Review article: Current indications and selection criteria for early liver transplantation in severe alcohol-associated hepatitis.

BACKGROUND: Alcohol-associated hepatitis (AH) is a severe inflammatory form of alcohol-associated liver disease (ALD) that carries a high mortality rate. Early liver transplantation for severe AH is increasingly available. However, specific criteria for referral and selection remain a subject of debate. AIMS: To provide a narrative review of the natural history, diagnostic criteria and indications for referral for early liver transplantation for severe AH. METHODS: We searched PubMed for articles published through August 2023. Key search terms were 'alcoholic hepatitis,' 'alcohol-associated hepatitis,' 'abstinence,' 'alcohol relapse,' and 'liver transplantation.' RESULTS: Previously, a six-month period of alcohol abstinence was required before patients with ALD were considered for liver transplantation. However, studies in recent years have demonstrated that, among carefully selected patients, patients who received early transplants have much higher survival rates than patients with similarly severe disease who did not undergo transplants (77% vs. 23%). Despite these successes, early liver transplantation remains controversial, as these patients have typically not undergone treatment for alcohol use disorder, with the ensuing risk of returning to alcohol use. CONCLUSIONS: While early liver transplantation for AH has survival benefits, many patients would not have received treatment for alcohol use disorder. An integrated approach to evaluating candidacy for early liver transplantation is needed.

Single-center experience with early liver transplantation for acute alcohol-related hepatitis-Limitations of the SALT score and directions for future study.

Alcohol-related liver disease (ALD) is the leading indication for liver transplantation worldwide. Since Mathurin et al. described their experience in providing early liver transplantation for patients with ALD in 2011, other centers have followed suit with generally favorable survival outcomes. This patient population poses a unique clinical challenge given the expedited nature of the evaluation and the lack of any significant sobriety period prior to transplantation. The SALT (Sustained Alcohol Use Post-Liver Transplant) score is a standardized psychometric tool increasingly used to help stratify the risk of relapse and guide listing decisions for these challenging clinical situations. In 2018, our center introduced a protocol for early liver transplantation for acute alcohol-related hepatitis (AAH). In this article, we offer a retrospective review of 26 patients transplanted between May 2018 and May 2021, including at least 1-year follow-up, and compare outcomes to initial SALT scores; we further identify additional factors that may impact post-transplant success. As transplant committees continue to weigh the ethical dilemma of denying lifesaving treatment against the obligation to remain stewards of a limited resource, we aim to contribute to a more nuanced understanding of risk regarding early transplantation for ALD.

Analyzing the utility of renal replacement therapy to manage hepatorenal syndrome in alcoholic hepatitis without liver transplantation: a nationwide analysis.

BACKGROUND: Hepatorenal syndrome (HRS) frequently complicates alcoholic hepatitis (AH) and portends poor survival in this population. Published literature indicates mixed benefits from renal replacement therapy (RRT) for HRS refractory to medical management. Therefore, we sought to assess the utilization of RRT in AH and clinical outcomes at a national level. METHODS: Using the International Classification of Diseases, Tenth Revision (ICD-10) codes, we identified adult patients with AH with a coexisting diagnosis of HRS from the National Readmission Database 2016 through 2019. Mortality, morbidity, and resource utilization were compared. We compared proportions using the Fisher exact test and computed adjusted P-values based on multivariate regression analysis. Analyses were performed using Stata, version 14.2, considering a two-sided P < 0.05 as statistically significant. RESULTS: A total of 73 203 patients with AH were included in the analysis (mean age 46.2 years). A total of 3620 individuals had HRS diagnosis (5%), of which 14.7% (n: 532) underwent RRT. HRS patients receiving RRT had a higher mortality rate than those who did not (adjusted odds ratio [aOR] 1.8, 95% confidence interval [CI]: 1.3-2.6, P: 0.01), along with higher resource utilization. Only those patients with HRS who underwent liver transplantation (LT) experienced a mortality reduction (24.4% for those not receiving RRTs and 36.5% for those receiving RRT). CONCLUSIONS: RRT is associated with higher mortality and morbidity when offered to patients with AH and HRS, who do not undergo LT. Therefore, our results suggest careful selection of AH patients when deciding to initiate RRT for HRS.

