Frequency and Outcomes of Liver Transplantation for Nonalcoholic Steatohepatitis in the United States

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1 GASTROENTEROLOGY 2011;141: Frequency and Outcomes of Liver Transplantation for Nonalcoholic Steatohepatitis in the United States MICHAEL R. CHARLTON,* JUSTIN M. BURNS, RACHEL A. PEDERSEN, KYMBERLY D. WATT,* JULIE K. HEIMBACH, and ROSS A. DIERKHISING Divisions of *Gastroenterology and Hepatology, Biomedical Statistics and Informatics, and Transplantation Surgery, Mayo Clinic, Rochester, Minnesota; and Division of Transplantation Surgery, University of Cincinnati, Cincinnati, Ohio This article has an accompanying continuing education activity on page e22. Learning Objective: Upon completion of this CME exercise, successful learners will be able to review the comparative frequency, associations and outcomes of liver transplantation for NASH. See Covering the Cover synopsis on page BACKGROUND & AIMS: The relative frequency of nonalcoholic steatohepatitis (NASH) as an indication for liver transplantation and comparative outcomes following transplantation are poorly understood. METHODS: We analyzed the Scientific Registry of Transplant Recipients for primary adult liver transplant recipients from 2001 to RESULTS: From 2001 to 2009, 35,781 patients underwent a primary liver transplant, including 1959 for who NASH was the primary or secondary indication. The percentage of patients undergoing a liver transplant for NASH increased from 1.2% in 2001 to 9.7% in NASH is now the third most common indication for liver transplantation in the United States. No other indication for liver transplantation increased in frequency during the study period. Compared with other indications for liver transplantation, recipients with NASH are older ( vs years; P.001), have a larger body mass index ( 30 kg/m 2 ) (63% vs 32%; P.001), are more likely to be female (47% vs 29%; P.001), and have a lower frequency of hepatocellular carcinoma (12% vs 19%; P.001). Survival at 1 and 3 years after liver transplantation for NASH was 84% and 78%, respectively, compared with 87% and 78% for other indications (P.67). Patient and graft survival for liver recipients with NASH were similar to values for other indications after adjusting for level of creatinine, sex, age, and body mass index. CONCLUSIONS: NASH is the third most common indication for liver transplantation in the United States and is on a trajectory to become the most common. Outcomes for patients undergoing a liver transplant for NASH are similar to those for other indications. Keywords: Liver Disease; Organ Transplantation; Complications of Obesity; Steatosis. The rising global prevalence of obesity has been well documented. The World Health Organization estimates that, worldwide, 1.6 billion adults are overweight (body mass index [BMI] 25 kg/m 2 ) and 400 million are obese (BMI 30 kg/m 2 ). 1 The prevalence of obesity in the United States is currently estimated to be 28.7% of the male population and 34.1% of the female population. 2 The most recent national census estimates that there are 310,430,000 people living in the United States. 3 The prevalences of the most severe classes of obesity are rising sharply, with a shift to the right in BMI distribution with class III obesity (BMI 40 kg/m 2 ) quadrupling and BMI 50 kg/m 2 quintupling between 1986 and A recent cross-sectional analysis of an ethnically diverse population in the United States found the prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) to be 30% and 12%, respectively, prevalences that are broadly similar to other cross-sectional analyses. 5,6 Increases in the prevalence of severe obesity are likely to be mirrored by increases in the prevalence and severity of complications of obesity, including NASH NAFLD is regarded as an emerging public health issue, but the frequency with which patients with NAFLD progress to cirrhosis with hepatic decompensation is not known with any precision. Although liver disease secondary to NASH has been projected to become the leading indication for liver transplantation in the next 10 to 20 years, 9 direct evidence for an increasing relative frequency of NASH as an indication for liver transplantation has, to date, been lacking. A previous analysis of data from the Scientific Registry of Transplant Recipients (SRTR) reported that the proportion of patients with cirrhotic-stage NASH undergoing a liver transplant has increased from 0.1% or less in to 3.5% in 2005, suggesting a modest increase in frequency of NASH as an indication for liver transplantation. 15 This previous analysis was somewhat limited by the relatively short time that NASH had appeared on the dropdown list from which transplant centers select primary diagnoses (NASH was Abbreviations used in this paper: BMI, body mass index; CC, cryptogenic cirrhosis; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; SRTR, Scientific Registry of Transplant Recipients by the AGA Institute /$36.00 doi: /j.gastro

