BACKGROUND:Recurrent alcohol use is a major determinant of liver-related outcomes in patients recovering from alcohol-associated hepatitis (AH). However, the timing and predictors of return to drinking (RTD) are not well-studied. METHODS:We analyzed alcohol use among patients with AH enrolled in two AlcHepNet multicenter studies: a Phase 2b randomized controlled trial and a prospective observational study. TimeLine FollowBack (TLFB) assessed drinking at each visit. RTD was defined as any alcohol use since the previous visit. The cumulative incidence of RTD was evaluated using the Fine-Gray method, with death as a competing risk. Factors associated with RTD were evaluated using univariate and multivariate Cox regression. RESULTS:Among 518 patients alive at Day 28, RTD occurred in 7.7%, 21.7%, and 30.8% at 30, 90, and 180 days, respectively. Patients with moderate AH (mAH, MELD 11-19, n = 103) had a higher RTD incidence at 180 days than those with severe AH (sAH, MELD ≥20, n = 415) (44.3% vs. 27.5%; p = 0.01). RTD was associated with higher AUDIT scores, family history of alcohol use disorder (AUD), lower education, greater alcohol use at baseline, lower MELD scores, and less ascites (all p ≤ 0.01). In multivariable analysis, >20 drinking days in the prior month was associated with increased risk of RTD (HR: 3.46, 95% CI: 2.21-5.39), whereas college education or higher was protective (HR: 0.53, 95% CI: 0.32-0.88). CONCLUSION:RTD occurred in 22% of AH patients within 90 days postrecovery, highlighting the need for early AUD interventions. Frequent drinking days at baseline and lower education were strongly linked to early RTD.

INTRODUCTION:Alcohol-associated hepatitis (AH) is a severe condition with high short-term mortality. Identifying key predictors of poor outcomes is critical for guiding therapeutic strategies. Mean arterial pressure (MAP), a key determinant of tissue perfusion and systemic hemodynamics, may play a pivotal role in prognosis. METHODS:We analyzed a multicenter, prospective cohort of 323 patients hospitalized with AH, with validation in an independent cohort of 290 patients. Survival was evaluated using Kaplan-Meier curves and compared with the log-rank (Mantel-Cox) test. Cox proportional hazards models were used to estimate hazard ratios for mortality, adjusted for Model for end stage liver disease score. Mechanistic insights were explored through assessment of cardiovascular biomarkers. RESULTS:A baseline MAP <80 mm Hg was associated with significantly higher mortality at both 28 days (27.3% vs 8.0%) and 90 days (40.3% vs 15.6%; P < 0.001 for both). This association persisted after adjusting for Model for end stage liver disease score, age, and baseline hepatic encephalopathy. The incidence of infections during follow-up was similar across MAP groups (27.6% vs 22.8%), but acute kidney injury occurred more frequently in the MAP <80 mm Hg group (62% vs 38%, P < 0.001). In the validation cohort, patients with MAP <80 mm Hg also demonstrated significantly lower 28-day transplant-free survival. Although B-type natriuretic peptide and plasma renin levels were altered in patients with AH, they did not correlate with MAP values. DISCUSSION:A baseline MAP <80 mm Hg is an independent predictor of short-term and mid-term mortality in patients with AH. Strategies aimed at restoring hemodynamic stability may improve outcomes in this high-risk population.

