JHEP Reports最新文献

{"title":"Epidemiological comparison of cirrhosis to other long-term health conditions in the United Kingdom.","authors":"Hamish Innes, Joanne Morling, Stephan Buch, Timothy J Kendall, Jonathan A Fallowfield, Indra Neil Guha","doi":"10.1016/j.jhepr.2026.102069","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102069","url":null,"abstract":"<p><strong>Background: </strong>Although cirrhosis is a serious long-term health condition (LTC), it tends to receive little attention from healthcare policymakers. Here, we sought to describe how cirrhosis compares to other LTCs to inform priority-setting discussions.</p><p><strong>Methods: </strong>We analysed data from the Our Future Health (OFH) study, a cohort of ∼1.7 million individuals from England, United Kingdom. Self-reported diagnosis status for cirrhosis and 15 benchmark LTCs (including type 1 diabetes, type 2 diabetes, Parkinson's disease, chronic kidney disease, schizophrenia, and stage 4 cancer) were ascertained from the enrolment questionnaire. Each LTC was profiled with respect to: sociodemographic characteristics; mortality; comorbidity burden; and late diagnosis. Furthermore, information on each LTC's trajectory (i.e., increasing, stable, or decreasing over time) was determined from background mortality data over the last decade.</p><p><strong>Results: </strong>The study cohort included 1,613,777 participants, of whom 2,606 (0.2%) reported a diagnosis of cirrhosis. Mortality elevation for participants with cirrhosis versus without was substantial (HR: 7.46; P<0.001, with adjustment for age/sex) and comparable to dementia (HR:7.60), stage 4 cancer (HR:7.06), whilst higher than schizophrenia (HR:4.46) and heart failure (HR:4.01). People with cirrhosis had more co-existing health conditions/diseases than other LTCs (i.e., elevated prevalence for 58/145 distinct health conditions; second only to stage 4 cancer). Area-based deprivation score was third highest for cirrhosis, behind COPD and schizophrenia. Late diagnosis of cirrhosis was commonplace, with <15% of new-onset liver failure reporting cirrhosis at enrolment. Cirrhosis also exhibited an upward trajectory, with mortality increasing by ∼20% in the last decade.</p><p><strong>Conclusion: </strong>Cirrhosis is an anomaly LTC with respect to its deprivation, comorbidity, mortality, upward trajectory, and late diagnosis profile. Our data provide comparative evidence to inform priority-setting discussions with policymakers.</p><p><strong>Impact and implications: </strong>Various levers are available to policy makers for reducing incidence of liver cirrhosis. However, other health conditions are often prioritised by policy makers ahead of cirrhosis; the decision-making process around this is not always transparent nor grounded in evidence. This study explores the characteristics of cirrhosis relative to other long-term conditions through a public-health lens. Our findings may guide priority-setting discussions between policy makers, advocates and other stakeholders and may shift current discourse onto a more empirical footing.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102069"},"PeriodicalIF":8.7,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227779","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":"Phase 2 study of fazpilodemab, a FGFR1/Klothoβ agonist, in metabolic dysfunction-associated steatohepatitis (MASH).","authors":"Arun J Sanyal, Yixuan Zou, Lu Zhang, Ajit Dash, Jill Fredrickson, Johnny Gutierrez, Kenta Yoshida, Yanqiu Liu, Rebecca Kunder, Maria Wilson, Chin Wong","doi":"10.1016/j.jhepr.2026.102068","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102068","url":null,"abstract":"<p><strong>Background & aims: </strong>Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease with limited treatment options. Fazpilodemab, a bispecific antibody targeting fibroblast growth factor receptor 1 (FGFR1) and Klotho β (KLB), showed promising trends in liver health markers in type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease.</p><p><strong>Methods: </strong>This Phase 2 randomized study evaluated the efficacy, safety, and pharmacokinetics of fazpilodemab in patients with MASH and hepatic steatosis. Patients were randomized to receive fazpilodemab or placebo subcutaneously every 2 weeks for 52 weeks. The primary endpoint was MASH resolution without fibrosis worsening at Week 52. Secondary endpoints included histological improvement from baseline (≥2 points reduction in MAS with ≥ 1-point reduction in either lobular inflammation or hepatocellular ballooning and no worsening of fibrosis stage), fibrosis improvement from baseline (≥1 MASH CRN fibrosis stage) and no worsening of steatohepatitis (no increase in MAS for ballooning, inflammation, or steatosis), and changes in hepatic fat fraction. Safety, PK, and immunogenicity were also assessed.</p><p><strong>Results: </strong>A total of 46 patients (fazpilodemab 50 mg [n=11], 75 mg [n=11], or 100 mg [n=11]; and placebo [n=13]) were enrolled, of whom 23 had Week 52 or early termination biopsy. The proportion of patients achieving resolution of MASH without worsening of fibrosis was 37.5% (3/8) in the 50 mg arm, 14.3% (1/7) in the 75 mg arm, and 33.3% (2/6) in the 100 mg arm, compared to 16.7% (1/6) in the placebo arm. For the secondary endpoints, improvements in liver histology and fibrosis were numerically higher in fazpilodemab-treated patients; transient improvements in hepatic fat fraction were observed. Fazpilodemab was adequately tolerated, with no new safety signals identified.</p><p><strong>Conclusions: </strong>While the study was prematurely terminated, fazpilodemab demonstrated a safety profile consistent with previous studies. No definite conclusion could be drawn regarding the preliminary fazpilodemab efficacy profile due to the limited sample size and early dropouts.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov, NCT04171765 IMPACT AND IMPLICATIONS: Dual targeting of FGFR1 and Klotho β (KLB) with fazpilodemab demonstrated preliminary signals in liver histology and steatosis reduction alongside a favorable safety profile in patients with MASH. Although early trial termination precludes definitive efficacy conclusions, these findings support FGFR1 agonism as a viable strategy for future drug development in metabolic liver disease.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102068"},"PeriodicalIF":8.7,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216352","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":"Physical Activity and Frailty in patients with Advanced Chronic Liver Disease: A prospective study.","authors":"Felicity Rhian Williams, Jonathan Ian Quinlan, Amritpal Dhaliwal, Thomas Nicholson, Leigh Breen, Carolyn Greig, Ahmed Mohamed Elsharkawy, Janet Margaret Lord, Alex V Rowlands, Matthew James Armstrong","doi":"10.1016/j.jhepr.2026.102072","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102072","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and aims: &lt;/strong&gt;Physical frailty is associated with adverse outcomes in advanced chronic liver disease (AdvCLD). Tailoring physical activity prescriptions to minimise frailty is challenging because the volume and intensity of habitual activity remain undefined in AdvCLD. This prospective study aimed to (a) compare device-assessed 24-hour activity profiles in AdvCLD and healthy controls, (b) identify predictors of poor activity and associated frailty, and (c) determine the physical activity profiles required to minimise frailty in AdvCLD.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Ambulatory patients with AdvCLD (Birmingham, UK) and healthy controls wore 24-hour GENEActiv® wrist accelerometers for 14-days. Clinical characteristics, frailty and physical activity outcomes (i.e. volume and intensity of most active accumulated/continuous time-periods) were collected.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Forty-three AdvCLD patients (65% male, median age 56, UKELD 52; 53% ArLD) and 17 healthy age/sex-matched controls (59% male, median age 47) were recruited. AdvCLD patients spent more time inactive (56% vs 48%, p=0.005), less in moderate activity (3% vs 7%, p&lt;0.0001), moved less intensively during their most active minute (313.4 mg vs 691.9 mg, p&lt;0.001), and didn't sustain moderate activity (∼slow walking) beyond one minute (30-times less than health controls). Even 'robust' patients with AdvCLD (23%) didn't sustain moderate continuous activity beyond two minutes. ArLD patients were the least active (volume 13.4[4.6] vs 29.2[8.9] mg, p&lt;0.01). Exploratory analysis revealed older age, refractory ascites and Liver Frailty Index were associated with lower levels of physical activity (all p&lt;0.05).