Pub Date : 2026-02-01Epub Date: 2025-11-26DOI: 10.1016/j.jhepr.2025.101691
Lorenz Grossar , Sarah Raevens , Anja Geerts , Hans Van Vlierberghe , Xavier Verhelst
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Pub Date : 2026-02-01Epub Date: 2025-12-17DOI: 10.1016/j.jhepr.2025.101713
Dong Yun Kim , Hyun-Soo Zhang , Jae Seung Lee , Hye Won Lee , Mi Na Kim , Beom Kyung Kim , Seung Up Kim , Do Young Kim , Sang Hoon Ahn , Hyun Woong Lee , Heon Yung Gee , Jung Il Lee , Jun Yong Park
<div><h3>Background & Aims</h3><div>Genetic information is not yet used for the clinical diagnosis of advanced fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Herein, we investigated whether incorporating genetic information regarding <em>PNPLA3</em> and <em>TM6SF2</em> into existing non-invasive fibrosis scoring systems could improve their predictive accuracy, particularly in patients with type 2 diabetes mellitus (T2DM), a high-risk population for MASLD-related complications.</div></div><div><h3>Methods</h3><div>Data were collected from a cohort of 637 patients with biopsy-proven MASLD. All participants underwent liver stiffness measurement (LSM), serum marker analysis, and genotyping for <em>PNPLA3</em> (rs738409), <em>TM6SF2</em> (rs58542926), and other relevant single nucleotide polymorphisms. We evaluated the benefit of adding genetic information to existing non-invasive tests (NITs) – including the Agile 3+, Fibrosis-4 (FIB-4) index, and NAFLD fibrosis score (NFS).</div></div><div><h3>Results</h3><div>Decision curve analysis in the validation cohort (n = 238) demonstrated that incorporating <em>PNPLA3</em> and <em>TM6SF2</em> genetic information marginally enhanced net clinical benefit across all three models over a range of threshold probabilities (10-50%). At a 30% threshold probability, the net benefit of genotype-enhanced models increased from 22.0 to 22.8 per 100 patients for Agile 3+, from 17.0 to 18.4 for NFS, and from 13.0 to 16.9 for FIB-4. In the T2DM subgroup (n = 121), genotype incorporation led to small but statistically significant improvements in discrimination for NFS (AUROC increase: 0.053, <em>p</em> = 0.001) and FIB-4 (AUROC increase: 0.058, <em>p</em> = 0.010), while Agile 3+ showed a favorable trend (AUROC increase: 0.016, <em>p</em> = 0.058).</div></div><div><h3>Conclusions</h3><div>Incorporating <em>PNPLA3</em> and <em>TM6SF2</em> genetic information into non-invasive fibrosis scoring systems for MASLD provides limited but measurable improvements, with statistically significant AUROC gains for NFS and FIB-4, particularly among patients with T2DM. Further validation is required before routine clinical implementation can be recommended.</div></div><div><h3>Impact and implications</h3><div>Our research demonstrates that incorporating <em>PNPLA3</em> and <em>TM6SF2</em> genetic information into non-invasive fibrosis tests provides modest but measurable improvements in clinical utility for patients with metabolic dysfunction-associated steatotic liver disease, particularly those with type 2 diabetes mellitus – a high-risk population prone to accelerated fibrosis progression and liver-related complications. These findings are relevant for clinicians managing these patients, as genotype-enhanced models (particularly NAFLD fibrosis score and Fibrosis-4 index) showed statistically significant improvements in diagnostic accuracy, enabling better identification of patients requiri
{"title":"Integration of PNPLA3 and TM6SF2 genotypes provides incremental improvement in advanced fibrosis prediction among MASLD patients with type 2 diabetes mellitus","authors":"Dong Yun Kim , Hyun-Soo Zhang , Jae Seung Lee , Hye Won Lee , Mi Na Kim , Beom Kyung Kim , Seung Up Kim , Do Young Kim , Sang Hoon Ahn , Hyun Woong Lee , Heon Yung Gee , Jung Il Lee , Jun Yong Park","doi":"10.1016/j.jhepr.2025.101713","DOIUrl":"10.1016/j.jhepr.2025.101713","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Genetic information is not yet used for the clinical diagnosis of advanced fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Herein, we investigated whether incorporating genetic information regarding <em>PNPLA3</em> and <em>TM6SF2</em> into existing non-invasive fibrosis scoring systems could improve their predictive accuracy, particularly in patients with type 2 diabetes mellitus (T2DM), a high-risk population for MASLD-related complications.</div></div><div><h3>Methods</h3><div>Data were collected from a cohort of 637 patients with biopsy-proven MASLD. All participants underwent liver stiffness measurement (LSM), serum marker analysis, and genotyping for <em>PNPLA3</em> (rs738409), <em>TM6SF2</em> (rs58542926), and other relevant single nucleotide polymorphisms. We evaluated the benefit of adding genetic information to existing non-invasive tests (NITs) – including the Agile 3+, Fibrosis-4 (FIB-4) index, and NAFLD fibrosis score (NFS).</div></div><div><h3>Results</h3><div>Decision curve analysis in the validation cohort (n = 238) demonstrated that incorporating <em>PNPLA3</em> and <em>TM6SF2</em> genetic information marginally enhanced net clinical benefit across all three models over a range of threshold probabilities (10-50%). At a 30% threshold probability, the net benefit of genotype-enhanced models increased from 22.0 to 22.8 per 100 patients for Agile 3+, from 17.0 to 18.4 for NFS, and from 13.0 to 16.9 for FIB-4. In the T2DM subgroup (n = 121), genotype incorporation led to small but statistically significant improvements in discrimination for NFS (AUROC increase: 0.053, <em>p</em> = 0.001) and FIB-4 (AUROC increase: 0.058, <em>p</em> = 0.010), while Agile 3+ showed a favorable trend (AUROC increase: 0.016, <em>p</em> = 0.058).</div></div><div><h3>Conclusions</h3><div>Incorporating <em>PNPLA3</em> and <em>TM6SF2</em> genetic information into non-invasive fibrosis scoring systems for MASLD provides limited but measurable improvements, with statistically significant AUROC gains for NFS and FIB-4, particularly among patients with T2DM. Further validation is required before routine clinical implementation can be recommended.</div></div><div><h3>Impact and implications</h3><div>Our research demonstrates that incorporating <em>PNPLA3</em> and <em>TM6SF2</em> genetic information into non-invasive fibrosis tests provides modest but measurable improvements in clinical utility for patients with metabolic dysfunction-associated steatotic liver disease, particularly those with type 2 diabetes mellitus – a high-risk population prone to accelerated fibrosis progression and liver-related complications. These findings are relevant for clinicians managing these patients, as genotype-enhanced models (particularly NAFLD fibrosis score and Fibrosis-4 index) showed statistically significant improvements in diagnostic accuracy, enabling better identification of patients requiri","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101713"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034363","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}
Pub Date : 2026-02-01Epub Date: 2025-11-29DOI: 10.1016/j.jhepr.2025.101699
Maria de Brito Nunes , Maria Gabriela Delgado , Jaume Bosch , Annalisa Berzigotti
Background & Aims
Transjugular intrahepatic portosystemic shunt (TIPS) is an established treatment for complications of portal hypertension (variceal bleeding and refractory ascites). Sarcopenia affects 40–70% of patients with cirrhosis. We evaluated the improvement in sarcopenia after TIPS, the proportion of patients developing overt hepatic encephalopathy (HE) after TIPS and its association with sarcopenia, and the association between sarcopenia and mortality after TIPS.
