JHEP Reports最新文献

{"title":"Interleukin-18 binding protein deficiency results in gut microbiota dysbiosis and aggravated diet-induced MASH in mice","authors":"Emmanuel Somm , Elodie Perroud , Yunju Jo , Karina Lindner , Frédérique Ino , Sophie A. Montandon , Christelle Veyrat-Durebex , Franck Bontems , Florian Visentin , Nadia Gaïa , Vladimir Lazarevic , Anne-Claude Gavin , Jacques Schrenzel , Dongryeol Ryu , Karim Gariani , Cem Gabay , François R. Jornayvaz","doi":"10.1016/j.jhepr.2025.101629","DOIUrl":"10.1016/j.jhepr.2025.101629","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) are now the most prevalent hepatic disorders worldwide. Growing evidence implicates physiological alterations in the gut–liver axis and gut microbiota dysbiosis in this process. IL-18-binding protein (IL-18BP) forms high affinity complexes with IL-18, thus blocking its interaction with IL-18 receptors.</div></div><div><h3>Methods</h3><div>We used high-fat diet (HFD) and methionine choline deficient (MCD) diet to model MASLD/MASH in wild-type (WT) male mice (n = 6–8 mice per group). We also studied antimicrobial peptides (AMPs) production, gut microbiota composition, and liver phenotype in <em>Il18bp</em><sup><em>-/-</em></sup> male mice on both HFD and MCD diets (n = 5–7 mice per group). We manipulated gut microbiota of <em>Il18bp</em><sup><em>-/-</em></sup> and WT male mice through administration of phages, antibiotics, and through co-housing experiments (n = 4–8 mice per group).</div></div><div><h3>Results</h3><div>Feeding WT mice with a HFD or an MCD diet led to a decrease in ileal AMPs expressions (respectively, by 63% and 37% for <em>Lyz1</em>; by 47% and 84% for <em>Ang4</em>; by 86% and 46% for <em>Pla2g2a</em>) and an enrichment in gut proteobacteria (respectively, by 7- and 23-fold for α-proteobacteria; by 2.1- and 1.7-fold for δ-proteobacteria; by 14- and 20-fold for γ-proteobacteria) when compared with standard chow diet (<em>p</em> <0.05). These changes were associated with a reduction in the ileal <em>Il18bp</em> expression (respectively, by 77% and 46%) in HFD and MCD diet-fed WT mice <em>vs.</em> chow diet-fed WT mice (<em>p</em> <0.05). <em>Il18bp</em><sup><em>-/-</em></sup> mice exhibited a decrease in gut AMPs expression and storage (AMP granules area/crypt respectively decreased by 57% and 62.5% in <em>Il18bp</em><sup><em>-/-</em></sup> <em>vs.</em> WT mice on HFD and MCD diets). Moreover, <em>Clostridium/Turicimonas/Escherichia</em> bacteria were constitutively over-represented in gut microbiota of <em>Il18bp</em><sup><em>-/-</em></sup> <em>vs.</em> WT mice in a diet-amplified manner. Compared with WT mice, <em>Il18bp</em><sup><em>-/-</em></sup> mice exhibited increased diet-induced hepatic damage (circulating alanine aminotransferase 84 <em>vs.</em> 41 U/L on HFD; 1,218 <em>vs.</em> 738 U/L on MCD diet, <em>p</em> <0.05), inflammation (liver tumor necrosis factor-alpha content 72 <em>vs.</em> 35 pg/g protein on HFD; 441 <em>vs.</em> 169 pg/g protein on MCD diet, <em>p</em> <0.05), and fibrosis (Sirius red 1.45 <em>vs.</em> 0.36% on HFD; 1.64 <em>vs.</em> 0.65% on MCD diet, <em>p</em> <0.01). These changes occurred independently of steatosis modification. Phages, antibiotic, and co-housing experiments revealed that specific gut microbiota featuring <em>Il18bp</em><sup><em>-/-</em></sup> mice is implicated in their exacerbated liver inflammation and fibro","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101629"},"PeriodicalIF":7.5,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733852","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":"Orphan drug uttroside B impedes MASH progression and HCC development in experimental models","authors":"Tennyson P. Rayginia , Chenicheri K. Keerthana , Sreekumar U. Aiswarya , Sadiq C. Shifana , S. Jannet , Sanjay Suresh Varma , P. Maria Joy , Mundanattu Swetha , Shirly James , J.S. Aparna , Yadu Vijayan , Archana Payickattu Retnakumary , Lekshmi R. Nath , Kalishwaralal Kalimuthu , Vishnu Sunil Jaikumar , Sankar Sundaram , Nikhil Ponnoor Anto , Noah Isakov , Kuzhuvelil B. Harikumar , Ravi S. Lankalapalli , Ruby John Anto","doi":"10.1016/j.jhepr.2025.101626","DOIUrl":"10.1016/j.jhepr.2025.101626","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by excessive accumulation of fat, accompanied by inflammation and liver injury, ultimately triggering chronic conditions, including fibrosis and cirrhosis, which may progress to hepatocellular carcinoma (HCC). Uttroside B (Utt-B), a phytosaponin isolated in our lab, has gained global recognition owing to its anti-HCC potential and is currently a United States FDA-designated ‘orphan drug’ against HCC. The present study highlights Utt-B as a propitious candidate drug against MASH and MASH-induced HCC.