years versus transplantation, 11.0 years; p ⫽ 0.34). For patients undergoing EHBR who did not have cholangiocarcinoma at the time of operation (n ⫽ 73), the 3-, 5-, and 10-year actuarial overall survival rates were 85.4%, 76.4%, and 52.7%, respectively. On statistical analyses, 2 factors were independently associated with worse overall survival in patients with PSC treated with EHBR: 2-month postoperative bilirubin ⱖ 2 mg/dL (hazards ratio ⫽ 10.16; 95% CI, 3.55 to 29.03; p ⬍ 0.001) and presence of cirrhosis (hazards ratio ⫽ 7.09; 95% CI, 2.36 to 21.31; p ⬍ 0.001) (Table 4). Other factors, including preoperative creatinine, bilirubin level, prothrombin time (INR), and drop in postoperative bilirubin level were not statistically significant on univariate or multivariate analyses. To better understand the impact of postoperative bilirubin level and cirrhosis on survival after EHBR, we performed stratified analyses (Table 5). These analyses revealed that longterm outcomes worsened as postoperative bilirubin levels increased. In fact, 5-year survival was markedly different in patients who had post-EHBR bilirubin levels ⬍ 2 ng/dL (91.3%) versus 2 to 4 ng/dL (60.5%) versus ⬎ 4 ng/dL (43.4%) (p ⬍ 0.001). No PSC patient who underwent EHBR and had a postoperative bilirubin ⬎ 4 ng/dL was alive at 10 years. Cirrhosis was also a powerful predictor of outcomes among patients undergoing EHBR. Specifically, noncirrhotic patients had markedly better short- and longterm outcomes versus cirrhotic patients. At 1 year, only 60.2%
Table 4. Factors Associated with Survival after Extrahepatic Biliary Resection in Patients with Primary Sclerosing Cholangitis (Univariate and Multivariate Analyses) Variable
Age Preoperative Creatinine Albumin INR Bilirubin ⱖ 2 mg/dL Postoperative Bilirubin* ⱖ 2 mg/dL Bilirubin change Cirrhosis
Univariate analyses Hazards ratio (95% CI)
p Value
Multivariate analyses Hazards ratio (95% CI)
p Value
1.02 (0.99–1.05)
0.135
1.04 (1.01–1.08)
0.019
0.94 (0.37–2.35) 0.61 (0.33–1.13) 4.82 (0.40–57.88) 2.00 (0.85–4.69)
0.892 0.119 0.215 0.112
0.43 (0.10–1.85) 0.39 (0.17–0.88) 1.86 (0.06–55.02) 1.21 (0.40–3.69)
0.257 0.023 0.720 0.739
4.10 (1.86–9.03) 1.02 (0.97–1.08) 4.59 (1.96–10.75)
⬍ 0.001 0.427 ⬍ 0.001
10.16 (3.55–29.03) 1.02 (0.97–1.07) 7.09 (2.36–21.31)
⬍ 0.001 0.434 ⬍ 0.001
*Bilirubin measured 2 months after operation. EHBR, extrahepatic biliary resection.
Vol. 206, No. 5, May 2008
Surgical Resection for Primary Sclerosing Cholangitis
Pawlik et al
827
Table 5. Overall Survival after Extrahepatic Biliary Resection Stratified by Postoperative Bilirubin Levels and Presence of Cirrhosis Variable
Postoperative bilirubin* (mg/dL) ⱕ2 2⫺4 ⬎4 Presence of cirrhosis Yes No
Proportion surviving (%) 3y 5y
10 y
p Value
100 87.3 80.2
97.2 73.2 60.3
91.3 60.0 43.3
68.5 29.2 0
⬍ 0.001
60.0 95.6
60.0 89.6
36.0 83.3
12.0 60.2
1y
⬍ 0.001
*Bilirubin measured 2 months after operation.
of cirrhotic patients were alive, compared with a survival rate of 95.6% for noncirrhotic patients (p ⬎ 0.001). Similarly, longterm survival was markedly worse in cirrhotic versus noncirrhotic patients, with median survival being 4.1 years and 14.4 years, respectively (p ⬍ 0.001). Cirrhotic patients who underwent EHBR also had a lower 5and 10-year survival rate (36.0% and 12.0%, respectively) compared with noncirrhotic patients (83.3% and 60.2%, respectively) (p ⬍ 0.001). In comparison, patients undergoing transplantation who did not have cholangiocarcinoma at the time of OLT (n ⫽ 44) had a median survival of 10.9 years and 3-, 5-, and 10-year overall survival rates of 87.4%, 67.3%, and 57.0%, respectively. As such, although cirrhotic patients who underwent EHBR fared poorly, outcomes for noncirrhotic PSC patients treated with EHBR were comparable with those of patients after transplantation (Fig. 2). No cholangiocarcinoma developed in any PSC patient treated with EHBR at followup. Seven patients (n ⫽ 4, noncirrhotic; n ⫽ 3; cirrhotic) treated with EHBR ultimately required OLT for worsening hepatic function. In longterm followup, the incidence of PSCrelated causes of death was the same in patients initially treated with EHBR (14.2%) versus transplantation (12.3%) (p ⫽ 0.23).
DISCUSSION PSC is a rare disease that can lead to end-stage liver disease, cirrhosis, and cholangiocarcinoma in some, but not all, patients. Although symptomatic patients have a reported median survival of 12 years from the time of PSC diagnosis,20-22 asymptomatic patients have better longterm outcomes, with about 70% of patients alive at 16 years.23 Liver transplantation is generally accepted as the therapeutic option of choice in patients with PSC and cirrhosis.4,24,25 Treatment of PSC patients who do not have cirrhosis is more controversial. Although PSC can involve both intrahepatic and extrahepatic bile ducts, in most pa-
tients the hepatic duct bifurcation is the region most severely involved.11,18,26 Some investigators11 have believed that these bifurcation strictures result in increased cholestasis, which is not obvious because of the lack of intrahepatic duct dilation secondary to ductal fibrosis. Although stenting and dilation of biliary strictures are technically feasible to treat these lesions,4,5,27,28 the results are often not durable.13 As such, EHBR with hepatic duct bifurcation resection has been advocated for some patients with PSC.10-14,17 In addition, the Hopkins group has favored reconstruction using bilateral transhepatic silicone elastomer stents, with the stents left in longterm. This approach requires changing of the stents at interventional radiology every several months as an outpatient procedure. Few reports have investigated the benefit of EHBR for PSC, either alone10-12,17,29,30 or relative to transplantation.14 Such data are particularly important, given issues of transplant organ allocation and appropriate use of limited resources.
Figure 2. Although cirrhotic patients who underwent extrahepatic biliary resection (EHBR) fared poorly (p ⬍ 0.001 versus others), outcomes for noncirrhotic primary sclerosing cholangitis patients treated with EHBR were comparable with those of patients treated with transplantation.