BACKGROUND AND AIMS:Increased circulating pro-inflammatory cytokine levels correlate with mortality in severe alcohol-associated hepatitis (AH), but their kinetics during disease progression or response to treatment remain unexplored. We longitudinally assessed circulating biomarkers in a severe AH cohort enrolled in a multicenter, double-blind clinical trial. APPROACH AND RESULTS:Eighty-nine patients with severe AH (MELD≥20) from 4 US sites were randomly assigned to treatment with IL-1 receptor antagonist (IL-1Ra) + pentoxifylline + zinc (anakinra: 47) or methylprednisolone + placebo (steroid: 42). Plasma levels of 43 indicators of AH pathology (inflammation, bacterial translocation, liver regeneration, tissue remodeling, and cell activation) were assessed on days 0, 7, 28, 90, and 180 after enrollment, and in 27 healthy controls. Baseline characteristics and cytokine levels were similar between treatment groups but significantly different compared with healthy controls. Consistent with anakinra administration, day 7 IL-1Ra levels were significantly increased in the anakinra group, accompanied by elevated levels of several other cytokines. IL-1β levels were increased in the steroid group on day 28. Strong correlations were observed between IL-1α and IL-17A, as well as IL-1β and IL-13, both before and during treatment. Although the dysregulated biomarkers demonstrated improving trends in survivors, most did not normalize by day 180. Markers associated with 90-day mortality were distinct between the treatment groups with few exceptions (IL-13-absolute level; sonic hedgehog and sTNF-R1-level change). CONCLUSIONS:Circulating cytokine and immune biomarkers dynamically change in AH during treatment, disease progression, and/or resolution. Our results highlight the importance of treatment-specific biomarkers in future clinical trials.

Severe alcohol-associated hepatitis (sAH) has been associated with a high 30-day mortality rate. Corticosteroids are used in patients with sAH with limitations. There are no biomarkers measured upon hospitalization that predict responsiveness to corticosteroids. The role of signal regulatory protein (SIRP)-α, a receptor that regulates inflammation, has not been studied in patients with AH. In prospective test and validation cohorts of sAH patients treated with corticosteroids, plasma cytokines and SIRPα levels were measured. Studies in Sirpa-/- mice and in vitro studies were performed to characterize the impact of Sirpa-/- and cleavage. Plasma SIRPα levels were elevated at baseline in corticosteroid nonresponders (CS-NR) versus responders (CS-R) in both cohorts. Plasma SIRPα levels were elevated with disease severity and mortality. In CS-NR patients, proinflammatory cytokines were increased. In mice, Sirpα cleavage was induced by ethanol and lipopolysaccharide and associated with A disintegrin and metalloproteinase domain-containing protein (Adam)-10 activity and cytokine release. Adam10 inhibition reduced Sirpα cleavage and cytokine release. In an experimental model of alcohol-associated liver disease, Sirpa-/- mice developed exacerbated liver injury and inflammation. Based on these findings, plasma SIRPα is a potential biomarker for responsiveness to corticosteroids and prognosis. Sirpa-/- mice developed a hyperinflammatory phenotype similar to SIRPα cleavage in humans. Future clinical studies are necessary to validate plasma SIRPα as a biomarker to guide the use of corticosteroids in patients with sAH.

Metabolic and alcohol-related liver disease (MetALD) is a newly defined entity within the spectrum of steatotic liver disease, characterized by the interplay of cardiometabolic risk factors and alcohol consumption. The evolving epidemiology and complex pathophysiology of MetALD present unique challenges and opportunities for clinical trial design. Inclusion criteria should require simultaneous evidence of metabolic dysfunction (at least two cardiometabolic features) and verified quantifiable alcohol exposure recorded over the preceding 3–6 months. Traditional histological end points are limited by invasiveness, sampling error and interpretative variability. Thus, imaging modalities, serum-based fibrosis biomarkers and quantitative measures of alcohol intake are gaining relevance as non-invasive, reproducible and patient-centric end points aiming to improve trial feasibility. Furthermore, incorporating alcohol biomarkers, stratifying patients by metabolic risk factor burden, and using adaptive designs of trials might enhance the precision and generalizability of MetALD clinical trials. Although uncertainties remain regarding optimal patient selection criteria, event rates and the dynamic interplay between metabolic dysfunction and alcohol intake, ongoing research efforts aim to refine diagnostic criteria, standardize methodologies and validate novel end points. These advances will ultimately accelerate drug development, improve trial efficiency and foster interventions to treat MetALD. Metabolic and alcohol-related liver disease presents challenges in clinical trials due to complex pathophysiology. This Review discusses noninvasive imaging, serum biomarkers and adaptive designs as modalities to enhance patient-centric end points, aiming to refine diagnostics and improve drug development.

