JHEP ReportsPub Date : 2025-06-01DOI: 10.1016/j.jhepr.2025.101402
Patrick McKiernan , Jesus Quintero Bernabeu , Muriel Girard , Giuseppe Indolfi , Eberhard Lurz , Palak Trivedi
{"title":"Reply to: “Comment on opinion paper on the diagnosis and treatment of progressive familial intrahepatic cholestasis”","authors":"Patrick McKiernan , Jesus Quintero Bernabeu , Muriel Girard , Giuseppe Indolfi , Eberhard Lurz , Palak Trivedi","doi":"10.1016/j.jhepr.2025.101402","DOIUrl":"10.1016/j.jhepr.2025.101402","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 6","pages":"Article 101402"},"PeriodicalIF":9.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144221776","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}
JHEP ReportsPub Date : 2025-05-31DOI: 10.1016/j.jhepr.2025.101469
Lorenz Balcar , Marta Tonon , Joan Valls , Valeria Calvino , Lucie Simonis , Jan Embacher , Roberta Gagliardi , Christian Sebesta , Leonie Hafner , Antonio Accetta , Lukas Hartl , Mattias Mandorfer , Michael Trauner , Paolo Angeli , Thomas Reiberger , Juan Carlos García-Pagán , Georg Semmler , Salvatore Piano
{"title":"Risk of portal hypertensive complications preventable by TIPS in patients with ascites","authors":"Lorenz Balcar , Marta Tonon , Joan Valls , Valeria Calvino , Lucie Simonis , Jan Embacher , Roberta Gagliardi , Christian Sebesta , Leonie Hafner , Antonio Accetta , Lukas Hartl , Mattias Mandorfer , Michael Trauner , Paolo Angeli , Thomas Reiberger , Juan Carlos García-Pagán , Georg Semmler , Salvatore Piano","doi":"10.1016/j.jhepr.2025.101469","DOIUrl":"10.1016/j.jhepr.2025.101469","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Transjugular intrahepatic portosystemic shunt (TIPS) is an effective treatment of recurrent/refractory ascites in patients with cirrhosis. The aim of this study is to identify patients with ascites as index decompensation who are at risk of developing portal hypertension (PH)-related complications within 12 months that seem preventable by TIPS.</div></div><div><h3>Methods</h3><div>We included 451 patients from two tertiary care centres (Vienna and Padua, derivation cohort) with clinically significant ascites (grade 2/3) as a single first decompensating event and without contraindications for TIPS placement. Multivariable logistic regression analysis was used to identify variables independently associated with a composite endpoint of PH-related complications (encephalopathy excluded), liver transplantation, or liver-related death. A classification tree was used to identify patients at highest risk for these PH-related complications. Risk estimates were validated in a temporal validation cohort from Vienna (n = 84).</div></div><div><h3>Results</h3><div>In the derivation cohort (mean age 56 ± 11 years; 69% male; 51% alcohol-related cirrhosis; 44% ascites grade 3; median model for end-stage liver disease [MELD] 12 points), 152 (34%) patients developed the composite endpoint within 12 months. A model including ascites grade, sodium, and MELD accurately predicted the occurrence of this composite endpoint (area under the receiver operator characteristics curve: 0.79 [95% CI: 0.75–0.84]). Two high-risk clusters were identified: patients with grade 3 ascites and either (i) sodium ≤135 mmol/L, or (ii) MELD ≥12 points, with a pooled absolute risk of 64.3% (derivation cohort) and 68.9% (validation cohort) to develop the composite endpoint.</div></div><div><h3>Conclusions</h3><div>Patients with first decompensation caused by ascites grade 3 and either sodium ≤135 mmol/L or MELD ≥12 are at high risk for PH-related complications that are likely preventable by early TIPS placement. A trial investigating ‘early’ TIPS in this at-risk population is warranted.</div></div><div><h3>Impact and implications</h3><div>We identified ascites grade, sodium, and model for end-stage liver disease (MELD) as key predictors of portal hypertension-related complications that may be preventable by TIPS in patients with ascites. Specifically, patients with ascites grade 3 and either sodium ≤135 mmol/L or MELD ≥12 are at risk to experience early clinical deterioration and may benefit from TIPS. A trial investigating ‘early’ TIPS in this at-risk population is warranted.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 8","pages":"Article 101469"},"PeriodicalIF":9.5,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144571553","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}
