© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Clin Transplant 2014: 28: 521–529 DOI: 10.1111/ctr.12343
Clinical Transplantation
Histologically proven non-alcoholic fatty liver disease and clinically related factors in recipients after liver transplantation Kim H, Lee K, Lee K-W, Yi N-J, Lee HW, Hong G, Choi Y, You T, Suh S-W, Jang JJ, Suh K-S. Histologically proven non-alcoholic fatty liver disease and clinically related factors in recipients after liver transplantation. Abstract: Non-alcoholic fatty liver disease (NAFLD) affects a substantial proportion of the world population, and its prevalence has been increasing. The study was aimed at evaluating the prevalence and peri-transplant risk factors for post-liver transplantation (LT) NAFLD. A retrospective review was performed for adult recipients who underwent late protocol biopsy (>1 yr after LT) between August 2010 and December 2012. Hepatic steatosis was reviewed and graded by hepatopathologists, and the peri-transplant factors were analyzed for relationships to histologically proven NAFLD. Total 166 biopsies had been performed in 156 recipients. NAFLD was present in 27.1% at a mean period of 35.4 months between LT and biopsy, moderate and severe steatosis (≥33%) consisted of 28.9%. In multivariate analysis, preLT alcoholic cirrhosis (odds ratio [OR] 8.031, p = 0.003), obesity at biopsy (OR 3.873, p = 0.001), and preexisting donor graft steatosis (OR 3.147, p = 0.022) were significant risk factors for post-LT NAFLD. In conclusion, NAFLD represented a considerable portion of recipients, but this prevalence was not higher than those for general population. Three risk factors were significantly related to post-LT NAFLD, and recipients with those factors should be monitored for NAFLD. Furthermore, possible progression to non-alcoholic steatohepatitis (NASH) or fibrosis and metabolic syndrome should be considered in future studies.
Hyeyoung Kima,b, Kyoungbun Leec, Kwang-Woong Leea, NamJoon Yia, Hae Won Leea,b, Geun Honga, YoungRok Choia, Tae Youa, Suk-Won Suha, Ja June Jangc and Kyung-Suk Suha a
Department of Surgery, College of Medicine, Seoul National University, bDepartment of Surgery, Seoul Metropolitan Government, Boramae Medical Center, Seoul National University and cDepartment of Pathology, College of Medicine, Seoul National University, Seoul, Republic of Korea Key words: biopsy – hepatic steatosis – histology – steatohepatitis – steatosis – transplant Corresponding author: Kyung-Suk Suh, MD, Department of Surgery, College of Medicine, Seoul National University, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea. Tel.: +82-2-2072-3789; fax: +82-2-766-3975; e-mail: [email protected] and [email protected] Conflict of interest: The authors of this manuscript have no conflict of interests to disclose. Accepted for publication 13 February 2014
Non-alcoholic fatty liver disease (NAFLD) affects a substantial proportion of the general population in the world, and its prevalence has been increasing. The disease has attracted much academic attention in the recent years, especially, in association with obesity and metabolic syndrome, and in liver-related morbidity and mortality (1). In the context of liver transplantation (LT), recipients are at increased risk developing a number of features of the metabolic syndrome, such as diabetes mellitus (DM), weight gain, hypertension, and hyperlipidemia and are more predisposed to NAFLD, when compared to the general population (2–5). As outcomes of LT have improved, the main management concerns have been shifting from pre-
vention of early acute rejection to the maintenance of late and long-term graft survival and reduction in adverse effects associated with immunosuppressive agents (6). However, little is known about the prevalence and clinical significance of fatty liver disease or hepatic steatosis in liver transplant recipients. Moreover, NAFLD in liver transplant recipients is equivocal, and very little has been published regarding this condition in the increasing numbers of liver transplant recipients. Therefore, this study was designed with the following aims: (i) to evaluate the prevalence of NAFLD among recipients after the first year of LT and (ii) to investigate the peri-transplant risk factors related to NAFLD.