Methods
We conducted a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Eligible studies included adults with cirrhosis and sarcopenia assessed by computed tomography (CT), using the skeletal muscle index (L3-SMI), or psoas muscle index (L3-PMI). We searched in eight databases for randomized trials, cohort studies, and case–control, cross-sectional, and case series studies.
Results
Twenty studies were included. The pooled prevalence of sarcopenia in patients with cirrhosis undergoing TIPS was 55.4% (95% CI 41.7–68.2%). Among these, sarcopenia improved in 57% of patients (95% CI 48–65%) after TIPS, with a mean L3-SMI increase of 4.53 cm2/m2 (range: 2.4–6.9 cm2/m2). Sarcopenia was associated with higher odds of overt HE (pooled odds ration [OR] = 3.40, 95% CI 1.85–6.25, p <0.001) and a higher proportion of overt HE (43%, 95% CI 26–61%) than in patients without sarcopenia (12%, 95% CI 7–20%). The proportionate mortality after TIPS was 18.3% (95% CI 14.6–22.8%), across 6–33.6 months of follow-up. The association between sarcopenia and mortality was not significant (HR: 1.95, 95% CI 0.89–4.31, p = 0.078).
Conclusions
In patients with cirrhosis and sarcopenia, TIPS is often followed by an improvement in sarcopenia. Sarcopenia is associated with higher odds of overt HE, whereas the effect of sarcopenia on mortality after TIPS remains uncertain.
Impact and implications
Sarcopenia affects over half of patients with cirrhosis undergoing transjugular intrahepatic portosystemic shunt (TIPS) placement. This meta-analysis shows that TIPS is associated with sarcopenia improvement in >50% of patients, suggesting potential benefits beyond portal pressure reduction. Sarcopenia increases the risk of overt hepatic encephalopathy, whereas its effect on post-TIPS mortality remains inconclusive. These findings support routine assessment of sarcopenia to improve risk stratification and clinical decision-making. However, results should be interpreted cautiously because of study heterogeneity and the retrospective nature of the included data. Prospective studies are needed to confirm these findings and refine patient selection for TIPS.
背景：经颈静脉肝内门静脉系统分流术（TIPS）是治疗门静脉高压并发症（静脉曲张出血和难治性腹水）的常用方法。40-70%的肝硬化患者患有肌肉减少症。我们评估了TIPS后肌肉减少症的改善情况，TIPS后发生显性肝性脑病（HE）的患者比例及其与肌肉减少症的关系，以及TIPS后肌肉减少症与死亡率的关系。方法根据系统评价和荟萃分析首选报告项目（PRISMA）指南进行系统评价和荟萃分析。符合条件的研究包括肝硬化和肌肉减少症的成年人，通过计算机断层扫描（CT）评估，使用骨骼肌指数（L3-SMI）或腰肌指数（L3-PMI）。我们在8个数据库中检索了随机试验、队列研究、病例对照、横断面和病例系列研究。结果共纳入20项研究。接受TIPS治疗的肝硬化患者中肌肉减少症的总患病率为55.4% （95% CI 41.7-68.2%）。其中，57%的患者（95% CI 48-65%）在TIPS后肌肉减少症得到改善，L3-SMI平均增加4.53 cm2/m2（范围：2.4-6.9 cm2/m2）。肌少症患者明显HE发生率较高（合并比值比[OR] = 3.40, 95% CI 1.85-6.25, p <0.001），且明显HE发生率（43%,95% CI 26-61%）高于无肌少症患者（12%,95% CI 7-20%）。在6-33.6个月的随访中，TIPS后的比例死亡率为18.3% （95% CI 14.6-22.8%）。肌肉减少症与死亡率之间的相关性不显著（HR: 1.95, 95% CI 0.89-4.31, p = 0.078）。结论肝硬化合并肌少症患者，TIPS治疗后肌少症常得到改善。肌少症与明显HE的几率较高相关，而肌少症对TIPS术后死亡率的影响仍不确定。影响和意义超过一半的肝硬化患者接受经颈静脉肝内门静脉系统分流术（TIPS）。这项荟萃分析显示，TIPS与50%患者肌肉减少症的改善有关，提示除了降低门静脉压力之外的潜在益处。肌少症增加明显肝性脑病的风险，而其对tips术后死亡率的影响仍不确定。这些发现支持对肌肉减少症进行常规评估，以改善风险分层和临床决策。然而，由于研究的异质性和纳入数据的回顾性性质，结果应谨慎解释。需要前瞻性研究来证实这些发现并完善TIPS的患者选择。
{"title":"Outcomes after TIPS in patients with cirrhosis and sarcopenia: A systematic review and meta-analysis","authors":"Maria de Brito Nunes , Maria Gabriela Delgado , Jaume Bosch , Annalisa Berzigotti","doi":"10.1016/j.jhepr.2025.101699","DOIUrl":"10.1016/j.jhepr.2025.101699","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Transjugular intrahepatic portosystemic shunt (TIPS) is an established treatment for complications of portal hypertension (variceal bleeding and refractory ascites). Sarcopenia affects 40–70% of patients with cirrhosis. We evaluated the improvement in sarcopenia after TIPS, the proportion of patients developing overt hepatic encephalopathy (HE) after TIPS and its association with sarcopenia, and the association between sarcopenia and mortality after TIPS.</div></div><div><h3>Methods</h3><div>We conducted a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Eligible studies included adults with cirrhosis and sarcopenia assessed by computed tomography (CT), using the skeletal muscle index (L3-SMI), or psoas muscle index (L3-PMI). We searched in eight databases for randomized trials, cohort studies, and case–control, cross-sectional, and case series studies.</div></div><div><h3>Results</h3><div>Twenty studies were included. The pooled prevalence of sarcopenia in patients with cirrhosis undergoing TIPS was 55.4% (95% CI 41.7–68.2%). Among these, sarcopenia improved in 57% of patients (95% CI 48–65%) after TIPS, with a mean L3-SMI increase of 4.53 cm<sup>2</sup>/m<sup>2</sup> (range: 2.4–6.9 cm<sup>2</sup>/m<sup>2</sup>). Sarcopenia was associated with higher odds of overt HE (pooled odds ration [OR] = 3.40, 95% CI 1.85–6.25, <em>p</em> <0.001) and a higher proportion of overt HE (43%, 95% CI 26–61%) than in patients without sarcopenia (12%, 95% CI 7–20%). The proportionate mortality after TIPS was 18.3% (95% CI 14.6–22.8%), across 6–33.6 months of follow-up. The association between sarcopenia and mortality was not significant (HR: 1.95, 95% CI 0.89–4.31, <em>p</em> = 0.078).</div></div><div><h3>Conclusions</h3><div>In patients with cirrhosis and sarcopenia, TIPS is often followed by an improvement in sarcopenia. Sarcopenia is associated with higher odds of overt HE, whereas the effect of sarcopenia on mortality after TIPS remains uncertain.</div></div><div><h3>Impact and implications</h3><div>Sarcopenia affects over half of patients with cirrhosis undergoing transjugular intrahepatic portosystemic shunt (TIPS) placement. This meta-analysis shows that TIPS is associated with sarcopenia improvement in >50% of patients, suggesting potential benefits beyond portal pressure reduction. Sarcopenia increases the risk of overt hepatic encephalopathy, whereas its effect on post-TIPS mortality remains inconclusive. These findings support routine assessment of sarcopenia to improve risk stratification and clinical decision-making. However, results should be interpreted cautiously because of study heterogeneity and the retrospective nature of the included data. Prospective studies are needed to confirm these findings and refine patient selection for TIPS.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101699"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034365","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}
