Journal of Hepatology最新文献

{"title":"Genomic and transcriptomic signatures of sequential carcinogenesis from papillary neoplasm to biliary tract cancer","authors":"Taek Chung, Seungho Oh, Jeongsoo Won, Jiho Park, Jeong Eun Yoo, Ho Kyoung Hwang, Gi Hong Choi, Chang Moo Kang, Dai Hoon Han, Sangwoo Kim, Young Nyun Park","doi":"10.1016/j.jhep.2025.01.007","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.01.007","url":null,"abstract":"<h3>Background &amp; Aims</h3>Papillary neoplasms of the biliary tree, including intraductal papillary neoplasms (IPN) and intracholecystic papillary neoplasms (ICPN), are recognized as precancerous lesions. However, the genetic characteristics underlying sequential carcinogenesis remain unclear.<h3>Methods</h3>Whole-exome sequencing was performed on 166 neoplasms (33 intrahepatic IPNs, 44 extrahepatic IPNs, and 89 ICPNs), and 41 associated carcinomas. Nine available cases were also subjected to spatial transcriptomic analysis.<h3>Results</h3>Mutations in the MAPK (48%), genomic integrity maintenance (42%), and Wnt/β-catenin (33%) pathways were prevalent in intrahepatic IPNs, extrahepatic IPNs, and ICPNs, respectively. <em>KRAS</em> mutations were enriched in intrahepatic IPN (42%, <em>P</em>&lt;0.001), whereas <em>SMAD4</em> mutations were enriched in extrahepatic IPN (21%, <em>P</em>=0.005). ICPNs frequently exhibit <em>CTNNB1</em> mutations, particularly in low-grade lesions. Mutational signature analysis revealed that SBS1 and SBS5 signatures were homogeneously enriched in intrahepatic IPN, in contrast to the heterogeneous distribution of SBS1, SBS2, SBS5, SBS13, SBS7b, and SBS23 in extrahepatic IPN and ICPN. Copy number aberrations gradually increased from low- to high-grade intraepithelial neoplasia and eventually to carcinoma. Phylogenetic analysis revealed that 89% of carcinomas were derived from IPN/ICPN through sequential carcinogenesis, with the majority sharing driver mutations between IPN/ICPN and carcinoma. Furthermore, multifocal, independent carcinogenesis events were observed in IPNs/ICPNs, resulting in mutationally distinct carcinoma lesions. Carcinogenesis of IPN/ICPN occurs in multiple subclones through mutational accumulation and transcriptomic alterations that affect vascular development, cell morphogenesis, extracellular matrix organization, and growth factor response.<h3>Conclusions</h3>With the largest IPN/ICPN cohort reported to date, our study provides a genome- and spatial transcriptome-level portrait of sequential carcinogenesis and differences in the anatomical location of biliary papillary neoplasms.<h3>Impact and implications</h3>Biliary tract cancer is a fatal malignancy. However, its genome-level sequential carcinogenesis from intraepithelial neoplasia to carcinoma has not yet been evaluated in a sufficiently large cohort. Papillary lesions of the bile duct and gallbladder are collectively termed intraductal papillary neoplasms (IPN) of the bile duct and intracholecystic papillary neoplasms (ICPN), respectively. They are primarily diagnosed based on histopathological studies. This study provides a comprehensive mutational and spatial transcriptomic landscape of papillary neoplasms of the bile duct and gallbladder. The results of this study offer insights into the mechanism of sequential carcinogenesis in papillary biliary tract tumors, pathology-genomics correlation, and potential therapeutic targets.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"45 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988734","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":"Reading through circular RNAs in MASLD: new diagnostic and therapeutic opportunities may come around","authors":"Maite G. Fernandez-Barrena, Matias A. Avila","doi":"10.1016/j.jhep.2025.01.006","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.01.006","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Funding</h2>Work in the authors’ laboratory is funded by: Grant PID2022-136616OB-I00 funded by MCIN/AEI/10.13039/501100011033 and by FEDER UE and PID2020-120387RB-I00 funded by MCIN/AEI/10.13039/501100011033; grant ERA-NET TRANSCAN-3 TRANSCAN2022-784-024; grant from Scientific Foundation of the Spanish Association Against Cancer (AECC) LABAE20011GARC. M.G.F.