Early Liver Transplantation for Severe Alcoholic Hepatitis in the United States A Single-Center Experience

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1 American Journal of Transplantation 2016; 16: Wiley Periodicals Inc. Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: /ajt Early Liver Transplantation for Severe Alcoholic Hepatitis in the United States A Single-Center Experience G. Y. Im 1, *, L. Kim-Schluger 1, A. Shenoy 1, E. Schubert 3, A. Goel 4, S. L. Friedman 4, S. Florman 1 and T. D. Schiano 1 1 Recanati/Miller Transplantation Institute,Division of Liver Diseases, Department of Medicine, The Icahn School of Medicine at Mount Sinai,New York, NY 2 Department of Psychiatry,The Icahn School of Medicine at Mount Sinai,New York, NY 3 Social Work Services,The Mount Sinai Medical Center, New York, NY 4 Division of Liver Diseases,Department of Medicine, The Icahn School of Medicine at Mount Sinai,New York, NY *Corresponding author: Gene Y. Im, gene. im@mountsinai.org Early liver transplantation (LT) in European centers reportedly improved survival in patients with severe alcoholic hepatitis (AH) not responding to medical therapy. Our aim was to determine if a strategy of early LT for severe AH could be applied successfully in the United States. We reviewed 111 patients with severe AH at our center from January 2012 to January The primary end point was mortality at 6 months or early LT, with a secondary end point of alcohol relapse after LT. Survival was compared between those receiving early LT and matched patients who did not. Using a process similar to the European trial, 94 patients with severe AH not responding to medical therapy were evaluated for early LT. Overall, 9 (9.6%) candidates with favorable psychosocial profiles underwent early LT, comprising 3% of all adult LT during the study period. The 6-month survival rate was higher among those receiving early LT compared with matched controls (89% vs. 11%, p<0.001). Eight recipients are alive at a median of 735 days with 1 alcohol relapse. Early LT for severe AH can achieve excellent clinical outcomes with low impact on the donor pool and low rates of alcohol relapse in highly selected patients in the United States. Abbreviations: AH, alcoholic hepatitis; ALD, alcoholic liver disease; AR, alcohol rehabilitation; DF, discriminant function; LT, liver transplantation Received 04 June 2015, revised 16 August 2015 accepted for publication 31 August 2015 and Introduction Alcoholic hepatitis (AH) is an acute, inflammatory syndrome of jaundice and liver injury that occurs in a subset of patients after decades of heavy alcohol use (mean intake, approximately 100 g/day) (1 3). While mild forms of AH improve with conservative management, those with severe AH not responding to glucocorticoids as identified by the Lille score (a score of >0.45 after 7 days of medical therapy) have a mortality rate that may exceed 70% at 6 months (1,4). The recent STOPAH trial further narrowed the limited therapeutic options for severe AH to primarily glucocorticoids, which carry substantial risks (5,6). Because most liver transplant centers require a minimum of 6 months of sobriety and participation in alcohol rehabilitation (AR) before candidate acceptance for listing, severe AH nonresponders are largely ineligible for liver transplantation (LT) (7). The validity of the 6-month rule in predicting alcohol relapse is controversial, but there is increasing recognition that certain patients may have a low risk of relapse after LT despite violation of the 6- month rule (7 11). In a prospective, multicenter trial, investigators in France and Belgium demonstrated that early LT performed for severe AH not responding to glucocorticoids is feasible and improves survival with low rates of alcohol relapse in highly selected candidates (12). While this study generated significant interest, its approach has not been reported from other LT centers, especially in North America. To account for differences in population, social norms, access to medical care, organ allocation, and psychosocial evaluation performance, we sought to apply this strategy of early LT for patients with severe AH at an LT center in the United States. Materials and Methods Study population Patients hospitalized at the Mount Sinai Medical Center through the emergency department or via interhospital transfer and evaluated by a hepatologist for severe AH were prospectively identified from January 2012 to January Patient electronic medical records were retrospectively reviewed for demographic, medical, surgical, and psychosocial data and outcomes. Severe AH was diagnosed on clinical grounds (some with supporting liver biopsy results) and defined as a Maddrey s discriminant function (DF) greater than 32, the threshold for consideration of glucocorticoid or other AH-specific therapies (13,14). Patients with DF greater 841