JHEP ReportsPub Date : 2025-05-30DOI: 10.1016/j.jhepr.2025.101465
Anh Thu Nguyen-Lefebvre , Soumita Ghosh , Cristina Baciu , Bima J. Hasjim , Sara Naimimohasses , Graziano Oldani , Elisa Pasini , Michael Brudno , Nazia Selzner , Jeffrey Wrana , Mamatha Bhat
{"title":"Modelling the liver’s regenerative capacity across different clinical conditions","authors":"Anh Thu Nguyen-Lefebvre , Soumita Ghosh , Cristina Baciu , Bima J. Hasjim , Sara Naimimohasses , Graziano Oldani , Elisa Pasini , Michael Brudno , Nazia Selzner , Jeffrey Wrana , Mamatha Bhat","doi":"10.1016/j.jhepr.2025.101465","DOIUrl":"10.1016/j.jhepr.2025.101465","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Liver regeneration is essential for recovery following injury, but this process can be impaired by factors such as sex, age, metabolic disorders, fibrosis, and immunosuppressive therapies. We aimed to identify key transcriptomic, proteomic, and serum biomarkers of regeneration in mouse models under these diverse conditions using systems biology and machine learning approaches.</div></div><div><h3>Methods</h3><div>Six mouse models, each undergoing 75% hepatectomy, were used to study regeneration across distinct clinical contexts: young males and females, aged mice, stage 2 fibrosis, steatosis, and tacrolimus exposure. A novel contrastive deep learning framework with triplet loss was developed to map regenerative trajectories and identify genes associated with regenerative efficiency.</div></div><div><h3>Results</h3><div>Despite achieving ≥75% liver mass restoration by day 7, regeneration was significantly delayed in aged, steatotic, and fibrotic models, as indicated by reduced Ki-67 staining on day 2 (<em>p <</em>0.0001 for all). Interestingly, fibrotic livers exhibited reduced collagen deposition and partial regression to stage 1 fibrosis post-hepatectomy. Transcriptomic and proteomic analyses revealed consistent downregulation of cell cycle genes in impaired regeneration. The deep learning model integrating clinical and transcriptomic data predicted regenerative outcomes with 87.9% accuracy. SHAP (SHapley Additive exPlanations) highlighted six key predictive genes: <em>Wee1, Rbl1, Gnl3, Mdm2, Cdk2</em>, and <em>Ccne2</em>. Proteomic validation and human SPLiT-seq (split-pool ligation-based transcriptome sequencing) data further supported their relevance across species.</div></div><div><h3>Conclusions</h3><div>This study identifies conserved cell cycle regulators underlying efficient liver regeneration and provides a predictive framework for evaluating regenerative capacity. The integration of deep learning and multi-omics profiling provides a promising approach to better understand liver regeneration and may help guide therapeutic strategies, especially in complex clinical settings.</div></div><div><h3>Impact and implications</h3><div>The aim of this study was to identify key transcriptomic, proteomic, and serum biomarkers of regeneration in mouse models under diverse conditions, using systems biology and machine learning approaches. Key molecular drivers of liver regeneration across diverse clinical conditions were identified using innovative deep learning and multi-omics approaches. By identifying conserved cell cycle genes predictive of regenerative outcomes, this study offers a powerful framework to assess and potentially enhance liver recovery in older patients, those with fibrosis or steatosis, and/or those under immunosuppression.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 8","pages":"Article 101465"},"PeriodicalIF":9.5,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144656422","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}
JHEP ReportsPub Date : 2025-05-29DOI: 10.1016/j.jhepr.2025.101466
Emma Vanderschueren , Wim Laleman , Lawrence Bonne , Geert Maleux , David R. Wagner , Chyon Yeh , Andrea Calvo , Oriol Sendino , Angels Gines , Anna Baiges , Marco J. Bruno , Juan Carlos Garcia-Pagan , Schalk van der Merwe