Pub Date : 2026-02-01Epub Date: 2025-11-05DOI: 10.1016/j.jhepr.2025.101672
Maria Serena Longhi , Giorgina Mieli-Vergani , Diego Vergani
{"title":"Regulatory T-cells in autoimmune hepatitis: An historical perspective with hints to the future","authors":"Maria Serena Longhi , Giorgina Mieli-Vergani , Diego Vergani","doi":"10.1016/j.jhepr.2025.101672","DOIUrl":"10.1016/j.jhepr.2025.101672","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101672"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146187912","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}
Pub Date : 2026-02-01Epub Date: 2025-10-17DOI: 10.1016/j.jhepr.2025.101642
Georg Kramer , Benedikt Simbrunner , Mathias Jachs , Lorenz Balcar , Benedikt Silvester Hofer , Nina Dominik , Lukas Hartl , Michael Schwarz , Georg Semmler , Christian Sebesta , Paul Thöne , Sophia Geisselbrecht , Benjamin Maasoumy , Eduardo Alvarez , Martin Sebastian McCoy , Oleksandr Petrenko , Jiří Reiniš , Philipp Schwabl , Albert F. Stättermayer , Michael Trauner , Thomas Reiberger
<div><h3>Background & Aims</h3><div>Invasive measurement of hepatic venous pressure gradient (HVPG) is the gold standard for diagnosing clinically significant portal hypertension (CSPH, <em>i.e.</em> HVPG ≥10 mmHg), which indicates an increased risk of decompensation. We evaluated the blood-based Vienna 3P/5P models for non-invasive assessment of portal hypertension (PH) severity and their prognostic value. Their performance was compared to HVPG, liver stiffness measurement (LSM) and the ANTICIPATE±NASH model.</div></div><div><h3>Methods</h3><div>Patients with compensated advanced chronic liver disease (cACLD) who underwent HVPG measurement and LSM within the prospective VICIS (Vienna Cirrhosis Study) were included. We assessed the ability of each model to detect CSPH and severe PH (HVPG ≥16 mmHg), predict decompensation, and stratify risk. Outcome prediction was further validated in an external cohort.</div></div><div><h3>Results</h3><div>Among 266 patients with diverse etiologies of cACLD, median HVPG was 11 (8-16) mmHg with a CSPH and severe PH prevalence of 62.8% and 25.6%, respectively. The 3P/5P models correlated with HVPG (both <em>p <</em>0.001), achieving AUROCs of 0.704 (5P) for CSPH and 0.800 (5P) for severe PH prediction. During a median follow-up of 23.9 (15.3-32.6) months, 48 (18%) patients decompensated. HVPG and the 5P model showed similar time-dependent AUROCs (at 0.5 and 1 year: 0.753-0.822), superior to ANTICIPATE±NASH (AUROCs: 0.689-0.691) and LSM (AUROCs: 0.621-0.636). The 5P (adjusted subdistribution hazard ratio [aSHR]: 1.32, <em>p</em> <em><</em>0.001) and 3P (aSHR: 1.15, <em>p =</em> 0.010) models predicted decompensation independent from age, sex, LSM, etiological cure and non-selective beta blocker use. Proposed cut-offs for the 3P/5P models distinguished between patients at low and high risk of decompensation (Grays test <em>p <</em>0.001).</div></div><div><h3>Conclusion</h3><div>The blood-based 3P/5P models demonstrated significant prognostic value for predicting hepatic decompensation and identifying patients with cACLD at high risk. Importantly, the 5P model performed comparably to HVPG.</div></div><div><h3>Impact and implications</h3><div>This study addresses the clinical need for accessible, reliable, and cost-effective non-invasive tools to predict hepatic decompensation in patients with compensated advanced chronic liver disease, given the limited availability of hepatic venous pressure gradient and liver stiffness measurement. By demonstrating that the Vienna 3P/5P models – machine learning tools based solely on routine laboratory parameters – achieve comparable prognostic accuracy to hepatic venous pressure gradient and outperform other non-invasive tools, such as liver stiffness measurement or the ANTICIPATE±NASH model, these findings have significant implications for clinicians providing care for patients with compensated advanced chronic liver disease. The models' simplicity, repeatability and
{"title":"Blood-based Vienna 3P/5P risk models accurately predict first hepatic decompensation in compensated advanced chronic liver disease","authors":"Georg Kramer , Benedikt Simbrunner , Mathias Jachs , Lorenz Balcar , Benedikt Silvester Hofer , Nina Dominik , Lukas Hartl , Michael Schwarz , Georg Semmler , Christian Sebesta , Paul Thöne , Sophia Geisselbrecht , Benjamin Maasoumy , Eduardo Alvarez , Martin Sebastian McCoy , Oleksandr Petrenko , Jiří Reiniš , Philipp Schwabl , Albert F. Stättermayer , Michael Trauner , Thomas Reiberger","doi":"10.1016/j.jhepr.2025.101642","DOIUrl":"10.1016/j.jhepr.2025.101642","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Invasive measurement of hepatic venous pressure gradient (HVPG) is the gold standard for diagnosing clinically significant portal hypertension (CSPH, <em>i.e.