Liver International最新文献

{"title":"A Conserved FABP5high Macrophage Subset Promotes Fibrosis and Carcinogenesis in Advanced Liver Disease","authors":"Wenhao Ge,&nbsp;Lifeng Ma,&nbsp;Yu Huang,&nbsp;Weigao E,&nbsp;Shujing Lai,&nbsp;Bijun Cui,&nbsp;Jingjing Wang,&nbsp;Yutian Ji,&nbsp;Daiyuan Liu,&nbsp;Song Ye,&nbsp;Yang Kong,&nbsp;Jiarong Zhou,&nbsp;Chengxuan Yu,&nbsp;Yingsheng Wu,&nbsp;Qiang Sun,&nbsp;Dongkai Zhou,&nbsp;Wei Zhu,&nbsp;Yuan Ding,&nbsp;Xiaoping Han,&nbsp;Guoji Guo,&nbsp;Weilin Wang","doi":"10.1111/liv.70262","DOIUrl":"https://doi.org/10.1111/liv.70262","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>The relationship between chronic liver disease and liver cancer remains poorly understood, and treatment options for advanced liver disease remain limited. This study aims to elucidate the dynamic evolution of cellular and molecular alterations from normal liver to diseased liver.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Single-cell RNA sequencing was performed to profile the dynamic cellular variations from normal liver to diseased liver. Bioinformatics analyses were employed to assess tumour heterogeneity and the evolution of tumour microenvironment. Molecular biology validations were performed to investigate the findings.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Through single-cell RNA sequencing, we constructed a human liver landscape consisting of more than 130 000 single cells, from normal, cirrhotic tissue, primary liver cancer and paired adjacent tissues. We profiled both inter- and intra-tumour heterogeneity of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. A dual role of the pro-fibrosis and pro-carcinogenesis FABP5^high macrophage subset was shown to be conserved throughout the progression of liver fibrosis and carcinogenesis; markers, spatial localization, origin, and functional pathways associated with FABP5^high macrophages were identified through in vitro and in vivo validation. Metabolic reprogramming of these conserved FABP5^high macrophages is implicated in the formation of cirrhotic and cancerous niches. Additionally, we also identified a subset of RGCC+COL4A1+ endothelial cells enriched in HCC tissues, which might experience endothelial-mesenchymal transition and orchestrate the proliferation and invasion of cancer cells via angiogenesis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings provide insights into the evolution from chronic liver disease to liver cancer. These insights will contribute to the development of novel cell subset-based therapeutics based on immunotherapy and targeted therapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 9","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70262","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to Letter to the Editor: ‘Nanoplastics and MASLD: Unveiling Interorgan Crosstalk and Environmental Modulators’","authors":"Jinsol Han,&nbsp;Hayeong Jeong,&nbsp;Ahyeon Sung,&nbsp;Yung Hyun Choi,&nbsp;Youngmi Jung","doi":"10.1111/liv.70303","DOIUrl":"https://doi.org/10.1111/liv.70303","url":null,"abstract":"","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 9","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144905579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to Letter to the Editor: “Chronic Nanoplastic Exposure as a Novel Risk Amplifier for MASLD Progression”","authors":"Jinsol Han,&nbsp;Hayeong Jeong,&nbsp;Ahyeon Sung,&nbsp;Yung Hyun Choi,&nbsp;Youngmi Jung","doi":"10.1111/liv.70313","DOIUrl":"https://doi.org/10.1111/liv.70313","url":null,"abstract":"","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 9","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144905578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In-Reply to Letter From Yang Et al.","authors":"Nishi H. Patel,&nbsp;Annie Y. Chen,&nbsp;Carla Osiowy,&nbsp;Valerie Durkalski Mauldin,&nbsp;William M. Lee,&nbsp;Carla S. Coffin,&nbsp;Constantine J. Karvellas,&nbsp;the US Acute Liver Failure Study Group","doi":"10.1111/liv.70307","DOIUrl":"https://doi.org/10.1111/liv.70307","url":null,"abstract":"","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 9","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144897721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Magnesium Isoglycyrrhizinate Combined With Steroid Is Superior to Steroid Monotherapy in Checkpoint Inhibitor-Induced Liver Injury","authors":"Yang Zhi,&nbsp;Yinuo Dong,&nbsp;Xiaoyun Li,&nbsp;Wei Zhong,&nbsp;Xiaohong Lei,&nbsp;Mingyang Ma,&nbsp;Sha