Early liver transplant for alcohol-associated liver disease has excellent survival but higher rates of harmful alcohol use.

BACKGROUND AND AIMS: Early liver transplantation for alcohol-associated liver disease (ALD) has increased worldwide. Short-term outcomes have been favorable, but data on longer-term outcomes are lacking. METHODS: Single-center retrospective study of primary LT recipients between 2010-2020, with follow-up through July 1, 2022. Survival analysis was performed using log rank, Cox models, and Kaplan-Meier method. Cox models were created to identify variables associated with mortality, logistic regression to identify variables associated with post-LT alcohol use. RESULTS: Of 708 patients who underwent LT, 110 (15.5%) had ALD and abstinence <6 months prior to LT (ELT), 234 (33.1%) had ALD and alcohol abstinence >6 months (SLT), and 364 (51.4%) had non-ALD diagnoses. Median follow-up was 4.6 years (IQR 2.6, 7.3). ELT recipients were younger (p=0.001) with median abstinence pre-LT of 61.5 days. On adjusted Cox model, post-LT survival was similar in ELT and SLT (HR 1.31, p=0.30) and superior to non-ALD (HR 1.68, p=0.04). Alcohol use (40.9% vs 21.8%, p<0.001) and harmful alcohol use (31.2% vs 16.0%, p=0.002) were more common in ELT recipients. Harmful alcohol use was associated with post-LT mortality on univariate (HR 1.69, p=0.03), but not multivariable regression (HR 1.54, p=0.10). Recurrence of decompensated ALD trended toward more common in ELT (9.1% vs 4.4%, p=0.09). Greater than 6 months pre-LT abstinence was associated with a decreased risk of harmful alcohol use (OR 0.42, p=0.001), but not in a multivariable model (OR 0.71, p=0.33). CONCLUSIONS: Patients who undergo ELT for ALD have similar or better survival than other diagnoses in the first 10-years after LT despite a higher incidence of post-LT alcohol use.

Serum aryl hydrocarbon receptor activity is associated with survival in patients with alcohol-associated hepatitis.

BACKGROUND AND AIMS: Patients with alcohol-associated hepatitis (AH) have an altered fecal metabolome, including reduced microbiota-derived tryptophan metabolites, which function as ligands for aryl hydrocarbon receptor (AhR). The aim of this study was to assess serum AhR ligand activity in patients with AH. APPROACH AND RESULTS: The study included 74 controls without AUD, 97 patients with AUD, and 330 patients with AH from 2 different multicenter cohorts (InTeam: 134, AlcHepNet: 196). Serum AhR activity was evaluated using an AhR reporter assay with HepG2-Lucia cells incubated with serum for 24 hours. Serum AhR activity was significantly higher in patients with AH compared with both controls (1.59 vs. 0.96-fold change, p < 0.001) and patients with AUD (1.59 vs. 0.93, p < 0.001). In both AH cohorts, patients with AhR activity ≥ 2.09 had significantly lower cumulative survival rates at 30, 60, 90, and 180 days compared to those with AhR activity < 2.09. When serum AhR activity was used to further stratify patients with severe AH, the cumulative 30, 60, 90, and 180-day survival rates for patients with severe AH and the AhR activity ≥ 2.09 group were all significantly lower than those with an AhR activity < 2.09 group. CONCLUSIONS: Serum AhR activity was significantly higher in patients with AH compared with controls and individuals with AUD, and this increased activity was associated with higher mortality. Consequently, serum AhR activity holds potential as a prognostic marker.

The potential role of infusions of T regulatory cells in inducing and maintaining liver allograft tolerance.

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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.

Psychosocial assessment in liver transplantation (LT): an analysis of short-term outcomes.

