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Background and Aims: Alcohol-associated hepatitis (AH) poses significant short-term mortality. Existing prognostic models lack precision for 90-day mortality. Utilizing artificial intelligence in a global cohort, we sought to derive and validate an enhanced prognostic model., Approach and Results: The Global AlcHep initiative, a retrospective study across 23 centers in 12 countries, enrolled patients with AH per National Institute for Alcohol Abuse and Alcoholism criteria. Centers were partitioned into derivation (11 centers, 860 patients) and validation cohorts (12 centers, 859 patients). Focusing on 30 and 90-day postadmission mortality, 3 artificial intelligence algorithms (Random Forest, Gradient Boosting Machines, and eXtreme Gradient Boosting) informed an ensemble model, subsequently refined through Bayesian updating, integrating the derivation cohort's average 90-day mortality with each center's approximate mortality rate to produce posttest probabilities. The ALCoholic Hepatitis Artificial INtelligence Ensemble score integrated age, gender, cirrhosis, and 9 laboratory values, with center-specific mortality rates. Mortality was 18.7% (30 d) and 27.9% (90 d) in the derivation cohort versus 21.7% and 32.5% in the validation cohort. Validation cohort 30 and 90-day AUCs were 0.811 (0.779-0.844) and 0.799 (0.769-0.830), significantly surpassing legacy models like Maddrey's Discriminant Function, Model for End-Stage Liver Disease variations, age-serum bilirubin-international normalized ratio-serum Creatinine score, Glasgow, and modified Glasgow Scores ( p < 0.001). ALCoholic Hepatitis Artificial INtelligence Ensemble score also showcased superior calibration against MELD and its variants. Steroid use improved 30-day survival for those with an ALCoholic Hepatitis Artificial INtelligence Ensemble score > 0.20 in both derivation and validation cohorts., Conclusions: Harnessing artificial intelligence within a global consortium, we pioneered a scoring system excelling over traditional models for 30 and 90-day AH mortality predictions. Beneficial for clinical trials, steroid therapy, and transplant indications, it's accessible at: https://aihepatology.shinyapps.io/ALCHAIN/ ., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background & Aims: The development of acute kidney injury (AKI) in the setting of alcohol-associated hepatitis (AH) portends a poor prognosis. Whether the presence of AH itself drives worse outcomes in patients with cirrhosis and AKI is unknown., Methods: Retrospective cohort study of 11 hospital networks of consecutive adult patients admitted in 2019 with cirrhosis and AKI. AKI phenotypes, clinical course, and outcomes were compared between AH and non-AH groups., Results: A total of 2062 patients were included, of which 303 (15%) had AH, as defined by National Institute on Alcohol Abuse and Alcoholism (NIAAA) criteria. Patients with AH, compared to those without, were younger and had higher Model for End-stage Liver Disease-Sodium (MELD-Na) scores on admission. AKI phenotypes significantly differed between groups (p < 0.001) with acute tubular necrosis occurring more frequently in patients with AH. Patients with AH reached more severe peak AKI stage, required more renal replacement therapy, and had higher 90-day cumulative incidence of death (45% [95% CI: 39%-51%] vs. 38% [95% CI: 35%-40%], p = 0.026). Using no AH as reference, the unadjusted sHR for 90-day mortality was higher for AH (sHR: 1.24 [95% CI: 1.03-1.50], p = 0.024), but was not significant when adjusting for MELD-Na, age and sex. However, in patients with hepatorenal syndrome, AH was an independent predictor of 90-day mortality (sHR: 1.82 [95% CI: 1.16-2.86], p = 0.009)., Conclusions: Hospitalised patients with cirrhosis and AKI presenting with AH had higher 90-day mortality than those without AH, but this may have been driven by higher MELD-Na rather than AH itself. However, in patients with hepatorenal syndrome, AH was an independent predictor of mortality., (© 2024 John Wiley & Sons Ltd.)