{"title":"Endoscopic ultrasound-guided portosystemic pressure gradient measurement vs. transjugular balloon occlusion measurement in patients with cirrhosis (ENCOUNTER): A bicentric EU study","authors":"Emma Vanderschueren , Wim Laleman , Lawrence Bonne , Geert Maleux , David R. Wagner , Chyon Yeh , Andrea Calvo , Oriol Sendino , Angels Gines , Anna Baiges , Marco J. Bruno , Juan Carlos Garcia-Pagan , Schalk van der Merwe","doi":"10.1016/j.jhepr.2025.101466","DOIUrl":"10.1016/j.jhepr.2025.101466","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Patients with cirrhosis and portal hypertension are at increased risk of hepatic decompensation and liver-related mortality. While the hepatic venous pressure gradient (HVPG) is the accepted method for quantifying portal hypertension, its measurement and limited availability pose challenges. Endoscopic ultrasound-guided portal pressure gradient (EUS-PPG) provides a direct alternative. The ENCOUNTER study is the first to compare EUS-PPG to HVPG in the same patient, simultaneously.</div></div><div><h3>Methods</h3><div>This prospective, international, bicentric study included patients referred for HVPG or transjugular intrahepatic portosystemic shunt (TIPS) placement at the University Hospital of Leuven (Belgium) and Hospital Clinic Barcelona (Spain). Patients underwent standard-of-care HVPG, followed by simultaneous HVPG and EUS-PPG measurements under propofol general anesthesia.</div></div><div><h3>Results</h3><div>The final analysis included 21 patients with cirrhosis undergoing simultaneous HVPG and EUS-PPG measurements, of whom 15 received TIPS. Mean HVPG and EUS-PPG values under general anesthesia were comparable (11.9 ± 5.2 <em>vs.</em> 10.9 ± 5.6 mmHg, <em>p =</em> 0.2332) and showed good correlation (r = 0.74, <em>p =</em> 0.0001). The individual pressure components also showed a good correlation (portal vein: r = 0.85, <em>p <</em>0.0001; hepatic vein: r = 0.72, <em>p =</em> 0.0003). In patients receiving TIPS, direct transjugular portal pressure measurements demonstrated an excellent correlation with EUS-guided portal pressures (r = 0.91, <em>p <</em>0.0001). Technical success was achieved in all cases, with no adverse events associated with the EUS-PPG procedure.</div></div><div><h3>Conclusion</h3><div>EUS-PPG is a reliable and safe alternative to HVPG for the direct measurement of portal pressure. However, attention must be paid to technical challenges, including the potential overestimation of EUS-guided hepatic vein pressures and the impact of general anesthesia, which may alter pressure measurements and subsequently affect risk classification.</div></div><div><h3>Impact and implications</h3><div>The ENCOUNTER study is the first study to directly compare endoscopic ultrasound-guided portal pressure gradient (EUS-PPG) with hepatic venous pressure gradient (HVPG) in the same patients, simultaneously. EUS-PPG is a safe and reliable direct alternative to HVPG for measuring portal pressure. However, technical challenges, including the potential overestimation of EUS-guided hepatic vein pressures and the impact of general anesthesia must be considered. EUS-PPG is particularly attractive for patients with chronic liver disease who have conflicting non-invasive test results, require additional endoscopic procedures, or in cases where HVPG may underestimate true portal pressure.</div></div><div><h3>ClinicalTrials.gov</h3><div>NCT04987034.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 8","pages":"Article 101466"},"PeriodicalIF":9.5,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144597386","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}
JHEP ReportsPub Date : 2025-05-27DOI: 10.1016/j.jhepr.2025.101448
Francesca Terracciani , Antonio De Vincentis , Daphne D’Amato , Laura Cristoferi , Alessio Gerussi , Pietro Invernizzi , Miki Scaravaglio , Ester Vanni , Daniela Campion , Anna Morgando , Vincenzo Valiani , Vincenzo Boccaccio , Filomena Morisco , Lorenzo Surace , Ilaria Cavalli , Guido Delle Monache , Federico Salomone , Donatella Ieluzzi , Debora Angrisani , Raffaella Tortora , Scudu Chiara
