Yip, Terry Cheuk-FungLee, Hye WonLin, HuapengTsochatzis, EmmanuelPetta, SalvatoreBugianesi, ElisabettaYoneda, MasatoZheng, Ming-HuaHagström, HannesBoursier, JérômeCalleja, José LuisGoh, George Boon-BeeChan, Wah-KheongGallego-Durán, RocioSanyal, Arun Jde Lédinghen, VictorNewsome, Philip NFan, Jian-GaoCastéra, LaurentLai, MichelleFournier-Poizat, CélineWong, Grace Lai-HungPennisi, GraziaArmandi, AngeloNakajima, AtsushiLiu, Wen-YueShang, Yingde Saint-Loup, MarcLlop, ElbaTeh, Kevin Kim JunLara-Romero, CarmenAsgharpour, AmonMahgoub, SaraChan, Mandy Sau-WaiCanivet, Clemence MRomero-Gomez, ManuelKim, Seung UpWong, Vincent Wai-Sun2025-07-312025-07-312025-01-23Yip TC, Lee HW, Lin H, Tsochatzis E, Petta S, Bugianesi E, Yoneda M, Zheng MH, Hagström H, Boursier J, Calleja JL, Goh GB, Chan WK, Gallego-Durán R, Sanyal AJ, de Lédinghen V, Newsome PN, Fan JG, Castéra L, Lai M, Fournier-Poizat C, Wong GL, Pennisi G, Armandi A, Nakajima A, Liu WY, Shang Y, de Saint-Loup M, Llop E, Teh KKJ, Lara-Romero C, Asgharpour A, Mahgoub S, Chan MS, Canivet CM, Romero-Gomez M, Kim SU, Wong VW. Prognostic performance of the two-step clinical care pathway in metabolic dysfunction-associated steatotic liver disease. J Hepatol. 2025 Aug;83(2):304-314. doi: 10.1016/j.jhep.2025.01.014.1600-064110.1016/j.jhep.2025.01.01439863175S0168-8278(25)00021-239863175https://westmid.openrepository.com/handle/20.500.14200/8116Background & aims: Current guidelines recommend a two-step approach for risk stratification in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) involving Fibrosis-4 index (FIB-4) followed by liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) or similar second-line tests. This study aimed to examine the prognostic performance of this approach. Methods: The VCTE-Prognosis study was a longitudinal study of patients with MASLD who had undergone VCTE examinations at 16 centres from the US, Europe and Asia with subsequent follow-up for clinical events. The primary endpoint was incident liver-related events (LREs), defined as hepatic decompensation and/or hepatocellular carcinoma. Results: Of 12,950 patients (mean age 52 years, 41% female, 12.1% LSM >12 kPa), baseline FIB-4, at cut-offs of 1.3 (or 2.0 for age ≥65) and 2.67, classified 66.3% as low-risk and 9.8% as high-risk, leaving 23.9% in the intermediate-risk zone. After classifying intermediate FIB-4 patients as low-risk if LSM was <8.0 kPa and high-risk if LSM was >12.0 kPa, 81.5%, 4.6%, and 13.9% of the full cohort were classified as low-, intermediate-, and high-risk, respectively. At a median (IQR) follow-up of 47 (23-72) months, 248 (1.9%) patients developed LREs. The 5-year cumulative incidence of LREs was 0.5%, 1.0% and 10.8% in the low-, intermediate- and high-risk groups, respectively. Replacing LSM with Agile 3+, Agile 4, and FAST did not reduce the intermediate-risk zone or improve event prediction. Classifying intermediate FIB-4 patients by LSM <10 kPa (low-risk) and >15 kPa (high-risk) reduced the intermediate-risk zone while maintaining predictive performance. Conclusions: The non-invasive two-step approach of FIB-4 followed by LSM is effective in classifying patients at different risks of LREs. Impact and implications: Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as one of the leading causes of cirrhosis and hepatocellular carcinoma worldwide, but only a minority of patients will develop these complications. Therefore, it is necessary to use non-invasive tests instead of liver biopsy for risk stratification. Additionally, as most patients with MASLD are seen in primary care instead of specialist settings, cost and availability of the tests should be taken into consideration. In this multicentre study, the use of the Fibrosis-4 index followed by liver stiffness measurement by vibration-controlled transient elastography effectively identified patients who would later develop liver-related events. The results support current recommendations by various regional guidelines on a clinical care pathway based on non-invasive tests to diagnose advanced liver fibrosis.enCopyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.Diseases & disorders of systemic, metabolic or environmental originGastroenterologyArticle