The landscape of inpatient admissions for alcoholic hepatitis in the era of early liver transplantation.

INTRODUCTION AND OBJECTIVES: Liver transplant (LT) is a recent option available in the United States (US) to treat those with severe, refractory alcoholic hepatitis (AH). We examined changes in clinical characteristics of patients admitted with AH and tracked hospital outcomes as practice changes involving LT have shifted. MATERIALS AND METHODS: Using the National Inpatient Sample, we performed a cross-sectional analysis of patients admitted with AH during the years 2016-2020 in the US. Differences in clinical characteristics over time were assessed. To compare outcomes between 2016-2017 (when LT was less common) and 2018-2020 (when LT was more common), we conducted linear and logistic regression. Propensity-score matching was used to compare outcomes between patients with and without LT. RESULTS: From 2016-2017 to 2018-2020, patients admitted with AH tended to have a higher frequency of infection (p = 0.006), hepatorenal syndrome (<0.001), and ascites (<0.001). Hospital costs and length of stay (LOS) were highest in transplant hospitals, and costs rose over time in both non-transplant (NT) teaching and non-teaching hospitals (p < 0.001). Mortality decreased in NT teaching hospitals [aOR 0.7 (95% CI: 0.6-0.8)] and slightly decreased in NT non-teaching hospitals [aOR 0.7 (95% CI: 0.5-1.0)]. In the propensity-matched cohort involving LT versus non-LT patients, there was a 10% absolute reduction in-hospital mortality, but this came at a higher cost (p < 0.001) and length of stay (p < 0.001). CONCLUSIONS: The severity of AH has been increasing over time, yet mortality has declined after adjusting for severity of disease. Patients who underwent LT survived; however, the healthcare burden of LT is substantial.

Outcomes following liver transplant for alcohol-associated liver disease: comparing alcohol-associated hepatitis and cirrhosis.

BACKGROUND: Liver transplant (LT) is a highly effective therapy for refractory severe alcohol-associated hepatitis (SAH), but optimal selection criteria remain unknown. We aim to evaluate the outcomes of patients who received LT for alcohol-associated liver disease at our center following the introduction of updated selection criteria, including the removal of the minimum sobriety requirement. METHODS: Data were collected on all patients who underwent LT for alcohol-associated liver disease from January 1, 2018, to September 30, 2020. Patients were divided into SAH and cirrhosis cohorts based on disease phenotype. RESULTS: One hundred twenty-three patients underwent LT for alcohol-associated liver disease, including 89 (72.4%) for cirrhosis and 34 (27.6%) for SAH. There was no difference in 1- (97.1 ± 2.9% vs. 97.7 ± 1.6%, p = 0.97) and 3-year (97.1 ± 2.9% vs. 92.4 ± 3.4%, p = 0.97) survival between SAH and cirrhosis cohorts. Return to alcohol use was more frequent in the SAH cohort at 1 year (29.4 ± 7.8% vs. 11.4 ± 3.4%, p = 0.005) and 3 years (45.1 ± 8.7% vs. 21.0 ± 6.2%, p = 0.005) including higher frequencies of both slips and problematic drinking. Unsuccessful alcohol use counseling (HR 3.42, 95% CI 1.12-10.5) and prior alcohol support meetings (HR 3.01, 95% CI 1.03-8.83) predicted a return to harmful alcohol use patterns in early LT recipients. Both duration of sobriety (c-statistic 0.32 (95% CI 0.34-0.43) and SALT score (c-statistic 0.47, 95% CI 0.34-0.60) were independently poor predictors of return to harmful drinking. CONCLUSION: Survival following LT was excellent in both SAH and cirrhosis cohorts. Higher rates of return to alcohol use highlight the importance of further individualized refinement of selection criteria and improved support following LT.

Early liver transplantation for severe acute alcohol-related hepatitis after more than a decade of experience.

