BACKGROUND & AIMS:Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disorder, with few optimal pharmacotherapies. Ongoing studies are providing evidence that histone acetylation contributes to the progression of MASLD. This study investigated the alterations of specific histone acetylation sites in MASLD tissues and the effects of B029-2, a small-molecule inhibitor targeting p300/CBP acetylation activity, in mouse models of progressive fatty liver disease. METHODS:The acetylation of H3K27/H3K18/H3K9 was assessed in liver samples from MASLD patients and mice. The effect of the B029-2 in MASLD was assessed in MASLD models. A ChIP assay was conducted to investigate the epigenetic regulatory mechanism of ACSL4. Hepatic-specific Acsl4-knockout and overexpression mice were generated to validate the role of ACSL4 in MASLD. RESULTS:We observed a significant increase in p300 HAT activity, p300/CBP-induced H3K18ac and H3K27ac levels in MASLD and B029-2 markedly reduced hepatic steatosis in vitro and in vivo. Transcriptome analysis revealed that B029-2 inhibited the expression of genes in the triglyceride biosynthetic process and long-chain fatty-acyl-CoA biosynthetic process. ChIP assay showed that H3K18ac, H3K27ac and p300 bind to the promoter region of ACSL4, and their binding is reduced by B029-2 treatment. AAV-mediated hepatic-specific overexpression of Acsl4 attenuated the effect of B029-2 on MASLD in mice, while hepatic-specific Acsl4-deficient in mice blocked the effect of B029-2. CONCLUSIONS:p300/CBP-mediated H3K18ac and H3K27ac regulate ACSL4-dependent lipid biosynthesis in MASLD and might be a potential therapeutic target for the treatment of MASLD.
The differentiation between benign and malignant biliary strictures remains a significant clinical challenge. Recent studies have suggested that next generation sequencing (NGS) can improve the diagnostic accuracy. However, evidence on its performance in routine clinical practice is limited. Therefore, validation of the diagnostic value of NGS using real-world clinical data is warranted. We compared the performance of NGS analysis of cholangiocellular carcinoma (CCC)-associated mutations in endoscopic biopsies with that of histopathology, CA19-9 and cross-sectional imaging. NGS showed higher sensitivity for malignancy (65%) compared to histopathology (52%) at similar specificity (96% vs. 100%). The combination of NGS and histopathology further increased sensitivity for malignancy to 78% (p = 0.03) at similar specificity (96%). Our data provide support for the use of NGS in the diagnostic workup of biliary strictures.
BACKGROUND AND AIMS:Liver sinusoidal endothelial cells (LSECs) are liver-resident antigen-presenting cells that induce immune tolerance, a feature exploited by persistent viruses. Toll-like receptor (TLR) ligands can override this tolerance, but whether metabolic reprogramming underlies LSEC activation remains unknown. We investigated whether TLR ligand-induced functional changes in LSECs require glycolysis and explored the underlying mechanisms. METHODS:LSECs from wild-type and chronic hepatitis B virus (HBV) replication mice were stimulated with TLR2 ligand P3C or TLR9 ligand ODN1826. LSEC maturation, cytokine production and T cell-priming capacity were assessed. Glycolytic flux was measured by metabolomics and Seahorse analysis. The glycolysis inhibitor 2-deoxy-D-glucose (2-DG) was used, and mTORC1 pathway involvement was examined. RESULTS:The TLR2 ligand P3C promoted LSEC maturation, while the TLR9 ligand ODN1826 enhanced IL-12 production. Both ligands potentiated LSEC-induced T cell responses. In LSECs isolated from a mouse model of chronic HBV replication, P3C and ODN1826 also induced maturation and enhanced T cell-activating capacity, albeit to a weaker extent. Metabolomics and Seahorse analyses revealed that TLR2/9 ligands enhanced glycolysis and oxidative phosphorylation in LSECs, accompanied by activation of the mTORC1/HIF-1α/c-Myc axis. Blocking glycolysis with 2-DG significantly reduced co-stimulatory molecule expression on P3C-stimulated LSECs and IL-12 production by ODN1826-stimulated LSECs in both wild-type and chronic HBV models. Mechanistically, 2-DG suppressed the mTORC1 pathway, thereby attenuating TLR ligand-induced responses. CONCLUSIONS:TLR ligand-induced activation and pro-inflammatory functions of LSECs critically depend on glycolysis via the mTORC1 signalling pathway. This reveals a key metabolic mechanism underlying LSEC immune regulation during innate stimulation.