Acute on chronic liver failure (ACLF) is a unique disease process associated with significant short-term mortality wherein patients with either chronic liver disease or cirrhosis suffer rapid decompensation in hepatic function accompanied by extrahepatic organ failures. Alcohol-associated hepatitis (AH) is a common precipitant of ACLF and has been shown to uniquely affect the pathophysiology of systemic and hepatic immune responses in patients with ACLF. Treatment of AH-associated ACLF includes supportive measures as well as treatment directed at AH; however, AH-directed therapies unfortunately remain limited and are of suboptimal efficacy., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Alcohol-associated hepatitis (AH) is among the deadliest liver diseases, but its incidence is poorly defined. The aim of our study was to define the incidence of AH meeting the National Institute on Alcohol Abuse and Alcoholism criteria and to identify risk factors for AH., Methods: We conducted a retrospective cohort study using the Rochester epidemiology project database on adult patients hospitalized with AH between January 1, 2000 and December 31, 2018. Patients were screened using ICD-9 codes and then included if they met the National Institute on Alcohol Abuse and Alcoholism criteria on manual chart review. Baseline demographics, comorbidities, access to care, liver-related complications, and outcomes were obtained. The HOUsing-based index of SocioEconomic status index was used to measure socioeconomic status. Incidence rates were calculated in cases per 100,000 person-years of follow-up., Results: Among 204 patients, the cumulative AH incidence was 6.8 per 100,000 person-years. Between 2000-2004 and 2015-2018, AH incidence among males increased from 8.4 to 14.7 per 100,000 py, whereas AH incidence among females increased by 7-fold from 0.8 to 5.9 per 100,000 py. Such increases among females were accompanied by increases in comorbid depression and anxiety. The proportion of patients with AH in the lower socioeconomic status quartiles increased from 62.9% between 2000 and 2004 to 73.3% between 2015 and 2019., Conclusions: The incidence of AH is increasing rapidly, especially among females and individuals of lower socioeconomic status. There are areas of unmet need in preventative measures and treatments for comorbid psychiatric disorders in patients at high risk of AH., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Objective: To develop a new scoring system that more accurately predicts 30-day mortality in patients with alcohol-associated hepatitis (AH)., Methods: A cohort of consecutive adults diagnosed with AH at a single academic center from January 1, 1998, to December 31, 2018, was identified for model derivation. Multivariate logistic regression was used to create a new scoring system to predict 30-day mortality. External validation of this score was performed on a multicenter retrospective cohort., Results: In the derivation cohort of 266 patients, the 30-day mortality rate was 19.2%. The following variables were found to be significantly associated with mortality on multivariate analysis: age (P=.002), blood urea nitrogen (P=.003), albumin (P=.01), bilirubin (P=.02), and international normalized ratio (P=.001). A model incorporating these variables, entitled the Mortality Index for Alcohol-Associated Hepatitis (MIAAH), achieved a C statistic of 0.86. Comparison of the accuracy of the MIAAH to existing prognostic models, including the Model for End-Stage Liver Disease and Maddrey Discriminant Function, showed that the highest concordance was achieved by the MIAAH and that this difference was significant. In the validation cohort of 249 patients, the MIAAH C statistic decreased to 0.73 and was found to be significantly superior to the Maddrey Discriminant Function but not to the Model for End-Stage Liver Disease., Conclusion: The MIAAH competes with the current prognostication models and is at a minimum as accurate as these existing scores in identifying patients with AH at high risk of short-term mortality. Furthermore, the MIAAH demonstrates advantageous performance characteristics in its ability to increasingly accurately dichotomize patients into those at highest risk of death and those likely to survive., (Copyright © 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Acute kidney injury is seen in approximately 30% of patients with severe alcohol-associated hepatitis (AH) and is associated with increased mortality. Controversy exists surrounding initiation of renal replacement therapy (RRT) in these patients, as most are ineligible for early transplantation., Aims: The primary aim was to identify predictors of survival and identify patients who may benefit from RRT as a bridge to transplant or recovery., Methods: A retrospective multicenter cohort of adult patients with AH, who received RRT, was developed, including patients from two North American and one European liver