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INTRODUCTION: Several scoring systems predict mortality in alcohol-associated hepatitis (AH), including the Maddrey discriminant function (mDF) and model for end-stage liver disease (MELD) score developed in the United States, Glasgow alcoholic hepatitis score in the United Kingdom, and age, bilirubin, international normalized ratio, and creatinine score in Spain. To date, no global studies have examined the utility of these scores, nor has the MELD-sodium been evaluated for outcome prediction in AH. In this study, we assessed the accuracy of different scores to predict short-term mortality in AH and investigated additional factors to improve mortality prediction. METHODS: Patients admitted to hospital with a definite or probable AH were recruited by 85 tertiary centers in 11 countries and across 3 continents. Baseline demographic and laboratory variables were obtained. The primary outcome was all-cause mortality at 28 and 90 days. RESULTS: In total, 3,101 patients were eligible for inclusion. After exclusions (n = 520), 2,581 patients were enrolled (74.4% male, median age 48 years, interquartile range 40.9-55.0 years). The median MELD score was 23.5 (interquartile range 20.5-27.8). Mortality at 28 and 90 days was 20% and 30.9%, respectively. The area under the receiver operating characteristic curve for 28-day mortality ranged from 0.776 for MELD-sodium to 0.701 for mDF, and for 90-day mortality, it ranged from 0.773 for MELD to 0.709 for mDF. The area under the receiver operating characteristic curve for mDF to predict death was significantly lower than all other scores. Age added to MELD obtained only a small improvement of AUC. DISCUSSION: These results suggest that the mDF score should no longer be used to assess AH's prognosis. The MELD score has the best performance in predicting short-term mortality. [ABSTRACT FROM AUTHOR]

Background/Objectives: Bacterial infections (BI) are a major cause of mortality in patients with alcohol-associated hepatitis (AH); however, only a few studies have investigated BI in AH in the last decade. Therefore, we aimed to assess the features and outcomes of BI in patients with AH. Methods: This observational descriptive study included patients with AH admitted to a tertiary academic hospital between 2016 and 2021. Clinical and complete microbiological data were recorded and complications, including acute-on-chronic liver failure (ACLF), and mortality over 90-days were compared between infected and noninfected patients. Results: Overall, 115 patients with AH were recruited and 75 had severe AH; among them, 66 started corticosteroid treatment. We identified 69 cases of BI in 44 patients; the incidence of BI upon hospital discharge was 32.2%, which reached 38.2% at 90 days. The predominant infection site was the chest (35%). Among the identified bacteria (52.1%), half were gram positive and half gram negative. A low rate of multidrug-resistant bacteria (14%) was also noted. Infected patients during hospitalization ( n = 37) exhibited higher rates of hepatic decompensation and ACLF ( p = 0.001) and lower survival (81.8% vs. 95.8%, p = 0.015) than did noninfected patients ( n = 78). In-hospital infected patients (n = 22) exhibited worse survival (72.7%) than did those infected upon admission (93.3%) or noninfected patients (94.9%) ( p = 0.009). Corticosteroid-treated patients displayed a nonsignificant increase in the total number of BI; however, without greater mortality. Conclusions: BI were common in our cohort of patients with AH. Patients with in-hospital infections commonly experienced serious complications, including high ACLF and death rates. Infections diagnosed upon admission were treated without affecting survival.