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Ambulatory patients with AdvCLD, especially ArLD, have drastically reduced volumes of habitual physical activity and didn't sustain moderate intensity beyond one-minute. Short bursts of higher-intensity activity are realistic physical activity goals and are associated with less frailty in AdvCLD.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Impact and implications: &lt;/strong&gt;Physical frailty is prevalent and associated with adverse outcomes in patients with advanced chronic liver disease (AdvCLD). Inactivity drives physical frailty, yet prescribing effective physical activity interventions remains challenging due to unclear volume and intensity parameters. Utilising high resolution, wrist-worn accelerometers and robust frailty measures we show that ambulatory patients with AdvCLD, especially those with alcohol-related liver disease (ArLD), have markedly lower volumes of habitual physical activity and did not sustain more than one minute of moderate intensity activity, (30-fold less than age/sex matched healthy controls). Additionally, in exploratory analysis, the liver frailty index (LFI) predicted activity volume and intensity, supporting its utility as a practical tool to guide physical activity prescription. Refractory ascites, higher frailty indices","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102072"},"PeriodicalIF":8.7,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206846","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":"Azathioprine versus mycophenolate mofetil in treatment-naive autoimmune hepatitis: 3-year follow-up of the CAMARO-trial.","authors":"Charlotte D Slooter, Romée Jalm Snijders, Anna E C Stoelinga, Katinka M A Gerrits, Tom J G Gevers, Simon Pape, Maaike Biewenga, Adriaan J van der Meer, Maarten E Tushuizen, Ulrich H W Beuers, Floris F van den Brand, Matthijs Kramer, Robert C Verdonk, Hendrik J M de Jonge, Jan Maarten Vrolijk, Sjoerd F Bakker, Thomas Vanwolleghem, Martine Amc Baven Pronk, Nicole M F van Gerven, Marijn G M Sijtsma, Ilona M Kerkhof, Brechje C van Eijck, Manon C van IJzendoorn, Margot van Herwaarden, Maartje Bartelink, Kerem Sebib Korkmaz, Aad P van den Berg, Daphne M Hotho, Maureen M J Guichelaar, Frank Govaert, Sita Jansen, Sanne K van der Wiel, Leendert H Oterdoom, Leslie A Noach, Remco van Dijk, Amar D Levens, Bart van Hoek, Ynto S de Boer, Joost P H Drenth","doi":"10.1016/j.jhepr.2026.102058","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102058","url":null,"abstract":"<p><strong>Background & aims: </strong>The CAMARO trial demonstrated superior short-term tolerability and response rates of mycophenolate mofetil (MMF) versus azathioprine (AZA), both combined with prednisolone, in treatment-naïve autoimmune hepatitis (AIH). We evaluated long-term outcomes.</p><p><strong>Methods: </strong>Patients enrolled in the multicenter randomized CAMARO trial were retrospectively followed for up to 3 years after treatment initiation. Co-primary endpoints were trial-assigned treatment with normalized alanine aminotransferase (ALT) at 3 years and time to biochemical response (normalization of ALT and immunoglobulin G).</p><p><strong>Results: </strong>Three-year follow-up was available for 67 patients (96%; 30 AZA, 37 MMF). At 3 years, 57% versus 76% remained on trial-assigned treatment with normalized ALT (p = 0.099). Median time to biochemical response was 64 versus 16 weeks (adjusted HR 2.74, 95% CI 1.49-5.06; p = 0.001). Among patients without ALT normalization at 24 weeks, 6/12 AZA-treated and 6/11 MMF-treated patients subsequently normalized ALT. Among patients remaining on randomized treatment at 24 weeks, subsequent treatment discontinuation occurred in 5/24 (21%) with AZA and 7/37 (19%) with MMF. Steroid-free ALT normalization (64% vs. 66%) and adverse event rates during year 3 (70% vs. 74%) were comparable (both p > 0.05). Five-year liver-related event-free survival was 70% (95% CI 55-93%) with AZA and 85% (95% CI 71-100%) with MMF (p = 0.080).</p><p><strong>Conclusions: </strong>MMF was associated with faster biochemical response and numerically better overall tolerability. Among patients tolerating their assigned treatment during the initial treatment phase, subsequent outcomes were comparable between AZA and MMF. The substantial treatment burden with both therapies highlights the need for improved treatment options.</p><p><strong>Clinical trial number: </strong>NCT02900443.