transplant centers., Results: Fifty-five patients were included. Survival was 26/55 (47.3%) at 30 days, 17/55 (30.9%) at 3 months, and 15/55 (27.2%) at 6 months. Of those who survived 6 months, 2/15 (13.3%) received simultaneous liver and kidney transplantation, 11/15 (73.3%) had spontaneous recovery of kidney function, and 2/15 (13.3%) remained on RRT. Of patients who survived at least 3 months, 8/17 (47%) completed addiction treatment. Predictors of mortality were pre-RRT MELD (OR 1.10, 1.02-1.19) and pre-RRT MELD-Na (OR 1.14, 1.03-1.27). Pre-RRT MELD-Na < 35 was associated with lower 6-month mortality (OR 0.23, 0.06 - 0.81). Of patients with pre-RRT MELD-Na < 35, 50% survived 6 months compared to 18% of patients with pre-RRT MELD-Na ≥ 35., Conclusions: Although RRT has a limited role in patients with decompensated cirrhosis, ineligible for transplant, it may be used in select patients with AH. This may allow for spontaneous recovery with alcohol abstinence or completion of addiction treatment prior to transplant., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Alcohol-associated hepatitis (AAH) is a severe form of liver injury with mortality as high as 30%-40% at 90 days. As a result of altered immune function in AAH, bacterial infections are common and are associated with poor outcomes. However, determining the risk and subsequent development of infection in patients with AAH remain challenging. We performed a retrospective study of consecutive patients admitted with a diagnosis of AAH at two independent tertiary centers from 1998 to 2018 (test cohort, n = 286) who developed infections following hospitalization. The diagnosis of AAH was confirmed by manual chart review according to the recent National Institute on Alcohol Abuse and Alcoholism definition. Infections were categorized by location and time of diagnosis as hospital-acquired infection (48 hours after admission until discharge) and posthospital infections (up to 6 months following discharge). The cohort was 66% men, and the median age was 48 (21-83) years. Corticosteroids were used in 32% of all patients with AAH. The overall infection rate was 24%. Of those with infections, 46% were hospital acquired and 54% were acquired after hospitalization. Variables found to be significant risk factors for bacterial infection included the presence of ascites on admission (hazard ratio [HR], 2.06), corticosteroid administration (HR, 1.70), Model for End-Stage Liver Disease (MELD) >23 (HR, 2.61), and white blood cell (WBC) count on admission per point (HR, 1.02). Conclusion: In this multicenter cohort study of patients hospitalized with AAH, MELD score, ascites, WBC count, and use of corticosteroids were identified as significant predictors of the development of bacterial infection. We created a novel predictive equation that may be used to aid in the identification of patients with AAH at high risk of infection., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background and Aims: Alcoholic hepatitis (AH) is diagnosed by clinical criteria, although several objective scores facilitate risk stratification. Extracellular vesicles (EVs) have emerged as biomarkers for many diseases and are also implicated in the pathogenesis of AH. Therefore, we investigated whether plasma EV concentration and sphingolipid cargo could serve as diagnostic biomarkers for AH and inform prognosis to permit dynamic risk profiling of AH subjects., Approach and Results: EVs were isolated and quantified from plasma samples from healthy controls, heavy drinkers, and subjects with end-stage liver disease (ESLD) attributed to cholestatic liver diseases and nonalcoholic steatohepatitis, decompensated alcohol-associated cirrhosis (AC), and AH. Sphingolipids were quantified by tandem mass spectroscopy. The median plasma EV concentration was significantly higher in AH subjects (5.38 × 10 11 /mL) compared to healthy controls (4.38 × 10 10 /mL; P < 0.0001), heavy drinkers (1.28 × 10 11 /mL; P < 0.0001), ESLD (5.35 × 10 10 /mL; P < 0.0001), and decompensated AC (9.2 × 10 10 /mL; P < 0.0001) disease controls. Among AH subjects, EV concentration correlated with Model for End-Stage Liver Disease score. When EV counts were dichotomized at the median, survival probability for AH subjects at 90 days was 63.0% in the high-EV group and 90.0% in the low-EV group (log-rank P value = 0.015). Interestingly, EV sphingolipid cargo was significantly enriched in AH when compared to healthy controls, heavy drinkers, ESLD, and decompensated AC (P = 0.0001). Multiple sphingolipids demonstrated good diagnostic and prognostic performance as biomarkers for AH., Conclusions: Circulating EV concentration and sphingolipid cargo signature can be used in the diagnosis and differentiation of AH from heavy drinkers, decompensated AC, and other etiologies of ESLD and predict 90-day survival permitting dynamic risk profiling., (© 2020 by the American Association for the Study of Liver Diseases.)