Background and Aims: Alcohol relapse after surviving an episode of alcohol-associated hepatitis (AH) is common. However, the clinical features, risk factors, and prognostic implications of recurrent alcohol-associated hepatitis (RAH) are not well described., Approach and Results: A registry-based study was done of patients admitted to 28 Spanish hospitals for an episode of AH between 2014 and 2021. Baseline demographics and laboratory variables were collected. Risk factors for RAH were investigated using Cox regression analysis. We analyzed the severity of the index episodes of AH and compared it to that of RAH. Long-term survival was assessed by Kaplan-Meier curves and log-rank tests. A total of 1118 patients were included in the analysis, 125 (11%) of whom developed RAH during follow-up (median: 17 [7-36] months). The incidence of RAH in patients resuming alcohol use was 22%. The median time to recurrence was 14 (8-29) months. Patients with RAH had more psychiatric comorbidities. Risk factors for developing RAH included age <50 years, alcohol use >10 U/d, and history of liver decompensation. RAH was clinically more severe compared to the first AH (higher MELD, more frequent ACLF, and HE). Moreover, alcohol abstinence during follow-up was less common after RAH (18% vs. 45%, p <0.001). Most importantly, long-term mortality was higher in patients who developed RAH (39% vs. 21%, p = 0.026), and presenting with RAH independently predicted high mortality (HR: 1.55 [1.11-2.18])., Conclusions: RAH is common and has a more aggressive clinical course, including increased mortality. Patients surviving an episode of AH should undergo intense alcohol use disorder therapy to prevent RAH., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: Alcohol-associated hepatitis (AH) is associated with significant mortality. Model for End-Stage Liver Disease (MELD) score is used to predict short-term mortality and aid in treatment decisions. MELD is frequently updated in the course of AH. However, once the most updated MELD is known, it is uncertain if previous ones still have prognostic value, which might be relevant for transplant allocation and trial design. We aimed to investigate the predictive performance of updated MELDs in a prospectively collected cohort of patients with AH by the InTeam consortium., Methods: Three hundred seven patients (with 859 MELD values within 60 d of admission) fulfilled the inclusion criteria. The main endpoint was time to death or transplant up to 90 days. We used a joint model approach to assess the predictive value of updated MELDs., Results: Updated MELD measurements had a strong prognostic value for death/transplant (HR: 1.20, 95% CI: 1.14-1.27) (p < 0.0001). Previous MELD values did not add predictive value to the most current MELD. We also showed that MELD at day 28 (MELD28) had a significant predictive value for subsequent mortality/transplant in a landmark analysis (HR: 1.18, 95% CI: 1.12-1.23). We show that the use of an ordinal scale including death, transplant, and MELD28 as a trial outcome could substantially reduce the sample size required to demonstrate short-term benefit of an intervention., Conclusion: We show that updated MELDs during the trajectory of AH predict subsequent mortality or the need for transplant. MELD28 inclusion in an ordinal outcome (together with death or transplant) could increase the efficiency of randomized controlled trials., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background and Aims: Alcohol use disorder has been reported in patients undergoing bariatric procedures, but the pattern of alcohol consumption has not been evaluated. We investigated the prevalence, risk factors, and impact of binge drinking (BD) at the time of surgery and during follow-up., Methods: A prospective, longitudinal study of subjects undergoing bariatric surgery was included in the LABS-2 registry between 2006 and 2009. Participants with AUDIT questionnaire at the time of surgery and a minimum of 12 months follow-up were included. BD was defined as consuming ≥5 drinks on at least 1 occasion in the previous month. Liver biopsies were obtained during bariatric procedures in not all cases. Survival analysis was performed with the adjusted Cox regression model and competing risk., Results: A total of 2257 subjects were included, with a median follow-up of 79 months. The prevalence of BD at time of surgery was 12%, and it raised up to 23% during follow-up. Patients with BD predominantly had a binge eating disorder (OR=1.35 [95% CI: 1.04-1.76]), regularly consumed fast food [OR=1.4 (95% CI: 1.07-1.85)] and used other drugs (OR=2.65 [95% CI: 1.74-4.04]). Within liver biopsies evaluation, BD showed higher hepatic iron deposits (OR=3.00 [95% CI: 1.25-7.21]). BD at the time of surgery was associated with a higher risk of BD during follow-up (OR=10.49 [95% CI: 7.86-14.00]) and long-term mortality (HR: 3.21 [95% CI: 1.67-6.18]). Specific causes of death in these patients with BD were liver disease (p=0.020), suicide (p=0.015), neoplasms (p=0.034), and respiratory (p=0.025)., Conclusions: The prevalence of BD in patients undergoing bariatric surgery is high and increases the risk of postoperative liver disease, suicides, and long-term mortality., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Chronic hepatitis E virus (HEV) in persons with immune impairment has a progressive course leading to a rapid progression to liver cirrhosis. However, prospective data on chronic HEV is scarce. The aim of this study was to determine the prevalence and risk factors for chronic HEV infection in subjects with immune dysfunction and elevated liver enzymes., Patients and Methods: CHES is a multicenter prospective study that included adults with elevated transaminases values for at least 6 months and any of these conditions: transplant recipients, HIV infection, haemodialysis, liver cirrhosis, and immunosuppressant therapy. Anti-HEV IgG/IgM (Wantai ELISA) and HEV-RNA by an automated highly sensitive assay (Roche diagnostics) were performed in all subjects. In addition, all participants answered an epidemiological survey., Results: Three hundred and eighty-one patients were included: 131 transplant recipients, 115 cirrhosis, 51 HIV-infected subjects, 87 on immunosuppressants, 4 hemodialysis. Overall, 210 subjects were on immunosuppressants. Anti-HEV IgG was found in 94 (25.6%) subjects with similar rates regardless of the cause for immune impairment. HEV-RNA was positive in 6 (1.6%), all of them transplant recipients, yielding a rate of chronic HEV of 5.8% among solid-organ recipients. In the transplant population, only therapy with mTOR inhibitors was independently associated with risk of chronic HEV, whereas also ALT values impacted in the general model., Conclusions: Despite previous abnormal transaminases values, chronic HEV was only observed among solid-organ recipients. In this population, the rate of chronic HEV was 5.8% and only therapy with mTOR inhibitors was independently associated with chronic hepatitis E., (Copyright © 2023. Publicado por Elsevier España, S.L.U.)