521
Kim et al. Materials and methods LT and follow-up
A retrospective review was identified 1084 cases of LT, which had been performed between January 1999 and December 2011 at Seoul National University Hospital (Seoul, Korea). Among these, 913 recipients were adults. All of the adult patients received blood group compatible grafts from deceased or living donors. Each recipient had received induction with 20 mg of intravenous basiliximab (an interleukin-2 receptor antagonist) within two h before LT and on postoperative day 4. Initially, basal immunosuppressive regimen was based on a calcineurin inhibitor (mostly, tacrolimus) and steroids. Since 2010, mycophenolate mofetil was administrated as a part of the initial triple immunosuppressive regimen or was introduced during follow-up as maintenance immunosuppressive agent. Calcineurin inhibitor was started within five d after LT. Tacrolimus and cyclosporine doses were adjusted according to individual clinical need with respective target whole blood trough levels around 8–12 ng/mL and 200– 300 ng/mL for the first month after LT, followed by 5–8 ng/mL and 100–200 ng/mL thereafter. The mycophenolate mofetil dose was 1.0 g daily (500 mg twice a day) for most patients. Intravenous methylprednisolone 500 mg was given intraoperatively before portal perfusion and was tapered from 200 mg to 20 mg within six d. Thereafter, oral prednisolone was continued at 20 mg daily and was tapered to 0–5 mg/d after about six months post-LT. Outpatient follow-up was usually conducted once a week for the first month after discharge and was gradually lengthened to every three or four months, with additional visits as clinically necessary. A complete laboratory investigation, including liver function tests and blood calcineurin inhibitor trough level, was conducted at each follow-up. All patients with a history of alcohol consumption were advised to remain abstinent after LT, and any alcohol consumption after LT was considered inappropriate and noted in the records. Significant alcohol consumption after LT was determined and recorded by doctors through appropriate history taken from the patients and their family at each follow-up. For all grafts, liver biopsies were carried out by surgeons during operation of procurement or donor hepatectomy. As part of routine management, liver biopsies were performed from postoperative day 7–14 and as clinically indicated afterward. Since August 2010, this practice was
522
augmented with additional biopsies at one yr, three yr, and five yr post-LT. In the case of hepatitis C virus-related patients, liver biopsies were repeated more frequently at three, six, and 12 months post-LT with annual biopsies thereafter. In all cases, an informed consent was obtained from each patient before biopsy. Patient selection
The study group included all adult patients who had a histologically proven hepatic steatosis after the first year of transplantation. Hepatic steatosis was defined as micro- and macrovesicular lipid accumulations of 5% or more on biopsy specimens. This cohort (steatosis group) was compared with the group of patients who underwent a liver biopsy during the same period without proven hepatic steatosis (control group; no steatosis group). In the present study, we excluded patients who underwent event-driven biopsy or who were 1.2 (%)
No steatosis (n = 121)
Steatosis (n = 45)
p-Values
54.22 7.83 23.18 2.79 32 (26.4)
51.40 9.20 25.44 2.77 25 (55.6)
0.051
Clin Transplant 2014: 28: 521–529 DOI: 10.1111/ctr.12343
Clinical Transplantation
Histologically proven non-alcoholic fatty liver disease and clinically related factors in recipients after liver transplantation Kim H, Lee K, Lee K-W, Yi N-J, Lee HW, Hong G, Choi Y, You T, Suh S-W, Jang JJ, Suh K-S. Histologically proven non-alcoholic fatty liver disease and clinically related factors in recipients after liver transplantation. Abstract: Non-alcoholic fatty liver disease (NAFLD) affects a substantial proportion of the world population, and its prevalence has been increasing. The study was aimed at evaluating the prevalence and peri-transplant risk factors for post-liver transplantation (LT) NAFLD. A retrospective review was performed for adult recipients who underwent late protocol biopsy (>1 yr after LT) between August 2010 and December 2012. Hepatic steatosis was reviewed and graded by hepatopathologists, and the peri-transplant factors were analyzed for relationships to histologically proven NAFLD. Total 166 biopsies had been performed in 156 recipients. NAFLD was present in 27.1% at a mean period of 35.4 months between LT and biopsy, moderate and severe steatosis (≥33%) consisted of 28.9%. In multivariate analysis, preLT alcoholic cirrhosis (odds ratio [OR] 8.031, p = 0.003), obesity at biopsy (OR 3.873, p = 0.001), and preexisting donor graft steatosis (OR 3.147, p = 0.022) were significant risk factors for post-LT NAFLD. In conclusion, NAFLD represented a considerable portion of recipients, but this prevalence was not higher than those for general population. Three risk factors were significantly related to post-LT NAFLD, and recipients with those factors should be monitored for NAFLD. Furthermore, possible progression to non-alcoholic steatohepatitis (NASH) or fibrosis and metabolic syndrome should be considered in future studies.
