Non-invasive risk-based surveillance of hepatocellular carcinoma in patients with metabolic dysfunction-associated steatotic liver disease

Jimmy Che-To Lai^#^{1

2}, Boyu Yang^#¹, Hye Won Lee^#³, Huapeng Lin⁴, Emmanuel A Tsochatzis⁵, Salvatore Petta⁶, Elisabetta Bugianesi⁷, Masato Yoneda⁸, Ming-Hua Zheng⁹, Hannes Hagström^{10

11}, Jerome Boursier^{12

13}, Jose Luis Calleja¹⁴, George Boon-Bee Goh¹⁵, Wah-Kheong Chan¹⁶, Rocìo Gallego-Duràn¹⁷, Arun J Sanyal¹⁸, Victor de Lédinghen¹⁹, Philip Noel Newsome²⁰, Jian-Gao Fan²¹, Laurent Castera²², Michelle Lai²³, Céline Fournier-Poizat¹⁹, Grace Lai-Hung Wong^{1

2}, Grazia Pennisi⁶, Angelo Armandi⁷, Atsushi Nakajima⁸, Wen-Yue Liu²⁴, Ying Shang¹⁰, Marc de Saint-Loup¹², Elba Llop¹⁴, Kevin Kim Jun Teh¹⁵, Carmen Lara-Romero¹⁷, Amon Asgharpour¹⁸, Sara Mahgoub²⁵, Mandy Sau-Wai Chan¹⁹, Clemence M Canivet^{12

13}, Manuel Romero-Gómez¹⁷, Seung Up Kim²⁶, Vincent Wai-Sun Wong^{27

2}, Terry Cheuk-Fung Yip^{27

2}

Affiliations

¹ Medical Data Analytics Centre, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
² Li Ka Shing Institute of Helath Sciences and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
³ Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
⁴ Department of Gastroenterology and Hepatology, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
⁵ University College London Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK.
⁶ Sezione di Gastroenterologia, Di.Bi.M.I.S, University of Palermo, Palermo, Italy.
⁷ Department of Medical Sciences, Division of Gastroenterology and Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Torino, Italy.
⁸ Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
⁹ MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
¹⁰ Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
¹¹ Division of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
¹² Hepato-Gastroenterology and Digestive Oncology Department, Angers University Hospital, Angers, France.
¹³ HIFIH Laboratory, SFR ICAT 4208, Angers University, Angers, France.
¹⁴ Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
¹⁵ Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore.
¹⁶ Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
¹⁷ Digestive Diseases Unit and CIBERehd, Virgen del Rocío University Hospital, Seville, Spain.
¹⁸ Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
¹⁹ Echosens, Paris, France.
²⁰ Roger Williams Institute of Liver Studies, Faculty of Life Sciences and Medicine, King's College London, the Foundation of Liver Research, and King's College Hospital, London, UK.
²¹ Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, China.
²² Université Paris Cité, UMR1149 (CRI), INSERM, Paris, France; Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris (AP-HP), Clichy, France.
²³ Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
²⁴ Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
²⁵ National Institute for Health Research, Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, UK.
²⁶ Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea tcfyip@cuhk.edu.hk ksukorea@yuhs.ac wongv@cuhk.edu.hk.
²⁷ Medical Data Analytics Centre, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong tcfyip@cuhk.edu.hk ksukorea@yuhs.ac wongv@cuhk.edu.hk.

^# Contributed equally.

PMID: 40541300
DOI: 10.1136/gutjnl-2025-334981

Non-invasive risk-based surveillance of hepatocellular carcinoma in patients with metabolic dysfunction-associated steatotic liver disease

Jimmy Che-To Lai et al. Gut. 2025.

. 2025 Jul 17:gutjnl-2025-334981.

doi: 10.1136/gutjnl-2025-334981. Online ahead of print.