Background & Aims: Alcohol-related hepatitis (AH) encompasses a high mortality. AH might be a concomitant event in patients with acute variceal bleeding (AVB). The current study aimed to assess the prevalence of AH in patients with AVB and to compare the clinical outcomes of AH patients to other alcohol-related liver disease (ALD) phenotypes and viral cirrhosis., Methods: Multicentre, observational study including 916 patients with AVB falling under the next categories: AH (n = 99), ALD cirrhosis actively drinking (d-ALD) (n = 285), ALD cirrhosis abstinent from alcohol (a-ALD) (n = 227) and viral cirrhosis (n = 305). We used a Cox proportional hazards model to calculate adjusted hazard ratio (HR) of death adjusted by MELD., Results: The prevalence of AH was 16% considering only ALD patients. AH patients exhibited more complications. Forty-two days transplant-free survival was worse among AH, but statistical differences were only observed between AH and d-ALD groups (84 vs. 93%; p = 0.005), when adjusted by MELD no differences were observed between AH and the other groups. At one-year, survival of AH patients (72.7%) was similar to the other groups; when adjusted by MELD mortality HR was better in AH compared to a-ALD (0.48; 0.29-0.8, p = 0.004). Finally, active drinkers who remained abstinent presented better survival, independently of having AH., Conclusions: Contrary to expected, AH patients with AVB present no worse one-year survival than other patients with different alcohol-related phenotypes or viral cirrhosis. Abstinence influences long-term survival and could explain these counterintuitive results., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The prevalence and impact of alcohol withdrawal syndrome (AWS) in patients with alcohol-associated hepatitis (AH) are unknown. In this study, we aimed to investigate the prevalence, predictors, management, and clinical impact of AWS in patients hospitalized with AH., Methods: A multinational, retrospective cohort study enrolling patients hospitalized with AH at 5 medical centres in Spain and in the USA was performed between January 1st, 2016 to January 31st, 2021. Data were retrospectively retrieved from electronic health records. Diagnosis of AWS was based on clinical criteria and use of sedatives to control AWS symptoms. The primary outcome was mortality. Multivariable models controlling for demographic variables and disease severity were performed to determine predictors of AWS (adjusted odds ratio [OR]) and the impact of AWS condition and management on clinical outcomes (adjusted hazard ratio [HR])., Findings: In total, 432 patients were included. The median MELD score at admission was 21.9 (18.3-27.3). The overall prevalence of AWS was 32%. Lower platelet levels (OR = 1.61, 95% CI 1.05-2.48) and previous history of AWS (OR = 2.09, 95% CI 1.31-3.33) were associated with a higher rate of incident AWS, whereas the use of prophylaxis decreased the risk (OR = 0.58, 95% CI 0.36-0.93). The use of intravenous benzodiazepines (HR = 2.18, 95% CI 1.02-4.64) and phenobarbital (HR = 2.99, 95% CI 1.07-8.37) for AWS treatment were independently associated with a higher mortality. The development of AWS increased the rate of infections (OR = 2.24, 95% CI 1.44-3.49), the need for mechanical ventilation (OR = 2.49, 95% CI 1.38-4.49), and ICU admission (OR = 1.96, 95% CI 1.19-3.23). Finally, AWS was associated with higher 28-day (HR = 2.31, 95% CI 1.40-3.82), 90-day (HR = 1.78, 95% CI 1.18-2.69), and 180-day mortality (HR = 1.54, 95% CI 1.06-2.24)., Interpretation: AWS commonly occurs in patients hospitalized with AH and complicates the hospitalization course. Routine prophylaxis is associated with a lower prevalence of AWS. Prospective studies should determine diagnostic criteria and prophylaxis regimens for AWS management in patients with AH., Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors., Competing Interests: The authors declare no conflict of interest regarding this manuscript., (© 2023 The Authors.)