2 1250 CHARLTON ET AL GASTROENTEROLOGY Vol. 141, No. 4 bilirubin, and international normalized ratio to account for skewed distributions. Patient and graft survival were estimated using the Kaplan Meier method. Univariate and multivariable analyses were assessed by stratified Cox proportional hazard models, where centers were the strata. A P value of.05 was considered significant for all statistical methods used. The statistical analyses were completed using SAS 9.2 (SAS Institute Inc, Cary, NC). Figure 1. The frequencies of hepatitis C infection, alcoholic liver disease, NASH, and NASH 50% CC for liver transplantation among adults in the United States between 2001 and 2009 are shown. NASH and NASH 50% CC have increased in each of the study years. NASH is currently the third most common indication for liver transplantation. added to the list in 2001). In addition, NASH is known to recur following liver transplantation, 16 potentially attenuating posttransplant patient and graft survival. We performed a comprehensive analysis of the SRTR with the goal of determining temporal changes in the frequency of NASH as an indication for liver transplantation and of how patient and graft survival for patients with NASH compare with other indications for liver transplantation. Patients and Methods Study Population The study cohort included 35,781 adult patients (18 years of age or older) who underwent a liver transplant in the United States from January 1, 2001, to December 31, Each patient is only represented once in the cohort; thus, a second transplant during the study period was not included. Demographic, laboratory, radiologic, clinical, and surgical information was analyzed. Clinical data obtained at the time of transplant included age at transplant, sex, age, ethnicity, primary liver disease, BMI, creatinine level, sodium level, bilirubin level, international normalized ratio, albumin level, and height. Donor age, height, donation after cardiac death (yes/no), warm ischemia time, cold ischemia time, and surgical assessment of graft quality were also determined. In addition to NASH, clinical diagnoses that were analyzed included hepatitis C virus (HCV) infection, alcoholic liver disease, hepatitis B virus infection, cryptogenic cirrhosis (CC), primary sclerosing cholangitis, primary biliary cirrhosis, and autoimmune hepatitis. Because a substantial proportion of cases of CC are likely to have been secondary to NASH, longitudinal analyses were also performed for NASH plus 50% of CC and NASH plus CC with high BMI (greater than 30 kg/m 2 ). Diagnoses were assigned by transplant centers without prerequisite diagnostic or confirmatory criteria. The primary end points of this analysis were patient death and graft loss (defined as graft failure requiring retransplant or death). Statistical Analysis Continuous variables were summarized with means and SDs, and frequencies and percents were used for categorical variables. The only variables log-transformed were creatinine, Results A total of 35,781 patients underwent a primary liver transplant from 2001 to NASH was documented as the primary or secondary indication for 1959 liver transplant recipients over the study period. Frequency of NASH as an Indication for Liver Transplantation The percentage of patients undergoing a liver transplant for NASH increased every year, from 1.2% in 2001 to 9.7% in 2009 (Figures 1 and 2). NASH was listed as the primary indication for 1840 recipients (93.9%) and as the secondary diagnosis in 119 cases (6.1%). When NASH was the secondary diagnosis, the most common primary diagnosis was CC (n 53). Other nonspecific primary diagnoses from the SRTR dropdown list of diagnoses (Cirrhosis: Cryptogenic-Idiopathic, Cirrhosis: Other, specify, Metabolic disease, Cirrhosis: Drug/Indust Exposure Other Specify, Cirrhosis: Chronic Active Hepatitis: Etiology Unknown) were listed as primary in a further 29 cases. Cryptogenic and similar designations thus accounted for 69% of cases in which NASH was not listed as the primary diagnosis. The remaining primary diagnoses when NASH was listed as the secondary diagnosis included hepatocellular carcinoma (HCC) (n 9), alcohol (n 13), HCV (n 5), autoimmune (n 5), 1 -antitrypsin (n 2), primary biliary cirrhosis (n 1), congenital hepatic fibrosis (n 1), and Crohn s disease (n 1). The absolute increase in the percentage of patients undergoing a liver transplant for NASH from 2001 to 2009 was 8.5% when Figure 2. The frequencies of specific indications for liver transplantation among adults in the United States are shown. ALD, alcoholic liver disease; HBV, hepatitis B virus; CC, cryptogenic cirrhosis; PSC, primary sclerosing cholangitis; PBC, primary biliary cirrhosis; AIH, autoimmune hepatitis.