In patients with severe acute alcohol-related hepatitis not responding to medical therapy, early liver transplantation (LT) represents the only effective therapy and, when performed within strict and well-defined protocols, it is associated with a clear survival benefit and acceptable rates of return to alcohol use after transplantation. However, there is still high variability in access to LT for patients with severe alcohol-related hepatitis, mainly due to a persistent overemphasis in the pre-LT evaluation on duration of pre-transplant abstinence and the stigma that patients with alcohol-related liver disease often experience, leading to marked inequity of access to this potentially lifesaving procedure and negative health outcomes. Therefore, there is an increasing need for prospective multicentre studies focusing on pre-transplant selection practices and on better interventions to treat alcohol use disorder after LT.

Early living donor liver transplantation for alcohol-associated hepatitis.

INTRODUCTION AND OBJECTIVES: Lately, there has been a steady increase in early liver transplantation for alcohol-associated hepatitis (AAH). Although several studies have reported favorable outcomes with cadaveric early liver transplantation, the experiences with early living donor liver transplantation (eLDLT) are limited. The primary objective was to assess one-year survival in patients with AAH who underwent eLDLT. The secondary objectives were to describe the donor characteristics, assess the complications following eLDLT, and the rate of alcohol relapse. MATERIALS AND METHODS: This single-center retrospective study was conducted at AIG Hospitals, Hyderabad, India, between April 1, 2020, and December 31, 2021. RESULTS: Twenty-five patients underwent eLDLT. The mean time from abstinence to eLDLT was 92.4 ± 42.94 days. The mean model for end-stage liver disease and discriminant function score at eLDLT were 28.16 ± 2.89 and 104 ± 34.56, respectively. The mean graft-to-recipient weight ratio was 0.85 ± 0.12. Survival was 72% (95%CI, 50.61-88) after a median follow-up of 551 (23-932) days post-LT. Of the 18 women donors,11 were the wives of the recipient. Six of the nine infected recipients died: three of fungal sepsis, two of bacterial sepsis, and one of COVID-19. One patient developed hepatic artery thrombosis and died of early graft dysfunction. Twenty percent had alcohol relapse. CONCLUSIONS: eLDLT is a reasonable treatment option for patients with AAH, with a survival of 72% in our experience. Infections early on post-LT accounted for mortality, and thus a high index of suspicion of infections and vigorous surveillance, in a condition prone to infections, are needed to improve outcomes.

Definition and measurement of alcohol-associated insight in early liver transplantation for acute alcohol-associated hepatitis: A systematic review.

BACKGROUND: Alcohol accounts for a large disease burden in hepatology and liver transplantation (LT) and across the globe. Clinical evaluations and decisions about LT candidacy are challenging because they rely on detailed psychosocial assessments and interpretations of psychiatric and substance use disorder data, which often must occur rapidly according to the acuity of end-stage liver disease. Such difficulties commonly occur during the process of candidate selection and liver allocation, particularly during early LT (eLT) in patients with acute alcohol-associated hepatitis (AAH). Patients with AAH commonly have very recent or active substance use, high short-term mortality, psychiatric comorbidities, and compressed evaluation and treatment timetables. LT clinicians report that patients' alcohol-associated insight (AAI) is among the most relevant psychosocial data in this population, yet no studies exist examining how LT teams define and use AAI in eLT or its effect on clinical outcomes. In April 2022, we searched Ovid MEDLINE, Elsevier Embase, EBSCOhost PsycInfo and CINAHL, and Wiley Cochrane Central Register of Controlled Trials for reports describing AAH populations who underwent eLT, which also described psychosocial evaluation parameters. The searches retrieved 1603 unique reports. After eligibility screening, 8 were included in the qualitative analysis. This systematic review reveals that AAI is a poorly defined construct that is not measured in a standardized way. Yet it is a commonly cited parameter in articles that describe the psychosocial evaluation and decision-making of patients undergoing eLT for AAH. This article also discusses the general challenges of assessing AAI during eLT for AAH, existing AAI definitions and rating scales, how AAI has been used to date in the broader hepatology and LT literature, and future areas for clinical and research progress.

Multicentered study of patient outcomes after declined for early liver transplantation in severe alcohol-associated hepatitis.