BACKGROUND AND AIMS:Body composition is increasingly recognised as a prognostic determinant in cirrhosis, particularly in liver transplant (LT) candidates. We aimed to assess adipose and muscle compartments on computed tomography (CT) before and after LT and to evaluate their associations with mortality. METHODS:We recruited prospectively 121 patients with cirrhosis listed for LT. CT scans at the third lumbar vertebral level were analysed to quantify cross-sectional area (cm2) and density (Hounsfield units, HU) of skeletal muscle, subcutaneous adipose tissue (SAT), and visceral adipose tissue. A subset underwent a CT-scan 6 months post-LT. RESULTS:Most patients were male (76%), and the median MELD score was 14 (IQR 10-20). High SAT density (> -83 HU in women; > -74 HU in men) was associated with higher pre-transplant mortality (p = 0.005) and with reduced overall survival during follow-up (p = 0.005) compared to lower SAT density. The combined phenotype of low muscle density and high SAT density identified the subgroup with the poorest survival (p = 0.002). From baseline to 6 months post-LT, SAT density decreased significantly (p = 0.0134), whereas muscle parameters did not change significantly. CONCLUSIONS:This prospective observational cohort study demonstrates that SAT density is a prognostic CT-derived marker in patients with cirrhosis awaiting LT with significant post-transplant dynamics. The impact of altered adipose tissue therefore warrants attention in this situation.
Platelets are increasingly recognized as active regulators of liver fibrosis, yet the relationship between systemic thrombocytopenia and intrahepatic platelet behaviour remains poorly understood. In selected etiological and stage-specific contexts, systemic thrombocytopenia may coexist with intrahepatic platelet enrichment and activation, making circulating platelet counts insufficient to reflect local fibrotic activity. This review synthesizes current evidence to define platelet dynamics along the circulation-spleen-liver axis and their multicellular crosstalk within the fibrotic microenvironment, aiming to clarify how platelets integrate into a self-reinforcing fibrogenic network and identify potential therapeutic strategies beyond correcting systemic thrombocytopenia. Systemic thrombocytopenia and intrahepatic platelet enrichment are not mutually exclusive; this paradox renders circulating platelet counts a poor surrogate for intrahepatic fibrotic activity. In the liver, platelets integrate thrombotic, inflammatory, angiogenic, and regenerative signals via mediator release (TGF-β1, PDGF-BB, CXCL4) and interactions with hepatocytes, Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), and hepatic stellate cells (HSCs). Platelet-hepatocyte crosstalk exerts opposing effects: injury amplification versus regeneration promotion. Platelet-KC interactions are pro-inflammatory and pro-fibrotic, yet include CLEC4F-mediated phagocytosis that limits excessive platelet accumulation. LSEC capillarization creates a pro-thrombotic niche, where platelet adhesion activates NF-κB, provides P-selectin docking for leukocytes, and drives microthrombosis. Platelet-HSC communication is directly pro-fibrotic via coordinated TGF-β1 and PDGF-BB signalling, reinforced by bidirectional loops. Therapeutically, correction of peripheral thrombocytopenia should be distinguished from investigational strategies aimed at modulating pathogenic intrahepatic platelet activity.