-B receives a Ramón y Cajal Program contract RYC2018-024475-I funded by MCIU/AEI/10.13039/501100011033 and ESF “Investing in your future”.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"13 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987955","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":"Zonal control of liver inflammation is orchestrated by periportal kupffer cells","authors":"Prakash Ramachandran","doi":"10.1016/j.jhep.2024.12.003","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.12.003","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Background and context</h2>Zonation of the liver along the porto-central axis has long been described, but the advent of high-resolution omics technologies has transformed our understanding of the molecular drivers of zonation. Indeed, the impact of zonation on the function of hepatocytes, sinusoidal endothelial cells and hepatic stellate cells has been well described in recent years. The spatial distribution of liver-resident macrophages, called Kupffer cells (KCs), is also zonated, with KCs predominantly residing</section></section><section><section><h2>Objectives, methods and findings</h2>In a recent article by Miyamoto <em>et al.</em> published in <em>Nature</em>,⁶ the authors aimed to provide new insights into how zonation affects immune responses in the liver. Spatial transcriptomics analysis suggested an anti-inflammatory environment in the periportal (zone 1) niche, findings the authors confirmed using a laser-burn model where neutrophils and monocytes preferentially accumulated in the pericentral (zone 3) rather than periportal zone. This zonal response was abrogated by KC depletion,</section></section><section><section><h2>Interpretation</h2>These data presented by Miyamoto and colleagues provide new insights into the zonal regulation of inflammatory responses in the liver, something which has not previously been well described. They have used cutting-edge models and intravital imaging approaches, which potentially also have broader applicability to study other aspects of zonal or spatially restrained injury responses in the liver. For example, the photolabeling approach they describe could be adapted to study cellular</section></section><section><section><h2>Financial support</h2>The author did not receive any financial support to produce this manuscript.</section></section><section><section><h2>Conflict of interest</h2>Please refer to the accompanying ICMJE disclosure forms for further details.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"42 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988402","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 Journal of Hepatology: A new team at 40","authors":"Vlad Ratziu, Frank Tacke","doi":"10.1016/j.jhep.2025.01.001","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.01.001","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Financial support</h2>The authors did not receive any financial support to produce this manuscript.</section></section><section><section><h2>Conflict of interest</h2>The authors of this study declare that they do not have any conflict of interest.Please refer to the accompanying ICMJE disclosure forms for further details.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"5 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988398","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":"JHEP at a glance (February 2025)","authors":"","doi":"10.1016/s0168-8278(24)02796-x","DOIUrl":"https://doi.org/10.1016/s0168-8278(24)02796-x","url":null,"abstract":"No Abstract","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"37 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987007","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":"MICROB-PREDICT works on identifying microbiome-based predictors and mechanisms of decompensated liver cirrhosis & ACLF, and develop personalised treatment strategies. Discover the project!","authors":"","doi":"10.1016/s0168-8278(24)02791-0","DOIUrl":"https://doi.org/10.1016/s0168-8278(24)02791-0","url":null,"abstract":"No