BACKGROUND: Early liver transplantation for alcohol-associated hepatitis is controversial in part because patients may recover, and obviate the need for liver transplantation. METHODS: In this retrospective study among 5 ACCELERATE-AH sites, we randomly sampled patients evaluated and then declined for liver transplantation for alcohol-associated hepatitis. All had Model of End-Stage Liver Disease (MELD) >20 and <6 months of abstinence. Recompensation was defined as MELD <15 without variceal bleeding, ascites, or overt HE requiring treatment. Multilevel mixed effects linear regression was used to calculate probabilities of recompensation; multivariable Cox regression was used for mortality analyses. RESULTS: Among 145 patients [61% men; median abstinence time and MELD-Na was 33 days (interquartile range: 13-70) and 31 (interquartile range: 26-36), respectively], 56% were declined for psychosocial reasons. Probability of 30-day, 90-day, 6-month, and 1-year survival were 76% (95% CI, 68%-82%), 59% (95% CI, 50%-66%), 49% (95% CI, 40%-57%), and 46% (95% CI, 37%-55%), respectively. Probability of 1-year recompensation was low at 10.0% (95% CI, 4.5%-15.4%). Among patients declined because of clinical improvement, 1-year probability of recompensation was 28.0% (95% CI, 5.7%-50.3%). Among survivors, median MELD-Na at 30 days, 90 days, and 1-year were 29 (interquartile range: 22-38), 19 (interquartile range : 14-29), and 11 (interquartile range : 7-17). Increased MELD-Na (adjusted HR: 1.13, p <0.001) and age (adjusted HR: 1.03, p <0.001) were associated with early (≤90 d) death, and only history of failed alcohol rehabilitation (adjusted HR: 1.76, p =0.02) was associated with late death. CONCLUSIONS: Liver recompensation is infrequent among severe alcohol-associated hepatitis patients declined for liver transplantation. Higher MELD-Na and age were associated with short-term mortality, whereas only history of failed alcohol rehabilitation was associated with long-term mortality. The distinction between survival and liver recompensation merits further attention.

Patients with a History of Bariatric Surgery Are 8 Years Younger at Presentation with Severe Alcoholic Hepatitis.

PURPOSE: Patients with prior bariatric surgery (BS) are at risk to develop alcohol use disorder (AUD) and alcohol-related liver disease (ALD). Severe alcoholic hepatitis (sAH) is one of the most severe manifestations of ALD with a 28-day mortality of 20-50%. The impact of prior BS on patients presenting with sAH was assessed. METHODS: From 01/2008 to 04/2021, consecutive patients admitted to a tertiary referral center with biopsy-proven sAH were included in a database. RESULTS: One hundred fifty-eight sAH patients of which 28 patients had a history of BS (BS group) were identified. Of this BS group, 24 patients underwent a Roux-en-Y gastric bypass (RYGB), 3 a biliopancreatic diversion, 1 an adjustable gastric band, and no patients a sleeve gastrectomy. The proportion of patients with BS increased threefold over time during the study period. Patients in the BS group were significantly younger at diagnosis of sAH (44.3 years vs 52.4 years), were more frequently female, and had a higher body mass index and a higher grade of steatosis on liver biopsy. The correlation between BS and a younger age at diagnosis remained significant in a multivariate regression analysis. There were no differences in disease severity between both groups. Furthermore, there were no differences in corticosteroid response, 28-day, 90-day, or 1-year survival. CONCLUSION: Prior BS is independently associated with a younger age of presentation with sAH, but is not independently associated with a different disease severity or outcome. These findings support the need for early detection of AUD in patients who underwent BS, in particular RYGB.

Liver transplantation for alcohol-associated hepatitis.

PURPOSE OF REVIEW: Early liver transplantation is emerging as a treatment option for severe alcohol-associated hepatitis refractory to pharmacotherapies. This review outlines the current status of transplantation for alcohol-associated hepatitis and the treatment of alcohol use disorder after liver transplantation. RECENT FINDINGS: Rates of early liver transplantation for alcohol-associated hepatitis are increasing with significant heterogeneity in practices across the Unites States. Recent studies have demonstrated a substantial survival benefit in patients transplanted for alcohol-associated hepatitis with improved outcomes in early vs. late transplantation, first vs. prior hepatic decompensation, and posttransplant abstinence/delayed relapse vs. early return to alcohol use. Several prediction algorithms have been developed to ascertain patients' risk of alcohol relapse and aid in candidate selection, though data on treatment of alcohol use disorders in transplant recipients remains limited. SUMMARY: Although controversial, early liver transplantation for severe alcohol-associated hepatitis has shown to be a lifesaving intervention. Additional research is needed to evaluate its long-term outcomes, optimize candidate selection, and understand treatment of alcohol use disorder posttransplant.