BACKGROUND: Our research showed that patients with alcohol-associated liver disease (ALD) had more severe liver disease than those without a diagnosis of ALD yet were less likely to be selected for transplant listing due to their increased psychosocial vulnerability. This study aims to answer whether this vulnerability translates to worse short-term outcomes after transplant listing. METHODS: A total of 187 patients were approved for liver transplant listing and are included in the present retrospective study. We collected dates of transplantation, retransplantation, death, and pathologic data for evidence of rejection, and reviewed alcohol biomarkers and documentation for evidence of alcohol use. RESULTS: The ALD cohort had higher Stanford Integrated Psychosocial Assessment for Transplant (SIPAT) scores (39.4 vs. 22.5, p <0.001) and Model for End-Stage Liver Disease (MELD)-Na scores (25.0 vs. 18.5, p <0.001) compared with the non-ALD cohort. Forty-nine (59.7%) subjects with ALD and 60 (57.1%, p =0.71) subjects without ALD subsequently received a liver transplant. Overall mortality was similar between the 2 groups (20.7% ALD vs. 21.0% non-ALD, p =0.97). Neither the SIPAT score (HR: 0.98, 95% CI: 0.96-1.00, p =0.11) nor MELD-Na score (HR 0.99, 95% CI 0.95-1.02, p =0.40) were associated with mortality. Patients with ALD were more likely to have alcohol biomarkers tested both before (84.1% vs. 24.8% non-ALD, p <0.001) and after liver transplantation (74.0% vs. 16.7% non-ALD, p <0.001). SIPAT score was associated with alcohol use after listing (OR: 1.03, 95% CI: 1.0-1.07, p =0.04), although a return to alcohol use was not associated with mortality (HR: 1.60, 95% CI: 0.63-4.10, p =0.33). CONCLUSION: Patients with ALD had higher psychosocial risk compared with patients without a diagnosis of ALD who were placed on the waitlist, but had similar short-term outcomes including mortality, transplantation, and rejection. Although a high SIPAT score was predictive of alcohol use, in the short-term, alcohol use after transplant listing was not associated with mortality.

Psychosocial Barriers and Their Impact on Hepatocellular Carcinoma Care in US Veterans: Tumor Board Model of Care.

Background: Psychosocial barriers, including low socioeconomic status, homelessness, alcohol and substance use disorders, and psychiatric disorders are prevalent in US veterans. Our study aims to identify the prevalence of psychosocial barriers in veterans diagnosed with hepatocellular carcinoma (HCC), and their impact on receipt of cancer care. Methods: A retrospective cohort study was performed of all veterans diagnosed with HCC at the William S. Middleton Memorial Veterans' Hospital in Madison, Wisconsin, whose tumor care was coordinated through a multidisciplinary tumor board. Outcomes included receipt of any HCC-specific therapy and overall survival. Results: From January 1, 2007, through December 31, 2016, 149 veterans were diagnosed with HCC. Substance use disorders were reported in 124 (83%) patients, psychiatric illness was documented in 55 (37%) patients, 23 (15%) patients had incomes below the poverty threshold, and 7 (5%) were experiencing homelessness. The mean (SD) distance traveled for care was 207.1 (277.9) km; travel and lodging assistance were accessed by 50 (34%) and 33 (22%) veterans, respectively. Seventy-one patients (48%) had HCC exceeding T2 stage at diagnosis. Curative treatment was offered to 78 (52%) patients, with 127 (85%) receiving any HCC-specific care. Median survival from diagnosis was 727 days (95% CI, 488-966). Conclusions: Psychosocial barriers were common in our veteran cohort. Individualizing care, and coordination of travel and lodging, assisted in enabling high rates of receipt of HCC-specific therapy and improving patient survival.

Hepatitis E prevalence and infection in solid-organ transplant recipients in the United States.

Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis worldwide. An increased risk for HEV infection has been reported in organ-transplant recipients, mainly from Europe. Prospective data on HEV prevalence in the United States (U.S.) organ transplant population are limited. To determine the prevalence and factors associated with HEV infection among solid organ transplant-recipients, we conducted a prospective, cross-sectional, multicentre study among transplant-recipients and age- and organ-matched waitlist patients. Participants answered a risk-exposure questionnaire and were tested for HEV-RNA (in-house PCR), HEV-IgG, and IgM (ELISA, Wantai). Among 456 participants, 224 were transplant-recipients, and 232 were waitlist patients. The mean age was 58 years, 35% female, and 74% White. HEV seroprevalence of the entire cohort was 20.2% and associated with older age (p < 0.0001) and organ transplantation (p = 0.02). The HEV seropositivity was significantly higher among transplant-recipients compared with waitlist patients (24% vs. 16.4%, p = 0.042). Among transplant recipients, relative-risk of being HEV seropositive increased with older age (RR = 3.4 [1.07-10.74] in patients >70 years compared with ≤50 years, p = 0.037); history of graft hepatitis (2.2 [1.27-3.72], p = 0.005); calcineurin inhibitor use (RR = 1.9 [1.03-3.34], p = 0.02); and kidney transplantation (2.4 [1.15-5.16], p = 0.02). HEV-RNA, genotype 3 was detected in only two patients (0.4%), both transplant-recipients. HEV seroprevalence was higher among transplant-recipients than waitlist patients. HEV should be considered in transplant-recipients presenting with graft hepatitis. Detection of HEV-RNA was rare, suggesting that progression to chronic HEV infection is uncommon in transplant-recipients in the U.S.

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.

Microwave Ablation as Bridging to Liver Transplant for Patients with Hepatocellular Carcinoma: A Single-Center Retrospective Analysis.

PURPOSE: To evaluate the efficacy and safety of microwave (MW) ablation as first-line locoregional therapy (LRT) for bridging patients with hepatocellular carcinoma (HCC) to liver transplant. MATERIALS AND METHODS: This retrospective study evaluated 88 patients who received percutaneous MW ablation for 141 tumors as first-line LRT for HCC and who were listed for liver transplantation at a single medical center between 2011 and 2019. The overall survival (OS) rate statuses after liver transplant, waitlist retention, and disease progression were evaluated using the Kaplan-Meier techniques. RESULTS: Among the 88 patients (72 men and 16 women; mean age, 60 years; Model for End-Stage Liver Disease score, 11.2) who were listed for transplant, the median waitlist time was 9.4 months (interquartile range, 5.5-18.9). Seventy-one (80.7%) patients received transplant after a median waitlist time of 8.5 months. Seventeen (19.3%) patients were removed from the waitlist; of these, 4 (4.5%) were removed because of tumors outside of the Milan criteria (HCC-specific dropout). No difference in tumor size or alpha-fetoprotein was observed in the transplanted versus nontransplanted patients at the time of ablation (2.1 vs 2.1 cm and 34.4 vs 34.7 ng/mL for transplanted vs nontransplanted, respectively; P > .05). Five (5.1%) of the 88 patients experienced adverse events after ablation; however, they all recovered. There were no cases of tract seeding. The local tumor progression (LTP) rate was 7.2%. The OS status after liver transplant at 5 years was 76.7%, and the disease-specific survival after LTP was 89.6%, with a median follow-up of 61 months for all patients. CONCLUSIONS: MW ablation appears to be safe and effective for bridging patients with HCC to liver transplant without waitlist removal from seeding, adverse events, or LTP.

Psychosocial Evaluation in Liver Transplantation for Patients with Alcohol-Related Liver Disease.

Content available: Author Interview and Audio Recording.

Clinical, histological and molecular profiling of different stages of alcohol-related liver disease.

OBJECTIVE: Alcohol-related liver disease (ALD) ranges from never-decompensated ALD (ndALD) to the life-threatening decompensated phenotype, known as alcohol-related hepatitis (AH). A multidimensional study of the clinical, histological and molecular features of these subtypes is lacking. DESIGN: Two large cohorts of patients were recruited in an international, observational multicentre study: a retrospective cohort of patients with ndALD (n=110) and a prospective cohort of patients with AH (n=225). Clinical, analytical, immunohistochemistry and hepatic RNA microarray analysis of both disease phenotypes were performed. RESULTS: Age and mean alcohol intake were similar in both groups. AH patients had greater aspartate amino transferase/alanine amino transferase ratio and lower gamma-glutamyl transferase levels than in ndALD patients. Patients with AH demonstrated profound liver failure and increased mortality. One-year mortality was 10% in ndALD and 50% in AH. Histologically, steatosis grade, ballooning and pericellular fibrosis were similar in both groups, while advanced fibrosis, Mallory-Denk bodies, bilirubinostasis, severe neutrophil infiltration and ductular reaction were more frequent among AH patients. Transcriptome analysis revealed a profound gene dysregulation within both phenotypes when compare to controls. While ndALD was characterised by deregulated expression of genes involved in matrisome and immune response, the development of AH resulted in a marked deregulation of genes involved in hepatocyte reprogramming and bile acid metabolism. CONCLUSIONS: Despite comparable alcohol intake, AH patients presented with worse liver function compared with ndALD patients. Bilirubinostasis, severe fibrosis and ductular reaction were prominent features of AH. AH patients exhibited a more profound deregulation of gene expression compared with ndALD patients.

