JHEP Reports最新文献

{"title":"Editorial Board page","authors":"","doi":"10.1016/S2589-5559(25)00334-9","DOIUrl":"10.1016/S2589-5559(25)00334-9","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 11","pages":"Article 101652"},"PeriodicalIF":7.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145462780","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":"Early mortality in atezolizumab/bevacizumab for HCC is associated with impaired liver function and alterations of systemic immunity","authors":"Ignazio Piseddu , Leonie S. Jochheim , Katrin Boettcher , Bernhard Scheiner , Friedrich Sinner , Simon Johannes Gairing , Matthias Thaler , Stefan Enssle , Monika Karin , Valentina Zarka , Alexander Philipp , Andreas Thalmeier , Jan Gaertig , Lorenz Balcar , Julia Martina Schütte , Julia S. Schneider , Katarina Ondrejkova , Monika Rau , Alexander Weich , David Anz , Najib Ben Khaled","doi":"10.1016/j.jhepr.2025.101513","DOIUrl":"10.1016/j.jhepr.2025.101513","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Atezolizumab/bevacizumab (atezo/bev) has revolutionized the standard of care for patients with unresectable hepatocellular carcinoma (HCC). However, only a subgroup of patients responds to atezo/bev and derives durable clinical benefit. This study aims to analyze the frequency and risk factors of early mortality (EM) in patients with HCC treated with atezo/bev.</div></div><div><h3>Methods</h3><div>This study uses data from a large, European real-world cohort and flow cytometry-based immunophenotyping of patient’s baseline PBMC. EM was defined as death from any cause within 90 days of treatment initiation. Logistic regression analysis was used to identify parameters associated with EM.</div></div><div><h3>Results</h3><div>A total of 317 patients with unresectable HCC treated with first-line atezo/bev were included. EM rate in the cohort was 15.8%, with a median survival of 12.6 months. The proportion of patients with preserved liver function and BCLC stage B was significantly lower in the EM cohort. The strongest predictor of EM was advanced liver disease in univariate analysis, as reflected by surrogates of impaired liver function such as Child–Pugh score (CPS) B (<em>p</em> <0.0001), albumin–bilirubin grade 2/3 (<em>p</em> = 0.026, <em>p</em> <0.0001) or high model for end-stage liver disease score (<em>p</em> <0.0001). CPS B remained a significant risk factor after adjusting for other variables. Biomarker analysis and immunophenotyping revealed high C-reactive protein, reduced lymphocyte frequencies, increased CD44 expression on regulatory T cells and elevated PD-L1 levels on CD8<sup>+</sup> T cells to be associated with EM.</div></div><div><h3>Conclusions</h3><div>EM rate was 15.8% in patients with HCC treated with atezo/bev. Significant risk factors for early death involved impaired liver function, elevated biomarkers of inflammation and alterations of systemic immunity.</div></div><div><h3>Impact and implications</h3><div>Although rare in clinical trial populations, early mortality (EM) is a significant concern following the initiation of immune checkpoint inhibitors in patients with hepatocellular carcinoma (HCC) in real-world cohorts, highlighting the need for adequate risk stratification and patient selection. Using data of a large, European real-world cohort as well as FACS-based immunophenotyping of baseline peripheral blood mononuclear cells, we comprehensively characterized the frequency, risk factors, and biomarkers associated with EM in atezo/bev-treated patients with HCC. We identified EM to represent a common event in patients with HCC after treatment initiation and demonstrated impaired liver function, elevated biomarkers of inflammation, and reduced lymphocyte frequencies and increased regulatory T cell activity to be associated with increased EM risk. These findings can help clinicians identify patients with HCC at high risk of EM, enabling adequate and informed decision-making r","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 11","pages":"Article 101513"},"PeriodicalIF":7.