{"title":"Long-term effectiveness, safety, and liver stiffness dynamics of PBC treatment with obeticholic acid in real-world","authors":"Francesca Terracciani , Antonio De Vincentis , Daphne D’Amato , Laura Cristoferi , Alessio Gerussi , Pietro Invernizzi , Miki Scaravaglio , Ester Vanni , Daniela Campion , Anna Morgando , Vincenzo Valiani , Vincenzo Boccaccio , Filomena Morisco , Lorenzo Surace , Ilaria Cavalli , Guido Delle Monache , Federico Salomone , Donatella Ieluzzi , Debora Angrisani , Raffaella Tortora , Scudu Chiara","doi":"10.1016/j.jhepr.2025.101448","DOIUrl":"10.1016/j.jhepr.2025.101448","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Several studies have assessed the short-term effectiveness and safety of obeticholic acid (OCA) in the real-world setting. We aimed to extend knowledge on the real-world effectiveness and safety of OCA treatment by expanding sample size and follow-up, and by exploring changes in liver stiffness measurement (LSM) over time.</div></div><div><h3>Methods</h3><div>The RECAPITULATE project involves centres belonging to the “Italian PBC registry” and/or the “Club Epatologi Ospedalieri” PBC working group. Effectiveness was evaluated as biochemical response according to POISE and normal range (NR) criteria (normal alkaline phosphatase/alanine aminotransferase/bilirubin). Safety was assessed as the incidence of <em>de novo</em>/worsening pruritus and discontinuation rate/causes. Available LSMs were also captured.</div></div><div><h3>Results</h3><div>We included 747 patients from 66 Italian centres: mean age 58 years; female/male 88%/14%; median follow-up 24 months [IQR 12-42]; 28% with cirrhosis, and 14% with autoimmune hepatitis (AIH)/PBC overlap syndrome. Probabilities of POISE and NR response increased from baseline to 57% and 20%, respectively, by the 42<sup>nd</sup> month. The probabilities of response were lower in patients with cirrhosis (<em>p =</em> 0.02 and <em>p =</em> 0.004 for POISE and NR), but not different between patients with AIH/PBC and pure PBC (<em>p =</em> 0.8). Overall, 130 patients (17%) discontinued treatment, mainly due to pruritus (36.9%), while 28.5% did so after developing hepatic events. The discontinuation rate was higher in patients with cirrhosis (<em>p <</em>0.001). LSM was available in 573 patients (∼77%), of whom 255 had multiple measurements. LSM variation over time differed based on the attainment of POISE biochemical response (expected mean annual variation -0.48 [-0.78, -0.19] in responders <em>vs</em>. +0.33 [-0.07, 0.73] in non-responders, respectively, <em>p</em> <0.001).</div></div><div><h3>Conclusions</h3><div>Our findings confirm the effectiveness and safety profiles of OCA in the medium/long term and demonstrate that biochemical response is associated with the change in LSM over time.</div></div><div><h3>Impact and Implications</h3><div>After the conditional approval of OCA for the treatment of PBC, the main confirmatory study failed to demonstrate OCA's ability to reduce liver-related events, leading the EMA to revoke the drug's marketing authorization. The ensuing scientific debate highlights an urgent need for further evidence from real-world practice. In the largest real-world series of patients treated with OCA to date, we confirm that the drug's effectiveness and safety profiles are maintained over a medium-to-long follow-up period. Valuable data for the management of the drug in relevant subgroups of patients, such as those with cirrhosis and autoimmune hepatitis/PBC overlap syndrome, are also provided. Our original results on liver stiffness measurement var","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 8","pages":"Article 101448"},"PeriodicalIF":9.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144597385","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}
JHEP ReportsPub Date : 2025-05-23DOI: 10.1016/j.jhepr.2025.101456
Zhen Xun , Xiaobao Yao , Caorui Lin , Xinyao Yang , Yanfang Zhang , Xin Yang , Yujue He , Renquan Jiang , Yanping Lan , Yuchen Ye , Detai Ye , Shanjian Chen , Ke Ma , Wennan Wu , Siyi Xu , Bin Yang , Can Liu , Jing Chen , Qi Zheng , Qishui Ou
{"title":"A novel therapy targeting the gut–liver axis for chronic hepatitis B: Ursodeoxycholic acid plus Bifidobacterium","authors":"Zhen Xun , Xiaobao Yao , Caorui Lin , Xinyao Yang , Yanfang Zhang , Xin Yang , Yujue He , Renquan Jiang , Yanping Lan , Yuchen Ye , Detai Ye , Shanjian Chen , Ke Ma , Wennan Wu , Siyi Xu , Bin Yang , Can Liu , Jing Chen , Qi Zheng , Qishui Ou","doi":"10.1016/j.jhepr.2025.101456","DOIUrl":"10.1016/j.jhepr.2025.101456","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Targeting the gut–liver axis is a promising strategy for treating liver diseases. We aimed to assess the therapeutic efficacy of targeting the gut microbiota-bile acid (BA) axis using ursodeoxycholic acid (UDCA) combined with the probiotic <em>Bifidobacterium</em> to treat chronic hepatitis B (CHB).