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ABSTRACT Background Alcohol‐associated hepatitis (AH) has high short‐term mortality, whereas current prognostic models mainly reflect liver and renal dysfunction. The Metabolic Vulnerability Index (MVX) is a nuclear magnetic resonance‐derived score comprising the Inflammation Vulnerability Index (IVX; small high‐density lipoprotein particles [S‐HDL‐P] and GlycA) and the Metabolic Malnutrition Index (MMX). We evaluated whether MVX, IVX, and IVX components improve 90‐day mortality prediction beyond Model for End‐Stage Liver Disease (MELD) in AH. Methods Serum samples from 196 patients with AH, 169 heavy‐drinking controls, and 351 healthy controls were analyzed by nuclear magnetic resonance spectroscopy. The primary outcome was 90‐day AH‐related mortality. Biomarkers were modeled continuously after standardization within the AH cohort; S‐HDL‐P was modeled per 1 SD decrease. Cox models were adjusted for MELD, age, sex, white blood cell count, and baseline antibiotic or corticosteroid use. Model performance was assessed using Akaike information criterion (AIC), likelihood‐ratio testing, and Harrell's C ‐statistic. Results Among patients with AH, 30 AH‐related deaths occurred within 90 days (15.3%). IVX and MVX were highest in AH cases and increased with AH severity, whereas MMX did not consistently differentiate severity. Lower S‐HDL‐P was independently associated with 90‐day mortality in fully adjusted models (HR, 1.84; 95% CI, 1.01–3.35; p = 0.045), whereas GlycA was not (HR, 0.86; 95% CI, 0.54–1.37; p = 0.527). Adding S‐HDL‐P improved fully adjusted MELD‐based model fit (AIC, 298.97 vs. 301.46; LR p = 0.034; C ‐statistic, 0.741 vs. 0.729). IVX showed supportive improvement in model fit and discrimination (AIC, 299.81; LR p = 0.056; C ‐statistic, 0.749). Continuous MELD interaction analyses supported risk separation for S‐HDL‐P (LR χ 2 = 6.20; p = 0.045) and IVX (LR χ 2 = 6.64; p = 0.036). Conclusions Lower S‐HDL‐P appears to be the principal short‐term prognostic component within the IVX domain in AH. S‐HDL‐P and IVX may refine MELD‐based 90‐day risk stratification, pending external validation.

Background: Noninvasive tests are well validated in metabolic dysfunction–associated steatotic liver disease, but evidence in metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-associated liver disease (ALD) is limited. We evaluated noninvasive test–based clinical care pathways for fibrosis risk stratification in MetALD and ALD. Methods: This is a multinational, multicenter, cross-sectional study across 35 centers in 16 countries (2013–2025), including adults with MetALD or ALD. Fibrosis was assessed by liver biopsy and/or vibration-controlled transient elastography (VCTE). In biopsy-proven participants, we analyzed the sequential pathway (Fibrosis-4 [FIB-4] first, followed by VCTE for indeterminate FIB-4) to identify advanced fibrosis (≥F3). Diagnostic accuracy was assessed using the AUC. Results: Among 893 participants (41.3% MetALD and 58.7% ALD), the median age was 52 [43.0–61.0] years, and 79.4% were male. The estimated prevalence of advanced fibrosis was 45% (32.2% in MetALD and 54.0% in ALD). Participants with MetALD had a more dysmetabolic profile but lower fibrosis stages than ALD. Among biopsy-proven participants, FIB-4 AUC was 0.720, and VCTE AUC was 0.833. FIB-4 performed better in MetALD than ALD (AUC 0.773 vs. 0.540), while VCTE accuracy was similar across groups. In the sequential pathways, the false-negative rate for advanced fibrosis (misclassified as low risk) was 6.8% (4.9% MetALD and 11.3% ALD). Conclusions: In biopsy-proven patients, FIB-4 performance was acceptable in MetALD but substantially weaker in ALD. The standard 2-step pathway performed adequately in MetALD but missed a clinically meaningful proportion of advanced fibrosis in ALD.