</em> HVPG ≥10 mmHg), which indicates an increased risk of decompensation. We evaluated the blood-based Vienna 3P/5P models for non-invasive assessment of portal hypertension (PH) severity and their prognostic value. Their performance was compared to HVPG, liver stiffness measurement (LSM) and the ANTICIPATE±NASH model.</div></div><div><h3>Methods</h3><div>Patients with compensated advanced chronic liver disease (cACLD) who underwent HVPG measurement and LSM within the prospective VICIS (Vienna Cirrhosis Study) were included. We assessed the ability of each model to detect CSPH and severe PH (HVPG ≥16 mmHg), predict decompensation, and stratify risk. Outcome prediction was further validated in an external cohort.</div></div><div><h3>Results</h3><div>Among 266 patients with diverse etiologies of cACLD, median HVPG was 11 (8-16) mmHg with a CSPH and severe PH prevalence of 62.8% and 25.6%, respectively. The 3P/5P models correlated with HVPG (both <em>p <</em>0.001), achieving AUROCs of 0.704 (5P) for CSPH and 0.800 (5P) for severe PH prediction. During a median follow-up of 23.9 (15.3-32.6) months, 48 (18%) patients decompensated. HVPG and the 5P model showed similar time-dependent AUROCs (at 0.5 and 1 year: 0.753-0.822), superior to ANTICIPATE±NASH (AUROCs: 0.689-0.691) and LSM (AUROCs: 0.621-0.636). The 5P (adjusted subdistribution hazard ratio [aSHR]: 1.32, <em>p</em> <em><</em>0.001) and 3P (aSHR: 1.15, <em>p =</em> 0.010) models predicted decompensation independent from age, sex, LSM, etiological cure and non-selective beta blocker use. Proposed cut-offs for the 3P/5P models distinguished between patients at low and high risk of decompensation (Grays test <em>p <</em>0.001).</div></div><div><h3>Conclusion</h3><div>The blood-based 3P/5P models demonstrated significant prognostic value for predicting hepatic decompensation and identifying patients with cACLD at high risk. Importantly, the 5P model performed comparably to HVPG.</div></div><div><h3>Impact and implications</h3><div>This study addresses the clinical need for accessible, reliable, and cost-effective non-invasive tools to predict hepatic decompensation in patients with compensated advanced chronic liver disease, given the limited availability of hepatic venous pressure gradient and liver stiffness measurement. By demonstrating that the Vienna 3P/5P models – machine learning tools based solely on routine laboratory parameters – achieve comparable prognostic accuracy to hepatic venous pressure gradient and outperform other non-invasive tools, such as liver stiffness measurement or the ANTICIPATE±NASH model, these findings have significant implications for clinicians providing care for patients with compensated advanced chronic liver disease. The models' simplicity, repeatability and ","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101642"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922546","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}
Pub Date : 2026-02-01Epub Date: 2025-10-17DOI: 10.1016/j.jhepr.2025.101647
Frederik Schliephake , Isabella Lurje , Deniz Uluk , Janina Eden , Zoltan Czigany , Justus Pein , Peri Husen , Cornelius Engelmann , Christoph Michalski , Marlene Kohlhepp , Pavel Strnad , Philipp Dutkowski , Frank Tacke , Ulf Peter Neumann , David Meierhofer , Georg Lurje
<div><h3>Background & Aims</h3><div>In liver transplantation, bile acid (BA) toxicity contributes to injury of both hepatocytes and cholangiocytes. While hypothermic oxygenated machine perfusion (HOPE) reduces ischemia–reperfusion injury (IRI) and improves clinical outcomes, its impact on bile composition remains unclear because of the lack of bile samples available after LT.</div></div><div><h3>Methods</h3><div>Bile, blood, and liver tissue were collected within a multicentric randomized controlled trial (NCT03124641), from 26 patients receiving extended criteria donation (ECD) allografts from donors after brain death (DBD). Fourteen donor livers were static cold stored (SCS group), while 12 livers underwent end-ischemic HOPE. Grafts were randomly assigned. BA levels and metabolic parameters were analyzed across samples with mass spectrometry. Expression of bile transporters and enzymes was assessed in liver biopsies before and after transplantation.</div></div><div><h3>Results</h3><div>Serum and biliary levels of hydrophobic BAs were positively correlated with IRI severity, such as serum aspartate aminotransferase and alanine aminotransferase, and decreased across postoperative days (POD) for all allografts (bile: POD-1 <em>vs.</em> POD-2/-3, <em>p</em> <0.001; blood: admission <em>vs.</em> POD-1–3, <em>p</em> <0.001). Expression of the hepatocyte bile transporters ABCB4 and ABCG8 decreased post-reperfusion (<em>p</em> = 0.045; <em>p</em> <0.001). In the SCS group, intrahepatic BA levels increased post-reperfusion (8.71 to 10.77 pmol/mg, <em>p</em> = 0.023), while biliary BA levels decreased postoperatively (POD-1 <em>vs.</em> POD-3, <em>p</em> = 0.06). The HOPE group showed higher biliary BA and phosphatidylcholine (PC) levels on POD-3 compared with the SCS group (total BAs: 2.30 × 10<sup>9</sup> <em>vs.</em> 2.03 × 10<sup>9</sup> peak area, <em>p</em> = 0.047; PC: 6.49 × 10<sup>8</sup> <em>vs.</em> 4.48 × 10<sup>8</sup> peak area, <em>p</em> = 0.031), and a decline in biliary BA/PC ratio.</div></div><div><h3>Conclusions</h3><div>This is the first randomized study demonstrating effects of HOPE treatment on bile composition following ECD-DBD liver transplantation. Protection from BA toxicity may represent a novel mechanism underlying the effects of HOPE.</div></div><div><h3>Clinical trials registration</h3><div>This trial is registered at <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> (NCT03124641).</div></div><div><h3>Impact and implications</h3><div>Worldwide liver allograft scarcity has led to the implementation of hypothermic oxygenated machine perfusion (HOPE) to enhance the safety of liver transplantation (LT) using extended criteria donors. However, its protective mechanisms remain incompletely understood, largely because of limited human data. In this study, we provide evidence that HOPE improves biliary lipid secretion after LT, limits intrahepatic bile acid accumulation upon allograft reperfusion, re