</div></div><div><h3>Methods</h3><div>BA profiles were characterized by mass spectrometry, and gut microbiota composition was analyzed using 16S rRNA sequencing in patients with CHB and healthy controls (HCs). The effects of UDCA and <em>Bifidobacterium</em> were assessed both in a preclinical model and in a 2-month clinical trial involving 22 patients with CHB who received either UDCA (250 mg twice daily; n = 6), <em>Bifidobacterium</em> (2 g twice daily; n = 6), or a combination of UDCA and <em>Bifidobacterium</em> (n = 10).</div></div><div><h3>Results</h3><div>UDCA was the most significantly decreased serum BA in patients with CHB compared to HCs (<em>p <</em>0.001), and had the strongest anti-HBV effect <em>in vitro</em> and <em>in vivo</em>. In the gut, the <em>Bifidobacterium</em> abundance was the most dramatically decreased fecal genus in patients with CHB (<em>p =</em> 0.018), and had the anti-HBV effect <em>in vivo</em>. Finally, combined treatment with UDCA and <em>Bifidobacterium</em> significantly reduced serum alanine aminotransferase (<em>p =</em> 0.008), HBV DNA (77% reduction; <em>p <</em>0.001), pregenomic RNA (59% reduction; <em>p <</em>0.001), and hepatitis B surface antigen (15% reduction; <em>p =</em> 0.002) levels. It also decreased NKG2A expression on natural killer (NK) cells and PD-1 expression on CD8<sup>+</sup> T cells by approximately 50% (<em>p</em> <0.01), while enhancing secretion of granzyme B, perforin, and interferon-γ by CD8<sup>+</sup> T and NK cells (<em>p</em> <0.05). These effects were superior to those achieved with either monotherapy.</div></div><div><h3>Conclusions</h3><div>Combined treatment with UDCA and <em>Bifidobacterium</em> promotes CD8<sup>+</sup> T/NK cell function and viral control in patients withCHB and may represent a promising adjunct therapy warranting further investigation.</div></div><div><h3>Impact and implications</h3><div>Targeting the gut microbiota-bile acid axis has the potential to treat chronic hepatitis B. Results from preclinical models and a clinical trial show that combination treatment with ursodeoxycholic acid plus the probiotic <em>Bifidobacterium</em> exerts antiviral effects in patients with chronic hepatitis B by promoting CD8<sup>+</sup> T cell and natural killer cell function. These findings may advance the understanding of HBV immunology and treatment options for chronic hepatitis B.</div></div><div><h3>Clinical Trial Number</h3><div>ChiCTR2200062861.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 8","pages":"Article 101456"},"PeriodicalIF":9.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144633294","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}
JHEP ReportsPub Date : 2025-05-14DOI: 10.1016/j.jhepr.2025.101453
Ignazio S. Piras, Janith Don, Nicholas J. Schork, Johanna K. DiStefano
{"title":"Genetic variants influencing liver fat in normal-weight individuals of European ancestry","authors":"Ignazio S. Piras, Janith Don, Nicholas J. Schork, Johanna K. DiStefano","doi":"10.1016/j.jhepr.2025.101453","DOIUrl":"10.1016/j.jhepr.2025.101453","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) occurs across a wide spectrum of body weights, yet the genetic determinants underlying hepatic steatosis in individuals with normal BMI remain underexplored. This study aimed to identify genetic variants associated with liver fat fraction in normal-weight individuals.</div></div><div><h3>Methods</h3><div>We performed a genome-wide association study (GWAS) using magnetic resonance imaging-proton density fat fraction (MRI-PDFF) data from 10,918 normal-weight participants (BMI <25 kg/m<sup>2</sup>) of European ancestry in the UK Biobank. Hepatic steatosis and liver fat content were assessed using both case–control (CC; 815 cases with MRI-PDFF ≥5% <em>vs</em>. 10,103 controls with MRI-PDFF <5%) and quantitative trait (QT; N = 10,918, with MRI-PDFF as a continuous outcome) designs. Fine mapping prioritized potential causal variants. Gene-level associations were evaluated using multi-marker analysis of genomic annotation (MAGMA), and liver-specific gene expression was imputed for transcriptome-wide association studies (TWAS).