Abstracts

1. Acute HEV Infection Is a Relevant Cause of Decompensation and ACLF in Patients With Liver Cirrhosis.

Dinkelborg K, Niehaus C, Bremer B, Wundes C, Tiede A, Petruch N, Deterding K, Kraft ARM, Hartleben B, Cornberg M, Wedemeyer H, Behrendt P, Maasoumy B. Liver Int. 2026 Jul;46(7):e70727. doi: 10.1111/liv.70727.

• BACKGROUND AND AIMS: Hepatitis E virus (HEV) infection is very frequent in Europe with more than 2 million annual infections. Patients with liver cirrhosis may face an increased risk of suffering from acute-on-chronic liver failure (ACLF) due to HEV infection. We explored the consequences and prevalence of infection in individuals with liver cirrhosis.

• METHODS: We retrospectively analysed the clinical outcome of all consecutive patients who were hospitalized at our center due to acute HEV infection and analysed their outcome between 2014 and 2024. Next, we tested 249 sera from 184 cirrhotic patients during individual episodes of acute hepatic decompensation for anti-HEV IgM and HEV-RNA to analyse the relevance of acute HEV infection as a triggering event. Finally, we established a single center cohort of patients with advanced liver cirrhosis, and assessed the anti-HEV IgG seroprevalence ($n = 332$).

• RESULTS: Over the past decade, 32 patients with liver cirrhosis who were hospitalized due to acute HEV infection were identified. Among these patients, 16 (50%) developed ACLF, resulting in five fatalities (31.3%) and three individuals (18.8%) requiring liver transplantation for survival. Of 249 sera obtained during acute hepatic decompensation, 11 (4.4%) were either HEV-RNA positive ($n = 2$) and/or anti-HEV IgM positive ($n = 10$), linking HEV infection to these acute decompensations. Screening of patients with liver cirrhosis for anti-HEV IgG showed that 67.2% of patients (223/332) were anti-HEV negative and thus at potential risk for future HEV infection.

• CONCLUSIONS: Patients with advanced liver cirrhosis are at risk of acute HEV infection, which is a relevant cause of hepatic decompensation and ACLF with high mortality in these patients.

2. Development and validation of the A-TANGO organ failure score for acute-on-chronic liver failure in global cohorts.

Engelmann C, Verma N, Qi T, Kerbert AJC, Pohl J, Morgan C, Kowalski M, Andreola F, Silva MO, Perez Hernandez JL, Palma-Fernandez R, Mendizabal M, Mendez-Guerrero O, Marin JL, Marciano S, Male-Velazquez R, González-Huezo MS, Gadano A, Bessone F, Benitez C, Beltran Galvis OA, Barradas MC, Jimenez MAA, Vagner-Danielsen K, Jarcuska P, Balogh B, Vitalis Z, Putignano A, Tufoni M, Manns M, Francoz C, Romero-Gomez M, Ryder S, Nahon P, Francque S, Özdogan O, Sole C, Ramos JP, Zoller H, Merli M, Bendtsen F, Berg T, Zipprich A, Gatti P, Acevedo J, Janicko M, Uschner FE, Gambino CG, Zaccherini G, Wang X, Zheng X, Deng G, Huang Y, Meng Z, Gao Y, Qian Z, Lu X, Lui F, Shi Y, Shang J, Zheng Y, He Y, Taneja S, Garg P, Van Vlierberghe H, Steib C, Stauber R, Soriano G, Mookerjee R, Gronbaek H, De Gottardi A, Coenraad M, Banares R, Zeuzem S, Gerbes A, Domenicali M, Saliba F, Durand F, Li H, Duseja A, Chen J, Jalan R. J Hepatol. 2026 Jul;85(1):91-105. doi: 10.1016/j.jhep.2026.02.017. Epub 2026 Feb 21.

• 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 $ge 15\%$ 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.

3. Atractylenolide I ameliorates acute-on-chronic liver failure (ACLF) by promoting autophagy and preserving mitochondrial function through mTOR inhibition.

Tang D, Tuo F, Chen J, Ding L, Wu YN, Wang R. Biochim Biophys Acta Mol Basis Dis. 2026 Jun;1872(5):168197. doi: 10.1016/j.bbadis.2026.168197. Epub 2026 Mar 10.

• ABSTRACT: Acute-on-chronic liver failure (ACLF) is a severe liver syndrome marked by systemic inflammation and high mortality, often complicated by autophagy impairment and mitochondrial dysfunction. This study investigates atractylenolide I (AT-1), a compound from Atractylodes macrocephala, for its potential to mitigate ACLF through modulation of mammalian target of rapamycin (mTOR) signaling, autophagy, and mitochondrial integrity. We hypothesized that AT-1 could attenuate ACLF-induced liver damage by enhancing autophagy and mitochondrial function. A rat ACLF model combining chronic liver injury induced by repeated bovine serum + Freund's adjuvant injections with an acute hepatic insult using lipopolysaccharide (LPS) and D-Galactosamine (D-GalN) and LPS-induced BRL 3 A liver cell line were treated with AT-1, with or without mTOR activator MHY1485. In vivo, AT-1 reduced liver fibrosis, inflammation, necrosis, and ALT/AST levels in ACLF rats, while improving autophagy proteins. In vitro, AT-1 enhanced cell viability, decreased apoptosis, and restored autophagic flux and mitochondrial health. The addition of MHY1485 partially reversed these benefits, suggesting the protective effects of AT-1 depend on mTOR inhibition. These findings propose AT-1 as a therapeutic candidate for ACLF by modulating autophagy and mitochondrial function.

4. Short-term mortality is reduced and low grade ACLF reversed by TIPS in patients with fluid overload: a case-control study.

Cervantes-Alvarez E, Gu W, Byrtus J, Meyer C, Treitl M, Euringer W, Gerbes A, Clària J, Aguilar F, Sauerbruch T, Rössle M, Bettinger D, Schultheiss M, Uschner FE, Brol MJ, Kimmann M, Meier JA, Peiffer KH, McCoy MS, Laleman W, Arroyo V, Praktiknjo M, Moreau R, Trebicka J. Clin Transl Gastroenterol. 2026 Jul 6. doi: 10.14309/ctg.0000000000001071. Online ahead of print.

• INTRODUCTION: Portal hypertension characterizes decompensated cirrhosis and its complications. It may trigger acute-on-chronic liver failure (ACLF) which carries a high mortality. Transjugular intrahepatic portosystemic shunt (TIPS) is the most efficient therapy for most portal hypertension-related complications including fluid overload (FO) defined as refractory or recurrent ascites, hepatorenal syndrome and/or hydrothorax. However, TIPS for FO in ACLF is questioned.

• METHODS: In this case-control study, patients from the prospective cohorts CANONIC ($n = 1324$) and German TIPS-Registry ($n = 724$) were screened for cases of FO and matched 1:1 by sex, age, MELD and presence and grade of ACLF. Clinical outcomes, ACLF status and mortality were assessed.

• RESULTS: The total population was 118 ACLF patients of whom 59 received TIPS and 59 did not. The main indication for TIPS was hepatorenal syndrome (61.0%). ACLF patients who did not receive TIPS had a higher 28-day cumulative mortality rate (22.0% vs. 5.1%, $p = 0.009$). At 28 days TIPS insertion in ACLF associated with a 78% mortality reduction ($ ext{HR } 0.22 [0.06 - 0.77]$). It further led to improvement of hepatic encephalopathy and the MELD-score. Additionally, ACLF resolution occurred in 61% of TIPS ACLF patients. The presence of coagulation and circulatory organ failures, and increased bilirubin, INR, MELD and CLIF-C OF associated with 28-day mortality. The survival benefit of TIPS was no longer observed after 90 days.

• CONCLUSIONS: TIPS decreased the 28-day mortality of patients with FO and ACLF. Thus, TIPS should be regarded as a bridging strategy—ideally for liver transplantation.

