Hepatology最新文献

{"title":"Pretreatment serum bile acid composition and predictability of subsequent response to odevixibat in patients with bile salt export pump (BSEP) deficiency","authors":"Mark Nomden, Folkert Kuipers, Willem S. Lexmond, Tao Gu, Velichka Valcheva, Erik Lindström, Henkjan J. Verkade","doi":"10.1097/hep.0000000000001430","DOIUrl":"https://doi.org/10.1097/hep.0000000000001430","url":null,"abstract":"Background &amp; Aims: Bile salt export pump (BSEP) deficiency, or progressive familial intrahepatic cholestasis type 2, is a genetic liver disease characterized by defective biliary bile acid secretion. Odevixibat, an ileal bile acid transporter inhibitor (IBATi), impairs intestinal reabsorption of conjugated bile acids, reducing serum bile acid (sBA) concentration in some patients with BSEP deficiency. We evaluated association of pretreatment sBA levels and composition, and subsequent response to odevixibat in patients with BSEP deficiency to improve our understanding of the mechanism. Approach &amp; Results: In this blinded <jats:italic toggle=\"yes\">post hoc</jats:italic> analysis, pretreatment sBAs from 41 odevixibat-treated patients with BSEP deficiency who participated in PEDFIC were analyzed using liquid chromatography-tandem mass spectrometry. Patients were divided into sBA responders (Rs) and non-responders (NRs). Association of pretreatment individual sBAs with subsequent response was evaluated and receiver operating characteristic (ROC) curves were constructed to identify discriminating cutoff values. Rs had higher pretreatment percentages of unconjugated cholic acid (CA; area under the ROC curve [AUC]: 0.70 [95% CI: 0.52–0.87; <jats:italic toggle=\"yes\">P</jats:italic>=0.03]), unconjugated chenodeoxycholic acid (CDCA; AUC: 0.73 [0.56–0.90]; <jats:italic toggle=\"yes\">P</jats:italic>=0.01), and concentration of CA + CDCA (AUC: 0.76 [0.61–0.92]; <jats:italic toggle=\"yes\">P</jats:italic>=0.001). When ≥1 of 3 cutoffs were reached, 36/41 (87.8%) patients with BSEP deficiency were correctly classified as subsequent Rs (17/19; sensitivity: 89.5%) or NRs (19/22; specificity: 86.4%). Conclusions: Higher pretreatment serum levels of unconjugated CA and CDCA are associated with subsequent response to odevixibat in patients with BSEP deficiency. Response to odevixibat may be related to residual biliary bile acid secretion capacity in patients with BSEP deficiency.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"109 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611221","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: Clonal hematopoiesis in MASLD-associated HCC: Variant burden may matter more than presence","authors":"Eva Katharina Messer, Janett Fischer, Anne Weigert, Klaus H. Metzeler, Thomas Berg","doi":"10.1097/hep.0000000000001466","DOIUrl":"https://doi.org/10.1097/hep.0000000000001466","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"693 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611050","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":"Salivary microbiome and serum metabolomics add to clinical biomarkers to predict 6-month hospitalizations in a multi-center cirrhosis outpatient cohort","authors":"Jasmohan S. Bajaj, K Rajender Reddy, Puneeta Tandon, Jennifer C. Lai, Jacqueline G. O’Leary, Florence Wong, Guadalupe Garcia-Tsao, Hugo E. Vargas, Patrick S. Kamath, Scott W. Biggins, Phillip Vutien, Jawaid Shaw, Ana Teresa Limon Miro, Chinmay Bera, Joseph P. McGinley, Masoumeh Sikaroodi, Brian J. Bush, Leroy R. Thacker, Patrick M. Gillevet","doi":"10.1097/hep.0000000000001462","DOIUrl":"https://doi.org/10.1097/hep.0000000000001462","url":null,"abstract":"Background &amp; Aims: Prognosticating outcomes such as hospitalizations in cirrhosis outpatients is challenging, especially with changing etiologies and demographics. Aim: Determine impact of multi-omic strategies on outcome prediction. Approach &amp; Results: NACSELD3 enrolls cirrhosis outpatients with controlled/eradicated etiologies from 10 centers and follows them systematically. At baseline, clinical/demographic and cirrhosis details were recorded and saliva and serum samples were collected for microbiome and metabolome analysis respectively. Multi-omic bioinformatic studies to determine interaction of microbiota and metabolites with clinical prediction of 6-month hospitalizations were performed. 565 patients (60.2 years, 68% men, 35% alcohol, 33% MASH, 21%, eradicated HCV with MELD3.0 12) were enrolled. 