Background/aims: Bariatric surgery can increase the risk of addictive disorders and nutritional deficiencies. The aim of this study was to evaluate the association between bariatric surgery and alcohol use disorder (AUD), alcohol-related liver disease (ALD), and psychiatric disorders associated with AUD. The impact of vitamin D deficiency in these associations was also investigated., Methods: A cross-sectional study was performed using the National Inpatient Sample database and its ICD-9 codes information. Diagnostic and comorbidity data from hospital discharges were obtained from patients with bariatric surgery and other abdominal surgeries between 2005 and 2015. The two groups were then compared for alcohol-related outcomes after propensity-score matching., Results: The final study cohort included 537,757 patients with bariatric surgery and 537,757 with other abdominal surgeries. The bariatric surgery group had an increased risk of AUD [odds ratio (OR): 1.90; 95% CI: 1.85-1.95], ALD [OR: 1.29; 95% CI: 1.22-1.37], cirrhosis [OR, 1.39; 95% CI: 1.37-1.42], and psychiatric disorders associated with AUD [OR, 3.59; 95% CI: 3.37-3.84]. Vitamin D deficiency did not impact in the association between bariatric surgery and AUD, ALD, or psychiatric disorders associated with AUD., Conclusions: Bariatric surgery is associated with an increased prevalence of AUD, ALD, and psychiatric disorders associated with AUD. These associations appear to be independent from vitamin D deficiency., (© 2023. The Author(s).)

The outcomes of patients with moderate renal impairment and the impact of liver disease etiology on renal function recovery after liver transplant alone (LTA) are largely unknown. We explored whether NAFLD patients with pre-LTA moderate renal dysfunction (GFR 25-45 ml/min/1.73 m 2 ) may be more susceptible to develop post-LTA severe renal dysfunction (GFR<15 ml/min/1.73 m 2 ) than ALD patients, as well as other overall outcomes. Using the UNOS/OPTN database, we selected patients undergoing liver transplant for NAFLD or ALD (2006-2016), 15,103 of whom received LTA. NAFLD patients with moderate renal dysfunction were more likely to develop subsequent GFR<15 ml/min/1.73 m 2 than ALD patients (11.1% vs. 7.38%, p < 0.001). Patients on short-term dialysis pre-LTA (≤12 weeks) were more likely to develop severe renal dysfunction (31.7% vs. 18.1%), especially in NAFLD patients, and were more likely to receive a further kidney transplant (15.3% vs. 3.7%) and had lower survival (48.6% vs. 50.4%) after LTA ( p < 0.001 for all). NAFLD was an independent risk factor for post-LTA severe renal dysfunction (HR = 1.2, p = 0.02). NAFLD patients with moderate renal dysfunction and those receiving short-term dialysis prior to LTA are at a higher risk of developing subsequent severe renal dysfunction. Underlying etiology of liver disease may play a role in predicting development and progression of renal failure in patients receiving LTA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fernández-Carrillo, Li, Ventura-Cots, Argemi, Dai, Clemente-Sánchez, Duarte-Rojo, Behari, Ganesh, Jonassaint, Tevar, Hughes, Humar, Molinari, Landsittel and Bataller.)

Liver disease is a major cause of premature death and disability in Europe. However, morbidity and mortality are not equally distributed in the population. In spite of this, there are few studies addressing the issue of health inequalities in Europe. In this Public Health Corner article, we compare the research conducted on health inequalities in Europe to other settings and highlight the main differences based upon an extensive review of the literature. We report that only 10.2% of studies were led by European institutions or conducted in European populations and that certain topics such as alcohol-related liver disease are largely overlooked. In addition, we discuss the relevance of including a health equity lens when conducting clinical, epidemiological and health systems' research in liver disease and set out the basic requirements to tackle health inequalities in liver disease in Europe., Competing Interests: Conflict of interest JMP reports having received consulting fees from Boehringer Ingelheim, MSD and Novo Nordisk, speaking fees from Gilead and Novo Nordisk, and travel expenses from Gilead, Rubió, Pfizer, Astellas, MSD, CUBICIN, and Novo Nordisk outside of the submitted work. He has received educational and research support from Gilead, Pfizer, Astellas, Accelerate, Novartis, Abbvie, ViiV, and MSD, as well as funds from European Commission/EFPIA IMI2 853966-2, IMI2 777377, H2020 847989, and ISCIII PI19/01898; JVL reports grants and speaker fees from AbbVie, Gilead Sciences and MSD and speaker fees from Genfit, Intercept and ViiV, outside of the submitted work; MVC is a recipient of the Juan Rodés grant JR19/00015; RB is a recipient of NIAAA grants U01AA021908 and U01AA020 and NIDDK P30DK120531821. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: There is a lack of consensus on the social determinants of Deaths of Despair (DoD), i.e., an increase in mortality attributed to drug overdose, alcohol-related liver disease, and suicide in the United States (USA) during recent years. The objective of this study was to review the scientific literature on DoD with the purpose of identifying relevant social determinants and inequalities related to these mortality trends., Methods: Scoping review focusing on the period 2015-2022 based on PubMed search. Articles were selected according to the following inclusion criteria: published between 1 January 2000 and 31 October 2021; including empirical data; analyzed DoD including the three causes defined by Case and Deaton; analyzed at least one social determinant; written in English; and studied DoD in the USA context only. Studies were excluded if they only analyzed adolescent populations. We synthesized our findings in a narrative report specifically addressing DoD by economic conditions, occupational hazards, educational level, geographical setting, and race/ethnicity., Results: Seventeen studies were included. Overall, findings identify a progressive increase in deaths attributable to suicide, drug overdose, and alcohol-related liver disease in the USA in the last two decades. The literature concerning DoD and social determinants is relatively scarce and some determinants have been barely studied. However different, however, large inequalities have been identified in the manner in which the causes of death embedded in the concept of DoD affect different subpopulations, particularly African American, and Hispanic populations, but blue collar-whites are also significantly impacted. Low socioeconomic position and education levels and working in jobs with high insecurity, unemployment, and living in rural areas were identified as the most relevant social determinants of DoD., Conclusions: There is a need for further research on the structural and intermediate social determinants of DoD and social mechanisms. Intersectional and systemic approaches are needed to better understand and tackle DoD and related inequalities.