828
Pawlik et al
Surgical Resection for Primary Sclerosing Cholangitis
Our research group has previously published on the topic of PSC and EHBR.10-14 In 1982, Pitt and colleagues10 reported on 17 patients during a 6-year period who were treated with EHBR without resection of the hepatic duct bifurcation. In that series, about three-quarters of patients had excellent or good results after operation and 82% of patients were alive at a mean followup of 52.2 months.10 In 1983 and 1988, Cameron and colleagues11,12 reported the Johns Hopkins’ experience. In these reports, all patients underwent resection of the hepatic duct bifurcation and insertion of bilateral transhepatic silicone elastomer stents. In a report of 31 patients with PSC who were managed with EHBR and longterm transhepatic stents, the 5-year survival rate was noted to be 71%.12 More recently, in 1998, Ahrendt and colleagues13 examined the results of EHBR, nonoperative endoscopic biliary dilation, and liver transplantation in 146 patients—50 of whom underwent EHBR. With a median followup of 62 months, the 5-year survival rate was 76%. Although these previous studies were important, they suffered from a number of shortcomings, including a smaller sample size and a relatively short median followup time for a disease with such a long natural history. The current study represents a substantial incremental improvement from our previous work for several reasons. First, by combining the experience of several institutions, we were able to assess a larger number of patients treated with EHBR (n ⫽ 77). Perhaps more importantly, median followup time in the current study (median 10.2 years) was twice that previously reported (median 5.2 years).13 As such, a larger amount of actual, rather than actuarial, longterm survival data were reported. In addition, unlike previous work, the current study focused on longterm outcomes of patients treated with EHBR, with a particular focus on morbidity, rate of readmission, and overall survival compared with transplantation. EHBR involved resection of the entire extrahepatic biliary tree, including the hepatic duct bifurcation. In most patients, the reconstruction involved bilateral hepaticojejunostomies and included use of bilateral transhepatic silicone elastomer stents. The majority of patients experienced no perioperative complications. In addition, in those patients who did experience morbidity, the severity of the complications was mild to moderate. Three patients died in the EHBR cohort for a perioperative mortality rate of 3.9%. Importantly, two of three postoperative deaths were patients with underlying cirrhosis. These data serve to emphasize that EHBR in PSC patients, particularly noncirrhotics, is associated with low perioperative morbidity and mortality when performed at a high-volume hepatopancreaticobiliary center. Although our data strongly support the safety of EHBR for noncirrhotic PSC patients, the impact
J Am Coll Surg
of EHBR on future liver transplantation was not assessed. Although several authors have cautioned that earlier biliary operation can increase morbidity associated with subsequent transplantation,24,31 other studies13,32 have reported that previous biliary operations had no effect on patient survival after transplantation. Importantly, data from the current study help to frame the context, and potential impact, of this clinical issue. Specifically, at ⬎ 10 years of followup, only 7 (9.1%) patients initially treated with EHBR required eventual transplantation. Of these seven patients, three had cirrhosis at the time of EHBR. Based on data from the current series and previous reports,15,32,33 these patients should have presumably undergone initial transplantation rather than EHBR. As such, in wellselected noncirrhotic patients, the empiric data would strongly suggest that “salvage” or subsequent transplantation is a relatively rare occurrence (⬃ 5%). In patients with PSC and underlying cirrhosis, transplantation clearly remains the best therapeutic option. Results for EHBR in the cohort of patients with cirrhosis were exceptionally poor. Roughly 40% of patients with underlying cirrhosis were dead at 1 year after EHBR, compared with only 5% of noncirrhotic patients (p ⬍ 0.001). Not surprisingly, longterm outcomes were similarly abysmal. At 10 years, survival was only 12% for cirrhotic patients and no patient with cirrhosis and a persistently elevated bilirubin was alive. Results with transplantation in this cohort of patients has been reported to be markedly better.15,21,32 Specifically, some investigators have reported an improvement in longterm survival after transplantation, when compared with predicted survival in high-risk cirrhotic PSC patients who were not transplanted.24,25 Our data support this contention, as patients treated with transplantation fared considerably better than patients with cirrhosis who underwent EHBR (Fig. 2). Although transplantation is clearly superior to EHBR in cirrhotic PSC patients, with longterm survival approaching 70% to 90%, graft survival still remains in the 50% to 60% range.32 In addition, recurrent PSC can occur in up to 12% to 15% of patients.34 Nontransplantation surgical approaches, such as EHBR, can be a better therapeutic option for noncirrhotic patients. Noncirrhotic patients treated with EHBR had 3-, 5-, and 10-year survival rates of 89.6%, 83.3%, and 60.2%. With a median followup of ⬎ 10 years, data from the current study substantiate that durable survival rates can be achieved with EHBR. Importantly, longterm survival rates were comparable between noncirrhotic PSC patients treated with EHBR versus transplantation patients. These results demonstrate that surgical resection offers an important, and equally efficacious, treatment modality for well-selected noncirrhotic patients. In addition to long-
Vol. 206, No. 5, May 2008
Pawlik et al
term survival, EHBR obviated the need for repeat biliary procedures and hospital readmissions. We report that EHBR markedly improved cholestasis, with ⬎ 70% of patients having a postoperative bilirubin ⬍ 2 mg/dL 2 months after EHBR. In addition, the majority of patients treated with EHBR also did not require hospital readmission. Whereas, preoperatively, many PSC patients required multiple hospitalizations, and repeat biliary procedures, at 1 and 3 years after EHBR ⬎ 80% and 50% of patients, respectively, were free from readmission. Only a small minority of patients (n ⫽ 5) experienced multiple hospitalizations (5 or more) for PSC-related reasons (eg, repeat biliary procedures/stent management). Development of cholangiocarcinoma is an important concern in patients with PSC, as it can occur in 8% to 30% of patients followed for ⬎ 10 years.2,6,7 Frequently, the indication for operation in patients with PSC and a dominant stricture is concern for cholangiocarcinoma. Importantly, in the current series of 70 patients at risk, at followup there was no incident case of cholangiocarcinoma in any PSC patient treated with EHBR. Although one might have expected that bile duct malignancy should have developed in several patients with time,7,24 the fact that the entire extrahepatic biliary tree, including the hepatic duct bifurcation, was resected might have dramatically decreased the risk of cancer. Transplantation data35 showing that most cancers (⬎ 70%) are found incidentally at the hepatic duct bifurcation in the explant also support this hypothesis. In addition, the majority of cholangiocarcinomas that develop in PSC patients present during the first 18 months of diagnosis.14 Clinicians should remain vigilant in the surveillance of PSC patients, as risk of cholangiocarcinoma remains elevated, regardless of whether patients are treated with EHBR or transplantation. In conclusion, EHBR was associated with not only low perioperative morbidity and mortality but also a substantial decrease in serum bilirubin levels and a low rate of repeat biliary procedures and PSC-related hospital readmissions. Although outcomes for cirrhotic patients treated with EHBR were very poor, noncirrhotic PSC patients experienced longterm survival comparable with that achieved after transplantation without the need for immunosuppression. As such, our data suggest that the need for transplantation can, potentially, be delayed considerably, or avoided, in well-selected PSC patients who present without cirrhosis. OLT should be reserved for those patients who present with PSC associated with hepatic cirrhosis. Author Contributions
Study conception and design: Pawlik, Olbrecht, Pitt, Gleisner
Surgical Resection for Primary Sclerosing Cholangitis
829
Acquisition of data: Pawlik, Olbrecht, Pitt, Gleisner, Choti, Schulick, Cameron Analysis and interpretation of data: Pawlik, Olbrecht, Pitt, Gleisner, Choti, Schulick, Cameron Drafting of manuscript: Pawlik, Olbrecht, Pitt, Gleisner, Cameron Critical revision: Pawlik, Olbrecht, Pitt, Gleisner, Choti, Schulick, Cameron
REFERENCES 1. Narayanan K, Williamson R, Zhang Y, et al. Efficient and precise engineering of a 200 kb beta-globin human/bacterial artificial chromosome in E. coli DH10B using an inducible homologous recombination system. Gene Ther 1999;6:442–447. 2. Worthington J, Chapman R. Primary sclerosing cholangitis. Orphanet J Rare Dis 2006;1:41. 3. Chapman RW, Arborgh BA, Rhodes JM, et al. Primary sclerosing cholangitis: a review of its clinical features, cholangiography, and hepatic histology. Gut 1980;21:870–877. 4. Lee YM, Kim DJ. Primary sclerosing cholangitis. Curr Treat Options Gastroenterol 2001;4:469–477. 5. Charatcharoenwitthaya P, Lindor KD. Primary sclerosing cholangitis: diagnosis and management. Curr Gastroenterol Rep 2006;8:75–82. 6. Kaya M, de Groen PC, Angulo P, et al. Treatment of cholangiocarcinoma complicating primary sclerosing cholangitis: the Mayo Clinic experience. Am J Gastroenterol 2001;96:1164– 1169. 7. Rosen CB, Nagorney DM, Wiesner RH, et al. Cholangiocarcinoma complicating primary sclerosing cholangitis. Ann Surg 1991;213:21–25. 8. Gaing AA, Geders JM, Cohen SA, Siegel JH. Endoscopic management of primary sclerosing cholangitis: review, and report of an open series. Am J Gastroenterol 1993;88:2000–2008. 9. Lee JG, Schutz SM, England RE, et al. Endoscopic therapy of sclerosing cholangitis. Hepatology 1995;21:661–667. 10. Pitt HA, Thompson HH, Tompkins RK, Longmire WP Jr. Primary sclerosing cholangitis: results of an aggressive surgical approach. Ann Surg 1982;196:259–268. 11. Cameron JL, Gayler BW, Herlong HF, Maddrey WC. Sclerosing cholangitis: biliary reconstruction with Silastic transhepatic stents. Surgery 1983;94:324–330. 12. Cameron JL, Pitt HA, Zinner MJ, et al. Resection of hepatic duct bifurcation and transhepatic stenting for sclerosing cholangitis. Ann Surg 1988;207:614–622. 13. Ahrendt SA, Pitt HA, Kalloo AN, et al. Primary sclerosing cholangitis: resect, dilate, or transplant? Ann Surg 1998;227: 412–423. 14. Ahrendt SA, Pitt HA, Nakeeb A, et al. Diagnosis and management of cholangiocarcinoma in primary sclerosing cholangitis. J Gastrointest Surg 1999;3:357–367; discussion 367–368. 15. Solano E, Khakhar A, Bloch M, et al. Liver transplantation for primary sclerosing cholangitis. Transplant Proc 2003;35:2431– 2434. 16. Sebagh M, Farges O, Kalil A, et al. Sclerosing cholangitis following human orthotopic liver transplantation. Am J Surg Pathol 1995;19:81–90.