2 Im et al than 32 not responding to medical therapy as defined by the Lille model as a score of greater than 0.45 after 7 days of medical therapy (or ineligible for medical therapy) were described as nonresponders (4,12). Patients with a Lille score of less than 0.45 were considered responders to medical therapy. Patients hospitalized for less than 7 days (for whom a Lille score could not be calculated) and with an early decline in serum bilirubin of 25% or greater were also considered responders (15). Medical therapy consisted of standard medical care for advanced liver disease at a quaternary LT center in the United States and a variety of AH-specific therapies by the referring providers and staff hepatologists. Severe AH nonresponders have such limited therapeutic options and dismal prognoses that early LT was considered in select patients as a rescue option. Candidate selection After adopting a written policy outlining the candidate selection process based on the European trial, our center began evaluating patients with severe AH for early LT in January 2012 (Figure 1). Patients with severe AH were selected as potential candidates for early LT based on the following criteria: nonresponse to medical therapy, severe AH as the patient s first liver-decompensating event, presence of good social support, and a favorable psychosocial profile suggesting a low risk of alcohol relapse with a signed agreement to lifelong alcohol abstinence (12). We excluded patients with concomitant chronic liver diseases like hepatitis virus B or C infection and those with hepatocellular carcinoma, HIV, severe comorbid conditions, or psychiatric disorders. Patients with previously controlled or newly diagnosed depression or anxiety disorders were not excluded. Unlike the European trial, patients with recent infection and gastrointestinal bleeding were still considered for early LT given their common concurrence with severe AH and poor outcomes (16). Comprehensive medical, surgical, psychosocial, and financial evaluations of the potential candidates were performed, as is routinely done for all potential LT candidates at our center. Psychosocial evaluations by a transplant psychiatrist and social worker were promptly performed after identification of nonresponse to expedite the LT evaluation. The social supports and health care providers of each candidate were contacted to more accurately assess the candidate s insight into their alcoholism, including prior alcohol counseling and liverdecompensating events. While based on methodology outlined by the European trial, our candidate selection process differed in several respects. Accounting for differences between residency training and LT centers in Europe compared with the United States, the medical team circles were adjusted to a committee comprising the staff hepatologist and hepatology fellow active in the care of the candidate, the transplant psychiatrist and social worker assessing the candidate, senior hepatologists, transplant surgeons, and financial coordinators in attendance at our weekly candidate selection meetings. Our center s written policy on early LT for severe AH and its details were reiterated at each selection committee meeting (see Supporting Information). The candidate s medical, surgical, psychosocial, and financial histories were thoroughly presented and reviewed. Decisions regarding candidate selection could be deferred to gather more psychosocial data. Complete consensus of the committee had to be reached before candidate acceptance for listing for early LT (12,17). Ultimately, each patient s candidacy was determined on a caseby-case basis and reviewed retrospectively for this study. Psychosocial evaluation study Prospectively gathered psychosocial evaluation data of two cohorts candidates provisionally accepted for early LT with favorable profiles and those declined due to poor profiles were compared by univariate and multivariate logistic regression analyses to identify variables associated with the determination of psychosocial profiles as favorable leading to acceptance for early LT. Case control study The early LT for severe AH recipients were matched to control patients with severe AH not responding to medical therapy, according to age, sex, ethnicity, DF, and Lille score. The control patients were selected from our center s AH database over a 2-year period before the start of our center s strategy of early LT for severe AH that were not a part of the prospectively identified study cohort. Statistical analysis Variables were compared between cohorts using the Student t-test and two-tailed v2 test. These analyses were performed using Stata 12.0 (StataCorp, College Station, TX). In the case control study, we estimated the patient s rate of survival by the Kaplan Meier method and compared survival between the two cohorts by using the log-rank test. Time was measured from the first day of physical presentation to our center to the last known date of follow-up or date of death from any cause. Figure 1: Early LT for severe AH candidate evaluation flowchart. AH, alcoholic hepatitis; LT, liver transplantation. Outcome The primary end point was mortality at 6 months or early LT. This is comparable to the European trial and informs the likelihood of survival if the 6-month rule had been applied. After early LT, alcohol consumption and enrollment in a program for AR when medically appropriate were assessed at short intervals during outpatient follow-up visits with random alcohol testing at the discretion of the AR program and/or hepatologist. 842 American Journal of Transplantation 2016; 16:

