Yu Shi, Ruoqi Zhou, Seung Up Kim, Terry Cheuk-Fung Yip, Salvatore Petta, Elisabetta Bugianesi, Masato Yoneda, Manuel Romero-Gomez, Emmanuel Tsochatzis, Philip Newsome, Hannes Hagström, George Boon-Bee Goh, Wah-Kheong Chan, José-Luis Calleja, Jerome Boursier, Arun J. Sanyal, Jian-Gao Fan, Laurent Castera, Victor de Ledinghen, Michelle Lai, Xiao-Dong Zhou, Vincent Wai-Sun Wong, Ming-Hua Zheng, On behalf of VCTE-Prognosis Study Group
Received March 4, 2026 Accepted May 10, 2026 Published online May 20, 2026
Background & Aims Liver stiffness measurement (LSM) is a key tool for risk stratification in MASLD, yet static thresholds fail to capture dynamic transition across risk strata. We aimed to characterize LSM-risk transitions and develop a time-updated, individualized model for predicting state transitions, liver-related events and death (LREs/death).
Method In a real-world MASLD cohort, we applied a multi-state, time-homogeneous Markov model to quantify annual transition probabilities and mean state occupancy times across LSM-defined low-, intermediate-, and high-risk strata. A Markov model incorporating age, sex, type 2 diabetes (T2D), hypertension was used to generate individualized, time-updated risk trajectories and probabilities of LREs/death.
Results Among 11,514 MASLD individuals with ≥2 VCTE assessments, the low-risk category demonstrated notable stability, with 92% remaining unchanged at 1 year and a mean occupancy time of 8.43 years (95%CI:7.94-8.95). Contrarily the intermediate-risk category was highly dynamic, with only 39% remaining unchanged after 1 year and a mean occupancy time of 0.92 years (95%CI:0.88-0.96). T2D, hypertension, obesity substantially shorten low-risk occupancy time, whereas antidiabetic medication was associated with more favorable transitions. Finally, we developed a dynamic, multi-state Markov model (DYNAMO) integrating longitudinal LSM-defined risk states with relevant covariates to generate individualized predictions of state transitions and risks of LREs/death.
Conclusions LSM-based strata in MASLD represent distinct and meaningful dynamic trajectory. In particular, the marked instability of the intermediate-risk state supports more frequent reassessment. By quantifying transition pathways, and time-updated risks of LREs/death, this model may inform the personalized surveillance intervals and risk-adapted management.
Background and aims Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B mutations. In this study, a novel gene therapy for WD was developed, and its efficacy and safety were evaluated in relevant animal models.
Methods Codon-optimized full-length or truncated ATP7B (tATP7B) genes were assembled with liver-specific mini promoters to construct an adeno-associated virus serotype 8 vector (AAV8). The expression and activity of these vectors were evaluated in HepG2 cells. AAV8-tATP7B viral particles were produced using a triple-plasmid cotransfection system under good manufacturing practice conditions. Long-term efficacy was evaluated in Atp7b-/- mice at three doses (5×10¹¹, 5×10¹², and 1×10¹³ vg/kg). Single-dose toxicity was assessed over 13 weeks in Sprague-Dawley rats and cynomolgus macaques.
Results In HepG2 cells, the ability of the truncated ATP7B to export copper was comparable to that of the full-length protein, but the expression efficiency was greater. Alkaline gel electrophoresis confirmed its better compatibility with AAV packaging limits while maintaining genomic integrity, supporting its selection for AAV8-tATP7B production. In a 24-week study in Atp7b-/- mice, AAV8-tATP7B restored copper homeostasis and liver function in a dose-dependent manner and significantly reversed existing liver injury. Toxicity studies in Sprague‒Dawley rats and cynomolgus monkeys revealed no systemic toxicity, whereas reversible liver changes were observed in cynomolgus monkeys at high doses; thus, 6×10¹³ vg/kg was established as the maximum tolerated dose.
Conclusions These results establish the efficacy and safety profile of AAV8-tATP7B and provide the rationale for its clinical translation in patients with WD.