Psychosocial Assessment Rather Than Severity of Liver Failure Dominates Selection for Liver Transplantation in Patients With Alcohol-Related Liver Disease.

The Stanford Integrated Psychosocial Assessment for Transplant (SIPAT) is a validated interview tool to assess psychosocial well-being in candidates for solid organ transplants, with higher scores indicating greater vulnerability. We hypothesized that patients with alcohol-related liver disease (ALD) undergoing liver transplantation (LT) evaluation would have higher SIPAT scores than candidates with non-ALD, but that only patients with ALD who have low scores would be selected. We analyzed retrospectively consecutive adults undergoing LT evaluation from June 2018 to December 2019. Comparisons between patients with ALD and patients with non-ALD were made using the nonparametric Wilcoxon rank sum test plus a multivariate analysis to determine independent predictors for approval. In the study cohort of 358 patients, there were 199 (56%) patients with ALD with a mean age of 55 years, and 133 (67%) were men. There were 159 (44%) patients with non-ALD with a mean age of 57 years, and 95 (60%) were men. Mean Model for End-Stage Liver Disease-sodium scores were similar for selected versus not selected patients with ALD (25 versus 25.6) and selected versus not selected patients with non-ALD (18.3 versus 17.4), although the ALD group had substantially higher Model for End-Stage Liver Disease scores. Patients with ALD had higher mean SIPAT composite and individual domain scores compared with their non-ALD counterparts. SIPAT scores were not affected by age or sex. Proportionately more candidates with non-ALD were selected compared to candidates with ALD (68% versus 42%; P < 0.001; odds ratio for approval of non-ALD versus ALD, 2.9; 95% confidence interval, 1.8-4.7; P < 0.001). Composite SIPAT scores were lower in the selected versus nonselected in both ALD and non-ALD groups, although the SIPAT scores were significantly higher in selected patients with ALD (median, 39) than selected patients with non-ALD (median, 23; P = 0.001). Psychosocial assessment has a greater influence than acuity of liver failure on the selection of patients with ALD for LT listing, whereas psychosocial assessment has a minor influence on the selection of non-ALD candidates.

Recovery and outcomes of patients denied early liver transplantation for severe alcohol-associated hepatitis.

BACKGROUND AND AIMS: Liver transplantation (LT) in alcohol-associated hepatitis (AH) remains controversial, in part because spontaneous recovery (SR) can occur. There is a paucity of data on SR in patients with severe AH who undergo LT evaluation. The purpose of this study was to determine factors associated with SR and survival in patients with severe AH who undergo LT evaluation. APPROACH AND RESULTS: This is a retrospective study of ALD patients with Model for End-Stage Liver Disease (MELD) >25 and <90 days abstinence who underwent LT evaluation at a single center between 2012 and 2018. One hundred forty-four patients (median age, 45.5 years; 68.1% male) were included. Forty-nine (34%) underwent LT and 95 (66%) patients did not undergo LT, and of those, 34 (23.6%) experienced SR. Factors associated with recovery were younger age (OR, 0.92; p = 0.004), lower index international normalized ratio (INR; 0.31; p = 0.03), and lower peak MELD (OR, 0.83; p = 0.02). Only 7 patients (20.6%) achieved a compensated state with a MELD <15 and absence of therapy for ascites or HE. Survival was improved in patients who underwent early LT when compared to SR. Survival was impaired in SR following relapse to alcohol use when compared to SR patients who abstained and LT recipients. Among all 6-month survivors of AH, alcohol use trended toward an association with mortality (HR, 2.05; p = 0.17), but only LT was associated with decreased mortality risk (HR, 0.20; p = 0.005). CONCLUSIONS: SR from AH after LT evaluation is associated with age, index INR, and lower peak MELD. Most recovered patients continue to experience end-stage complications. LT is the only factor associated with lower mortality.