Huang,&nbsp;Minyan Ye,&nbsp;Zuxiong Huang,&nbsp;Liqing Zheng,&nbsp;Lanlan He,&nbsp;Qinghui Niu,&nbsp;Zhonghua Lu,&nbsp;Jinyuan Zhang,&nbsp;Ze Yu,&nbsp;Jieting Tang,&nbsp;Yimin Mao","doi":"10.1111/liv.70310","DOIUrl":"https://doi.org/10.1111/liv.70310","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Steroids are the standard treatment for checkpoint inhibitor-induced liver injury (ChILI). However, concerns about their adverse effects and impacts on long-term outcomes highlight the need for alternative therapies. This study aims to evaluate the effectiveness of magnesium isoglycyrrhizinate (MgIG) in combination with steroids in ChILI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A multicentre, retrospective, propensity score matched case–control study was conducted based on electronic medical records in patients with ChILI from December 2019 to December 2022 in five tertiary hospitals. Cases were categorised into combination therapy group and steroid monotherapy group.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 229 cases were included, with 114 in the combination therapy group and 115 in the steroid group. The reduction in ALT on day 10 was significantly greater in the combination group (−148 [−232 to −44] vs. −98 [−239 to 8], <i>p</i> = 0.01). Combination therapy was more likely to achieve ALT normalisation (OR 2.13, 95% CI 1.11–4.09, <i>p</i> = 0.023), and a greater proportion of patients with ≤ grade 1 liver injury (43.9% vs. 24.4%, <i>p</i> = 0.002) on day 10. Notably, MgIG reduced the steroid dose (<i>p</i> = 0.023) and the proportion of patients requiring high-dose steroids in patients with high-grade liver injury (1.1% vs. 9.0%, <i>p</i> = 0.017). Length of stay was shorter in the combination group (15 [10–24] vs. 17 [13–28], <i>p</i> = 0.020).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Combination of MgIG and steroid outperformed steroid monotherapy by accelerating recovery, reducing the dose of steroids, and shortening length of stay in patients with ChILI.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 9","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144897720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to Letter to ‘Serum CRP in Durvalumab–Tremelimumab-Treated HCC: Expanding the Inflammatory Narrative’","authors":"Takeshi Hatanaka,&nbsp;Yutaka Yata,&nbsp;Satoru Kakizaki,&nbsp;Takashi Kumada","doi":"10.1111/liv.70309","DOIUrl":"https://doi.org/10.1111/liv.70309","url":null,"abstract":"","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 9","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144897723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ultrasound for the Detection of Gallbladder Malignancy in Primary Sclerosing Cholangitis","authors":"Johannes Altenmüller,&nbsp;Christiane Wiegard,&nbsp;Marcial Sebode,&nbsp;Ansgar W. Lohse,&nbsp;Christina Villard,&nbsp;Stergios Kechagias,&nbsp;Emma Nilsson,&nbsp;Fredrik Rorsman,&nbsp;Hanns-Ulrich Marschall,&nbsp;Kalle Jokelainen,&nbsp;Annika Bergquist,&nbsp;Martti Färkkilä,&nbsp;Christoph Schramm","doi":"10.1111/liv.70312","DOIUrl":"https://doi.org/10.1111/liv.70312","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>In primary sclerosing cholangitis (PSC), the risk for gallbladder malignancy is increased. Surveillance imaging is used for early diagnosis. The study aims to assess the reliability of ultrasound and magnetic resonance imaging (MRI) for the detection of gallbladder polyps in people with PSC and to define a polyp size as a cut-off at which cholecystectomy is indicated due to the high probability of a malignant finding.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this retrospective European multicentre study, we included 51 people with PSC who had cholecystectomy for gallbladder polyps detected on imaging using ultrasound and/or MRI within 6 months prior to cholecystectomy and a histology report available. As a control group, we included 102 people with PSC with other indications for cholecystectomy. Malignancy was defined as high-grade dysplasia or carcinoma on histology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Including all 153 patients, ultrasound was significantly more sensitive than MRI in detecting gallbladder polyps (<i>p</i> &lt; 0.001). MRI missed 3 of the 8 malignant polyps. Malignant polyps (<i>n</i> = 8, median size = 12.5 mm) were significantly larger than non-malignant polyps (<i>n</i> = 26, median size = 6 mm) on ultrasound (<i>p</i> &lt; 0.001). Ultrasound detected malignant polyps reliably (AUC = 0.91, <i>p</i> &lt; 0.001) with an optimal cut-off of 8 mm. This cut-off was defined in the Hamburg cohort and validated in a multicentre validation cohort with an AUC of 0.92 (<i>p</i> = 0.02).