LIVER TRANSPLANTATION 21:1295–1299, 2015
ORIGINAL ARTICLE
Liver Transplantation for Critically Ill Patients with Secondary Sclerosing Cholangitis: Outcome and Complications 1 € Torsten Voigtlander, Elmar Jaeckel,1 Frank Lehner,2 Michael P. Manns,1 and Tim O. Lankisch1 Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; and 2Department of General, Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany
1
Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) is a destructive cholangiopathy with a poor prognosis. Liver transplantation (LT) is an established therapeutic option in end-stage liver disease but is insufficiently evaluated in patients with SSC-CIP. Our aim was the retrospective analysis of the outcome and complications of patients with SSC-CIP undergoing LT between 2002 and 2012. Demographic characteristics, laboratory, transplantation, and follow-up data were compared to sex- and age-matched patients undergoing LT because of other reasons. Quality of life (QoL) before and after LT was assessed in a retrospective telephone interview. LT was performed in 21 patients with SSC-CIP. The main causes for intensive care unit admission comprised cardiothoracic surgery interventions (10/21, 48%), polytrauma (6/21, 29%), and pneumonia (3/21, 14%). Median follow-up period after LT was 82 months (interquartile range [IQR], 37-129) for patients with SSC-CIP and 83 months (IQR, 55-104) for control patients. Biopsy-proven rejection episodes in patients with SSC-CIP (4/ 21, 19%) were similar compared to control patients (12/60, 20%; P 5 0.93). Cytomegalovirus infections were equal in both groups (10/21, 48% versus 25/60, 42%; P 5 0.64). The 1-, 3-, and 5-year survival rates of patients with SSC-CIP versus control patients were 100% versus 98%, 86% versus 92%, and 76% versus 87%, respectively (P > 0.05). The QoL improved significantly after LT in SSC-CIP. In conclusion, LT is a valid option for patients with SSC-CIP with excellent longC 2015 AASLD. term outcome and improvement of QoL. Liver Transpl 21:1295-1299, 2015. V Received March 20, 2015; accepted May 27, 2015. Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) is a destructive cholangiopathy with a mortality rate of up to 50%.1-5 In general, secondary sclerosing cholangitis (SSC) can be divided into several subgroups based on the etiology of stricture formation.6,7 Chronic biliary obstruction and ischemic, toxic, infectious, and immunological processes may lead to SSC.6,7 SSC-CIP is a relatively new disease entity potentially based on ischemic injury of the bile ducts and repetitive episodes of cholangitis.1,2,4,8 SSC-CIP is
most often diagnosed via endoscopic retrograde cholangiography but neither diagnostic algorithms nor therapeutic approaches are sufficiently evaluated.1 Liver transplantation (LT) is an established therapeutic option in patients with end-stage liver disease.9,10 However, the data available for patients with SSC-CIP undergoing LT are scarce and ambiguous.11,12 Therefore, our aim was to analyze the outcome and complications in patients with SSC-CIP following LT in a large cohort.
Abbreviations: ALT, alanine aminotransferase; AP, alkaline phosphatase; CMV, cytomegalovirus; CRP, C-reactive protein; GGT, gamma-glutamyltransferase; HCC, hepatocellular carcinoma; ICU, intensive care unit; IQR, interquartile range; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; PSC, primary sclerosing cholangitis; QoL, quality of life; SSC, secondary sclerosing cholangitis; SSC-CIP, secondary sclerosing cholangitis in critically ill patients; ULN, upper limit of normal; WBC, white blood cells. Grants and financial support: Nothing to report. Address reprint requests to Tim O. Lankisch, M.D., Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany. Telephone: 149-511-532-2707; FAX: 149-511-532-3351; E-mail: [email protected] DOI 10.1002/lt.24192 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2015 American Association for the Study of Liver Diseases. V
€ 1296 VOIGTLANDER ET AL.