5. Midodrine versus placebo in patients with acute-on-chronic liver failure with ascites—A randomized trial (MIDAS trial).

Kulkarni AV, Venishetty S, Prasanna S, Iyengar S, Sarada SV, Premkumar M, Sharma M, Alla M, Rao PN, Reddy DN, Reddy KR. Hepatol Commun. 2026 May 22;10(6):e0966. doi: 10.1097/HC9.0000000000000966. eCollection 2026 Jun 1.

• BACKGROUND: Ascites is common in patients with acute-on-chronic liver failure (ACLF) and can complicate the course of ACLF due to circulatory dysfunction and hemodynamic compromise. Oral midodrine has been variably reported to improve hemodynamics and reduce complications of ascites in patients with decompensated cirrhosis, but its role in patients with high MELD ACLF remains unknown, which we aimed to assess.

• METHODS: In this single-center, double-blind, randomized trial, patients with ACLF were assigned 1:1 to receive midodrine (5–7.5 mg tid) or a placebo for 30 days, alongside standard care. Transplant-free survival (TFS) at 1 month was the primary outcome, while secondary outcomes included TFS at 3 months, the proportion of patients achieving ascites control, changes in mean arterial pressure (MAP) and plasma renin activity at 1 month, the incidence of cirrhosis complications, and diuretic-related complications.

• RESULTS: One hundred thirty patients with ACLF were enrolled. Midodrine use was not associated with improvement in TFS at 1 ($ ext{HR: } 0.99 [95\% ext{ CI: } 0.37{-}2.65]$) and 3 months ($ ext{HR: } 0.93 [95\% ext{ CI: } 0.48{-}1.8]$). Ascites control at day 30 (placebo: 9.2% [$95\% ext{ CI: } 3.5{-}19$] vs. midodrine: 20% [$95\% ext{ CI: } 12.3{-}33.5$]; $p = 0.08$) and 90 (placebo: 44.6% [$95\% ext{ CI: } 32.2{-}57.5$] vs. midodrine: 53.8% [$95\% ext{ CI: } 41{-}66.3$]; $p = 0.29$) was comparable. Midodrine increased the MAP (1.9 vs. 6.9 mm Hg; $p = 0.003$) with an insignificant reduction in plasma renin activity levels (delta change: $0.22 pm 1.6$ vs. $-1.6 pm 2.2$; $p = 0.09$). Cirrhosis-related and diuretic-related complications were similar in both groups.

• CONCLUSIONS: Midodrine increases MAP in patients with ACLF and high MELD scores without TFS benefit and does not reduce the rate of ascites-related complications.

6. Extracellular Vesicles Reflect Thrombo-Inflammatory, Endothelial and Tissue-Remodelling Changes in Cirrhosis.

Campello E, Zanetto A, Ferdinande K, Toffanin S, Bulato C, Radu C, Samà C, Spiezia L, Russo FP, Burra P, Senzolo M, Simioni P. Liver Int. 2026 Jul;46(7):e70723. doi: 10.1111/liv.70723.

• BACKGROUND AND AIMS: Cirrhosis is characterized by progressive immune dysregulation, endothelial dysfunction, and haemostatic imbalance. Circulating extracellular vesicles (EVs) have emerged as potential biomarkers reflecting these pathophysiological processes. We aimed to determine whether EVs mirror disease severity and predict liver-related outcomes in cirrhosis.

• METHODS: In this prospective single-centre study, patients with compensated, stable decompensated, or acutely decompensated cirrhosis were enrolled. EVs were isolated from platelet-poor plasma and quantified by flow cytometry to characterize platelet-, endothelial-, immune-, and CK18+ EVs, EVs expressing markers associated with endothelial anticoagulant pathways and tissue remodelling. Primary endpoints were first hepatic decompensation in compensated cirrhosis and a composite of further decompensation, acute-on-chronic liver failure, or liver-related mortality in acutely decompensated cirrhosis. Associations were analysed using Fine-Grey competing-risk models.

• RESULTS: We included 228 patients, including 75 compensated, 44 stable decompensated, and 109 acutely decompensated. Median follow-up was 418 days. EV profiling showed progressive increases in total, platelet-derived, endothelial-, immune-derived, and tissue remodelling-associated EVs across Child-Pugh stages, suggestive of increasing thrombo-inflammatory and endothelial perturbation. First hepatic decompensation occurred in 7 patients with compensated cirrhosis and was associated with higher MELD and Child-Pugh scores, alcohol-related aetiology, and lower platelet count. In univariate competing-risk analyses, higher levels of several EV subpopulations were associated with first decompensation, but these associations disappeared after adjustment for MELD. Among patients with decompensated cirrhosis, 65 developed further decompensation, ACLF, or liver-related death; higher CRP levels were associated with these events, whereas no EV subpopulation was associated with the composite outcome.

• CONCLUSIONS: Circulating EVs reflect cirrhosis severity and are suggestive of progressive thrombo-inflammatory, endothelial, and tissue-remodelling changes. However, EVs were not independently associated with clinical outcomes.

7. Integrated Multi-Omics Analysis and Experimental Validation Identify BCAT1 as a Critical Driver of Hepatocyte Pyroptosis in Acute-On-Chronic Liver Failure.

Li M, Lu B, Chen X, Kang M, Wang G, Wang L, Ye H, Pu F, Wang M, Wen W, Chen Y. FASEB J. 2026 Jun 15;40(11):e71840. doi: 10.1096/fj.202600199RR.

• ABSTRACT: Acute-on-chronic liver failure (ACLF) is characterized by profound metabolic dysfunction and high mortality. Identifying amino acid metabolism-related biomarkers is crucial for early diagnosis and therapeutic intervention. Amino acid metabolism-related genes (AAMGs) and ACLF transcriptomic data were integrated to identify core genes via weighted gene co-expression network analysis (WGCNA) and differential expression analysis. Three machine learning (ML) algorithms—Random Forest, SVM-RFE, and Boruta—were applied to screen hub genes. Specific cellular profiles and immune landscapes were characterized using single-cell RNA sequencing (scRNA-seq) and ssGSEA. The pathological role of BCAT1 was investigated in APAP-induced ACLF models. A total of 26 genes were identified at the intersection of module genes, DEGs, and AAMGs. ML confirmed a three-gene signature (BCAT1, RPS6, OAT) with high diagnostic accuracy. ScRNA-seq analysis further verified that BCAT1 is predominantly expressed in hepatocytes, indicating its cell-type specific role in liver injury progression. In vitro and in vivo experiments demonstrated that BCAT1 exacerbates hepatocyte injury by activating the GSDMD/Caspase-1-mediated pyroptosis pathway. Our study reveals that BCAT1 is a pivotal driver of hepatocyte pyroptosis in ACLF. Targeting the BCAT1-mediated metabolic-inflammatory axis offers a promising therapeutic strategy for managing ACLF.

8. Immune biomarkers predicting response to G-CSF in acute-on-chronic liver failure: results from a GRAFT trial sub-study.

Splith K, Berndt N, Haber PK, Wabitsch S, Feldbrügge L, Herber A, Franke A, Schmiedeknecht A, Mengwasser J, Bruns T, Reuken PA, Goeser T, Berg C, Wedemeyer H, Chang J, Mueller T, Aehling N, Lammert F, Galle PR, Jiang ZG, Robson SC, Engelmann C, Berg T, Schmelzle M. Hepatol Int. 2026 Jun;20(3):852-863. doi: 10.1007/s12072-026-11069-5. Epub 2026 Mar 7.