830
Pawlik et al
Surgical Resection for Primary Sclerosing Cholangitis
17. Myburgh JA. Surgical biliary drainage in primary sclerosing cholangitis. The role of the Hepp-Couinaud approach. Arch Surg 1994;129:1057–1062. 18. Ludwig J, Barham SS, LaRusso NF, et al. Morphologic features of chronic hepatitis associated with primary sclerosing cholangitis and chronic ulcerative colitis. Hepatology 1981;1:632–640. 19. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. Am Stat Assoc J 1958;53:457–480. 20. Broome U, Olsson R, Loof L, et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 1996;38:610–615. 21. Wiesner RH, Grambsch PM, Dickson ER, et al. Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis. Hepatology 1989;10:430–436. 22. Farrant JM, Hayllar KM, Wilkinson ML, et al. Natural history and prognostic variables in primary sclerosing cholangitis. Gastroenterology 1991;100:1710–1717. 23. Porayko MK, Wiesner RH, LaRusso NF, et al. Patients with asymptomatic primary sclerosing cholangitis frequently have progressive disease. Gastroenterology 1990;98:1594–1602. 24. Farges O, Malassagne B, Sebagh M, Bismuth H. Primary sclerosing cholangitis: liver transplantation or biliary surgery. Surgery 1995;117:146–155. 25. Abu-Elmagd KM, Malinchoc M, Dickson ER, et al. Efficacy of hepatic transplantation in patients with primary sclerosing cholangitis. Surg Gynecol Obstet 1993;177:335–344. 26. Cameron JL, Gayler BW, Sanfey H, et al. Sclerosing cholangitis. Anatomical distribution of obstructive lesions. Ann Surg 1984; 200:54–60. 27. Levy C, Lindor KD. Treatment options for primary biliary cirrhosis and primary sclerosing cholangitis. Curr Treat Options Gastroenterol 2003;6:93–103. 28. Johnson GK, Saeian K, Geenen JE. Primary sclerosing cholangitis treated by endoscopic biliary dilation: review and long-term follow-up evaluation. Curr Gastroenterol Rep 2006;8:147–155. 29. Yamamoto T, Hirohashi K, Kubo S, et al. Surgery for segmental primary sclerosing cholangitis. Hepatogastroenterology 2004; 51:668–671. 30. Hirai I, Ishiyama S, Fuse A, et al. Primary sclerosing cholangitis successfully treated by resection of the confluence of the hepatic duct. J Hepatobiliary Pancreat Surg 2001;8:169–173. 31. Ismail T, Angrisani L, Powell JE, et al. Primary sclerosing cholangitis: surgical options, prognostic variables and outcome. Br J Surg 1991;78:564–567. 32. Goss JA, Shackleton CR, Farmer DG, et al. Orthotopic liver transplantation for primary sclerosing cholangitis. A 12-year single center experience. Ann Surg 1997;225:472–481; discussion 481–473. 33. Becker NS, Rodriguez JA, Barshes NR, et al. Outcomes analysis for 280 patients with cholangiocarcinoma treated with liver transplantation over an 18-year period. J Gastrointest Surg 2007;12:117– 122. 34. Oldakowska-Jedynak U, Nowak M, Mucha K, et al. Recurrence of primary sclerosing cholangitis in patients after liver transplantation. Transplant Proc 2006;38:240–243. 35. Abu-Elmagd KM, Selby R, Iwatsuki S, et al. Cholangiocarcinoma and sclerosing cholangitis: clinical characteristics and effect on survival after liver transplantation. Transplant Proc 1993;25:1124–1125.
J Am Coll Surg
Discussion DR C WRIGHT PINSON (Nashville, TN): PSC is a chronic cholestatic disease, has had treatment advancements over the past 20 years. Dr Pawlik and colleagues have reexamined their experience with primary resection for this disease. The last time this group surveyed their results was in 1998. At that time they had 50 patients who had been treated with extrahepatic biliary resection and reconstruction and 28 who had undergone liver transplantation. In this current survey the numbers have increased to 77 patients in the resection group and 49 patients in the transplant group. But more importantly, these authors now have nine extra years of follow-up from their previous large patient cohort. The results are impressive. None of the 77 patients who underwent extrahepatic biliary resection and reconstruction subsequently developed cholangiocarcinoma. Excluding patients with cirrhosis, patients undergoing resection and reconstruction had comparable survival, 60% at 10 years follow-up, to patients who underwent transplantation. Interestingly, patients who underwent resection ad a higher complication rate, largely as a result of higher rates of cholangitis; I wondered if that is secondary to the postoperative long-term stenting and wonder if you still always use stents long term, and do you always have a policy of preoperative biliary drainage? The authors also showed the importance of properly selecting resection candidates. Patients with cirrhosis treated by primary resection had worse overall outcomes in univariate and multivariate analyses. The presence of cirrhosis increases the likelihood of death sevenfold. Only one of nine patients with cirrhosis treated by resection survived at the 10-year mark. I think we would all have to agree that liver transplantation is the treatment modality of choice for patients with cirrhosis. Importantly, this paper reemphasizes the value and role of resection in non-cirrhotic patients with PSC. That is not a well developed position. There is very little data. You won’t find anything currently better than this paper to make the case. Now for some questions: Did Bismuth criteria play a factor in your patient selection process? Are there any patients with Bismuth type 4 lesions who were treated with extrahepatic biliary resection? If so, how did their outcomes compare with those who had Bismuth type 1 through 3 lesions? In patients who underwent partial hepatectomy – I believe that was about 5% of your patients – in addition to hepaticojejunostomies, were the outcomes the same? In your experience, what is the most appropriate timing for the first surgical intervention? Is it after the patient fails a round of medical therapy or endoscopic treatment? Or do you have some other criteria in terms of timing? Your data show that patients whose postoperative bilirubin does not drop below 2 have worse overall outcomes, just like the cirrhotic groups. Importantly, I want to know if you have figured out a way to predict these patients up front and perhaps treat them with transplantation rather than resection. I presume this is a somewhat different group of patients from the cirrhotics. Finally, our studies have shown that quality of life parameters in patients with common bile duct injuries subsequently treated with reparative hepaticojejunostomy did not normalize even years after
women and is strongly associated with inflammatory bowel disease, particularly ulcerative colitis.2-5 PSC is also associated with increased risk of cholangiocarcinoma, with series showing cancer developing in 8% to 30% of patients with time.2,6,7 Although orthotopic liver transplantation (OLT) remains the only effective therapy for patients with PSC after development of end-stage liver disease, treatment ear-
Primary sclerosing cholangitis (PSC) is an idiopathic chronic cholestatic disease of the liver characterized by inflammation that leads to fibrosis and stricturing of the intra- and extrahepatic biliary tree. In most patients, PSC is progressive and eventually results in end-stage liver disease and cirrhosis.1 PSC occurs twice as often in men as in Competing Interests Declared: None. Dr Pawlik is supported by grant number 1KL2RR025006-01 from the National Center for Research Resources, a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Ana Gleisner is supported by an International Union Against Cancer/American Cancer Society Beginning Investigators Fellowship funded by the American Cancer Society and by a grant from CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior). This article represents the personal viewpoints of the authors and cannot be construed as a statement of official National Center for Research Resources or National Institutes of Health policy.