</div></div><div><h3>Methods</h3><div>MASH and MASH-induced HCC were developed in C57BL/6J mice using two distinct murine models: a high-fat diet model and a streptozotocin-induced steatohepatitis-derived HCC model, followed by i.p. administration of Utt-B. Protein expression analysis was performed using real-time quantitative reverse transcription-PCR and immunoblotting, while H&E, Oil Red O, Sirius Red, and Masson’s Trichrome were utilized for staining cells/tissues. Nanostring n-Counter analysis was used to investigate the mechanism underlying the antifibrotic effects of Utt-B in MASH-induced HCC. Proliferation and apoptosis markers were also evaluated. Statistical analyses were conducted using R and GraphPad-Prism with significance set at <em>p</em> <0.05.</div></div><div><h3>Results</h3><div>Utt-B ameliorated MASH-associated pathological features, including steatosis, hepatocyte ballooning, and inflammation (N = 6; non-alcoholic fatty liver disease activity score [NAS] <2, <em>p</em> <0.0001). Utt-B upregulated the expression of autophagy markers autophagy-related 7 (ATG-7), Beclin-1, and microtubule-associated protein 1A/1B-light chain (LC3-II), and downregulated the expression of α-smooth muscle actin (α-SMA), which indicates the activation of hepatic stellate cells. Utt-B also halted the progression of MASH to HCC by hindering development of fibrosis with simultaneous inhibition of proliferative signals and induction of apoptosis in murine models (N = 6; NAS <3, <em>p</em> <0.01).</div></div><div><h3>Conclusion</h3><div>Our investigation revealed effective impedance of MASH and its concomitant progression to HCC by Utt-B. Given the lack of anti-MASH drugs, these findings establish Utt-B as a potent drug for treating MASH and MASH-induced HCC.</div></div><div><h3>Impact and implications</h3><div>MASH, stage IV of non-alcoholic fatty liver disease, can lead to chronic conditions, including fibrosis and cirrhosis, elevating the risk of HCC. Impaired lipid metabolism, inflammation, inhibition of autophagy, and dysregulated collagen and extracellular matrix biosynthesis are key factors contributing to the advance of MASH to HCC. Our discovery of Utt-B, a phytosaponin that exhibits remarkable anti-HCC potential and is a United States FDA-designated orphan drug against HCC, has gained global recognition. The present study","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101626"},"PeriodicalIF":7.5,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034311","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":"Lactococcus A phages predict ACLF while Enterococcus B phages predict bacterial infection in decompensated cirrhosis","authors":"Lore Van Espen ,&nbsp;Maximilian Joseph Brol ,&nbsp;Lila Close ,&nbsp;Robert Schierwagen ,&nbsp;Wenyi Gu ,&nbsp;Marisa I. Keller ,&nbsp;Boglarka Balogh ,&nbsp;Anthony Fullam ,&nbsp;Lander De Coninck ,&nbsp;Tomohiro Nakamura ,&nbsp;Michael Kuhn ,&nbsp;Peer Bork ,&nbsp;Wim Laleman ,&nbsp;Jasmohan S. Bajaj ,&nbsp;Maria Papp ,&nbsp;Bernd Schnabl ,&nbsp;Jonel Trebicka ,&nbsp;Jelle Matthijnssens ,&nbsp;MICROB-PREDICT","doi":"10.1016/j.jhepr.2025.101622","DOIUrl":"10.1016/j.jhepr.2025.101622","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>As portal hypertension progresses in cirrhosis, bacterial translocation across a compromised gut barrier leads to endotoxemia, systemic inflammation and immune dysfunction. Gut phages play a key role in these processes by influencing bacteria-host interactions. This study explores the role of the human gut virome in acute decompensation of cirrhosis and acute-on-chronic liver failure (ACLF).