• BACKGROUND: 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), wa^{C}s to identify potential prognostic biomarkers in ACLF and to find markers that could be used to predict response to G-CSF tre^{C}atment.^{{C}{C}{C}{C}{C}}

  {C}{C}{C}{C}{C}{C}{C}{C}
  {C}{C}{C}{C}{C}{C}{C}{C}

   

• METHODS: Blood samples from 79 patients randomized in the GRAFT study to receive G-CS^{C}F (^{C}{C}{C}{C}$n = 40$) or standard medical therapy (^{C}{C}{C}{C}$n = 39$) were collected at different timepoi^{C}nts. Samples were analyzed for cells, cytokines, extracellular particles, cell-free DNA, and functional properties. An exploratory approac^{C}h was taken, whereby the measured variables were subjected to univariate and multivariate Cox analyses, and the patients were stratified into clus^{C}ters by unsupervised hierarchical clustering.^{C}

  {C}{C}{C}{C}{C}{C}{C}{C}
  {C}{C}{C}{C}{C}{C}{C}{C}

   

• RESULTS: Patients with ACLF had increased plasma levels of pro-inflammatory cytokines and increas^{C}ed 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 ($ ext{AUC: } 0.70; 95\% ext{ CI } 0.56{-}0.84$). Hierarchical clustering of circulating immune cell populations at baseline appeared to define a patient subset within the analyzed G-CSF-treated patients with improved median transplant-free survival (102 days vs 16 days; ^{C}{C}$p = 0.002$). In our study, a higher percentage of C^{C}D39+ lymphocytes serves as an independent predictor of unfavorable outcomes following G-CSF treatment ($ ext{HR: } 1.05, 95\% ext{ CI: } 1.01{-}1.09, p = 0.008$).^{C}{C}{C}

  {C}{C}{C}{C}{C}{C}{C}{C}
  {C}{C}{C}{C}{C}{C}{C}{C}

   

• CONCLUSION: VEGF-A appears to be a suitable biomarker for predicting the prognosis of patients with ACLF. With the help of hierarchical cell clusters, ACLF patients who could benefit from G-CSF therapy could be identified and selected prior to ^{C}treatment. CD39 expression on lymphocytes seems suitable to allow stratification. Further testing and validation are necessary and could help to adapt treatment op^{C}tions for each individua^{C}l patient.

  {C}{C}{C}{C}{C}{C}{C}{C}
  {C}{C}{C}{C}{C}{C}{C}{C}

   

9. Physical frailty is the most important predictor of early mortality in hospitalized patients with decompensated cirrhosis.

D'Arcangelo F, Vivian LM, Ferrarese A, Gambato M, Germani G, Senzolo M, Russo FP, Burra P, Zanetto A. Hepatol Commun. 2026 Jun 12;10(7):e0972. doi: 10.1097/HC9.0000000000000972. eCollection 2026 Jul 1.

• BACKGROUND: Frailty and sarcopenia are associated with mortality in cirrhosis. However, most data come from North American cohorts in the outpatient setting. We aimed to assess the impact of frailty and sarcopenia in a prospective cohort of inpatients with cirrhosis.

• METHODS: All patients with decompensated cirrhosis admitted to our unit between October 2021 and March 2023 were prospectively screened for recruitment. Frailty was assessed using the liver frailty index, while sarcopenia was assessed via skeletal muscle index on CT scans performed during hospitalization, respectively. All patients were followed for transplant-free survival as the primary outcome.

• RESULTS: We included 127 patients (median age 59 y; 68.5% male; median MELD score: 22; 70% with Child-Pugh C cirrhosis). At inclusion, 48.8% of patients were frail, and 60% were sarcopenic. Compared with robust and non-sarcopenic individuals, those with frailty and sarcopenia required ICU care more frequently during hospitalization. Moreover, frailty was associated with a longer hospital stay (15 [9-27] vs. 6.5 [4-15]; $p = 0.001$). During a median follow-up of 96 days (IQR 37-384), 39.4% patients died. Frailty and sarcopenia were associated with a higher mortality (60% vs. 20% and 58% vs. 38%, respectively; $p < 0.001$ and $p < 0.013$). However, in multivariate analysis, only frailty ($ ext{HR: } 2.218; 95\% ext{ CI: } 1.314{-}3.743; p = 0.003$) was an independent predictor of reduced transplant-free survival.

• CONCLUSIONS: Frailty emerges as the strongest, independent predictor of early mortality in cirrhosis patients with acute decompensation. Thus, its assessment via the liver frailty index should be performed to improve risk stratification and clinical management.

10. Role of Gram-Negative Bacterial Infections in Acute-On-Chronic Liver Failure.

Cadoli C, Müller V, Welsch C, Mühl H, Trebicka J, Kempf VAJ. Liver Int. 2026 Jul;46(7):e70710. doi: 10.1111/liv.70710.

• ABSTRACT: Acute-on-chronic liver failure (ACLF) is a systemic disease characterised by an acute clinical deterioration of pre-existing liver cirrhosis leading to multiple organ failure due to systemic inflammation. It may be triggered by the translocation of bacteria and bacterial compounds across the gut barrier. The transmigration of Gram-negative bacteria from the gut to the liver, along with the development of bacterial multidrug resistance, drives the progression of chronic liver disease from a compensated or stable decompensated state to acute organ failure associated with high mortality rates. Furthermore, bacterial infections such as peritonitis, pneumonia, urinary tract infections, and skin infections contribute to the onset of ACLF in affected patients. In this review, we examine how bacteria, their metabolites, and antimicrobial resistance contribute to the pathogenesis and outcomes of ACLF, independently of the ACLF definition.

11. Analyzing research advances in single-cell sequencing technology for immunopathological mechanisms in acute-on-chronic liver failure.

Zang SX, Cui CJ, Cui J, Zhang YL, Fu N, Nan YM. Zhonghua Gan Zang Bing Za Zhi. 2026 Jun 20;34(6):589-594. doi: 10.3760/cma.j.cn501113-20250715-00277.

• ABSTRACT: Acute-on-chronic liver failure (ACLF) is a clinical syndrome characterized by acute deterioration of liver function on the basis of chronic liver disease, primarily manifested as liver and/or extrahepatic organ failure. Due to its rapid progression and poor prognosis, ACLF poses a serious threat to the patient's life. The pathogenesis process of ACLF is extremely complex, with overactivation and dysregulation of the immune system playing key roles in disease development. The high heterogeneity and complexity of immune cells have limited systematic understanding of the disease mechanisms and hindered the development of new therapies. The rise of single-cell sequencing technology has enabled the exploration of gene expression profiles at the single-cell level with high resolution, offering significant application value in analyzing the immune microenvironment and pathogenesis of ACLF, thereby helping to promote the exploration and development of new treatment methods. This review summarizes recent key advances in the application of single-cell sequencing technology in ACLF research, providing a theoretical basis for clarifying the pathogenesis and developing novel targeted treatment strategies.

12. Prediction models for mortality in patients with acute on chronic liver failure: systematic review and critical appraisal.

Song T, Zhao J, Jiang B, Wang X, Li Z, Pang Q. Front Med (Lausanne). 2026 Jun 16;13:1829188. doi: 10.3389/fmed.2026.1829188. eCollection 2026.

• BACKGROUND: Acute-on-chronic liver failure (ACLF) is a severe syndrome with rapid progression and high short-to-medium-term mortality. Accurate prognostic risk stratification is essential for guiding clinical decisions and optimizing treatment. While numerous prediction models for ACLF have been developed, their performance and clinical applicability remain unclear, warranting a systematic evaluation to guide evidence-based model selection.

• METHODS: PubMed, Web of Science, Cochrane Library, and Embase were systematically searched from database inception to December 31, 2025. Data extraction and methodological assessment were conducted using CHARMS. Risk of bias was evaluated using PROBAST. A meta-analysis of c-statistics was performed using R software (version 4.4.2).

