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 & Aims Liver (LSM) and spleen (SSM) stiffness measurements correlate with hepatic venous pressure gradient (HVPG), the reference standard for defining clinically significant portal hypertension (CSPH, i.e. HVPG ≥10 mmHg). LSM, SSM and derived scores have been proposed for non-invasive CSPH risk assessment. Methods Compensated advanced chronic liver disease (cACLD) patients undergoing same-day HVPG, Supersonic (SSI)-LSM, and SSI-SSM were prospectively included. Reliable SSI-LSM and SSI-SSM were defined by IQR/Med ≤30%. SSI-LSM, SSI-SSM and derived Baveno VII rules, Anticipate-SSI, LPS-SSI, and the newly developed SSI-4PH (LSM/SSM, platelet count: PLT, BMI) model were evaluated in a derivation cohort (DeCo) and an external validation cohort (VaCo). Results The DeCo comprised 220 patients, paired reliable SSI-LSM/SSI-SSM measurements were available in 118 (53.6%) patients including 74.6% with CSPH. The VaCo comprised 86 eligible patients, of whom 73 (84.9%) had paired reliable measurements including 43.8% with CSPH.In reliable paired analyses, AUROCs for CSPH detection in the DeCo were 0.84 for Anticipate-SSI, 0.87 for LPS-SSI, and 0.90 for SSI-4PH; the corresponding AUROCs in the VaCo were 0.78, 0.77, and 0.73. At the fixed ≥75% predicted-risk threshold, specificity of SSI-4PH was 83.3% in the DeCo and 87.8% in the VaCo. Conclusions Reliable SSI-LSM and SSI-SSM provide robust non-invasive assessment of CSPH risk, however, the requirement of reliable (IQR/Med ≤30%) paired measurements may limit applicability. Combined SSI-LSM/SSM-based rules and multivariable models reduced gray-zone, and the SSI-4PH yielded a favorable decision-curve utility for CSPH risk assessment.

BACKGROUND AND AIMS:Endoscopic ultrasound-guided portal pressure gradient (EUS-PPG) measurement is a promising alternative to hepatic venous pressure gradient (HVPG) assessment, especially in settings where HVPG is unavailable or limited. The commercial 25-gauge (25G) system showed good correlation with the hepatic venous pressure gradient (HVPG). However, the 25G has drawbacks due to its small caliber and the proprietary pressure transducer. The aim of this study was to validate a custom-built 22G conventional intravascular pressure transducer system (22G EUS-PPG). METHODS:In this prospective cohort study, 26 patients underwent EUS-PPG measurement using both systems during the same session. The primary outcome was the correlation of PPG values. Secondary outcomes included the correlation and variability of portal vein pressure (PVP) and hepatic vein pressure (HVP) measured by both systems. RESULTS:PPG values showed excellent correlation of both systems (r = 0.901, p < 0.001). 25G EUS-PPG correctly identified clinically significant portal hypertension (CSPH, defined as PPG ≥ 10mmHg) in 25 of 26 (96.2%) cases. Portal vein and hepatic vein pressures also correlated significantly (r = 0.776 and r = 0.673, respectively) between both systems. Variability within both systems was very low to low. CONCLUSION:EUS-PPG measurements obtained using the commercial 25G and custom-built 22G EUS-PPG systems were validated. The custom-built 22G system excels due to pressure-tracing based quality control, availability and cost-efficiency.