PATIENTS AND METHODS Patients with SSC-CIP undergoing LT between 2002 and 2012 were identified by retrospective chart review. The diagnosis of SSC-CIP was established by a characteristic clinical course with acute deterioration of liver function test (elevation of bilirubin [>2fold upper limit of normal (ULN)], alkaline phosphatase [AP; >3-fold ULN], gamma-glutamyltransferase [GGT; >3-fold ULN]) during intensive care unit (ICU) treatment and the detection of typical endoscopic findings such as strictures and dilatations of the biliary system, rarefaction of the biliary tree with contrast filling defects, and presence of biliary casts (remnants of ischemic biliary epithelium). The pathological reports from the explanted livers were analyzed for confirmation of the diagnosis. Before ICU treatment, no patient with SSC had a history of preexisting liver disease. As a control group, sex- and agematched patients undergoing LT in the same time period were analyzed. Demographic characteristics, laboratory parameters at day of transplantation, surgical details, and complications after LT (rejection episodes [biopsy-proven], reactivation/infection of/with cytomegalovirus [CMV]) were extracted from the clinical and posttransplant database. The complete follow-up of patients was included until December 2014. The general quality of life (QoL), episodes of cholangitis, intensity of pruritus, the number of antibiotic treatment courses, and the necessity of hospital admission before LT (12 months) and after LT (12 months after discharge from hospital) were assessed retrospectively in a telephone interview in patients with SSC-CIP. For QoL assessment, a visual analogue scale from 0 to 10 was applied. The study protocol was approved by the local institutional ethics review board and is in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients.
Statistical Analysis Group data are presented as n (%) or median (interquartile range [IQR]). All data were tested for normality (Shapiro-Wilk test, Kolmogorov-Smirnov test). Continuous data of the study groups were compared using a Kruskal-Wallis test. In the case of statistical differences, a Mann-Whitney or Wilcoxon test was used to compare groups. Survival after LT was estimated using the Kaplan-Meier method. P values < 0.05 were considered statistically significant. The software used was the SPSS statistical package, version 19.0 (SPSS Inc., Chicago, IL) and GraphPad Prism, version 6.01 (GraphPad Inc., La Jolla, CA).
RESULTS In the study period, 96 patients developed SSC-CIP. The majority of patients died during ICU treatment (54/96, 56%), whereas 8 patients were on the waiting
LIVER TRANSPLANTATION, October 2015
TABLE 1. Reasons for ICU Admission in Patients Who Developed SSC-CIP Reasons for ICU Admission Cardiothoracic surgery interventions Transplantation Heart transplantation Lung transplantation Bypass surgery Polytrauma Pneumonia Major abdominal surgery Ischemic colitis Suppurative peritonitis
n (%) 10/21 7/10 3/10 4/10 3/10 6/21 3/21 2/21 1/2 1/2
(48) (70) (30) (40) (30) (29) (14) (10) (50) (50)
NOTE: The predominant causes for ICU admission were complicative cardiothoracic surgery interventions and polytrauma.
