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Incidence and Risk Factors for the Development of Prolonged Severe Intrahepatic Cholestasis After Pediatric Living-Donor Liver Transplantation
Incidence and Risk Factors for the Development of Prolonged Severe Intrahepatic Cholestasis After Pediatric Living-Donor Liver Transplantation S.H. Oh, K.M. Kim, D.Y. Kim, T. Kim, S. Hwang, K.-M. Park, Y.-J. Lee, and S.-G. Lee ABSTRACT The aim of this study is to evaluate the incidence, etiology, and risk facrors for prolonged severe intrahepatic cholestasis (PSIC) after 129 pediatric living-donor liver transplantations (LDLT). The incidence of PSIC was 25.6% (n ⫽ 33). Twenty-eight (84.8%) versus 5 (15.2%) children experienced early versus late PSIC, respectively. Among these 33 children with PSIC, 8 (24.2%) received a donor liver with mild to moderate fatty change, 4 (12.1%) with low graft– body weight ratios, and 4 (12.1%) with ABO incompatibility. The predominant etiologies were acute rejection (n ⫽ 15; 45.5%), chronic rejection (n ⫽ 6; 18.2%), virus (n ⫽ 3; 9.1%), vascular complications (n ⫽ 4; 12.1%), and initial graft dysfunction (n ⫽ 10; 30.3%). ABO incompatibility (P ⫽ .032; odds ratio [OR] 3.25), chronic rejection (P ⫽ .012; OR 4.76), and vascular complications (P ⫽ .046; OR 1.82) were significant variables associated with PSIC. Donor selection with ABO compatibility as well as early detection and management of chronic rejection and vascular complications may be important to prevet PSIC in LDLT. ROLONGED severe intrahepatic cholestasis (PSIC) after liver transplantation can indicate graft dysfunction.1– 4 For example, chronic rejection, which is often refractory to additional immunosuppressive treatment, includes progressive bile duct atrophy, resulting in prolonged cholestasis, eventuating in graft loss. Severe cholestasis after liver transplantation has been noted to cause a mortality twofold higher than that among adult patients free of this complication.1 The various causes of cholestastasis after liver transplantation are related not only to postoperative complications, but also to the preoperative condition of the donor graft.1–3 Prolonged ischemia time is known to be one of the main causes of PSIC among cadaveric liver transplantation,1,4 although its etiologies, incidence, and risk factors are still not entirely clear. The factors for PSIC among living-donor liver transplantations (LDLT) may be different, particularly where ischemia time is shortened. In addition, there has not been a study in pediatric liver transplantation. The aim of the present study is to evaluate the incidence, etiology, and risk factors for PSIC among children with LDLT.
P
METHODS We performed a retrospective single-center assessment of the demographic and clinical factors in children who underwent LDLT
from 1994 to 2008. For definition of PSIC, we modified the recommendations of the Royal Free Hospital of the United Kingdom.1,2 In this study, PSIC was defined by only serum bilirubin, because alkaline phosphatase (ALP) activity was variable according to age and other medical conditions among the pediatric group.5,6 PSIC was defined as an increase in serum bilirubin to ⬎6.0 mg/dL for a week in the absence of extrahepatic cholestasis. For the differential diagnosis of etiologies, we adopted the general guidelines, recommended by the Royal Free Hospital.2 Other clinical characteristics were defined as described in our previous report.7 Multiple logistic regressions were used to calculate odds ratios (ORs) of risk factors. Cumulative survival rates for PSIC and non-PSIC groups were calculated by the Kaplan-Meier method. A P value of ⬍.05 was considered to be statistically significant.