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., Competing Interests: Competing interests: JAl has received support to attend conferences from Gilead. BS has been consulting for Ferring Research Institute, Intercept Pharmaceuticals, HOST Therabiomics and Patara Pharmaceuticals. BS’s institution UC San Diego has received grant support from BiomX, NGM Biopharmaceuticals, CymaBay Therapeutics and Synlogic Operating Company., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Alcoholic hepatitis (AH) is associated with a high incidence of infection and mortality. Rifaximin reduces bacterial overgrowth and translocation. We aimed to study whether the administration of rifaximin as an adjuvant treatment to corticosteroids decreases the number of bacterial infections at 90 days in patients with severe AH compared to a control cohort., Methods: This was a multicentre, open, comparative pilot study of the addition of rifaximin (1200 mg/day/90 days) to the standard treatment for severe AH. The results were compared with a carefully matched historical cohort of patients treated with standard therapy and matching by age and model of end-stage liver disease (MELD). We evaluated bacterial infections, liver-related complications, mortality and liver function tests after 90 days., Results: Twenty-one and 42 patients were included in the rifaximin and control groups respectively. No significant baseline differences were found between groups. The mean number of infections per patient was 0.29 and 0.62 in the rifaximin and control groups, respectively (p = .049), with a lower incidence of acute-on-chronic liver failure (ACLF) linked to infections within the treatment group. Liver-related complications were lower within the rifaximin group (0.43 vs. 1.26 complications/patient respectively) (p = .01). Mortality was lower in the treated versus the control groups (14.2% vs. 30.9, p = .15) without significant differences. No serious adverse events were associated with rifaximin treatment., Conclusions: Rifaximin is safe in severe AH with a significant reduction in clinical complications. A lower number of infections and a trend towards a lower ACLF and mortality favours its use in these patients., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background and Aims: Lipoprotein Z (LP-Z) is an abnormal free cholesterol (FC)-enriched LDL-like particle discovered from patients with cholestatic liver disease. This study aims to define the diagnostic value of LP-Z in alcohol-associated hepatitis (AH) and interrogate the biology behind its formation., Approach and Results: We measured serum levels of LP-Z using nuclear magnetic resonance spectroscopy, a well-established clinical assay. Serum levels of LP-Z were significantly elevated in four AH cohorts compared with control groups, including heavy drinkers and patients with cirrhosis. We defined a Z-index, calculated by the ratio of LP-Z to total apolipoprotein B-containing lipoproteins, representing the degree of deviation from normal VLDL metabolism. A high Z-index was associated with 90-day mortality independent from the Model for End-Stage Liver Disease (MELD) and provided added prognosticative value. Both a Z-index ≤ 0.6 and a decline of Z-index by ≥0.1 in 2 weeks predicted 90-day survival. RNA-sequencing analyses of liver tissues demonstrated an inverse association in the expression of enzymes responsible for the extrahepatic conversion of VLDL to LDL and AH disease severity, which was further confirmed by the measurement of serum enzyme activity. To evaluate whether the FC in LP-Z could contribute to the pathogenesis of AH, we found significantly altered FC levels in liver explant of patients with AH. Furthermore, FC in reconstituted LP-Z particles caused direct toxicity to human hepatocytes in a concentration-dependent manner, supporting a pathogenic role of FC in LP-Z., Conclusions: Impaired lipoprotein metabolism in AH leads to the accumulation of LP-Z in the circulation, which is hepatotoxic from excessive FC. A Z-index ≤ 0.6 predicts 90-day survival independent from conventional biomarkers for disease prognostication., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