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145462782","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":"Predicting the need for early TIPS in patients with cirrhosis and ascites: More art than science","authors":"Alberto Zanetto , Marco Senzolo","doi":"10.1016/j.jhepr.2025.101515","DOIUrl":"10.1016/j.jhepr.2025.101515","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 11","pages":"Article 101515"},"PeriodicalIF":7.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145462776","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":"Pembrolizumab and stereotactic body radiotherapy combined in advanced hepatocellular carcinoma post sorafenib – A phase II trial (PEMRAD)","authors":"Grainne M. O’Kane ,&nbsp;Aruz Mesci ,&nbsp;Raymond W. Jang ,&nbsp;Aisling Barry ,&nbsp;Cynthia M. Bocaya ,&nbsp;Giselle M. Boukhaled ,&nbsp;Holly Acton ,&nbsp;David Doddington ,&nbsp;Rowena Rodrigo ,&nbsp;Leo M.L. Chan ,&nbsp;Babak Noamani ,&nbsp;Harry Harvey ,&nbsp;Andrew Elia ,&nbsp;Rhoda Law ,&nbsp;Rebecca Prince ,&nbsp;Mark Doherty ,&nbsp;Anna Dodd ,&nbsp;David K. Wong ,&nbsp;Lisa Wang ,&nbsp;Ben X. Wang ,&nbsp;Jennifer J. Knox","doi":"10.1016/j.jhepr.2025.101658","DOIUrl":"10.1016/j.jhepr.2025.101658","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>There is strong rationale for integrated approaches combining immune checkpoint inhibitors with locoregional therapies in hepatocellular carcinoma (HCC).</div></div><div><h3>Methods</h3><div>The PEMRAD phase II trial investigated pembrolizumab in combination with stereotactic body radiation therapy (SBRT) in patients with advanced HCC following progression on sorafenib. Patients received pembrolizumab on Day 1, and SBRT commenced on Day 2. Up to 10 hepatic lesions (&lt;20 cm) were treated with SBRT. Pembrolizumab was continued every 21 days until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was objective response rate (ORR) by RECIST v1.1, with a hypothesized improvement to 40% for the combination. Tissue and liquid biopsies were collected for correlative analyses, including immunohistochemistry, longitudinal blood cytometry by time-of-flight, and serum cytokine assessment.</div></div><div><h3>Results</h3><div>Between March 2018 and March 2023, 18 of a planned 22 patients were enrolled; 11 (61%) had macrovascular invasion (MVI) and 15 (83%) had extrahepatic metastases. Viral hepatitis was the underlying etiology in 50%. The ORR was 41% (95% CI 18–67%). Median progression-free survival was 5.4 months (2.8–9.9) and median overall survival was 12.6 months (5.7–25.8). Of 34 liver lesions treated with SBRT, only three progressed, in two patients. Among the 11 patients with MVI, 5 (45%) achieved a response, including one complete response. Treatment-related adverse events of grade ≥3 occurred in four patients (22%). One treatment-related death due to myocarditis was observed. Peripheral immunophenotyping showed that higher abundance of CD8⁺CD103⁺ T cells correlated with improved survival, whereas higher natural killer cell abundance was associated with inferior outcomes.</div></div><div><h3>Conclusion</h3><div>The combination of SBRT and pembrolizumab demonstrated a high response rate as second-line therapy for advanced HCC and warrants further evaluation, particularly in patients with MVI.</div></div><div><h3>Impact and implications</h3><div>This study demonstrates that combining stereotactic body radiotherapy with pembrolizumab is feasible and yields promising response rates in patients with advanced, previously treated hepatocellular carcinoma, including those with macrovascular invasion – a group typically associated with poor outcomes. These findings support further evaluation of this integrated approach and provide important guidance for the design of future clinical trials aimed at improving outcomes in advanced hepatocellular carcinoma.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101658"},"PeriodicalIF":7.