163 (29%) required 6-month hospitalizations; most (75%) were liver-related. Those hospitalized had worse cirrhosis severity, co-morbidity indices, but similar demographics and oral health variables. Salivary microbiome alpha-diversity was lower (1.96±0.48 vs. 2.09±0.45, <jats:italic toggle=\"yes\">p</jats:italic>=0.018) with greater pathobionts (<jats:italic toggle=\"yes\">Streptococcus</jats:italic>, <jats:italic toggle=\"yes\">Treponema, Enterococcaceae)</jats:italic> and lower commensal genera (<jats:italic toggle=\"yes\">Veillonella, Prevotella, Haemophilus</jats:italic>, <jats:italic toggle=\"yes\">Lachnospiraceae</jats:italic> spp) at baseline. Serum metabolomics showed significant separation at baseline between hospitalized/not patients using supervised analyses with microbial-origin (phenyllactate, secondary bile acids, indoles), choline moieties, and polyamine/GABA (3-ureidopropionate/spermidine) metabolites being most prominent. Area-under-the curve using random forest for clinical, microbial, and metabolomic variables were higher than that of these individually. Latent factor analysis showed clinical variables (MELD3.0, hemoglobin and albumin) with the greatest impact followed by salivary microbiota and then serum microbiome for hospitalization prediction. Conclusion: In a multi-center North American outpatient cirrhosis cohort with controlled etiologies, serum metabolomics and salivary microbiome add to clinical variables to prognosticate 6-month hospitalization.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"10 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593919","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":"Liver resection with and without vascular resection versus transplantation for de novo perihilar cholangiocarcinoma","authors":"Yawen Dong, Zhihao Li, Vanja Podrascanin, John E. Eaton, Sumera I. Ilyas, Gregory J. Gores, Susanne G. Warner, Ty S. Diwan, David M. Nagorney, Julie K. Heimbach, Rory L. Smoot, Timucin Taner, Patrick P. Starlinger","doi":"10.1097/hep.0000000000001449","DOIUrl":"https://doi.org/10.1097/hep.0000000000001449","url":null,"abstract":"Background &amp; Aims: The optimal treatment strategy for de novo pCCA remains debated. This study compares outcomes between liver transplantation following neoadjuvant chemoradiation (RT+LT) and liver resection (LR), with (LR+VR) and without vascular resection (LR w/o VR). Methods: This single-center, retrospective study included de novo pCCA patients treated at Mayo Clinic Rochester (1993-2023) with curative-intent surgery. Patients underwent either (1) LR, classified as LR+VR or LR w/o VR, or (2) RT+LT following the transplant protocol. Overall survival (OS) and recurrence-free survival (RFS) were analyzed using as-treated (AT) and intention-to-treat (ITT) approaches, incorporating competing risk analysis and direct matching. Results: In the AT analysis, RT+LT showed superior median OS compared to LR w/o VR (78.0 vs. 58.2 mo, <jats:italic toggle=\"yes\">p</jats:italic>=0.03) and LR+VR (25.8 mo, <jats:italic toggle=\"yes\">p</jats:italic>&lt;0.001). Considering dropout rates (RT+LT: 41%, LR: 28%), ITT analysis showed no significant OS difference between LR and RT+LT (31.7 vs. 38.5 mo, <jats:italic toggle=\"yes\">p</jats:italic>=0.19). In matched AT analysis, RT+LT had no significant survival benefit over LR w/o VR (50.6 vs. 140.6 mo, <jats:italic toggle=\"yes\">p</jats:italic>=0.08) or LR+VR (25.8 mo, <jats:italic toggle=\"yes\">p</jats:italic>=0.11). Perioperative mortality was 4% (RT+LT), 7% (LR w/o VR), and 8% (LR+VR). Conclusion: Both LR and RT+LT achieve excellent oncological outcomes in selected de novo pCCA patients. Key challenges remain dropouts during neoadjuvant therapy in patients planned for LT and high perioperative mortality for patients undergoing LR. OS doubles in LR+VR patients compared to dropouts, supporting LR+VR as a viable option for LT-ineligible patients. Appropriate patient selection is crucial, as those not undergoing surgery suffer from a dismal prognosis.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"32 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578383","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":"Peripheral blood Foxp3-High tregs: A novel prognostic biomarker in hepatocellular carcinoma","authors":"Tung-Hung Su, Eui-Cheol Shin","doi":"10.1097/hep.0000000000001464","DOIUrl":"https://doi.org/10.1097/hep.0000000000001464","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"7 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578039","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":"Aging disrupts hepatocyte zonation homeostasis in mice and humans","authors":"Saloni Sinha, Qazi Ali, Tuo Zhang, Duc Huy T-Nguyen, Silvia