© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Clin Transplant 2014: 28: 713–721 DOI: 10.1111/ctr.12364
Clinical Transplantation
Improved survival outcomes in patients with non-alcoholic steatohepatitis and alcoholic liver disease following liver transplantation: an analysis of 2002–2012 United Network for Organ Sharing data Wong RJ, Chou C, Bonham CA, Concepcion W, Esquivel CO, Ahmed A. Improved survival outcomes in patients with nonalcoholic steatohepatitis and alcoholic liver disease following liver transplantation: an analysis of 2002–2012 United Network for Organ Sharing data. Abstract: There is an increasing trend of patients with hepatocellular carcinoma (HCC) and non-alcoholic fatty liver disease undergoing liver transplantation in the US. Our study utilized data from the 2002 to 2012 United Network for Organ Sharing registry to evaluate model for endstage liver disease era trends in US liver transplantations focused on patients with non-alcoholic steatohepatitis (NASH), hepatitis C (HCV), alcoholic liver disease (ALD), and HCC. Survival outcomes were stratified by liver disease etiology and compared across time periods using Kaplan–Meier and Cox proportional hazards models. Patients with NASH were more likely to be women, had higher body mass index (BMI), and had higher prevalence of diabetes and cardiac disease. However, overall long-term survival was significantly higher in patients with NASH and ALD (p < 0.001). Compared to HCV, patients with NASH had significantly higher post-transplantation survival (HR 0.69, 95% CI 0.63–0.77), and lower risk of graft failure (HR 0.76, 95% CI 0.69–0.83). Despite having higher BMI and higher prevalence of diabetes and cardiac disease, patients with NASH had better post-liver transplantation survival compared to patients with HCV or HCC. Patients with ALD also had superior survival outcomes. However, these survival differences were limited to patients without HCC that underwent liver transplantation.
Chronic liver disease is a leading cause of morbidity and mortality in the United States (US) (1). Chronic hepatitis C virus (HCV) infection and hepatocellular carcinoma (HCC) are the two leading etiologies of liver disease in the US (2). While etiology-specific therapies are available for patients with chronic liver diseases, a large proportion will continue to develop progressive liver damage and end-stage liver disease requiring liver transplantation (LT). The liver is the second leading solid organ transplanted in the US. Data from the United Network for Organ Sharing (UNOS) and Organ Procurement and Transplantation Network (OPTN) estimate that nearly 16 000 individuals are currently
Robert J. Wonga, Christina Choua, Clark A. Bonhamb, Waldo Concepcionb, Carlos O. Esquivelb and Aijaz Ahmeda a
Division of Gastroenterology and Hepatology, Stanford University School of Medicine and b Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
Key words: hepatitis C – hepatocellular carcinoma – model for end-stage liver disease – non-alcoholic steatohepatitis Corresponding author: Aijaz Ahmed, MD, Division of Gastroenterology and Hepatology, Liver Transplant Program, Department of Medicine, Stanford University School of Medicine, 750 Welch Road, Suite 210, Palo Alto, CA 94304, USA. Tel.: 650 498 6091; fax: 650 498 5692; e-mail: [email protected] Conflict of interest: None. Accepted for publication 16 March 2014
on the waitlist for LT (3, 4). In 2012, 6256 patients underwent LT and 6422 patients died while waiting for LT (3, 4). Hepatitis C virus is currently the leading indication for LT in the US (3–5). Since the introduction of the model for endstage liver disease (MELD) in 2002 for the prioritization of patients with LT on the waitlist, several changes in the epidemiology of chronic liver diseases have occurred (5, 6). Increasing awareness and improvement in screening programs for earlier detection of HCC have led to increasing HCC diagnosis. Furthermore, the implementation of MELD exception policies that award additional points to patients with HCC within defined criteria has increased the proportion of patients with HCC
713
Wong et al.
on the liver transplant waitlist as well as those that actually receive LT (7, 8). Hepatitis C virus infection among the “baby boomer” generation has led to a large cohort of patients with chronic HCV who have or will develop progressive liver disease that requires LT (9). While more effective antiviral therapies introduced in 2008 along with the advent of newer more effective HCV therapies have demonstrated success in treatment of chronic HCV, its effect on the epidemiology of LT recipients is unclear (10). In addition, the worsening obesity epidemic in the US has led to concern over increasing incidence of obesity-related metabolic diseases, including non-alcoholic fatty liver disease (NAFLD), and it has been predicted that NASH in the near future will be the leading indication for LT in the US (5, 11–16). To study the impact of the changing epidemiology of chronic liver diseases in the US, this study performed a detailed analysis of liver transplant recipients from 2002 to 2012 with a focus on HCV, NASH, alcoholic liver disease (ALD), and HCC.