3 Early LT for Severe Alcoholic Hepatitis The secondary end point of alcohol relapse after early LT was defined as alcohol consumption of four or more drinks in a day or at least one drink for 4 or more days in succession after LT (18 21). On the other hand, a slip was defined as any brief alcohol consumption episode followed by resumed abstinence after early LT (21,22). The retrospective medical record review was approved by the Mount Sinai Institutional Review Board Committee, and no donor organs were obtained from executed prisoners or other institutionalized persons. Results During the 3-year study period, 111 consecutive patients hospitalized for severe AH were prospectively identified (Table 1). Seventeen (15%) patients were responders to medical therapy and successfully discharged, with 82% survival at 6 months. There were 94 (85%) patients who were nonresponders or ineligible for AH-specific therapies with poor prognostic scores. A variety of different AH-specific therapies were used, reflecting both local practices before patient transfer and those of our hepatologists. Less than half of the nonresponders received any AH-specific therapies due to the high incidence of hepatorenal syndrome, gastrointestinal bleeding, and sepsis. This cohort of nonresponders was predicted to have very poor outcomes according to several validated AH prediction models. Within this highest risk cohort, 20 (21%) patients had favorable psychosocial profiles and were provisionally accepted as candidates, of whom 15 Table 1: Characteristics of 111 patients with severe alcoholic hepatitis Characteristic Responders Nonresponders Early LT recipients p-value Number of patients Age, median years (range) 46 (29 63) 48.5 (26 68) 41 (30 60) 0.32 Women, n (%) 9 (53) 40 (43) 4 (44) 0.43 Ethnicity, n (%) Caucasian 12 (71) 54 (57) 8 (89) 0.53 Hispanic 4 (24) 17 (18) 0 African American 0 13 (14) 0 Asian 1 (6) 8 (9) 1 (11) Maddrey s discriminant function, median (range) 58 (34 96) 74.5 (34 273) 92 (50 133) 0.02 MELD score, median (range) 26 (12 37) 31 (16 52) 39 (27 42) <0.01 Lille score, median (range) ( ) ( ) ( ) <0.01 Glasgow alcoholic hepatitis score, median (range) 7 (6 9) 8 (5 11) 8 (7 9) 0.01 ABIC score, median (range) 7.89 ( ) 9.32 ( ) 9.39 ( ) 0.02 AH-specific treatment, n (%) None 9 (53) 45 (48) 4 (44) 0.95 Glucocorticoids 3 (18) 13 (14) 1 (11) 0.35 Pentoxifylline 4 (24) 16 (17) Glucocorticoids plus pentoxifylline 1 (6) 13 (14) 3 (33) 0.32 Glucocorticoids plus NAC 0 7 (7) 1 (11) 0.25 Complications, n (%) Infection 9 (53) 56 (60) 5 (56) 0.61 Ascites 4 (24) 26 (28) 4 (44) 0.72 Pulmonary 1 (6) 26 (28) 2 (22) 0.05 Urinary 3 (18) 17 (18) C. difficile 4 (24) 7 (7) 2 (22) 0.04 Bacteremia 1 (6) 13 (14) 1 (11) 0.36 Fungal 0 6 (6) Hepatorenal syndrome 3 (18) 65 (69) 8 (88) <0.01 Renal replacement therapy 1 (6) 37 (39) 7 (78) 0.01 Gastrointestinal bleeding 4 (24) 26 (28) Mechanical ventilation 0 34 (36) 0 <0.01 Interhospital transfer 9 (53) 71 (76) 7 (78) 0.07 First liver-decompensating event 6 (35) 42 (45) 8 (89) 0.43 Favorable psychosocial profile N/A 20 (21) 9 (100) Listed for liver transplantation 0 15 (16) 9 (100) <0.01 Mortality 1 month 0 50 (53) 0 <0.01 Mortality 6 months 3 (18) 66 (70) 1 (11) <0.01 The p-value is of comparison of responders to nonresponders. LT, liver transplantation; NAC, N-acetylcysteine. Four responders, 17 nonresponders, and two early LT recipients had multiple infections. Data incomplete. Includes nine early LT recipients. American Journal of Transplantation 2016; 16:

4 Im et al (16%) survived to listing for early LT. Ultimately, nine (10%) candidates underwent early LT for severe AH. Among the nine recipients, two underwent combined liver kidney transplantation for hemodialysis longer than 12 weeks and anuric renal failure before listing. Liver allografts were obtained through deceased donation (Table S1). The median time from presentation to our center to listing for early LT was 10.5 days, and from listing to early LT, 5 days (Table 2). The median Model for End-stage Liver Disease (MELD) score at the time of listing was 39, consistent with the high rate of complications in the nine recipients before early LT. Alcoholic hepatitis was confirmed in all nine early LT recipients by explant liver histology, with the majority having cirrhosis. Psychosocial characteristics of recipients More than three-quarters of the nonresponder cohort had poor psychosocial profiles and were not accepted as candidates for early LT. There were 15 candidates declined for both medical and psychosocial reasons but who had incomplete psychosocial profiles due to critical illness and/or profound hepatic encephalopathy. Post-hoc application of two established alcohol relapse prediction models, the High Risk Alcoholism Relapse scale and the Geneva model, failed to show utility in the selection of candidates for early LT or prediction of relapse (23). Sixteen variables informing the psychosocial profiles of the nine early LT recipients are listed in Table 3. We compared the 20 provisionally accepted candidates with favorable profiles to 59 candidates who were declined for early LT due to poor profiles (Table 4). On univariate analysis, these eight variables were significantly associated with candidate selection for early LT: presence of good insight, first liver-decompensating event, agreement with collaterals on alcohol use, recent life stressor leading to increased alcohol use, a previously undiagnosed