3 October 2011 LIVER TRANSPLANTATION FOR NASH 1251 NASH as a primary or secondary diagnosis was considered. When patients with NASH as a secondary diagnosis were excluded, the frequency of liver transplantation for NASH increased from 1.01% in 2001 to 8.51% in 2009, also an increase of 8.5%. When combined with a random 50% of liver transplants performed for CC, the proportion of liver transplants for this group (NAFLD) increased from 6.7% in 2001 to 12.9% in NASH is now the third most common indication for liver transplantation in the United States. No other indication for liver transplantation increased in frequency during the study period. Characteristics of Liver Transplant Recipients With NASH When compared with other indications (HCV, alcoholic liver disease, CC, cholestatic, and autoimmune) for liver transplantation, recipients with NASH are older ( vs years; P.001), have a larger BMI ( 30 kg/m 2, 63% vs 32%; P.001), are more likely to be female (47% vs 29%; P.001), and have a lower frequency of concomitant HCC (12% vs 19%; P.001). None of the other measured recipient/donor characteristics were statistically significantly different between recipients with NASH and recipients with other indications for liver transplantation. The frequency of obesity (BMI 30 kg/m 2 ) among patients with CC in each of the study years was 38.6%, 39.4%, 38.8%, 38.3%, 32.1%, 43.4%, 32.8%, 39.1%, and 31.4% in 2001, 2002, 2003, 2004, 2005, 2006, 2007, 2008, and 2009, respectively. Comparative Posttransplant Outcomes Patient survival estimates at 1 and 3 years after liver transplantation for NASH were 84% and 78%, respectively, compared with 86% and 79% for CC and 87% and 78% for other indications of liver transplantation (P.67) (Figures 3 and 4). Overall 3-year graft survival was Figure 3. Kaplan Meier analysis showing graft survival among patients undergoing primary liver transplantation for patients with NASH, CC, and other indications for liver transplantation is shown. In this analysis, there was no significant difference in graft survival in the first 3 postoperative years. Figure 4. Three-year patient and graft survival according to indication for liver transplantation among adults in the United States are shown. CC, cryptogenic cirrhosis; HBV, hepatitis B virus; AIH, autoimmune hepatitis; PSC, primary sclerosing cholangitis. 76% for patients with NASH. Patient and graft survival after liver transplantation for recipients with NASH was similar to that for other indications in multivariate analysis after adjusting for creatinine level, sex, age, and BMI. Discussion Although the prevalences of NAFLD and NASH are quite well known, the frequency with which NASH results in cirrhosis with decompensation has been difficult to ascertain. One indication of the importance of NASH as a cause of end-stage liver disease is the frequency of NASH as an indication for liver transplantation, currently and over the course of time. The most important findings of this study are that NASH is the third most common indication for liver transplantation in the United States and that the frequency of NASH as an indication is steadily increasing. NASH is the only indication for liver transplantation that was seen to increase over the study period, from 1.2% in 2001 to 9.7% in These figures almost certainly substantially underestimate the frequency of NASH as an indication for liver transplantation. Hepatic steatosis, which is ubiquitous in noncirrhotic NASH, can dissipate following the development of cirrhosis, 16,17 making the diagnosis of NASH less likely. Phenotypically, patients with a pretransplant diagnosis of CC are quite similar to patients with cirrhosis known to be due to NASH 16,18,19 and have rates of posttransplant NASH that are comparable to patients for whom a diagnosis of NASH was apparent before transplant. 20 If half of the patients whose primary cause of liver disease was characterized as CC in fact had NASH as the primary cause, the frequency of NASH as an indication for liver transplantation would be 12%. Either of these estimates of the frequency of NASH as a cause of end-stage liver disease (9.7% or 12%) ignores the impact of concurrent NASH contributing to the histologic and clinical progression of other etiologies of liver disease, such as HCV or alcohol. Based on these results, there can be little doubt that NASH is an increasingly important cause of endstage liver disease and is already placing a substantial burden on an overstretched donor organ supply.