list for LT and 13 patients were lost for follow-up. We identified 21 patients with SSC-CIP undergoing LT between 2002 and 2012. In all explanted livers, pathological findings compatible with ischemic cholangitis were documented. Diseases leading to ICU treatment are displayed in Table 1. Complicative cardiothoracic surgery interventions and polytrauma were the predominant causes for ICU admission. Median time interval from admission to ICU and development of SSC-CIP was 53 days (IQR, 35-89 days). Median time interval from diagnosis to LT was 432 days (IQR, 143731 days). As a control group, sex- and age-matched patients undergoing LT were analyzed. The main reasons for LT in the control group were alcoholic liver disease (55/60, 92%) and others (5/60, 8%). Median follow-up period after LT was 82 months (IQR, 37-129 months) for patients with SSC-CIP and 83 months (IQR, 55-104 months) for control patients, respectively (until December 2014). Demographic characteristics, laboratory parameters at day of transplantation, surgical details, and complications after LT are illustrated in Table 2. Demographic characteristics were similar in both groups (P > 0.05). Patients with SSC-CIP showed significantly higher cholestatic and inflammatory parameters compared to control patients. The immunosuppressive regimen applied was equal. Posttransplant complications regarding CMV infection and rejection episodes (biopsy-proven) did not differ significantly (P > 0.05). In the complete follow-up period, 6 patients with SSC-CIP and 9 control patients died. Causes of death included pneumonia (44%, n 5 4), biliary sepsis (33%, n 5 3), hepatocellular carcinoma (HCC; 11%, n 5 1), and posttransplant lymphoproliferative disorder (11%, n 5 1) for control patients and biliary sepsis (83%, n 5 5) and HCC (17%, n 5 1) for patients with SSC-CIP. Death from biliary sepsis was not associated with 1 of the SSC-CIP subgroups (Table 1). Four out of 5 patients with biliary sepsis died in our hospital and initially presented with signs of systemic inflammation
€ VOIGTLANDER ET AL. 1297
LIVER TRANSPLANTATION, Vol. 21, No. 10, 2015
TABLE 2. Patient Characteristics
Sex, male/female Age, years Laboratory values WBC/nL CRP mg/L ALT U/L AP U/L GGT U/L Bilirubin lmol/L MELD score Transplantation data Duct-to-duct anastomosis Cold ischemia time, minutes Warm ischemia time, minutes Operation time, minutes Tacrolimus Cyclosporine Steroid Mycophenolate mofetil CMV infection Rejection Death during follow-up
Control Patients (n 5 60)
SSC-CIP (n 5 21)
P Value
45/15 48 (42-53)
16/5 45 (37-55)
0.91 0.94
5.5 (4.5-7.6) 10 (5-25) 66 (44-90) 140 (102-190) 88 (56-199) 45 (32-76) 23 (21-27)
8.6 (6.4-10.3) 22 (10-37) 78 (69-147) 836 (534-1588) 393 (132-1289) 184 (68-233) 22 (18-28)
ORIGINAL ARTICLE
Liver Transplantation for Critically Ill Patients with Secondary Sclerosing Cholangitis: Outcome and Complications 1 € Torsten Voigtlander, Elmar Jaeckel,1 Frank Lehner,2 Michael P. Manns,1 and Tim O. Lankisch1 Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; and 2Department of General, Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany
1
Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) is a destructive cholangiopathy with a poor prognosis. Liver transplantation (LT) is an established therapeutic option in end-stage liver disease but is insufficiently evaluated in patients with SSC-CIP. Our aim was the retrospective analysis of the outcome and complications of patients with SSC-CIP undergoing LT between 2002 and 2012. Demographic characteristics, laboratory, transplantation, and follow-up data were compared to sex- and age-matched patients undergoing LT because of other reasons. Quality of life (QoL) before and after LT was assessed in a retrospective telephone interview. LT was performed in 21 patients with SSC-CIP. The main causes for intensive care unit admission comprised cardiothoracic surgery interventions (10/21, 48%), polytrauma (6/21, 29%), and pneumonia (3/21, 14%). Median follow-up period after LT was 82 months (interquartile range [IQR], 37-129) for patients with SSC-CIP and 83 months (IQR, 55-104) for control patients. Biopsy-proven rejection episodes in patients with SSC-CIP (4/ 21, 19%) were similar compared to control patients (12/60, 20%; P 5 0.93). Cytomegalovirus infections were equal in both groups (10/21, 48% versus 25/60, 42%; P 5 0.64). The 1-, 3-, and 5-year survival rates of patients with SSC-CIP versus control patients were 100% versus 98%, 86% versus 92%, and 76% versus 87%, respectively (P > 0.05). The QoL improved significantly after LT in SSC-CIP. In conclusion, LT is a valid option for patients with SSC-CIP with excellent longC 2015 AASLD. term outcome and improvement of QoL. Liver Transpl 21:1295-1299, 2015. V Received March 20, 2015; accepted May 27, 2015. Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) is a destructive cholangiopathy with a mortality rate of up to 50%.1-5 In general, secondary sclerosing cholangitis (SSC) can be divided into several subgroups based on the etiology of stricture formation.6,7 Chronic biliary obstruction and ischemic, toxic, infectious, and immunological processes may lead to SSC.6,7 SSC-CIP is a relatively new disease entity potentially based on ischemic injury of the bile ducts and repetitive episodes of cholangitis.1,2,4,8 SSC-CIP is
most often diagnosed via endoscopic retrograde cholangiography but neither diagnostic algorithms nor therapeutic approaches are sufficiently evaluated.1 Liver transplantation (LT) is an established therapeutic option in patients with end-stage liver disease.9,10 However, the data available for patients with SSC-CIP undergoing LT are scarce and ambiguous.11,12 Therefore, our aim was to analyze the outcome and complications in patients with SSC-CIP following LT in a large cohort.