Hepatitis C virus (HCV) diagnosis in low- and middle-income countries (LMICs) relies on costly and technically demanding centralized laboratory services. This review aims to synthesize evidence on Point-of-Care (POC) HCV testing in LMICs to inform scale-up for HCV elimination. We searched Medline, Embase, PsycINFO, and the Cochrane Library for studies on decentralized POC HCV testing in LMICs between 2010 and 2022. Two reviewers independently conducted eligibility assessment and full text review. Testing uptake and linkage data were extracted using Excel, then descriptively synthesized to identify common patterns. Our systematic review identified 2018 reports of which 1603 underwent title and abstract screening. Among them, 58 met the eligibility criteria, but only 20 reports proceeded to data extraction. Of these, 16 examined feasibility and effectiveness, showing high testing uptake and linkage to care. In the 11 reports where services provided onsite testing and/or treatment, uptake of testing and/or treatment exceeded 90%. Four studies assessed HCV self-testing among high-risk populations and showed high acceptability (91%-99%). Studies evaluating oral-based self-testing among high-risk populations reported higher recommendation rates (94%-99%) compared to that of blood-based testing (86.1%). Our findings suggest that decentralized HCV testing and care models likely improve testing uptake and treatment success in LMICs, given the high rates of retention in care and cure.
BACKGROUND AND AIMS:Alcohol use disorder (AUD) coexisting with cirrhosis carries high morbidity and mortality, with no approved pharmacotherapy for AUD. We evaluated the safety and efficacy of naltrexone, an opioid receptor antagonist, in patients with compensated alcohol-associated cirrhosis (AaC) and AUD. METHODS:One hundred patients with compensated AaC and DSM-5 AUD were randomised 1:1 to naltrexone (50 mg/day) or placebo for 12 weeks. The primary endpoint was point-prevalence abstinence at 12 weeks, defined as no alcohol use in the four preceding weeks. Secondary endpoints included craving (Obsessive Compulsive Drinking Scale [OCDS]-Obsessive and Compulsive subscales), lapses, relapses, and hepatic safety. Standardised psychosocial support was provided to both arms. RESULTS:Baseline characteristics were well matched between groups (mean MELD 12.6 vs. 12.7; CTP score 5.9 vs. 6.2; age 42.9 vs. 44.3 years). AUDIT and OCDS scores were comparable between groups. Abstinence at 12 weeks was significantly higher with naltrexone: 64% (32/50) versus 22% (11/50), p < 0.001; OR 10.86 (95% CI: 1.89-62.2). Naltrexone significantly reduced lapses at 3 months (28% vs. 54%, p = 0.008) and showed a trend toward fewer heavy-drinking relapses (12% vs. 28%, p = 0.07). Maintenance of abstinence at 6 months favoured naltrexone (22% vs. 8%, p = 0.09). No patient developed hepatic decompensation attributable to study medication, and no AST/ALT elevation exceeding 5× ULN was observed in either group. Mean craving scores were lower with naltrexone by week 12 than with placebo: OCDS-O score (6.63 ± 1.16 vs. 9.29 ± 1.78, p < 0.01) and OCDS-C score (6.35 ± 1.23 vs. 9.02 ± 1.86, p < 0.01). Adverse events were comparable between the groups. CONCLUSION:Naltrexone is safe and effective in patients with compensated alcohol-associated cirrhosis, achieving a threefold higher abstinence rate and significantly reducing craving compared with placebo. These findings support the use of naltrexone as a pharmacological option in patients with compensated AaC and AUD. TRIAL REGISTRATION:NCT04391764.
ABSTRACT The Paris International Liver Meeting (January 19–21, 2026) brought together leading hepatology experts to discuss transformative advances in chronic liver disease management. The meeting highlighted pivotal developments reflecting the field's evolution from disease characterisation toward precision, mechanism‐based therapeutics. Metabolic dysfunction‐associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction‐associated steatohepatitis (MASH), were highlighted, marking the transition to an era of approved disease‐modifying therapies. Resmetirom and semaglutide are now approved for MASH with F2–F3 fibrosis, with a robust pipeline generating anti‐fibrotic signals through FGF21 analogs, pan‐peroxisome proliferator‐activated receptor (PPAR) agonists, and incretin‐based dual and triple agonists. Non‐invasive tests have evolved beyond their original diagnostic role to enable prognostic stratification, screening of at‐risk populations, treatment selection, and monitoring of therapeutic response. This evolution is not limited to MASLD, but extends to other chronic liver diseases, including primary biliary cholangitis (PBC) and portal hypertension, as highlighted by the recommendations of the Baveno Consensus Workshops. Hepatitis B and D are moving toward functional cure strategies, with simplified HBV treatment algorithms based on fibrosis and viral load, supported by biomarkers for risk stratification and safe treatment discontinuation. In parallel, HDV management is transitioning from a severe disease to one with emerging suppressive and potential curative l through bulevirtide and novel HBsAg‐targeting and RNA‐silencing therapies, respectively. Management of PBC has advanced with novel PPAR agonists that improve cholestatic biochemistry and pruritus, supported by individualised risk stratification. However, significant treatment gaps persist, with fewer than half of eligible PBC patients receiving second‐line therapy, and fatigue remains a major unmet clinical need. Furthermore, effective pharmacotherapies for primary sclerosing cholangitis (PSC) remain a major challenge, and no approved disease‐modifying treatments are currently available. Finally, for patients with hepatocellular carcinoma (HCC), immunotherapy combinations can achieve unprecedented long‐term survival in selected populations of patients. Collectively, these advances define a new era of hepatology centered on precision medicine, earlier intervention, and mechanism‐driven therapeutic strategies.