背景和目的在肝移植中，胆汁酸（BA）毒性可导致肝细胞和胆管细胞损伤。虽然低温氧合机灌注（HOPE）可以减少缺血再灌注损伤（IRI）并改善临床结果，但由于缺乏肝胆样本，其对胆汁成分的影响尚不清楚。方法在一项多中心随机对照试验（NCT03124641）中收集了26例脑死亡（DBD）后接受延长标准捐赠（ECD）同种异体移植的患者的胆汁、血液和肝组织。14例供肝静冷保存（SCS组），12例肝缺血末HOPE。移植物随机分配。用质谱法分析样品中的BA水平和代谢参数。在移植前后肝活检中评估胆汁转运蛋白和酶的表达。结果血清和胆汁中疏水BAs水平与IRI严重程度呈正相关，如血清天冬氨酸转氨酶和丙氨酸转氨酶，并且在所有同种异体移植物术后（POD）天内下降（胆汁：POD-1 vs. POD-2/-3, p <0.001；血液：入院vs. POD-1 -3, p <0.001）。再灌注后肝细胞胆汁转运体ABCB4和ABCG8的表达降低（p = 0.045; p <0.001）。在SCS组，再灌注后肝内BA水平升高（8.71至10.77 pmol/mg, p = 0.023），而术后胆道BA水平下降（POD-1 vs. POD-3, p = 0.06）。与SCS组相比，HOPE组在POD-3上显示出更高的胆道BA和磷脂酰胆碱（PC）水平（总BAs: 2.30 × 109比2.03 × 109峰面积，p = 0.047; PC: 6.49 × 108比4.48 × 108峰面积，p = 0.031），胆道BA/PC比值下降。结论：这是首个证明HOPE治疗对ECD-DBD肝移植术后胆汁成分影响的随机研究。对BA毒性的保护可能是HOPE作用的一种新机制。临床试验注册本试验在ClinicalTrials.gov注册（NCT03124641）。影响和意义世界范围内同种异体肝脏移植的稀缺性导致了低温氧合机灌注（HOPE）的实施，以提高使用扩展标准供体的肝移植（LT）的安全性。然而，其保护机制仍然不完全清楚，主要是因为有限的人类数据。在本研究中，我们提供的证据表明，HOPE可以改善肝移植后的胆脂分泌，限制同种异体移植物再灌注时肝内胆汁酸的积累，降低胆汁酸与磷脂酰胆碱的比值，促进肝移植后血清胆汁酸水平的正常化。我们的研究结果表明，对胆汁酸毒性的保护可能构成HOPE作用的新机制。
{"title":"Effects of hypothermic oxygenated machine perfusion on bile composition after liver transplantation – Findings from a randomized controlled trial","authors":"Frederik Schliephake , Isabella Lurje , Deniz Uluk , Janina Eden , Zoltan Czigany , Justus Pein , Peri Husen , Cornelius Engelmann , Christoph Michalski , Marlene Kohlhepp , Pavel Strnad , Philipp Dutkowski , Frank Tacke , Ulf Peter Neumann , David Meierhofer , Georg Lurje","doi":"10.1016/j.jhepr.2025.101647","DOIUrl":"10.1016/j.jhepr.2025.101647","url":null,"abstract":"<div><h3>Background & Aims</h3><div>In liver transplantation, bile acid (BA) toxicity contributes to injury of both hepatocytes and cholangiocytes. While hypothermic oxygenated machine perfusion (HOPE) reduces ischemia–reperfusion injury (IRI) and improves clinical outcomes, its impact on bile composition remains unclear because of the lack of bile samples available after LT.</div></div><div><h3>Methods</h3><div>Bile, blood, and liver tissue were collected within a multicentric randomized controlled trial (NCT03124641), from 26 patients receiving extended criteria donation (ECD) allografts from donors after brain death (DBD). Fourteen donor livers were static cold stored (SCS group), while 12 livers underwent end-ischemic HOPE. Grafts were randomly assigned. BA levels and metabolic parameters were analyzed across samples with mass spectrometry. Expression of bile transporters and enzymes was assessed in liver biopsies before and after transplantation.</div></div><div><h3>Results</h3><div>Serum and biliary levels of hydrophobic BAs were positively correlated with IRI severity, such as serum aspartate aminotransferase and alanine aminotransferase, and decreased across postoperative days (POD) for all allografts (bile: POD-1 <em>vs.</em> POD-2/-3, <em>p</em> <0.001; blood: admission <em>vs.</em> POD-1–3, <em>p</em> <0.001). Expression of the hepatocyte bile transporters ABCB4 and ABCG8 decreased post-reperfusion (<em>p</em> = 0.045; <em>p</em> <0.001). In the SCS group, intrahepatic BA levels increased post-reperfusion (8.71 to 10.77 pmol/mg, <em>p</em> = 0.023), while biliary BA levels decreased postoperatively (POD-1 <em>vs.</em> POD-3, <em>p</em> = 0.06). The HOPE group showed higher biliary BA and phosphatidylcholine (PC) levels on POD-3 compared with the SCS group (total BAs: 2.30 × 10<sup>9</sup> <em>vs.</em> 2.03 × 10<sup>9</sup> peak area, <em>p</em> = 0.047; PC: 6.49 × 10<sup>8</sup> <em>vs.</em> 4.48 × 10<sup>8</sup> peak area, <em>p</em> = 0.031), and a decline in biliary BA/PC ratio.</div></div><div><h3>Conclusions</h3><div>This is the first randomized study demonstrating effects of HOPE treatment on bile composition following ECD-DBD liver transplantation. Protection from BA toxicity may represent a novel mechanism underlying the effects of HOPE.</div></div><div><h3>Clinical trials registration</h3><div>This trial is registered at <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> (NCT03124641).</div></div><div><h3>Impact and implications</h3><div>Worldwide liver allograft scarcity has led to the implementation of hypothermic oxygenated machine perfusion (HOPE) to enhance the safety of liver transplantation (LT) using extended criteria donors. However, its protective mechanisms remain incompletely understood, largely because of limited human data. In this study, we provide evidence that HOPE improves biliary lipid secretion after LT, limits intrahepatic bile acid accumulation upon allograft reperfusion, re","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101647"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922399","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}
Pub Date : 2026-02-01Epub Date: 2025-11-10DOI: 10.1016/j.jhepr.2025.101669
Xinjia Wang , Eun Hee Ha , Lu Bian , Zhuoying Feng , Fan Zhang , Kyle O’Shaughnessy , Lei Wang , Andrea Hochwald , Yifei Zheng , Weibo Chen , Yujie Zhang , Xianfang Wu
Background & Aims
Activated HSCs are known to drive fibrogenesis, but their fate following injury resolution remains unclear. We aimed to investigate whether human activated HSCs revert to a less activated state, and to characterize features of such reversion using a human induced pluripotent stem cell (hiPSC)-derived multicellular liver model.