</div></div><div><h3>Results</h3><div>We identified 241 genome-wide significant variants in the CC-GWAS and 418 in the QT-GWAS, with most located on chromosomes 19 and 22, including known loci such as <em>PNPLA3</em>, <em>TM6SF2</em>, and <em>SAMM50</em>. Fine-mapping analyses prioritized three candidate causal variants in <em>SUGP1</em>, <em>GATAD2A</em>, and <em>MAU2</em>. MAGMA identified eight genes in CC-GWAS and 19 in QT-GWAS, including a novel association with <em>RFXANK</em>. TWAS supported the involvement of <em>MBOAT7</em> and <em>SAMM50</em>, with fine mapping further implicating <em>SAMM50</em> as a likely causal gene.</div></div><div><h3>Conclusions</h3><div>This study, one of the first to detect genome-wide associations for hepatic steatosis in normal-weight individuals, identified both novel and established genetic loci. These findings highlight the role of genetic susceptibility independent of obesity-related pathways and may inform targeted strategies for MASLD prevention and treatment in this understudied population.</div></div><div><h3>Impact and implications</h3><div>This study provides new insights into the genetic risk factors underlying metabolic dysfunction-associated steatotic liver disease in individuals with a normal BMI, a group often under-represented in steatotic liver disease research. Leveraging large-scale genomic and imaging data from the UK Biobank, we identified both known and novel variants associated with liver fat accumulation, emphasizing that genetic predisposition can drive hepatic steatosis independently of excess adiposity. While the study is based on individuals of European ancestry, future research should assess the relevance of these findings in more diverse populations to ensure broader clinical applicability. These results may help inform future strategies for early risk str","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 8","pages":"Article 101453"},"PeriodicalIF":9.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144549641","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}
JHEP ReportsPub Date : 2025-05-14DOI: 10.1016/j.jhepr.2025.101454
Amaia Navarro-Corcuera , Yiwei Zhu , Fanglin Ma , Neha Gupta , Haley Asplund , Bruno Cogliati , Jerry E. Chipuk , Oren Rom , Scott L. Friedman , Brian E. Sansbury , Xin Huang , Bishuang Cai
{"title":"Resolvin D1-mediated cellular crosstalk protects against MASH","authors":"Amaia Navarro-Corcuera , Yiwei Zhu , Fanglin Ma , Neha Gupta , Haley Asplund , Bruno Cogliati , Jerry E. Chipuk , Oren Rom , Scott L. Friedman , Brian E. Sansbury , Xin Huang , Bishuang Cai","doi":"10.1016/j.jhepr.2025.101454","DOIUrl":"10.1016/j.jhepr.2025.101454","url":null,"abstract":"<div><h3>Background & aims</h3><div>Recent studies have highlighted the beneficial effect of resolvin D1 (RvD1), a docosahexaenoic acid-derived specialized pro-resolving mediator, on chronic liver diseases, but the underlying mechanisms are not well understood. Our study aimed to determine the role and mechanism of RvD1-mediated cellular crosstalk in metabolic dysfunction-associated steatohepatitis (MASH).</div></div><div><h3>Methods</h3><div>RvD1 was administered to mice with experimental MASH, followed by bulk and single cell RNA sequencing (scRNA-seq) analysis. Primary liver cells, including primary hepatocytes, Kupffer cells (KCs), T cells, and hepatic stellate cells (HSCs), were isolated for co-culture experiments to elucidate the effect of RvD1 on cell death, inflammation, and fibrosis.</div></div><div><h3>Results</h3><div>Hepatic tissue levels of RvD1 were decreased in murine (n = 5–6, <em>p</em> <0.01) and human MASH (n = 9–10, <em>p</em> <0.05). Administering RvD1 reduced hepatocellular death, inflammation, and liver fibrosis in MASH (n = 4–5, <em>p</em> <0.05). Mechanistically, RvD1 reduced hepatocyte death by suppressing endoplasmic reticulum (ER) stress. Co-culture experiments with primary liver cells showed that conditioned media from palmitic acid-treated hepatocytes activated KCs, T cells, and HSCs; however, those effects were abolished from RvD1-pretreated hepatocytes. Moreover, RvD1 directly suppressed T cell activation and IFNγ production, leading to reduced Stat1-Cxcl10 signaling in KCs.</div></div><div><h3>Conclusions</h3><div>RvD1 reduced hepatocyte death and DAMP production by alleviating ER stress-mediated apoptosis, leading to decreased activation of KCs, T cells, and HSCs. This study highlights the novel role of RvD1-mediated cellular crosstalk among different liver cells in MASH.