From the Department of Pediatrics (S.H.O., K.M.K.) and Surgery (D.Y.K., T.K., S.H., K.-M.P., Y.-J.L., S.-G.L.), Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea. Address correspondence to Kyung Mo Kim, MD, Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College Of Medicine, 388-1 Pungnap-Dong, Songpa-Gu, Seoul 138-736, Korea. E-mail: kmkim@amc. seoul.kr
0041-1345/11/$–see front matter doi:10.1016/j.transproceed.2011.06.013
© 2011 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2400
Transplantation Proceedings, 43, 2400 –2402 (2011)
CHOLESTASIS OF PEDRIATRIC LDLT
2401
RESULTS
From 1994 to 2008, 125 children underwent 129 LDLTs (4 retransplantations). The median patient age was 22.7 months (range ⫽ 6 months to 15.8 years). The most common etiologies for liver transplantation were biliary atresia and acute liver failure. The incidence of PSIC was 25.6% (n ⫽ 33). Twenty-eight children (84.8%) had early and 5 (15.2%) late PSIC (Table 1). The mortality was much higher among children with and statistically related to PSIC (Fig 1). The 1- and 5-year survival rates of the PSIC group were 72.7% and 55.0%, respectively, versus 96.3% and 95.4%, respectively, for the non-PSIC group (P ⬍ .005). Factors that have been reported to be causes of PSIC are shown in Table 1 Among the 33 children with PSIC, 8 (24.2%) received living-donor livers with mild to moderate fatty changes, 4 (12.1%) with low graft– body weight ratio, and 4 (12.1%) with ABO incompatibility. The predominant etiologies after transplantation were an acute rejection episode (45.5%; n ⫽ 15), initial graft dysfunction (30.3%; n ⫽ 10), chronic rejection (18.2%; n ⫽ 6), early blood stream infection (24.2%; n ⫽ 8), viral infection (9.1%; n ⫽ 3), and vascular complications (12.1%; n ⫽ 4). ABO incompatibility (P ⫽ .032; OR 3.25), chronic rejection (P ⫽ .012; OR 4.76), and vascular complications (P ⫽ .046; OR 1.82) were significant associated variables (Table 2). DISCUSSION
Although severe, persistent cholestasis is believed to be related to both patient and graft loss, its incidence and risk factors have been poorly studied. Using the definition of Table 1. Cause of Prolonged Severe Intrahepatic Cholestasis Cause of PSIC
ABO incompatibility GBWR ⬍ 1.0 Acute rejection Mild to moderate Severe Chronic rejection Viral infection CMV hepatitis EBV-related PTLD Vessel problems PV thrombosis HA thrombosis VOD EBSI Initial graft dysfunction Mild & transient Severe Preoperative condition (acute liver failure)
Early PSIC n ⫽ 28 (84.8%)
Late PSIC n ⫽ 5 (15.2%)
Total n ⫽ 33
2 3 8 5 3 4 3 1 2 3 1 1 1 6 8 4 2 2
2 1 7 6 1 2 0 0 0 1 1 0 0 2 2 2 0 0
4 (12.1%) 4 (12.1%) 15 (45.5%) 11 4 6 (18.2%) 3 (9.1%) 1 2 4 (12.1%) 2 1 1 8 (24.2%) 10 (30.3%) 6 2 2
Abbreviations: PSIC, prolonged severe intrahepatic cholestasis; GBWR, graft– body weight ratio; CMV, cytomegalovirus; EBV, Ebstein-Barr virus; PTLD, posttransplantation lymphoproliferative disease; PV, portal vein; HA, hepatic artery; VOD, veno-occlusive disease; EBSI, early bloodstream infection.
Fig 1. Survival of children with persistent severe intrahepatic cholestasis. The survival rates of the prolonged severe intrahepatic cholestasis (PSIC) group at 1 and 5 years were 72.7% and 55.0%, respectively, and the survival rates of the non-PSIC group at 1 and 5 years were 96.3% and 95.4%, respectively (P ⬍ .005 by Kaplan-Meier method).
PSIC recommended by the Royal Free Hospital,1,2 Fusai et al reported a 25% incidence of PSIC associated with the use of intraoperative cryoprecipitate and platelet transfusions. ABO incompatibility, suboptimal graft appearance, inpatient status before transplantation, and early bacteremia. Notably, cellular rejection was not a risk factor. Using the histologic definition of Williams et al,7 a small-scaled study by Adler et al reported a 40% PSIC incidence.8 The Table 2. Risk Factors of Prolonged Severe Intrahepatic Cholestasis Characteristics
PSIC n ⫽ 33
Non-PSIC n ⫽ 96
P Value
Age, mean, mo Gender, M:F ALF vs. others ABO incompatibility Fatty liver Old donor age GBWR ⬍1.0 Living unrelated vs related Initial graft dysfunction Acute rejection Chronic rejection EBSI Viral diseases Vessel complications
56.2 ⫾ 53.2 14:19 8 (24.2%) 4 (12.1%) 8 (24.2%) 2 (6.0%) 4 (12.1%) 2 (6.1%) 10 (30.3%) 15 (45.5%) 6 (18.2%) 8 (24.2%) 3 (9.1%) 4 (12.1%)
46.0 ⫾ 45.9 43:53 18 (18.8%) 5 (5.2%) 21 (21.9%) 13 (13.5%) 11 (11.4%) 6 (6.3%) 21 (21.9%) 64 (66.7%) 2 (2.1%) 24 (25.0%) 13 (13.5%) 23 (24.0%)
NS NS NS .032 NS NS NS NS NS NS .012 NS NS .046
Abbreviations as in Table 1.