© 2008 by the American College of Surgeons Published by Elsevier Inc.
Presented at the Southern Surgical Association 119th Annual Meeting, Hot Springs, VA, December 2007. Received November 29, 2007; Accepted December 1, 2007. From the Departments of Surgery, Johns Hopkins University Hospital, Baltimore, MD (Pawlik, Olbrecht, Gleisner, Choti, Schulick, Cameron) and Indiana University School of Medicine, Indianapolis, IN (Pitt). Correspondence address: Timothy M Pawlik, MD, MPH, FACS, Department of Surgery, Johns Hopkins University Hospital, Halsted 614, 600 N Wolfe St, Baltimore, MD, 21287. email: [email protected]
822
ISSN 1072-7515/08/$34.00 doi:10.1016/j.jamcollsurg.2007.12.015
Vol. 206, No. 5, May 2008
Pawlik et al
Surgical Resection for Primary Sclerosing Cholangitis
823
Abbreviations and Acronyms
EHBR INR OLT PSC
⫽ ⫽ ⫽ ⫽
extrahepatic biliary resection international normalized ratio orthotopic liver transplantation primary sclerosing cholangitis
lier in the course of the disease remains controversial. Currently, early treatment options include medical therapy, endoscopic or percutaneous dilation or stenting,8,9 and various surgical procedures. Beginning in the early 1980s, several studies examined the use of surgical resection of the extrahepatic biliary tree for treatment of PSC.10-14 It was noted that even though PSC usually involved the entire intra- and extrahepatic biliary tree, the most severe stricturing was at the hepatic duct bifurcation. Most of these series involved resecting the bifurcation and the entire extrahepatic biliary tree. These studies were limited because of their small sample size and inadequate longterm followup. As such, many surgeons continue to consider OLT as the only definitive form of therapy for patients with PSC and dominant strictures.15,16 Other investigators10,12-14,17 have advocated for extrahepatic biliary resection (EHBR) in carefully selected noncirrhotic patients with PSC. The role of surgical treatment and general management of noncirrhotic patients with PSC remains unclear. The purpose of this study was to investigate the role of EHBR and determine perioperative morbidity and longterm survival in the largest cohort of patients with the longest followup of any series published to date.
METHODS Between 1981 and 2006, 126 patients with PSC underwent EHBR at the Johns Hopkins University Hospital (n ⫽ 65), Indiana University (n ⫽ 5), and the Medical College of Wisconsin (n ⫽ 7), or OLT at Johns Hopkins University Hospital (n ⫽ 49). The study was approved by the institutional review boards at the respective institutions. Only patients with a diagnosis of PSC at the time of operation were included in the current study. Specifically, all patients had cholangiographic findings consistent with a diagnosis of PSC, including stricturing of the bile ducts.18 Often, the most severe stricturing was at the hepatic duct bifurcation. Cholangiographic findings were supported by a clinical history and histologic specimens consistent with PSC. Operations were usually performed because of persistent hyperbilirubinemia and a dominant stricture, usually at the bifurcation (Fig. 1). Operations were occasionally performed to rule out cholangiocarcinoma. Nine patients with PSC and cholangiocarcinoma based on pathology results were included in the current study. Patients with scle-
Figure 1. (A) Preoperative cholangiogram with right transhepatic stent across right hepatic duct stricture. (B) Postoperative cholangiogram after resection of hepatic duct bifurcation, bilateral cholangiojejunostomies, and transhepatic stents.
rosing cholangitis because of any known secondary causes were excluded. All patients undergoing EHBR underwent excision of the hepatic duct bifurcation and the extrahepatic biliary tree. Generally, reconstruction through bilateral hepatic jejunostomies also included insertion of bilateral transhepatic silicone elastomer stents, which were left in longterm. After operation, all patients were followed regularly and monitored prospectively. Standard demographic, clinico-
824
Pawlik et al
Surgical Resection for Primary Sclerosing Cholangitis
J Am Coll Surg
Table 1. Clinical Characteristics of Study Patients Stratified by Operation Type (n ⫽ 126) Variable
Demographics Age (y), mean ⫾ SD Male gender Race, n (%) Caucasian African American Other Presenting symptoms, n (%) Jaundice Pruritus Pain History of cholangitis Associated diseases, n (%) Inflammatory bowel disease Ulcerative colitis Crohn’s disease NOS None Cirrhosis Portal hypertension Splenomegaly Diabetes Preoperative laboratory values, mean ⫾ SD Bilirubin (mg/dL) Creatinine (mg/dL) Prothrombin time (INR) Albumin (g/dL) MELD Previous biliary drainage, n (%) Percutaneous approach Endoscopic approach Previous hospitalization(s)
EHBR (n ⴝ 77)
Transplantation (n ⴝ 49)
50.1 ⫾ 13.7 47 (61.0)
46.2 ⫾ 11.5 33 (67.3)
0.101 0.473
63 (81.8) 13 (16.9) 1 (1.3)
39 (79.6) 8 (16.3) 2 (4.1)
0.756
62 (80.5) 37 (48.1) 30 (39.0) 30 (39.0)
44 (89.8) 28 (57.1) 23 (46.9) 22 (44.9)
0.165 0.320 0.377 0.509
20 (20.6) 9 (11.7) 1 (1.3) 47 (61.0) 9 (11.7) 5 (6.5) 4 (5.2) 11 (14.3)
22 (44.9) 14 (28.6) 3 (6.1) 10 (20.4) 39 (79.6) 30 (61.2) 30 (61.2) 4 (8.2)
0.028 0.017 0.132 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 0.301
5.6 ⫾ 6.9 1.0 ⫾ 0.4 1.1 ⫾ 0.1 3.7 ⫾ 0.6 13.0 ⫾ 4.0
9.2 ⫾ 10.6 0.9 ⫾ 0.4 1.3 ⫾ 0.5 3.2 ⫾ 0.8 15.7 ⫾ 7.4
52 (67.5) 47 (61.0) 59 (76.6)
9 (18.4) 35 (71.4) 41 (83.7)
p Value
0.006 0.198 0.008 0.001 0.03 ⬍ 0.001 0.233 0.340
EHBR, extrahepatic biliary resection; INR, international normalized ratio; MELD, Model of End-Stage Liver Disease; NOS, not otherwise specified.
pathologic, and procedure-specific data were collected for each patient. Specifically, data on presenting symptoms, history of biliary procedures, underlying liver disease and cirrhosis, and surgical details were recorded. Additional information on perioperative bilirubin levels, morbidity, number of readmissions, subsequent need for biliary intervention or drainage, and incidence of cholangiocarcinoma was also determined. Longterm data on need for salvage OLT and survival were recorded. Summary statistics were obtained using established methods and presented as percentages, mean or median values, as appropriate; variance was reported as ⫾ SD. Longterm survival was estimated using the nonparametric product limit method (Kaplan and Meier).19 Differences in survival were examined using the log-rank test. Factors associated with recurrence and survival were examined using
univariate and multivariate analyses. Univariate analyses were performed using chi-square test for categorical data or t-test for continuous data. Multivariate analyses were done using Cox regression models. Hazards ratio and 95% confidence intervals were estimated and a p value ⬍ 0.05 was considered significant. All statistical analyses were performed using SPSS version 11.5 (SPSS, Inc).