</div></div><div><h3>Impact and implications</h3><div>MASH is a growing healthcare burden worldwide. However, current treatments for MASH and its sequelae remain limited. Recent studies highlighted the therapeutic benefit of specialized pro-resolving mediators (SPMs), including RvD1, in liver diseases. However, the mechanisms underlying these beneficial effects are not well understood. Based on a series of co-culture primary cell experiments and unbiased transcriptomic analyses, we show that RvD1-mediated cellular crosstalk among hepatocytes and nonparenchymal cells protects against MASH progression. Our study provides a new mechanistic insight into the role of RvD1 in MASH and highlights its therapeutic potential to treat this condition.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 8","pages":"Article 101454"},"PeriodicalIF":9.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144571552","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}
JHEP ReportsPub Date : 2025-05-10DOI: 10.1016/j.jhepr.2025.101452
Karen Vagner Danielsen , Jens Dahlgaard Hove , Puria Nabilou , Thit Mynster Kronborg , Signe Wiese , Hartwig Roman Siebner , Robert Scott , Susan T. Francis , Guruprasad P. Aithal , Søren Møller , Flemming Bendtsen
{"title":"Mapping the hemodynamic effects of terlipressin in patients with hepatorenal syndrome using advanced magnetic resonance imaging","authors":"Karen Vagner Danielsen , Jens Dahlgaard Hove , Puria Nabilou , Thit Mynster Kronborg , Signe Wiese , Hartwig Roman Siebner , Robert Scott , Susan T. Francis , Guruprasad P. Aithal , Søren Møller , Flemming Bendtsen","doi":"10.1016/j.jhepr.2025.101452","DOIUrl":"10.1016/j.jhepr.2025.101452","url":null,"abstract":"<div><h3>Background & aims</h3><div>Terlipressin improves renal function in ∼40% of patients with hepatorenal syndrome–acute kidney injury (HRS-AKI). Nonetheless, the pathophysiological mechanisms of terlipressin remain unclear. Therefore, we investigated the cardiovascular changes that occur after terlipressin is given to patients with HRS-AKI.</div></div><div><h3>Methods</h3><div>Cardiac and phase-contrast magnetic resonance imaging were used to assess cardiac function, as well as renal, splanchnic, and peripheral blood flow changes after the first bolus of 2 mg terlipressin in 10 patients with HRS-AKI, six of whom also had acute-on-chronic liver failure. Hemodynamic changes were analyzed using the Wilcoxon matched-pairs signed-rank test. Patients were followed prospectively to investigate any associations between terlipressin-induced hemodynamic changes and clinical outcomes.</div></div><div><h3>Results</h3><div>Cardiac output (CO) decreased by 15% following terlipressin (<em>p</em> <0.01). Despite this decrease in CO, renal artery blood flow increased by 23% (<em>p</em> <0.01), and the renal artery blood flow percentage of CO increased by 49% (<em>p</em> = 0.01). Superior mesenteric artery blood flow and femoral artery blood flow decreased by 27% and 40%, respectively (both <em>p</em> <0.01). Mean arterial pressure (MAP) and systemic vascular resistance increased by 13% and 32%, respectively (both <em>p</em> <0.01). Baseline renal artery blood flow correlated with serum creatinine (<em>p</em> <0.01). By contrast, changes in renal artery blood flow and other cardiocirculatory variables did not correlate with changes in serum creatinine after terlipressin or with mortality.</div></div><div><h3>Conclusions</h3><div>Terlipressin increases renal artery blood flow, reduces CO, and alleviates splanchnic and peripheral vasodilatation. These effects, combined with an increase in MAP, appear to explain the therapeutic benefits of terlipressin in patients with HRS-AKI.</div></div><div><h3>Impact and implications</h3><div>This study is the first to provide a detailed mapping of the hemodynamic changes following terlipressin treatment in patients critically ill with HRS-AKI. The results indicate that the beneficial effects of terlipressin are driven by selective peripheral and splanchnic vasoconstriction, which redistributes blood flow, normalizes MAP, and ultimately improves renal perfusion despite reduced cardiac output. This study also highlights the advantages of using magnetic resonance imaging as a non-invasive method to evaluate pharmacological interventions, with the potential to contribute to future advances in personalized medicine for patients with cirrhosis.</div></div><div><h3>Clinical Trials registration</h3><div>NCT03483272.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 8","pages":"Article 101452"},"PeriodicalIF":9.5,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144549642","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}