Hanna, Jason Sethiadi, Erika Hissong, Robert E Schwartz","doi":"10.1097/hep.0000000000001451","DOIUrl":"https://doi.org/10.1097/hep.0000000000001451","url":null,"abstract":"Background and Aims: Aging-induced degenerative changes in the liver are not inherently pathologic but pose an increased risk for liver diseases. However, the molecular mechanisms underlying aging-induced hepatic dyshomeostasis remain incompletely characterized. Here, we investigate how aging alters liver architecture, cellular communication, and hepatocyte zonation. Approach and Results: Histological analyses of aged (&gt;24-month-old) wild-type mouse livers showed no fibrosis, but a uniform cellular enlargement compared to young (2-month-old) mouse livers. For an unbiased characterization of aging-driven changes, we used single-nucleus RNA sequencing and found that aged livers had altered cell-cell interactions and hepatocyte zonation with zone-specific transcriptomic changes. Immunostaining confirmed aging-induced expansion of ASS1<jats:sup>+</jats:sup>, CYP2E1<jats:sup>+</jats:sup> and GS<jats:sup>+</jats:sup> hepatic zones, and an aberrant expression of ASS1<jats:sup>+</jats:sup>-GS<jats:sup>+</jats:sup> “bi-zonal” hepatocytes, causing loss of distinct zonation. Mechanistically, this breakdown was associated with downregulation of key zonation regulators (<jats:italic toggle=\"yes\">Ctnnb1</jats:italic>, <jats:italic toggle=\"yes\">Foxo1, Tcf7l2</jats:italic>) and compensatory alterations in Wnt and Rspo3 signaling from NPCs. To assess translational relevance, liver biopsies from young (≤25YO) and aged (&gt;60YO) human donors were analyzed, revealing comparable zonal alterations and supporting the conservation of these aging-associated phenotypes across species. Conclusion: These findings reveal that aging causes loss of distinct hepatic zonation and alters intercellular communication through widespread transcriptional and architectural remodeling of liver cell types. The emergence of bi-zonal hepatocytes and expansion of hepatic zones in aged livers represent key hallmarks of hepatic aging. Our study provides new insights into mechanisms of liver aging and may inform therapeutic strategies targeting age-associated liver dysfunction.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"10 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578390","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: Clarifying the impact of response criteria and locoregional therapy on complete response outcomes in patients with hepatocellular carcinoma following immunotherapy","authors":"Bernhard Scheiner, Matthias Pinter","doi":"10.1097/hep.0000000000001460","DOIUrl":"https://doi.org/10.1097/hep.0000000000001460","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"149 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578037","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":"Environmental Risk Factors for Liver Cancer","authors":"Katherine A. McGlynn, Cody Z. Watling, Brenda Y. Hernandez, John D. Groopman","doi":"10.1097/hep.0000000000001463","DOIUrl":"https://doi.org/10.1097/hep.0000000000001463","url":null,"abstract":"In the 2021 Report on Carcinogens, the National Toxicology Program of the United States listed 63 known human carcinogens. While many of the listed agents are environmental factors, only two, aflatoxin and vinyl chloride, have been definitely linked to types of liver cancer. Aflatoxin is well known to increase the risk of hepatocellular carcinoma (HCC), while vinyl chloride is a cause of angiosarcoma of the liver. A number of other environmental factors have been studied for an association with liver cancers, such as air pollution, per- and polyfluoroalkyl substances, cyanobacteria, pesticides, aristolochic acid, polycyclic aromatic hydrocarbons, asbestos, arsenic, and organic solvents, however limited evidence exists for these exposures. It is the goal of this review article to examine what is currently known about environmental risk factors and liver cancer and suggest which ones should have the highest priority for further research.