Hyeyoung Kima,b, Kyoungbun Leec, Kwang-Woong Leea, NamJoon Yia, Hae Won Leea,b, Geun Honga, YoungRok Choia, Tae Youa, Suk-Won Suha, Ja June Jangc and Kyung-Suk Suha a
Department of Surgery, College of Medicine, Seoul National University, bDepartment of Surgery, Seoul Metropolitan Government, Boramae Medical Center, Seoul National University and cDepartment of Pathology, College of Medicine, Seoul National University, Seoul, Republic of Korea Key words: biopsy – hepatic steatosis – histology – steatohepatitis – steatosis – transplant Corresponding author: Kyung-Suk Suh, MD, Department of Surgery, College of Medicine, Seoul National University, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea. Tel.: +82-2-2072-3789; fax: +82-2-766-3975; e-mail: [email protected] and [email protected] Conflict of interest: The authors of this manuscript have no conflict of interests to disclose. Accepted for publication 13 February 2014
Non-alcoholic fatty liver disease (NAFLD) affects a substantial proportion of the general population in the world, and its prevalence has been increasing. The disease has attracted much academic attention in the recent years, especially, in association with obesity and metabolic syndrome, and in liver-related morbidity and mortality (1). In the context of liver transplantation (LT), recipients are at increased risk developing a number of features of the metabolic syndrome, such as diabetes mellitus (DM), weight gain, hypertension, and hyperlipidemia and are more predisposed to NAFLD, when compared to the general population (2–5). As outcomes of LT have improved, the main management concerns have been shifting from pre-
vention of early acute rejection to the maintenance of late and long-term graft survival and reduction in adverse effects associated with immunosuppressive agents (6). However, little is known about the prevalence and clinical significance of fatty liver disease or hepatic steatosis in liver transplant recipients. Moreover, NAFLD in liver transplant recipients is equivocal, and very little has been published regarding this condition in the increasing numbers of liver transplant recipients. Therefore, this study was designed with the following aims: (i) to evaluate the prevalence of NAFLD among recipients after the first year of LT and (ii) to investigate the peri-transplant risk factors related to NAFLD.
521
Kim et al. Materials and methods LT and follow-up
A retrospective review was identified 1084 cases of LT, which had been performed between January 1999 and December 2011 at Seoul National University Hospital (Seoul, Korea). Among these, 913 recipients were adults. All of the adult patients received blood group compatible grafts from deceased or living donors. Each recipient had received induction with 20 mg of intravenous basiliximab (an interleukin-2 receptor antagonist) within two h before LT and on postoperative day 4. Initially, basal immunosuppressive regimen was based on a calcineurin inhibitor (mostly, tacrolimus) and steroids. Since 2010, mycophenolate mofetil was administrated as a part of the initial triple immunosuppressive regimen or was introduced during follow-up as maintenance immunosuppressive agent. Calcineurin inhibitor was started within five d after LT. Tacrolimus and cyclosporine doses were adjusted according to individual clinical need with respective target whole blood trough levels around 8–12 ng/mL and 200– 300 ng/mL for the first month after LT, followed by 5–8 ng/mL and 100–200 ng/mL thereafter. The mycophenolate mofetil dose was 1.0 g daily (500 mg twice a day) for most patients. Intravenous methylprednisolone 500 mg was given intraoperatively before portal perfusion and was tapered from 200 mg to 20 mg within six d. Thereafter, oral prednisolone was continued at 20 mg daily and was tapered to 0–5 mg/d after about six months post-LT. Outpatient follow-up was usually conducted once a week for the first month after discharge and was gradually lengthened to every three or four months, with additional visits as clinically necessary. A complete laboratory investigation, including liver function tests and blood calcineurin inhibitor trough level, was conducted at each follow-up. All patients with a history of alcohol consumption were advised to remain abstinent after LT, and any alcohol consumption after LT was considered inappropriate and noted in the records. Significant alcohol consumption after LT was determined and recorded by doctors through appropriate history taken from the patients and their family at each follow-up. For all grafts, liver biopsies were carried out by surgeons during operation of procurement or donor hepatectomy. As part of routine management, liver biopsies were performed from postoperative day 7–14 and as clinically indicated afterward. Since August 2010, this practice was
522
augmented with additional biopsies at one yr, three yr, and five yr post-LT. In the case of hepatitis C virus-related patients, liver biopsies were repeated more frequently at three, six, and 12 months post-LT with annual biopsies thereafter. In all cases, an informed consent was obtained from each patient before biopsy. Patient selection
The study group included all adult patients who had a histologically proven hepatic steatosis after the first year of transplantation. Hepatic steatosis was defined as micro- and macrovesicular lipid accumulations of 5% or more on biopsy specimens. This cohort (steatosis group) was compared with the group of patients who underwent a liver biopsy during the same period without proven hepatic steatosis (control group; no steatosis group). In the present study, we excluded patients who underwent event-driven biopsy or who were 1.2 (%)
No steatosis (n = 121)
Steatosis (n = 45)
p-Values
54.22 7.83 23.18 2.79 32 (26.4)
51.40 9.20 25.44 2.77 25 (55.6)
0.051
