Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis

Ferenc E. Mózes, Jenny A. Lee, Yasaman Vali, Osama Alzoubi, Katharina Staufer, Michael Trauner, Rafael Paternostro, Rudolf E. Stauber, Adriaan G. Holleboom, Anne Marieke van Dijk, Anne Linde Mak, Jérôme Boursier, Marc de Saint Loup, Toshihide Shima, Elisabetta Bugianesi, Silvia Gaia, Angelo Armandi, Shalimar, Monica Lupșor-Platon, Vincent Wai Sun WongGuanlin Li, Grace Lai Hung Wong, Jeremy Cobbold, Thomas Karlas, Johannes Wiegand, Giada Sebastiani, Emmanuel Tsochatzis, Antonio Liguori, Masato Yoneda, Atsushi Nakajima, Hannes Hagström, Camilla Akbari, Masashi Hirooka, Wah Kheong Chan, Sanjiv Mahadeva, Ruveena Rajaram, Ming Hua Zheng, Jacob George, Mohammed Eslam, Salvatore Petta, Grazia Pennisi, Mauro Viganò, Sofia Ridolfo, Guruprasad Padur Aithal, Naaventhan Palaniyappan, Dae Ho Lee, Mattias Ekstedt, Patrik Nasr, Estelle Sandt, Manuela Tonini, LITMUS Investigators, Michael Pavlides*

*Corresponding author for this work

    Research output: Contribution to journalArticleResearchpeer-review

    18 Citations (Scopus)


    Background: Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD. Methods: This was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0–4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0–2 vs F3 vs F4; LSM: <10 vs 10 to <20 vs ≥20 kPa; FIB-4: <1·3 vs 1·3 to ≤2·67 vs >2·67; NFS: <–1·455 vs –1·455 to ≤0·676 vs >0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226. Findings: Of 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44–63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33–91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62–0·81) for histology, 0·76 (0·70–0·83) for LSM-VCTE, 0·74 (0·64–0·82) for FIB-4, and 0·70 (0·63–0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression. Interpretation: Simple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases. Funding: Innovative Medicines Initiative 2.

    Original languageEnglish
    Pages (from-to)704-713
    Number of pages10
    JournalThe Lancet Gastroenterology and Hepatology
    Issue number8
    Publication statusPublished - Aug 2023


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