</div></div><div><h3>Methods</h3><div>The fecal virome was longitudinally assessed by metagenomic sequencing in two independent cohorts: 93 patients (292 samples) with acute decompensation or ACLF from the PREDICT study, and 94 patients (94 samples) with decompensated cirrhosis undergoing TIPS (transjugular intrahepatic portosystemic shunt) surgery collected in a tertiary care setting. Besides descriptive analysis, phages were grouped according to their predicted bacterial host and lifestyle, and associated with clinical parameters.</div></div><div><h3>Results</h3><div>Phage alpha-diversity was higher in patients with ACLF and correlated with ACLF severity. In the absence of ACLF, the phageome was dominated by virulent phages, but in ACLF, temperate phages became more prevalent. Genus-level analysis showed that phageomes were highly patient-specific. <em>Lactococcus A</em> phages were the only phage-host group predicting ACLF development (odds ratio [OR] = 14; Fisher test <em>p</em> = 0.0129). <em>Enterococcus B</em> phages (OR = 14.7; <em>p</em> = 0.0015; adj. <em>p</em> = 0.037) and their bacterial hosts (OR = 2.8; <em>p</em> = 0.020) were significantly more prevalent in cases of proven systemic bacterial infection. The presence of both phage families was linked to increased 90-day mortality rates.</div></div><div><h3>Conclusion</h3><div>ACLF is characterized by increased fecal virome diversity and a shift from virulent toward temperate phages at disease onset. Our study links <em>Lactococcus A</em> phages to ACLF development, and <em>Enterococcus B</em> phages to bacterial infection, while both are associated with increased 90-day mortality.</div></div><div><h3>Clinical trial number</h3><div>NCT03056612.</div></div><div><h3>Impact and implications</h3><div>The human gut virome is a poorly investigated part of the human gut microbiome, especially in the context of decompensated cirrhosis and acute-on-chronic liver failure. This study identified two phage groups (<em>Lactococcus A</em> phages and <em>Enterococcus B</em> phages) with particular prognostic value. In the future, virome analysis of fecal samples could be useful for patient stratification in clinical practice.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101622"},"PeriodicalIF":7.5,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682309","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":"Challenges in the diagnosis and treatment of genetic cholestasis in adults","authors":"Richard J. Thompson ,&nbsp;Silvia Vilarinho ,&nbsp;Rosa Miquel ,&nbsp;Verena Keitel","doi":"10.1016/j.jhepr.2025.101625","DOIUrl":"10.1016/j.jhepr.2025.101625","url":null,"abstract":"<div><div>Disorders of bile formation and bile flow along the intra- and extrahepatic bile ducts are summarised under the term cholestasis. Clinically, conditions resulting in retention of biliary constituents such as bile acids within hepatocytes (termed primary cholestasis) need to be distinguished from diseases characterised by bile duct injury (termed cholangiopathies). Some cholangiopathies may also cause retention of biliary constituents within hepatocytes, resulting in secondary cholestasis. Genetic variants in a multitude of genes can contribute to the development of both primary cholestasis and cholangiopathies. Assessing the contribution of identified genetic variants to the clinical presentation in adults is complicated by factors such as environmental exposure, comorbidities, and medication intake. The diagnostic workup in adults with cholestasis should first consider common causes of primary cholestasis and cholangiopathies. If the aetiology remains unclear, liver histology and/or genetic testing should be pursued. Until recently, treatment for these conditions was largely supportive. However pharmacological interruption of the enterohepatic circulation of bile acids now offers the possibility of more specific intervention. Moreover, for those conditions in which the bile duct epithelium is the main site of injury, ursodeoxycholic acid remains essential. Multidisciplinary case discussions can help facilitate diagnosis and guide management.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101625"},"PeriodicalIF":7.