RESULTS Table 1 shows the clinicopathologic features of 126 patients with PSC included in the study. Overall, there were 80 (63.5%) men and 46 (36.5%) women; median patient age was 49 years old. The majority of patients presented clinically with pain, pruritus, and jaundice (Table 1). Of 126 patients with PSC, 77 patients were managed with
Vol. 206, No. 5, May 2008
Pawlik et al
EHBR, and 49 underwent liver transplantation. Patients who underwent EHBR were similar in age to those who underwent transplantation (median age EHBR, 50 years versus transplantation, 46 years; p ⫽ 0.10). The majority (n ⫽ 47; 61.0%) of EHBR patients did not have a history of inflammatory bowel disease, but most transplantation patients had a history of either ulcerative colitis (n ⫽ 22; 44.9%) or Crohn’s disease (n ⫽ 14; 28.6%) (p ⬍ 0.001). Underlying hepatic cirrhosis was more common among transplantation patients (n ⫽ 39; 79.6%) compared with EHBR patients (n ⫽ 9; 11.7%) (p ⬍ 0.001). As expected, portal hypertension and splenomegaly were also more frequent in patients undergoing transplantation versus EHBR (Table 1). Although mean creatinine level did not differ significantly between EHBR (1.0 ⫾ 0.4 mg/dL) and transplantation (0.9 ⫾ 0.4 mg/dL) cohorts (p ⫽ 0.198), there was a difference in mean prothrombin time/international normalized ratio (INR) and albumin levels. Specifically, EHBR patients had both a higher mean preoperative albumin (3.7 ⫾ 0.6 g/dL) and a lower INR (1.1 ⫾ 0.1) than transplantation patients (albumin, 3.2 ⫾ 0.8 g/dL; INR, 1.3 ⫾ 0.5; both p ⬍ 0.01). In addition, mean preoperative bilirubin was lower in patients undergoing EHBR (5.6 ⫾ 6.9 mg/dL) versus those managed with transplantation (9.2 ⫾ 10.6 mg/dL) (p ⫽ 0.006). EHBR patients who did not have cirrhosis had an even lower preoperative bilirubin level (4.5 ⫾ 5.0 mg/dL). As such, the mean preoperative Model of End-Stage Liver Disease score was lower in EHBR patients (all EHBR patients: 13.0 ⫾ 4.0; noncirrhotic EHBR patients: 12.6 ⫾ 3.8) compared with transplantation patients (15.7 ⫾ 7.4) (p ⫽ 0.03). Before operation, most patients had a history of preoperative biliary drainage. Preoperative biliary drainage involved both endoscopic (n ⫽ 82; 65.1%) and percutaneous (n ⫽ 61; 48.4%) management. Although the majority of patients in the EHBR group had undergone endoscopic (n ⫽ 47; 61.0%) and percutaneous (n ⫽ 52; 67.5%) procedures, transplantation patients were more likely to have undergone a preoperative endoscopic (n ⫽ 35; 71.4%) rather than percutaneous intervention (n ⫽ 9; 18.4%) (p ⬍ 0.001). At the time of operation, surgical treatment was OLT in 49 patients. Of those 77 patients who underwent resection, in 73 (94.8%) patients, the procedure consisted of EHBR, including resection of the hepatic duct bifurcation, and reconstruction—generally with the insertion of bilateral transhepatic silicone elastomer biliary stents—or EHBR with concomitant hepatic resection in 4 (5.2%) patients. On final surgical pathology, 4 (5.2%) patients treated with EHBR were noted to have cholangiocarcinoma, compared with 5 (10.2%) transplantation patients. There were 8 deaths (EHBR, n ⫽ 3; transplantation,
Surgical Resection for Primary Sclerosing Cholangitis
825
Table 2. Details of Perioperative Complications
Variable
Cholangitis Biliary leak/biloma GI bleeding Wound infection Nonbiliary sepsis Infectious complications Liver failure Respiratory complications Bleeding Abscess
EHBR (n ⴝ 77) n %
Transplantation (n ⴝ 49) n %
p Value
18 7 6 4 4
23.5 9.1 7.8 5.2 5.2
3 4 2 4 9
6.1 8.2 4.1 8.2 18.3
0.234 0.682 1.00 0.723 0.022
3 2
3.9 2.6
3 1
6.1 2.0
1.00 1.00
2 1 0
2.6 1.3 0
5 4 1
10.2 8.2 2.0
0.137 0.032 0.430
EHBR, extrahepatic biliary resection; GI, gastrointestinal.
n ⫽ 5) within 30 days of operation, for a perioperative mortality rate of 3.9% for EHBR and 10.2% for OLT. Overall complication rate was 33.9% (EHBR, 38.7% versus transplantation, 22.5%; p ⫽ 0.04). Common complications included cholangitis (n ⫽ 21; 16.7%), nonbiliary sepsis (n ⫽ 13; 10.3%), biliary leak/biloma (n ⫽ 11; 8.7%), bleeding (n ⫽ 8; 6.3%), and wound infection (n ⫽ 8; 6.3%) (Table 2). In those patients who experienced a complication, when postoperative morbidity was stratified by severity level, most complications were mild to moderate, requiring only symptomatic, noninvasive, or invasive management without residual dysfunction (EHBR, 70.1% versus transplantation, 75.5%; p ⫽ 0.33). In both cohorts, only a minority of patients experienced complications leading to residual dysfunction or death (EHBR, 3.9% versus transplantation, 10.2%; p ⫽ 0.14). After operation, bilirubin levels decreased substantially (Table 3). Specifically, patients treated with EHBR had a mean 3.8 mg/dL drop in bilirubin levels when preoperative versus postsurgery levels at 2 months were compared (p ⬍ 0.01). Although the initial mean bilirubin level was higher in transplantation patients compared with EHBR patients, mean bilirubin 2 months after operation was similar between the 2 groups (EHBR, 3.1 mg/dL versus transplantation, 2.9 mg/dL; p ⫽ 0.89). As such, transplantation patients on average experienced an overall greater drop in mean bilirubin levels after operation, although this difference was not statistically significant (p ⫽ 0.39). The majority of patients in both groups had a mean postoperative bilirubin ⬍ 2 mg/dL (EHBR, 73.3% versus transplantation, 75.0%; p ⫽ 0.60). Many patients treated with EHBR plus insertion of bilateral silicone elastomer stents had their stents left in longterm. These patients required stent ex-
826
Pawlik et al
Surgical Resection for Primary Sclerosing Cholangitis
Table 3. Pre- and Postoperative Bilirubin Levels Stratified by Type of Operation (n ⫽ 126) Variable
EHBR (n ⴝ 77)
Transplantation p (n ⴝ 49) Value
Preoperative bilirubin (mg/dL), n (%) ⬍2 26 (43.3) ⱖ2 34 (56.7) Mean 5.6 ⫾ 6.9 Postoperative* bilirubin (mg/dL), n (%) ⬍2 44 (73.3) ⱖ2 16 (26.7) Mean 3.1 ⫾ 6.0 Pre- to postoperative bilirubin change (mg/dL), mean ⫾ SD ⫺3.8 ⫾ 7.4
7 (21.9) 25 (78.1) 9.2 ⫾ 10.6
0.002 0.006
24 (75.0) 8 (25.0) 2.9 ⫾ 5.7
0.60 0.898
⫺5.8 ⫾ 11.1
0.39
*Bilirubin measured 2 months after operation. EHBR, extrahepatic biliary resection.