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.

Abstract Introduction Biliary fibrosis and inflammation are central to the pathogenesis of cholangiopathies such as primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Inflammatory and fibrogenic stimuli, such as transforming growth factor-β (TGFβ) and lipopolysaccharide (LPS) signaling, drive these processes, but their underlying transcriptional mechanisms in cholangiocytes remain incompletely defined. We investigated the role of Runt-related transcription factor 1 (RUNX1) as a transcriptional co-regulator of fibroinflammatory signaling in cholangiocytes. Methods Human PSC-derived cholangiocytes (PSC-Cs) and mouse large biliary epithelial cells (MLEs) were subjected to RUNX1 knockdown or pharmacologic inhibition (Ro5-3335 or AI-10-104). Cytokine secretion was profiled by Luminex multiplexing; RUNX1 genomic binding and protein interactome were assessed by ChIP-qPCR, ChIP-seq, and LC-MS/MS. In vivo , Mdr2 −/− mice received Ro5-3335, and cholangiocyte-selective Runx1 knockout mice (Krt19-CreERT) were challenged with a DDC diet, followed by evaluation of fibrosis and inflammation. Results RUNX1 expression was significantly increased in cholangiocytes from PSC and PBC patients, and Mdr2 −/− mice. RUNX1 knockdown or inhibition reduced IL6, TNFα, and other proinflammatory cytokines in PSC-Cs and attenuated TGFβ-, LPS-, and TNFα-induced Il6 and Ccl2 expression in MLEs. ChIP-qPCR and ChIP-seq revealed TGFβ-induced RUNX1 binding to the Il6 promoter and 727 additional genomic sites enriched for fibrosis and inflammatory pathways; predicted upstream regulators included TGFβ, TNF, and NFκB signaling. Proteomic analysis identified TGFβ-induced RUNX1 interactions with SMAD2 and NFκB2. In vivo , Ro5-3335 treatment in Mdr2 −/− mice reduced hepatic collagen, ECM gene expression, immune cell infiltration, and serum liver injury markers and bile acids. Similarly, cholangiocyte-specific Runx1 deletion mitigated fibrosis, inflammation, and liver injury in DDC-fed mice. Conclusion RUNX1 is a central transcriptional hub integrating TGFβ and inflammatory signals in cholangiocytes. Its inhibition attenuates biliary fibrosis and inflammation in cholestatic models, supporting RUNX1 as a potential therapeutic target in fibroinflammatory cholangiopathies.

Introduction: Although the role of cardiometabolic risk factors (CMRF) has been characterized in steatotic liver disease, their role in the severity of alcohol-associated hepatitis (AH) remains unclear. We aimed to evaluate the impact of CMRF on mortality. Methods: Multinational prospective cohort study (2015–2024) including hospitalized patients with severe AH across 32 centers in 14 countries. Diagnosis of AH was made using the NIAAA criteria. Analyses included adjusted competing-risk models by age, sex, ethnicity, history of cirrhosis, CMRF, corticosteroid use, MELD, and ACLF grade, with liver transplantation as a competing risk. Results: 936 participants were included; mean age 48±11.2 years, and 88.9% were male. At least one CMRF was present in 46.6%; median body mass index (BMI) was 24.2 kg/m 2 [IQR: 22.8–28.2], prevalence of diabetes 17.6%, hypertension 16.5%, and dyslipidemia 5.8%. Median MELD was 24.4 [19.3–31.4], 86.7% had severe AH, and 180-day survival was 72.9%. Survival did not differ by CMRF status (log-rank p =0.453). In adjusted competing-risk models, higher age (sHR 1.02; 95%CI:1.01–1.04), greater alcohol intake (per g/day; sHR 1.001; 95%CI:1.000–1.002), MELD (sHR 1.04; 95%CI:1.01–1.06), and ACLF grade 2–3 (sHR 2.34 and 4.34) predicted mortality. However, no individual CMRF independently increased mortality. A prespecified non-linear BMI analysis showed modestly lower mortality between 25–40 kg/m², with a higher risk above 40 kg/m². Conclusion: Among patients with severe AH, metabolic dysfunction was not associated with increased mortality. Although a higher BMI was associated with slightly lower mortality in AH, this may reflect better nutritional status rather than a true protective effect.

