BACKGROUND & AIMS:Acute-on-chronic liver failure (ACLF) is characterised by multiorgan failure and high short-term mortality in hospitalised patients with acute decompensation of cirrhosis. Although the EASL-CLIF criteria are widely used for diagnosis and prognostication, evolving definitions of organ dysfunction and emerging therapies require updated, tailored criteria to improve diagnostic accuracy, treatment assessment, and applicability in clinical trials. We aimed to develop and validate the A-TANGO organ failure (OF) score to refine ACLF diagnosis and enhance its utility for treatment response evaluation and risk stratification. METHODS:We performed a retrospective analysis of prospective observational cohorts. The derivation cohort comprised three EF-CLIF consortium studies conducted in Europe and Latin America (CANONIC, PREDICT, ACLARA; n = 3,896). Validation cohorts included one study from India (Ambi-spective study n = 2,055) and one from China (CATCH-LIFE; n = 2,568). Patients were enrolled between 2011 and 2023, with follow-up completed in 2023. The primary objective was to redefine thresholds for organ dysfunction and failure using three subscores per organ, with subscore 3 corresponding to ≥15% 28-day mortality and defining organ failure. RESULTS:Compared with the CLIF-C OF score, the A-TANGO OF score introduced revised thresholds for organ failure and added an ACLF grade 4 to address the wide mortality variation within CLIF-C OF grade 3. A-TANGO identified more organ failures, increasing ACLF diagnosis from 24% to 36% and improving the net reclassification index by 16%, while maintaining similar predictive accuracy for 28- and 90-day mortality. Two additional prognostic models (A-TANGO ACLF-WBC and A-TANGO ACLF-CRP) demonstrated strong associations with 28- and 90-day mortality and improved prognostic performance. Findings were confirmed in external validation cohorts. CONCLUSIONS:The A-TANGO OF score is a reproducible and comprehensive tool for ACLF diagnosis with preserved prognostic performance, validated across large international cohorts. It provides a robust framework for clinical trials by enabling more accurate diagnosis, reducing required sample sizes, and offering clinically meaningful endpoints such as ACLF resolution for treatment response assessment. IMPACT AND IMPLICATIONS:The A-TANGO organ failure (OF) score provides a scientifically justified advancement in ACLF research by refining organ-specific dysfunction thresholds and introducing a new grade 4, thereby addressing limitations in current EASL-CLIF criteria and improving identification of high-risk patients. These findings are important for clinicians, researchers, and healthcare systems globally, as they increase detection of organ failure, enhance risk stratification, and enable more accurate prediction of short-term mortality in hospitalized patients with cirrhosis. The A-TANGO OF score and its associated prognostic scores (ACLF-WBC and ACLF-CRP) can be applied in clinical practice to guide treatment decisions, and serve as reliable, measurable endpoints in clinical trials evaluating emerging therapies. Although limitations such as missing data, cohort-specific recruitment differences, and historical classification criteria exist, the consistent and robust performance of the A-TANGO scores across large, multinational cohorts highlights their potential applicability and utility on a global scale.

BACKGROUND:Previous exposure to hepatitis B virus (HBV) may influence the risk of developing hepatocellular carcinoma (HCC) and other liver-related events (LRE), in particular in patients after HCV cure. Previous studies were not conclusive and there are only few large studies on this topic from Europe. METHODS:We analysed clinical endpoints (≥ 3-point increase in MELD score, oesophageal variceal bleeding, ascites, encephalopathy, liver transplantation, death, with/without HCC; HCC alone) in patients cured from HCV. Data were obtained from the German Hepatitis C Registry. Patients after organ transplantation, a history of HCC, HIV co-infection, or HBsAg positivity were excluded. A subanalysis was conducted in patients with cirrhosis. Statistical analyses included logistic regression to identify predictors of clinical endpoints and Kaplan-Meier curves to analyse the influence of HBV serological markers. RESULTS:A cohort of 6198 patients fulfilled inclusion criteria, the median time of follow-up was 2.5 years (range 0.04-8.01). Serological evidence of previous HBV exposure was present in 1889 patients (anti-HBc positive). In patients with cirrhosis, univariate analyses identified anti-HBc positivity (odds ratio [OR], 1.48), cirrhosis (OR, 4.89), features of portal hypertension (ascites (OR, 5.66), oesophageal varices (OR, 4.88)), diabetes (OR, 3.23), and malignancies (OR, 10.34) as risk factors for composite LRE. In multivariable analysis, anti-HBc positivity (OR, 1.53) and cirrhosis (OR, 4.63) remained independent risk factors for the composite endpoints, whereas anti-HBc positivity was not associated with HCC or Kaplan-Meier survival analyses. CONCLUSIONS:Resolved HBV infection was not associated with the development of HCC or survival in Caucasians after HCV cure. Although anti-HBc positivity was linked to composite outcomes, its clinical relevance appears limited. TRIAL REGISTRATION:The registry was registered at the German Clinical Trials Register (DRKS; IDDRKS00009717).