Hepatic vein catheterization (HVC) in man was first performed 80 years ago in the wake of right-sided heart catheterization. Several new methods, recognitions and concepts followed, especially the indirect Fick-method for determination of splanchnic blood flow. Five years passed before pressure measurements were performed and routine HVCs were done in liver patients. Later came splanchnic kinetics of test substances, dyes, metabolites, hormones and bioactive material and counter current wedged and balloon occlusion pressure. HVC has been a prerequisite for our understanding of the pathogenesis of portal hypertension and variceal bleeding leading to serial measurements, stratification, quantification and treatment of portal hypertension, and transvenous liver biopsy and portosystemic stent insertion (TIPS) followed. Measurements and pathophysiology of formation and amelioration of ascites advanced with HVC, likewise pathophysiology of known and new diseases in other organs, secondary to liver disease (kidney, heart, lung, systemic circulation). The hepatic venous pressure gradient (HVPG, i.e., wedged-to-free hepatic venous pressure) is today considered the gold standard for portal pressure measurement in intrasinusoidal and postsinusoidal portal hypertension. In spite of substantial developments in route, catheter type, pressure measurements and -registration, fluoroscopy, transvascular technique, etc. the basic concepts are the same today. New advanced technology, materials, imaging techniques and IT-power have together with the inborn dynamics of the catheterization given a progressive development, and there are potentials of further refinement and applications in science, clinical physiology, gastroenterology and hepatology.
BACKGROUND & AIMS:Prognostic non-invasive tests for liver-related events in compensated cirrhosis are needed. Endotrophin, a fragment of type VI alpha 3 collagen involved in fibrosis and inflammation, has been associated with adverse outcomes in several chronic diseases. This study examined the association between baseline endotrophin levels, measured by nordicPRO-C6 (PRO-C6), and liver-related events in advanced hepatitis C virus (HCV)-related liver disease. METHODS:nordicPRO-C6 was assessed in baseline serum from 339 patients with advanced liver fibrosis from the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. The prognostic value of PRO-C6 was evaluated. RESULTS:Baseline serum levels of PRO-C6 were significantly higher in patients with cirrhosis and PRO-C6 was an independent prognostic marker for liver-related events. Each doubling of PRO-C6 was associated with increased hazard of liver-related events in all patients (hazard ratio (HR) = 2.22, 95% confidence interval (CI) 1.57-3.14, p < 0.0001), and in patients with cirrhosis (HR = 1.71, 95% CI 1.14-2.58, p = 0.01). CONCLUSION:Endotrophin assessed by PRO-C6 is an independent prognostic marker for liver-related events in patients with advanced liver fibrosis and ongoing inflammation due to HCV, particularly in those with cirrhosis, from the HALT-C trial. PRO-C6 may be useful for risk stratification in end-stage liver disease. However, validation in non-interferon-treated cohorts and across chronic liver diseases of varying etiologies is required to confirm its prognostic value for liver-related events.
BACKGROUND:The gut microbiota contributes to liver cirrhosis (LC), yet the gut virome and its cross-kingdom ecology with bacteria are less well defined. METHODS:To characterize LC-associated virome alterations and assess their clinical relevance, we reanalyzed publicly available faecal metagenomes from patients with LC and healthy controls. After quality control and removal of human reads, sequences were mapped to the Chinese Gut Viral Catalogue at 95% nucleotide similarity, viral operational taxonomic units (vOTUs) were annotated using the latest ICTV framework, and viral functions were inferred by KEGG annotation. Differential vOTUs and bacterial species, virus-bacteria networks and random forest classifiers were constructed with internal and external validation. RESULTS:LC showed reduced viral richness and Shannon diversity, and a distinct Bray-Curtis separation from controls. Ten viral families and 473 vOTUs differed between groups (59 LC-enriched). KEGG-based profiling highlighted functional shifts in LC-enriched viruses, including increased K01185 (lysozyme) and K02172 (blaR1). Virus-bacteria networks were markedly sparser in LC than in controls (130 vs. 509 significant correlations). A virome-based random forest model distinguished patients from controls with high accuracy in internal (optimal AUC = 0.911) and external (optimal AUC = 0.773) validation cohorts, and the model combining viral and bacterial features achieved similarly robust performance. CONCLUSIONS:LC is associated with disrupted gut viral-bacterial ecology, and virome features show promise as non-invasive biomarkers, warranting longitudinal and mechanistic follow-up.
The patatin-like phospholipase 3 (PNPLA3) I148M genetic variant is highly associated with steatotic liver disease. In the SURPASS-3 MRI substudy, tirzepatide significantly reduced liver fat content (LFC) versus insulin degludec in insulin-naïve patients with type 2 diabetes with metabolic dysfunction-associated steatotic liver disease. The influence of PNPLA3 I148M allele on changes in LFC in response to tirzepatide is unknown. This post hoc analysis evaluated changes in MRI-assessed LFC and cardiometabolic parameters by presence (genotypes GG and CG) or absence (genotype CC) of the PNPLA3 I148M allele after 52-week treatment. Tirzepatide-treated participants experienced significant reductions in LFC, weight, HbA1c, and overall greater improvement in lipids and liver enzymes regardless of the presence of PNPLA3 I148M allele. Findings were consistent across genotype subgroups. In this exploratory analysis, the presence of PNPLA3 I148M allele did not seem to affect tirzepatide-induced improvement in LFC and several cardiometabolic parameters in patients with type 2 diabetes. Trial Registration: ClinicalTrials.gov identifier: NCT03882970.
BACKGROUND & AIMS:Chronic hepatitis B (CHB) remains a leading cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide, yet treatment uptake is suboptimal even in high-resource settings. This pan-Canadian study aimed to quantify treatment gaps within the Canadian Hepatitis B Network (CanHepB) Registry, compare characteristics of treatment-eligible but untreated patients to those receiving therapy, and assess patient and specialist perspectives on barriers to treatment. METHODS:A cross-sectional, retrospective analysis of 1983 adults with CHB followed in 18 Canadian hepatitis B specialty clinics between January 2018 and November 2024. Treatment eligibility was determined using the 2018 Canadian Association for the Study of the Liver guidelines. An anonymous survey captured patient-reported barriers and perspectives (n = 191), while a separate survey evaluated specialist perceptions (n = 54). RESULTS:Among 881 untreated patients, 46.4% (n = 409) were treatment eligible. Compared with the treatment group (n = 1087), the treatment-eligible but untreated patients were younger (median 47.3 vs. 54.5 years), more frequently female (54.2% vs. 39.7%), and more likely to be of Black/African/Caribbean origin (18.2% vs. 9.7%). They had a lower prevalence of cirrhosis (2.4% vs. 20.3%), HCC (0.7% vs. 9.3%), and hypertension (17.1% vs. 22.9%), but a higher prevalence of steatotic liver disease (36.4% vs. 24.6%) and dyslipidemia (14.7% vs. 10.8%). Among untreated respondents, concerns included side effects, the need for long-term therapy, and lack of curative options. Conversely, specialists identified cost as the primary barrier and side effects as the least concerning. CONCLUSION:This nationwide study reveals a significant treatment gap in CHB care, driven by demographic disparities and a mismatch between patient concerns and clinician perceptions.