changes every several months at interventional radiology as an outpatient procedure. As some investigators do not consider EHBR a definitive form of therapy for patients with PSC, we were particularly interested in examining readmission and repeat biliary procedure rates in the EHBR cohort. The majority of patients treated with EHBR did not require any readmissions at either 1-year (81.3%) or 3-year (57.1%) followup. In fact, 3 years after EHBR, only 26.5% of patients had 1 to 3 PSC-related readmissions, and 16.2% of patients required more than 3 PSC-related readmissions. Overall, within 1 year of EHBR, 16 patients were readmitted, for a total of 19 hospitalizations (PSC-related, n ⫽ 17 versus non⫺PSC-related, n ⫽ 2). Reasons for readmission varied and included cholangitis after biliary stent change (n ⫽ 9), cholangitis (n ⫽ 4), and biliary leak/hemobilia (n ⫽ 2). Two patients with cirrhosis who
J Am Coll Surg
underwent EHBR were readmitted for liver failure and transplant evaluation. At 3 years, 21 patients had experienced readmission to the hospital, with the most common reason for readmission being biliary stent change (n ⫽ 12). At 3 years after EHBR, median number of PSC-related admissions was 0 (range 0 to 14). Median followup for the entire cohort of patients was ⬎ 10 years (EHBR, 10.2 years versus transplantation, 11.0 years; p ⫽ 0.34). For patients undergoing EHBR who did not have cholangiocarcinoma at the time of operation (n ⫽ 73), the 3-, 5-, and 10-year actuarial overall survival rates were 85.4%, 76.4%, and 52.7%, respectively. On statistical analyses, 2 factors were independently associated with worse overall survival in patients with PSC treated with EHBR: 2-month postoperative bilirubin ⱖ 2 mg/dL (hazards ratio ⫽ 10.16; 95% CI, 3.55 to 29.03; p ⬍ 0.001) and presence of cirrhosis (hazards ratio ⫽ 7.09; 95% CI, 2.36 to 21.31; p ⬍ 0.001) (Table 4). Other factors, including preoperative creatinine, bilirubin level, prothrombin time (INR), and drop in postoperative bilirubin level were not statistically significant on univariate or multivariate analyses. To better understand the impact of postoperative bilirubin level and cirrhosis on survival after EHBR, we performed stratified analyses (Table 5). These analyses revealed that longterm outcomes worsened as postoperative bilirubin levels increased. In fact, 5-year survival was markedly different in patients who had post-EHBR bilirubin levels ⬍ 2 ng/dL (91.3%) versus 2 to 4 ng/dL (60.5%) versus ⬎ 4 ng/dL (43.4%) (p ⬍ 0.001). No PSC patient who underwent EHBR and had a postoperative bilirubin ⬎ 4 ng/dL was alive at 10 years. Cirrhosis was also a powerful predictor of outcomes among patients undergoing EHBR. Specifically, noncirrhotic patients had markedly better short- and longterm outcomes versus cirrhotic patients. At 1 year, only 60.2%
Table 4. Factors Associated with Survival after Extrahepatic Biliary Resection in Patients with Primary Sclerosing Cholangitis (Univariate and Multivariate Analyses) Variable
Age Preoperative Creatinine Albumin INR Bilirubin ⱖ 2 mg/dL Postoperative Bilirubin* ⱖ 2 mg/dL Bilirubin change Cirrhosis
Univariate analyses Hazards ratio (95% CI)
p Value
Multivariate analyses Hazards ratio (95% CI)
p Value
1.02 (0.99–1.05)
0.135
1.04 (1.01–1.08)
0.019
0.94 (0.37–2.35) 0.61 (0.33–1.13) 4.82 (0.40–57.88) 2.00 (0.85–4.69)
0.892 0.119 0.215 0.112
0.43 (0.10–1.85) 0.39 (0.17–0.88) 1.86 (0.06–55.02) 1.21 (0.40–3.69)
0.257 0.023 0.720 0.739
4.10 (1.86–9.03) 1.02 (0.97–1.08) 4.59 (1.96–10.75)
⬍ 0.001 0.427 ⬍ 0.001
10.16 (3.55–29.03) 1.02 (0.97–1.07) 7.09 (2.36–21.31)
⬍ 0.001 0.434 ⬍ 0.001
*Bilirubin measured 2 months after operation. EHBR, extrahepatic biliary resection.
Vol. 206, No. 5, May 2008
Surgical Resection for Primary Sclerosing Cholangitis
Pawlik et al
827
Table 5. Overall Survival after Extrahepatic Biliary Resection Stratified by Postoperative Bilirubin Levels and Presence of Cirrhosis Variable
Postoperative bilirubin* (mg/dL) ⱕ2 2⫺4 ⬎4 Presence of cirrhosis Yes No
Proportion surviving (%) 3y 5y
10 y
p Value
100 87.3 80.2
97.2 73.2 60.3
91.3 60.0 43.3
68.5 29.2 0
⬍ 0.001
60.0 95.6
60.0 89.6
36.0 83.3
12.0 60.2
1y
⬍ 0.001
*Bilirubin measured 2 months after operation.
of cirrhotic patients were alive, compared with a survival rate of 95.6% for noncirrhotic patients (p ⬎ 0.001). Similarly, longterm survival was markedly worse in cirrhotic versus noncirrhotic patients, with median survival being 4.1 years and 14.4 years, respectively (p ⬍ 0.001). Cirrhotic patients who underwent EHBR also had a lower 5and 10-year survival rate (36.0% and 12.0%, respectively) compared with noncirrhotic patients (83.3% and 60.2%, respectively) (p ⬍ 0.001). In comparison, patients undergoing transplantation who did not have cholangiocarcinoma at the time of OLT (n ⫽ 44) had a median survival of 10.9 years and 3-, 5-, and 10-year overall survival rates of 87.4%, 67.3%, and 57.0%, respectively. As such, although cirrhotic patients who underwent EHBR fared poorly, outcomes for noncirrhotic PSC patients treated with EHBR were comparable with those of patients after transplantation (Fig. 2). No cholangiocarcinoma developed in any PSC patient treated with EHBR at followup. Seven patients (n ⫽ 4, noncirrhotic; n ⫽ 3; cirrhotic) treated with EHBR ultimately required OLT for worsening hepatic function. In longterm followup, the incidence of PSCrelated causes of death was the same in patients initially treated with EHBR (14.2%) versus transplantation (12.3%) (p ⫽ 0.23).
DISCUSSION PSC is a rare disease that can lead to end-stage liver disease, cirrhosis, and cholangiocarcinoma in some, but not all, patients. Although symptomatic patients have a reported median survival of 12 years from the time of PSC diagnosis,20-22 asymptomatic patients have better longterm outcomes, with about 70% of patients alive at 16 years.23 Liver transplantation is generally accepted as the therapeutic option of choice in patients with PSC and cirrhosis.4,24,25 Treatment of PSC patients who do not have cirrhosis is more controversial. Although PSC can involve both intrahepatic and extrahepatic bile ducts, in most pa-
tients the hepatic duct bifurcation is the region most severely involved.11,18,26 Some investigators11 have believed that these bifurcation strictures result in increased cholestasis, which is not obvious because of the lack of intrahepatic duct dilation secondary to ductal fibrosis. Although stenting and dilation of biliary strictures are technically feasible to treat these lesions,4,5,27,28 the results are often not durable.13 As such, EHBR with hepatic duct bifurcation resection has been advocated for some patients with PSC.10-14,17 In addition, the Hopkins group has favored reconstruction using bilateral transhepatic silicone elastomer stents, with the stents left in longterm. This approach requires changing of the stents at interventional radiology every several months as an outpatient procedure. Few reports have investigated the benefit of EHBR for PSC, either alone10-12,17,29,30 or relative to transplantation.14 Such data are particularly important, given issues of transplant organ allocation and appropriate use of limited resources.
Figure 2. Although cirrhotic patients who underwent extrahepatic biliary resection (EHBR) fared poorly (p ⬍ 0.001 versus others), outcomes for noncirrhotic primary sclerosing cholangitis patients treated with EHBR were comparable with those of patients treated with transplantation.