Joseph Rabbat, Boyu Yang, Hye Won Lee, Huapeng Lin, Emmanuel Tsochatzis, Salvatore Petta, Elisabetta Bugianesi, Masato Yoneda, Ming-Hua Zheng, Hannes Hagström, Jérôme Boursier, José Luis Calleja, George Boon-Bee Goh, Wah-Kheong Chan, Rocio Gallego-Durán, Arun J. Sanyal, Victor de Lédinghen, Philip N Newsome, Jian-Gao Fan, Laurent Castéra, Michelle Lai, Céline Fournier-Poizat, Grace Lai-Hung Wong, Mirko Zoncape, Grazia Pennisi, Angelo Armandi, Atsushi Nakajima, Wen-Yue Liu, Ying Shang, Marc de Saint-Loup, Elba Llop, Kevin Kim Jun Teh, Carmen Lara-Romero, Amon Asgharpour, Sara Mahgoub, Mandy Sau-Wai Chan, Clemence M Canivet, Manuel Romero-Gomez, Vincent Wai-Sun Wong, Seung Up Kim, Terry Cheuk-Fung Yip
Clin Mol Hepatol 2026;32(1):289-304. Published online November 11, 2025
Background/Aims Current guidelines recommend a 2-step approach for identifying advanced fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD), using Fibrosis-4 index (FIB-4) followed by liver stiffness measurement (LSM) via vibration-controlled transient elastography (VCTE). However, some patients may exhibit discordant results. This study evaluates the histological severity and outcomes in patients with discordant FIB-4 and LSM results.
Methods This secondary analysis of the VCTE-Prognosis study included 12,950 patients evaluated for MASLD at 16 tertiary centers, of whom 2,915 underwent liver biopsy. Patients were categorized into four groups based on established FIB-4 (1.3) and LSM (8 kPa) cutoffs.
Results F3–F4 fibrosis was observed in 6.4%, 13.7%, 30.6%, and 62.4% in low-FIB-4-low-LSM (n=6,403), high-FIB-4-low-LSM (n=3,017), low-FIB-4-high-LSM (n=1,363), and high-FIB-4-high-LSM (n=2,167) groups, respectively. During a median follow-up of 47.4 months, 248 patients experienced hepatic decompensation, hepatocellular carcinoma, liver transplantation, or liver-related death. The incidence rates of liver-related events (LREs) were 0.67, 1.19, 2.58, and 21.30 per 1,000 person-years, respectively. Compared to low-FIB-4-low-LSM patients, those with low-FIB-4-high-LSM (adjusted subdistribution hazard ratio [aSHR] 4.12) and high-FIB-4-high-LSM (aSHR 21.38) had a significantly higher risk of LREs, while high-FIB-4-low-LSM patients did not. Similar findings were observed when hepatic decompensation and hepatocellular carcinoma were analyzed separately.
Conclusions Approximately 30% of patients in tertiary centers exhibit discordant FIB-4 and LSM results, with LSM more likely reflecting true severity. While some patients with discordant results may have advanced fibrosis, the overall incidence of LREs remains low.
Citations
Citations to this article as recorded by
Are FIB-4 and liver stiffness measurement interchangeable for HCC risk stratification in MASLD? Yimeng Zhou, Xue Meng JHEP Reports.2026; : 101852. CrossRef
High Prevalence of Metabolic Dysfunction–Associated Steatohepatitis With Significant Fibrosis in Primary Care and Endocrinology Clinics Srilaxmi Kalavalapalli, Eddison Godinez Leiva, Andrea Ortiz Rocha, Anu Sharma, Diana Barb, Nathaly Cuervo‐Pardo, Kelly Y. Chun, Toni R. Prezant, Margery A. Connelly, Jens T. Rosenberg, Joseph R. Grajo, Fernando Bril, Kenneth Cusi Diabetes, Obesity and Metabolism.2026; 28(7): 6184. CrossRef
The Evolution of MASLD Management: From Revised Nomenclature to Disease-Modifying Therapies Karolina Kornatowska, Szymon Kopciał, Mateusz Wiekiera, Adrianna Wiekiera, Paweł Budzik, Mateusz Tyniec, Kamal Morshed Gastroenterology Insights.2026; 17(2): 33. CrossRef
Metabolic dysfunction–associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, has become the most common form of chronic liver disease in children. The spectrum of pediatric MASLD ranges from simple steatosis to steatohepatitis, fibrosis, cirrhosis, and in rare cases, hepatocellular carcinoma. Its pathogenesis involves a complex interplay among genetic, epigenetic, and environmental factors, along with alterations in the gut microbiota and its associated metabolites. Given the staggering prevalence and the distinct etiopathogenesis of pediatric MASLD, characterization of the gut microbiota and microbial products could facilitate the development of diagnostic tools and inform targeted therapeutic strategies. Current research on the gut microbiome in the context of pediatric MASLD is limited by small sample size, inadequate use of liver biopsy, methodological inconsistencies in sequencing, and confounding effects from metabolic comorbidities. In this review, we summarize clinical studies on alterations in the gut microbiota and microbial products (short-chain fatty acids, bile acids, and ethanol) that impact the pathogenesis of pediatric MASLD. We discuss the therapeutic potential of dietary modification, pharmacological treatments, and probiotics in improving disease progression by summarizing current clinical studies. Enhancing our understanding of the gut-liver axis may aid in the development of effective therapeutic strategies for pediatric MASLD.