Abbreviations: ALT, alanine aminotransferase; AP, alkaline phosphatase; CMV, cytomegalovirus; CRP, C-reactive protein; GGT, gamma-glutamyltransferase; HCC, hepatocellular carcinoma; ICU, intensive care unit; IQR, interquartile range; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; PSC, primary sclerosing cholangitis; QoL, quality of life; SSC, secondary sclerosing cholangitis; SSC-CIP, secondary sclerosing cholangitis in critically ill patients; ULN, upper limit of normal; WBC, white blood cells. Grants and financial support: Nothing to report. Address reprint requests to Tim O. Lankisch, M.D., Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany. Telephone: 149-511-532-2707; FAX: 149-511-532-3351; E-mail: [email protected] DOI 10.1002/lt.24192 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2015 American Association for the Study of Liver Diseases. V
€ 1296 VOIGTLANDER ET AL.
PATIENTS AND METHODS Patients with SSC-CIP undergoing LT between 2002 and 2012 were identified by retrospective chart review. The diagnosis of SSC-CIP was established by a characteristic clinical course with acute deterioration of liver function test (elevation of bilirubin [>2fold upper limit of normal (ULN)], alkaline phosphatase [AP; >3-fold ULN], gamma-glutamyltransferase [GGT; >3-fold ULN]) during intensive care unit (ICU) treatment and the detection of typical endoscopic findings such as strictures and dilatations of the biliary system, rarefaction of the biliary tree with contrast filling defects, and presence of biliary casts (remnants of ischemic biliary epithelium). The pathological reports from the explanted livers were analyzed for confirmation of the diagnosis. Before ICU treatment, no patient with SSC had a history of preexisting liver disease. As a control group, sex- and agematched patients undergoing LT in the same time period were analyzed. Demographic characteristics, laboratory parameters at day of transplantation, surgical details, and complications after LT (rejection episodes [biopsy-proven], reactivation/infection of/with cytomegalovirus [CMV]) were extracted from the clinical and posttransplant database. The complete follow-up of patients was included until December 2014. The general quality of life (QoL), episodes of cholangitis, intensity of pruritus, the number of antibiotic treatment courses, and the necessity of hospital admission before LT (12 months) and after LT (12 months after discharge from hospital) were assessed retrospectively in a telephone interview in patients with SSC-CIP. For QoL assessment, a visual analogue scale from 0 to 10 was applied. The study protocol was approved by the local institutional ethics review board and is in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients.
Statistical Analysis Group data are presented as n (%) or median (interquartile range [IQR]). All data were tested for normality (Shapiro-Wilk test, Kolmogorov-Smirnov test). Continuous data of the study groups were compared using a Kruskal-Wallis test. In the case of statistical differences, a Mann-Whitney or Wilcoxon test was used to compare groups. Survival after LT was estimated using the Kaplan-Meier method. P values < 0.05 were considered statistically significant. The software used was the SPSS statistical package, version 19.0 (SPSS Inc., Chicago, IL) and GraphPad Prism, version 6.01 (GraphPad Inc., La Jolla, CA).