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From model to man: Understanding Tregs' dual role in MASLD","authors":"Janine Dywicki ,&nbsp;Laura Elisa Buitrago-Molina ,&nbsp;Anna K. Baumann ,&nbsp;Ana C. Davalos-Misslitz ,&nbsp;Celina M. Hendriks ,&nbsp;Katharina L. Hupa-Breier ,&nbsp;Maren Lieber ,&nbsp;Jerome Schlue ,&nbsp;Matthias Blüher ,&nbsp;Heike Bantel ,&nbsp;Christine S. Falk ,&nbsp;Christian Koenecke ,&nbsp;Freya Wellhöner ,&nbsp;Benjamin Heidrich ,&nbsp;Michael P. Manns ,&nbsp;Fatih Noyan ,&nbsp;Heiner Wedemeyer ,&nbsp;Richard Taubert ,&nbsp;Elmar Jaeckel ,&nbsp;Matthias Hardtke-Wolenski","doi":"10.1016/j.jhepr.2025.101619","DOIUrl":"10.1016/j.jhepr.2025.101619","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD) affects around 30% of the world's population and is often associated with metabolic conditions such as obesity, diabetes and hypertension. Approximately 10-20% of metabolic dysfunction-associated steatotic liver disease cases progress to metabolic dysfunction-associated steatohepatitis (MASH), which significantly increases the risk of liver cancer. While intrahepatic immune responses involving CD4+ and CD8+ T cells are potential therapeutic targets, their role in the pathogenesis of MASH is not fully understood. Regulatory T cells (Tregs), whose involvement has been controversial, require further investigation.</div></div><div><h3>Methods</h3><div>In this study, we investigated the impact of adaptive immunity on MASH using a high-fat/high-carbohydrate diet (HF-HCD) model in wild-type and <em>Rag2</em>-deficient C57BL/6 mice, supplemented with human liver samples.</div></div><div><h3>Results</h3><div>Our results showed that HF-HCD induced glucose intolerance and MASH, independent of adaptive immunity. Surprisingly, HF-HCD increased intrahepatic Treg numbers and the Treg/Teff ratio but did not alleviate the disease; instead, this increase correlated with greater disease severity. With progressing metabolic inflammation, an increased proportion of Tregs also expressed IL-17, which correlated with more severe liver pathology.</div></div><div><h3>Conclusions</h3><div>The observed expansion of Tregs and the resulting increase in the Treg/Teff ratio did not protect against MASH but correlated with more severe disease in both mice and humans, consistent with a pro-inflammatory shift towards IL-17-producing (T_H17-skewed) cells. These findings highlight the complex role of adaptive immunity in MASH progression and provide potential targets for future immunomodulatory therapies.</div></div><div><h3>Impact and implications</h3><div>Diet-induced steatohepatitis can develop without adaptive immunity, yet IL-17A-expressing Foxp3⁺ T regulatory cells (Tregs) and CD8⁺ T cells markedly amplify hepatocellular injury and fibrosis. By separating initiating (macrophage-driven) from amplifying (adaptive) immune signals, our study refines current pathogenic models and provides hepatologists and immunologists with stage-specific therapeutic targets. For clinicians and trial designers, the data indicate that stabilizing Tregs or selectively dampening pro-inflammatory T-cell subsets could complement metabolic interventions in metabolic dysfunction-associated steatotic liver disease/steatohepatitis, whereas indiscriminate Treg expansion might be counter-productive. Because the conclusions are drawn from a murine model, translation to humans will require validation in patient-derived tissues and non-invasive immune biomarkers.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101619"},"PeriodicalIF":7.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145569494","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":"Binge drinking acutely induces hepatic steatosis which is readily reversible: A real-world observational study in healthy adults","authors":"Kristoffer Kjærgaard ,&nbsp;Jeppe Mygind Yeoman ,&nbsp;Peter Lykke Eriksen ,&nbsp;Anne Catrine Daugaard Mikkelsen ,&nbsp;Emilie Eifer Møller ,&nbsp;Ann-Sophie Frees Wietz ,&nbsp;Andressa de Zawadzki ,&nbsp;Lars Christian Gormsen ,&nbsp;Sara Heebøll ,&nbsp;Hendrik Vilstrup ,&nbsp;Karen Louise Thomsen","doi":"10.1016/j.jhepr.2025.101623","DOIUrl":"10.1016/j.jhepr.2025.101623","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Binge drinking is a common pattern of alcohol intake often considered particularly harmful. However, its immediate effects on the development of hepatic steatosis and early alcohol-related liver injury are not well established. This study aimed to investigate the acute effects of binge drinking on the liver and its reversibility in healthy individuals.