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., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Corticosteroids are the only effective therapy for severe alcohol-associated hepatitis (AH), defined by a model for end-stage liver disease (MELD) score >20. However, there are patients who may be too sick to benefit from therapy. Herein, we aimed to identify the range of MELD scores within which steroids are effective for AH., Methods: We performed a retrospective, international multicenter cohort study across 4 continents, including 3,380 adults with a clinical and/or histological diagnosis of AH. The main outcome was mortality at 30 days. We used a discrete-time survival analysis model, and MELD cut-offs were established using the transform-the-endpoints method., Results: In our cohort, median age was 49 (40-56) years, 76.5% were male, and 79% had underlying cirrhosis. Median MELD at admission was 24 (19-29). Survival was 88% (87-89) at 30 days, 77% (76-78) at 90 days, and 72% (72-74) at 180 days. A total of 1,225 patients received corticosteroids. In an adjusted-survival-model, corticosteroid use decreased 30-day mortality by 41% (hazard ratio [HR] 0.59; 0.47-0.74; p <0.001). Steroids only improved survival in patients with MELD scores between 21 (HR 0.61; 0.39-0.95; p = 0.027) and 51 (HR 0.72; 0.52-0.99; p = 0.041). The maximum effect of corticosteroid treatment (21-30% survival benefit) was observed with MELD scores between 25 (HR 0.58; 0.42-0.77; p <0.001) and 39 (HR 0.57; 0.41-0.79; p <0.001). No corticosteroid benefit was seen in patients with MELD >51. The type of corticosteroids used (prednisone, prednisolone, or methylprednisolone) was not associated with survival benefit (p = 0.247)., Conclusion: Corticosteroids improve 30-day survival only among patients with severe AH, especially with MELD scores between 25 and 39., Lay Summary: Alcohol-associated hepatitis is a condition where the liver is severely inflamed as a result of excess alcohol use. It is associated with high mortality and it is not clear whether the most commonly used treatments (corticosteroids) are effective, particularly in patients with very severe liver disease. In this worldwide study, the use of corticosteroids was associated with increased 30-day, but not 90- or 180-day, survival. The maximal benefit was observed in patients with an MELD score (a marker of severity of liver disease; higher scores signify worse disease) between 25-39. However, this benefit was lost in patients with the most severe liver disease (MELD score higher than 51)., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

No therapies have been proven to increase survival after a hepatic encephalopathy (HE) episode. We hypothesize that two doses of albumin could improve 90-day survival rates after a HE episode., Methods: (1) A randomized double-blind, placebo-controlled trial (BETA) was conducted in 12 hospitals. The effect of albumin (1.5 g/kg at baseline and 1 g/kg on day 3) on 90-day survival rates after a HE episode grade II or higher was evaluated. (2) A meta-analysis of individual patient's data for survival including two clinical trials (BETA and ALFAE) was performed., Results: In total, 82 patients were included. Albumin failed to increase the 90-day transplant-free survival (91.9% vs. 80.5%, p = 0.3). A competing risk analysis was performed, observing a 90-day cumulative incidence of death of 9% in the albumin group vs. 20% in the placebo ( p = 0.1). The meta-analysis showed a benefit in the albumin group, with a lower rate of clinical events (death or liver transplant) than patients in the placebo (HR, 0.44; 95% CI, 0.21-0.82), when analyzed by a competing risk analysis (90-days mortality rate of 11% in the albumin group vs. 30% in the placebo, p = 0.02)., Conclusions: Repeated doses of albumin might be beneficial for patient's survival as an add-on therapy after an HE episode, but an adequately powered trial is needed.

The 10-item Alcohol Use Disorders Identification Test (AUDIT-10) and its shorter form, AUDIT-Consumption (AUDIT-C), are questionnaires used to characterize severity of drinking. We hypothesized that liver injury and short-term outcomes of alcohol-associated hepatitis (AH) would correlate with a patient's recent alcohol consumption as determined by AUDIT-10 and AUDIT-C. We analyzed a prospective international database of patients with AH diagnosed based on the National Institute on Alcohol Abuse and Alcoholism (NIAAA) standard definitions. All patients were interviewed using AUDIT-10. Primary outcomes included the discriminatory ability of the AUDIT-10 and AUDIT-C scores for predicting survival status at 28 and 90 days and severity of liver injury, as measured by Model for End-Stage Liver Disease-sodium (MELD-Na). The relationship between AUDIT scores and survival status was quantified by calculating the area under the curve of the receiver operating characteristic analysis. The relationship between AUDIT scores and MELD-Na was examined using correlation coefficients. In 245 patients (age range 25-75 years; 35% female), we found no correlation between AUDIT-10 or AUDIT-C scores and either 28- or 90-day mortality. Similarly, there was no correlation between AUDIT-10 and AUDIT-C and MELD-Na scores. There was a strong positive correlation between MELD-Na and 28- and 90-day mortality. Additional measures of severity of alcohol use (average grams of alcohol consumed per day, years of drinking, convictions for driving under the influence, and rehabilitation attempts) and psychosocial factors (marriage, paid employment, and level of social support) had no influence on MELD-Na. In patients presenting with AH, AUDIT-10 and AUDIT-C were predictors of neither clinical severity of liver disease nor short-term mortality, suggesting that level of alcohol consumption in the prior year is not key to the presenting features or outcome of AH., (Copyright © 2021 by the American Association for the Study of Liver Diseases.)