Methods
We used a hiPSC-derived liver culture containing hepatocytes, HSCs, and macrophages. HSCs were activated by HCV infection or a lipotoxic milieu modeling metabolic dysfunction-associated steatotic liver disease (MASLD) and subjected to injury resolution through antiviral treatment or replacement with a healthy medium. Reverted HSCs were characterized via gene expression profiling, functional assays, and single-cell RNA sequencing (scRNA-seq). The role of macrophage-derived IL-10 in HSC reversion was investigated through receptor knockdown and cytokine treatment experiments.
Results
Following either HCV clearance or withdrawal of lipotoxic stress, activated HSCs reverted to a less activated state, regaining lipid droplets and vitamin A storage while re-expressing quiescent HSC markers. scRNA-seq revealed heterogeneity among reverted HSCs, identifying subpopulations expressing apoptotic, senescent, or quiescent-like signatures. A distinct lipid-high, PTK2-low population closely resembled naïve quiescent HSCs. Functional assays demonstrated that rHSCs retained partial quiescence but exhibited heightened sensitivity to fibrogenic re-stimulation (n = 4, p <0.05). Mechanistically, macrophage-derived IL-10 promoted HSC reversion by inducing vitamin A metabolism-related genes, including LRAT and RBP1 (n = 4, p <0.01).
Conclusions
Activated human HSCs demonstrate plasticity, reverting to a quiescent-like state following resolution of viral or metabolic injury, although they remain primed for reactivation. Macrophage-derived IL-10 plays a critical role in driving this reversion by regulating vitamin A metabolism. These findings provide insights into HSC dynamics and suggest potential therapeutic avenues for liver fibrosis by targeting HSC reversion.
Impact and implications
Removing the cause of liver injury—curing hepatitis C or withdrawing lipotoxic stress—allows scar-forming liver cells (hepatic stellate cells) to partly revert to a healthier, vitamin-A-storing state; single-cell profiling reveals its heterogeneity and identify a subset nearing true quiescence. This rebound depends on intercellular interaction, in part on the immune signal IL-10 from macrophages, yet reverted cells remain easier to re-activate. These findings provide insights into dynamics of hepatic stellate cells and suggest potential therapeutic avenues for liver fibrosis by targeting stellate cell reversion.
背景和目的：已知活化的hsc可驱动纤维形成，但它们在损伤消退后的命运仍不清楚。我们的目的是研究人类激活的造血干细胞是否会恢复到低激活状态，并使用人类诱导多能干细胞（hiPSC）衍生的多细胞肝脏模型来表征这种恢复的特征。方法采用hipsc来源的肝脏培养，其中包含肝细胞、造血干细胞和巨噬细胞。HCV感染或模拟代谢功能障碍相关脂肪变性肝病（MASLD）的脂毒性环境激活造血干细胞，并通过抗病毒治疗或用健康培养基替代来修复损伤。通过基因表达谱、功能测定和单细胞RNA测序（scRNA-seq）对修复的造血干细胞进行表征。通过受体敲除和细胞因子处理实验研究巨噬细胞来源的IL-10在HSC逆转中的作用。结果在HCV清除或脂毒性应激解除后，活化的HSC恢复到低活化状态，恢复脂滴和维生素a储存，同时重新表达静止的HSC标记物。scRNA-seq揭示了恢复的造血干细胞之间的异质性，鉴定了表达凋亡、衰老或静止样特征的亚群。一个明显的高脂、低ptk2的人群与naïve静止hsc非常相似。功能分析表明，rHSCs保持部分静止，但对纤维原性再刺激表现出更高的敏感性（n = 4, p <0.05）。在机制上，巨噬细胞来源的IL-10通过诱导维生素A代谢相关基因，包括LRAT和RBP1，促进HSC的逆转（n = 4, p <0.01）。结论：活化的人造血干细胞表现出可塑性，在病毒或代谢损伤消退后恢复到静止状态，尽管它们仍处于激活状态。巨噬细胞来源的IL-10通过调节维生素a代谢在驱动这种逆转中起关键作用。这些发现提供了对HSC动力学的深入了解，并提出了通过靶向HSC逆转治疗肝纤维化的潜在治疗途径。影响和意义消除肝损伤的原因——治疗丙型肝炎或消除脂毒性应激——允许疤痕形成的肝细胞（肝星状细胞）部分恢复到更健康的维生素a储存状态；单细胞分析揭示了其异质性，并确定了接近真正静止的子集。这种反弹依赖于细胞间的相互作用，部分依赖于巨噬细胞的免疫信号IL-10，但恢复的细胞仍然更容易重新激活。这些发现提供了对肝星状细胞动力学的深入了解，并提出了通过靶向星状细胞逆转治疗肝纤维化的潜在治疗途径。
{"title":"Single-cell analysis of heterogeneity in reverted hiPSC-derived human hepatic stellate cells","authors":"Xinjia Wang , Eun Hee Ha , Lu Bian , Zhuoying Feng , Fan Zhang , Kyle O’Shaughnessy , Lei Wang , Andrea Hochwald , Yifei Zheng , Weibo Chen , Yujie Zhang , Xianfang Wu","doi":"10.1016/j.jhepr.2025.101669","DOIUrl":"10.1016/j.jhepr.2025.101669","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Activated HSCs are known to drive fibrogenesis, but their fate following injury resolution remains unclear. We aimed to investigate whether human activated HSCs revert to a less activated state, and to characterize features of such reversion using a human induced pluripotent stem cell (hiPSC)-derived multicellular liver model.</div></div><div><h3>Methods</h3><div>We used a hiPSC-derived liver culture containing hepatocytes, HSCs, and macrophages. HSCs were activated by HCV infection or a lipotoxic milieu modeling metabolic dysfunction-associated steatotic liver disease (MASLD) and subjected to injury resolution through antiviral treatment or replacement with a healthy medium. Reverted HSCs were characterized via gene expression profiling, functional assays, and single-cell RNA sequencing (scRNA-seq). The role of macrophage-derived IL-10 in HSC reversion was investigated through receptor knockdown and cytokine treatment experiments.</div></div><div><h3>Results</h3><div>Following either HCV clearance or withdrawal of lipotoxic stress, activated HSCs reverted to a less activated state, regaining lipid droplets and vitamin A storage while re-expressing quiescent HSC markers. scRNA-seq revealed heterogeneity among reverted HSCs, identifying subpopulations expressing apoptotic, senescent, or quiescent-like signatures. A distinct lipid-high, PTK2-low population closely resembled naïve quiescent HSCs. Functional assays demonstrated that rHSCs retained partial quiescence but exhibited heightened sensitivity to fibrogenic re-stimulation (n = 4, <em>p</em> <0.05). Mechanistically, macrophage-derived IL-10 promoted HSC reversion by inducing vitamin A metabolism-related genes, including <em>LRAT</em> and <em>RBP1</em> (n = 4, <em>p</em> <0.01).</div></div><div><h3>Conclusions</h3><div>Activated human HSCs demonstrate plasticity, reverting to a quiescent-like state following resolution of viral or metabolic injury, although they remain primed for reactivation. Macrophage-derived IL-10 plays a critical role in driving this reversion by regulating vitamin A metabolism. These findings provide insights into HSC dynamics and suggest potential therapeutic avenues for liver fibrosis by targeting HSC reversion.