Background and Aims: Interleukin-22 has beneficial effects on inflammation and impaired hepatic regeneration that characterize alcohol-associated hepatitis (AH). F-652 is a recombinant fusion protein of human interleukin-22 and immunoglobulin G2 fragment crystallizable. This study aims to assess the safety and efficacy signals of F-652 in patients with moderate and severe AH., Approach and Results: A phase-2 dose-escalating study was carried out. F-652 (10 μg/kg, 30 μg/kg, or 45 μg/kg) administered on days 1 and 7 was tested in 3 patients each with moderate (Model for End-Stage Liver Disease [MELD] scores: 11-20) and severe AH (MELD scores: 21-28). Safety was defined by absence of serious adverse events and efficacy was assessed by Lille score, changes in MELD score, and serum bilirubin and aminotransferases at days 28 and 42. Three independent propensity-matched comparator patient cohorts were used. Plasma extracellular vesicles and multiplex serum cytokines were measured to assess inflammation and hepatic regeneration. Eighteen patients (9 moderate and 9 severe AH) were enrolled, 66% were male, and the mean age was 48 years. The half-life of F-652 following the first dose was 61-85 hours. There were no serious adverse events leading to discontinuation. The MELD score and serum aminotransferases decreased significantly at days 28 and 42 from baseline (P < 0.05). Day-7 Lille score was 0.45 or less in 83% patients as compared with 6%, 12%, and 56% among the comparator cohorts. Extracellular vesicle counts decreased significantly at day 28 (P < 0.013). Cytokine inflammatory markers were down-regulated, and regeneration markers were up-regulated at days 28 and 42., Conclusions: F-652 is safe in doses up to 45 μg/kg and associated with a high rate of improvement as determined by Lille and MELD scores, reductions in markers of inflammation and increases in markers of hepatic regeneration. This study supports the need for randomized placebo-controlled trials to test the efficacy of F-652 in AH., (© 2019 by the American Association for the Study of Liver Diseases.)