Methods Study design
A retrospective cohort analysis of the 2002–2012 UNOS/OPTN database (3, 4) was performed to evaluate current trends in LT in the US. Given the implementation of MELD for the prioritization of LT among waitlist patients in 2002, this year was chosen as the lower limit of our study period to ensure consistency of comparisons. Data source and definitions
Patients were obtained from the UNOS/OPTN registry, a recognized source of LT data in the US. The etiology of liver disease among liver transplant recipients is listed in Table 1. Among patients with chronic liver disease, HCV, NASH, ALD, and HCC accounted for 82.9% of LT recipients. Thus, our study focused on these four groups, which included a total of 41 289 adult patients (age: 18 yr or older). In addition to etiology of liver disease, demographic (e.g., age, sex, race/ethnicity, body mass index [BMI]), clinical (e.g., presence of diabetes or cardiac disease), and liver-disease-related data were analyzed (e.g., MELD score, ascites, hepatic encephalopathy, bacterial peritonitis, portal vein thrombosis, transjugular intrahepatic portosystemic shunt [TIPS]). Time on the waiting list prior to receiving LT as well as receipt of simultaneous kidney transplantation was included in the
714
Table 1. Etiology of liver transplantations in the US, UNOS 2002– 2012 % Acute liver diseases Fulminant Chronic liver diseases Hepatitis C Hepatitis B Alcoholic Hepatocellular carcinoma NASH Autoimmune PBC/PSC Metabolic diseases
N
6.3
3386
39.3 3.0 15.0 10.0 13.4 3.0 7.8 2.1
20 901 1608 7962 5326 7100 1618 4167 1103
NASH, non-alcoholic steatohepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis. Metabolic diseases include hemochromatosis, Wilson’s disease and alpha-1 anti-trypsin disease.
analysis. To evaluate trends in post-LT survival with progression of time, year of LT was categorized by 2002–2004, 2005–2007, 2008–2010, and 2011–2012. Outcome measures and statistical analysis
Overall demographic, clinical, and LT-related patient characteristics were stratified by etiology of liver disease. Chi-square tests were used to compare categorical variables, and analysis of variance was used to compare continuous variables between each group. Non-parametric tests were utilized for non-normally distributed variables. Overall longterm post-LT patient survival and graft survival were stratified by etiology of liver disease and evaluated using Kaplan–Meier methods and log-rank testing for quality of survivor functions. Trends in one-, three-, and five-yr post-LT patient survival and graft survival were also stratified by etiology of liver disease. Multivariate Cox proportional hazards models were utilized to identify independent predictors of post-LT patient survival and graft survival. Forward stepwise regression methods were employed, and variables demonstrating significant associations in the bivariate model (p < 0.10) or those with biological significance a priori (e.g., age and sex) were included in the final multivariate model. The final model included adjustments for age, sex, race/ethnicity, BMI, presence of diabetes or cardiac disease, etiology of liver disease, presence of ascites, hepatic encephalopathy, bacterial peritonitis, portal vein thrombosis, TIPS, simultaneous kidney transplantation, year of diagnosis, and waitlist time. Statistical significance was met with a two-tailed p-value < 0.05. All statistical analyses were performed using the
Liver transplantation trends in the US Stata statistical package (version 10; Stata Corporation, College Station, TX, USA).