Early liver transplantation (eLT) for alcohol-associated liver disease (ALD), defined as transplantation with less than 6 months of alcohol abstinence, has emerged as a standard intervention for carefully selected patients unresponsive to medical therapy. Rising ALD prevalence, driven by increased alcohol use, particularly among patients in early adulthood, and exacerbated by the COVID-19 pandemic, has led to an increased demand for eLT for ALD. Recent studies have demonstrated that eLT can yield survival outcomes comparable to standard liver transplantation, although patient selection remains challenging, with return to drinking (RTD) after transplant a primary concern. Various psychosocial evaluation tools can help identify candidates at lower risk for RTD, but predictive accuracy remains limited due to the complex, individualized nature of alcohol use disorder among ALD patients. Multidisciplinary approaches to managing alcohol use disorder, such as integrated care models, are increasingly being adopted to improve outcomes and achieve sustained alcohol abstinence after transplant. Despite the recent increase in eLT for ALD, international practices vary widely, with countries like the United States, France, and Belgium leading in adoption, whereas others still impose strict sobriety requirements. Notably, racial, ethnic, and geographic disparities in access to eLT for ALD have emerged, highlighting the need for more standardized and equitable practices. This review traces the development and expansion of eLT in ALD, addressing selection and management challenges, while proposing a biopsychosocial framework to optimize patient and graft outcomes across the liver transplantation continuum.

Background and Aims:Alcohol use disorder (AUD) pharmacotherapy reduces hepatic decompensation and mortality in patients with alcohol-associated liver disease (ALD). We aimed to characterize the use of AUD pharmacotherapy in a large national cohort. Methods:Adults with AUD were identified in PharMetrics Plus for Academics-a nationally representative claims database of commercially insured Americans. We examined receipt of AUD therapy and associated treatment patterns. Results:A total of 28,625 patients with AUD were identified: 1640 (5.7%) had ALD, among whom 439 (1.5%) had acute alcohol-associated hepatitis (AAH). Pharmacotherapy was prescribed in 14.5% of patients without ALD, 2.3% with ALD cirrhosis, and 9.8% with AAH. The most prescribed medication was gabapentin (9.4%). Among those receiving pharmacotherapy, one-time prescriptions were observed in 28.4% of patients without ALD, 10.7% with ALD cirrhosis, and 18.6% with AAH. The median time from diagnosis to receipt of pharmacotherapy was 10 months (interquartile range [IQR] 1.5-29.2). On regression analysis, nonsubstance use psychiatric diagnosis (adjusted odds ratio [aOR]: 2.71; 95% confidence interval [CI] [2.51, 2.93]) and female sex (aOR: 1.32; 95% CI [1.22, 1.42]) were associated with receipt of pharmacotherapy, while ALD cirrhosis (aOR: 0.22; 95% CI [0.14, 0.32]) and hepatic decompensation (aOR: 0.07; 95% CI [0.02, 0.16]) were associated with not receiving pharmacotherapy. Conclusion:AUD pharmacotherapy appeared underutilized in a large cohort of commercially insured U.S. adults, particularly among patients with ALD and hepatic decompensation. Providers caring for patients with AUD across the spectrum of liver disease should be aware of potential underutilization of these medications, especially among males and patients with cirrhosis.

BACKGROUND:How parental alcohol use disorder and liver disease-related mortality influence the risk and the outcomes of alcohol-associated hepatitis (AH) in the offspring is unknown. METHODS:We analyzed data from 2 prospective observational studies of AH cases and heavy drinking controls (HDCs). Family history of parental alcohol use disorder and liver disease mortality was assessed at the study entry. Logistic regression and Cox proportional hazard models were used to assess the influences of family history on AH development and outcome. RESULTS:Data from 1356 participants in two prospective cohorts (926 AH cases and 430 HDC) were combined and analyzed. Parental alcohol use disorder was found in 56.9% of AH cases and 61.1% of HDC; parental death due to liver disease was reported in 7.5% of AH cases and 5.7% of HDC. Multivariable logistic regression showed that parental liver disease-related mortality was associated with more than a doubled risk of AH development in the offspring after controlling for their demographic characteristics and drinking behavior (OR=2.26, 95% CI: [1.22, 4.20]). Moreover, among the AH cases, having a parent die of liver disease significantly increased the 90-day mortality of study participants after adjusting for the effects of other risk factors (HR=2.26, 95% CI: [1.05, 4.86]). CONCLUSIONS:The study highlights the influences of parental death due to liver disease on AH development and mortality. Identifying patients at risk of AH through family history might help facilitate discussions on reducing alcohol consumption.