Background & Aims: Patients admitted to the hospital for alcoholic hepatitis (AH) are at increased risk of readmission and death. We aimed to identify factors associated with readmission, alcohol relapse, and mortality., Methods: We performed a retrospective analysis of consecutive patients admitted with AH to a tertiary care hospital from 1999 through 2016 (test cohort, n = 135). We validated our findings in a prospective analysis of patients in a multi-center AH research consortium from 2013 through 2017 (validation cohort, n = 159). Alcohol relapse was defined as any amount of alcohol consumption within 30 days after hospital discharge. Early alcohol rehabilitation was defined as residential or outpatient addiction treatment or mutual support group participation within 30 days after hospital discharge., Results: Thirty-day readmission rates were 30% in both cohorts. Alcohol relapse rates were 37% in the test and 34% in the validation cohort. Following hospital discharge, 27 patients (20%) in the test cohort and 19 patients (16%) in the validation cohort attended early alcohol rehabilitation. There were 53 deaths (39%) in a median follow-up time of 2.8 years and 42 deaths (26%) in a median follow-up time of 1.3 years, respectively. In the test cohort, early alcohol rehabilitation reduced odds for 30-day readmission (adjusted odds ratios [AOR] 0.16; 95% CI, 0.04-0.65; P = .01), 30-day alcohol relapse (AOR, 0.11; 95% CI, 0.02-0.53; P < .001), and death (adjusted hazard ratio [AHR], 0.20; 95% CI, 0.05-0.56; P = .001). In the validation cohort early alcohol rehabilitation reduced odds for 30-day readmission (AOR, 0.30; 95% CI, 0.09-0.98; P = .04), 30-day alcohol relapse (AOR 0.09; 95% CI, 0.01-0.73; P = .02), and death (AHR, 0.20; 95% CI, 0.01-0.94; P = .04). A model combining alcohol rehabilitation and bilirubin identified patients with readmission to the hospital within 30 days with an area under the receiver operating characteristic curve of 0.73., Conclusions: In an analysis from two cohorts of patients admitted with AH, early alcohol rehabilitation can reduce risk of hospital readmission, alcohol relapse, and death and should be considered as a quality indicator in AH hospitalization treatment., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Identifying patients at high risk for acute kidney injury (AKI) during hospitalization among patients admitted with severe alcoholic hepatitis (AH) is an unmet clinical need. We performed a multicentric prospective cohort study using data from 4 different cohorts on well-characterized patients hospitalized with severe AH. Data collected on 773 AH patients from 4 cohorts across the globe were randomly split into test (n = 390) and validation (n = 383) cohorts. We found that 32% of the patients developed inpatient AKI in the test cohort. Approximately 60% of patients met criteria for systemic inflammatory response syndrome (SIRS) at admission. Hepatic encephalopathy, SIRS, and Model for End-Stage Liver Disease score at admission predicted inpatient AKI with odds ratios of 3.86, 2.24, and 1.14, respectively. The AKI risk score developed using these predictors stratified risk of inpatient AKI to low (score <3), moderate (3-4), and high (>4). These findings were replicated in the validation cohort. In the whole study cohort, patients with AKI had a lower 90-day survival (53% versus 77%; P < 0.001). Those with AKI risk score of >4 had significantly lower 90-day survival as compared with those with risk scores between 3 and 4 and <3 (47% versus 68% versus 88%; P < 0.001). In conclusion, AKI occurs frequently in AH patients and negatively impacts short-term mortality. The AKI risk score is useful in identifying patients at high risk for inpatient AKI and may be useful for developing new therapeutic strategies to prevent AKI in patients with AH., (Copyright © 2018 by the American Association for the Study of Liver Diseases.)

Purpose of Review: The majority of liver transplantation centers have required patients with alcohol-induced liver disease to demonstrate a period of abstinence (generally 6 months' duration) to qualify for transplant listing. This requirement has excluded patients with alcoholic hepatitis from transplant consideration. Since 2011, several studies have examined the outcomes of patients undergoing liver transplantation with brief abstinence as a lifesaving intervention for alcoholic hepatitis. This review includes each of the recent studies and discusses their implications for general transplant practice., Recent Findings: A Medical Literature Analysis and Retrieval System search revealed five published studies - three prospective and two retrospective - pertaining to liver transplantation for alcoholic hepatitis. Among patients with medication-nonresponsive alcoholic hepatitis, those who underwent transplantation had superior survival. Liver recipients with alcoholic hepatitis had comparable survival to those with 6 or more months of abstinence. Their relapse rates were not statistically different in the short term over those transplanted with longer abstinence, although some patients in each prospective cohort relapsed to drinking despite narrow inclusion criteria and extensive pretransplant staff reviews and posttransplant surveillance., Summary: Liver transplantation is a reasonable treatment consideration for highly selective cases of alcoholic hepatitis. Further research is needed to refine inclusion criteria, address posttransplant relapse prevention interventions, and monitor long-term outcomes.