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102058"},"PeriodicalIF":8.7,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149194118","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":"Hippo signaling drives mesenchymal cell fate and heterogeneity in liver cancer.","authors":"Natália Alves Souza, Weronika Kowalczyk, Soheil Soheily, Gauthier Canoot, Tessa Ostyn, Marina Corral-Ibáñez, Mohammad Sarfi, Hanne Hillen, Leticia Sansores-Garcia, Leen Van Huffel, Lore Spiessens, Jun Xie, Olivier Govaere, Iván M Moya, Tania Roskams, Georg Halder","doi":"10.1016/j.jhepr.2026.102064","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102064","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background & aims: &lt;/strong&gt;Liver cancer comprises a spectrum of cancers that include pure hepatocellular carcinoma, cholangiocarcinoma, and tumors with varying degrees of mixed hepatocytic, cholangiocytic, and mesenchymal traits. Such heterogeneity can elevate cancer aggressiveness and induce therapy resistance. However, mechanisms that promote cellular plasticity in cancer remain poorly understood. To study mechanisms driving heterogeneity in liver cancer, we developed a mouse model in which cholangiocarcinoma cells spontaneously acquire mesenchymal characteristics.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We induced liver cancer in mice by hydrodynamic tail vein injection of plasmids expressing activated versions of Notch, Akt, and KRas. We performed lineage tracing, single nucleus RNA-sequencing, and gain- and loss-of-function experiments of Hippo signaling to determine the mechanisms inducing tumor heterogeneity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Co-expression of activated Notch, Akt, and KRas led to the formation of aggressive intrahepatic cholangiocarcinoma (ICC) that presented a strong desmoplastic reaction and a heterogeneous population of cancer cells with varying levels of epithelial and mesenchymal features. Single-cell analysis showed that these tumors comprised cancer cells with cholangiocyte-like epithelial (N = 4006 cells) and mesenchymal (N = 605 cells) characters. Lineage tracing revealed that the mesenchymal cancer cells originated from the transdifferentiation of epithelial cancer cells. Mechanistically, we identified the Hippo pathway effectors Yap and Taz as drivers of this transition: high Yap/Taz levels correlated with the acquisition of mesenchymal features, Yap/Taz double mutant tumor cells were unable to transdifferentiate into mesenchymal tumor cells (N = 5, p = 0.007), and overexpression of Yap (N = 5, p = 0.008) or Taz (N = 5, p = 0.025) in pure ICC tumors driven by Notch and Akt led to the emergence of cancer cells with mesenchymal features.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Our data show that the Hippo pathway effectors Yap and Taz drive plasticity in liver cancer cells and promote the transdifferentiation of epithelial cholangiocarcinoma cells into tumor cells with mesenchymal characteristics.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Impact and implications: &lt;/strong&gt;Our study provides a mechanistic understanding of how cellular heterogeneity, a major challenge for treatment, develops in intrahepatic cholangiocarcinoma. We show that the Hippo pathway effectors Yap and Taz drive the transition of epithelial liver cancer cells into a mesenchymal state. These findings are important because they identify molecular mechanisms that promote cholangiocarcinoma plasticity and imply that therapeutic targeting of YAP/TAZ activity may inhibit cancer cell plasticity and enhance treatment efficacy in patients with cholangiocarcinoma and other cancers with similar molecular features. However, given the complexity of tumor signaling and the preclinical n","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102064"},"PeriodicalIF":8.7,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149194100","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":"Genetic Modulation of ALT Leads to Underestimation of Liver Injury in Male ALDH2*2 Drinkers.","authors":"Takuya Seike, Yi-Hsun Chen, Wei-Chung Chen, Pin-Ruei Huang, I-Chen Wu, Ming-Tsang Wu, Kenichi Harada, Taro Yamashita, Daria Mochly-Rosen","doi":"10.1016/j.jhepr.2026.102060","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102060","url":null,"abstract":"<p><strong>Background & aims: </strong>Serum alanine aminotransferase (ALT) is commonly used to detect hepatocellular injury. However, genetic and metabolic factors may modulate ALT levels. We focused on the potential impact of an in-activating mutation in aldehyde dehydrogenase 2 (ALDH2*2, rs671) polymorphism, prevalent among East Asians, on ALT levels and its interaction with alcohol consumption.