• RESULTS: A total of 9,447 studies were identified, with 185 ultimately included, covering 241 external validation cohorts evaluating 75 distinct prognostic models. Approximately 99.51% of analysis units were judged to have a high risk of bias, primarily due to insufficient numbers of outcome events, failure to account for data complexity, and inappropriate assessment of model performance. A total of 24 models met the criteria for meta-analysis at least at one time point, with c-statistics ranging from 0.58 to 0.84. Overall, model discrimination declined with longer prediction horizons, increasing the estimation uncertainty. ACLF-specific models (e.g., CLIF-C ACLF, COSSH ACLF, COSSH ACLF II) showed relatively better discrimination than general models. Among these, the CLIF-C ACLF showed a certain degree of stability across subgroups, though further validation is needed.

• CONCLUSION: The overall risk of bias in the included external validation studies was high, with most lacking calibration reports. Therefore, the current evidence primarily supports relative comparisons of model discrimination, but is insufficient to justify their use as precise probability-based tools for direct clinical decision-making. Most prediction models demonstrated moderate to good discrimination, though their performance declined with longer prediction horizons. COSSH ACLF, COSSH ACLF II, and CLIF-C ACLF showed relatively better discrimination than general models in the available evidence, though this advantage needs further confirmation in higher-quality studies. Future research should focus on well-designed, multicenter validation studies, with systematic evaluation of calibration and long-term predictive performance, to further strengthen the evidence base for ACLF prognostic prediction models.

13. Integrated analysis of transcriptome and metabolome reveals key metabolites-related genes in chronic liver failure.

Shu F, Huang Y, Zhang K, Lin Y, Li J, Long F, Mao D, Wang N. Genomics. 2026 Jul;118(4):111261. doi: 10.1016/j.ygeno.2026.111261. Epub 2026 May 19.

• OBJECTIVES: To identify molecular biomarkers associated with chronic liver failure (CLF) progression to acute-on-chronic liver failure (ACLF).

• METHODS: RNA-seq data from 8 CLF patients—stratified into high-severity (G, ACLF with total bilirubin $ge 171 mu ext{mol/L}$) and low-severity (L, stable CLF with total bilirubin $< 171 mu ext{mol/L}$) groups—along with 4 healthy controls were analyzed. Weighted gene co-expression network analysis (WGCNA) was performed to identify disease-associated gene modules.

• RESULTS: A total of 3,112 differentially expressed genes (DEGs) were identified, with KEGG analysis showing enrichment in innate immune pathways. Metabolomic profiling revealed 63 differentially expressed metabolites (DEMs), with four bile acids—Glycochenodeoxycholic acid, Glycocholic acid, Glycodeoxycholic acid, and Lithocholic acid—identified as key metabolites in bile acid biosynthesis pathways. Strong negative correlations were observed between these hydrophobic bile acids and 33 hub genes.

• CONCLUSIONS: Bile acid metabolism dysregulation and associated hub genes may contribute to CLF severity progression, warranting validation in larger cohorts.

14. Candesartan Cilexetil Restores Renal Endothelial Function Through Modulation of the ADMA-DDAH-eNOS Pathway in Experimental ACLF-Associated Renal Dysfunction.

Vairappan B, T S R, Mohandas S, Wright G. J Clin Exp Hepatol. 2026 Jul-Aug;16(4):103585. doi: 10.1016/j.jceh.2026.103585. Epub 2026 Jun 6.

• BACKGROUND/AIMS: Renal dysfunction is a frequent and life-threatening complication of advanced cirrhosis and is particularly common in acute-on-chronic liver failure (ACLF), where it is associated with high mortality and poor clinical outcomes. This study aimed to (1) elucidate the role of the renal asymmetric dimethylarginine (ADMA)-dimethylarginine dimethylaminohydrolase (DDAH)-endothelial nitric oxide synthase (eNOS) axis in cirrhosis $pm$ superimposed inflammation (mimicking ACLF) with renal dysfunction, and (2) evaluate the effects of CC on this pathway.

• METHODS: Male Wistar rats were administered carbon tetrachloride (15% v/v in corn oil, 0.5 mL/kg, twice weekly for 14 weeks) to induce cirrhosis with renal dysfunction. After 14 weeks, rats were randomized to receive CC (8 mg/kg orally for 2 weeks) before an acute lipopolysaccharide (LPS) challenge. All animals were sacrificed at week 16.

• RESULTS: $ ext{CCl}_4$-induced cirrhotic rats showed decreased mean arterial pressure (MAP), renal blood flow (RBF), and increased renal vascular resistance (RVR), and elevated kidney injury markers neutrophil gelatinase-associated lipocalin, blood urea nitrogen, and kidney injury molecule-1 along with heightened renal inflammation. Acute LPS administration further exacerbated these abnormalities. CC treatment markedly reduced renal injury and inflammatory markers in cirrhotic $pm$ LPS-challenged rats, although MAP, RBF, and RVR remained unchanged. In ACLF rats with renal dysfunction, CC significantly lowered renal ADMA levels and increased phosphorylated eNOS and DDAH-1 expression, while DDAH-2 expression decreased. CC also restored renal nitric oxide (NO) levels, enhanced antioxidant enzyme activity, and reduced oxidative stress.

• CONCLUSION: This study provides the first evidence that CC enhances renal NO bioavailability by upregulating DDAH-1 and eNOS expression and reducing ADMA accumulation, thereby improving renal endothelial function in cirrhosis with renal dysfunction. Targeting DDAH-1-mediated NO restoration may represent a promising therapeutic strategy for managing renal dysfunction in cirrhosis.

  15. Characterization of Multi-Stage Metabolic Alterations in Hepatitis B Virus-Related Acute-on-Chronic Liver Failure Using High-Coverage Metabolomics

• Full Citation: Zhang Z, Jiang H, Zhang G, Chen D, Su X, Li L, Li L. Metabolomics. 2026 Jun 16;22(4):93. doi: 10.1007/s11306-026-02462-0. PMID: 42301606.

• Abstract / Summary:

  • Introduction: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a severe clinical syndrome characterized by acute hepatic decompensation and systemic organ failure, leading to high short-term mortality.

  • Objectives & Methods: This study performed high-sensitivity untargeted metabolomic profiling on serum samples from 125 HBV-ACLF patients (staged across ACLF-1, ACLF-2, and ACLF-3 via COSSH criteria), 34 chronic hepatitis B (CHB) patients, and 32 healthy controls using chemical isotope labeling (CIL) LC-MS.

  • Key Findings:

    • Metabolic Trajectories: Identified over 2,000 amine/phenol-containing metabolites, showing dynamic stage-specific shifts (32 altered metabolites starting in CHB, rising to 91 in ACLF-1).

    • Pathways Affected: Significant increases were observed in $gamma$-glutamyl dipeptides and the tryptophan-kynurenine pathway, alongside decreases in the tryptophan-serotonin pathway.

    • Compensatory Response: Activation of cysteine, methionine, and taurine pathways highlighted systemic responses to heightened oxidative stress and hepatic injury

    • Here is the entire set from 16 to 29 presented with clean, consistent left-aligned formatting across every section.

      16. Impact of Non-Selective Beta-Blockers on Acute Kidney Injury Outcomes in Patients with Decompensated Cirrhosis

    • Full Citation: Incicco S, Patidar KR, Juanola A, et al. J Hepatol. 2026 Jul 15:S0168-8278(26)02717-0. doi: 10.1016/j.jhep.2026.06.043
    • Background & Aims: Current guidelines recommend discontinuing non-selective beta-blockers (NSBB) in patients with cirrhosis and acute kidney injury (AKI) based primarily on expert opinion. This international multicenter study evaluated the actual impact of NSBBs on AKI outcomes in decompensated cirrhosis.
    • Methods: Out of 1,238 hospitalized patients with decompensated cirrhosis and AKI, 503 were receiving NSBBs (propranolol 55%, carvedilol 45%). Analyses used Inverse Probability of Treatment Weighting (IPTW) to balance baseline demographics and liver disease severity.
    • Key Findings:
      • At AKI Diagnosis: NSBB treatment at diagnosis was associated with a higher likelihood of AKI resolution (sHR = 1.29, 95% CI: 1.12–1.48, p < 0.001) and reduced 28-day mortality (sHR = 0.70, 95% CI: 0.55–0.91, p = 0.006).
      • Continuation vs. Withdrawal: After excluding clinically unfeasible cases, continuing NSBBs showed no evidence of harm or worse AKI resolution (sHR = 0.84, p = 0.391) or 28-day mortality (sHR = 0.51, p = 0.089).
    • Conclusion: NSBB use at AKI onset is associated with improved renal recovery and survival; systematic withdrawal may be unnecessary, supporting personalized clinical decision-making.