4 1252 CHARLTON ET AL GASTROENTEROLOGY Vol. 141, No. 4 There are some notable limitations to our study that reflect the nature of data entered into the SRTR. The assignment of NASH, or any other etiology as a cause of liver disease, as a primary or secondary diagnosis requires no confirmatory criteria. This is also true for other liver diseases such as HCV (eg, detection of HCV RNA before transplantation is not a prerequisite for a diagnosis of HCV to be entered into the SRTR database). Although the lack of diagnostic criteria for NASH limits the precision of an SRTR-based analysis, the size of the study cohort (35,781 patients overall, with 1959 for who NASH was the primary or secondary indication) and the longitudinal nature of the analysis (10 years) add considerable strength and value. It is certain that there were patients who were listed in the SRTR as having NASH as their primary or secondary indication for whom it would have been more technically correct to characterize their liver disease as cryptogenic. All SRTR-based analyses require the presumption that listed diagnoses reflect actual disease, inevitably generating some uncertainty. This SRTR-based analysis should really be considered as reporting longitudinal trends in frequency as an indication and comparative outcomes for recipients believed to have NASH as the primary or secondary cause of liver disease. A further consideration is that it was possible that the observed increase in frequency of NASH as an indication for liver transplantation was secondary to an ascertainment bias, reflecting increased awareness of this diagnosis and the availability of NASH as a diagnosis that could be selected (rather than written in) among diagnostic categories entered into the SRTR database by transplant centers. NASH has appeared on the dropdown list of primary diagnoses as cirrhosis fatty liver (NASH) since Consistent with this effect, we observed a gradual and sustained decline in the frequency of CC (the other likely diagnosis for patients with NASH) as an indication for liver transplantation. Since 2001, however, NASH has increased as an indication for liver transplantation at twice the rate that CC has declined (ie, the frequency of NASH increases 1.0 percentage points/year on average and CC decreases 0.5 percentage points/year on average). Thus, while it is certain that some patients who were previously characterized as having CC are now classified as having NASH, increasing reclassification by transplant centers over time of CC as NASH could not account for the apparent increase in the frequency of NASH as an indication for liver transplantation. Factors that predict the severity of NASH, including obesity and insulin resistance, usually worsen following liver transplantation, 21,22 raising the theoretical concern that recurrence of NASH might impact posttransplant graft survival. NASH is known to recur following liver transplantation, 16,19,23,24 occasionally resulting in graft loss. An important observation in our SRTR analysis is that medium-term patient and graft survival for recipients with a primary or secondary indication of NASH were similar to that for recipients with other indications. Medium-term (3-year) patient and graft survival for recipients with NASH was not statistically significantly different than for other indications. This is despite the finding that recipients with NASH had a higher BMI than non- NASH recipients and may be presumed to have been at risk for other medical complications of obesity. We did not observe even a trend for inferior graft survival at 3 years posttransplantation when compared with non- NASH recipients as a whole. Approximately 5% of patients undergoing liver transplantation for NASH have been reported to have recurrence that progresses to cirrhosis in long-term follow-up, with a long-term absolute NASH recurrence-associated graft loss rate of 2.5% to 5%, with overall outcomes reported to be generally comparable to that for other indications. 16,25 28 Although the impact of NASH on longer-term patient or graft survival cannot be determined from these relatively short-term results, based on our observations, a meaningful negative association of NASH on medium-term primary or secondary posttransplant outcomes seems improbable. The SRTR data set does not include accurate information pertaining to causes of death and graft loss. The comparative frequency of causes of death and graft loss among patients undergoing liver transplantation for NASH cannot be reliably determined from an analysis of the SRTR data set. A further notable aspect of this analysis is the frequency of HCC among liver transplant recipients with NASH as a primary or secondary indication (12%). This was significantly less common than for other indications (19%, P.001). Nearly half of liver transplant recipients with HCC in the study period had HCV as the primary or secondary indication. Although NASH may be less of a risk factor for HCC than HCV infection, patients with cirrhosis secondary to NASH are clearly at risk for development of HCC. What do these results suggest the future holds in terms of evolution in the relative frequency of indications for liver transplantation? Based on the slopes of increase in frequency of NASH and decrease in frequency of HCV as indications, NASH will become the most common indication for liver transplantation between 2020 and Because NASH, with associated obesity and complications of the metabolic syndrome, is known to recur following liver transplantation, maintaining or improving outcomes following liver transplantation will require a new focus on strategies to limit the impact of these conditions on morbidity and mortality. In summary, NASH is now the third most common indication for liver transplantation in the United States and is the only indication consistently increasing in frequency. If current trends continue, NASH will become the most common indication for liver transplantation in the United States in the next 10 to 20 years. Medium-term patient and graft survival rates for patients undergoing a liver transplant for NASH are similar to those of other indications.

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