Alcohol-associated hepatitis (AH) is a severe form of alcohol-associated liver disease characterized by acute-onset jaundice and liver failure. AH carries a high mortality risk, particularly in severe cases. Although glucocorticoids have been the primary pharmacologic intervention for decades, their use is limited by a lack of long-term efficacy and significant side effects, and relative contraindications. For patients who do not respond to glucocorticoids, early liver transplantation is a life-saving option. However, only a few patients qualify for this intervention. In recent years, advances in translational medicine have uncovered key mechanisms in AH pathophysiology, including microbiome interactions, proinflammatory signaling, and disruptions in hepatocyte function. These insights have led to the exploration of innovative pharmacologic treatments, targeting pathways such as the gut-liver axis, oxidative stress, inflammation, and liver regeneration. Despite promising results from ongoing clinical trials, several challenges persist, including low patient recruitment and retention rates, heterogeneity in trial design, and the lack of standardized endpoints. This review assesses the current pharmacologic landscape of AH, with a focus on emerging therapies and the ongoing challenges in AH clinical trials.

ABSTRACTIntroductionAlcohol‐associated liver disease (ALD) disproportionately impacts men, racial and ethnic minorities, and individuals of low socioeconomic status; however, it's unclear how recent increases in ALD burden have impacted these disparities. We aimed to describe trends in racial, ethnic and socioeconomic disparities in alcohol‐associated hospital encounters.MethodsWe conducted a retrospective cohort study of adult hospital encounters with alcohol‐associated diagnoses from three health systems between January 2016 and December 2021. The cohort was divided into three eras: a ‘Historical Era,’ (Oct 2016—June 2018, used only for trends); ‘Era 1’ (July 2018—March 2020); and ‘Era 2’ (April 2020—December 2021). Kaplan Meier and Cox regression analyses were performed to identify factors associated with overall survival.ResultsWe identified 19,295 individuals with alcohol‐associated encounters (44.7% White, 29.8% Hispanic, and 21.8% non‐Hispanic Black (NHB) individuals), with a greater increase observed between eras 1 and 2 than the historical era and Era 1 (8.7% vs. 5.0%, p < 0.01). By age and sex, the greatest increases in encounters were observed in the youngest and oldest females but only the oldest males. By race and ethnicity, Hispanic individuals had greater increases in encounters compared to Black and White individuals (14.8% vs. 7.5% and 6.3%, p < 0.01). Older age (aSHR: 1.03, 95% CI: 1.03–1.0), higher MELD (aSHR: 1.08, 95% CI: 1.0–1.09), hepatic encephalopathy (aSHR: 1.42, 95% CI: 1.06–1.90), and hepatocellular carcinoma (HCC) (aSHR: 3.20, 95% CI: 2.29–4.49) were associated with increased mortality.ConclusionThe highest increases of alcohol‐associated encounters were observed amongst young Hispanic and NHB women, highlighting variation in trends by age, sex, race and ethnicity. These disparities merit further investigation to elucidate underlying mechanisms and develop tailored interventions to improve ALD burden and outcomes.