2402
incidence of PSIC in our pediatric group was 25.6%, which was similar to the Fusai et al study (25%). We excluded ALP as a criterion in the definition for a sample of reasons: First, children occasionally display marked transient elevations of ALP in the absence of detectable liver or bone diseases;5 and second, the normal range of ALP according to age is broad.6 Ischemia-reperfusion injury, initial graft dysfunction, infections, small-for-size syndrome, drugs, and acute rejection are known causes of early intrahepatic cholestasis after liver transplantation. Chronic rejection, hepatic artery problems, ABO incompatibility, and de novo malignancy cause late intrahepatic cholestasis. Injury from hypothermic storage with reperfusion is thought to be the main cause of early intrahepatic cholestasis. For example, grafts with ⬎13 hours of ischemia time have been reported to develop cholestasis in more than 52% of cases.4 However, the duration of ischemia time in LDLT is usually short; therefore, the cause may be different in this setting. In addition, suboptimal and small-sized grafts can be excluded through preoperative donor selection. Although it was prevalent (30%), most cases of initial graft dysfunction in our study were mild, rapidly improving postoperatively. However, ABO-incompatible and fatty grafts inevitably occasioned urgent transplantation cases. ABO incompatibility was a significant risk factor. Surprisingly, chronic rejection, which was a risk factor for PSIC, was the main cause of early PSIC in the present study. Most chronic rejections developed within 6 months postoperatively, suggesting insufficient immunosuppression among our series, as had been described in a previous report.7
OH, KIM, KIM ET AL
In conclusion, as many children as adults developed PSIC after transplantation. The survival rates of PSIC children was lower than those of non-PSIC children. Although there is some uncertainty among olverlapping causes and some controversy about methodology, our study suggested that donor selection with ABO compatibility as well as early detection and management of chronic rejection and vascular complications are important to prevent PSIC.
REFERENCES 1. Fusai G, Dhaliwal P, Rolando N, et al: Incidence and risk factors for the development of prolonged and severe intrahepatic cholestasis after liver transplantation. Liver Transpl 12:1626, 2006 2. Corbani A, Burroughs AK: Intrahepatic cholestasis after liver transplantation. Clin Liver Dis 12:111, 2008 3. Ben-Ari Z, Pappo O, Mor E: Intrahepatic cholestasis after liver transplantation. Liver Transpl 9:1005, 2003 4. Sanchez-Urdazpal L, Gores GJ, Ward EM, et al: Diagnostic features and clinical outcome of ischemic-type biliary complications after liver transplantation. Hepatology 17:605, 1993 5. Huh SY, Feldman HA, Cox JE, et al: Prevalence of transient hyperphosphatasemia among healthy infants and toddlers. Pediatrics 24:703, 2009 6. Oh SH, Kim KM, Kim DY, et al: Long-term outcomes of pediatric living donor liver transplantation at a single institution. Pediatr Transplant 14:870, 2010 7. Williams JW, Vera S, Peters TG, et al: Cholestatic jaundice after hepatic transplantation, A nonimmunologically mediated event. Am J Surg 151:65, 1986 8. Adler M, Deprez C, Rickaert F, et al: Cholestatic syndrome due to preservation injury after liver transplantation. Transplant Proc 20:644, 1988
P
METHODS We performed a retrospective single-center assessment of the demographic and clinical factors in children who underwent LDLT
from 1994 to 2008. For definition of PSIC, we modified the recommendations of the Royal Free Hospital of the United Kingdom.1,2 In this study, PSIC was defined by only serum bilirubin, because alkaline phosphatase (ALP) activity was variable according to age and other medical conditions among the pediatric group.5,6 PSIC was defined as an increase in serum bilirubin to ⬎6.0 mg/dL for a week in the absence of extrahepatic cholestasis. For the differential diagnosis of etiologies, we adopted the general guidelines, recommended by the Royal Free Hospital.2 Other clinical characteristics were defined as described in our previous report.7 Multiple logistic regressions were used to calculate odds ratios (ORs) of risk factors. Cumulative survival rates for PSIC and non-PSIC groups were calculated by the Kaplan-Meier method. A P value of ⬍.05 was considered to be statistically significant.