Results Overview
During the 2002–2012 period, there were 20 901 HCV, 7100 NASH, 7962 ALD, and 5326 HCC patients that underwent LT in the US. Patients with NASH and patients with HCC were significantly older than HCV and ALD patients at time of LT (Table 2). While the majority of patients were non-Hispanic white, HCV patients and HCC patients were more likely to be black compared to NASH and ALD (HCV, 9.6%; HCC, 9.8%; NASH, 3.5%; ALD, 3.7%, p < 0.001). A higher proportion of Asian ethnicity was also seen among patients with HCC (Table 2). Patients with nonalcoholic steatohepatitis had significantly higher mean BMI (NASH, 30.5 6.1 vs. HCV, 28.3 5.3 vs. ALD 28.0 5.4 vs. HCC, 28.2 5.2, p = 0.02). Higher rates of diabetes and cardiac disease were also seen in patients with NASH (Table 2). Compared to other groups, patients with HCC had lower medical MELD score and lower rates of decompensated liver disease, including ascites (HCC, 54.2% vs. NASH, 86.4% vs. HCV, 81.9% vs. ALD 88.7%, p < 0.001) and hepatic encephalopathy (HCC, 38.8% vs. NASH, 72.8% vs. HCV, 69.3% vs. ALD 77.3%, p < 0.001). Significantly higher rates
of bacterial peritonitis were seen in patients with ALD, and higher rates of portal vein thrombosis were seen in patients with NASH (Table 2). There was also a higher prevalence of existing TIPS in NASH and ALD patients compared with HCV and HCC patients (NASH, 11.2% vs. ALD 12.6%, vs. HCV, 9.2% vs. HCC, 3.4%, p < 0.001). While simultaneous kidney transplantation was uncommon, the highest rate was seen in patients with NASH and the lowest rate in patients with HCC. Living donor LT was most common in patients with NASH and least common in patients with HCC. The number of days on the waiting list prior to receiving LT was shortest for patients with HCC (216 332 d) and longest for patients with ALD (647 924 d) (Table 2). Overall post-LT patient and graft survivals
Overall long-term post-LT patient survival was significantly higher among NASH and ALD patients compared to HCV and HCC patients (Fig. 1A). Five-yr post-LT patient survival was 76.5% in patients with ALD, 75.6% in patients with NASH, 69.2% in patients with HCV, and 68.0% in patients with HCC, p < 0.001. Post-LT graft survival followed similar trends, with the highest survival seen among NASH and ALD patients (Fig. 1B). Five-yr post-LT graft survival was 72.8% in patients with ALD, 71.8% in patients with NASH, 64.5% in patients with HCV, and 64.8% in patients HCC, p < 0.001.
Table 2. Demographics of liver transplantation, UNOS 2002–2012
Age (mean SD) Male Race/ethnicity Non-Hispanic white Black Hispanic Asian BMI (mean SD) Diabetes Cardiac disease Medical MELD (mean SD) Ascites Hepatic encephalopathy Bacterial peritonitis Portal vein thrombosis TIPS Simultaneous kidney transplant Days on waiting list (mean SD) Five-yr post-LT patient survival Five-yr post-LT graft survival
HCV (N = 20 901)
NASH (N = 7100)
ALD (N = 7962)
HCC (N = 5326)
p-Value
53.8 7.1 70.2%
57.5 9.4 51.5%
54.1 8.6 75.3%
57.8 7.4 77.7%
0.04
Clin Transplant 2014: 28: 713–721 DOI: 10.1111/ctr.12364
Clinical Transplantation
Improved survival outcomes in patients with non-alcoholic steatohepatitis and alcoholic liver disease following liver transplantation: an analysis of 2002–2012 United Network for Organ Sharing data Wong RJ, Chou C, Bonham CA, Concepcion W, Esquivel CO, Ahmed A. Improved survival outcomes in patients with nonalcoholic steatohepatitis and alcoholic liver disease following liver transplantation: an analysis of 2002–2012 United Network for Organ Sharing data. Abstract: There is an increasing trend of patients with hepatocellular carcinoma (HCC) and non-alcoholic fatty liver disease undergoing liver transplantation in the US. Our study utilized data from the 2002 to 2012 United Network for Organ Sharing registry to evaluate model for endstage liver disease era trends in US liver transplantations focused on patients with non-alcoholic steatohepatitis (NASH), hepatitis C (HCV), alcoholic liver disease (ALD), and HCC. Survival outcomes were stratified by liver disease etiology and compared across time periods using Kaplan–Meier and Cox proportional hazards models. Patients with NASH were more likely to be women, had higher body mass index (BMI), and had higher prevalence of diabetes and cardiac disease. However, overall long-term survival was significantly higher in patients with NASH and ALD (p < 0.001). Compared to HCV, patients with NASH had significantly higher post-transplantation survival (HR 0.69, 95% CI 0.63–0.77), and lower risk of graft failure (HR 0.76, 95% CI 0.69–0.83). Despite having higher BMI and higher prevalence of diabetes and cardiac disease, patients with NASH had better post-liver transplantation survival compared to patients with HCV or HCC. Patients with ALD also had superior survival outcomes. However, these survival differences were limited to patients without HCC that underwent liver transplantation.