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver transplantation for hepatopulmonary syndrome: A systematic review and meta-analysis","authors":"Maïté Verstraeten ,&nbsp;Mattice De Clercq ,&nbsp;Hanne De Craemer ,&nbsp;Xavier Verhelst ,&nbsp;Sander Lefere ,&nbsp;Lindsey Devisscher ,&nbsp;Anja Geerts ,&nbsp;Hans Van Vlierberghe ,&nbsp;Michael B. Fallon ,&nbsp;Sarah Raevens","doi":"10.1016/j.jhepr.2025.101659","DOIUrl":"10.1016/j.jhepr.2025.101659","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Hepatopulmonary syndrome (HPS) is a severe pulmonary vascular complication of liver disease. Liver transplantation (LT) is the only definitive treatment, yet a contemporary synthesis of LT outcomes in HPS, alongside persisting uncertainties, is lacking.</div></div><div><h3>Methods</h3><div>We conducted a systematic review and meta-analysis of 22 studies to evaluate HPS prevalence, post-LT survival, and HPS resolution.</div></div><div><h3>Results</h3><div>Pooled HPS prevalence was 17.2% (11.6–24.7%, n = 1,171 studied patients) among patients with cirrhosis evaluated for LT, 26.1% (18.5–35.5%, n = 629) in patients with portal hypertension evaluated for LT and 21.6% (11.2–37.4%, n = 737) in LT recipients. Under current model for end-stage liver disease (MELD) exception policies, waitlist mortality was 13.1% (0.6–78.5%, n = 1,240 studied patients). Post-LT survival in patients with HPS was comparable to that in patients without HPS and aligned with international benchmarks. Pooled 1-year post-LT survival rates were 85.5% in prospective studies from the pre- and post-MELD era (n = 240 studied patients), 93.9% in the post-MELD era (n = 99), and 83.8% in registry-based studies (n = 800). Pooled estimates for 5-year post-LT survival rates were 85% (n = 144 studied patients), 92.9% (n = 99), and 76% (n = 739), respectively. Lower pre-LT PaO₂ correlated with poorer post-LT survival, especially in very severe HPS. HPS resolved after LT in 90.1% (71.7-97.0%, n = 80 studied patients) of patients at 6 months, with complete resolution within 1 year in all patients assessed. Key gaps remain regarding the influence of underlying liver disease on HPS progression, the optimal timing of LT, and factors affecting post-LT recovery.</div></div><div><h3>Conclusions</h3><div>LT offers substantial survival and clinical benefits for patients with HPS, with high rates of HPS resolution within a year. Patients with very severe HPS warrant closer monitoring, and further research is needed to address unresolved questions regarding disease trajectory and post-transplant outcomes.</div></div><div><h3>Impact and implications</h3><div>This systematic review and meta-analysis shows that liver transplantation (LT) is an effective treatment for hepatopulmonary syndrome (HPS), resulting in high rates of syndrome resolution and post-transplant survival comparable to patients without HPS. These findings support the continued use of MELD exception policies and underscore the importance of timely referral for LT. While outcomes are generally favorable, patients with very severe HPS may experience worse post-transplant outcomes, highlighting the need for more tailored clinical management. A key unmet need remains in understanding the role of underlying liver disease severity in the natural history of HPS, as well as the optimal timing for LT and factors influencing post-transplant recovery.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101659"},"PeriodicalIF":7.5,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836509","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":"PNPLA3 and TM6SF2 exacerbate the impact of alcohol and metabolic dysfunction on liver fibrosis","authors":"Sophie Gensluckner ,&nbsp;Helle Lindholm Schnefeld ,&nbsp;Jan Embacher ,&nbsp;Camilla Dalby Hansen ,&nbsp;Lorenz Balcar ,&nbsp;Katrine Tholstrup Bech ,&nbsp;Paul Thöne ,&nbsp;Nikolaj Torp ,&nbsp;Bernhard Wernly ,&nbsp;Laura Maarit Pikkupeura ,&nbsp;Stephan Zandanell ,&nbsp;Christian Datz ,&nbsp;Michael Strasser ,&nbsp;Mads Israelsen ,&nbsp;Mattias Mandorfer ,&nbsp;Torben Hansen ,&nbsp;Aleksander Krag ,&nbsp;Elmar Aigner ,&nbsp;Maja Thiele ,&nbsp;Georg Semmler","doi":"10.1016/j.jhepr.2025.101649","DOIUrl":"10.1016/j.jhepr.2025.101649","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Genetic predisposition (especially variants in <em>PNPLA3</em> and <em>TM6SF2</em>), metabolic dysfunction, and alcohol consumption are established risk factors for steatotic liver disease (SLD) and progression of fibrosis. However, the clinical relevance of their interaction and its implications for patient management remain unclear.