</p><p><strong>Methods: </strong>We analyzed Taiwan's Biobank data of 91,743 participants, 48.7% of whom were ALDH2*2 carriers, to assess the interaction between ALDH2 genotype, alcohol consumption and serum levels of liver enzymes. Mechanistic studies were conducted using ALDH2*2 knock-in (KI) mice exposed once to ethanol (1 g/kg), to evaluate ALT expression and serum levels, inflammation and liver injury. Integrative transcriptomic analyses, along with validation using publicly available datasets, were performed to identify transcriptional regulators of ALT.</p><p><strong>Results: </strong>Male ALDH2*1/*2 drinkers exhibited a significantly lower serum ALT levels compared to ALDH2*1/*1 drinkers, despite higher gamma-glutamyl transferase levels (p < 0.001). Following acute ethanol administration to ALDH2*1/*2 mice, serum ALT elevation remained minimal despite comparable or greater accumulation of lipid oxidation product, 4-hydroxynonenal, enhanced MAPK activation, increased chemokine expression, and markedly aggravated histological necrosis relative to ethanol-treated wildtype mice. Notably, hepatic Alt1 mRNA and ALT protein expression were significantly reduced in ethanol-treated ALDH2*1/*2 mice. Integrated ChIP-seq analysis suggested that the transcription factor Hnf4a/HNF4A may regulate Alt1/ALT1 transcription. Validation using publicly available datasets confirmed reduced hepatic ALT1 expression in early inflammatory states and in patients with alcoholic hepatitis.</p><p><strong>Conclusions: </strong>ALDH2 deficiency blunts serum ALT elevation following alcohol exposure by limiting hepatic ALT expression. These findings underscore the importance of considering ALDH2 genotype when interpreting serum ALT levels in male drinkers and provide a rationale for further investigation of genotype-informed ALT interpretation in East Asian populations.</p><p><strong>Impact and implications: </strong>We found that serum ALT levels may underestimate liver injury in alcohol-consuming individuals carrying the ALDH2*2 (inactive) allele; genetic background and environmental factors may be considered when interpreting liver injury based on serum ALT, a commonly used clinical biomarker. Since previous studies have shown that ALDH2*2 carriers are at increased risk of alcohol-related liver disease, incorporating genotype-informed clinical strategies may improve early detection and clinical outcomes. These findings are particularly important for East Asian populations, where ALDH2*2 is common.</p><p><strong>Clinical trial number: </strong>None.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102060"},"PeriodicalIF":8.7,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181793","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":"Spleen stiffness to rule out high-risk varices in advanced chronic liver disease: an individual patient data meta-analysis.","authors":"Elton Dajti, Xiaolong Qi, Jinjun Chen, Horia Stefanescu, Young Seo Cho, Christophe Cassinotto, Rui Gaspar, Lory S Crocè, Maha M Elsabaawy, Mirella Fraquelli, Ivica Grgurevic, Carmen Fierbinţeanu-Braticevici, Grace L H Wong, Renata Bende, Maciej K Janik, Flavia Fernandes, Laure Elkrief, Pierre-Emmanuel Rautou, Atsushi Nakajima, Romanas Zykus, Matthias Buechter, Giovanni Galati, Thomas Reiberger, Ekaterina O Liusina, Agustín Albillos, José Ignacio Fortea, Pik Eu Jason Chang, Natalie Lucchina, Masashi Hirooka, Giorgio Soardo, Davide Roccarina, Fabio Piscaglia, Giulia Manni, Francesco Azzaroli, Giovanni Marasco, Giovanni Barbara, Agostino Colli, Davide Festi, Annalisa Berzigotti, Federico Ravaioli, Antonio Colecchia","doi":"10.1016/j.jhepr.2026.102066","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102066","url":null,"abstract":"<p><strong>Background & aims: </strong>Management of esophageal varices (EV) is of critical importance in compensated advanced chronic liver disease. We conducted an individual patient data (IPD) meta-analysis to (i) investigate the performance of spleen stiffness measurement (SSM)-based algorithms using vibration-controlled transient elastography (VCTE) to rule out high-risk varices (HRV); (ii) develop a new model for diagnosing any grade EV.