Trasplante hepático en hepatitis alcohólica aguda: ¿debemos decir que no?

Alcohol liver disease is one of the main indications for liver transplantation (LT). Currently, an abstinence period <6 months is required to include a patient with alcohol liver disease on the waiting list, a period that has not been shown to reduce the risk of relapse. Alcoholic hepatitis is characterized by hepatic decompensation secondary to recent, excessive consumption of alcohol, and LT may be the option in a well-selected group of patients who do not respond to medical treatment, but due to established sobriety intervals are excluded, this requires a change in the criteria established by the committees. We propose an evaluation algorithm to consider alcoholic hepatitis unresponsive to medical treatment for LT.

La enfermedad hepática por alcohol es una de las principales indicaciones de trasplante hepático (TH). Actualmente se requiere un período de abstinencia > 6 meses para incluir a un paciente con enfermedad hepática por alcohol en lista de espera de TH, periodo que no ha demostrado disminuir el riesgo de recaída. La hepatitis aguda por alcohol se caracteriza por una descompensación hepática secundaria a un consumo de alcohol excesivo reciente, y el TH puede ser la única opción en un grupo bien seleccionado de pacientes que no responden al tratamiento médico, pero debido a los intervalos de sobriedad establecidos son excluidos, y esto requiere un cambio en los criterios establecidos por los comités. Proponemos un algoritmo de evaluación para considerar para TH la hepatitis aguda por alcohol no respondedora a tratamiento médico.

Effect of an Integrated Transplantation Mental Health Program on Alcohol Relapse After Liver Transplantation for Severe Alcoholic Hepatitis: A Single-Center Prospective Study.

BACKGROUND: Liver transplantation (LT) for severe alcohol-associated hepatitis (AH) remains controversial due to perceived increased recidivism risk after LT because of a lack of protracted abstinence before LT. Data on risk stratification for alcohol relapse after LT are limited. We sought to evaluate the utility of having a mental health program embedded in a transplantation center in risk assessment for alcohol relapse-free patient survival after LT. METHODS: We conducted a prospective analysis of all patients with a diagnosis of severe AH hospitalized at a single transplant center from April 2015 to April 2020. After a comprehensive mental health risk stratification, patients were either waitlisted for LT or declined for waitlisting. The primary endpoint was alcohol relapse-free patient survival rate for those who received LT. The secondary endpoint compared survival rates between patients who received LT and those who did not. The median follow-up was 10 months. RESULTS: Among the 83 patients included in the study, 54 patients were waitlisted for LT (65%, group 1) and 29 were declined (35%, group 2). Patient characteristics and median Model for End-Stage Liver Disease score on presentation were comparable for both cohorts (36 in group 1, 38 in group 2; P = .8). Group 1 had significantly better Stanford Integrated Psychosocial Assessment for Transplantation total scores (median 40 vs 57; P < .01), presence of social support (100% of patients in group 1 vs 76% in group 2; P < .01), and less prevalence of active tobacco smokers (30% in group 1 vs 66% in group 2; P < .01). For those who were not waitlisted, 72.5% experienced rapid deterioration of hepatic function. Among the 54 patients waitlisted, 29 patients received LT (54%), whereas 19 died while on the waiting list (35%). One- and 3-year patient survival after LT were 92.5% and 92.5%, respectively. The overall and sustained alcohol relapse rates after LT were 10.3% and 3.5%, respectively. CONCLUSION: Severe AH is a complex medical and mental health disease and requires an intense risk assessment for recidivism after LT. Our study shows that an integrated transplantation mental health program provides an accurate risk stratification for alcohol relapse after LT, a successful intervention to mitigate recidivism risk, and optimal short-term alcohol relapse-free patient survival. Future studies should focus on enhancing the guidelines for broader application.

Heterogeneity in Center Practices in Liver Transplantation for Alcohol-Associated Liver Disease in the United States.