    • 17. Proton Pump Inhibitors in Acute-on-Chronic Liver Failure: A Sheep in Sheep's Clothing

    • Full Citation: Rodríguez-Perálvarez ML. Rev Esp Enferm Dig. 2026 Jul;118(7):375-376. doi: 10.17235/reed.2026.12005/2026
    • Overview: Editorial comment reviewing the prospective multicenter study by García-Gavilán et al. regarding chronic proton pump inhibitor (PPI) therapy in patients with acute-on-chronic liver failure (ACLF).
    • Key Takeaway: Despite theoretical concerns regarding gut microbiome alterations, bacterial translocation, and spontaneous bacterial peritonitis in end-stage liver disease, empirical data demonstrate that chronic PPI use does not increase ACLF severity, complication rates, or mortality. Deprescribing PPIs in ACLF patients is not indicated if a valid medical reason for use exists.

    • 18. Proton Pump Inhibitors Do Not Impact on the Severity and Mortality of Acute-on-Chronic Liver Failure - Andalusian Multicentric Prospective Study

    • Full Citation: García-Gavilán MDC, Guerrero-Misas M, García-García AM, et al. Rev Esp Enferm Dig. 2026 Jul;118(7):377-383. doi: 10.17235/reed.2025.11547/2025
    • Background & Aims: Evaluated whether chronic PPI therapy increases ACLF severity (measured by CLIF-C-OF and CLIF-C-ACLF scores) and mortality at 28 days, 3 months, and 6 months.
    • Methods: Prospective cohort study enrolling 59 patients diagnosed with ACLF, stratified into chronic PPI users (n = 26) and non-users (n = 33).
    • Key Findings:
      • Inappropriate Prescriptions: 69% of chronic PPI users had no documented clinical indication.
      • No Impact on Outcomes: Chronic PPI use showed no significant association with ACLF severity scores (CLIF-C-OF p = 0.44; CLIF-C-ACLF p = 0.87) or mortality during admission (p = 0.63), at 28 days (p = 0.70), or at 3 months (p = 0.98).
    • Conclusion: Chronic PPI exposure is not independently associated with increased ACLF severity or short-term mortality, though inappropriate prescription rates remain high.

    • 19. Hepatic Encephalopathy Severity and Mortality Risk Stratification in Alcohol-Related Acute-on-Chronic Liver Failure

    • Full Citation: Glisic T, Korica B, Beronja B, et al. Diagnostics (Basel). 2026 Jun 5;16(11):1741. doi: 10.3390/diagnostics16111741
    • Objectives: Assessed whether the admission grade of hepatic encephalopathy (HE) via West Haven criteria predicts short-term mortality in patients with alcohol-related ACLF admitted to the ICU (n = 100).
    • Key Findings:
      • Survival Impact: Higher-grade HE was strongly associated with elevated 7-day (p = 0.031) and 28-day mortality (p = 0.002), alongside higher organ failure severity (CLIF-C OF, SOFA, and APACHE II scores, all p < 0.001).
      • Role of AKI: Acute kidney injury was independently associated with short-term mortality across both high- and low-grade HE groups.
    • Conclusion: Baseline HE grade provides robust mortality risk stratification in alcohol-related ACLF, with organ failure and AKI serving as key prognostic drivers.

    • 20. Stem Cell Therapies for Liver Cirrhosis: A GRADE Evaluation Through a Systematic Review

    • Full Citation: Prasad M, Shenoy P, Prabhakar T, et al. Ann Hepatol. 2026 Jun 15:102241. doi: 10.1016/j.aohep.2026.102241
    • Objectives: Systematically evaluated the overall efficacy and safety of stem cell therapy versus standard care or placebo in liver cirrhosis and ACLF using Cochrane RoB 2 and GRADE methodology across 19 studies.
    • Key Findings:
      • Mortality: Meta-analysis of 15 RCTs (n = 925) yielded a pooled risk ratio (RR) for mortality of 0.63 (95% CI: 0.43–0.91), but evidence certainty was rated very low due to high risk of bias and imprecision.
      • MELD Score: Meta-analysis of 10 RCTs (n = 250) demonstrated a modest reduction in MELD score (mean difference: -1.22, 95% CI: -2.25 to -0.19).
    • Conclusion: Current clinical evidence supporting stem cell therapy in cirrhosis and ACLF remains of very low certainty; routine adoption requires rigorous, high-quality RCTs.

    • 21. Association of Toll-like Receptor Gene Polymorphisms with Susceptibility to Hepatitis B Virus-Related Acute-on-Chronic Liver Failure

    • Full Citation: Zhang Q, Wang C, Niu D, Bai H, Xu F. Sci Rep. 2026 Jun 24. doi: 10.1038/s41598-026-58802-6
    • Objectives: Evaluated serum concentrations and genetic variants of TLR2, TLR4, and TLR9 as susceptibility factors for HBV-ACLF (n = 160) compared to chronic hepatitis B controls (n = 280) and healthy controls (n = 280).

    • 22. A Prospective Study of 12-Month Survival of Patients with Cirrhosis Admitted to Intensive Care

    • Full Citation: Au M, Mah XJ, Yeoh SW, et al. Intern Med J. 2026 Jun 22. doi: 10.1111/imj.70433
    • Objectives: Prospectively evaluated 12-month survival and compared liver-specific versus general ICU prognostic scores in 100 cirrhotic patients with unplanned ICU admissions.
    • Key Findings:
      • 12-Month Survival: Overall 12-month survival was 60%. Sepsis was the primary precipitant of ACLF and carried lower 30-day survival, whereas non-variceal upper GI bleeding had favorable 12-month outcomes.
      • Score Performance: In patients with ACLF (n = 57), day-1 MELD score best predicted long-term survival. In patients without ACLF, standard prognostic scores performed poorly (AUROC < 0.60).
    • Conclusion: Critically ill cirrhotic patients can achieve favorable long-term survival; distinguishing ACLF from non-ACLF guides appropriate scoring selection.

    • 23. Prognosis of Critically Ill Patients with Cirrhosis and Acute Kidney Injury Initiated on Dialysis

    • Full Citation: Kerns E, Agameya A, Abdelfattah A, et al. BMC Nephrol. 2026 Jun 11. doi: 10.1186/s12882-026-05096-5
    • Objectives: Investigated short- and medium-term survival outcomes in 131 ICU patients with cirrhosis and AKI who required kidney replacement therapy (KRT; 86.3% acute tubular necrosis, remainder HRS-AKI).
    • Key Findings:
      • Survival Outcomes: Overall survival was low, with 21.4% alive at 1 month and 15.3% alive at 6 months post-ICU admission (median post-KRT survival: 5 days).
      • Predictors of Mortality: Multivariable Cox regression showed that the overall CLIF-C ACLF score (HR = 1.03, p = 0.04), platelets (p = 0.02), and INR (p = 0.05) independently predicted survival, whereas MELD-Na, transplant listing status, and AKI etiology did not.
    • Conclusion: High mortality in dialyzed cirrhotic ICU patients is primarily driven by systemic extrarenal organ failures captured by CLIF-C ACLF, rather than isolated renal metrics.