</div></div><div><h3>Methods</h3><div>We cross-sectionally analyzed data from two cohorts: patients referred to tertiary liver care (N = 1,554) and individuals at risk for SLD (N = 1,728). Multivariable regression models with and without interaction terms were used to assess the independent and interactive effects of genetic risk variants, metabolic dysfunction (HOMA-IR, BMI), and alcohol intake on liver fibrosis severity as assessed by liver stiffness measurement (LSM).</div></div><div><h3>Results</h3><div>Mean age was 52 and 56 years in the Tertiary-care cohort and the At-risk cohort, respectively. Most participants were male, 23% and 53% suffered from obesity, and 39% and 58% were categorized as insulin resistant, respectively. Median LSM was 5.5 kPa and 4.7 kPa, with 21% and 9.6% having LSM ≥8 kPa, respectively. In total, 48% and 44% carried at least one <em>PNPLA3</em> G-allele (C/G or G/G), and 18% and 15% the <em>TM6SF2</em> T-allele (C/T or T/T), respectively. In multivariable regression without interaction terms, LSM was associated with HOMA-IR, alcohol consumption, BMI (At-risk cohort), <em>PNPLA3</em> and <em>TM6SF2</em>. However, when allowing for interactions, the independent effects of genetic risk variants disappeared. Instead, <em>PNPLA3</em> potentiated the association of HOMA-IR (<em>p</em> &lt;0.001/<em>p</em> = 0.016) and severe alcohol consumption (<em>p</em> &lt;0.001/<em>p</em> = 0.093) with LSM. <em>TM6SF2</em> amplified the effect of BMI (<em>p</em> = 0.006) and severe alcohol consumption (<em>p</em> &lt;0.001) on LSM in the Tertiary-care-cohort.</div></div><div><h3>Conclusions</h3><div>Our findings indicate that <em>PNPLA3</em> and <em>TM6SF2</em> variants do not act as independent determinants of liver fibrosis once gene–environment interactions are considered. Instead, they amplify the harmful effects of metabolic dysfunction and alcohol consumption in individuals evaluated for SLD, creating a synergistic risk profile.</div></div><div><h3>Impact and implications</h3><div>Our findings indicate that fibrosis progression in steatotic liver disease is mediated by an interaction of environmental risk factors (obesity, insulin resistance, alcohol consumption) and genetic risk variants, such as <em>PNPLA3</em> and <em>TM6SF2</em>, but not by genetic variants alone. This highlights the importance of acknowledging these gene–environment interactions for patient counselling and risk stratification.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101649"},"PeriodicalIF":7.5,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733850","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":"FGF1 ameliorates hepatic steatosis through acute activation of the unfolded protein response and VLDL production","authors":"Tim van Zutphen ,&nbsp;Dicky Struik ,&nbsp;Weilin Liu ,&nbsp;Sihao Liu ,&nbsp;Benan Pelin Sermikli ,&nbsp;Justina C. Wolters ,&nbsp;Henkjan J. Verkade ,&nbsp;Annette R. Atkins ,&nbsp;Michael Downes ,&nbsp;Ronald M. Evans ,&nbsp;Johan W. Jonker","doi":"10.1016/j.jhepr.2025.101660","DOIUrl":"10.1016/j.jhepr.2025.101660","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Metabolic dysfunction-associated steatotic liver disease (MASLD) is a serious chronic liver disease with limited therapeutic options. Fibroblast growth factor (FGF) analogs show promising therapeutic benefits for MASLD, yet the underlying mechanisms remain incompletely understood. Here, we studied the mechanism underlying the anti-steatotic properties of FGF1, the prototype member of the FGF family.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;The effect of FGF1 was studied in human and rodent hepatocytes and in obese mouse models exhibiting acute or chronic endoplasmic reticulum (ER) stress characteristic of MASLD. Metabolic analysis and proteomics were applied to evaluate liver physiology, ER stress and signaling.