Alcoholic hepatitis (AH) is associated with liver neutrophil infiltration through activated cytokine pathways leading to elevated chemokine expression. Super-enhancers are expansive regulatory elements driving augmented gene expression. Here, we explore the mechanistic role of super-enhancers linking cytokine TNFα with chemokine amplification in AH. RNA-seq and histone modification ChIP-seq of human liver explants show upregulation of multiple CXCL chemokines in AH. Liver sinusoidal endothelial cells (LSEC) are identified as an important source of CXCL expression in human liver, regulated by TNFα/NF-κB signaling. A super-enhancer is identified for multiple CXCL genes by multiple approaches. dCas9-KRAB-mediated epigenome editing or pharmacologic inhibition of Bromodomain and Extraterminal (BET) proteins, transcriptional regulators vital to super-enhancer function, decreases chemokine expression in vitro and decreases neutrophil infiltration in murine models of AH. Our findings highlight the role of super-enhancer in propagating inflammatory signaling by inducing chemokine expression and the therapeutic potential of BET inhibition in AH treatment., (© 2021. The Author(s).)

The chemokine system of ligands and receptors is implicated in the progression of alcohol-associated hepatitis (AH). Finding upstream regulators could lead to novel therapies. This study involved coordinated expression of chemokines in livers of healthy controls (HC) and patients with AH in 2 distinct cohorts of patients with various chronic liver diseases. Studies in cultured hepatocytes and in tissue-specific KO were used for mechanistic insight into a potential upstream regulator of chemokine expression in AH. Selected C-X-C chemokine members of the IL-8 chemokine family and C-C chemokine CCL20 were highly associated with AH compared with HC but not in patients with liver diseases of other etiologies (nonalcoholic fatty liver disease [NAFLD] and hepatitis C virus [HCV]). Our previous studies implicate macrophage migration inhibitory factor (MIF) as a pleiotropic cytokine/chemokine with the potential to coordinately regulate chemokine expression in AH. LPS-stimulated expression of multiple chemokines in cultured hepatocytes was dependent on MIF. Gao-binge ethanol feeding to mice induced a similar coordinated chemokine expression in livers of WT mice; this was prevented in hepatocyte-specific Mif-KO (MifΔHep) mice. This study demonstrates that patients with AH exhibit a specific, coordinately expressed chemokine signature and that hepatocyte-derived MIF might drive this inflammatory response.

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: Identification of SARS-CoV-2-infected patients at high-risk of poor prognosis is crucial. We aimed to establish predictive models for COVID-19 pneumonia severity in hospitalized patients., Methods: Retrospective study of 430 patients admitted in Vall d'Hebron Hospital (Barcelona) between 03-12-2020 and 04-28-2020 due to COVID-19 pneumonia. Two models to identify the patients who required high-flow-oxygen-support were generated, one using baseline data and another with also follow-up analytical results. Calibration was performed by a 1000-bootstrap replication model., Results: 249 were male, mean age 57.9 years. Overall, 135 (31.4%) required high-flow-oxygen-support. The baseline predictive model showed a ROC of 0.800 based on: SpO2/FiO2 (adjusted Hazard Ratio-aHR = 8), chest x-ray (aHR = 4), prior immunosuppressive therapy (aHR = 4), obesity (aHR = 2), IL-6 (aHR = 2), platelets (aHR = 0.5). The cut-off of 11 presented a specificity of 94.8%. The second model included changes on the analytical parameters: ferritin (aHR = 7.5 if ≥200ng/mL) and IL-6 (aHR = 18 if ≥64pg/mL) plus chest x-ray (aHR = 2) showing a ROC of 0.877. The cut-off of 12 exhibited a negative predictive value of 92%., Conclusions: SpO2/FiO2 and chest x-ray on admission or changes on inflammatory parameters as IL-6 and ferritin allow us early identification of COVID-19 patients at risk of high-flow-oxygen-support that may benefit from a more intensive disease management., Competing Interests: No authors have competing interests.