BACKGROUND AIMS:The clinical course and outcomes of alcohol-associated hepatitis (AH) remain poorly understood. Major adverse liver outcomes do not capture the added risk of return to drinking. We examined the natural history of AH and developed a composite endpoint using a contemporary observational cohort of AH. APPROACH RESULTS:A cohort of 1127 participants: 712 AH patients, 256 heavy drinking controls without clinically evident liver disease, and 159 healthy controls, were prospectively followed for 6 months at 8 United States centers as part of the Alcoholic Hepatitis Network (AlcHepNet) consortium. Outcomes included mortality and a composite endpoint (AlcHepNet composite index) that included death, liver transplantation, hepatic decompensation (new onset/worsening ascites, HE, variceal bleeding), liver-related hospital admission, MELD increase ≥5, and return to drinking. Of 712 AH patients (age 45±10.7 y; 59.1% male), 558 (79.0%) had severe and 148 (21.0%) had moderate AH, 232 (32.5%) died, and 86 (12.1%) underwent liver transplantation. Mortality rates in moderate AH and severe AH were 0.7% versus 17.2% (30 d), 3.4% versus 26.5% (90 d), and 8.8% versus 30.5% (180 d), respectively (all p <0.001). Composite liver/alcohol use events were noted in 459 (64.5%) AH patients. Higher MELD score, lower mean arterial pressure, and baseline leukocytosis were associated with higher 90-day mortality in AH (all p <0.05). College education and higher ALP were associated with lower mortality. Heavy drinking controls had low mortality (n=3; 1.2%). CONCLUSIONS:This large observational study showed a high incidence of composite liver and alcohol-use events within 6 months, reiterating the need for early interventions.

BACKGROUND:Larsucosterol is a DNA methyltransferase inhibitor in development for alcohol-associated hepatitis (AH), a disease for which there is no approved therapy. METHODS:In this phase 2b trial, patients with severe AH were randomly assigned 1:1:1 to receive 30 mg or 90 mg of larsucosterol or placebo; a second dose was administered after 72 hours if the patient remained hospitalized. All patients received supportive care as determined by investigators. Patients in the placebo group, if prescribed, received 32 mg of methylprednisolone, while patients in the larsucosterol groups received matching placebo capsules. The primary end point was 90-day mortality or liver transplant (LT) rate. The key secondary end point was 90-day mortality. We prespecified the reporting of U.S. results separately. RESULTS:Among 307 enrolled patients, 301 received at least one treatment dose. The difference in 90-day mortality or LT between the 30-mg or 90-mg larsucosterol and placebo groups did not reach statistical significance. Ninety-day mortality in the placebo and the 30-mg and 90-mg groups was 25 out of 103, 15 out of 102, and 17 out of 102, respectively. Among U.S. patients (76% of all enrolled patients), there were 21 deaths and 4 LTs among 77 patients in the placebo group, 8 deaths and 5 LTs among 73 patients in the 30-mg larsucosterol group, and 10 deaths and 8 LTs among 77 patients in the 90-mg larsucosterol group. In patients who were treated within less than 10 days of hospitalization (75%), mortality in the placebo group was 20 out of 79 (U.S. patients 17/57), mortality in the 30-mg larsucosterol group was 7 out of 74 (U.S. patients 4/57), and mortality in the 90-mg larsucosterol group was 13 out of 77 (U.S. patients 9/66). Most adverse events arising during treatment were attributable to hepatic disease, and there was no imbalance in adverse events that could not be ascribed to liver disease. CONCLUSIONS:The trial did not meet the primary end point of showing a beneficial effect of larsucosterol on 90-day mortality or LT in patients with severe AH. Equipoise has been established for a further trial of larsucosterol on AH survival. (The trial was funded by the DURECT Corporation; its ClinicalTrials.gov number is NCT04563026.).

Background: Brief alcohol interventions use patient-provider communication to promote alcohol cessation. We characterized the receipt of this intervention in chronic liver disease (CLD). Methods: We surveyed patients with CLD for weekly drinking patterns and examined associations with patient-provider communication receipt. Results: Among 840 participants, 82.1% and 56.5% reported ≥1 standard drink weekly and excessive alcohol consumption, respectively. Patient-provider communication was lower in noncirrhotic (adjusted odds ratio:0.34, 95% CI: 0.22–0.54) and nonalcohol-associated CLD (adjusted odds ratio: 0.22, 95% CI: 0.15–0.34) among individuals drinking ≥1 standard drink weekly, and similarly in noncirrhotic CLD (adjusted odds ratio: 0.45, 95% CI: 0.21–0.95) among those with excessive drinking. Conclusions: Brief alcohol interventions are underutilized in noncirrhotic and nonalcohol-associated CLD.