Abstract","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"15 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987005","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":"Introducing the Breakthrough Beyond the Journal series","authors":"Vlad Ratziu","doi":"10.1016/j.jhep.2024.12.028","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.12.028","url":null,"abstract":"No Abstract","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"29 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987008","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":"EASL Congress 2025: prepare and submit your late-breaker!","authors":"","doi":"10.1016/s0168-8278(24)02788-0","DOIUrl":"https://doi.org/10.1016/s0168-8278(24)02788-0","url":null,"abstract":"No Abstract","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"695 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987002","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":"Pan-PPAR agonist lanifibranor improves insulin resistance and hepatic steatosis in patients with T2D and MASLD","authors":"Diana Barb, Srilaxmi Kalavalapalli, Eddison Godinez Leiva, Fernando Bril, Philippe Huot-Marchand, Lucile Dzen, Jens T. Rosenberg, Jean-Louis Junien, Pierre Broqua, Andrea Ortiz Rocha, Romina Lomonaco, Jean-Louis Abitbol, Michael P. Cooreman, Kenneth Cusi","doi":"10.1016/j.jhep.2024.12.045","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.12.045","url":null,"abstract":"&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;Lanifibranor is a pan-PPAR agonist that improves glucose/lipid metabolism and reverses steatohepatitis and fibrosis in adults with MASH. We tested its effect on insulin resistance at the level of different target tissues in relationship to change in intrahepatic triglyceride (IHTG) content.&lt;h3&gt;Methods&lt;/h3&gt;This phase 2, single center, study randomized (1:1) 38 patients with T2D and MASLD to receive lanifibranor 800 mg or placebo for 24 weeks. The primary endpoint was the change in IHTG (&lt;sup&gt;1&lt;/sup&gt;H-MRS). The main prespecified secondary endpoint was the change in hepatic, muscle and adipose tissue insulin sensitivity using the gold-standard euglycemic hyperinsulinemic clamp technique measuring glucose turnover. Other secondary endpoints included changes in cardiometabolic parameters (i.e., HbA1c, lipid profile, adiponectin).&lt;h3&gt;Results&lt;/h3&gt;Lanifibranor compared to placebo significantly lowered IHTG (full analysis set [FAS] -44% vs. -12%, respectively; least squares mean difference -31%, 95% CI -51 to -12%; in completers -50% vs. -16%; both p&lt;0.01). More patients reached ≥30% IHTG reduction with lanifibranor compared to placebo (FAS 65% vs. 22%; completers 79% vs. 29%; both p&lt;0.01) and steatosis resolution (FAS 25% vs. 0%; p&lt;0.05). Lanifibranor significantly improved hepatic and peripheral insulin resistance (i.e., fasting endogenous [primarily hepatic] glucose production, hepatic IR, and insulin-stimulated muscle glucose disposal or Rd). Secondary metabolic endpoints also improved (fasting glucose, insulin, HOMA-IR, HbA1c; HDL-C), and adiponectin increased 2.4-fold (all p&lt;0.001). Lanifibranor caused modest weight gain (+2.7%). Adverse events were mild (gastrointestinal side effects, hemoglobin decrease) and drug-related TEAE leading to study discontinuation were balanced between groups.&lt;h3&gt;Conclusions&lt;/h3&gt;Lanifibranor significantly improves hepatic, muscle and adipose tissue insulin resistance. Lanifibranor treatment was safe and effective in reducing hepatic steatosis and cardiometabolic risk factors associated with metabolic dysfunction.