</p><p><strong>Methods: </strong>We systematically searched databases for studies reporting endoscopy and SSM-VCTE data in adult patients, collecting their IPD. The main outcome was ruling out HRV. The tested algorithms were: i) Baveno-VI criteria, liver stiffness measurement (LSM) <20 kPa and platelet count (PLT) >150x10⁹/L); ii) SSM ≤40 kPa; iii) combined Baveno-SSM criteria ≤40 kPa in patients outside Baveno VI criteria. We developed and internally validated logistic regression models to diagnose any grade EV.</p><p><strong>Results: </strong>Twenty studies comprising 2257 patients were included, with a summary HRV prevalence of 25%. The Baveno VI algorithm showed 100% (95%-CI:97-100%) sensitivity and 100% (95%-CI:95-100%) NPV; the rate of spared endoscopies was 17% (95%-CI:15-18%). The combined Baveno VI-SSM criteria performed best for ruling out HRV: 97% (95%-CI:94-99%) sensitivity, 98% (95%-CI:96-99%) NPV and rate of spared endoscopies of 35% (95%-CI: 34-38%). These results were robust in all sensitivity analyses, including patients with non-viral etiology (n=637) and studies using the 100 Hz module. We developed new logistic models with excellent accuracy for the diagnosis of EV, but the ability to identify patients at low risk (<10%) of EV was limited.</p><p><strong>Conclusion: </strong>This large, multicenter, international study validated spleen stiffness measurement as an accurate tool to assess high-risk esophageal varices. The combined Baveno-SSM algorithm performed best in ruling out HRV.</p><p><strong>Impact and implications: </strong>Spleen stiffness has been recommended to rule out high-risk varices, but the evidence supporting its use is of low-quality. Our individual patient data meta-analysis, which included more than 2200 patients with compensated cirrhosis, showed that spleen stiffness ≤40 kPa can rule out high-risk varices with a very low rate of false negatives. Its combination with Baveno VI criteria was the most efficient triage strategy, doubling the rate of endoscopies that could be safely avoided compared to using the Baveno VI criteria alone. The findings of our study strengthen the level of evidence supporting the use of spleen stiffness as an additional screening tool for high-risk varices.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102066"},"PeriodicalIF":8.7,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181824","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 Liver-Heart Axis: Linking Liver Stiffness to Early Cardiac Dysfunction in MASLD.","authors":"Anmol Malhotra, Balaji Musunuri, Ganesh Paramasivam, Ganesh Bhat, Athish Shetty, Shiran Shetty","doi":"10.1016/j.jhepr.2026.102067","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102067","url":null,"abstract":"<p><strong>Background and aims: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a systemic disorder with cardiovascular consequences. Conventional measures such as left ventricular ejection fraction fail to identify early myocardial impairment. The present prospective study was undertaken to evaluate subclinical myocardial dysfunction in MASLD using global longitudinal strain (GLS), assess its correlation with liver stiffness measurement (LSM), and identify its independent predictors.</p><p><strong>Methods: </strong>This prospective cross-sectional study included 128 patients with MASLD. GLS was assessed by speckle-tracking echocardiography, and liver stiffness was measured using vibration-controlled transient elastography (FibroScan). A GLS value ≥ 18% was considered abnormal (indicative of subclinical left ventricular dysfunction). Correlation and regression analyses were performed to identify predictors of subclinical myocardial dysfunction.</p><p><strong>Results: </strong>Subclinical myocardial dysfunction (GLS ≥ 18%) was detected in 74.2% of MASLD patients despite preserved ejection fraction. Liver stiffness correlated strongly with impaired GLS (r = 0.722, p < 0.001). Patients with abnormal GLS had significantly higher liver stiffness (8.98 ± 1.24 kPa vs. 6.95 ± 0.85 kPa, p < 0.001). Fibrosis stage showed a graded association with worsening GLS. On regression analysis, liver stiffness and body mass index (BMI) emerged as independent predictors of subclinical myocardial dysfunction, while steatosis (CAP) did not correlate with GLS.