Chronic liver disease is a leading cause of morbidity and mortality in the United States (US) (1). Chronic hepatitis C virus (HCV) infection and hepatocellular carcinoma (HCC) are the two leading etiologies of liver disease in the US (2). While etiology-specific therapies are available for patients with chronic liver diseases, a large proportion will continue to develop progressive liver damage and end-stage liver disease requiring liver transplantation (LT). The liver is the second leading solid organ transplanted in the US. Data from the United Network for Organ Sharing (UNOS) and Organ Procurement and Transplantation Network (OPTN) estimate that nearly 16 000 individuals are currently
Robert J. Wonga, Christina Choua, Clark A. Bonhamb, Waldo Concepcionb, Carlos O. Esquivelb and Aijaz Ahmeda a
Division of Gastroenterology and Hepatology, Stanford University School of Medicine and b Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
Key words: hepatitis C – hepatocellular carcinoma – model for end-stage liver disease – non-alcoholic steatohepatitis Corresponding author: Aijaz Ahmed, MD, Division of Gastroenterology and Hepatology, Liver Transplant Program, Department of Medicine, Stanford University School of Medicine, 750 Welch Road, Suite 210, Palo Alto, CA 94304, USA. Tel.: 650 498 6091; fax: 650 498 5692; e-mail: [email protected] Conflict of interest: None. Accepted for publication 16 March 2014
on the waitlist for LT (3, 4). In 2012, 6256 patients underwent LT and 6422 patients died while waiting for LT (3, 4). Hepatitis C virus is currently the leading indication for LT in the US (3–5). Since the introduction of the model for endstage liver disease (MELD) in 2002 for the prioritization of patients with LT on the waitlist, several changes in the epidemiology of chronic liver diseases have occurred (5, 6). Increasing awareness and improvement in screening programs for earlier detection of HCC have led to increasing HCC diagnosis. Furthermore, the implementation of MELD exception policies that award additional points to patients with HCC within defined criteria has increased the proportion of patients with HCC
713
Wong et al.
on the liver transplant waitlist as well as those that actually receive LT (7, 8). Hepatitis C virus infection among the “baby boomer” generation has led to a large cohort of patients with chronic HCV who have or will develop progressive liver disease that requires LT (9). While more effective antiviral therapies introduced in 2008 along with the advent of newer more effective HCV therapies have demonstrated success in treatment of chronic HCV, its effect on the epidemiology of LT recipients is unclear (10). In addition, the worsening obesity epidemic in the US has led to concern over increasing incidence of obesity-related metabolic diseases, including non-alcoholic fatty liver disease (NAFLD), and it has been predicted that NASH in the near future will be the leading indication for LT in the US (5, 11–16). To study the impact of the changing epidemiology of chronic liver diseases in the US, this study performed a detailed analysis of liver transplant recipients from 2002 to 2012 with a focus on HCV, NASH, alcoholic liver disease (ALD), and HCC.
Methods Study design
A retrospective cohort analysis of the 2002–2012 UNOS/OPTN database (3, 4) was performed to evaluate current trends in LT in the US. Given the implementation of MELD for the prioritization of LT among waitlist patients in 2002, this year was chosen as the lower limit of our study period to ensure consistency of comparisons. Data source and definitions
Patients were obtained from the UNOS/OPTN registry, a recognized source of LT data in the US. The etiology of liver disease among liver transplant recipients is listed in Table 1. Among patients with chronic liver disease, HCV, NASH, ALD, and HCC accounted for 82.9% of LT recipients. Thus, our study focused on these four groups, which included a total of 41 289 adult patients (age: 18 yr or older). In addition to etiology of liver disease, demographic (e.g., age, sex, race/ethnicity, body mass index [BMI]), clinical (e.g., presence of diabetes or cardiac disease), and liver-disease-related data were analyzed (e.g., MELD score, ascites, hepatic encephalopathy, bacterial peritonitis, portal vein thrombosis, transjugular intrahepatic portosystemic shunt [TIPS]). Time on the waiting list prior to receiving LT as well as receipt of simultaneous kidney transplantation was included in the
714
Table 1. Etiology of liver transplantations in the US, UNOS 2002– 2012 % Acute liver diseases Fulminant Chronic liver diseases Hepatitis C Hepatitis B Alcoholic Hepatocellular carcinoma NASH Autoimmune PBC/PSC Metabolic diseases
N
6.3
3386
39.3 3.0 15.0 10.0 13.4 3.0 7.8 2.1
20 901 1608 7962 5326 7100 1618 4167 1103
NASH, non-alcoholic steatohepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis. Metabolic diseases include hemochromatosis, Wilson’s disease and alpha-1 anti-trypsin disease.