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Ultrasound is more sensitive for the detection of gallbladder polyps than MRI in people with PSC. The best cut-off to differentiate between benign and malignant polyps was 8 mm. Ultrasound (gallbladder) and MRI (bile ducts) may thus be complementary methods for hepatobiliary malignancy surveillance in people with PSC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 9","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70312","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144897722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ivosidenib for IDH1-Mutant Intrahepatic Cholangiocarcinoma: Insights From a Multicenter Real-World Study","authors":"Monica Niger,&nbsp;Margherita Rimini,&nbsp;Florian Castet,&nbsp;Anna Melzer,&nbsp;Mario Domenico Rizzato,&nbsp;Tiziana Pressiani,&nbsp;Daniele Lavacchi,&nbsp;Giuseppe Aprile,&nbsp;Torsello Angela,&nbsp;Tiziana Saladino,&nbsp;Noventa Silvia,&nbsp;Pasqua Cito,&nbsp;Alessandro Pastorino,&nbsp;Eduardo Terán-Brage,&nbsp;Carolina Sciortino,&nbsp;Silvia Camera,&nbsp;Chiara Pircher,&nbsp;Mara Persano,&nbsp;Vincenzo Mazzaferro,&nbsp;Silvia Foti,&nbsp;Kreina Sharela Vega,&nbsp;Thomas J. Ettrich,&nbsp;Lorenzo Antonuzzo,&nbsp;Lorenza Rimassa,&nbsp;Sara Lonardi,&nbsp;Lukas Perkhofer,&nbsp;Teresa Macarulla,&nbsp;Filippo Pietrantonio,&nbsp;Andrea Casadei-Gardini","doi":"10.1111/liv.70295","DOIUrl":"https://doi.org/10.1111/liv.70295","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background &amp; Aims</h3>\u0000 \u0000 <p>Cholangiocarcinoma (CCA) is a rare cancer with limited therapeutic options and a poor prognosis. While first-line combination therapies have improved outcomes, second-line treatment remains challenging. Ivosidenib, an <i>IDH1</i> inhibitor, has shown promise in treating <i>IDH1</i> mutant CCA, but real-world data is limited. This study aims to evaluate ivosidenib's efficacy and safety in a large cohort of patients and compare it with second-line chemotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This observational, retrospective, multicenter study included patients with advanced <i>IDH1</i> mutant CCA treated with ivosidenib at 11 European institutions from May 2021 to September 2024. The primary endpoint was progression-free survival (PFS); the main secondary objectives were overall survival (OS), disease control rate (DCR), overall response rate (ORR) and safety. As a pre-planned exploratory objective, mPFS and OS of second-line ivosidenib and FOLFOX/CAPOX were compared by means of inverse probability of treatment weights (IPTW)-adjusted analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The study included 46 patients treated with Ivosidenib; 43.5% received ivosidenib as second line and 56.5% as ≥ third line. Median PFS and OS were 3.7 (95% CI, 2.2–36.5) and 11.5 months (95% CI, 9.5–36.5). DCR was 50.0%. Grade ≥ 3 adverse events occurred in 8.7% of patients. IPTW-adjusted mPFS was 6.9 months with ivosidenib and 2.1 months with FOLFOX/CAPOX (HR: 0.36, 95% CI, 0.20–0.64, <i>p</i> = 0.0005), while the mOS was 15.9 and 9.0 months with ivosidenib and FOLFOX/CAPOX, respectively (HR: 0.47, 95% CI, 0.23–0.96, <i>p</i> = 0.0405).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study suggests that ivosidenib is a valid option for patients affected by metastatic <i>IDH1</i> mutant CCA after at least one line of standard treatment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 9","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70295","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144897719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD44 in Group 1 Innate Lymphoid Cells Impacts the Development and Progression of Steatohepatitis","authors":"Manon Bourinet,&nbsp;Elodie Vieira,&nbsp;Déborah Rousseau,&nbsp;Stéphanie Bonnafous,&nbsp;Fréderic Soysouvanh,&nbsp;Axelle Strazzulla,&nbsp;Coline Elliot,&nbsp;Stéphanie Patouraux,&nbsp;Pierre S. Leclère,&nbsp;Iryna Moskalevska,&nbsp;Julien Cherfils-Vicini,&nbsp;Meri K. Tulic,&nbsp;Matthias Mack,&nbsp;Béatrice Bailly-Maitre,&nbsp;Véronique Orian-Rousseau,&nbsp;Antonio Iannelli,&nbsp;Arnauld Belmer,&nbsp;Albert Tran,&nbsp;Rodolphe Anty,&nbsp;Philippe Gual,&nbsp;Carmelo