</p><p><strong>Conclusions: </strong>MASLD patients demonstrate a high prevalence of early cardiac dysfunction that is strongly associated with liver stiffness. Myocardial strain imaging combined with liver stiffness measurement offers a valuable approach for early cardio-hepatic risk stratification and integrated care of MASLD patients.</p><p><strong>Impact and implications: </strong>MASLD confers a \"silent\" cardiac burden, with nearly three-quarters of patients showing subclinical left ventricular dysfunction despite normal ejection fraction. Our study identifies liver stiffness as the key correlate of this cardiac impairment, whereas steatosis alone was not correlated with myocardial dysfunction. These findings suggest that integrating myocardial strain imaging and liver stiffness assessment can enable earlier identification of at-risk MASLD patients, underscoring the need for multidisciplinary management bridging hepatology and cardiology.</p><p><strong>Clinical trial registration: </strong>CTRI/2024/02/062960 (Clinical Trials Registry - India).</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102067"},"PeriodicalIF":8.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181884","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":"Hepatocellular Carcinoma Overcomes Lipid Depletion by Utilizing Serine for Phospholipid Synthesis and Enhanced Survival.","authors":"Bichitra Paul, Monika Lewinska, Juan F Lafuente-Barquero, Ekaterina Zhuravleva, Mikel Ruiz de Gauna, Matthias Mattanovich, Xabier Buqué, Dawei Geng, Raissa Novais Rodrigues, Martin Woergaard Kjær, Sebastian Weber Nielsen, Blanca I Aldana, Jens U Marquardt, Patricia Aspichueta, Thomas Moritz, Jesper B Andersen","doi":"10.1016/j.jhepr.2026.102063","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102063","url":null,"abstract":"<p><strong>Background & aims: </strong>Metabolic vulnerabilities of hepatocellular carcinoma (HCC) remain largely unexplored functionally, though their deregulation is a major cancer hallmark. This study aims to investigate HCC tumor cells marked lipid-dependency and explore their distinct responses when grown in lipid starved conditions.</p><p><strong>Methods: </strong>We challenged 8 HCC tumor cell lines by lipid depletion, studying their functional phenotypes through lipidomics, metabolomics, transcriptomics, and metabolic fluxes to define how tumor cells may survive metabolic challenges such as lipid depletion.</p><p><strong>Results: </strong>HCC cell lines were functionally grouped as lipid-depletion sensitive (LD-S), characterized by high triglycerides and cholesterol esters, or lipid-depletion resistant (LD-R), marked by increased membrane lipids like phosphatidylcholine and phosphatidylethanolamine. Separation of these cell models was based on ranked functional phenotypes, including clonogenicity (P<0.0001), population doubling time (P<0.01), viability (P<0.001), and senescence (P<0.01) in LD-S at acute 48-hour lipid starvation. During lipid depletion, LD-R tumor cells survive by promoting serine uptake (serine utilization, P<0.0001) and carbon-donor incorporation into their lipid synthesis pathways such as membrane lipids (P<0.05) and fatty acids (P<0.01). Based on the mechanistic difference between LD-S and LD-R models, a lipid-response signature consisting of 150 distinct genes was constructed, distinguishing 519 HCC patients into two subgroups based on their lipid-dependency genotypes, correlating LD-R traits with lower survival (P<0.0001), higher vascular invasion (P<0.001), and distinct immune compositions based on cell deconvolution and single cell transcriptomics.</p><p><strong>Conclusions: </strong>Distinct sensitivity to lipid depletion underscores lipid metabolism as a therapeutic target offering new treatment options for HCC patients.</p><p><strong>Impact and implications: </strong>This study shows that hepatocellular carcinoma displays distinct lipid metabolic dependencies, with some tumors being highly sensitive to lipid depletion while others adapt through increased membrane lipid synthesis and extracellular serine utilization. These findings highlight a potential vulnerability in HCC metabolic reprogramming, suggesting that targeting lipid and serine-dependent pathways may offer new therapeutic strategies. Although the MASLD-associated HCC sample size was limited, the work provides important insight into tumor heterogeneity and establishes a foundation for future basic and clinical studies aimed at exploiting metabolic weaknesses in HCC.