analysis. To evaluate trends in post-LT survival with progression of time, year of LT was categorized by 2002–2004, 2005–2007, 2008–2010, and 2011–2012. Outcome measures and statistical analysis
Overall demographic, clinical, and LT-related patient characteristics were stratified by etiology of liver disease. Chi-square tests were used to compare categorical variables, and analysis of variance was used to compare continuous variables between each group. Non-parametric tests were utilized for non-normally distributed variables. Overall longterm post-LT patient survival and graft survival were stratified by etiology of liver disease and evaluated using Kaplan–Meier methods and log-rank testing for quality of survivor functions. Trends in one-, three-, and five-yr post-LT patient survival and graft survival were also stratified by etiology of liver disease. Multivariate Cox proportional hazards models were utilized to identify independent predictors of post-LT patient survival and graft survival. Forward stepwise regression methods were employed, and variables demonstrating significant associations in the bivariate model (p < 0.10) or those with biological significance a priori (e.g., age and sex) were included in the final multivariate model. The final model included adjustments for age, sex, race/ethnicity, BMI, presence of diabetes or cardiac disease, etiology of liver disease, presence of ascites, hepatic encephalopathy, bacterial peritonitis, portal vein thrombosis, TIPS, simultaneous kidney transplantation, year of diagnosis, and waitlist time. Statistical significance was met with a two-tailed p-value < 0.05. All statistical analyses were performed using the
Liver transplantation trends in the US Stata statistical package (version 10; Stata Corporation, College Station, TX, USA).
Results Overview
During the 2002–2012 period, there were 20 901 HCV, 7100 NASH, 7962 ALD, and 5326 HCC patients that underwent LT in the US. Patients with NASH and patients with HCC were significantly older than HCV and ALD patients at time of LT (Table 2). While the majority of patients were non-Hispanic white, HCV patients and HCC patients were more likely to be black compared to NASH and ALD (HCV, 9.6%; HCC, 9.8%; NASH, 3.5%; ALD, 3.7%, p < 0.001). A higher proportion of Asian ethnicity was also seen among patients with HCC (Table 2). Patients with nonalcoholic steatohepatitis had significantly higher mean BMI (NASH, 30.5 6.1 vs. HCV, 28.3 5.3 vs. ALD 28.0 5.4 vs. HCC, 28.2 5.2, p = 0.02). Higher rates of diabetes and cardiac disease were also seen in patients with NASH (Table 2). Compared to other groups, patients with HCC had lower medical MELD score and lower rates of decompensated liver disease, including ascites (HCC, 54.2% vs. NASH, 86.4% vs. HCV, 81.9% vs. ALD 88.7%, p < 0.001) and hepatic encephalopathy (HCC, 38.8% vs. NASH, 72.8% vs. HCV, 69.3% vs. ALD 77.3%, p < 0.001). Significantly higher rates
of bacterial peritonitis were seen in patients with ALD, and higher rates of portal vein thrombosis were seen in patients with NASH (Table 2). There was also a higher prevalence of existing TIPS in NASH and ALD patients compared with HCV and HCC patients (NASH, 11.2% vs. ALD 12.6%, vs. HCV, 9.2% vs. HCC, 3.4%, p < 0.001). While simultaneous kidney transplantation was uncommon, the highest rate was seen in patients with NASH and the lowest rate in patients with HCC. Living donor LT was most common in patients with NASH and least common in patients with HCC. The number of days on the waiting list prior to receiving LT was shortest for patients with HCC (216 332 d) and longest for patients with ALD (647 924 d) (Table 2). Overall post-LT patient and graft survivals
Overall long-term post-LT patient survival was significantly higher among NASH and ALD patients compared to HCV and HCC patients (Fig. 1A). Five-yr post-LT patient survival was 76.5% in patients with ALD, 75.6% in patients with NASH, 69.2% in patients with HCV, and 68.0% in patients with HCC, p < 0.001. Post-LT graft survival followed similar trends, with the highest survival seen among NASH and ALD patients (Fig. 1B). Five-yr post-LT graft survival was 72.8% in patients with ALD, 71.8% in patients with NASH, 64.5% in patients with HCV, and 64.8% in patients HCC, p < 0.001.
Table 2. Demographics of liver transplantation, UNOS 2002–2012
Age (mean SD) Male Race/ethnicity Non-Hispanic white Black Hispanic Asian BMI (mean SD) Diabetes Cardiac disease Medical MELD (mean SD) Ascites Hepatic encephalopathy Bacterial peritonitis Portal vein thrombosis TIPS Simultaneous kidney transplant Days on waiting list (mean SD) Five-yr post-LT patient survival Five-yr post-LT graft survival
HCV (N = 20 901)
NASH (N = 7100)
ALD (N = 7962)
HCC (N = 5326)
p-Value
53.8 7.1 70.2%
57.5 9.4 51.5%
54.1 8.6 75.3%
57.8 7.4 77.7%
0.04