RESULTS In the study period, 96 patients developed SSC-CIP. The majority of patients died during ICU treatment (54/96, 56%), whereas 8 patients were on the waiting
LIVER TRANSPLANTATION, October 2015
TABLE 1. Reasons for ICU Admission in Patients Who Developed SSC-CIP Reasons for ICU Admission Cardiothoracic surgery interventions Transplantation Heart transplantation Lung transplantation Bypass surgery Polytrauma Pneumonia Major abdominal surgery Ischemic colitis Suppurative peritonitis
n (%) 10/21 7/10 3/10 4/10 3/10 6/21 3/21 2/21 1/2 1/2
(48) (70) (30) (40) (30) (29) (14) (10) (50) (50)
NOTE: The predominant causes for ICU admission were complicative cardiothoracic surgery interventions and polytrauma.
list for LT and 13 patients were lost for follow-up. We identified 21 patients with SSC-CIP undergoing LT between 2002 and 2012. In all explanted livers, pathological findings compatible with ischemic cholangitis were documented. Diseases leading to ICU treatment are displayed in Table 1. Complicative cardiothoracic surgery interventions and polytrauma were the predominant causes for ICU admission. Median time interval from admission to ICU and development of SSC-CIP was 53 days (IQR, 35-89 days). Median time interval from diagnosis to LT was 432 days (IQR, 143731 days). As a control group, sex- and age-matched patients undergoing LT were analyzed. The main reasons for LT in the control group were alcoholic liver disease (55/60, 92%) and others (5/60, 8%). Median follow-up period after LT was 82 months (IQR, 37-129 months) for patients with SSC-CIP and 83 months (IQR, 55-104 months) for control patients, respectively (until December 2014). Demographic characteristics, laboratory parameters at day of transplantation, surgical details, and complications after LT are illustrated in Table 2. Demographic characteristics were similar in both groups (P > 0.05). Patients with SSC-CIP showed significantly higher cholestatic and inflammatory parameters compared to control patients. The immunosuppressive regimen applied was equal. Posttransplant complications regarding CMV infection and rejection episodes (biopsy-proven) did not differ significantly (P > 0.05). In the complete follow-up period, 6 patients with SSC-CIP and 9 control patients died. Causes of death included pneumonia (44%, n 5 4), biliary sepsis (33%, n 5 3), hepatocellular carcinoma (HCC; 11%, n 5 1), and posttransplant lymphoproliferative disorder (11%, n 5 1) for control patients and biliary sepsis (83%, n 5 5) and HCC (17%, n 5 1) for patients with SSC-CIP. Death from biliary sepsis was not associated with 1 of the SSC-CIP subgroups (Table 1). Four out of 5 patients with biliary sepsis died in our hospital and initially presented with signs of systemic inflammation
€ VOIGTLANDER ET AL. 1297
LIVER TRANSPLANTATION, Vol. 21, No. 10, 2015
TABLE 2. Patient Characteristics
Sex, male/female Age, years Laboratory values WBC/nL CRP mg/L ALT U/L AP U/L GGT U/L Bilirubin lmol/L MELD score Transplantation data Duct-to-duct anastomosis Cold ischemia time, minutes Warm ischemia time, minutes Operation time, minutes Tacrolimus Cyclosporine Steroid Mycophenolate mofetil CMV infection Rejection Death during follow-up
Control Patients (n 5 60)
SSC-CIP (n 5 21)
P Value
45/15 48 (42-53)
16/5 45 (37-55)
0.91 0.94
5.5 (4.5-7.6) 10 (5-25) 66 (44-90) 140 (102-190) 88 (56-199) 45 (32-76) 23 (21-27)
8.6 (6.4-10.3) 22 (10-37) 78 (69-147) 836 (534-1588) 393 (132-1289) 184 (68-233) 22 (18-28)