Abstract 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.

Background and Aims: Metabolic dysfunction–associated steatohepatitis (MASH) is a progressive liver disease that poses significant public health challenges. Although liver biopsy remains the gold standard for diagnostic and prognostic use in patients with MASH, its invasiveness limits its practical application in routine care and large-scale trials. This narrative review explores the growing role of noninvasive tests in the assessment of disease progression and treatment efficacy in MASH. Approach and Results: This review represents expert opinion synthesizing current literature on the most widely used noninvasive tests being assessed as frontline biomarkers for identification of patients with metabolic dysfunction–associated steatotic liver disease at risk of outcomes and/or in need of pharmacological intervention, and that are being used to assess treatment response in the context of clinical trials, and how they may be translated into clinical practice. Among these, elastography and the enhanced liver fibrosis test are highlighted for their potential to replace liver biopsy in clinical settings and trials. These methods are analyzed for their accuracy and ability to monitor therapeutic response, emphasizing their growing importance in providing reliable measures of clinical improvement as drug development efforts for MASH intensify. Conclusions: This synthetic review aims to provide a roadmap for federal regulators updating and potentially revising the requirements for demonstrating histologic improvement in MASH clinical trials, and for practitioners to translate this information into clinical practice. The ultimate goal is to reduce the reliance on liver biopsy while maintaining the rigor necessary to evaluate therapeutic efficacy, thus accelerating the path to approval for new MASH treatments.

INTRODUCTION: Despite the widespread use of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC), many patients remain at risk of progression. Emerging data suggest that normalization of alkaline phosphatase (ALP) and total bilirubin (TB)—particularly when TB < 0.6 times the upper limit of normal (× ULN)—is associated with improved outcomes compared with ALP reduction to < 1.5 × ULN. This study investigated the association between ALP normalization in response to UDCA and long-term clinical outcomes in a real-world cohort of patients with PBC. METHODS: We compared complication-free survival in patients achieving an ALP > ULN and < 1.5 × ULN (adequate response) with those with an ALP ≤ ULN on UDCA monotherapy. Complication-free survival was defined as the absence of serious liver-related clinical events. Restricted mean survival time was used to quantify survival time gained. RESULTS: Patients achieving normal ALP and/or TB ≤ 0.6 × ULN demonstrated significantly improved complication-free survival compared with those with an adequate ALP response. Event-free survival was extended by 1.34 years (95% CI: 0.56, 2.11; P = 0.001) for ALP normalization alone, 3.7 years (95% CI: 3.11, 4.29; P < 0.001) for TB ≤ 0.6 × ULN, and 4.51 years (95% CI: 4.13, 4.88; P < 0.001) for those meeting both criteria. The risk of severe clinical events was reduced in patients achieving ALP normalization (hazard ratio [HR] 0.34; 95% CI: 0.15, 0.80; P = 0.01), TB ≤ 0.6 × ULN (HR 0.23; 95% CI: 0.09, 0.55; P = 0.001), or both (HR 0.14; 95% CI: 0.05, 0.38; P < 0.001). High-risk patients, defined by liver stiffness measurement ≥ 10 kPa or clinical, histological, or laboratory evidence of cirrhosis or portal hypertension, derived the greatest benefit. DISCUSSION: Achieving normal ALP and TB ≤ 0.6 × ULN is associated with significantly improved complication-free survival, particularly in high-risk patients. These findings highlight the potential of biochemical thresholds as a meaningful therapeutic goal in PBC management.