</div></div><div><h3>Methods</h3><div>Healthy adults were studied in a real-world setting before, the day after, and 10 days after attending a 3-day festival. The participants were alcohol abstinent 1 week prior to the first visit and between the last two visits. Each visit included liver MRI-proton density fat fraction and elastography, and blood tests. Alcohol and food intake were self-reported during the festival, and blood alcohol concentration was measured once daily.</div></div><div><h3>Results</h3><div>Fifteen participants (9 male, 6 female) aged 36 ± 5 years with a BMI of 23.2 ± 2.7 kg/m² completed the study. They consumed 186 ± 56 g of alcohol per day resulting in a 2.5-fold increase in hepatic fat fraction from 1.9% (IQR 1.6%-2.5%) to 4.6% (IQR 2.4%-5.7%), <em>p</em> &lt;0.0001. Six participants (40%) developed steatosis; compared to those without steatosis, they had higher baseline BMI, triglycerides and glucagon, and lower free fatty acids, while there was no difference in alcohol or energy consumption. Binge drinking also increased liver stiffness and triglycerides, while LDL-cholesterol decreased. After 10 days of abstinence, all outcome measures were normalised.</div></div><div><h3>Conclusions</h3><div>Three days of recreational binge drinking increased liver fat content and stiffness in most participants. This early consequence of excessive alcohol intake was resolved after 10 days of abstinence, suggesting that the acute hepatic effects of binge drinking are readily reversible if followed by short-term abstinence.</div></div><div><h3>Impact and implications</h3><div>Binge drinking is considered a high-risk pattern of alcohol intake associated with various health hazards, yet its immediate effects on the liver are not well understood. This study provides direct real-world evidence that one episode of binge drinking (3 days) can acutely induce hepatic steatosis in healthy individuals, particularly those with subclinical metabolic dysfunction. Importantly, all consequences of binge drinking were normalised following 10 days of alcohol abstinence. These findings offer timely insight into the health risks of recreational binge drinking and contribute knowledge with potential implications for public health messaging and recommendations, clinical guidance, and alcohol policies.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101623"},"PeriodicalIF":7.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145594694","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":"Epidemiology, clinical, molecular features, and prognosis of early-onset biliary tract cancer: A systematic review and meta-analysis","authors":"Erman Akkus ,&nbsp;Antonella Cammarota ,&nbsp;Laura Izquierdo-Sanchez ,&nbsp;Jesus M. Banales ,&nbsp;Alejandro Forner ,&nbsp;Ana Lleo ,&nbsp;Rocio I.R. Macias ,&nbsp;Angela Lamarca ,&nbsp;Mohamed Bouattour","doi":"10.1016/j.jhepr.2025.101613","DOIUrl":"10.1016/j.jhepr.2025.101613","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Early-onset gastrointestinal cancers represent a growing global health concern. Among these, early-onset biliary tract cancer (EO-BTC) remains relatively understudied. In this systematic review, we synthesize current evidence for EO-BTC.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;A comprehensive systematic literature search was performed across multiple databases. Original studies investigating epidemiology, risk factors, clinical presentation, pathological and/or molecular features, treatment, and prognosis of EO-BTC were included and synthesized. Meta-analyses were performed using the Mantel–Haenszel and generic inverse variance methods with random-effects models.