    • 24. Conversion to LCP Tacrolimus Mitigates Calcineurin-Induced Nephrotoxicity in Patients After Liver Transplantation

    • Full Citation: Brol MJ, Munske I, Kabar I, et al. Clin Transplant. 2026 Jun;40(6):e70602. doi: 10.1111/ctr.70602
    • Objectives: Examined whether converting liver transplant recipients from standard-release tacrolimus (SR-Tac, n = 107) to extended-release LCP-tacrolimus (LCPT, n = 63) improves the concentration-to-dose ratio and renal function over 24 months.
    • Key Findings:
      • Bioavailability: LCPT achieved significantly higher concentration-to-dose ratios during Year 1 (p = 0.003) and Year 2 (p = 0.004).
      • Renal Preservation: LCPT patients demonstrated improvements in mean estimated glomerular filtration rate (eGFR), while SR-Tac patients experienced a mean eGFR decline of -5.4 mL/min/1.73m² at 24 months (p < 0.001).
    • Conclusion: Switching to LCP-tacrolimus mitigates calcineurin inhibitor-induced nephrotoxicity in liver transplant recipients without compromising graft function.

    • 25. Clinical Characteristics and Outcomes of Invasive Fungal Infections in Critically Ill Patients with Liver Cirrhosis

    • Full Citation: Seeßle J, Pelivan E, Kirchner M, et al. BMC Infect Dis. 2026 Jun 4;26(1):1088. doi: 10.1186/s12879-026-13709-5
    • Objectives: Assessed the prevalence, onset timing, and survival impact of invasive fungal infections (IFIs) among 488 cirrhotic patients admitted to the ICU.
    • Key Findings:
      • Prevalence & Timing: IFI occurred in 6.1% of patients (46.7% invasive candidiasis, 53.3% invasive pulmonary aspergillosis), with median onset times of 14.5 and 17.5 days in the ICU, respectively.
      • Risk Profile: Patients with IFI presented with significantly higher baseline MELD scores (p < 0.001), severe ACLF (p = 0.009), higher baseline bacterial infection rates, and markedly reduced 30- and 90-day survival.
    • Conclusion: Routine fungal surveillance is essential for high-risk ICU cirrhotic patients, particularly those with ACLF and early bacterial co-infections.

    • 26. Smaller Lateral-to-Medial Tibial Plateau Ratios Are Strongly Correlative With Anterior Cruciate Ligament Tears and Reconstruction Failures

    • Full Citation: Ihn HE, Hunter CDR, Mortensen AJ, et al. Arthroscopy. 2026 Jun;42(6):1030-1038. doi: 10.1002/arj.70149
    • Objectives: Evaluated the lateral-to-medial tibial plateau (LTP/MTP) length ratio on T1 MRI among intact ACL controls (ACLi), primary ACL tears (ACLp), and failed ACL reconstructions (ACLf).
    • Key Findings:
      • Primary Tear Predictor: A smaller LTP/MTP ratio was lower in ACLp (0.79) and ACLf (0.77) versus ACLi controls (0.84, p < 0.001) and was the primary independent predictor of primary ACL tears (OR = 0.87).
      • Revision Failure Predictors: Reconstruction failure was independently predicted by smaller LTP/MTP ratio (OR = 0.82), increased posterior tibial slope (OR = 1.38 per 1° increase), and narrower tibial eminence width (OR = 0.70).
    • Conclusion: The LTP/MTP ratio represents an anatomical risk factor for primary ACL tears and subsequent graft failure.

    • 27. Functional Liver Imaging Score (FLIS): A Prognostic Biomarker for Acute-on-Chronic Liver Failure and Liver-Related Mortality

    • Full Citation: Poetter-Lang S, Balcar L, Ba-Ssalamah A, et al. JHEP Rep. 2026 Jun 17:101928. doi: 10.1016/j.jhepr.2026.101928
    • Objectives: Evaluated whether semiquantitative FLIS (0–6 scale from gadoxetic acid-enhanced MRI) and quantitative MRI parameters predict ACLF and liver-related mortality in 210 patients with advanced chronic liver disease (ACLD).
    • Key Findings:
      • Risk Stratification: Lower FLIS independently predicted ACLF development or liver-related death in acutely decompensated patients (adjusted SHR = 2.37, 95% CI: 1.08–5.17, p = 0.031), controlling for MELD-Na, albumin, and etiology.
      • Quantitative Parameters: Quantitative enhancement metrics (RLE, REB, LPC) distinguished acute decompensation from stable ACLD but failed to predict ACLF or mortality.
    • Conclusion: Semiquantitative FLIS is a validated imaging biomarker that independently predicts ACLF and liver-related mortality during acute decompensation.

    • 28. Distinct Amino Acid Metabolic Subtypes Predict Prognosis and Stratify Treatment Response in Acute-on-Chronic Liver Failure

    • Full Citation: Zheng H, Yu S, Zhou T, et al. Hepatol Int. 2026 Jun;20(3):864-874. doi: 10.1007/s12072-026-11077-5
    • Objectives: Applied metabolomic clustering in a prospective cohort of 142 ACLF patients to identify distinct amino acid subtypes and evaluate differential survival responses to artificial liver support (ALS).
    • Key Findings:
      • Metabolic Subtypes: Cluster 2 showed severe amino acid dysregulation (branched-chain amino acids and glutamine pathways) and significantly higher 90-day mortality (p = 0.032).
      • Treatment Response: IPTW-adjusted modeling showed distinct treatment interaction: ALS provided significant survival benefits in Cluster 1, but reduced benefit in Cluster 2.
    • Conclusion: Baseline amino acid metabolic profiling provides precise subtype stratification to identify ACLF patients most likely to benefit from artificial liver support.

    • 29. Bioartificial Livers Developed From Gene-Edited Pig Hepatocyte Organoids Improve Amino Acid and Lipid Profiles in Patients With Liver Failure

    • Full Citation: He Y, Deng Y, Zhu X, et al. MedComm (2020). 2026 May 31;7(6):e70795. doi: 10.1002/mco2.70795
    • Objectives: Developed a bioartificial liver (BAL) system utilizing CRISPR/Cas9 GGTA1-knockout primary porcine hepatocytes co-cultured into organoids with R-spondin1-overexpressing human endothelial cells (R-HUVECs).
    • Key Findings:
      • Detoxification: Ex vivo perfusion of plasma from ACLF patients through the organoid BAL system significantly reduced toxic metabolites, including ammonia and bilirubin.
      • Metabolic Normalization: Comprehensive profiling demonstrated clear restoration and stabilization of amino acid and lipid pathways in treated plasma.
    • Conclusion: Gene-edited porcine hepatocyte organoids offer a scalable cell source for bioartificial liver devices, effectively stabilizing metabolic homeostasis in severe liver failure.

    •  

    • Key Findings:
      • Elevated TLR Levels: Patients with HBV-ACLF exhibited significantly higher serum concentrations of TLR2, TLR4, and TLR9 compared to CHB controls (p < 0.05).
      • Genetic Markers: The TLR2 -196 to -174 deletion variant (D/D genotype: OR = 1.87, p = 0.012) and TLR9 rs187084 polymorphism (C/C genotype: OR = 2.66, p = 0.021) were identified as independent risk factors for HBV-ACLF.
      •  
    • Conclusion: Specific TLR2 and TLR9 gene polymorphisms are strongly associated with genetic susceptibility to HBV-ACLF.