</div></div><div><h3>Impact and implications</h3><div>Removing the cause of liver injury—curing hepatitis C or withdrawing lipotoxic stress—allows scar-forming liver cells (hepatic stellate cells) to partly revert to a healthier, vitamin-A-storing state; single-cell profiling reveals its heterogeneity and identify a subset nearing true quiescence. This rebound depends on intercellular interaction, in part on the immune signal IL-10 from macrophages, yet reverted cells remain easier to re-activate. These findings provide insights into dynamics of hepatic stellate cells and suggest potential therapeutic avenues for liver fibrosis by targeting stellate cell reversion.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101669"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145882438","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}
Pub Date : 2026-02-01Epub Date: 2025-11-13DOI: 10.1016/j.jhepr.2025.101678
Lina Zhang , Barbora Gromova , Du Hanh Nguyen , Cortney Cagle , Graziela S. Gomes , William Li , Li Gao , Wei Zhang , Jonathon J. Graham , Na Wang , Ahmadreza Kalbasi , Eva Csizmadia , Angelina Wei , Jessica Cassavaugh , Alan Bonder , Vilas Patwardhan , Sizun Jiang , Satya K. Kota , Maria Serena Longhi
<div><h3>Background & Aims</h3><div>Regulatory T cell (Treg) dysfunction is a hallmark of autoimmune hepatitis (AIH), a serious hepatopathy often progressing to end-stage liver disease despite immunosuppression. Treg impairment in AIH has been linked to defective signaling through the aryl hydrocarbon receptor (AhR), a modulator of adaptive immunity. Herein, we investigated whether increased estrogen receptor alpha (ERα), an AhR non-canonical binding partner, impacts Treg immunity and contributes to the sex bias observed in AIH.</div></div><div><h3>Methods</h3><div>Tregs were isolated from the peripheral blood of pre-menopausal, post-menopausal and male patients with AIH, as well as controls. Their function, stability, transcriptome and response to AhR were assessed in the absence or presence of methylpiperidinopyrazole (MPP), an ERα-selective antagonist. Therapeutic effects of MPP were tested in a model of Concanavalin-A-induced liver injury in humanized mice.</div></div><div><h3>Results</h3><div>ERα was upregulated in Tregs from pre-menopausal females with AIH (1.1 ± 0.3) compared with healthy pre-menopausal females (0.4 ± 0.1; <em>p</em> = 0.038), and in pre-menopausal compared with post-menopausal females with AIH (0.3 ± 0.1; <em>p</em> = 0.04). In pre-menopausal females with AIH, MPP enhanced Treg suppressive capacity (2.5-fold increase; <em>p</em> = 0.001), restored response to AhR activation (2-fold increase; <em>p</em> = 0.03), and reduced functional plasticity, evidenced by decreased IL-17A and RORC expression under pro-inflammatory conditions. MPP also ameliorated Concanavalin-A-induced hepatitis in <em>NOD/scid/gamma</em> mice reconstituted with human CD4+ ERα+ cells, as shown by reduced ALT levels (101 ± 24 <em>vs</em>. 25 ± 8; <em>p</em> = 0.024), diminished hepatic inflammation on histology, and increased intrahepatic CD4+FOXP3+ and CD4+CD39+ T-cell frequencies. Bioinformatic and inhibition analyses identified hypoxia-inducible factor-1α as a key inducer of ERα in AIH Tregs.</div></div><div><h3>Conclusions</h3><div>ERα upregulation drives Treg dysfunction in pre-menopausal females with AIH and likely contributes to the sex bias in the disease. ERα blockade stabilizes Tregs and limits inflammation <em>in vivo</em>, representing a promising therapeutic strategy to enhance and sustain immune tolerance in AIH.</div></div><div><h3>Impact and implications</h3><div>Regulatory T cell (Treg) dysfunction plays a key role in the breakdown of immune tolerance in autoimmune hepatitis (AIH), a severe hepatopathy that often progresses to end-stage liver disease despite immunosuppression. Here we report that upregulation of estrogen receptor-alpha (ERα) alters Treg function and stability in pre-menopausal females with AIH, and that blockade of ERα using a specific antagonist stabilizes Tregs and curbs inflammation in humanized mice with liver injury. These findings implicate aberrant ERα signaling in the sex bias of AIH and support ERα inhibiti
{"title":"Inhibition of estrogen receptor alpha stabilizes regulatory T cell function in autoimmune hepatitis","authors":"Lina Zhang , Barbora Gromova , Du Hanh Nguyen , Cortney Cagle , Graziela S. Gomes , William Li , Li Gao , Wei Zhang , Jonathon J. Graham , Na Wang , Ahmadreza Kalbasi , Eva Csizmadia , Angelina Wei , Jessica Cassavaugh , Alan Bonder , Vilas Patwardhan , Sizun Jiang , Satya K. Kota , Maria Serena Longhi","doi":"10.1016/j.jhepr.2025.101678","DOIUrl":"10.1016/j.jhepr.2025.101678","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Regulatory T cell (Treg) dysfunction is a hallmark of autoimmune hepatitis (AIH), a serious hepatopathy often progressing to end-stage liver disease despite immunosuppression. Treg impairment in AIH has been linked to defective signaling through the aryl hydrocarbon receptor (AhR), a modulator of adaptive immunity. Herein, we investigated whether increased estrogen receptor alpha (ERα), an AhR non-canonical binding partner, impacts Treg immunity and contributes to the sex bias observed in AIH.</div></div><div><h3>Methods</h3><div>Tregs were isolated from the peripheral blood of pre-menopausal, post-menopausal and male patients with AIH, as well as controls. Their function, stability, transcriptome and response to AhR were assessed in the absence or presence of methylpiperidinopyrazole (MPP), an ERα-selective antagonist. Therapeutic effects of MPP were tested in a model of Concanavalin-A-induced liver injury in humanized mice.