Patterns of Alcohol Use After Early Liver Transplantation for Alcoholic Hepatitis.

BACKGROUND & AIMS: Early liver transplantation (LT) for alcoholic hepatitis (AH) is lifesaving but concerns regarding return to harmful alcohol use remain. We sought to identify distinct patterns of alcohol use post-LT to inform pre-LT candidate selection and post-LT addiction care. METHODS: Detailed post-LT alcohol use data was gathered retrospectively from consecutive patients with severe AH at 11 ACCELERATE-AH sites from 2006-2018. Latent class analysis identified longitudinal patterns of alcohol use post-LT. Logistic and Cox regression evaluated associations between patterns of alcohol use with pre-LT variables and post-LT survival. A microsimulation model estimated the effect of selection criteria on overall outcomes. RESULTS: Of 153 LT recipients, 1-, 3-, and 5-year survival were 95%, 88% and 82%. Of 146 LT recipients surviving to home discharge, 4 distinct longitudinal patterns of post-LT alcohol use were identified: Pattern 1 [abstinent](n = 103; 71%), pattern 2 [late/non-heavy](n = 9; 6.2%), pattern 3 [early/non-heavy](n = 22; 15%), pattern 4 [early/heavy](n = 12; 8.2%). One-year survival was similar among the 4 patterns (100%), but patients with early post-LT alcohol use had lower 5-year survival (62% and 53%) compared to abstinent and late/non-heavy patterns (95% and 100%). Early alcohol use patterns were associated with younger age, multiple prior rehabilitation attempts, and overt encephalopathy. In simulation models, the pattern of post-LT alcohol use changed the average life-expectancy after early LT for AH. CONCLUSIONS: A significant majority of LT recipients for AH maintain longer-term abstinence, but there are distinct patterns of alcohol use associated with higher risk of 3- and 5-year mortality. Pre-LT characteristics are associated with post-LT alcohol use patterns and may inform candidate selection and post-LT addiction care.

Trajectory of Serum Bilirubin Predicts Spontaneous Recovery in a Real-World Cohort of Patients With Alcoholic Hepatitis.

BACKGROUND AND AIMS: Alcoholic hepatitis (AH) is a severe condition with poor short-term prognosis. Specific treatment with corticosteroids slightly improves short-term survival but is associated with infection and is not used in many centers. A reliable method to identify patients who will recover spontaneously will minimise the numbers of patients who experience side effects of available treatments. METHODS: We analysed the trajectory of serum bilirubin concentration over the course of hospital admissions in patients with AH to predict spontaneous survival and the need for treatment. RESULTS: data from 426 patients were analysed. Based on bilirubin trajectory, patients were categorized into three groups: 'fast fallers' (bilirubin <0.8 x admission value at day 7), 'static' (bilirubin of >0.9 - <1.2 x admission value) and 'rapid risers' (bilirubin of ≥1.2 x admission bilirubin). Fast fallers had significantly better 90-day survival compared to other groups (log rank p < .001), and showed no benefit of corticosteroid therapy (OR for survival at 28 days of treatment, 0.94, 95% CI 0.06 - 8.41). These findings remained even amongst patients with severe disease based on initial DF, GAHS or MELD scores. CONCLUSIONS: We present an intuitive method of classifying patients with AH based on the trajectory of bilirubin over the first week of admission. It is complimentary to existing scores that identify candidates for corticosteroid treatment or assess response to treatment. This method identifies a group of patients with AH who recover spontaneously and can avoid corticosteroid therapy.