Citations
Citations to this article as recorded by
Obesity, Metabolic Syndrome and MASLD in Children: Inflammation as the Missing Link—A Short Narrative Review Mihaela-Andreea Podeanu, Claudiu Marinel Ionele, Raluca Elena Sandu, Ion Rogoveanu, Mioara Desdemona Stepan, Carmen Elena Niculescu, Sergiu-Marian Cazacu, Ștefănița Bianca Vintilescu Life.2026; 16(2): 310. CrossRef
Artificial intelligence for metabolic dysfunction-associated steatotic liver disease diagnosis: A systematic review Ruijuan Wang, Chang Liu, Mei Xue, Jun Qian, Yue Hu Computers in Biology and Medicine.2026; 208: 111619. CrossRef
Comparison of the identification and practicability of non-invasive diagnostic indicators under NAFLD, MAFLD and MASLD in China: a cross-sectional study Xin-Yun Tan, Hui-Hui Zou, Xinjuan Huang, Man-Jie Guo, Ruo-Ling Yu, Xue-Lian Liu, Ting Peng, Xuan Yang, Chun-Xiang Qin BMJ Open.2026; 16(4): e094809. CrossRef
Correspondence to editorial on “Bariatric surgery reduces long-term mortality in patients with metabolic dysfunction-associated steatotic liver disease and cirrhosis” Nicholas A. Rouillard, Linda Henry, Mindie H. Nguyen Clinical and Molecular Hepatology.2025; 31(2): e173. CrossRef
Reply to correspondence on “Bariatric surgery reduces long-term mortality in patients with metabolic dysfunction-associated steatotic liver disease and cirrhosis” Jing Zeng, Jian-Gao Fan Clinical and Molecular Hepatology.2025; 31(2): e218. CrossRef
Engineered nutrient-stimulated hormonal multi-agonists for precision targeting of obesity and metabolic disorders Yun Kyung Cho, Chang Hee Jung Clinical and Molecular Hepatology.2026; 32(2): 464. CrossRef
Effects of Zaozhu Yinchen Decoction on a Rat Model of Nonalcoholic Steatohepatitis via Regulation of Myeloid-Derived Suppressor Cells Wenyang Zhang, Yujie Wang, Yaoyu Liu, Xiaoting Zheng, Tianxiang Wang, Xinyi Kwan, Ruobing Liu, Qi Liu, Hongli Zhuang, Huiqing Liang, Shaodong Chen Hepatic Medicine: Evidence and Research.2026; Volume 18: 1. CrossRef
AMPK Activation and Lipid Homeostasis Regulation in MASLD: Investigating the Hepatoprotective and Anti‐Inflammatory Effects of Meta‐Capridin Medium‐Chain Triglycerides Alireza Doagoo, Sajad Ehtiati, Reza Ataei kachouei, Seyyed Hossein Khatami, Shima Rajaei, Maral Jalilzadeh, Nastaran Hamed, Fatemeh Namvarjah, Reyhane Ahmadzade, Marjan Ajami, Farzaneh Salmani, Somayeh Mahmoodi Baram, Mitra Rezaei, Majid Sirati-Sabet, Hoj Journal of Food Biochemistry.2025;[Epub] CrossRef
Evaluating causal protective effect of dual GLP-1R/GIPR agonists on MASLD: A Mendelian randomization and colocalization study Yangke Cai, Siyuan Xie, Liyi Xu, Jiamin Chen, Jianting Cai European Journal of Pharmacology.2025; 1005: 178088. CrossRef
Reply to correspondence on “Comparison of glucagon-like peptide-1 receptor agonists and thiazolidinediones on treating nonalcoholic fatty liver disease: a network meta-analysis” Tian-Yi Ren, Mohammed Eslam, Jian-Gao Fan Clinical and Molecular Hepatology.2024; 30(4): 1039. CrossRef
Correspondence to editorial on “Comparison of glucagon-like peptide-1 receptor agonists and thiazolidinediones on treating nonalcoholic fatty liver disease: a network meta-analysis” Hayeon Kim, Min Jeong Park, Myeong Gyu Kim, Kyungim Kim Clinical and Molecular Hepatology.2024; 30(4): 989. CrossRef