Axis I psychiatric disorder, stable employment, longer sobriety duration, and being a good historian. On multivariate analysis, the presence of good insight and the first liver-decompensating event remained statistically significant (p<0.01). Financial characteristics of recipients Of the 15 candidates listed for early LT, nine (60%) had private insurance and the remainder had public insurance (five Medicaid, one Veterans Affairs). While the reporting of sobriety duration was never required, insurance approval for LT listing was contingent, in part, upon achieving psychosocial clearance in 67%, rather than compliance with the 6-month rule. The remainder of insurance sources did not require reporting of psychosocial clearance. Overall, there was universal insurance approval of early LT for severe AH without any denials or the requirement for appeals. Survival and outcomes Eight (89%) of nine early LT for severe AH recipients survived, with a 6-month mortality or early LT rate of 70% in the nonresponder cohort and 62% overall. The intention-to-treat early LT and survival rates were 60% and 53%, respectively. Despite antimicrobial prophylaxis, two-thirds of the early LT recipients had bacterial infec- Table 2: Characteristics of the nine early liver transplant recipients Recipient Characteristic Insurance Private Private Public Private Private Private Private Public Public Blood type A A A A B O A B O Time from presentation to listing, days Time from listing to early LT, days MELD at early LT, n Explant histology AH-S4, AH-S3, AH-S4 AH-S4 AH-S4 AH-S4 AH-S4 AH-S3 AH-S3 A1AT A1AT Complications after early LT CDI E. coli UTI None VRE None RecurrentCDI, C. freundii CNS line None opioid-dependence septic shock sepsis Rejection episode Graft dysfunction Alive Alcohol relapse + N/A AR attendance N/A + + Return to employment N/A Length of follow-up, days N/A LT, liver transplantation; AH, alcoholic hepatitis; S, stage (Scheuer classification); A1AT, alpha1-antitrypsin deficiency; CDI, Clostridium difficile infection; UTI, urinary tract infection; VRE, vancomycin resistant Enterococcus faecium bacteremia; CNS, coagulase negative staphylococci; AR, alcohol rehabilitation; +, yes;, no. 844 American Journal of Transplantation 2016; 16:

5 Early LT for Severe Alcoholic Hepatitis Table 3: Psychosocial profiles of the nine early liver transplant recipients Recipient Characteristic Age, years Sex M F M F F F M M M Alcoholic drinks per day, n Last alcohol use, days First liver-decompensating event Good insight into alcoholism Good social support Presence of life partner Presence of children Family history of alcoholism Recent life stressor Undiagnosed Axis I psychiatric disorder Agreement with collaterals on alcohol use Stable employment history Cigarette smoking + Illicit drug use M, male; F, female; +, yes;, no. Table 4: Comparison of accepted candidates and candidates declined for poor psychosocial profiles for early liver transplant Variables Declined candidates Accepted candidates p Value Number of patients, n 59* 20 Age, median years Women, n (%) 36 (61) 9 (45) 0.21 Ethnicity, n (%) Caucasian 28 (47) 16 (80) 0.11 Hispanic 14 (24) 1 (5) African American 9 (15) 1 (5) Asian 6 (10) 2 (10) First liver-decompensating event, n (%) 21 (36) 19 (95) <0.01 Alcoholic drinks per day, median Type of alcohol, n (%) Liquor 46 (78) 16 (80) 0.85 Wine 16 (27) 9 (45) 0.14 Beer 13 (22) 4 (20) 0.85 Duration of alcohol use, median years Last alcohol use, mean days <0.01 Family history of alcoholism, n (%) 25 (42) 12 (60) 0.17 Presence of life partner, n (%) 37 (63) 14 (70) 0.56 Good social support, n (%) 52 (88) 20 (100) 0.11 Stable employment history, n (%) 17 (29) 13 (65) <0.01 Insight into alcoholism, n (%) Poor 38 (64) 1 (5) Developing 17 (29) 1 (5) Good 4 (68) 18 (90) <0.01 Recent life stressor, n (%) 22 (37) 16 (80) <0.01 Prior Axis I psychiatric diagnosis, n (%) 18 (31) 7 (35) 0.71 Undiagnosed Axis I psychiatric disorder, n (%) 11 (19) 11 (55) <0.01 Good historian, n (%) 22 (37) 16 (80) <0.01 Agreement with collaterals on alcohol use, n (%) 39 (66) 18 (90) 0.04 Illicit drug use, n (%) 6 (10) 1 (5) 0.48 Cigarette smoking, n (%) 14 (24) 4 (20) 0.73 Presence of children, n (%) 34 (58) 9 (45) 0.33 *Fifteen candidates were declined for both medical and psychosocial reasons but had incomplete psychosocial profiles due to critical illness and/or encephalopathy. Types of alcohol were not mutually exclusive so percentages >100%. American Journal of Transplantation 2016; 16:

6 Im et al tions but no fungal infections (Table 2). There were four reoperations, each occurring 1 day after early LT for bleeding and washout. Seven of nine recipients underwent perioperative hemodialysis with renal recovery and cessation of hemodialysis at a median of 3 days after early LT. Recipient 6 had recurrent Clostridium difficile infections and developed chronic abdominal pain requiring chronic opioid treatment. Recipient 7 had prolonged respiratory failure requiring tracheostomy and later died of necrotizing pancreatitis with Citrobacter freundii related septicemia and multiorgan failure 16 weeks after early LT. All recipients received tacrolimus-based immunosuppression with no rejection episodes and were discharged from our center at a median of 16 days after early LT. In the case control