  • 30. Optimal Timing of Therapeutic Plasma Exchange and Hepatic Encephalopathy Severity as Predictors of Clinical Outcome in Liver Failure: A Retrospective Observational Study

  • Full Citation: Charmode JS, Das S, Aishwarya V, et al. J Clin Apher. 2026 Jun;41(3):e70131. doi: <-block _nghost-ng-c2614856368="">10.1002/jca.70131
  • Background & Aims: Evaluated clinical outcomes and response predictors in 22 liver failure patients undergoing therapeutic plasma exchange (TPE) as a bridging therapy.
  • Methods: Retrospective observational study analyzing demographic details, HE grade, timing of TPE initiation, laboratory parameters, and clinical outcomes.
  • Key Findings:
    • HE Grade Impact: Patients with lower HE grades showed significantly better clinical improvement ($ge 1$-grade HE improvement with hemodynamic stabilization and biochemical recovery, $p = 0.031$).
    • Timing & Biomarkers: Earlier initiation of TPE ($< 10$ days) showed a trend toward improved outcomes. Significant post-TPE reductions were observed in total bilirubin, INR, ALT, and AST, though biochemical recovery did not always correlate with clinical response.
  • Conclusion: Early TPE improves biochemical recovery and may prevent progression to advanced encephalopathy; larger prospective studies are needed to determine optimal timing.

  • 31. Acute-on-Chronic Liver Failure Triggered by Postpartum Variceal Bleeding in a Patient with Alcohol-Associated Liver Disease

  • Full Citation: Kobayashi Y, Kimura T, Yamazaki T, et al. Clin J Gastroenterol. 2026 Jun;19(3):646-651. doi: <-block _nghost-ng-c2614856368="">10.1007/s12328-026-02307-2
  • Case Report: Details a 41-year-old woman with alcohol-associated cirrhosis who conceived via IVF (with no varices visible on screening one year prior to delivery) who developed massive hematemesis on postpartum day 4 following a cesarean section.
  • Course & Management: The bleed precipitated ACLF with grade 4 hepatic encephalopathy and coagulopathy. Hemorrhage was controlled via endoscopic variceal ligation, while HE was managed with TPE and hemodiafiltration.
  • Conclusion: The patient achieved full recovery without liver transplantation. The immediate postpartum period represents a highly vulnerable window due to rapid hemodynamic shifts, suggesting repeat endoscopic screening during pregnancy may be warranted in selected patients.

  • 32. Low-Volume Plasma Exchange Following Double Plasma Molecular Adsorption System in Acute-On-Chronic Liver Failure: A Plasma-Sparing Strategy

  • Full Citation: Chen X, Yu L, Huang Y, et al. J Clin Apher. 2026 Jun;41(3):e70144. doi: <-block _nghost-ng-c2614856368="">10.1002/jca.70144
  • Background & Aims: Investigated whether combining Double Plasma Molecular Adsorption System (DPMAS) with low-volume plasma exchange (LVP: 600–800 mL, $n = 76$) provides non-inferior outcomes to half-volume plasma exchange (HVP: 1000–1200 mL, $n = 58$) in ACLF.
  • Key Findings:
    • Clinical & Survival Parity: Both groups demonstrated significant improvements in liver enzymes, bilirubin, ammonia, coagulation profiles, and severity scores ($p < 0.05$). 28-day transplant-free survival was comparable ($74\%$ vs $76\%$, $p = 0.92$).
    • Resource Efficiency: The LVP group achieved $40\%$ fresh frozen plasma conservation ($539 ext{ mL}$ vs $1050 ext{ mL}$) and significantly reduced hospitalization costs ($p < 0.05$) with equivalent safety profiles.
  • Conclusion: DPMAS sequential LVP is a feasible, safe, and plasma-sparing strategy for managing ACLF without compromising short-term survival.

  • 33. Association Between Albumin-Bilirubin Score, Model for End-Stage Liver Disease Score, Platelet-Albumin-Bilirubin Score, and Acute-on-Chronic Liver Failure Complications: A Cross-Sectional Study in a Chinese Population

  • Full Citation: Xie J, Pei X, Wang L, Ma X, Xie Y. Eur J Gastroenterol Hepatol. 2026 Aug 1;38(8):959-970. doi: <-block _nghost-ng-c2614856368="">10.1097/MEG.0000000000003221
  • Background & Aims: Cross-sectional analysis of 2,104 ACLF patients (APASL 2019 criteria) evaluating the performance of ALBI, MELD, and PALBI scores calculated within 48 hours of admission to predict major complications.
  • Key Findings:
    • Predictive Value: Per SD increase, ALBI independently predicted six major complications (ascites, HE, HRS, coagulopathy, splenomegaly, and SBP) with adjusted ORs ranging from 1.98 to 8.73, while MELD yielded ORs from 2.58 to 7.26.
    • Comparative Accuracy: ROC curve analysis demonstrated that MELD consistently achieved higher overall AUC values compared to ALBI and PALBI. Non-linear dose-response relationships were observed ($p_{ ext{nonlinearity}} < 0.005$).
  • Conclusion: ALBI, MELD, and PALBI reliably stratify the risk of major ACLF complications, aiding early risk prediction and targeted clinical monitoring.

  • 34. Dynamic Gut Microbiota Shift in Chronic Liver Disease Progression: Machine Learning Models and the E/Er Ratio as a Predictive Biomarker

  • Full Citation: Mengting D, Zhaoyang J, Jingjing D, et al. J Transl Med. 2026 Jun 25. doi: <-block _nghost-ng-c2614856368="">10.1186/s12967-026-08499-y
  • Background & Aims: Profiled 10 key gut bacterial clusters via qPCR in 947 patients across the liver disease spectrum (CLD, compensated cirrhosis, decompensated cirrhosis, and ACLF) to model disease transitions.
  • Key Findings:
    • Microbial Shift: Pro-inflammatory to anti-inflammatory microbial ratios increased 5.4-fold from CLD to ACLF.
    • Predictive Models: Random Forest models predicted stage transitions effectively, performing best in the DC-to-ACLF transition ($ ext{AUC} = 0.961$).
    • Novel Biomarker: The Enterococcus / Eubacterium rectale (E/Er) ratio served as a robust non-invasive biomarker identifying critical turning points along the gut-liver axis.
  • Conclusion: Chronic liver disease progression is driven by a shift to a pro-inflammatory, pathogen-dominant microbiome; ML models using the E/Er ratio assist in early risk stratification.

  • 35. Symptomatic Hypocalcemia Is Uncommon in Patients with Liver Disease Undergoing Low-Volume Plasma Exchange by Centrifugal Technique

  • Full Citation: Benny S, Gayathiri KC, Alexander V, et al. Transfus Apher Sci. 2026 Jun;65(3):104407. doi: <-block _nghost-ng-c2614856368="">10.1016/j.transci.2026.104407
  • Background & Aims: Evaluated post-procedure hypocalcemia in 276 patients undergoing 924 sessions of low-volume centrifugal plasma exchange (PLEX-LV; $50\%$ calculated plasma volume) with standard calcium gluconate ($20 ext{ mL}$ $10\%$) supplementation.
  • Key Findings:
    • Incidence: Post-PLEX hypocalcemia occurred in 39 patients ($14.1\%$) across 54 sessions ($5.8\%$). Only 2 patients ($0.7\%$) experienced symptomatic hypocalcemia, both recovering promptly with intravenous calcium.
    • Risk Factor: Multivariable analysis identified the presence of Acute Liver Injury / Acute Liver Failure (ALI/ALF) as the sole independent predictor of hypocalcemia ($ ext{OR} = 6.85$, $p < 0.001$), primarily driven by rodenticide toxicity cases.
  • Conclusion: Symptomatic hypocalcemia is rare during centrifugal PLEX-LV when routine intravenous calcium supplementation is administered.