Nonalcoholic steatohepatitis (NASH) is an aggressive form of nonalcoholic fatty liver disease (NAFLD) characterized by steatosis-associated inflammation and liver injury. Without effective treatment or management, NASH can have life-threatening outcomes. Evaluation and identification of NASH patients at risk for adverse outcomes are therefore important. Key issues in screening NASH patients are the assessment of advanced fibrosis, differentiation of NASH from simple steatosis, and monitoring of dynamic changes during follow-up and treatment. Currently, NASH staging and evaluation of the effectiveness for drugs still rely on pathological diagnosis, despite sample error issues and the subjectivity associated with liver biopsy. Optimizing the pathological assessment of liver biopsy samples and developing noninvasive surrogate methods for accessible, accurate, and safe evaluation are therefore critical. Although noninvasive methods including elastography, serum soluble biomarkers, and combined models have been implemented in the last decade, noninvasive diagnostic measurements are not widely applied in clinical practice. More work remains to be done in establishing cost-effective strategies both for screening for at-risk NASH patients and identifying changes in disease severity. In this review, we summarize the current state of noninvasive methods for detecting steatosis, steatohepatitis, and fibrosis in patients with NASH, and discuss noninvasive assessments for screening at-risk patients with a focus on the characteristics that should be monitored at follow-up.
Citations
Citations to this article as recorded by
Efficacy of Orlistat on Cardiometabolic Indices in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A GRADE-Assessed Systematic Review and Meta-Analysis of RCTs Mehdi Karimi, Seyed Morteza Ali Pourfaraji, Peyvand Parhizkar Roudsari, Samira Pirzad Current Therapeutic Research.2026; 104: 100822. CrossRef
MAP17 is a Novel NASH Progression Biomarker Associated with Macrophage Infiltration, Immunotherapy Response, and Oxidative Stress Zhiwei Huang, Jiatong Chen, Shenglu Liu, Xin Xiang, Yang Long, Peng Tan, Wenguang Fu Journal of Inflammation Research.2025; Volume 18: 601. CrossRef
A Novel Point-of-Care Prediction Model for Steatotic Liver Disease: Expected Role of Mass Screening in the Global Obesity Crisis Jeayeon Park, Goh Eun Chung, Yoosoo Chang, So Eun Kim, Won Sohn, Seungho Ryu, Yunmi Ko, Youngsu Park, Moon Haeng Hur, Yun Bin Lee, Eun Ju Cho, Jeong-Hoon Lee, Su Jong Yu, Jung-Hwan Yoon, Yoon Jun Kim Gut and Liver.2025; 19(1): 126. CrossRef
Innovative nanomedicine approaches for the management of nonalcoholic fatty liver disease Limeng Li, Weiqi Gao, Fengyang Yao, Jiayi Li, Wei Sang, Ruiping Zhang Journal of Controlled Release.2025; 382: 113680. CrossRef
Multiparametric Quantitative Ultrasound as a Potential Imaging Biomarker for Noninvasive Detection of Nonalcoholic Steatohepatitis: A Clinical Feasibility Study Trina Chattopadhyay, Hsien-Jung Chan, Duy Chi Le, Chiao-Yin Wang, Dar-In Tai, Zhuhuang Zhou, Po-Hsiang Tsui Diagnostics.2025; 15(17): 2214. CrossRef
Agile 3+ and Metabolic Dysfunction-Associated Fatty Liver Disease:
Detecting Advanced Fibrosis based on Reported Liver Stiffness
Measurement in FibroScan and Laboratory Findings Mohammadjavad Sotoudeheian The International Journal of Gastroenterology and Hepatology Diseases.2024;[Epub] CrossRef
Does metabolic dysfunction-associated steatotic liver disease affect the ocular circulation? Nihat Aydın, Mustafa Capraz, Burcu Akman, Seyma Nur Altınok, Melek Tufek, Caner Kara Photodiagnosis and Photodynamic Therapy.2026; 57: 105334. CrossRef
Association of atherogenic index of plasma and cardiometabolic index with all-cause mortality and cardiovascular disease in NAFLD patients: NHANES 1999–2018 Chaojie Yu, Chen Qiu, Qian Zhang, Wenrui Wang, Siqi Liu, Zhenjing Jin Cardiovascular Diabetology.2026;[Epub] CrossRef