Authors

Affiliations

¹ Medical Data Analytics Centre, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
² Li Ka Shing Institute of Helath Sciences and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
³ Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
⁴ Department of Gastroenterology and Hepatology, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
⁵ University College London Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK.
⁶ Sezione di Gastroenterologia, Di.Bi.M.I.S, University of Palermo, Palermo, Italy.
⁷ Department of Medical Sciences, Division of Gastroenterology and Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Torino, Italy.
⁸ Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
⁹ MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
¹⁰ Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
¹¹ Division of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
¹² Hepato-Gastroenterology and Digestive Oncology Department, Angers University Hospital, Angers, France.
¹³ HIFIH Laboratory, SFR ICAT 4208, Angers University, Angers, France.
¹⁴ Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
¹⁵ Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore.
¹⁶ Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
¹⁷ Digestive Diseases Unit and CIBERehd, Virgen del Rocío University Hospital, Seville, Spain.
¹⁸ Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
¹⁹ Echosens, Paris, France.
²⁰ Roger Williams Institute of Liver Studies, Faculty of Life Sciences and Medicine, King's College London, the Foundation of Liver Research, and King's College Hospital, London, UK.
²¹ Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, China.
²² Université Paris Cité, UMR1149 (CRI), INSERM, Paris, France; Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris (AP-HP), Clichy, France.
²³ Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
²⁴ Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
²⁵ National Institute for Health Research, Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, UK.
²⁶ Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea tcfyip@cuhk.edu.hk ksukorea@yuhs.ac wongv@cuhk.edu.hk.
²⁷ Medical Data Analytics Centre, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong tcfyip@cuhk.edu.hk ksukorea@yuhs.ac wongv@cuhk.edu.hk.

^# Contributed equally.

PMID: 40541300
DOI: 10.1136/gutjnl-2025-334981

Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of the general population and is the fastest growing cause of hepatocellular carcinoma (HCC). Current guidelines recommend HCC surveillance in patients with cirrhosis when annual HCC incidence exceeds 1% without specifying the role of non-invasive tests in patient selection.

Objective: To define non-invasive test thresholds to select patients with MASLD for HCC surveillance.

Design: A multicentre longitudinal study of adults with MASLD from 16 tertiary centres in the USA, Europe and Asia between February 2004 and January 2023. Primary outcome was incident HCC.

Results: 12 950 patients had Fibrosis-4 index (FIB-4) and liver stiffness measurement (LSM) (mean age 51.7 years; 41.1% male). At a median follow-up of 47.7 (IQR 23.3-72.3) months, 109 (0.8%) developed HCC. FIB-4 was below the low cut-off (<1.3 if aged <65 years and <2.0 if aged ≥65 years), between the low cut-off and <2.67, 2.67 to <3.25, and ≥3.25 in 66.3%, 23.9%, 3.4% and 6.4% of patients; the corresponding annual HCC incidence was 0.07%, 0.17%, 0.77% and 1.18%. As a stand-alone test, the annual HCC incidence exceeded 0.2% for LSM ≥10 kPa and 1% for LSM ≥20 kPa. If LSM was performed as a second step only among patients with FIB-4 above the low cut-off, the annual HCC incidence exceeded 0.2% for LSM ≥10 kPa and 1% for LSM ≥15 kPa.

Conclusion: HCC surveillance should be offered to patients with MASLD with FIB-4 ≥3.25 or LSM ≥20 kPa. When a two-step approach is adopted, LSM ≥15 kPa in patients with increased FIB-4 predicts a high HCC risk.

Keywords: FATTY LIVER; HEPATOCELLULAR CARCINOMA; SURVEILLANCE.

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Conflict of interest statement