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102063"},"PeriodicalIF":8.7,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168521","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 landscape of hepatocellular carcinoma recurrence after liver transplantation: a nationwide 14-year study.","authors":"Massih Ningarhari, Mathurine Leray, Audrey Coilly, Eric Vibert, Eric Assenat, Astrid Herrero, Jose Ursic-Bedoya, Camille Henry, Line-Carolle Ntandja-Wandji, Elise Lemaitre, Alexandre Louvet, Philippe Mathurin, Emmanuel Boleslawski, Fabien Robin, Thomas Uguen, Pauline Houssel-Debry, Camille Besch, François Faitot, Manon Allaire, Filomena Conti, Olivier Scatton, Giuliana Amaddeo, Daniele Sommacale, Jean-Baptiste Hiriart, Louis Marjary, Faiza Chermak, Laurence Chiche, Olivier Roux, Claire Francoz, Federica Dondero, Teresa Antonini, Domitille Erard, Jean-Marie Peron, Nassim Kamar, Bleuenn Brusset, Thomas Decaens, Laure Elkrief, Hélène Barraud, Ephrem Salamé, René Gerolami, Sophie Chopinet, Jérôme Dumortier, Olivier Boillot, Sébastien Dharancy, Guillaume Lassailly","doi":"10.1016/j.jhepr.2026.102062","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.102062","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background & aims: &lt;/strong&gt;Recurrence of hepatocellular carcinoma (r-HCC) remains a major determinant of post-transplant (LT) outcomes. The 2024 ILTS-ILCA consensus highlighted the need for contemporary data assessing how evolving selection criteria and therapeutic strategies over the past 15 years have influenced prognosis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We conducted a retrospective study including all patients diagnosed with r-HCC following LT between 2008 and 2020 across 15 French transplant centres. Recurrence patterns, post-recurrence survival, and overall transplant outcomes were analysed, including temporal trends and the impact of AFP model implementation in 2013.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We analysed 388 patients with r-HCC, median time to recurrence was 19.1 months, with 26.3% occurring beyond 3 years. Earlier recurrence was associated with tumour-related factors (AFP and Milan criteria, αFP kinetics), and later recurrence with patient-related factors (HCV recurrence, alcohol relapse, grade 2 obesity). Following AFP model implementation, time to recurrence shortened (p&lt;0.001). Surgical/ablative treatments improved survival in r-HCC in a subgroup of patients with single organ involvement of liver, lung or lymph nodes. Survival did not improve between patients diagnosed before 2016, between 2016 and 2018, or after 2018 (p=0.09). Calcineurin inhibitors or mycophenolate mofetil had no impact on survival, whereas mTOR inhibitor use was associated with significantly longer survival (20.7 vs 13.2 months, p=0.001).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;r-HCC is a heterogeneous disease distinct from HCC in non-transplanted patients. Earlier recurrences following extended selection criteria implementation warrant caution. Surgical/ablative approaches should be prioritized even for extrahepatic disease. Despite expanded TKI options since 2016, outcomes of systemic treatment did not show statistical improvement. Post-recurrence mTOR inhibitors should be evaluated in clinical trials.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Impact and implications: &lt;/strong&gt;This nationwide cohort study provides updated data on recurrence of hepatocellular carcinoma (HCC) after liver transplantation in the modern era, a special population excluded from major HCC trials, highlighting major heterogeneity in patients' trajectories before and after recurrence, variations across eras of selection criteria and systemic therapies, and an urgent unmet need as the approval of second-generation TKIs after 2016 did not incrementally improve survival. The study results are important for transplant hepatologists and liver oncologists to optimize patient selection for liver transplantation, to individualize prolongation of surveillance beyond the current ILTS-ILCA 3-year window recommendation based on patient-related risk factors for late recurrences, and prioritize radical treatments with curative intent for selected patients with single organ involvement of liver, lungs or lymph nodes, ra","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"102062"},"PeriodicalIF":8.7,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149790","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}