Background Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than 18 million individuals in Germany. Life-style choices including alcohol, coffee and smoking are frequent but prospective data are rare. Methods The German SLD-Registry aims to describe clinical characteristics and observe outcomes in secondary and tertiary care. Detailed data on life-style choices are prospectively collected. Results Baseline data of 903 patients were analysed. 40% (363/903) reported low grade alcohol consumption (mean 1.4 g/day). The alcohol subgroup had higher ferritin (152 vs. 205 ng/ml) but less frequently high-risk fibrosis scores (FIB-4 >2.67 8.5 vs. 15%; NFS >0.675 9.3 vs. 17%) or LS >= 9.6 kPa (25 vs. 73%; OR 0.546 [0.41-0.73], p<0.001). Smokers (current 83/544, former 136/544) had a trend towards higher CAP (326 and 314 vs. 305dB in never smokers (325/544)). No association of smoking to LS >= 9.6 kPa or cirrhosis stage could be observed (OR 0.94 [0.62-1.43], p=0.78). LS >= 9.6 kPa tended to be less frequent in coffee consumers (1-2 cups/day 229/464, 3-4 cups/day 117/464, >5 cups/day 36/464) than in non-consumers (36, 23 and 28% vs. 45%). CAP was not different between these groups. The OR for coffee consumers was reduced (0.58 [0.97-0.34]; p=0.04) with a significant dose dependency (p<0.003). Conclusion Alcohol and coffee consumption are frequent among MASLD patients. Low grade alcohol and any degree coffee consumption were associated with a decreased risk of advanced liver fibrosis. Our data may confirm the beneficial effects of coffee and indicate that very low alcohol consumption may at least not exert relevant unfavourable effects.

The efficacy of granulocyte-colony stimulating factor (G-CSF) treatment for acute-on-chronic liver failure (ACLF) remains controversial. The aim of this study, which is a secondary analysis of the GRAFT study (NCT02669680), was to identify potential prognostic biomarkers in ACLF and to find markers that could be used to predict response to G-CSF treatment. Blood samples from 79 patients randomized in the GRAFT study to receive G-CSF (n = 40) or standard medical therapy (n = 39) were collected at different timepoints. Samples were analyzed for cells, cytokines, extracellular particles, cell-free DNA, and functional properties. An exploratory approach was taken, whereby the measured variables were subjected to univariate and multivariate Cox analyses, and the patients were stratified into clusters by unsupervised hierarchical clustering. Patients with ACLF had increased plasma levels of pro-inflammatory cytokines and increased absolute levels of specific cell populations when compared to healthy controls. ROC curve analysis suggested that plasma VEGF-A levels at baseline (timepoint) are a prognostic factor of transplant-free survival (AUC: 0.70; 95

Objective:Liver diseases represent a major global health burden. Growth Differentiation Factor 15 (GDF-15), a stress-induced cytokine, has been suggested to protect against fibrosis progression through neuro-metabolic-immunologic pathways and to regulate energy and lipid homeostasis, potentially influencing hepatic steatosis. This study evaluated the role of GDF-15 in steatosis and fibrosis, considering prior liver injury, alcohol intake, insulin resistance, and obesity. Design and methods:In this retrospective cohort study, 626 participants from a large population-based cohort were analyzed. Associations of baseline GDF-15, alcohol intake, FIB-4 score, and metabolic risk factors with hepatic steatosis and fibrosis over 6 years were examined using linear regression models. Results:In participants with elevated baseline FIB-4, the interaction of GDF-15 and FIB-4 was positively associated with follow-up liver stiffness (β = 0.47, p = 0.045). Interactions between GDF-15 and higher alcohol intake (3rd/4th quantiles) were negatively associated with stiffness (β = -1.68, p = 0.002; β = -1.43, p = 0.038). GDF-15 was positively associated with follow-up steatosis (β = 37.14, p = 0.006). Higher HOMA-IR (3rd/4th quantile) was linked to increased steatosis (β = 31.15, p = 0.032; β = 38.15, p = 0.023), whereas interactions of HOMA-IR × GDF-15 were inversely associated (β = -38.98, p = 0.008; β = -38.54, p = 0.019), suggesting a protective modulation. Conclusions:GDF-15 appears to modulate hepatic steatosis and fibrosis in individuals with metabolic or lifestyle risk factors, supporting its potential as a therapeutic target and warranting further investigation of the neuro-metabolic-immunologic axis.