Competing interests: JCTL served as a speaker for Gilead Sciences and Abbott and an advisory board committee for Gilead Sciences and Boehringer Ingelheim. EAT served as a consultant for Pfizer, Novo Nordisk, Boehringer and Siemens Healthineers and a speaker for Novo Nordisk, Echosens and Dr Falk. SP served as a speaker or advisor for AbbVie, Echosens, MSD, Novo Nordisk, Pfizer and Resalis. EB served as a consultant for Boehringer, MSD, Novo Nordisk and Pfizer and a speaker for MSD, Novo Nordisk and Madrigal. She received research grants from Gilead Sciences. MY received research grant from Gilead Sciences and served as a speaker for KOWA. AN received research grants from Mochida Pharmaceutical, Astellas Pharma, ASKA Pharmaceutical, Biofermin Pharmaceutical and EA Pharma and served as a speaker for Mochida Pharmaceutical, KOWA, Biofermin Pharmaceutical, MSD, Boehringer, Novo Nordisk, GlaxoSmithKline and EA Pharma. HH served as a consultant for AstraZeneca and a hepatic events adjudication committee member for KOWA and GW Pharma. His institution has received research funding from AstraZeneca, Echosens, Gilead Sciences, Intercept, MSD and Pfizer. JB served as a consultant for AstraZeneca, Echosens, Intercept and Siemens, a speaker for AbbVie, Gilead Sciences, Intercept and Siemens and an advisory board member for Bristol Myers Squibb, Intercept, Pfizer, MSD and Novo Nordisk. His institution has received research funding from Diafir, Echosens, Intercept, Inventiva and Siemens. JLC served as a consultant and speaker for Echosens, Gilead Sciences and AbbVie. BBGG served as a consultant for Roche and Ionis Pharmaceuticals and a speaker for Echosens, Viatris, Abbott and Novo Nordisk. W-KC served as a consultant for Abbott, Roche, AbbVie, Novo Nordisk and Boehringer Ingelheim and a speaker for Abbott, Novo Nordisk, Echosens, Hisky Medical and Viatris. AJS served as a consultant for 89Bio, Akero, Allergan, Alnylam Pharmaceuticals, Amgen Inc, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Gilead Sciences, Histoindex, Intercept Pharmaceuticals, Inventiva, Madrigal, Merck, Novartis, Novo Nordisk, Pfizer, Poxel, Salix Pharmaceuticals, Siemens, Sun Pharmaceutical Industries Inc, Terns and Valeant Pharmaceuticals and a data safety monitoring board or advisory board member for Bard Peripheral Vascular Inc, NGM Biopharmaceuticals and Sequana. He has received research funding from Albireo, Allergan, Echosens, Eli Lilly, Gilead Sciences, Intercept Pharmaceuticals, Mallinckrodt LLC, Merck, Novo Nordisk, Perspectum, Pfizer, Salix Pharmaceuticals and Zydus and holds the stocks of Durect, Exhalenz, Genfit and Tiziana. MR-G served as a consultant for Siemens and a speaker for Siemens and Echosens. He has received research funding from Siemens, Echosens and Novo Nordisk. PNN served as a consultant for Novo Nordisk, Boehringer Ingelheim, Gilead Sciences, Intercept, Poxel Pharmaceuticals, Pfizer, BMS, Eli Lilly, Madrigal and GSK and a speaker for Novo Nordisk and AiCME. He has received research funding from Novo Nordisk. LC served as a consultant for Boston Pharmaceutical, Echosens, Gilead, GSK, Madrigal, MSD, Novo Nordisk, Pfizer, Sagimet and Siemens Healthineers and a speaker for Echosens, Gilead, Inventiva, Madrigal and Novo Nordisk. CF is an employee of Echosens. GL-HW served as a consultant for AstraZeneca, Gilead Sciences, GlaxoSmithKline and Janssen and a speaker for Abbott, AbbVie, Bristol Myers Squibb, Echosens, Furui, Gilead Sciences, GlaxoSmithKline and Roche. She has received research funding from Gilead Sciences. MS-WC is an employee of Echosens. VW-SW served as a consultant or advisory board member for AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet Biosciences, TARGET PharmaSolutions and Visirna and a speaker for Abbott, AbbVie, Gilead Sciences, Novo Nordisk and Unilab. He has received a research grant from Gilead Sciences and is a co-founder of Illuminatio Medical Technology. TC-FY has served as an advisory committee member and a speaker for Gilead Sciences.

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Non-invasive risk-based surveillance of hepatocellular carcinoma in patients with metabolic dysfunction-associated steatotic liver disease

Affiliations

Non-invasive risk-based surveillance of hepatocellular carcinoma in patients with metabolic dysfunction-associated steatotic liver disease

Authors

Affiliations

Abstract

Conflict of interest statement

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