Luci","doi":"10.1111/liv.70299","DOIUrl":"https://doi.org/10.1111/liv.70299","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Innate lymphoid cells (ILCs) play pivotal roles in inflammation and fibrosis, which are key features of chronic liver diseases. The contribution of group 1 ILCs, including natural killer (NK) cells and helper-like ILC1s, to liver inflammation during steatohepatitis and metabolic dysfunction-associated steatotic liver diseases (MASLD) is still a matter of debate and requires further investigation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We engineered a mouse model of specific deficiency of CD44 in group 1 ILCs and challenged mice with diet-induced obesity and MASLD or diet-induced steatohepatitis. We performed in vitro studies and co-cultured LPS-stimulated liver NK cells with hepatocytes and macrophages to analyse the inflammatory response.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>As group 1 ILCs expressed the cell surface molecule CD44, its specific targeting was used to investigate if CD44 could affect the development of liver inflammation. Here, we found that CD44 deficiency in group 1 ILCs was sufficient to decrease the absolute number of hepatic NKp46⁺ ILCs, NK cells and ILC1s in chow diet and in response to diet induced-MASLD or steatohepatitis. CD44 deficiency in group 1 ILCs aggravated liver complications by exacerbating hepatic injury, inflammation, and fibrosis, which was also associated with inflammatory and osteopontin⁺ macrophages accumulation. The absence of CD44 in NK cells enhanced their inflammatory phenotypes in response to LPS, which in turn triggered release of pro-inflammatory mediators by hepatocytes and macrophages.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings reveal a novel role for CD44 in regulating the dynamics of group 1 ILCs, which in turn affects steatohepatitis and MASLD development.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 9","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70299","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144894420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Divergence Between MASLD and Metabolic Syndrome: Distinct Clinical Phenotypes and Risk Stratification Implications","authors":"Mariana M. Ramírez-Mejía,&nbsp;Sandra M. Barbalho,&nbsp;Guadalupe Ponciano-Rodríguez,&nbsp;Mohammed Eslam,&nbsp;Jacob George,&nbsp;Ming-Hua Zheng,&nbsp;Nahum Méndez-Sánchez","doi":"10.1111/liv.70305","DOIUrl":"https://doi.org/10.1111/liv.70305","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the leading cause of chronic liver disease worldwide. Metabolic syndrome (MetS) has traditionally been used as an indicator to define metabolic dysfunction, but it may not fully reflect the risk spectrum of MASLD, underscoring the need to better understand its clinical heterogeneity. The aim of this study was to explore phenotypic heterogeneity within MASLD, in particular its overlap and divergence from MetS to improve clinical stratification.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We applied an unsupervised clustering approach in a discovery cohort of 600 adults recruited through a local health screening programme, using standardised clinical and metabolic variables to identify distinct phenotypes. Associations between clustering, MASLD and MetS were assessed. External validation was performed on an independent cohort of 407 individuals using cluster centroids derived from the discovery cohort.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the two-cluster model, we identified a low-risk group with favourable profiles and a high-risk group enriched for MASLD and MetS. The three-cluster model further refined these patterns, revealing an intermediate group characterised by MASLD without MetS, with heterogeneous yet clinically relevant metabolic features. Cluster structures were preserved in the validation cohort. Cluster membership was significantly associated with steatosis and liver fibrosis parameters.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings underscore the phenotypic heterogeneity of MASLD and its partial divergence from MetS. As MetS may not fully capture the spectrum of metabolic dysfunction in MASLD, phenotype-based approaches grounded in clinical and metabolic data may enhance risk stratification and support more individualised management strategies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 9","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144894362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}