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;In total, 32 studies were included. EO-BTC incidence varied by anatomical subtype, with a notable increase in early-onset intrahepatic cholangiocarcinoma. Disparities in ethnicity and socioeconomic status were apparent between younger and older patients. Clinically, the disease was often diagnosed at a more advanced stage in younger patients (for stage IV, odds ratio [OR], 1.31; 95% CI, 1.19–1.43; &lt;em&gt;p&lt;/em&gt; &lt;0.001; &lt;em&gt;I&lt;/em&gt;&lt;sup&gt;&lt;em&gt;2&lt;/em&gt;&lt;/sup&gt;, 62%) and was associated with a higher prevalence of intrahepatic cholangiocarcinoma (OR, 1.41; 95% CI, 1.23–1.61; &lt;em&gt;p&lt;/em&gt; &lt;0.001; &lt;em&gt;I&lt;/em&gt;&lt;sup&gt;&lt;em&gt;2&lt;/em&gt;&lt;/sup&gt;, 49%). &lt;em&gt;FGFR2&lt;/em&gt; fusions were significantly more common in early-onset cases (OR, 2.81; 95% CI, 2.31–3.64; &lt;em&gt;p&lt;/em&gt; &lt;0.001; &lt;em&gt;I&lt;/em&gt;&lt;sup&gt;&lt;em&gt;2&lt;/em&gt;&lt;/sup&gt;, 0%). Younger patients had fewer comorbidities and more frequently received curative-intent local and systemic therapies (surgery: OR, 1.38; 95% CI, 1.22–1.57; &lt;em&gt;p&lt;/em&gt; &lt;0.001; &lt;em&gt;I&lt;/em&gt;&lt;sup&gt;&lt;em&gt;2&lt;/em&gt;&lt;/sup&gt;, 85%). Prognostic data were heterogeneous; however, pooled analysis suggested a trend to improved OS in patients with early-onset disease (unadjusted hazard ratio [HR], 0.84; 95% CI, 0.75–0.93; &lt;em&gt;p&lt;/em&gt; = 0.001; &lt;em&gt;I&lt;/em&gt;&lt;sup&gt;&lt;em&gt;2&lt;/em&gt;&lt;/sup&gt;, 81%); adjusted HR, 0.78; 95% CI, 0.66–0.94; &lt;em&gt;p&lt;/em&gt; = 0.007; &lt;em&gt;I&lt;/em&gt;&lt;sup&gt;&lt;em&gt;2&lt;/em&gt;&lt;/sup&gt;, 91%).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;EO-BTC represents a clinically and molecularly distinct subset within biliary tract cancers, with emerging epidemiological patterns, a higher prevalence of actionable molecular alterations, and differences in treatment allocation. Further prospective and age-stratified studies are needed to guide age-adapted detection and therapeutic strategies.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;PROSPERO ID&lt;/h3&gt;&lt;div&gt;CRD420251039039.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;This systematic review highlights that EO-BTC exhibits different epidemiological and molecular patterns compared with later-onset disease, including a higher prevalence of intrahepatic subtypes and greater frequency of targetable alterations, such as &lt;em&gt;FGFR2&lt;/em&gt; fusions. These findings underscore the importance of incorporating routine molecular profiling and the integration of stratified manag","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101613"},"PeriodicalIF":7.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682307","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":"Comparative effectiveness of antidiabetic therapies on hepatic decompensation in patients with type 2 diabetes: A target trial emulation","authors":"Jonggi Choi ,&nbsp;Ana Verma ,&nbsp;Vy H. Nguyen ,&nbsp;Eric Przybyszewski ,&nbsp;Jiunn Song ,&nbsp;Allison Carroll ,&nbsp;Megan Michta ,&nbsp;Erik Almazan ,&nbsp;Tracey G. Simon ,&nbsp;Raymond T. Chung","doi":"10.1016/j.jhepr.2025.101624","DOIUrl":"10.1016/j.jhepr.2025.101624","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;The comparative effectiveness of antidiabetic therapies on hepatic outcomes in patients with type 2 diabetes mellitus (T2DM) is not well established.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We conducted a retrospective new-user cohort study emulating a target trial using electronic health records from the Mass General Brigham health system (USA) between January 2012 and June 2024. Adults with T2DM who newly initiated sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP4is), or sulfonylureas were included. Propensity scores were estimated using prespecified clinical and high-dimensional covariates, and overlap weighting was applied to achieve covariate balance.