INTRODUCTION: Alcohol-related liver disease (ALD) is now the leading indication for liver transplantation (LT) in the United States (US). It remains unclear how centers are managing the medical and psychosocial issues associated with these patients. METHODS: We conducted a web-based survey of LT centers in the United States to identify center-level details on peri-LT management of ALD and related issues. RESULTS: Of the 117 adult LT centers, 100 responses (85.5%) were collected, representing all Organ Procurement and Transplantation Network regions. For alcohol-associated cirrhosis, 70.0% of the centers reported no minimum sobriety requirement while 21.0% required 6 months of sobriety. LT for severe alcohol-associated hepatitis was performed at 85.0% of the centers. Monitoring protocols for pre-LT and post-LT alcohol use varied among centers. DISCUSSION: Our findings highlight a change in center attitudes toward LT for ALD, particularly for severe alcohol-associated hepatitis.

Early Liver Transplantation for Severe Alcohol-Associated Hepatitis and a History of Prior Liver Decompensation.

INTRODUCTION: In the published studies of early liver transplantation (LT) for alcohol-associated hepatitis (AH), patients with a prior liver decompensation are excluded. The appropriateness of this criteria is unknown. METHODS: Among 6 American Consortium of Early Liver Transplantation for Alcohol-Associated Hepatitis sites, we included consecutive early LT for clinically diagnosed AH between 2007 and 2020. Patients were stratified as first vs prior history of liver decompensation, with the latter defined as a diagnosis of ascites, hepatic encephalopathy, variceal bleeding, or jaundice, and evidence of alcohol use after this event. Adjusted Cox regression assessed the association of first (vs prior) decompensation with post-LT mortality and harmful (i.e., any binge and/or frequent) alcohol use. RESULTS: A total of 241 LT recipients (210 first vs 31 prior decompensation) were included: median age 43 vs 38 years ( P = 0.23), Model for End-Stage Liver Disease Sodium score of 39 vs 39 ( P = 0.98), and follow-up after LT 2.3 vs 1.7 years ( P = 0.08). Unadjusted 1- and 3-year survival among first vs prior decompensation was 93% (95% confidence interval [CI] 89%-96%) vs 86% (95% CI 66%-94%) and 85% (95% CI 79%-90%) vs 78% (95% CI 57%-89%). Prior (vs first) decompensation was associated with higher adjusted post-LT mortality (adjusted hazard ratio 2.72, 95% CI 1.61-4.59) and harmful alcohol use (adjusted hazard ratio 1.77, 95% CI 1.07-2.94). DISCUSSION: Prior liver decompensation was associated with higher risk of post-LT mortality and harmful alcohol use. These results are a preliminary safety signal and validate first decompensation as a criterion for consideration in early LT for AH patients. However, the high 3-year survival suggests a survival benefit for early LT and the need for larger studies to refine this criterion. These results suggest that prior liver decompensation is a risk factor, but not an absolute contraindication to early LT.

Artificial intelligence to identify harmful alcohol use after early liver transplant for alcohol-associated hepatitis.

Early liver transplantation (LT) for alcohol-associated hepatitis (AH) is the fastest growing indication for LT, but prediction of harmful alcohol use post-LT remains limited. Among 10 ACCELERATE-AH centers, we examined psychosocial evaluations from consecutive LT recipients for AH from 2006 to 2017. A multidisciplinary panel used content analysis to develop a maximal list of psychosocial variables. We developed an artificial intelligence model to predict post-LT harmful alcohol use. The cohort included training (N = 91 among 8 centers) and external validation (N = 25 among 2 centers) sets, with median follow-up of 4.4 (IQR 3.0-6.0) years post-LT. In the training set, AUC was 0.930 (95%CI 0.862-0.998) with positive predictive value of 0.891 (95%CI 0.620-1.000), internally validated through fivefold cross-validation. In the external validation set, AUC was 0.692 (95%CI 0.666-0.718) with positive predictive value of 0.82 (95%CI 0.625-1.000). The model identified specific variables related to social support and substance use as highly important to predict post-LT harmful alcohol use. We retrospectively developed and validated a model that identified psychosocial profiles at LT predicting harmful alcohol use post-LT for AH. This preliminary model may inform selection and post-LT management for AH and warrants prospective evaluation in larger studies among all alcohol-associated liver disease being considered for early LT.