Hepatology International最新文献

{"title":"Response to letter to editor: toward more precise and generalizable evidence on MASLD and pregnancy risks.","authors":"Young Mi Jung, Geum Joon Cho, Won Kim","doi":"10.1007/s12072-026-11033-3","DOIUrl":"10.1007/s12072-026-11033-3","url":null,"abstract":"","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"1524-1525"},"PeriodicalIF":7.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146124800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AGEX: a comprehensive database of clinically relevant genetic variants associated with Alagille syndrome across diverse populations.","authors":"Priya Sharma, Vishnu Prasad, Bhanu Teja Korra, Rohan Grotra, Rohan Malik, Rahul Kumar, Deepti Abbey","doi":"10.1007/s12072-026-11074-8","DOIUrl":"10.1007/s12072-026-11074-8","url":null,"abstract":"<p><strong>Background: </strong>Alagille syndrome (ALGS) is a rare multisystem disorder primarily caused by pathogenic variants in JAG1 and NOTCH2. Although its genetic basis is well established, existing variant repositories often lack comprehensive clinical annotation, sufficient ethnic representation, and open accessibility. These limitations reduce their translational relevance and hinder genotype-phenotype correlation and evidence-based molecular diagnosis. To address this gap, we developed AGEX (Alagille Genetics Exploration Database), a curated, open-access resource integrating genetic variants with phenotype and population frequency data.</p><p><strong>Methods: </strong>AGEX ( http://agexbase.iitd.ac.in ) was constructed through a systematic literature review from 1999-2025, supplemented with unpublished case reports from Indian ALGS patients. Variants were curated and classified according to ACMG/AMP guidelines, with pathogenicity predictions derived from multiple in silico tools. Population allele frequency data were integrated from gnomAD, All of Us, and IndiGenome databases. Domain-level mutation mapping was performed to assess variant distribution across functional protein regions. Additionally, a prototype ALGS Severity Tier Calculator was developed to integrate genotype and phenotype parameters for semi-quantitative clinical stratification.</p><p><strong>Results: </strong>AGEX compiles 260 variants, including 231 in JAG1 and 29 in NOTCH2, reported across 20 global populations. Four previously unreported variants were identified. Domain-level analysis revealed recurrent clustering of mutations within the DSL and EGF-like domains of JAG1, emphasizing their importance in Notch signaling. The database provides an interactive interface enabling variant browsing, phenotype-linked queries, and population-level analyses, along with a prototype severity scoring framework.</p><p><strong>Conclusion: </strong>AGEX represents the first dedicated integrative database for ALGS, enabling variant browsing, population-specific analyses, and phenotype-linked searches. While further longitudinal clinical validation is required, AGEX represents the first dedicated, integrative database for ALGS. By centralizing variant and clinical data, AGEX aims to accelerate diagnosis, improve patient stratification, and facilitate precision medicine strategies targeting Notch pathway dysregulation, serving as a scalable model for other rare disorder genomics.</p>","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"1409-1419"},"PeriodicalIF":7.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147493395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Letter to the Editor: \"Critical appraisal of MASLD subtypes and pregnancy outcome associations in a nationwide cohort\".","authors":"Sohana Memon, Gaaitri Lohano, Govinda Lohano","doi":"10.1007/s12072-026-11036-0","DOIUrl":"10.1007/s12072-026-11036-0","url":null,"abstract":"","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"1526-1527"},"PeriodicalIF":7.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophil extracellular traps drive cholangiocyte injury via ZNF709-TP53-MDM2 pathway in primary biliary cholangitis.","authors":"Mingxin Su, Zhenfeng Tian, Miao Yu, Enlai Huang, Jinjian Liang, Bingrong Hu, Yinting Chen","doi":"10.1007/s12072-026-11128-x","DOIUrl":"10.1007/s12072-026-11128-x","url":null,"abstract":"<p><strong>Background: </strong>Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease in which many patients respond inadequately to ursodeoxycholic acid (UDCA) and may progress to liver failure. Although research on PBC has primarily centered on lymphocyte-mediated mechanisms, increasing evidence implicates neutrophils in autoimmunity, yet their role in PBC remains unclear.</p><p><strong>Methods: </strong>Cytokine screening of patient sera collected from our medical center was performed to identify NETs-inducing factors. Transcriptomic profiling was conducted to determine the molecular effects of NETs on cholangiocytes. The therapeutic effects of the neutrophil elastase inhibitor sivelestat on NETs-associated injury were evaluated in dnTGFβRII and 2OA-BSA murine models of PBC.</p><p><strong>Results: </strong>We identify NETs as a critical mediator linking immune activation to biliary injury. NETs formation was markedly elevated in PBC patient samples and murine models. Exploratory cytokine profiling of patient serum samples prioritized resistin as a leading candidate mediator of NETs formation, and elevated circulating resistin levels were confirmed in an independent clinical cohort. Further analysis of patient clinical data revealed that circulating resistin levels were positively correlated with cholestasis. Transcriptomic profiling demonstrated that NETs exposure downregulated ZNF709 and activated the TP53-MDM2 pathway in cholangiocytes, leading to epithelial injury and PBC-like phenotypic changes. In vivo, treatment with sivelestat significantly reduced biliary inflammation and fibrosis, while combination therapy with UDCA produced synergistically therapeutic benefits.</p><p><strong>Conclusions: </strong>These findings identify a resistin-NETs-ZNF709 axis that links neutrophil activation to cholangiocyte injury in PBC and suggest that targeting NETs-associated injury with sivelestat may represent a potential strategy to improve current PBC therapies.</p>","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"1446-1462"},"PeriodicalIF":7.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148411511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Global ACLF Consensus : the 'Istanbul Document'.","authors":"Anand V Kulkarni, Ashok Choudhury, Vinod Arora, Abdul Kadir Dokmeci, Abraham Koshy, Ahmet Gurakar, Ajay Duseja, Akash Roy, Akash Shukla, Aleksander Krag, Alfred Wei Chieh Kow, Ananta Shrestha, Apichat Kaewdech, Ashish Goel, Ashish Kumar, Ashwani K Singal, Aung Hlaing Bwa, Chanunta Hongthanakorn, Cosmas Rinaldi Adithya Lesmana, Daniel Huang, Darrell Crawford, Debbie Shawcross, Deniz Balchi, Dhiraj Agrawal, Diana A Payawal, Do Seon Song, Dong Joon Kim, Fernando Bessone, George K Lau, Giacomo Germani, Girish Kumar Pati, Grace L Su, Guan-Huei Lee, Gupse Adali, Gyongyi Szabo, Hasmik Ghazinian, Jacob George, James Fung, Jasmohan Bajaj, P Javed, Jidong Jia, Jimmy Che-To Lai, Jin Jun Chen, Jonel Trebicka, Jun Li, Kavish Patidar, Kemal Fariz Kalista, Ken Liu, Kessarin Thanapirom, Lai Wei, M Golam Azam, Madhumita Premkumar, Madunil Niriella, Manasa Alla, Mangesh Pagadala, Manoj Kumar, Manuel Mendizabal, Mario Guimaraes Pessoa, Mark Dhinesh Muthiah, Masao Omata, Mazen Noureddin, Md Fazal Karim, Mithun Sharma, Mohamed Alboraie, Mohamed Elbasiony, Murat Harputluoglu, Narendra Singh Choudhary, Nazia Selzner, Necati Ormeci, Nelia Hernandez, Nipun Verma, Paolo Angeli, Phunchai Charatcharoenwitthaya, Prabir Maji, Pravin Rathi, R K Dhiman, Rahul Kumar, Rakhi Maiwall, Ramazan Idilman, Richard Moreau, Rino A Gani, Rosmawati Mohamed, S S Hamid, Sanjeev Sachdeva, Senamjit Kaur, Shahinul Alam, Soe Thiha Maung, Soek-Siam Tan, T R Sowmya, K C Sudhamshu, Sumana Ramachandra, Sunil Kumar Dadhich, Sunil Taneja, Suprabhat Giri, Surender Singh, Tao Chen, Tarana Gupta, Tushar Madke, V M Dayal, Venishetty Shantan, Viniyendra Pamecha, Wong Yu Jun, Xiaolong Qi, Yoon Jun Kim, Zaigham Abbas, Zobair M Younossi, Shiv Kumar Sarin","doi":"10.1007/s12072-026-11136-x","DOIUrl":"10.1007/s12072-026-11136-x","url":null,"abstract":"<p><p>The Kyoto Consensus introduced a key conceptual shift in characterizing acute-on-chronic liver failure (ACLF) patients into Type-A and Type-B phenotypes. A day-long meeting was convened at Istanbul during APASL 2026 to assess the real-world applicability of Type-A and Type-B ACLF across continents. The objective was that physicians could recognize ACLF as a unified disease entity, and quality research and new therapeutic options with defined end-points could be undertaken. Data from APASL ACLF Research Consortium (AARC), EASL-CLIF and NACSELD were assessed and discussed in detail. While the applicability of Type-A and Type-B varied across cohorts, the definition required to be appended. The experts unanimously agreed that 'liver failure' as identified by serum bilirubin of ≥ 5 mg/dl and INR ≥ 1.5 should be the 'core' for both Type-A and Type-B ACLF. Type-A ACLF is considered when \"a patient with compensated advanced chronic liver disease or compensated cirrhosis presents with index decompensation as liver failure followed by development of ascites and/or hepatic encephalopathy within 4 weeks.\" Type-B ACLF is considered when \"a patient with prior or concurrent decompensated cirrhosis presents with acute decompensation as liver failure accompanied by one or more extrahepatic organ failures.\" New definitions of organ dysfunction and failure, as well as endpoints for clinical trials, were also deliberated and finalized. The \"Istanbul Report\", presents a milestone evidence based consensus document carrying harmonization of various aspects of ACLF, incorporating current evidence, critically analyzed unanimous recommendations, and key areas for future studies.</p>","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"1281-1294"},"PeriodicalIF":7.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bepirovirsen induces innate immune proteins independent of HBV.","authors":"Jared L Delahaye, Shihyun You, Kai Fu, Scott Van Buren, Cheng Zhu, William Jordan, Avijit Ray, Johannes M Freudenberg, Kristen M Consalvo, Luca Pagliaroli, Sohil Joshi, Puneet Dhawan, Dickens Theodore, Melanie Paff, Jill Walker, Jennifer M Singh","doi":"10.1007/s12072-026-11134-z","DOIUrl":"10.1007/s12072-026-11134-z","url":null,"abstract":"<p><strong>Background: </strong>Bepirovirsen, an antisense oligonucleotide that targets all hepatitis B virus (HBV) mRNAs, is in development for the treatment of chronic HBV infection. Clinical studies have demonstrated that bepirovirsen has multiple mechanisms of action, including lowering HBV DNA, reducing viral protein production, and inducing immune activation. Post hoc analysis of biomarker samples from three studies was performed to further characterize changes in soluble protein biomarkers after bepirovirsen dosing.</p><p><strong>Methods: </strong>Across three studies (CS3 [NCT02981602] in participants with chronic HBV infection; PFS [NCT06058390] and QTc [NCT06422767] in healthy volunteers) participants received bepirovirsen (150 mg, 300 mg, or 450 mg) or placebo. Longitudinal serum samples were taken for exploratory proteomics analysis. Relative expression of soluble proteins, including immune-related biomarkers, was measured, and differential expression was determined across arms. Clustering analysis was performed to identify kinetic patterns.</p><p><strong>Results: </strong>Bepirovirsen induced significant, transient protein differential expression in the hours after dosing, while there were relatively minor changes in placebo. There were many similarities in protein biomarkers induced in CS3 participants with chronic HBV infection and in the two healthy volunteer studies. Additionally, bepirovirsen treatment increased abundance of many proteins to a higher degree with increasing dose.</p><p><strong>Conclusions: </strong>These findings strengthen the association between bepirovirsen treatment and changes in innate immune-related proteins and indicate that this effect does not require the presence of HBV. The kinetic patterns of protein expression suggest that there are multiple waves of protein induction, which could impact recruitment and activation of innate and adaptive immune cell types.</p><p><strong>Clinical trial number: </strong>NCT02981602, NCT06058390, NCT06422767.</p>","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"1318-1328"},"PeriodicalIF":7.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13676563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148669383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing the understanding and management of metabolic dysfunction-associated steatotic liver disease in colorectal cancer patients: insights and future directions.","authors":"Zhexian Liu, Na Li","doi":"10.1007/s12072-025-10947-8","DOIUrl":"10.1007/s12072-025-10947-8","url":null,"abstract":"","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"1499-1500"},"PeriodicalIF":7.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145400644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Commentary on \"Machine learning prediction of rapid HBsAg seroclearance at week 24 in inactive carriers treated with pegylated interferon.","authors":"Si Li, Meihan Guo, Dapeng Ding","doi":"10.1007/s12072-025-11007-x","DOIUrl":"10.1007/s12072-025-11007-x","url":null,"abstract":"","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"1514-1515"},"PeriodicalIF":7.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145911369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prolactin acts on proopiomelanocortin neurons to regulate hepatic lipid metabolism.","authors":"Ye Zhu, Kexin Wu, Tianyu Wu, Da Fang, Pengzi Zhang, Jin Wang, Yan Bi","doi":"10.1007/s12072-026-11099-z","DOIUrl":"10.1007/s12072-026-11099-z","url":null,"abstract":"<p><strong>Objective: </strong>To elucidate the central mechanism of pituitary-derived prolactin (PRL) in hepatic lipid homeostasis and identify therapeutic targets for metabolic dysfunction-associated fatty liver disease (MASLD).</p><p><strong>Methods: </strong>High-fat diet (HFD)-fed mice induced MASLD. PRL⁻/⁻ mice, POMC neuron-specific PRL receptor (PRLR) conditional knockout mice, AAV-mediated PRLR knockdown, and central/peripheral PRL administration were used to explore PRL's central regulatory role. Metabolic phenotyping, histological/biochemical assays, immunofluorescence, electrophysiology, RNA-seq, 6-OHDA-induced sympathetic denervation, and primary hepatocyte experiments were performed to evaluate phenotypes, neuronal activity and underlying mechanisms.</p><p><strong>Results: </strong>PRL deficiency exacerbated HFD-induced hepatic lipid deposition, and central intracerebroventricular PRL alleviated hepatic steatosis in HFD-fed PRL⁻/⁻ and wild-type mice more rapidly than peripheral intraperitoneal PRL. PRLR was highly expressed in hypothalamic arcuate nucleus POMC neurons, which PRL selectively activated by enhancing neuronal excitability. POMC-specific PRLR knockout abrogated PRL's anti-steatotic effects and aggravated HFD-induced hepatic lipid accumulation. Mechanistically, central PRL enhanced hepatic sympathetic outflow to suppress de novo lipogenesis via the FASN pathway.</p><p><strong>Conclusion: </strong>PRL acts on hypothalamic POMC neurons to enhance hepatic sympathetic activity, suppressing FASN-mediated lipogenesis and maintaining lipid homeostasis. This novel PRL-driven brain-liver circuit highlights central PRL signaling as a promising MASLD therapeutic target.</p>","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"1395-1408"},"PeriodicalIF":7.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148156051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HBV RNA, HBcrAg, and HBsAg levels at year 6 do not predict HCC risk in patients with cirrhosis on long-term entecavir therapy.","authors":"Hung-Hsuan Pan, Tung-Hung Su, Tsung-Hui Hu, Wan-Long Chuang, Wei-Wen Su, Chun-Che Lin, Cheng-Yuan Peng, Chia-Chi Wang, Yao-Chun Hsu, Yi-Wen Huang, Kuo-Chih Tseng, Chih-Lin Lin, Sheng-Shun Yang, Fat-Moon Suk, Shih-Jer Hsu, Tsung-Ming Chen, Ming-Jong Bair, Cheng-Kuan Lin, Tai-Chung Tseng, Jia-Horng Kao","doi":"10.1007/s12072-026-11137-w","DOIUrl":"10.1007/s12072-026-11137-w","url":null,"abstract":"<p><strong>Background and aims: </strong>The prognostic value of on-treatment hepatitis B virus (HBV) RNA, hepatitis B core-related antigen (HBcrAg), and quantitative hepatitis B surface antigen (HBsAg) for hepatocellular carcinoma (HCC) risk in patients with chronic hepatitis B (CHB) remains uncertain. We evaluate the predictive roles of these viral markers in patients with CHB receiving long-term entecavir therapy.</p><p><strong>Methods: </strong>This prospective, multicenter study enrolled patients with CHB-related cirrhosis undergoing long-term entecavir treatment and HCC surveillance in Taiwan. Serum HBV RNA, HBcrAg, and HBsAg levels were measured at enrollment. Multivariable regression identified predictors of HBV RNA positivity and HCC development.</p><p><strong>Results: </strong>Overall, 451 patients were included. After a median of 6.2 years of antiviral therapy, the median levels of HBV RNA, HBcrAg, and HBsAg were 0.9 log10 copies/mL, 3.2 log10 U/mL, and 2.4 log10 IU/mL, respectively. During a median 3.3-year follow-up, 55 developed HCC. 57.2% of patients had detectable HBV RNA. HBV RNA detectability was associated with older age, lower alanine aminotransferase (ALT), HBeAg positivity, and higher HBsAg and HBcrAg levels. In multivariable analysis, higher fibrosis-4 (FIB-4) index (adjusted subdistribution hazard ratio [aSHR], 1.10; 95% confidence interval [CI] 1.00-1.21) and elevated alpha-fetoprotein (AFP) (aSHR, 1.01; 95% CI 1.00-1.01) independently predicted HCC development, whereas the three viral markers did not.</p><p><strong>Conclusion: </strong>After a 6-year entecavir therapy, 57.2% of patients with CHB-related cirrhosis had detectable HBV RNA. Year-6 HBV RNA, HBcrAg, and HBsAg levels were not predictive of HCC, while FIB-4 index and AFP remained independent predictors.</p>","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"1329-1339"},"PeriodicalIF":7.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148697513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}