JHEP ReportsPub Date : 2025-05-10DOI: 10.1016/j.jhepr.2025.101450
Lina Jegodzinski , Lorena Rudolph , Darko Castven , Friedhelm Sayk , Ashok Kumar Rout , Bandik Föh , Laura Hölzen , Svenja Meyhöfer , Andrea Schenk , Susanne N. Weber , Monika Rau , Sebastian M. Meyhöfer , Jörn M. Schattenberg , Marcin Krawczyk , Andreas Geier , Alvaro Mallagaray , Ulrich L. Günther , Jens U. Marquardt
{"title":"PNPLA3 I148M variant links to adverse metabolic traits in MASLD during fasting and feeding","authors":"Lina Jegodzinski , Lorena Rudolph , Darko Castven , Friedhelm Sayk , Ashok Kumar Rout , Bandik Föh , Laura Hölzen , Svenja Meyhöfer , Andrea Schenk , Susanne N. Weber , Monika Rau , Sebastian M. Meyhöfer , Jörn M. Schattenberg , Marcin Krawczyk , Andreas Geier , Alvaro Mallagaray , Ulrich L. Günther , Jens U. Marquardt","doi":"10.1016/j.jhepr.2025.101450","DOIUrl":"10.1016/j.jhepr.2025.101450","url":null,"abstract":"<div><h3>Background & Aims</h3><div>The <em>PNPLA3</em> rs738409 polymorphism is the most abundant genetic risk factor associated with progression of metabolic dysfunction-associated steatotic liver disease (MASLD) to steatohepatitis (MASH) and fibrosis. Although fasting and feeding affect <em>PNPLA3</em> expression, molecular insights into the pathophysiological influence remain scarce.</div></div><div><h3>Methods</h3><div>We analyzed 353 serum samples of patients with MASLD from two German tertiary centers using nuclear magnetic resonance (NMR)-proteometabolomics. Patients were stratified by <em>PNPLA3</em> rs738409 C>G genotype: ‘CC’, ‘CG’, and ‘GG’. Metabolites, lipoproteins, and glycoproteins were assessed based on fasting status.</div></div><div><h3>Results</h3><div><em>PNPLA3</em> GG displayed a distinct metabolic profile, with notable alterations between fasting and non-fasting states. During the latter, GG carriers showed lower levels of VLDL-1, reflecting impaired triglyceride (TG) efflux from hepatocytes. Following an overnight fast, GG carriers exhibited higher tricarboxylic acid cycle metabolites and ketone bodies, overall indicating increased β-oxidation likely attributed to lower <em>PNPLA3</em> expression, facilitating unrestricted adipose triglyceride lipase activity and consecutive increased hepatic TG secretion. In addition, the ketogenic amino acid lysine, critical for mitochondrial carnitine transport, was significantly reduced (GG 0.14 <span><math><mrow><mo>±</mo></mrow></math></span> 0.09 mM <em>vs.</em> CC 0.18 <span><math><mrow><mo>±</mo></mrow></math></span> 0.08 mM, <em>q</em> = 0.015). Consistently, TGs were enriched in LDL and HDL particles, and an increased number of intermediate-density lipoproteins emerged as a distinct marker in fasted GG carriers (GG 202.9 <span><math><mrow><mo>±</mo></mrow></math></span> 68.2 mg/dl <em>vs.</em> CC 160.8 <span><math><mrow><mo>±</mo></mrow></math></span> 65.6 mg/dl, <em>q</em> = 0.007). These metabolic changes were enhanced in patients with type 2 diabetes mellitus and/or obesity.</div></div><div><h3>Conclusions</h3><div>Our findings suggest a dichotomous pattern of increased hepatic lipid storage during feeding and excessive lipid oxidation during fasting, which exceeds metabolic capacity, inducing cellular toxicity in <em>PNPLA3</em> GG carriers. This interplay fuels a detrimental fasting/non-fasting cycle, thus pointing to the need for preventive strategies.</div></div><div><h3>Impact and Implications</h3><div>The <em>PNPLA3</em> rs738409 (p.I148M) polymorphism is the most prevalent genetic risk factor for metabolic dysfunction-associated steatotic liver disease progression and is influenced by fasting and feeding cycles. However, the pathophysiological consequences of this regulation remain poorly understood. Nuclear magnetic resonance-proteometabolomics reveals a distinct signature in homozygous <em>PNPLA3</em> GG carriers that changes significantly with fasting status","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 8","pages":"Article 101450"},"PeriodicalIF":9.5,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144517994","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}