BACKGROUND:Acute-on-chronic liver failure (ACLF) is characterised by systemic inflammation and organ failures in patients with decompensated liver cirrhosis. In the absence of specific approved treatments, ACLF is associated with a high short-term mortality. In this study, we aimed to evaluate the investigational drug VS-01, a liposomal formulation for intraperitoneal infusion, in patients with decompensated liver cirrhosis, ascites, and covert hepatic encephalopathy, to inform further studies in patients with more advanced disease (eg, overt hepatic encephalopathy and ACLF). METHODS:This phase 1b, first-in-human, open-label, non-randomised, single ascending and multiple dose study was conducted at the Hospital of the Goethe University Frankfurt in Germany. Eligible patients had decompensated liver cirrhosis, ascites requiring paracentesis, and covert hepatic encephalopathy (ie, minimal or grade 1 according to West Haven criteria) and were aged 18-60 years in part A of the study and 18-64 years in part B. The main exclusion criterion was organ failures meeting the definition of ACLF. Patients received single ascending doses of VS-01 (15 mL/kg, 30 mL/kg, and 45 mL/kg) in part A and multiple doses (34-42 mL/kg per day on 4 consecutive days) in part B, in addition to standard care. VS-01 was administered intraperitoneally over 60 min using a standard paracentesis catheter, with a dwell time of 2 h in part A and on days 2 and 3 of part B and a dwell time of 3 h on days 1 and 4 of part B. At the end of the dwell time, VS-01 was passively drained and the peritoneal cavity was washed. Patients were followed up in hospital for 7 days after the last dose. The primary endpoint was the safety and tolerability of VS-01, including the incidence and severity of treatment-related adverse events (TEAEs) and serious adverse events, vital signs, electrocardiograms (ECGs), and laboratory abnormalities. Safety was analysed in the safety analysis set, defined as all patients who received at least one dose of VS-01. This study was registered with EudraCT, 2018-004606-25, and is complete. FINDINGS:Patients were recruited between Sept 23, 2019, and Dec 18, 2020. Of 15 patients screened, nine were assigned to part A (n=3 per dose level; male:female=7:2) and three were assigned to part B (male:female=1:2). No serious adverse events were reported. 20 TEAEs were reported in seven (58%) of 12 patients (four events in part A; 16 in part B). Most TEAEs were mild (14) and short in duration (19 resolved during follow-up). One TEAE-an overdose of VS-01 (26·4 mL/kg instead of 15 mL/kg; CTCAE grade 1) in part A-was considered to be definitely related to VS-01. Two (10%) of 20 TEAEs were judged to be possibly related to VS-01: one episode of grade 1 extravasation at the infusion site (part A, 45 mL/kg), which resolved within 3 days, and one episode of grade 2 pleural effusion on day 11 (part B, 41·8 mL/kg), which required no therapeutic procedure. Six (30%) of 20 TEAEs (reported in three [25%] patients) were of grade 3 but none were deemed to be treatment-related. No patients discontinued the study or VS-01 due to adverse events. The most common TEAEs were gastrointestinal disorders (seven [35%] of 20 events, reported in four [33%] of 12 patients). No clinically significant changes in vital signs, ECGs, or laboratory values were noted in any patient. INTERPRETATION:VS-01 was generally well tolerated with a favourable safety profile in patients with decompensated liver cirrhosis, ascites, and covert hepatic encephalopathy. The results of this study supported the initiation of proof-of-concept studies in larger cohorts of patients with decompensated cirrhosis and ACLF. FUNDING:Versantis AG.

Background & Aims:The prevalence and evolution of acute-on-chronic liver failure (ACLF), particularly extrarenal organ failures, in patients with cirrhosis and acute kidney injury (AKI) are not well characterized. This study investigated the development and progression of ACLF in patients with cirrhosis who develop AKI, aiming to improve understanding of disease course during the critical period following AKI onset. Methods:We conducted a retrospective cohort study of hospitalized patients with cirrhosis and AKI at two tertiary centers between 2010 and 2023. Data on AKI etiology, treatment, ACLF development and progression, and survival were collected. Multivariable regression models were used to assess associations between baseline and AKI-related characteristics, ACLF outcomes, and mortality. Results:A total of 672 patients (71% male) were included. AKI progression or non-response to therapy occurred in 47% of patients. ACLF was present at the time of AKI diagnosis in 406 patients (60%); among these, 106 (26%) experienced ACLF progression, predominantly involving renal, respiratory, and circulatory failure. Of the 266 patients without ACLF at AKI diagnosis (40%), 101 (38%) subsequently developed ACLF, most commonly with renal, respiratory, and liver failure. In multivariable analysis, patients with hepatorenal syndrome-AKI (HRS-AKI) or other/mixed AKI etiologies had a higher risk of ACLF development compared to those with pre-renal AKI (odds ratio [OR] 9.67, 95% CI 3.96-23.57; OR 4.98, 95% CI 1.78-12.95, respectively). HRS-AKI and AKI stage 2 were independently associated with ACLF progression after adjustment for MELD score and relevant clinical risk factors (OR 2.31, 95% CI 1.08-4.95; OR 2.35, 95% CI 1.03-5.36). The cumulative incidence of death was 47% at 90 days after AKI diagnosis (95% CI 44-51). Conclusions:Patients with cirrhosis who develop AKI are at high risk of ACLF development and mortality. Respiratory failure is the most frequent extrarenal organ failure among patients who develop ACLF or experience ACLF progression. Impact and implications:This study highlights the significant risk of acute-on-chronic liver failure development in patients with cirrhosis and acute kidney injury (AKI), particularly in those with hepatorenal syndrome-AKI or other/mixed types of AKI. Given the high short-term mortality observed, early recognition and risk stratification of AKI in cirrhosis are crucial. These findings are particularly relevant for hepatologists, nephrologists, and intensivists, as they underscore the need for improved therapeutic strategies targeting AKI non-responders. Future prospective studies should not only explore targeted interventions to improve outcomes in this high-risk population but also aim to elucidate the underlying pathophysiology driving AKI progression and acute-on-chronic liver failure development in patients with cirrhosis and AKI.