828
Pawlik et al
Surgical Resection for Primary Sclerosing Cholangitis
Our research group has previously published on the topic of PSC and EHBR.10-14 In 1982, Pitt and colleagues10 reported on 17 patients during a 6-year period who were treated with EHBR without resection of the hepatic duct bifurcation. In that series, about three-quarters of patients had excellent or good results after operation and 82% of patients were alive at a mean followup of 52.2 months.10 In 1983 and 1988, Cameron and colleagues11,12 reported the Johns Hopkins’ experience. In these reports, all patients underwent resection of the hepatic duct bifurcation and insertion of bilateral transhepatic silicone elastomer stents. In a report of 31 patients with PSC who were managed with EHBR and longterm transhepatic stents, the 5-year survival rate was noted to be 71%.12 More recently, in 1998, Ahrendt and colleagues13 examined the results of EHBR, nonoperative endoscopic biliary dilation, and liver transplantation in 146 patients—50 of whom underwent EHBR. With a median followup of 62 months, the 5-year survival rate was 76%. Although these previous studies were important, they suffered from a number of shortcomings, including a smaller sample size and a relatively short median followup time for a disease with such a long natural history. The current study represents a substantial incremental improvement from our previous work for several reasons. First, by combining the experience of several institutions, we were able to assess a larger number of patients treated with EHBR (n ⫽ 77). Perhaps more importantly, median followup time in the current study (median 10.2 years) was twice that previously reported (median 5.2 years).13 As such, a larger amount of actual, rather than actuarial, longterm survival data were reported. In addition, unlike previous work, the current study focused on longterm outcomes of patients treated with EHBR, with a particular focus on morbidity, rate of readmission, and overall survival compared with transplantation. EHBR involved resection of the entire extrahepatic biliary tree, including the hepatic duct bifurcation. In most patients, the reconstruction involved bilateral hepaticojejunostomies and included use of bilateral transhepatic silicone elastomer stents. The majority of patients experienced no perioperative complications. In addition, in those patients who did experience morbidity, the severity of the complications was mild to moderate. Three patients died in the EHBR cohort for a perioperative mortality rate of 3.9%. Importantly, two of three postoperative deaths were patients with underlying cirrhosis. These data serve to emphasize that EHBR in PSC patients, particularly noncirrhotics, is associated with low perioperative morbidity and mortality when performed at a high-volume hepatopancreaticobiliary center. Although our data strongly support the safety of EHBR for noncirrhotic PSC patients, the impact
J Am Coll Surg
of EHBR on future liver transplantation was not assessed. Although several authors have cautioned that earlier biliary operation can increase morbidity associated with subsequent transplantation,24,31 other studies13,32 have reported that previous biliary operations had no effect on patient survival after transplantation. Importantly, data from the current study help to frame the context, and potential impact, of this clinical issue. Specifically, at ⬎ 10 years of followup, only 7 (9.1%) patients initially treated with EHBR required eventual transplantation. Of these seven patients, three had cirrhosis at the time of EHBR. Based on data from the current series and previous reports,15,32,33 these patients should have presumably undergone initial transplantation rather than EHBR. As such, in wellselected noncirrhotic patients, the empiric data would strongly suggest that “salvage” or subsequent transplantation is a relatively rare occurrence (⬃ 5%). In patients with PSC and underlying cirrhosis, transplantation clearly remains the best therapeutic option. Results for EHBR in the cohort of patients with cirrhosis were exceptionally poor. Roughly 40% of patients with underlying cirrhosis were dead at 1 year after EHBR, compared with only 5% of noncirrhotic patients (p ⬍ 0.001). Not surprisingly, longterm outcomes were similarly abysmal. At 10 years, survival was only 12% for cirrhotic patients and no patient with cirrhosis and a persistently elevated bilirubin was alive. Results with transplantation in this cohort of patients has been reported to be markedly better.15,21,32 Specifically, some investigators have reported an improvement in longterm survival after transplantation, when compared with predicted survival in high-risk cirrhotic PSC patients who were not transplanted.24,25 Our data support this contention, as patients treated with transplantation fared considerably better than patients with cirrhosis who underwent EHBR (Fig. 2). Although transplantation is clearly superior to EHBR in cirrhotic PSC patients, with longterm survival approaching 70% to 90%, graft survival still remains in the 50% to 60% range.32 In addition, recurrent PSC can occur in up to 12% to 15% of patients.34 Nontransplantation surgical approaches, such as EHBR, can be a better therapeutic option for noncirrhotic patients. Noncirrhotic patients treated with EHBR had 3-, 5-, and 10-year survival rates of 89.6%, 83.3%, and 60.2%. With a median followup of ⬎ 10 years, data from the current study substantiate that durable survival rates can be achieved with EHBR. Importantly, longterm survival rates were comparable between noncirrhotic PSC patients treated with EHBR versus transplantation patients. These results demonstrate that surgical resection offers an important, and equally efficacious, treatment modality for well-selected noncirrhotic patients. In addition to long-
Vol. 206, No. 5, May 2008
Pawlik et al
term survival, EHBR obviated the need for repeat biliary procedures and hospital readmissions. We report that EHBR markedly improved cholestasis, with ⬎ 70% of patients having a postoperative bilirubin ⬍ 2 mg/dL 2 months after EHBR. In addition, the majority of patients treated with EHBR also did not require hospital readmission. Whereas, preoperatively, many PSC patients required multiple hospitalizations, and repeat biliary procedures, at 1 and 3 years after EHBR ⬎ 80% and 50% of patients, respectively, were free from readmission. Only a small minority of patients (n ⫽ 5) experienced multiple hospitalizations (5 or more) for PSC-related reasons (eg, repeat biliary procedures/stent management). Development of cholangiocarcinoma is an important concern in patients with PSC, as it can occur in 8% to 30% of patients followed for ⬎ 10 years.2,6,7 Frequently, the indication for operation in patients with PSC and a dominant stricture is concern for cholangiocarcinoma. Importantly, in the current series of 70 patients at risk, at followup there was no incident case of cholangiocarcinoma in any PSC patient treated with EHBR. Although one might have expected that bile duct malignancy should have developed in several patients with time,7,24 the fact that the entire extrahepatic biliary tree, including the hepatic duct bifurcation, was resected might have dramatically decreased the risk of cancer. Transplantation data35 showing that most cancers (⬎ 70%) are found incidentally at the hepatic duct bifurcation in the explant also support this hypothesis. In addition, the majority of cholangiocarcinomas that develop in PSC patients present during the first 18 months of diagnosis.14 Clinicians should remain vigilant in the surveillance of PSC patients, as risk of cholangiocarcinoma remains elevated, regardless of whether patients are treated with EHBR or transplantation. In conclusion, EHBR was associated with not only low perioperative morbidity and mortality but also a substantial decrease in serum bilirubin levels and a low rate of repeat biliary procedures and PSC-related hospital readmissions. Although outcomes for cirrhotic patients treated with EHBR were very poor, noncirrhotic PSC patients experienced longterm survival comparable with that achieved after transplantation without the need for immunosuppression. As such, our data suggest that the need for transplantation can, potentially, be delayed considerably, or avoided, in well-selected PSC patients who present without cirrhosis. OLT should be reserved for those patients who present with PSC associated with hepatic cirrhosis. Author Contributions
Study conception and design: Pawlik, Olbrecht, Pitt, Gleisner
Surgical Resection for Primary Sclerosing Cholangitis
829
Acquisition of data: Pawlik, Olbrecht, Pitt, Gleisner, Choti, Schulick, Cameron Analysis and interpretation of data: Pawlik, Olbrecht, Pitt, Gleisner, Choti, Schulick, Cameron Drafting of manuscript: Pawlik, Olbrecht, Pitt, Gleisner, Cameron Critical revision: Pawlik, Olbrecht, Pitt, Gleisner, Choti, Schulick, Cameron
REFERENCES 1. Narayanan K, Williamson R, Zhang Y, et al. Efficient and precise engineering of a 200 kb beta-globin human/bacterial artificial chromosome in E. coli DH10B using an inducible homologous recombination system. Gene Ther 1999;6:442–447. 2. Worthington J, Chapman R. Primary sclerosing cholangitis. Orphanet J Rare Dis 2006;1:41. 3. Chapman RW, Arborgh BA, Rhodes JM, et al. Primary sclerosing cholangitis: a review of its clinical features, cholangiography, and hepatic histology. Gut 1980;21:870–877. 4. Lee YM, Kim DJ. Primary sclerosing cholangitis. Curr Treat Options Gastroenterol 2001;4:469–477. 5. Charatcharoenwitthaya P, Lindor KD. Primary sclerosing cholangitis: diagnosis and management. Curr Gastroenterol Rep 2006;8:75–82. 6. Kaya M, de Groen PC, Angulo P, et al. Treatment of cholangiocarcinoma complicating primary sclerosing cholangitis: the Mayo Clinic experience. Am J Gastroenterol 2001;96:1164– 1169. 7. Rosen CB, Nagorney DM, Wiesner RH, et al. Cholangiocarcinoma complicating primary sclerosing cholangitis. Ann Surg 1991;213:21–25. 8. Gaing AA, Geders JM, Cohen SA, Siegel JH. Endoscopic management of primary sclerosing cholangitis: review, and report of an open series. Am J Gastroenterol 1993;88:2000–2008. 9. Lee JG, Schutz SM, England RE, et al. Endoscopic therapy of sclerosing cholangitis. Hepatology 1995;21:661–667. 10. Pitt HA, Thompson HH, Tompkins RK, Longmire WP Jr. Primary sclerosing cholangitis: results of an aggressive surgical approach. Ann Surg 1982;196:259–268. 11. Cameron JL, Gayler BW, Herlong HF, Maddrey WC. Sclerosing cholangitis: biliary reconstruction with Silastic transhepatic stents. Surgery 1983;94:324–330. 12. Cameron JL, Pitt HA, Zinner MJ, et al. Resection of hepatic duct bifurcation and transhepatic stenting for sclerosing cholangitis. Ann Surg 1988;207:614–622. 13. Ahrendt SA, Pitt HA, Kalloo AN, et al. Primary sclerosing cholangitis: resect, dilate, or transplant? Ann Surg 1998;227: 412–423. 14. Ahrendt SA, Pitt HA, Nakeeb A, et al. Diagnosis and management of cholangiocarcinoma in primary sclerosing cholangitis. J Gastrointest Surg 1999;3:357–367; discussion 367–368. 15. Solano E, Khakhar A, Bloch M, et al. Liver transplantation for primary sclerosing cholangitis. Transplant Proc 2003;35:2431– 2434. 16. Sebagh M, Farges O, Kalil A, et al. Sclerosing cholangitis following human orthotopic liver transplantation. Am J Surg Pathol 1995;19:81–90.
