Hepatology最新文献

{"title":"The linoleic acid-derived leukotoxin 9,10-DiHOME drives immunosuppression in patients with acute-on-chronic liver failure.","authors":"Bryan J Contreras, Berta Romero-Grimaldo, María Belén Sánchez-Rodríguez, Mireia Casulleras, Marta Duran-Güell, Maria Papp, Richard Moreau, Jonel Trebicka, Joan Clària, Cristina López-Vicario","doi":"10.1097/HEP.0000000000001770","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001770","url":null,"abstract":"<p><strong>Background aims: </strong>Patients with acutely decompensated cirrhosis (ADC) present severe immune dysfunction characterized by smoldering systemic inflammation and persistent immunosuppression rendering them at increased risk of bacterial infections and acute-on-chronic liver failure (ACLF).</p><p><strong>Approach results: </strong>We explored the profile of 98 immunomodulatory lipid mediators in ADC patients with and without ACLF and their effects on leukocyte function. We performed LC-MS/MS-based lipidomics of 308 plasma samples longitudinally collected from 93 ADC patients with and without ACLF and integrated expression and flow cytometry data with functional assays in leukocytes. Lipidomics identified the linoleic acid-derived leukotoxin 9,10-dihydroxy-12-octadecenoic acid (9,10-DiHOME) as the only lipid mediator elevated in ACLF. 9,10-DiHOME levels followed the disease severity course and peaked when patients acquired infections and developed ACLF. Leukocytes from ADC patients showed increased expression of soluble epoxide hydrolase (sEH), the enzyme responsible for 9,10-DiHOME biosynthesis. In polymorphonuclear leukocytes, 9,10-DiHOME impaired degranulation, phagocytosis, and respiratory burst capacities. In mononuclear leukocytes, this lipid mediator induced the expression of the immunosuppressive marker MerTK, impaired their ability to produce cytokines in response to LPS and disrupted mitochondrial dynamics and autophagic responses. Inhibition of sEH in vivo reduced immunosuppressive responses in peritoneal macrophages and significantly attenuated MerTK expression in liver macrophages.</p><p><strong>Conclusions: </strong>These findings indicate that increased levels of the leukotoxin 9,10-DiHOME weakens immune-cell defensive responses and position sEH as a potential drug target in ADC.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined HDV RNA and Anti-HDV measurement for the management of HBV/HDV coinfection.","authors":"Gabriele Ricco, Daniela Cavallone, Piero Colombatto, Barbara Coco, Filippo Oliveri, Francesco Damone, Giovanni Petralli, Veronica Romagnoli, Antonio Salvati, Lidia Surace, Alessia Calì, Barbara Vianello, Ferruccio Bonino, Maurizia Rossana Brunetto","doi":"10.1097/HEP.0000000000001776","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001776","url":null,"abstract":"<p><strong>Background aims: </strong>Virologic profiling is mandatory for the clinical management of Hepatitis-B-surface-Antigen (HBsAg) carriers, positive for antibody against Hepatitis-Delta-Virus (anti-HDV). We analysed the correlations between serum HDV RNA, anti-HDV, HBV-markers and liver disease in a single centre cohort study.</p><p><strong>Approach results: </strong>Virologic, biochemical, imaging/histologic characteristics were studied in 146 consecutive HBsAg/anti-HDV carriers at baseline; in 31 Interferon-treated patients HDV/HBV markers were measured at end of therapy (EOT), 24 weeks after EOT and end of follow-up (EOF). HDV RNA was quantified by Altostar-Quantification-Kit (Altona Diagnostics) and anti-HDV by 10-fold endpoint dilutions (Liaison-XL-Murex anti-HDV, DiaSorin). Liver disease was absent in 9/10 (90%) HDV RNA negative/anti-HDV positive (all ≤1:100) and 2/136 (1.5%) viremic individuals (HDV RNA<500 IU/mL and anti-HDV≤1:100). The remaining 134 had liver disease (CHD), 110 (82.0%) cirrhosis; all but one had anti-HDV≥1:1,000; HDV RNA levels were higher in cirrhotics [5.86 (4.93-6.43) vs 5.01 (3.58-5.79) Log IU/mL, p=0.004], viremia peaking in early [6.02 (5.21-6.56) Log IU/mL] versus advanced cirrhosis [5.44 (4.71-6.06) Log IU/mL, p=0.006]. HDV RNA correlated with anti-HDV, HBsAg, HBcrAg and ALT (p<0.001). At multivariate HDV RNA independently associated with liver disease stage (β=0.244, p=0.003), ALT (β=0.220, p=0.001), and HBsAg levels (β=0.515, p<0.001). All but one of the 16 IFN responders had anti-HDV≤1:100 at EOF; all relapsers/non responders had anti-HDV≥1:1,000.</p><p><strong>Conclusions: </strong>Combined HDV RNA and anti-HDV quantification provides complementary information for characterizing HBV/HDV infection and monitoring treatment response. Declining anti-HDV levels associate with virological control. These results prompt prospective multicentre studies of their role in the clinical and therapeutic management of patients with HBV/HDV coinfection.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction: Capn4 overexpression underlies tumor invasion and metastasis after liver transplantation for hepatocellular carcinoma.","authors":"Dou-Sheng Bai, Zhi Dai, Jian Zhou, Yin-Kun Liu, Shuang-Jian Qiu, Chang-Jun Tan, Ying-Hong Shi, Cheng Huang, Zheng Wang, Yi-Feng He, Jia Fan","doi":"10.1097/HEP.0000000000001727","DOIUrl":"10.1097/HEP.0000000000001727","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"83 5","pages":"E162"},"PeriodicalIF":15.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147696923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FIB-4 fails to identify significant liver fibrosis in people with HIV: A large multinational screening study.","authors":"Felice Cinque, Sahar Saeed, Francesca Farina, Dana Kablawi, Jihoon Lim, Antonio Cascio, Claudia Gioè, Emmanuel Tsochatzis, Rosa Lombardi, Ahmed Cordie, Rahma Mohamed, Ahmed M Kamel, Gamal Esmat, Alessandra Bandera, Jovana Milic, Dominik Benke, Fauzi Elamouri, Jürgen K Rockstroh, Giovanni Guaraldi, Giada Sebastiani","doi":"10.1097/HEP.0000000000001773","DOIUrl":"10.1097/HEP.0000000000001773","url":null,"abstract":"<p><strong>Background and aims: </strong>Steatotic liver disease (SLD) and liver fibrosis are major comorbidities in people with HIV (PWH). Guidelines recommend stepwise screening using the Fibrosis-4 (FIB-4) index followed by transient elastography (TE), yet its accuracy and the extent of FIB-4 misclassification in PWH remain uncertain. We evaluated the diagnostic performance of FIB-4 against TE, quantified missed fibrosis, and assessed whether metabolic and HIV-specific factors improve risk prediction.</p><p><strong>Approach and results: </strong>We conducted a multinational study of 4,917 PWH without viral hepatitis coinfection or hazardous alcohol intake undergoing TE screening across seven centers. SLD was defined by controlled attenuation parameter >275 dB/m and classified as metabolic dysfunction-associated SLD (MASLD) or metabolic dysfunction-associated alcohol-related liver disease (MetALD). Significant fibrosis (liver stiffness measurement [LSM] ≥8 kPa) was present in 12.6% of participants, advanced fibrosis (LSM ≥11 kPa) in 6.1%, and SLD in 21.7% (20.6% MASLD, 1.1% MetALD). FIB-4 showed modest accuracy for significant fibrosis (AUROC 0.69, 95% CI 0.67-0.72) and misclassified 36% of fibrosis cases as low risk (FIB-4 <1.3). Performance was poorer in MASLD than in non-MASLD (AUROC 0.60 vs 0.76; p <0.001). Participants with false-negative FIB-4 exhibited a more metabolic phenotype, including higher BMI and steatosis. Incorporating metabolic and HIV-specific factors improved discrimination and reclassification and enabled development of the FIB-HIV score, which outperformed FIB-4 (AUROC 0.78 vs 0.69; p <0.001).</p><p><strong>Conclusions: </strong>In PWH, liver fibrosis is common and frequently missed by FIB-4, particularly in MASLD. TE-centered screening strategies augmented by metabolic and HIV-specific indicators may improve early fibrosis detection and risk stratification.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Locoregional lactate dehydrogenase inhibition potentiates therapy and overcomes treatment resistance in hepatocellular carcinoma.","authors":"Daniel J Boehmler, Ryan J Baron, Jennifer A Brain, Ariful Islam, Yohan Kim, Alexey Gurevich, Nicholas R Perkons, Alexander I Zavriyev, Rudra Amin, Jessica Andrew-Udoh, Erena Tuzneen Supan, Ryan El Ghazal, Stephen J Hunt, George McClung, David Tischfield, Daniel Ackerman, Aalim M Weljie, Kelley Weinfurtner, Nicolas Skuli, Terence P Gade","doi":"10.1097/HEP.0000000000001775","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001775","url":null,"abstract":"<p><strong>Background aims: </strong>Metabolic inhibitors have demonstrated limited efficacy for cancer therapy due to metabolic plasticity and systemic toxicity. Locoregional therapies (LRT), such as transarterial embolization (TAE) or transarterial chemoembolization (TACE), generate ischemic stress that reprograms the tumor microenvironment (TME) toward glycolytic dependency, creating an opportunity to sensitize hepatocellular carcinoma (HCC) to metabolic inhibition. This study investigated whether pharmacologic inhibition of lactate dehydrogenase (LDH) with NCATS-SM1441 could exploit TAE-induced metabolic vulnerabilities to improve therapeutic efficacy in HCC.</p><p><strong>Approach results: </strong>Human HCC cell lines were exposed to replete or ischemic (TAE-like) conditions and treated with the LDH inhibitor NCATS-SM1441. Glucose/lactate flux, adenosine triphosphate (ATP) levels, and viability were assessed. In vivo, a diethylnitrosamine (DEN)-induced rat HCC model was treated with intraarterial NCATS-SM1441, TAE, or their combination. Drug distribution, tumor metabolism, necrosis, and survival were analyzed using mass spectrometry imaging, histopathology, T2-weighted magnetic resonance imaging (MRI), and survival metrics. Ischemic conditions induced LDHA expression and glycolytic flux, enhancing susceptibility to LDH inhibition. The combination of intraarterial NCATS-SM1441 before embolization increased intratumoral drug accumulation, reduced systemic exposure, and synergized with TAE to suppress lactate production, promote tumor necrosis, and significantly extend local progression-free survival.</p><p><strong>Conclusions: </strong>TAE conditions the TME to create a therapeutically targetable glycolytic dependency. Combining TAE with LDH inhibition overcomes key limitations of metabolic inhibitors as monotherapies, enhancing local control and survival with minimal systemic toxicity, supporting integration of metabolism-targeted agents with LRT for unresectable HCC.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"B-BEST: Profiling the intrahepatic HBV reservoir at single-cell resolution.","authors":"Armando Andres Roca Suarez, Barbara Testoni, Fabien Zoulim","doi":"10.1097/HEP.0000000000001779","DOIUrl":"10.1097/HEP.0000000000001779","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GLP-1 receptor agonist-SGLT-2 inhibitor combination and risk of major adverse liver and cardiovascular outcomes in adults with MASLD and type 2 diabetes.","authors":"Xianhua Mao,Hong Fan,Man-Fung Yuen,Ramsey Cheung,Wai-Kay Seto,Mindie H Nguyen","doi":"10.1097/hep.0000000000001771","DOIUrl":"https://doi.org/10.1097/hep.0000000000001771","url":null,"abstract":"BACKGROUND AIMSGlucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors individually benefit patients with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to evaluate the effect of GLP-1 receptor agonist-SGLT-2 inhibitor combination on the risk of major adverse liver and cardiovascular outcomes compared with either agent alone among patients with MASLD and type 2 diabetes (T2D).METHODSThis is a target trial emulation study using data from U.S. Marketscan Databases. Propensity score-matched cohorts were built to compare (1) 4606 patients who received GLP-1 receptor agonist-SGLT-2 inhibitor combination with 18424 who received only GLP-1 receptor agonist, and (2) 5368 patients who received this combination with 21472 who received only SGLT-2 inhibitor. Cox regression models were conducted in on-treatment designs.RESULTSCompared with GLP-1 receptor agonists, GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a 39% lower risk of major adverse liver outcomes (HR 0.61 [95%CI 0.49 to 0.77]) and a 35% lower risk of major adverse cardiovascular events (HR 0.65 [0.60 to 0.70]) during a median follow-up of 6.3 months. Compared with SGLT-2 inhibitors, the combination was associated with a 43% lower risk of major adverse liver outcomes (HR 0.57 [0.46 to 0.69]) and a 20% lower risk of major adverse cardiovascular events (HR 0.80 [0.75 to 0.86]) during a median follow-up of 6.0 months.CONCLUSIONIn this study, GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a lower risk of major adverse liver and cardiovascular outcomes compared with either agent alone among patients with MASLD and T2D.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"32 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147735265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and validation of risk stratification models for hepatocellular cancer: A framework from the translational liver cancer consortium","authors":"Fasiha Kanwal, Ziding Feng, Yujin Hoshida, Jagpreet Chhatwal, Vincent Wai-Sun Wong, George N. Ioannou, Pierre Nahon, William Lotter, Jing Ning, Bachir Taouli, Guillermo Marquez, Sidney W. Fu, Amit G. Singal","doi":"10.1097/hep.0000000000001745","DOIUrl":"https://doi.org/10.1097/hep.0000000000001745","url":null,"abstract":"Clinical practice guidelines recommend hepatocellular cancer (HCC) surveillance in patients with cirrhosis from any etiology and those with chronic hepatitis B virus (HBV) infection and additional risk factors. However, HCC incidence varies across groups. Several risk stratification models using clinical factors and/or biomarkers have been derived to facilitate tailored HCC surveillance. Although risk stratification models are used for patients with hepatitis B, few have been sufficiently validated in patients with cirrhosis. Indeed, many unanswered questions related to the development, validation, and impact evaluation of risk stratification models must be addressed before widespread implementation can be recommended. The National Cancer Institute’s Translational Liver Cancer (TLC) Consortium was established to advance research focused on risk stratification and early detection of liver cancer. The TLC convened a multidisciplinary group, including clinicians, scientists, biostatisticians, and technology experts from the United States, Asia, and Europe, to provide a framework for the development, validation, and implementation of risk stratification models. The framework defines 4 phases of risk stratification model development and validation: <jats:italic toggle=\"yes\">phase 1</jats:italic> —development and internal validation, <jats:italic toggle=\"yes\">phase 2</jats:italic> —decision rule development, <jats:italic toggle=\"yes\">phase 3</jats:italic> —external validation, and <jats:italic toggle=\"yes\">phase 4</jats:italic> —impact evaluation. The group also defined a set of recommendations to improve the rigor of development and validation of HCC risk stratification strategies. This framework can inform best practices and highlight necessary steps for endorsement by practice guidelines and regulatory agencies, highlighting a path toward implementation in clinical practice.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"67 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147725950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The hitchhiker's guide to personalized immunotherapy: How tertiary lymphoid structures predict adjuvant treatment success in HCC.","authors":"Muhammed Dogukan Aksu","doi":"10.1097/hep.0000000000001729","DOIUrl":"https://doi.org/10.1097/hep.0000000000001729","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"67 1","pages":"1021-1022"},"PeriodicalIF":13.5,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147702043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum: Tertiary lymphoid structures in hepatocellular carcinoma: influence on immune cell profiles in tumors and on efficacy of adjuvant PD-1 inhibitor therapy after hepatectomy","authors":"Jia-Yong Su, Jian-Rong Li, Li-Xin Pan, Yi-Li Ma, Wei Tian, Yu-Mian Jiang, Ping-Ping Guo, Le Li, Zhu-Jian Deng, Zhen-Zhen Li, Cheng-Piao Luo, Rong-Rui Huo, Liang Ma, Jian-Hong Zhong","doi":"10.1097/hep.0000000000001517","DOIUrl":"https://doi.org/10.1097/hep.0000000000001517","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"22 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147702432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}