Background and Aims: Alcoholic hepatitis (AH) is a severe manifestation of alcohol-associated liver disease (ALD) with high mortality. Although gut bacteria and fungi modulate disease severity, little is known about the effects of the viral microbiome (virome) in patients with ALD., Approach and Results: We extracted virus-like particles from 89 patients with AH who were enrolled in a multicenter observational study, 36 with alcohol use disorder (AUD), and 17 persons without AUD (controls). Virus-like particles from fecal samples were fractionated using differential filtration techniques, and metagenomic sequencing was performed to characterize intestinal viromes. We observed an increased viral diversity in fecal samples from patients with ALD, with the most significant changes in samples from patients with AH. Escherichia-, Enterobacteria-, and Enterococcus phages were over-represented in fecal samples from patients with AH, along with significant increases in mammalian viruses such as Parvoviridae and Herpesviridae. Antibiotic treatment was associated with higher viral diversity. Specific viral taxa, such as Staphylococcus phages and Herpesviridae, were associated with increased disease severity, indicated by a higher median Model for End-Stage Liver Disease score, and associated with increased 90-day mortality., Conclusions: In conclusion, intestinal viral taxa are altered in fecal samples from patients with AH and associated with disease severity and mortality. Our study describes an intestinal virome signature associated with AH., (© 2020 by the American Association for the Study of Liver Diseases.)

Alcohol-related liver disease (ALD) is the most frequent cause of advanced chronic liver disease worldwide. Excessive and prolonged alcohol use leads to ALD, which ranges from early forms such as alcoholic fatty liver (AFL) and alcoholic steatohepatitis (ASH), through progressive fibrosis to cirrhosis and the development of hepatocellular cancer (HCC). In addition, patients with underlying ALD and continuous alcohol use can develop alcoholic hepatitis (AH), which presents a rapid progression of liver failure and has a high short-term mortality. Genetic, environmental and epigenetic factors influence the progression of ALD to more severe forms. The pathogenesis of ALD is complex and involves multiple pathways. Recent translational studies have demonstrated a key role of the gut-liver axis and innate immunity in hepatocellular damage and fibrosis. In severe forms, hepatocellular de-differentiation and systemic inflammation contribute to liver failure and multiorgan failure. Alcohol abstinence is the cornerstone of therapy for ALD and the prevention of its complications, but the efficacy and accessibility of psycho-familial-social interventions is still poor and effective public health policies to limit problematic alcohol use need to be implemented. Prednisolone is the only current option for AH, with a transient beneficial effect over placebo. For patients with decompensated ALD-cirrhosis and/or development of HCC, liver transplantation (LT) may be required. In recent years, early LT is being increasingly offered to carefully selected AH patients, with excellent long-term survival. New trials of AH treatments are currently ongoing, and translational studies in human samples are paving the way to new promising targeted therapies.

Chronic alcohol consumption causes increased intestinal permeability and changes in the intestinal microbiota composition, which contribute to the development and progression of alcohol-related liver disease. In this setting, little is known about commensal fungi in the gut. We studied the intestinal mycobiota in a cohort of patients with alcoholic hepatitis, patients with alcohol use disorder, and nonalcoholic controls using fungal-specific internal transcribed spacer amplicon sequencing of fecal samples. We further measured serum anti-Saccharomyces cerevisiae antibodies (ASCA) as a systemic immune response to fungal products or fungi. Candida was the most abundant genus in the fecal mycobiota of the two alcohol groups, whereas genus Penicillium dominated the mycobiome of nonalcoholic controls. We observed a lower diversity in the alcohol groups compared with controls. Antibiotic or steroid treatment was not associated with a lower diversity. Patients with alcoholic hepatitis had significantly higher ASCA levels compared to patients with alcohol use disorder and to nonalcoholic controls. Within the alcoholic hepatitis cohort, patients with levels of at least 34 IU/mL had a significantly lower 90-day survival (59%) compared with those with ASCA levels less than 34 IU/mL (80%) with an adjusted hazard ratio of 3.13 (95% CI, 1.11-8.82; P = 0.031). Conclusion: Patients with alcohol-associated liver disease have a lower fungal diversity with an overgrowth of Candida compared with controls. Higher serum ASCA was associated with increased mortality in patients with alcoholic hepatitis. Intestinal fungi may serve as a therapeutic target to improve survival, and ASCA may be useful to predict the outcome in patients with alcoholic hepatitis., (© 2019 by the American Association for the Study of Liver Diseases.)