830
Pawlik et al
Surgical Resection for Primary Sclerosing Cholangitis
17. Myburgh JA. Surgical biliary drainage in primary sclerosing cholangitis. The role of the Hepp-Couinaud approach. Arch Surg 1994;129:1057–1062. 18. Ludwig J, Barham SS, LaRusso NF, et al. Morphologic features of chronic hepatitis associated with primary sclerosing cholangitis and chronic ulcerative colitis. Hepatology 1981;1:632–640. 19. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. Am Stat Assoc J 1958;53:457–480. 20. Broome U, Olsson R, Loof L, et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 1996;38:610–615. 21. Wiesner RH, Grambsch PM, Dickson ER, et al. Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis. Hepatology 1989;10:430–436. 22. Farrant JM, Hayllar KM, Wilkinson ML, et al. Natural history and prognostic variables in primary sclerosing cholangitis. Gastroenterology 1991;100:1710–1717. 23. Porayko MK, Wiesner RH, LaRusso NF, et al. Patients with asymptomatic primary sclerosing cholangitis frequently have progressive disease. Gastroenterology 1990;98:1594–1602. 24. Farges O, Malassagne B, Sebagh M, Bismuth H. Primary sclerosing cholangitis: liver transplantation or biliary surgery. Surgery 1995;117:146–155. 25. Abu-Elmagd KM, Malinchoc M, Dickson ER, et al. Efficacy of hepatic transplantation in patients with primary sclerosing cholangitis. Surg Gynecol Obstet 1993;177:335–344. 26. Cameron JL, Gayler BW, Sanfey H, et al. Sclerosing cholangitis. Anatomical distribution of obstructive lesions. Ann Surg 1984; 200:54–60. 27. Levy C, Lindor KD. Treatment options for primary biliary cirrhosis and primary sclerosing cholangitis. Curr Treat Options Gastroenterol 2003;6:93–103. 28. Johnson GK, Saeian K, Geenen JE. Primary sclerosing cholangitis treated by endoscopic biliary dilation: review and long-term follow-up evaluation. Curr Gastroenterol Rep 2006;8:147–155. 29. Yamamoto T, Hirohashi K, Kubo S, et al. Surgery for segmental primary sclerosing cholangitis. Hepatogastroenterology 2004; 51:668–671. 30. Hirai I, Ishiyama S, Fuse A, et al. Primary sclerosing cholangitis successfully treated by resection of the confluence of the hepatic duct. J Hepatobiliary Pancreat Surg 2001;8:169–173. 31. Ismail T, Angrisani L, Powell JE, et al. Primary sclerosing cholangitis: surgical options, prognostic variables and outcome. Br J Surg 1991;78:564–567. 32. Goss JA, Shackleton CR, Farmer DG, et al. Orthotopic liver transplantation for primary sclerosing cholangitis. A 12-year single center experience. Ann Surg 1997;225:472–481; discussion 481–473. 33. Becker NS, Rodriguez JA, Barshes NR, et al. Outcomes analysis for 280 patients with cholangiocarcinoma treated with liver transplantation over an 18-year period. J Gastrointest Surg 2007;12:117– 122. 34. Oldakowska-Jedynak U, Nowak M, Mucha K, et al. Recurrence of primary sclerosing cholangitis in patients after liver transplantation. Transplant Proc 2006;38:240–243. 35. Abu-Elmagd KM, Selby R, Iwatsuki S, et al. Cholangiocarcinoma and sclerosing cholangitis: clinical characteristics and effect on survival after liver transplantation. Transplant Proc 1993;25:1124–1125.
J Am Coll Surg
Discussion DR C WRIGHT PINSON (Nashville, TN): PSC is a chronic cholestatic disease, has had treatment advancements over the past 20 years. Dr Pawlik and colleagues have reexamined their experience with primary resection for this disease. The last time this group surveyed their results was in 1998. At that time they had 50 patients who had been treated with extrahepatic biliary resection and reconstruction and 28 who had undergone liver transplantation. In this current survey the numbers have increased to 77 patients in the resection group and 49 patients in the transplant group. But more importantly, these authors now have nine extra years of follow-up from their previous large patient cohort. The results are impressive. None of the 77 patients who underwent extrahepatic biliary resection and reconstruction subsequently developed cholangiocarcinoma. Excluding patients with cirrhosis, patients undergoing resection and reconstruction had comparable survival, 60% at 10 years follow-up, to patients who underwent transplantation. Interestingly, patients who underwent resection ad a higher complication rate, largely as a result of higher rates of cholangitis; I wondered if that is secondary to the postoperative long-term stenting and wonder if you still always use stents long term, and do you always have a policy of preoperative biliary drainage? The authors also showed the importance of properly selecting resection candidates. Patients with cirrhosis treated by primary resection had worse overall outcomes in univariate and multivariate analyses. The presence of cirrhosis increases the likelihood of death sevenfold. Only one of nine patients with cirrhosis treated by resection survived at the 10-year mark. I think we would all have to agree that liver transplantation is the treatment modality of choice for patients with cirrhosis. Importantly, this paper reemphasizes the value and role of resection in non-cirrhotic patients with PSC. That is not a well developed position. There is very little data. You won’t find anything currently better than this paper to make the case. Now for some questions: Did Bismuth criteria play a factor in your patient selection process? Are there any patients with Bismuth type 4 lesions who were treated with extrahepatic biliary resection? If so, how did their outcomes compare with those who had Bismuth type 1 through 3 lesions? In patients who underwent partial hepatectomy – I believe that was about 5% of your patients – in addition to hepaticojejunostomies, were the outcomes the same? In your experience, what is the most appropriate timing for the first surgical intervention? Is it after the patient fails a round of medical therapy or endoscopic treatment? Or do you have some other criteria in terms of timing? Your data show that patients whose postoperative bilirubin does not drop below 2 have worse overall outcomes, just like the cirrhotic groups. Importantly, I want to know if you have figured out a way to predict these patients up front and perhaps treat them with transplantation rather than resection. I presume this is a somewhat different group of patients from the cirrhotics. Finally, our studies have shown that quality of life parameters in patients with common bile duct injuries subsequently treated with reparative hepaticojejunostomy did not normalize even years after