Hepatology最新文献

{"title":"Reply: Don't forget to discuss TIPS in patients surviving an episode of alcoholic hepatitis.","authors":"Jordi Gratacós-Ginès, Meritxell Ventura-Cots, Elisa Pose","doi":"10.1097/HEP.0000000000001040","DOIUrl":"10.1097/HEP.0000000000001040","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"E19-E20"},"PeriodicalIF":12.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141877999","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":"Efficacy and safety of bintrafusp alfa in 2 phase I expansion cohorts with advanced HCC.","authors":"Ho Yeong Lim, Jeong Heo, Julio A Peguero, Baek-Yeol Ryoo, Thomas Decaens, Fabrice Barlesi, Markus H Moehler, Genevieve Jehl, S Peter Eggleton, Marcis Bajars, James L Gulley","doi":"10.1097/HEP.0000000000001054","DOIUrl":"10.1097/HEP.0000000000001054","url":null,"abstract":"<p><strong>Background and aims: </strong>Simultaneous inhibition of the TGF-β and programmed cell death 1 ligand 1 pathways provides a potential novel treatment approach. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β \"trap\") fused to a human IgG1 monoclonal antibody blocking programmed cell death 1 ligand 1, was evaluated in patients with advanced HCC.</p><p><strong>Approach and results: </strong>In this global, open-label, phase I study (NCT02517398), patients with programmed cell death 1 ligand 1-unselected HCC who failed or were intolerant to ≥1 line of sorafenib received bintrafusp alfa 1200 mg every 2 weeks in a dose-escalation (n = 38) or dose-expansion (n = 68) cohort until confirmed progression, unacceptable toxicity, or trial withdrawal. The primary endpoint was the best overall response per Response Evaluation Criteria in Solid Tumors version 1.1 by an independent review committee. Secondary endpoints included investigator-assessed best overall response, safety, and pharmacokinetics. Median follow-up times (range) were 41.4 (39.8-44.2) and 38.6 (33.5-39.7) months in the dose-escalation and dose-expansion cohorts, respectively. The objective response rate was below the prespecified 20% objective response rate threshold set to evaluate the efficacy of bintrafusp alfa in both cohorts (10.5% and 8.8%, respectively). Median overall survival and progression-free survival, respectively, were 13.8 and 1.5 months in the dose-escalation cohort and 13.5 and 1.4 months in the dose-expansion cohort. Treatment-related adverse events occurred in 78.9% and 64.7% of patients in the respective cohorts (grade ≥3 in 18.4% and 25.0% of patients).</p><p><strong>Conclusions: </strong>Bintrafusp alfa showed moderate clinical activity and a safety profile consistent with previous studies of bintrafusp alfa in patients with advanced HCC.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"32-43"},"PeriodicalIF":12.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply: Aspirin and GLP-1RAs-The missing confounders of empagliflozin for MASLD without diabetes mellitus?","authors":"Ka Shing Cheung, Wai K Leung","doi":"10.1097/HEP.0000000000001034","DOIUrl":"10.1097/HEP.0000000000001034","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"E23"},"PeriodicalIF":12.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141756008","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":"Macrophage hitchhiking for systematic suppression in postablative multifocal HCC.","authors":"Xuehan Li, Yan Zhang, Shun Li, Jiaqi Shi, Caiqi Liu, Xianjun Li, Yingjing Li, Shengnan Luo, Yuan Wang, Shihui Lai, Mingwei Li, Meng Zhang, Linlin Sun, Xiaoxue Du, Meng Zhou, Fan Xing, Qian Zhang, Zhiguang Wu, Tongsen Zheng","doi":"10.1097/HEP.0000000000000903","DOIUrl":"10.1097/HEP.0000000000000903","url":null,"abstract":"<p><strong>Background and aims: </strong>HCC, particularly the multifocal HCC, features aggressive invasion and dismal prognosis. Locoregional treatments were often refractory to eliminate tumor tissue, resulting in residual tumor cells persisting and subsequent progression. Owing to problematic delivery to the tumor tissue, systemic therapies, such as lenvatinib (LEN) therapy, show limited clinical benefit in preventing residual tumor progression. Therefore, more advanced strategies for postablative multifocal HCC are urgently needed.</p><p><strong>Approach and results: </strong>Motivated by the chemotaxis in tumor penetration of macrophages, we report a strategy named microinvasive ablation-guided macrophage hitchhiking for the targeted therapy toward HCC. In this study, the strategy leverages the natural inflammatory gradient induced by ablation to guide LEN-loaded macrophages toward tumor targeting, which increased by ~10-fold the delivery efficiency of LEN in postablative HCC in vivo. Microinvasive ablation-guided macrophage hitchhiking has demonstrated significant antitumor activity in various HCC models, including the hydrodynamic tail vein injection multifocal HCC mouse model and the orthotopic xenograft HCC rabbit model, systematically inhibiting residual tumor progression after ablation and prolonging the median survival of tumor-bearing mice. The potential antitumor mechanism was explored using techniques such as flow cytometry, ELISA, and immunohistochemistry. We found that the strategy significantly suppressed tumor cell proliferation and neovascularization, and such enhanced delivery of LEN stimulated systemic immune responses and induced durable immune memory.</p><p><strong>Conclusions: </strong>The macrophage hitchhiking strategy demonstrates exceptional therapeutic efficacy and biosafety across various species, offering promising prospects for clinical translation in controlling residual tumor progression and improving outcomes following HCC ablation.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"44-59"},"PeriodicalIF":12.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140847008","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":"MASLD/MetALD and mortality in individuals with any cardio-metabolic risk factor: A population-based study with 26.7 years of follow-up.","authors":"Minsun Kwak, Hyun-Seok Kim, Zhenghui Gordon Jiang, Yee Hui Yeo, Hirsh D Trivedi, Mazen Noureddin, Ju Dong Yang","doi":"10.1097/HEP.0000000000000925","DOIUrl":"10.1097/HEP.0000000000000925","url":null,"abstract":"<p><strong>Background and aims: </strong>A new term, metabolic dysfunction-associated steatotic liver disease (MASLD), has been proposed by a multi-society expert panel. However, it remains unclear whether hepatic steatosis per se in MASLD contributes to an increased risk of mortality in individuals with any cardio-metabolic risk factor (CMRF), which is also a significant risk factor for increased mortality. This study aimed to compare all-cause and cause-specific mortality between the \"MASLD/MetALD\" and \"no steatotic liver disease (SLD)\" groups in individuals with any CMRF.</p><p><strong>Approach and results: </strong>A population-based cohort study was conducted using 10,750 participants of the Third National Health and Nutrition Examination Survey. All-cause and cause-specific (cardiovascular, cancer, diabetes, and liver) mortality risks were compared between the \"MASLD,\" \"MetALD,\" and \"no SLD\" groups using the Cox proportional hazards model with complex survey design weights, adjusted for confounders. Over 26 years, the \"MASLD\" group did not show significantly increased all-cause (adjusted HR 1.04[95% CI: 0.95-1.14], p = 0.413), cardiovascular (0.88 [0.75-1.04], p = 0.139), or cancer (1.06[0.84-1.33], p = 0.635) mortality risk compared to the \"no SLD\" group in individuals with any CMRF. The MetALD group was associated with increased all-cause (1.41 [1.05-1.89], p = 0.022), cancer (2.35 [1.33-4.16], p = 0.004), and liver (15.04 [2.96-76.35], p = 0.002) mortality risk compared with the no SLD group. This trend was more pronounced in the MetALD group with advanced fibrosis assessed by Fibrosis-4 (FIB-4).</p><p><strong>Conclusions: </strong>In individuals with CMRF, the presence of steatotic liver disease (MASLD) alone did not increase the risk of mortality, except in cases with more alcohol consumption (MetALD). Therefore controlling metabolic risk factors and reducing alcohol consumption in people with MASLD or MetALD will be crucial steps to improve long-term health outcomes.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"228-237"},"PeriodicalIF":12.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140915333","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":"Letter to the Editor: Utilization of beta-blockers in patients with portal hypertension and peripheral artery disease.","authors":"Jon M Hoover","doi":"10.1097/HEP.0000000000001008","DOIUrl":"10.1097/HEP.0000000000001008","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"E4"},"PeriodicalIF":12.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141578429","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":"m 6 A-mediated gluconeogenic enzyme PCK1 upregulation protects against hepatic ischemia-reperfusion injury.","authors":"Shanshan Yu, Xiao Liu, Yan Xu, Lijie Pan, Yihan Zhang, Yanli Li, Shuai Dong, Dan Tu, Yuetong Sun, Yiwang Zhang, Zhuowei Zhou, Xiaoqi Liang, Yiju Huang, Jiajie Chu, Silin Tu, Chang Liu, Huaxin Chen, Wenjie Chen, Mian Ge, Qi Zhang","doi":"10.1097/HEP.0000000000000716","DOIUrl":"10.1097/HEP.0000000000000716","url":null,"abstract":"<p><strong>Background and aims: </strong>Ischemia-reperfusion (I/R) injury frequently occurs during liver surgery, representing a major reason for liver failure and graft dysfunction after operation. The metabolic shift from oxidative phosphorylation to glycolysis during ischemia increased glucose consumption and accelerated lactate production. We speculate that donor livers will initiate gluconeogenesis, the reverse process of glycolysis in theory, to convert noncarbohydrate carbon substrates (including lactate) to glucose to reduce the loss of hepatocellular energy and foster glycogen storage for use in the early postoperative period, thus improving post-transplant graft function.</p><p><strong>Approach and results: </strong>By analyzing human liver specimens before and after hepatic I/R injury, we found that the rate-limiting enzyme of gluconeogenesis, PCK1, was significantly induced during liver I/R injury. Mouse models with liver I/R operation and hepatocytes treated with hypoxia/reoxygenation confirmed upregulation of PCK1 during I/R stimulation. Notably, high PCK1 level in human post-I/R liver specimens was closely correlated with better outcomes of liver transplantation. However, blocking gluconeogenesis with PCK1 inhibitor aggravated hepatic I/R injury by decreasing glucose level and deepening lactate accumulation, while overexpressing PCK1 did the opposite. Further mechanistic study showed that methyltransferase 3-mediated RNA N6-methyladinosine modification contributes to PCK1 upregulation during hepatic I/R injury, and hepatic-specific knockout of methyltransferase 3 deteriorates liver I/R injury through reducing the N6-methyladinosine deposition on PCK1 transcript and decreasing PCK1 mRNA export and expression level.</p><p><strong>Conclusions: </strong>Our study found that activation of the methyltransferase 3/N6-methyladinosine-PCK1-gluconeogenesis axis is required to protect against hepatic I/R injury, providing potential intervention approaches for alleviating hepatic I/R injury during liver surgery.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"94-110"},"PeriodicalIF":12.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138796778","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 fade-out of HCV coinfection in people who live with HIV.","authors":"Georg Semmler, Mattias Mandorfer","doi":"10.1097/HEP.0000000000000922","DOIUrl":"10.1097/HEP.0000000000000922","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"11-13"},"PeriodicalIF":12.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140849504","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":"Novel proteomic signatures may indicate MRI-assessed intrahepatic fat state and changes: The DIRECT PLUS clinical trial.","authors":"Dana T Goldberg, Anat Yaskolka Meir, Gal Tsaban, Ehud Rinott, Alon Kaplan, Hila Zelicha, Nora Klöting, Uta Ceglarek, Berend Iserman, Ilan Shelef, Philip Rosen, Matthias Blüher, Michael Stumvoll, Ohad Etzion, Meir J Stampfer, Frank B Hu, Iris Shai","doi":"10.1097/HEP.0000000000000867","DOIUrl":"10.1097/HEP.0000000000000867","url":null,"abstract":"<p><strong>Background and aims: </strong>We demonstrated in the randomized 18-month DIRECT PLUS trial (n = 294) that a Mediterranean (MED) diet, supplemented with polyphenol-rich Mankai duckweed, green tea, and walnuts and restricted in red/processed meat, caused substantial intrahepatic fat (IHF%) loss compared with 2 other healthy diets, reducing NAFLD by half, regardless of similar weight loss. Here, we investigated the baseline proteomic profile associated with IHF% and the changes in proteomics associated with IHF% changes induced by lifestyle intervention.</p><p><strong>Approach and results: </strong>We calculated IHF% by proton magnetic resonance spectroscopy (normal IHF% <5% and abnormal IHF% ≥5%). We assayed baseline and 18-month samples for 95 proteomic biomarkers.Participants (age = 51.3 ± 10.8 y; 89% men; and body mass index = 31.3 ± 3.9 kg/m 2 ) had an 89.8% 18-month retention rate; 83% had eligible follow-up proteomics measurements, and 78% had follow-up proton magnetic resonance spectroscopy. At baseline, 39 candidate proteins were significantly associated with IHF% (false discovery rate <0.05), mostly related to immune function pathways (eg, hydroxyacid oxidase 1). An IHF% prediction based on the DIRECT PLUS by combined model ( R2 = 0.47, root mean square error = 1.05) successfully predicted IHF% ( R2 = 0.53) during testing and was stronger than separately inputting proteins/traditional markers ( R2 = 0.43/0.44). The 18-month lifestyle intervention induced changes in 18 of the 39 candidate proteins, which were significantly associated with IHF% change, with proteins related to metabolism, extracellular matrix remodeling, and immune function pathways. Thrombospondin-2 protein change was higher in the green-MED compared to the MED group, beyond weight and IHF% loss ( p = 0.01). Protein principal component analysis revealed differences in the third principal component time distinct interactions across abnormal/normal IHF% trajectory combinations; p < 0.05 for all).</p><p><strong>Conclusions: </strong>Our findings suggest novel proteomic signatures that may indicate MRI-assessed IHF state and changes during lifestyle intervention. Specifically, carbonic anhydrase 5A, hydroxyacid oxidase 1, and thrombospondin-2 protein changes are independently associated with IHF% change, and thrombospondin-2 protein change is greater in the green-MED/high polyphenols diet.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"198-211"},"PeriodicalIF":12.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140304199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Obeticholic acid as second-line therapy for primary biliary cholangitis: Does target trial emulation solve the issue?","authors":"Therese Bittermann, Douglas E. Schaubel","doi":"10.1097/hep.0000000000001198","DOIUrl":"https://doi.org/10.1097/hep.0000000000001198","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"31 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867112","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}