</div></div><div><h3>Results</h3><div>ERα was upregulated in Tregs from pre-menopausal females with AIH (1.1 ± 0.3) compared with healthy pre-menopausal females (0.4 ± 0.1; <em>p</em> = 0.038), and in pre-menopausal compared with post-menopausal females with AIH (0.3 ± 0.1; <em>p</em> = 0.04). In pre-menopausal females with AIH, MPP enhanced Treg suppressive capacity (2.5-fold increase; <em>p</em> = 0.001), restored response to AhR activation (2-fold increase; <em>p</em> = 0.03), and reduced functional plasticity, evidenced by decreased IL-17A and RORC expression under pro-inflammatory conditions. MPP also ameliorated Concanavalin-A-induced hepatitis in <em>NOD/scid/gamma</em> mice reconstituted with human CD4+ ERα+ cells, as shown by reduced ALT levels (101 ± 24 <em>vs</em>. 25 ± 8; <em>p</em> = 0.024), diminished hepatic inflammation on histology, and increased intrahepatic CD4+FOXP3+ and CD4+CD39+ T-cell frequencies. Bioinformatic and inhibition analyses identified hypoxia-inducible factor-1α as a key inducer of ERα in AIH Tregs.</div></div><div><h3>Conclusions</h3><div>ERα upregulation drives Treg dysfunction in pre-menopausal females with AIH and likely contributes to the sex bias in the disease. ERα blockade stabilizes Tregs and limits inflammation <em>in vivo</em>, representing a promising therapeutic strategy to enhance and sustain immune tolerance in AIH.</div></div><div><h3>Impact and implications</h3><div>Regulatory T cell (Treg) dysfunction plays a key role in the breakdown of immune tolerance in autoimmune hepatitis (AIH), a severe hepatopathy that often progresses to end-stage liver disease despite immunosuppression. Here we report that upregulation of estrogen receptor-alpha (ERα) alters Treg function and stability in pre-menopausal females with AIH, and that blockade of ERα using a specific antagonist stabilizes Tregs and curbs inflammation in humanized mice with liver injury. These findings implicate aberrant ERα signaling in the sex bias of AIH and support ERα inhibiti","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101678"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145882439","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}
Pub Date : 2026-02-01Epub Date: 2025-12-06DOI: 10.1016/j.jhepr.2025.101706
Theresa Kirchner , Norman Junge , Nicole Henjes , Stephanie Loges , Muhammed Yuksel , Wojciech Janczyk , Claudine Lalanne , Kalliopi Zachou , Ye H. Oo , Jérôme Gournay , Simon Pape , Joost PH. Drenth , Amédée Renand , George N. Dalekos , Luigi Muratori , Piotr Socha , Cigdem Arikan , Yun Ma , Heiner Wedemeyer , Ulrich Baumann , Richard Taubert
<div><h3>Background & Aims</h3><div>The diagnosis of juvenile autoimmune hepatitis (AIH) is challenging given its heterogeneous presentation. Autoantibodies, typically detected by immunofluorescence testing (IFT), together with liver histology, represent key diagnostic features. Polyreactive immunoglobulin G (pIgG) has recently emerged as a complementary biomarker in AIH. This retrospective multicentre study aimed to compare ELISA-based autoantibody testing and IFT on HEp-2 cells with the gold standard of IFT on rodent tissue sections in children with autoimmune and non-autoimmune liver diseases.</div></div><div><h3>Methods</h3><div>Autoantibody detection was performed centrally at Hannover Medical School using three commercial antinuclear antibody (ANA) ELISAs, one commercial F-actin ELISA, one in-house pIgG ELISA, and IFT on HEp-2 cells, in comparison to the gold standard of IFT on rodent tissue sections. Samples from children with AIH (n = 69), autoimmune sclerosing cholangitis (AISC; n = 13) and other liver diseases (n = 120) were analysed from nine European centres.</div></div><div><h3>Results</h3><div>The AUCs for the detection of AIH/AISC were moderate to good for ANA detection by IFT (gold standard of rodent tissue AUC: 0.748; HEp-2 AUC: 0.756) and were comparable to ELISA-based detection (0.622-0.772). Anti-smooth muscle antibody (SMA) IFT on rodent tissue yielded an AUC of 0.694. Specificity was increased to 100% by including the SMA staining pattern of vessels, glomeruli and tubules. ELISA-based quantification of anti-F-actin (AUC = 0.868) and pIgG (AUC = 0.844) showed the highest AUCs. While the majority of F-actin–positive children were pIgG-positive (80.3%), pIgG was also detected in 52.4% of F-actin–negative children with AIH.</div></div><div><h3>Conclusion</h3><div>ELISA-based assays provide reliable ANA detection comparable to IFT. Anti-F-actin and pIgG ELISAs showed the highest accuracy for predicting juvenile AIH/AISC and may complement existing diagnostic criteria.</div></div><div><h3>Impact and implications</h3><div>Autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) are rare paediatric liver diseases that can be difficult to distinguish from other hepatopathies. Autoantibody testing is central to diagnosis, yet paediatric performance across platforms has been poorly standardised and sparsely reported. In this multicentre comparison (202 sera from nine expert centres across eight European countries), indirect immunofluorescence (IFT) on rodent tissue showed suboptimal discrimination at the commonly advocated 1:20 cut-off, whereas accuracy for ANA and SMA improved markedly at 1:320. ANA detection by IFT on HEp-2 cells and by ELISA was comparable to rodent tissue IFT. ELISAs for F-actin and pIgG achieved the highest AUCs for identifying AIH/AISC and may complement current diagnostics. Substantial inter-platform discordance for ANA underscores the need for harmonisation. Collectively, these data support t
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