study, the early LT for severe AH recipients and control patients were statistically well matched (Table S2). The 6-month survival rate was significantly higher among patients undergoing early LT (89%) than among matched controls (11%, p<0.001) (Figure 2). Congruent with previous studies of severe AH nonresponders, the control patients acutely had high rates of mortality. Two-thirds of the deaths in the control group occurred within 1 month after presentation to our center, highlighting the benefit of performing early LT for severe AH. Burden of early LT for severe AH During the study period, 292 adult liver transplants were performed at our center, with alcoholic liver disease (ALD) as the indication in 10%. The nine early LT for severe AH recipients comprised 3% of the total and 31% of those transplants for ALD overall. The non-ah, ALD recipients had a median abstinence period of 25 months before LT. In total, 18 (90%) of 20 provisionally accepted early LT candidates, and seven (78%) early LT recipients were referred from other hospitals via interhospital transfer, including three for second opinion evaluation from other LT centers not performing early LT for severe AH. Figure 2: Kaplan Meier estimates of survival in nine early liver transplant recipients and nine matched controls. Follow-up and assessment of alcohol relapse Eight (89%) of nine early LT for severe AH recipients are alive at a median follow-up of 735 days (range, days). All surviving recipients had liver enzyme and creatinine levels that returned to within normal range by 28 days after early LT. Hepatology follow-up visits were frequent in the first 6 months after early LT, with a median of 15 visits at a median interval of 11 days. All recipients enrolled in AR programs when deemed medically feasible by their hepatologist at a median of 130 days after early LT. Recipient 3 had self-reported slips of 60 and 15 g of alcohol at 84 and 260 days after early LT, respectively, without further consumption based on self-reporting and serial urine ethyl glucuronide testing (24 26). Neither episode was associated with symptoms or abnormal liver enzymes. Alcohol relapse was diagnosed in recipient 5 at 180 days after LT due to elevated liver tests and positive urine ethyl glucuronide and confirmed by the presence of AH on liver biopsy. She has maintained good graft function but likely has ongoing alcohol consumption. There were no slips or relapses reported or noted in the other recipients. Discussion In this early report of an initial US experience with a strategy of early LT for severe AH, we demonstrate that excellent clinical outcomes can be achieved with low burden on the donor pool and low rates of alcohol relapse. Nonresponders to medical therapy for severe AH experienced a dismal 6-month mortality rate of 70%, comparable to that of previous studies (27 30). The high proportion of nonresponders was likely due to referral bias, as more than two-thirds of this cohort was composed of interhospital transfers, which increased over time for early LT consideration and highlights the key role of local providers. In addition, concerns about potential denial of coverage by private or public insurers due to short sobriety duration limiting access to early LT were unfounded, which is consistent with a recent survey of LT centers (21,32,32). In practice, attempting to replicate the European methodology in the United States was not straightforward. It required programmatic changes: revised policies, increased inpatient transfer and service volume, a dedicated addiction team, and candid multidisciplinary discussions of complex medical and psychosocial profiles of potential candidates. Despite these obstacles, our study confirms the findings of Mathurin and colleagues in a North American patient cohort. Despite higher median MELD scores at the time of LT, the 6-month survival of early LT for severe AH recipients (89%) was superior to that of recipients in the European trial (77%) and matched control nonresponders (11%) (12). This former difference may be related to a smaller study cohort, less glucocorticoid exposure, and local factors, particularly the presence of Aspergillus infections described in France and Belgium (12,33). 846 American Journal of Transplantation 2016; 16:

7 Early LT for Severe Alcoholic Hepatitis Of the 20 nonresponder candidates with favorable psychosocial profiles, 15 (75%) survived to listing, with nine (45%) undergoing early LT, including two combined liver kidney tranplants. Uncontrolled infection in the setting of liver failure was the most frequent cause of candidate attrition (7 of 11, 63%), followed by aspiration-related respiratory failure (27%). The median active waitlist time for the six candidates who died while waiting for early LT was 8 days, compared with 5 days for the nine recipients. In contrast, all candidates listed for early LT in the European trial eventually underwent LT (12). This reflects the grim prognosis of the nonresponder cohort and the scarcity of organs in our region and highlights the need for an expeditious and organized effort with prompt decision-making. Despite a high rate of complications, eight of nine early LT recipients are alive with excellent graft function at a median of about 2 years. These results, coupled with early reports and