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Among 38,524 eligible patients, 12,344 initiated GLP-1RAs, 5,233 SGLT2is, 3,717 DPP4is, and 17,230 sulfonylureas. Over a median follow-up of 3.1 years, 1,743 hepatic decompensation events occurred. In the intention-to-treat analysis, GLP-1RAs (hazard ratio [HR] 0.58, 95% CI 0.38–0.88) and SGLT2is (HR 0.65, 95% CI 0.43–0.98) were associated with significantly lower risk compared with sulfonylureas. Pairwise analyses also showed reduced risk with GLP-1RAs (HR 0.59, 95% CI 0.39–0.89) and SGLT2is (HR 0.66, 95% CI 0.43–1.00) compared with DPP4is, with no significant difference between GLP-1RAs and SGLT2is. In the per-protocol analysis (1,151 events), GLP-1RAs (HR 0.43, 95% CI 0.22–0.82) remained strongly protective, while SGLT2is showed a trend toward reduced risk (HR 0.61, 95% CI 0.33–1.12). Sensitivity analyses excluding early events or using alternative weighting approaches produced consistent results.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;In patients with T2DM, initiation of GLP-1RAs or SGLT2is was associated with substantially lower risk of hepatic decompensation compared with sulfonylureas and DPP4is. These findings support their preferential use in clinical practice.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;This study provides robust real-world evidence on the comparative effectiveness of four major antidiabetic drug classes in reducing hepatic decompensation among patients with type 2 diabetes mellitus. Our findings suggest that glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors are associated with substantially lower risk of hepatic decompensation compared with sulfonylureas and dipeptidyl peptidase-4 inhibitors, supporting their preferential use in patients with coexisting diabetes and liver disease risk. These results are particularly relevant for clinicians managing patients with type 2 diabetes who may have unrecognized metabolic dysfunction-associated steatotic liver disease or other chronic liver diseases. In practice, these findings can help guide therapeutic decision-making by integrating liver-related outcomes into antidiabetic drug selection. However, future pros","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101624"},"PeriodicalIF":7.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145569427","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 fibrosis is associated with clinical and economic burden of cardiovascular disease in MASH","authors":"Kathleen Corey ,&nbsp;Anurag Mehta ,&nbsp;Kamal Kant Mangla ,&nbsp;Abhishek Shankar Chandramouli ,&nbsp;Ahsan Shoeb ,&nbsp;Niels Krarup ,&nbsp;Margarida Augusto ,&nbsp;Katrine Grau ,&nbsp;Sharat Varma ,&nbsp;Elisabetta Bugianesi","doi":"10.1016/j.jhepr.2025.101621","DOIUrl":"10.1016/j.jhepr.2025.101621","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The clinical and economic burden of cardiovascular (CV) disease (CVD) in patients with metabolic dysfunction-associated steatohepatitis (MASH) is incompletely understood. The unCoVer–MASH cohort study aimed to assess the association of CVD-related burden with fibrosis (Fibrosis-4 index [FIB-4]) in patients with MASH in a real-world US database.</div></div><div><h3>Methods</h3><div>Adult patients with an ICD code for non-alcoholic steatohepatitis (NASH; October 2015–June 2022) were included if they had ≥1 FIB-4 measurement calculated from data obtained within 180 days before or 30 days after the NASH diagnosis (index date), ≥12 months of data prior to the index date (baseline period), and no diagnostic evidence of cirrhosis at baseline. FIB-4 categories were low (&lt;1.30), intermediate (1.30–2.67), and high (&gt;2.67). Risk of CV events was assessed during follow-up, and hazard ratios (HRs) were calculated using Cox proportional hazards models. CVD-related economic burden and resource utilization were also assessed.</div></div><div><h3>Results</h3><div>Of 715 patients included at baseline,102 had high, 201 had intermediate, and 412 had low FIB-4 scores. The risk of any CV event was significantly greater in the high (HR 3.44; 95% CI 2.22–5.34; <em>p</em> &lt;0.001) and intermediate (HR 1.53; 95% CI 1.02–2.31; <em>p</em> = 0.040) FIB-4 groups compared with the low group. The risk remained significant after adjustment for CV risk factors in patients with high <em>vs</em>. low FIB-4 (HR 2.026; 95% CI 1.215–3.380; <em>p</em> = 0.007). Additionally, CV-related healthcare resource utilization and CV-related costs increased with higher FIB-4 scores.