  • 36. Dual Targeted Gene Delivery Strategy Mediated by GalNAc-Modified Lipid Nanoparticles Enhances Liver Regeneration Through Specific Knockdown of MKK4

  • Full Citation: Zhai XP, Xing JH, Hou LS, et al. Mater Today Bio. 2026 Mar 24;38:103059. doi: <-block _nghost-ng-c2614856368="">10.1016/j.mtbio.2026.103059
  • Background & Aims: Developed a hepatocyte-targeted siRNA delivery system (GalNAc-LNP-siMKK4) to specifically silence mitogen-activated protein kinase kinase 4 (MKK4) and trigger liver regeneration without off-target MKK7 inhibition.
  • Key Findings:
    • Targeting Efficacy: GalNAc-functionalized LNPs showed high stability, biocompatibility, and targeted uptake by hepatocytes via asialoglycoprotein receptors.
    • Therapeutic Impact: In vitro and in vivo models demonstrated that MKK4 knockdown promoted hepatocyte proliferation, suppressed apoptosis, and accelerated recovery of liver function.
  • Conclusion: Specific MKK4 silencing via GalNAc-modified LNPs offers a viable gene-therapy approach to stimulate liver regeneration in ACLF.

  • 37. Short Inter-Treatment Interval Treatment With Artificial Liver Support System Reduces 90-Day Transplant-Free Mortality in Patients With Hepatitis B Virus-Related Acute-On-Chronic Liver Failure: A Retrospective Observational Study

  • Full Citation: Fu J, Chen F, Yang W, Chen T, Xu J. Artif Organs. 2026 Jun 15. doi: <-block _nghost-ng-c2614856368="">10.1111/aor.70186
  • Background & Aims: Compared short inter-treatment interval treatment (SIIT) versus long inter-treatment interval treatment (LIIT) using an Artificial Liver Support System (ALSS) in 149 patients with HBV-ACLF.
  • Key Findings:
    • Biochemical Improvement: By Day 7 post-treatment, total and direct bilirubin levels cleared more effectively in the SIIT group than in the LIIT group ($p < 0.01$).
    • Survival Benefit: 90-day transplant-free mortality was significantly lower in the SIIT group compared to the LIIT group ($12.8\%$ vs $29.6\%$, $p < 0.001$). Baseline MELD score independently predicted mortality ($ ext{OR} = 1.815$, $p < 0.001$).
  • Conclusion: Shortening the interval between ALSS sessions enhances liver function recovery and reduces 90-day transplant-free mortality in HBV-ACLF.

  • 38. Hepatitis E Virus Infection as a Trigger of Hepatic Decompensation: A Single-Center Prospective and Cross-Sectional Study From Rosario, Argentina

  • Full Citation: Acosta J, Galimberti A, Bessone F, et al. J Med Virol. 2026 Jun;98(6):e70988. doi: <-block _nghost-ng-c2614856368="">10.1002/jmv.70988
  • Background & Aims: Investigated the prevalence and clinical impact of Hepatitis E Virus (HEV) infection as a potential trigger for acute decompensation (AD) or ACLF in a non-endemic region (Argentina).
  • Key Findings:
    • Baseline Seroprevalence: Anti-HEV IgG seroprevalence in cirrhotic patients was $5.2\%$ ($95\% ext{ CI: } 2.2 ext{--}11.5\%$), matching regional healthy blood donor rates. No acute cases (anti-HEV IgM or HEV RNA positive) were detected at baseline.
    • Longitudinal Outcomes: Among 19 patients developing decompensation (including 6 ACLF cases) over 24 months, none showed evidence of acute HEV infection.
  • Conclusion: HEV exposure is low among cirrhotic patients in Argentina and is unlikely to serve as a primary trigger for acute decompensation or ACLF in low-endemic settings.

  •  

The Institute of Liver and Biliary Sciences is unique in nurturing a vibrant research culture in a clinical setting to ridge the gap between the bench and bedside. To fully understand the diseases that affect the “hepato-pancreato-billiary highway” it is imperative to have cutting edge technologies established at the institute in order to test hypothesis and implement ideas in a multi-disciplinary format. In this regard a major thrust areas of the department includes Genomics and Transcriptomics, Molecular Virology,Molecular Immunology, Cancer Cell Biology, Haematopietic Cell Biology and regenerative Medicine. To accelerate in these areas the department has also established a core “ILBS-NIH laboratory of Molecular Immunology” and established small animal house facility. Department is also setting up the state of the art core facilities and Tissue bank which would serve as a nodal research center in the country. The research is funded solely by extramural grants from various national and international funding agencies. The department has also set up several international tie ups with or without funding from govt. agencies. A multidisciplinary approach is being used to address various pressing needs in the area of liver disease progression and these include: molecular immunology, identification of microRNAs by Next Generation sequencing, role of gut metagenome in gut-liver axis, proteomic and meatbolomic approaches to identify biomarkers in acute on chronic liver failure, animal models of cirrhosis and acute liver failures, role of tissue microenvironment in liver regeneration and mechanistic roles of liver degeneration such as apoptosis and cellular senescence.

Educational Activities

In 2013, the Indo-German Workshop on Regenerative Medicine in Liver Diseases was conducted at the Institute of Liver & Biliary Sciences (ILBS) under the auspices of Indian Council of Medical Research (ICMR) and Federal Ministry of Education and Research, Germany. A total number of 7 premier institutes from Germany and 13 major clinical and research institutes from India were represented in the meeting. ILBS-NIH laboratory of Molecular Immunology, has started a training program on Flow cytometry and conducted Flow cytometry workshop, where all national and international students, postdoctoral fellows and Faculties attended the workshop.

Department’s Achievements

In 2013, along with basic research proposals, Laboratory of Molecular immunology has also received International funding for studying the immunogenetics in the naive Chronic HBV and HCV patients. Department of research has developed new protocols and established international MOU’s with NIAID, NIH,USA, Baylor Institute for Immunology, USA, Gilead Sciences, California. From research department, many students have presented their ongoing work in the prestigious national and international conferences like AASLD, EASL, Hepatology 360 and ISG. Group was also recognized by many international collaborators and they have provided visiting fellowships to young investigators.

Clinical Research

The clinical research facility at the Institute of Liver and Biliary Sciences, conducts multi-centric, global, complex clinical trials of new therapies, molecules to meet the unmet need of medical sciences. Such complex clinical research and epidemiological studies are being conducted by the ILBS clinical faculty and dedicated staff specialized in conducting clinical trials as per the international standards, which are highly specialized in the area of liver and biliary sciences and have a vast experience in medical research with major publications. Experienced research staffs sphered studies through a required safety approval by the ILBS’s highly competent Institutional Ethics Committee and Drug Controller General of India. ILBS carry out Clinical Trials in various areas like drug trials, in-house, national & international projects. The Clinical Research Department of ILBS is run by a team comprising of Director, Associate Professor, Assistant Professor, Epidemiologist, Clinical Trial Coordinator and Research Assistants who coordinate the various activities and maintain quality in research as per ICH-GCP Guidelines and other regulatory authorities. The Clinical Research at ILBS provides the bridge between medical research and patient care. Patients, however, may derive benefit from clinical trials by gaining early access to new treatments. Most, however, have altruistic motives and participate in order to further the understanding or treatment of particular diseases. Patients who join clinical trials receive access to new treatments and the dedicated attention from physicians, research nurses and coordinators. Many participants are also motivated by helping future patients, as many studies may not influence treatment for years. In a short span, the facility of clinical research has established itself and attained vital position in the Institute’s objective and mission of being pioneer institution in research. Currently there are many clinical trials ongoing in different stages. In almost every clinical trial we have enrolled highest numbers of patients globally at ILBS which has enhanced the image of the Institution and set standards of clinical research among one of the top at the International level. We are being looked by multinational companies and CROs as major recruiting site with state of art facilities and dedicated staff.

Clinical Department Achievements

Dr. Ankit Bharadwaj

Presented an oral presentation at the meeting of the American Association for Study of the Liver Diseases (AASLD) 2013 held in Washington DC, USA on 4th November, 2013.

Presented an oral paper in Best of AASLD meeting held on 7th and 8th of December 2013 in Mumbai.