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"9 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578040","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":"Biliary YB-1/GLI2 axis facilitates ductular reaction and promotes hepatic stellate cell activation via SPP1/Integrin αvβ1 signaling during liver fibrogenesis","authors":"Yuecheng Guo, Qingqing Zhang, Binghang Li, Weiming Dai, Bo shen, Zhenyang Shen, Junjun Wang, Qichao Ge, Hanjing Zhangdi, Guangwen Chen, Qidi Zhang, Xiaobo Cai, Hui Dong, Guangjian Fan, Lungen Lu, Fei Li","doi":"10.1097/hep.0000000000001458","DOIUrl":"https://doi.org/10.1097/hep.0000000000001458","url":null,"abstract":"Background &amp; Aims: Emerging evidence suggests that ductular reactive cells (DRCs)-mediated ductular reaction (DR) accelerates the activation of hepatic stellate cells (HSCs) and contributes to liver fibrogenesis. Previous studies implicated Y-box binding protein 1 (YB-1) in promoting DRC expansion. This study aims to investigate the mechanisms underlying YB-1-mediated DR and its role in HSC activation. Approach &amp; Results: YB-1 was highly expressed in DRCs in human injured livers. CK19<jats:sup>CreERT</jats:sup> mice were crossed with YB-1<jats:sup>flox/flox</jats:sup> mice to generate DRC-specific YB-1 knockout mice. DRC-specific YB-1 deletion attenuated DR and liver injury induced by 3,5-methoxycarbonyl-1,4-dihydrocollidine (DDC) feeding and carbon tetrachloride (CCl<jats:sub>4</jats:sub>) treatment. Transcriptomic analyses, along with chromatin immunoprecipitation and luciferase assays, revealed that YB-1 transcriptionally regulated GLI2 and promoted DRC proliferation. Pharmacological inhibition of GLI2 significantly attenuated DR and liver fibrosis in DDC and CCl<jats:sub>4</jats:sub> mouse models. Transwell co-culture assay indicated that YB-1/GLI2 axis in DRCs drived HSC activation. Liquid chromatography-mass spectrometry combined with bioinformatic analyses identified secreted phosphoprotein 1 (SPP1) as the key molecule linking YB-1/GLI2-mediated DR to HSC activation. SPP1 was highly expressed in human injured livers and interacted with integrins. DRC-specific YB-1 knockout decreased the co-localization of SPP1 and integrin αvβ1 receptors in mouse fibrotic livers. Blocking integrin αvβ1 receptors in HSCs suppressed their activation, which was induced by DRC-derived SPP1. Conclusions: YB-1/GLI2 axis promotes DRC proliferation and SPP1 secretion, which facilitates HSC activation through integrin αvβ1 receptors. This study highlights the YB-1/GLI2/SPP1 signaling pathway as a potential target for therapeutic intervention in liver fibrosis.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"32 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578252","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":"Prognostic significance of mild ascites in patients with cirrhosis","authors":"Nicolas Chong Lugon, Anahita Rabiee, Catherine Mezzacappa, David E. Kaplan, Tamar H. Taddei, Guadalupe Garcia-Tsao","doi":"10.1097/hep.0000000000001452","DOIUrl":"https://doi.org/10.1097/hep.0000000000001452","url":null,"abstract":"Background: Overt (clinically detectable) ascites is the most common decompensating event in cirrhosis and is associated with a high mortality. The impact of mild ascites (only detectable by imaging) remains unclear. Methods: Retrospective cohort study in patients with cirrhosis using the Veterans Outcomes and Costs Associated with Liver Disease (VOCAL) cohort. Imaging reports at time of diagnosis of cirrhosis were analyzed using natural language processing and classified in three groups: no ascites, grade 1 (G1) or mild ascites, and grade 2/3 (G2/G3) or overt ascites. Mortality was compared across the groups using the Kaplan-Meier method and multivariable Cox proportional hazards analysis. Results: 41,669 patients were included in the study: 28,628 (68.7%) without ascites, 4,046 (9.7%) with G1, and 6,268 (15.0%) with G2/G3 ascites. Median follow-up time was 7.7 years (IQR 5.1-10.6). In patients with G1 (mild) ascites, median survival was 3.9 years (IQR 1.8-8.3), significantly lower than in those without ascites (6.5 years; IQR 3.1-12.2, <jats:italic toggle=\"yes\">p</jats:italic>&lt;0.0001) but significantly higher than in those with G2/G3 ascites (3.5 years; IQR 1.5-7.9, <jats:italic toggle=\"yes\">p</jats:italic>&lt;0.0001). After adjusting for potential confounders, the presence of any grade of ascites was associated with a higher hazard of mortality: G1 ascites (HR 1.50; 95% CI 1.44-1.57, <jats:italic toggle=\"yes\">p</jats:italic>&lt;0.001) and G2/G3 ascites (HR 1.63; 95% CI 1.57-1.69, <jats:italic toggle=\"yes\">p</jats:italic>&lt;0.001). These results were consistent across multiple sensitivity analyses. Conclusion: Grade 1 (mild or subclinical) ascites is associated with poorer survival compared to no ascites and represents an intermediate prognostic stage between compensated and decompensated cirrhosis.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"20 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547233","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}