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;We show that FGF1 reduces hepatic triglyceride (TG) levels in obese mice (51%, &lt;em&gt;p &lt;&lt;/em&gt;0.01, n = 8) via acute stimulation of very-low-density lipoprotein (VLDL, 3.9-fold, &lt;em&gt;p &lt;&lt;/em&gt;0.01, n = 8) secretion in an ER stress-dependent manner. This anti-steatotic effect was independent of adipose FGF receptor 1, which is required for the glucose-lowering effect of FGF1. Mechanistically, activation of the unfolded protein response (UPR), resulting in stabilization of apolipoprotein B (ApoB, 1.8-fold, &lt;em&gt;p &lt;&lt;/em&gt;0.01, n = 8), the main structural protein component of atherogenic lipoprotein particles, was identified as the key mechanism by which FGF1 drives VLDL secretion. Post-translational control of ApoB by FGF1 was potentiated by pre-existing ER stress. FGF1 stimulated major regulators of protein synthesis, and during ER stress, all three branches of the UPR were activated. In ER stress-primed lean mice, FGF1 adopted novel TG secretion activity (2.2-fold, &lt;em&gt;p &lt;&lt;/em&gt;0.05, n = 6). Conversely, alleviation of ER stress in obese mice suppressed FGF1-stimulated VLDL-TG production (49%, n = 11, &lt;em&gt;p &lt;&lt;/em&gt;0.05).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;These results define ER stress-dependent modulation of VLDL secretion as a mechanism underlying the anti-steatotic activity of FGF1. Targeting the FGF-UPR pathway may thus have therapeutic potential for treating MASLD.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;Fibroblast growth factors show therapeutic potential in both preclinical models and clinical trials for treating metabolic dysfunction-associated steatotic liver disease, a highly prevalent condition with limited treatment options. Identifying the mechanisms underlying their anti-steatotic effects may accelerate clinical development. Our finding that triglyceride secretion is the major driver of the anti-steatotic action of FGF1, together with the involvement of an adaptive unfolded protein response, provides deeper insight into the therapeutic potential of this pathway. These results also highlight possible implications for liver physiology and for the circulating lipoprotein profile, with relevance for both efficacy and safety considerati","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101660"},"PeriodicalIF":7.5,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145814290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply to: “Managing PFIC 7 with odevixibat: Alleviation of pruritus and biochemical response”","authors":"Angelo Di Giorgio","doi":"10.1016/j.jhepr.2025.101644","DOIUrl":"10.1016/j.jhepr.2025.101644","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101644"},"PeriodicalIF":7.5,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836507","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 multi-omic basis for hepatic encephalopathy recurrence: Analysis of the THEMATIC trial","authors":"Jasmohan S. Bajaj ,&nbsp;Andrew Fagan ,&nbsp;Richard K. Sterling ,&nbsp;Masoumeh Sikaroodi ,&nbsp;Mary Leslie Gallagher ,&nbsp;Hannah Lee ,&nbsp;Scott C. Matherly ,&nbsp;Amy Bartels ,&nbsp;Travis Mousel ,&nbsp;Brian C. Davis ,&nbsp;Puneet Puri ,&nbsp;Michael Fuchs ,&nbsp;Leroy R. Thacker ,&nbsp;Joseph P. McGinley ,&nbsp;Alexander Khoruts ,&nbsp;Patrick M. Gillevet","doi":"10.1016/j.jhepr.2025.101634","DOIUrl":"10.1016/j.jhepr.2025.101634","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;The THEMATIC trial demonstrated that fecal microbiota transplantation (FMT) reduces recurrence of hepatic encephalopathy (HE) in patients already receiving lactulose and rifaximin. The aim of this analysis was to identify multi-omic predictors of HE recurrence among THEMATIC trial participants.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;The THEMATIC trial enrolled patients with cirrhosis and HE who received oral or enema FMT &lt;em&gt;vs.&lt;/em&gt; placebo (1–3 administrations) and were followed for 6 months. Outcomes included safety and HE recurrence. Serum, urine, and stool samples were collected at baseline and post-FMT for all participants. Stool metagenomics, serum and urine metabolomics, inflammatory cytokines, and clinical data were analyzed. Differences between patients with and without HE recurrence were assessed using pathway, random forest, and latent factor analyses.