studies showing equivalent outcomes between AH and ALD LT recipients, demonstrate that the medical and surgical feasibility of early LT for severe AH is high (12,34 39). Excluding recipient 5, who violated the first liver-decompensating event criterion, a one-way sensitivity analysis of data for candidates accepted based on the preestablished inclusion criteria demonstrates similar end points: 87.5% survival at 6 months and no alcohol relapses (but one recipient with slips). However, the suitability of this controversial indication for LT crucially depends on the appropriate selection of candidates with low risk of relapse (6,10,11,21,40 43). Because approximately 90% of candidates evaluated in the European trial were declined for early LT due to poor psychosocial profiles, we prioritized the psychosocial evaluation as the primary next-step following identification of nonresponse to medical therapy to avoid unnecessary utilization of resources required of a complete LT evaluation. Approbation by the addiction team to shift away from the 6-month rule to a comprehensive and nonjudgmental risk assessment was paramount in implementing a strategy of early LT for severe AH (10,40 44). In this way, honesty and candor about alcohol use become advantageous, reflecting positively on a candidate s insight, compared with the promotion of subterfuge by the 6-month rule (20). A learning curve to these complicated evaluations was anticipated, so the same addiction team (A.S. and E.S.) assessed each potential candidate when feasible. We provisionally accepted 21% of all nonresponders as candidates for early LT, a rate consistent with the published Lille and Brussels center acceptance rates in the European trial (12). We found the empirically derived criterion of the first liver-decompensating event to be useful ethically to prioritize those who were previously unaware of their liver disease from alcohol but vague and problematic to define, making the transparency of the decision-making process more difficult. Eliciting a precise drinking history from every potential candidate (without overt hepatic encephalopathy) and their social supports while seeking confirmation from pertinent providers regarding knowledge of abnormal liver tests and alcohol counseling is time consuming but crucial to reduce bias and improve transparency. To help define a potential first liver-decompensating event, we asked this question: When faced with the knowledge that their alcohol use was linked to a negative effect on their medical health, did the candidate stop drinking? If no, then the candidate s presentation with severe AH was not considered their first decompensating event, as it demonstrated poor insight and decision-making. We analyzed our prospectively gathered psychosocial profile data to gain insight into our selection process. While the presence of good social support was a minimal requirement, it was similar between the accepted and declined groups, suggesting minimal impact (Table 4). We also observed that patients with increased drinking as a form of self-medication for undiagnosed depression or anxiety and triggered by a recent life stressor were more likely to have a reversible pattern of addiction. The presence of good insight and the first liver-decompensating event were significantly associated with candidate selection on multivariate analysis. This was an expected finding, as the other eight significant variables on univariate analysis often constitute good insight. These variables should be gathered and emphasized in psychosocial evaluations of early LT candidates. There was an overall incidence of one alcohol relapse and two slips involving two of the eight surviving early LT recipients at a median of 2 years. These are at or lower than the rates expected after LT for recipients with ALD who achieved 6 or more months of sobriety (44 46). The distinction made between relapse and slip is important as longitudinal studies have demonstrated divergent outcomes between these drinking patterns after LT (45). The single case of alcohol relapse after LT occurred in recipient 5, who had violated the first liverdecompensating event criterion. After an initial decline for early LT, she attended an AR program for several weeks despite hospitalizations with a subsequent acceptance for listing given her adherence to recommendations and young age. While she has returned to employment with good graft function, her ALD/nonalcoholic fatty liver disease index (ANI) remains high (47). She also had delayed follow-up with the addiction team at more than 20 weeks after LT, suggesting a need for structured and ongoing addiction team visits after early LT to reinforce the abstinence and AR agreements. This also demonstrates the importance of the first liver-decompensating event criterion as a reflection of a candidate s insight into their addiction and the learning curve that a center can face when implementing the strategy of early LT. Adding to the utility of early LT for severe AH was the finding that half of the surviving recipients American Journal of Transplantation 2016; 16:

8 Im et al returned to employment. In contrast, typically only onequarter of all LT recipients return to employment, with even lower rates for those with ALD (48). This study has several limitations. First, severe AH was diagnosed clinically and mostly without liver biopsies. All biopsies of suspected AH and liver explants demonstrated the presence of AH, but two recipients had unexpected histologic evidence of alpha-1 antitrypsin deficiency. A biopsy-all strategy may have yielded a small proportion of alternate diagnoses that could have influenced decisionmaking (49). Second, the control group was not matched for psychosocial profiles, with possible bias in the selection process given the absence of an equitable, objective, and validated tool to predict the risk of alcohol relapse, as in the European trial. However, there were no statistically significant differences between the nine early LT recipients and the remainder of the nonresponder cohort in terms of age, sex, ethnicity, AH prediction models, AHspecific treatment, and infections (data not shown). Last, this was a single-center retrospective study performed at a high-volume transplant center in the United States with a consistent and dedicated addiction team in a region with a significant shortage of organs. Application of this strategy at other LT centers with different patient populations, regional organ-sharing pressures or allocation and medical, surgical, and psychiatric expertise will be important to assess its broader reproducibility and utility. In conclusion, we have shown that an initial experience with a strategy of early LT for severe AH at a single-center in the United States is highly effective with excellent graft and patient survival, low burden on the donor pool, and low rates of relapse. Careful adaptation of methodology, adherence to the first-decompensating event criterion and a commitment to equitably performing comprehensive psychosocial evaluations of potential candidates are paramount to the transparency and reproducibility of this strategy. Optimizing candidate selection at low risk of alcohol relapse after early LT and fostering life-long abstinence will be critical areas of future study. Acknowledgments The authors thank Swapna Vaidya and the RMTI transplant social workers for providing early comments on the study and the members of the Recanati/Miller Transplantation Institute for their contributions to the research. Gene Im received support for this work from the National Institutes of Health Loan Repayment Program. This work was presented in brief abstract form at the 64th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting on November 3, Author Contributions Dr Im was responsible for conception, design, data collection, analysis, statistics, and writing of the article. Dr Kim-Schluger was responsible for conception, design, analysis, and critical edits. Dr Shenoy was responsible for design, data collection, analysis, and critical edits. Dr Schubert was responsible for data collection and analysis. Dr Goel was responsible for data collection, analysis, and statistics. Dr Friedman was responsible for conception, analysis, and critical edits. Dr Florman was responsible for conception and critical edits. Dr Schiano was responsible for conception, design, analysis, and critical edits. Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. References 1. Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med 2009; 360: Naveau S, Giraud V, Borotto E, et al. Excess weight risk factor for alcoholic liver disease. Hepatology 1997; 25: Dunn W, Jamil LH, Brown LS, et al. MELD accurately predicts mortality in patients with alcoholic hepatitis. Hepatology 2005; 41: Louvet A, Naveau S, Abdelnour M, et al. The Lille model: A new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology 2007; 45: Louvet A, Wartel F, Castel H, et al. Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor. Gastroenterology 2009; 137: Thursz MR, Richardson P, Allison M, et al. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med 2015; 372: Dureja P, Lucey MR. The place of liver transplantation in the treatment of severe alcoholic hepatitis. J Hepatol 2010; 52: Beresford TP, Turcotte JG, Merion R. A rational approach to liver transplantation for the alcoholic patient. Psychosomatics 1990; 31: Rice JP, Lucey MR. Should length of sobriety be a major determinant in liver transplant selection? Curr Opin Organ Transplant 2013; 18: Lucey MR. Liver transplantation in patients with alcoholic liver disease. Liver Transpl 2011; 17: Brown RS. Transplantation for alcoholic hepatitis: Time to rethink the 6-month rule. N Engl J Med 2011; 365: Mathurin P, Moreno C, Samuel D, et al. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med 2011; 365: O Shea RS, Dasarathy S, McCullough AJ, et al. Alcoholic liver disease. Hepatology 2010; 51: Mathurin P, Louvet A, Duhamel A, et al. Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: A randomized clinical trial. JAMA 2013; 310: American Journal of Transplantation 2016; 16:

9 Early LT for Severe Alcoholic Hepatitis 15. Mathurin P, Abdelnour M, Ramond MJ, et al. Early change in bilirubin levels is an important prognostic factor in severe alcoholic hepatitis treated with prednisolone. Hepatology 2003; 38: Rudler M, Mouri S, Charlotte F, et al. Prognosis of treated severe alcoholic hepatitis in patients with gastrointestinal bleeding. J Hepatol 2015; 62: Volk ML, Biggins SW, Huang MA, et al. Decision making in liver transplant selection committees: a multicenter study. Ann Intern Med 2011; 155: Fuller RK. Definition and diagnosis of relapse to drinking. Liver Transpl Surg 1997; 3: DiMartini A, Dew MA, Day N, et al. Trajectories of alcohol consumption following liver transplantation. Am J Transplant 2010; 10: Weinrieb RM, Van Horn DH, McLellan AT, et al. Interpreting the significance of drinking by alcohol-dependent liver transplant patients: Fostering candor is the key to recovery. Liver Transpl 2000; 6: Lucey MR. Liver transplantation for alcoholic liver disease. Nat Rev Gastroenterol Hepatol 2014; 11: Leong J, Im GY. Evaluation and selection of the patient with alcoholic liver disease for liver transplant. Clin Liver Dis 2012; 16: Im GY, Vaidya S, Schubert ES, et al. Utility of alcohol relapse prediction models in the selection of patients with severe alcoholic hepatitis considered for early liver transplantation in the United States. Hepatology 2013; 58(Suppl 1): 142A. 24. Piano S, Marchioro L, Gola E, et al. Assessment of alcohol consumption in liver transplant candidates and recipients: The best combination of the tools available. Liver Transpl 2014; 20: Staufer K, Andresen H, Vettorazzi E, et al. Urinary ethyl glucuronide as a novel screening tool in patients pre- and post-liver transplantation improves detection of alcohol consumption. Hepatology 2011; 54: Babor TF, Steinberg K, Anton R, et al. Talk is cheap: Measuring drinking outcomes in clinical trials. J Stud Alcohol 2000; 61: Stewart S, Prince M, Bassendine M, et al. A randomized trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis. J Hepatol 2007; 47: Theodossi A, Eddleston AL, Williams R. Controlled trial of methylprednisolone therapy in severe acute alcoholic hepatitis. Gut 1982; 23: Mathurin P, Duchatelle V, Ramond MJ, et al. Survival and prognostic factors in patients with severe alcoholic hepatitis treated with prednisolone. Gastroenterology 1996; 110: Mathurin P, Mendenhall CL, Carithers RL Jr, et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): Individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH. J Hepatol 2002; 36: Everhart JE, Beresford TP. Liver transplantation for alcoholic liver disease: A survey of transplantation programs in the United States. Liver Transpl Surg 1997; 3: Hasanin M, Dubay DA, McGuire BM, et al. Liver transplantation for alcoholic hepatitis: A survey of liver transplant centers. Liver Transpl 2015; Jul Gustot T, Maillart E, Bocci M, et al. Invasive aspergillosis in patients with severe alcoholic hepatitis. J Hepatol 2014; 60: Castel H, Moreno C, Antonini T, et al. Early transplantation improves survival of non-responders to steroids in severe alcoholic hepatitis: A challenge to the 6 month rule of abstinence. Hepatology 2009; 50(Suppl 4): 307A. 35. Ibrahim A, Hanouneh IA, Humberson A, et al. Ohio Solid Organ Transplantation Consortium (OSOTC) exception criteria for early liver transplantation (LT) in severe alcoholic hepatitis. Hepatology 2014; 60(Suppl 4): 73A. 36. Lee BP, Victor DW, Ghobrial RM, et al. Early liver transplantation in severe alcoholic hepatitis: The U.S. experience. Hepatology 2014; 60(Suppl 4): 462A. 37. Tome S, Martinez-Rey C, Gonzalez-Quintela A, et al. Influence of superimposed alcoholic hepatitis on the outcome of liver transplantation for end-stage alcoholic liver disease. J Hepatol 2002; 36: Wells JT, Said A, Agni R, et al. The impact of acute alcoholic hepatitis in the explanted recipient liver on outcome after liver transplantation. Liver Transpl 2007; 13: Singal AK, Bashar H, Anand BS, et al. Outcomes after liver transplantation for alcoholic hepatitis are similar to alcoholic cirrhosis: exploratory analysis from the UNOS database. Hepatology 2012; 55: Volk M. Liver transplantation for alcoholic hepatitis. Gastroenterology 2012; 142: Burroughs AK. Liver transplantation for severe alcoholic hepatitis saves lives. J Hepatol 2012; 57: Shawcross DL, O Grady JG. The 6-month abstinence rule in liver transplantation. Lancet 2010; 376: Forrest EH, Lucey MR. Rescue liver transplantation for severe alcoholic hepatitis: Arriving where we started? Hepatology 2013; 57: Fuller RK. Definition and diagnosis of relapse to drinking. Liver Transpl Surg 1997; 3: DiMartini A, Dew MA, Day N, et al. Trajectories of alcohol consumption following liver transplantation. Am J Transplant 2010; 10: Tang H, Boulton R, Gunson B, et al. Patterns of alcohol consumption after liver transplantation. Gut 1998; 43: Dunn W, Angulo P, Sanderson S, et al. Utility of a new model to diagnose an alcohol basis for steatohepatitis. Gastroenterology 2006; 131: Huda A, Newcomer R, Harrington C, et al. High rate of unemployment after liver transplantation: Analysis of the United Network for Organ Sharing database. Liver Transpl 2012; 18: Elphick DA, Dube AK, McFarlane E, et al. Spectrum of liver histology in presumed decompensated alcoholic liver disease. Am J Gastroenterol 2007; 102: Supporting Information Additional Supporting Information may be found in the online version of this article. Additional Supporting Information may be found in the online version of this article. Supplemental Materials Table S1: Deceased donor characteristics. Table S2: Results of case-control comparisons of nine early liver transplant recipients and nine matched controls. American Journal of Transplantation 2016; 16: