Hepatology最新文献

{"title":"Hepatectomy alters adjuvant anti-PD-1 action in a mouse model of HCC but does not compromise neoadjuvant efficacy.","authors":"Roqiya Bouguerra,Sofia El Hajji,Charles Wassmer,Arnaud Bakaric,Florence Slits,Beat Moeckli,Laura Rubbia-Brandt,Stéphanie Lacotte,Christian Toso","doi":"10.1097/hep.0000000000001575","DOIUrl":"https://doi.org/10.1097/hep.0000000000001575","url":null,"abstract":"BACKGROUND AIMSImmune checkpoint inhibitors (ICI) have transformed the management of advanced hepatocellular carcinoma (HCC), yet their integration in the perioperative setting remains insufficiently explored. This study aims to investigate the effect of hepatectomy on the tumor microenvironment and assess whether neoadjuvant or adjuvant anti-PD-1 therapy offers improved therapeutic outcomes.METHODSUsing a murine orthotopic HCC model, a non-curative partial hepatectomy was performed, removing a non-tumor-bearing lobe with anti-PD-1 administered as neoadjuvant or adjuvant therapy. In a separate experiment, curative hepatectomy (resection of the tumor-bearing lobe) was performed to evaluate recurrence and survival.RESULTSAnti-PD-1 therapy significantly reduced tumor growth in non-surgical settings (p=0.0094), but its efficacy was lost in the adjuvant setting. This loss correlates with reduced infiltration of effector memory CD103⁺CD8⁺ T cells, increased expression of exhaustion markers (TIM-3, LAG-3), and accumulation of myeloid-derived suppressor cells (MDSC). MDSC depletion at the time of surgery improved adjuvant efficacy (p=0.0084), and delaying adjuvant ICI partially rescued responses, indicating a temporary postoperative immunosuppressive window. By contrast, neoadjuvant anti-PD-1 therapy significantly reduced tumor burden (p=0.0005), enhanced immune cell infiltration, and increased the expression of key activation markers on CD8+ cells (Tbx21, Gzma, Cxcr6, Cd69). Moreover, neoadjuvant treatment significantly reduced recurrence rates compared to sham treatment (35% vs. 68%, p=0.0405) and improved survival (p=0.0373), which was not achieved with adjuvant therapy.CONCLUSIONSPartial hepatectomy disrupts antitumor immunity and limits adjuvant ICI efficacy. Neoadjuvant anti-PD-1 immunotherapy offers a superior strategy compared to adjuvant immunotherapy in enhancing immune responses and reducing HCC recurrence.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"32 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339079","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: Assessing HCC incidence and surveillance thresholds in non-cirrhotic MASLD.","authors":"Nirbaanjot Walia,Samuel Hui,Michael Braude","doi":"10.1097/hep.0000000000001586","DOIUrl":"https://doi.org/10.1097/hep.0000000000001586","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"106 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351818","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":"Serum bile acid levels predict the development of portal hypertension and high-risk esophageal varices following successful Kasai in biliary atresia.","authors":"Emilie Grimaud,Antoine Gardin,Oanez Ackermann,Dalila Habes,Bogdan Hermeziu,Alice Thébaut,Solène Le Cam,Stéphanie Franchi-Abella,Virginie Lambert,Virginie Fouquet,Luca Pio,Florent Guérin,Mathieu Duché,Emmanuel Jacquemin,Marion Almes,Emmanuel Gonzales","doi":"10.1097/hep.0000000000001592","DOIUrl":"https://doi.org/10.1097/hep.0000000000001592","url":null,"abstract":"BACKGROUND AIMSBiliary atresia can lead to portal hypertension (PH), high-risk esophageal varices (HRV) and liver transplantation, despite successful Kasai procedure (KP). Serum bile acids (sBA) can reflect residual cholestasis in patients with successful KP. We investigated the predictive value of sBA measured during the first year post-KP on the development of PH and HRV within 5 years post-KP.APPROACH RESULTSIn this retrospective monocentric observational study, we included biliary atresia patients who underwent a successful KP, defined as a total serum bilirubin level of ≤25 μmol/L within 6 months post-KP, and in whom sBA were measured during the first year post-KP (n=60). We collected clinical, biological and digestive endoscopic data up to 5 years post-KP to assess the occurrence of PH and HRV. Predictive values of sBA were analyzed using receiver operating characteristic curves. sBA measured at a median time of 6 months (range: 4.5-9) and of 11 months (range: 9-12) post-KP, predicted PH at 3 and 5 years post-KP, with AUCs between 0.89 and 0.93 (p<0.0003) and the occurrence of HRV before 5 years post-KP with AUCs between 0.74 and 0.75 (p<0.04). sBA thresholds of 56 μmol/L and 30 μmol/L at a median time of 6 and 11 months post-KP, respectively, predicted HRV within 5 years post-KP with a sensitivity of 100%.CONCLUSIONIn biliary atresia patients with successful KP, sBA is an early biomarker predicting the development of PH and HRV within 5 years post-KP.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"105 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351825","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":"Glutamine synthetase loss in β-catenin-mutant hepatocellular carcinoma promotes tumor burden through macrophage metabolic reprogramming.","authors":"Evan R Delgado,Panari Patel,Junyan Tao,Yekaterina Krutsenko,Silvia Liu,Daniel Green,Raghad Alzubali,Brandon M Lehrich,Jai-Jun Liu,Tyler Yasaka,Minakshi Poddar,Sucha Singh,Vik Meadows,Aaron W Bell,Xin Chen,Aatur Singhi,Satdarshan P Monga","doi":"10.1097/hep.0000000000001591","DOIUrl":"https://doi.org/10.1097/hep.0000000000001591","url":null,"abstract":"BACKGROUND AIMSActivating β-catenin gene (CTNNB1) mutations are seen in 30% of all hepatocellular cancer (HCC). These tumors are a molecularly distinct subclass characterized in majority of cases by the presence of tumor-wide glutamine synthetase (GS), increased glutamine, mTOR activation, and susceptibility to mTOR inhibitors. Here, we investigate impact of GS loss from β-catenin-mutated HCCs.APPROACHTCGA was assessed for CTNNB1-mutated HCCs with differential Glul (encoding GS) expression for survival. Glul was conditionally deleted from hepatocytes and/or macrophages in HCCs co-expressing mutant-CTNNB1 (T41A) and mutant Nrf2 in mice. Macrophage depletion was also performed by Clodranate treatment. Tumors were characterized by histology and single cell spatial transcriptomics.RESULTSCTNNB1-mutated HCC patients with low Glul showed poor survival. β-Catenin-mutated HCCs lacking GS exhibited aggressive disease due to altered glutamate/glutamine availability, forcing metabolic adaptation through upregulation of macrophage Glul permitting mTOR activation and susceptibility to mTOR inhibitors, but switching macrophage function from immunosurveillance to immunosuppression. Glul loss from tumors did not interfere with β-catenin-dependent tumor zonation and responsiveness to β-catenin inhibition. Depleting macrophages using clodronate or conditionally deleting Glul from macrophages in GS-deficient, β-catenin-mutant HCCs, both decreased tumor burden and improved survival.CONCLUSIONSWe demonstrate unique metabolic dependency of β-catenin-mutated HCCs on GS in tumor cells which is diverted to macrophages upon GS elimination in tumor cells. This adaptation alters macrophage metabolism and function leading to compromised immunosurveillance and greater tumor burden. Our study reveals a metabolic dynamic between HCC cells and macrophages with impact on tumor biology.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"52 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351780","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":"Reply: Assessing HCC incidence and surveillance thresholds in non-cirrhotic MASLD.","authors":"Binu V John,Dustin Bastaich,Amit G Singal,Bassam Dahman","doi":"10.1097/hep.0000000000001587","DOIUrl":"https://doi.org/10.1097/hep.0000000000001587","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"32 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331906","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":"Reclassifying pediatric NAFLD using the steatotic liver disease framework: a multicenter retrospective study from the NASH CRN.","authors":"Tin Bo Nicholas Lam,Katherine P Yates,Sheila L Noon,Kimberly P Newton,Mark H Fishbein,Jean P Molleston,Stavra A Xanthakos,Ajay K Jain,Miriam B Vos,Niviann M Blondet,Krupa R Mysore,Cynthia A Behling,Laura A Wilson,Jeffrey B Schwimmer, ","doi":"10.1097/hep.0000000000001577","DOIUrl":"https://doi.org/10.1097/hep.0000000000001577","url":null,"abstract":"BACKGROUND AIMSThe terminology for hepatic steatosis and nonalcoholic fatty liver disease (NAFLD) was revised under the umbrella of steatotic liver disease (SLD), with metabolic dysfunction-associated steatotic liver disease (MASLD) as the primary subtype. MASLD is defined by hepatic steatosis plus at least one cardiometabolic risk factor (CMRF). A new category, Met-ALD, describes MASLD with alcohol consumption below the defined thresholds for alcohol-associated liver disease (ALD). While adult studies have demonstrated strong concordance between NAFLD and MASLD, the applicability of this framework in children remains unclear.APPROACH RESULTSWe assessed children clinically diagnosed with NAFLD and enrolled in the NASH CRN who had available liver histology. Clinical and demographic data, including body mass index (BMI), hepatotoxic medication use, and alcohol intake, were analyzed. Liver biopsies were centrally reviewed to confirm hepatic steatosis and evaluate for alternative etiologies. Participants were reclassified using the SLD framework. Among 1,019 children diagnosed with NAFLD, 858 (84%) met MASLD criteria. The average number of CMRFs per participant was 2.7±1.1; 41 (4.7%) met all five. Thirty-three participants (3.2%) were reclassified as Met-ALD, a prevalence that rose to 5.4% among adolescents. Sixty-six children (6.5%) were reclassified as drug-induced SLD.CONCLUSIONSMost children with NAFLD met MASLD criteria, but nearly 1 in 6 were reclassified based on alcohol use or medication exposure. These findings highlight the need for a systematic diagnostic approach accounting for metabolic risk factors, alcohol use, and medication-related liver injury.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"8 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305765","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":"When \"remission\" isn't enough: The unseen burden of autoimmune hepatitis.","authors":"Guneet Sidhu","doi":"10.1097/hep.0000000000001507","DOIUrl":"https://doi.org/10.1097/hep.0000000000001507","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"3 1","pages":"1037-1038"},"PeriodicalIF":13.5,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305763","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":"MSR1+ macrophages passivate antitumor immunity by inducing ITM2A+ CD4T exhaustion differentiation.","authors":"Shuai Wang,PeiHan Wu,Nan Xu,ZhaoFeng Xiao,YanPeng Liu,WeiXiang Bian,LiJun Meng,RuiCen Guo,YingXi Xu,HongDa Ding","doi":"10.1097/hep.0000000000001578","DOIUrl":"https://doi.org/10.1097/hep.0000000000001578","url":null,"abstract":"BACKGROUND AIMSImmune-checkpoint inhibitors target the membrane protein; however, the role of membrane proteins in antitumor immunity remains poorly elucidated. In this study, we aimed to explore the role of membrane proteins and unearth potential membrane proteins that can be targeted.METHODSWe initially screened prognosis-related membrane proteins based on The Cancer Genome Atlas Program and International Cancer Genome Consortium databases. Whole-gene, T-cell-specific or CD8T-cell-specific integral membrane protein 2A (ITM2A) knockout mice were constructed and used for orthotopic transplantation or as plasmid-derived spontaneous hepatocellular carcinoma (HCC) models to explore the role of ITM2A in the TME. Through scRNA sequencing, TimiGP analysis, molecular dynamics simulations, and biochemical experiments, the molecular mechanisms underlying the MSR1-ITM2A-TCR signaling regulatory axis were explored. Finally, bioengineering technologies were used to design and construct a new CD4T-targeted antibody-drug conjugate (ADC).RESULTSHigh ITM2A expression in HCC indicated a superior prognosis, which was associated with richer immune cell infiltration in the TME. The results of the single-cell RNA-sequencing of the HCC model in genetically knocked-out mice suggest that ITM2A influences the TCR signaling of TILs in the TME. This inference was confirmed in conditional ITM2A knockout mice. MSR1+macrophages induced CD4T exhaustion by disrupting the ITM2A-ZAP70 axis during TCR activation. ADC (ZEA-αCD4) treatment effectively inhibited tumor growth, independent of the classical αPDL1 immunotherapy.CONCLUSIONSMSR1+macrophages promote tumor-infiltrating ITM2A+CD4T exhaustion differentiation by regulating the ITM2A-ZAP70 axis. ZEA-αCD4 specifically targeted MSR1-ITM2A interaction to activate antitumor immunity and improve the efficacy of αPDL1 immunotherapy.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"220 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305776","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":"Who improves, who doesn't and why? Defining improvement and drivers of outcomes in pediatric MASLD.","authors":"Kevin B Harris,Sumera I Ilyas","doi":"10.1097/hep.0000000000001506","DOIUrl":"https://doi.org/10.1097/hep.0000000000001506","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"84 1","pages":"1043-1044"},"PeriodicalIF":13.5,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305762","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":"Bundle it up-Care bundles for spontaneous bacterial peritonitis.","authors":"Gowthami Kanagalingam,Juan Pablo Arab","doi":"10.1097/hep.0000000000001508","DOIUrl":"https://doi.org/10.1097/hep.0000000000001508","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"104 1","pages":"1041-1042"},"PeriodicalIF":13.5,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305766","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}