</div></div><div><h3>Conclusions</h3><div>Patients with MASH and high baseline FIB-4 scores were at an increased risk of CV events and had higher CV-related healthcare costs and resource utilization.</div></div><div><h3>Impact and implications</h3><div>Studies specifically evaluating the clinical and economic burden of CVD in patients with MASH, without diagnostic evidence of cirrhosis, are lacking. In the current study, the clinical and economic burden of CVD in such patients was associated with baseline liver fibrosis severity, as assessed using baseline FIB-4 score, indicating a higher CV burden among patients with higher fibrosis severity. These results are important for both clinicians and payers, as they illustrate that tackling the CV-related burden in MASH is likely to have an appreciable impact on both clinical and economic outcomes.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101621"},"PeriodicalIF":7.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682306","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":"Transcriptome of monocytes from liver, brain and bone marrow reveals organ-specific features in aging and alcohol misuse","authors":"Martí Ortega-Ribera ,&nbsp;Radhika Joshi ,&nbsp;Sergi Guixé-Muntet ,&nbsp;Veronika Brezani ,&nbsp;Prashanth Thevkar Nagesh ,&nbsp;Viliam Brezani ,&nbsp;Arman Patel ,&nbsp;Yuan Zhuang ,&nbsp;Mrigya Babuta ,&nbsp;Jordi Gracia-Sancho ,&nbsp;Gyongyi Szabo","doi":"10.1016/j.jhepr.2025.101603","DOIUrl":"10.1016/j.jhepr.2025.101603","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Aging and alcohol misuse independently alter monocyte (MO) and macrophage (MØ) function, leading to impaired antimicrobial responses. However, how alcohol misuse contributes to impaired MO/MØ function during aging remains unclear.</div></div><div><h3>Methods</h3><div>We compared the transcriptomes of MOs and MØs from alcohol-modulated niches (liver, brain, and bone marrow [BM]) in young (3-month-old) and old (20–24-month-old) female C57BL/6N mice (n = 4–6 per group). Statistical significance was determined using two-way ANOVA.</div></div><div><h3>Results</h3><div>MO/MØ transcriptomes showed unique organ-specific responses to aging and alcohol. Aging elicited a common deregulation of pathogen-responsive pathways, while alcohol misuse commonly inhibited IFN signaling in the aged populations. Our studies on intercellular communication using ligand-receptor interactions revealed that BM MOs were the least communicative and liver MØs were the most communicative. Alcohol misuse specifically increased MO/MØ communication in aging. We also identified and validated specific pathways driving inter-organ MO/MØ crosstalk in alcohol misuse during aging, including APOE-TREM2 signaling from the liver to microglia and the NRXN2 and SPP1 pathways.</div></div><div><h3>Conclusion</h3><div>Our results provide a unique insight into the heterogeneity of the MO/MØ transcriptome and define the inter-organ crosstalk between BM, liver, and brain during aging and alcohol misuse.</div></div><div><h3>Impact and implications</h3><div>Aging and alcohol misuse are linked to immune dysfunction, systemic inflammation, and altered innate immune responses. Here, we examined monocyte/macrophage responses in the liver, brain, and bone marrow of young and aged mice under alcohol exposure at the transcriptomic level. We observed that aging and alcohol predominantly elicited organ-specific changes in gene expression, with minimal overlap between the monocyte/macrophage populations across different tissues. However, aging commonly upregulated pathogen response pathways while alcohol misuse inhibited interferon signaling. We also assessed cell-cell communication by analyzing ligand-receptor expression in the different monocyte/macrophage populations and identified candidate molecules (APOE, TREM2, NRXN2, SPP1) from the top pathways guiding inter-organ signaling specifically in aging and alcohol misuse. Our findings have generated a unique repository and provide novel insights on how aging and alcohol impact tissue-specific monocytes/macrophages and their crosstalk.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101603"},"PeriodicalIF":7.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145569491","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}