From the Department of Pediatrics (S.H.O., K.M.K.) and Surgery (D.Y.K., T.K., S.H., K.-M.P., Y.-J.L., S.-G.L.), Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea. Address correspondence to Kyung Mo Kim, MD, Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College Of Medicine, 388-1 Pungnap-Dong, Songpa-Gu, Seoul 138-736, Korea. E-mail: kmkim@amc. seoul.kr
0041-1345/11/$–see front matter doi:10.1016/j.transproceed.2011.06.013
© 2011 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2400
Transplantation Proceedings, 43, 2400 –2402 (2011)
CHOLESTASIS OF PEDRIATRIC LDLT
2401
RESULTS
From 1994 to 2008, 125 children underwent 129 LDLTs (4 retransplantations). The median patient age was 22.7 months (range ⫽ 6 months to 15.8 years). The most common etiologies for liver transplantation were biliary atresia and acute liver failure. The incidence of PSIC was 25.6% (n ⫽ 33). Twenty-eight children (84.8%) had early and 5 (15.2%) late PSIC (Table 1). The mortality was much higher among children with and statistically related to PSIC (Fig 1). The 1- and 5-year survival rates of the PSIC group were 72.7% and 55.0%, respectively, versus 96.3% and 95.4%, respectively, for the non-PSIC group (P ⬍ .005). Factors that have been reported to be causes of PSIC are shown in Table 1 Among the 33 children with PSIC, 8 (24.2%) received living-donor livers with mild to moderate fatty changes, 4 (12.1%) with low graft– body weight ratio, and 4 (12.1%) with ABO incompatibility. The predominant etiologies after transplantation were an acute rejection episode (45.5%; n ⫽ 15), initial graft dysfunction (30.3%; n ⫽ 10), chronic rejection (18.2%; n ⫽ 6), early blood stream infection (24.2%; n ⫽ 8), viral infection (9.1%; n ⫽ 3), and vascular complications (12.1%; n ⫽ 4). ABO incompatibility (P ⫽ .032; OR 3.25), chronic rejection (P ⫽ .012; OR 4.76), and vascular complications (P ⫽ .046; OR 1.82) were significant associated variables (Table 2). DISCUSSION
Although severe, persistent cholestasis is believed to be related to both patient and graft loss, its incidence and risk factors have been poorly studied. Using the definition of Table 1. Cause of Prolonged Severe Intrahepatic Cholestasis Cause of PSIC
ABO incompatibility GBWR ⬍ 1.0 Acute rejection Mild to moderate Severe Chronic rejection Viral infection CMV hepatitis EBV-related PTLD Vessel problems PV thrombosis HA thrombosis VOD EBSI Initial graft dysfunction Mild & transient Severe Preoperative condition (acute liver failure)
Early PSIC n ⫽ 28 (84.8%)
Late PSIC n ⫽ 5 (15.2%)
Total n ⫽ 33
2 3 8 5 3 4 3 1 2 3 1 1 1 6 8 4 2 2
2 1 7 6 1 2 0 0 0 1 1 0 0 2 2 2 0 0
4 (12.1%) 4 (12.1%) 15 (45.5%) 11 4 6 (18.2%) 3 (9.1%) 1 2 4 (12.1%) 2 1 1 8 (24.2%) 10 (30.3%) 6 2 2
Abbreviations: PSIC, prolonged severe intrahepatic cholestasis; GBWR, graft– body weight ratio; CMV, cytomegalovirus; EBV, Ebstein-Barr virus; PTLD, posttransplantation lymphoproliferative disease; PV, portal vein; HA, hepatic artery; VOD, veno-occlusive disease; EBSI, early bloodstream infection.
Fig 1. Survival of children with persistent severe intrahepatic cholestasis. The survival rates of the prolonged severe intrahepatic cholestasis (PSIC) group at 1 and 5 years were 72.7% and 55.0%, respectively, and the survival rates of the non-PSIC group at 1 and 5 years were 96.3% and 95.4%, respectively (P ⬍ .005 by Kaplan-Meier method).