&lt;h3&gt;Impact and implications&lt;/h3&gt;No prior studies have evaluated the effect of lanifibranor on insulin sensitivity at the level of muscle, liver and adipose tissue and its relationship to changes in intrahepatic triglyceride (IHTG) content in insulin resistant subjects with MASLD and T2D. We observed a significant decrease in IHTG after 24 weeks of treatment (by ∼50%, p &lt; 0.001 versus placebo) that was associated with a major improvement in hepatic and peripheral (Rd) insulin sensitivity, restoration of adipose tissue function with more than two-fold increase in plasma adiponectin concentration and improvement in cardiometabolic risk factors. This is the first in-depth study on how a pan-PPAR approach reverses steatosis and metabolic dysfunction in patients with T2D and MASLD. It has important clinical implications because it offers proof-of-concept that by targeting t","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"23 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981466","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":"From the Editor’s Desk...","authors":"Philip Newsome, Frank Tacke, Heiner Wedemeyer, Lorenza Rimassa, Annalisa Berzigotti, Tom H. Karlsen, Vlad Ratziu","doi":"10.1016/j.jhep.2024.11.023","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.11.023","url":null,"abstract":"&lt;h2&gt;Section snippets&lt;/h2&gt;&lt;section&gt;&lt;section&gt;&lt;section&gt;&lt;h2&gt;Peg-IFNα reduces relapse in HBeAg-negative patients after NA cessation&lt;/h2&gt;This issue included two interesting manuscripts which could imply new indications for Peg-IFNα for the personalised management of hepatitis B. &lt;span&gt;&lt;span&gt;&lt;strong&gt;Li, Qiu, Liu and coworkers&lt;/strong&gt;&lt;/span&gt;&lt;svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"&gt;&lt;path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"&gt;&lt;/path&gt;&lt;/svg&gt;&lt;/span&gt; performed a randomised-controlled trial to &lt;strong&gt;explore if Peg-IFNα could reduce post-treatment relapse after stopping nucleo(s)tide analogues (NAs).&lt;/strong&gt; One hundred and eighty HBeAg-negative patients who had been treated for at least 2.5 years with NAs were randomised to 48 weeks of Peg-IFNα therapy or no therapy after stopping NAs. A&lt;/section&gt;&lt;/section&gt;&lt;/section&gt;&lt;section&gt;&lt;section&gt;&lt;section&gt;&lt;h2&gt;Sequential Peg-IFN after bepirovirsen may reduce post-treatment relapse in chronic hepatitis B&lt;/h2&gt;Alongside the selection of the month, &lt;span&gt;&lt;span&gt;&lt;strong&gt;Buti, Heo and coworkers&lt;/strong&gt;&lt;/span&gt;&lt;svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"&gt;&lt;path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"&gt;&lt;/path&gt;&lt;/svg&gt;&lt;/span&gt; also performed a randomised-controlled trial to assess whether &lt;strong&gt;Peg-IFNα treatment could reduce post-treatment HBV relapse after 12 or 24 weeks of therapy with the oligonucleotide bepirovirsen&lt;/strong&gt;. This is a very important study for the field. More than 100 patients were treated with bepirovirsen for 12 or 24 weeks followed by another 24 weeks of Peg-IFNα. All patients received NAs which were continued throughout the study. Interestingly,&lt;/section&gt;&lt;/section&gt;&lt;/section&gt;&lt;section&gt;&lt;section&gt;&lt;section&gt;&lt;h2&gt;MicroRNAs as therapeutic agents for liver fibrosis&lt;/h2&gt;The 2024 Nobel Prize in Physiology or Medicine was awarded jointly to Victor Ambros and Gary Ruvkun for their groundbreaking discovery of microRNAs (miRNAs), which are small RNA molecules that play an essential role in regulating gene expression. Aiming at discovering key miRNAs in the pathogenesis of liver fibrosis, &lt;span&gt;&lt;span&gt;&lt;strong&gt;Markovic and coworkers&lt;/strong&gt;&lt;/span&gt;&lt;svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"&gt;&lt;path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"&gt;&lt;/path&gt;&lt;/svg&gt;&lt;/span&gt; performed functional screenings in primary human hepatic myofibroblasts, followed by validation in mouse models and a human liver bud model, and identified&lt;/section&gt;&lt;/section&gt;&lt;/section&gt;&lt;section&gt;&lt;section&gt;&lt;section&gt;&lt;h2&gt;Association of food insecurity with the prevalence of MASLD and liver-related mortality&lt;/h2&gt;While the global burden of MASLD continues to increase, the regional influences of food insecurity and healthcare access remain unknown. &lt;span&gt;&lt;span&gt;&lt;strong&gt;Younossi and coworkers&lt;/strong&gt;&lt;","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"30 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987006","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}