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;HE recurred in 10 of 60 patients (17%), with significantly higher recurrence in the placebo &lt;em&gt;vs&lt;/em&gt;. the FMT groups (40% &lt;em&gt;vs.&lt;/em&gt; 8%; &lt;em&gt;p&lt;/em&gt; = 0.005). Due to the low recurrence rate in the FMT arms, all patients with recurrence were combined and compared with those without recurrence. Stool metagenomics showed that the abundance of short-chain fatty acid (SCFA) producers (&lt;em&gt;Faecalibacterium, Eubacterium, Bacteroides, Blautia&lt;/em&gt; spp.) was lower, while that of GABA-producing taxa (&lt;em&gt;Lactobacillus, Bifidobacterium&lt;/em&gt; spp.) was higher, in patients with recurrence. Urine and serum metabolomes separated HE recurrence groups on PLS-DA, with serum butyrate and isobutyrate being most significantly associated (&lt;em&gt;p&lt;/em&gt; = 0.008). Pathway analyses revealed upregulation of GABA and neurotransmitter pathways in patients with HE recurrence. Random forest and latent factor analysis indicated that SCFA producers and secondary bile acids were protective, whereas IL-6, GABA producers, nicotine metabolites, and primary bile acids were associated with HE recurrence.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Secondary analysis of the THEMATIC randomized controlled trial indicates that HE recurrence in patients on lactulose and rifaximin is associated with distinct microbiome and metabolomic profiles, particularly involving SCFAs, GABA metabolism, bile acids, and IL-6.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;Fecal microbiota transplantation (FMT) reduced hepatic encephalopathy (HE) recurrence in patients receiving lactulose and rifaximin in the THEMATIC trial, but the multi-omic mechanisms underlying this effect were unclear. In this secondary analysis, we found that HE recurrence – regardless of FMT or placebo assignment – was associated with distinct multi-omic signatures, including reduced short-chain fatty acid-producing and increased pathobiont taxa, lower urinary and serum short-chain fatty acids, secondary bile acids, and acetaminophen derivatives, and higher GABA-related and nicotine metabolite","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101634"},"PeriodicalIF":7.5,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786926","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":"Blood-based Vienna 3P/5P risk models accurately predict first hepatic decompensation in compensated advanced chronic liver disease","authors":"Georg Kramer ,&nbsp;Benedikt Simbrunner ,&nbsp;Mathias Jachs ,&nbsp;Lorenz Balcar ,&nbsp;Benedikt Silvester Hofer ,&nbsp;Nina Dominik ,&nbsp;Lukas Hartl ,&nbsp;Michael Schwarz ,&nbsp;Georg Semmler ,&nbsp;Christian Sebesta ,&nbsp;Paul Thöne ,&nbsp;Sophia Geisselbrecht ,&nbsp;Benjamin Maasoumy ,&nbsp;Eduardo Alvarez ,&nbsp;Martin Sebastian McCoy ,&nbsp;Oleksandr Petrenko ,&nbsp;Jiří Reiniš ,&nbsp;Philipp Schwabl ,&nbsp;Albert F. Stättermayer ,&nbsp;Michael Trauner ,&nbsp;Thomas Reiberger","doi":"10.1016/j.jhepr.2025.101642","DOIUrl":"10.1016/j.jhepr.2025.101642","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Invasive measurement of hepatic venous pressure gradient (HVPG) is the gold standard for diagnosing clinically significant portal hypertension (CSPH, &lt;em&gt;i.e.&lt;/em&gt; 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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;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 &lt;em&gt;p &lt;&lt;/em&gt;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, &lt;em&gt;p&lt;/em&gt; &lt;em&gt;&lt;&lt;/em&gt;0.001) and 3P (aSHR: 1.15, &lt;em&gt;p =&lt;/em&gt; 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 &lt;em&gt;p &lt;&lt;/em&gt;0.001).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;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":"2025-10-17","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}