PSIC recommended by the Royal Free Hospital,1,2 Fusai et al reported a 25% incidence of PSIC associated with the use of intraoperative cryoprecipitate and platelet transfusions. ABO incompatibility, suboptimal graft appearance, inpatient status before transplantation, and early bacteremia. Notably, cellular rejection was not a risk factor. Using the histologic definition of Williams et al,7 a small-scaled study by Adler et al reported a 40% PSIC incidence.8 The Table 2. Risk Factors of Prolonged Severe Intrahepatic Cholestasis Characteristics
PSIC n ⫽ 33
Non-PSIC n ⫽ 96
P Value
Age, mean, mo Gender, M:F ALF vs. others ABO incompatibility Fatty liver Old donor age GBWR ⬍1.0 Living unrelated vs related Initial graft dysfunction Acute rejection Chronic rejection EBSI Viral diseases Vessel complications
56.2 ⫾ 53.2 14:19 8 (24.2%) 4 (12.1%) 8 (24.2%) 2 (6.0%) 4 (12.1%) 2 (6.1%) 10 (30.3%) 15 (45.5%) 6 (18.2%) 8 (24.2%) 3 (9.1%) 4 (12.1%)
46.0 ⫾ 45.9 43:53 18 (18.8%) 5 (5.2%) 21 (21.9%) 13 (13.5%) 11 (11.4%) 6 (6.3%) 21 (21.9%) 64 (66.7%) 2 (2.1%) 24 (25.0%) 13 (13.5%) 23 (24.0%)
NS NS NS .032 NS NS NS NS NS NS .012 NS NS .046
Abbreviations as in Table 1.
2402
incidence of PSIC in our pediatric group was 25.6%, which was similar to the Fusai et al study (25%). We excluded ALP as a criterion in the definition for a sample of reasons: First, children occasionally display marked transient elevations of ALP in the absence of detectable liver or bone diseases;5 and second, the normal range of ALP according to age is broad.6 Ischemia-reperfusion injury, initial graft dysfunction, infections, small-for-size syndrome, drugs, and acute rejection are known causes of early intrahepatic cholestasis after liver transplantation. Chronic rejection, hepatic artery problems, ABO incompatibility, and de novo malignancy cause late intrahepatic cholestasis. Injury from hypothermic storage with reperfusion is thought to be the main cause of early intrahepatic cholestasis. For example, grafts with ⬎13 hours of ischemia time have been reported to develop cholestasis in more than 52% of cases.4 However, the duration of ischemia time in LDLT is usually short; therefore, the cause may be different in this setting. In addition, suboptimal and small-sized grafts can be excluded through preoperative donor selection. Although it was prevalent (30%), most cases of initial graft dysfunction in our study were mild, rapidly improving postoperatively. However, ABO-incompatible and fatty grafts inevitably occasioned urgent transplantation cases. ABO incompatibility was a significant risk factor. Surprisingly, chronic rejection, which was a risk factor for PSIC, was the main cause of early PSIC in the present study. Most chronic rejections developed within 6 months postoperatively, suggesting insufficient immunosuppression among our series, as had been described in a previous report.7
OH, KIM, KIM ET AL
In conclusion, as many children as adults developed PSIC after transplantation. The survival rates of PSIC children was lower than those of non-PSIC children. Although there is some uncertainty among olverlapping causes and some controversy about methodology, our study suggested that donor selection with ABO compatibility as well as early detection and management of chronic rejection and vascular complications are important to prevent PSIC.
REFERENCES 1. Fusai G, Dhaliwal P, Rolando N, et al: Incidence and risk factors for the development of prolonged and severe intrahepatic cholestasis after liver transplantation. Liver Transpl 12:1626, 2006 2. Corbani A, Burroughs AK: Intrahepatic cholestasis after liver transplantation. Clin Liver Dis 12:111, 2008 3. Ben-Ari Z, Pappo O, Mor E: Intrahepatic cholestasis after liver transplantation. Liver Transpl 9:1005, 2003 4. Sanchez-Urdazpal L, Gores GJ, Ward EM, et al: Diagnostic features and clinical outcome of ischemic-type biliary complications after liver transplantation. Hepatology 17:605, 1993 5. Huh SY, Feldman HA, Cox JE, et al: Prevalence of transient hyperphosphatasemia among healthy infants and toddlers. Pediatrics 24:703, 2009 6. Oh SH, Kim KM, Kim DY, et al: Long-term outcomes of pediatric living donor liver transplantation at a single institution. Pediatr Transplant 14:870, 2010 7. Williams JW, Vera S, Peters TG, et al: Cholestatic jaundice after hepatic transplantation, A nonimmunologically mediated event. Am J Surg 151:65, 1986 8. Adler M, Deprez C, Rickaert F, et al: Cholestatic syndrome due to preservation injury after liver transplantation. Transplant Proc 20:644, 1988