Association between nonalcoholic fatty liver disease and stroke: a cross-sectional study Shuai Zhou, Ge Mang, Hu Zhou, Shuoqi Zhang, Adam A. Dmytriw, Baocheng Gao, Shengquan Huang, Shuaifeng Yang, Lide Jin, Yongfa Zhang, Jiaqi Jin, Tianhua Li International Journal of Surgery.2026; 112(5): 11170. CrossRef
No association between steatotic liver disease and atherosclerosis among Brazilian
travestis
and transgender women: a cross-sectional study
Rodrigo de Carvalho Moreira, Emilia Moreira Jalil, Hugo Perazzo, Marcelo Cunha, Eduarda Grinsztejn, Isabele Moura, Mônica Derrico, Laylla Monteiro, Biancka Fernandes do Nascimento, Ronaldo Ismério Moreira, Valdiléa Gonçalves Veloso, Beatriz Grinsztejn, Sa International Journal of Transgender Health.2026; : 1. CrossRef
Correspondence on Editorial regarding “Screening and prediction of nonalcoholic fatty liver disease using a peripheral insulin resistance index: Potential benefits and limitations” Jun-Hyuk Lee, Kyongmin Park, Hye Sun Lee, Hoon-Ki Park, Jee Hye Han, Sang Bong Ahn Clinical and Molecular Hepatology.2023; 29(1): 185. CrossRef
Impact of metabolic risk factors on hepatic and cardiac outcomes in patients with alcohol- and non-alcohol-related fatty liver disease Jihye Lim, Hyunji Sang, Ha Il Kim JHEP Reports.2023; 5(6): 100721. CrossRef
Organ cross-talk: molecular mechanisms, biological functions, and therapeutic interventions for diseases Huiting Che, Yidan Gao, Yonghu Xu, Hui Xu, Roland Eils, Mei Tian Signal Transduction and Targeted Therapy.2026;[Epub] CrossRef
Probiotics as emerging adjuncts in metabolic associated fatty liver disease therapy-a systemic review Radha Samyuktha Reddy Narem, Vani Mathakala, Sri Tejaswi Sallabathula, Vijaya Lakshmi Peddiboyina, Uma Maheswari devi Palempalli BMC Gastroenterology.2026;[Epub] CrossRef
Lactobacillus plantarum 1-2-3 inhibits ferroptosis by regulating dysregulated fatty acid metabolism to protect mice from high-fat diet-induced MAFLD Meihua Zhang, Shuo Zhang, Huixian Wu, Laizhi Xu, Peichao Gao, Yixin Gao, Wentao Fan, Suquan Song Free Radical Biology and Medicine.2025; 238: 137. CrossRef
Probiotics as a therapeutic strategy for metabolic dysfunction-associated steatotic liver disease: A systematic review and meta-analysis Jing Lu, Xiaoxiao Dong, Ziqi Gao, Huizhen Yan, Dilireba Shataer, Liang Wang, Yanan Qin, Minwei Zhang, Jiayi Wang, Jie Cui, Shengyang Zhou Current Research in Food Science.2025; 11: 101138. CrossRef
Metabolic dysfunction-associated steatotic liver disease (MASLD): emerging insights into gut microbiota interactions and therapeutic perspectives Wenchu Qian, Ling He, Chenxue Fu, Tiantian Zeng, Hanyu Wang, Haifang Li Exploration of Digestive Diseases.2025;[Epub] CrossRef
Gut microbial signatures associated with the Indian lean MASLD phenotype Priyankar Dey Frontiers in Nutrition.2025;[Epub] CrossRef
The effects of next generation probiotics on metabolic dysfunction-associated steatotic liver disease: a parallel, double-blind, randomized, placebo-controlled trial Sung-Min Won, Hyunchae Joung, In Gyu Park, Sang Hak Han, Young Lim Ham, Ji Sook Han, Yoojin Kwon, Dong Joon Kim, Ki Tae Suk Journal of Translational Medicine.2025;[Epub] CrossRef
Supplementation of Lactobacillus plantarum ATCC14917 mitigates non-alcoholic fatty liver disease in high-fat-diet-fed rats Xingjian Wen, Hejing Liu, Xiaoling Luo, Li Lui, Jiuyu Fan, Yajing Xing, Jia Wang, Xingfang Qiao, Na Li, Guixue Wang Frontiers in Microbiology.2023;[Epub] CrossRef
First
Prev
