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.

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.

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests KS is an employee of Versantis AG. MT received speaker fees from BMS, Falk Foundation, Gilead, Intercept, Janssen, MSD, and Roche; advised for AbbVie, Albireo, BiomX, Boehringer Ingelheim, Falk Pharma, Genfit, Gilead, Hightide, Intercept, Janssen, MSD, Novartis, Phenex, Pliant, Regulus, Siemens, and Shire; received travel grants from AbbVie, Falk, Gilead, Intercept, and Janssen; and received research grants from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda, and UltraGenyx. MT is also co-inventor of patents on the medical use of norUDCA filed by the Medical Universities of Graz and Vienna. AGH reports consultancy for Julius Clinical, Novo Nordisk, Echosens, Inventiva, and has received research grants from Novo Nordisk and Gilead. EB has served as a consultant or advisory board member for Boehringer Ingelheim, Gilead Sciences, Intercept, Merck, Novo Nordisk, Pfizer, ProSciento, and as a speaker for Gilead Sciences, Intercept, Merck, Novo Nordisk, and Pfizer. EB has also received a research grant from Gilead Sciences for fatty liver research. VW-SW has served as a consultant or advisory board member for 3V-BIO, AbbVie, Allergan, Boehringer Ingelheim, Center for Outcomes Research in Liver Diseases, Echosens, Gilead Sciences, Hanmi Pharmaceutical, Intercept, Merck, Novartis, Novo Nordisk, Perspectum, Pfizer, ProSciento, Sagimet Biosciences, TARGET PharmaSolutions, and Terns; and as a speaker for AbbVie, Bristol-Myers Squibb, Echosens, and Gilead Sciences. VW-SW has also received a research grant from Gilead Sciences for fatty liver research. TK and JW received unrestricted research grants from Echosens. TK has served as a speaker for Echosens. GPA has served as a consultant and an advisory board member for Pfizer, Inventiva Pharma, GlaxoSmithKline, and KaNDy Therapeutics; has been a consultant to BerGenBio, Median Technologies, FRACTYL, Amryt Pharmaceuticals, and AstraZeneca; and has given presentations on behalf of Roche Diagnostics and Medscape all through the University of Nottingham contract. GS has acted as speaker for Merck, Gilead, AbbVie, Novo Nordisk, and Pfizer; served as an advisory board member for Pfizer, Merck, Novo Nordisk, Gilead, and Intercept; and has received unrestricted research funding from Theratechnologies. ETs has served on the advisory boards for Boehringer, Pfizer, NovoNordisk, Orphalan, Univar, and Alexion; and has been a speaker for NovoNordisk and Dr Falk. MY received research support from Kowa Co. HH's institutions have received research grants from Astra Zeneca, EchoSens, Gilead, Intercept, MSD, and Pfizer. W-KC has served as a consultant or advisory board member for AbbVie, Boehringer Ingelheim, and Novo Nordisk; and as a speaker for Hisky Medical and Viatris. SM received honorarium fees from Echosens. MV has served as a consultant or a speaker for Gilead Sciences and Intercept Pharmaceuticals. VdL reports consultancy fees for AbbVie, BMS, Echosens, Gilead Sciences, Intercept Pharmaceuticals, MSD, Myr-Pharma, Pfizer, Supersonic Imagine, and Tillotts. MN has been on the advisory board or has been a consultant for 89BIO, Altimmune, BI, Gilead, cohBar, Cytodyn, Pfizer, GSK, Novo Nordisk, EchoSens, Madrigal, NorthSea, Perspectum, Terns, Takeda, Sami-Sabina group, Siemens, and Roche diagnostic; has received research support from Allergan, Akero, BMS, Gilead, Galmed, Galectin, Genfit, Conatus, Corcept, Enanta, Madrigal, Novartis, Pfizer, Shire, TERNS, Viking, and Zydus; and is a shareholder or has stocks in Anaetos, Chrownwell, Cytodyn, Ciema, Rivus Pharma, and Viking. CF-P is employed by Echosens. AG has served as a speaker and consultant for AbbVie, Alexion, AstraZeneca, Bayer, BMS, CSL Behring, Eisai, Falk, Gilead, Heel, Intercept, Ipsen, Merz, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, Sequana; and received research funding from Intercept, Falk, and Novartis. MM is employed by Novartis. TT is employed by Pfizer. QMA is coordinator of the IMI2 LITMUS consortium; has received research grant funding from AbbVie, Allergan/Tobira, AstraZeneca, GlaxoSmithKline, Glympse Bio, Novartis Pharma AG, Pfizer, Vertex; has received consultancy fees on behalf of Newcastle University for Abbott Laboratories, Acuitas Medical, Allergan/Tobira, Blade, BNN Cardio, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly, Galmed, Genfit, Gilead, Grunthal, HistoIndex, Indalo, Imperial Innovations, Intercept Pharma Europe, Inventiva, IQVIA, Janssen, Kenes, Madrigal, MedImmune, Metacrine, NewGene, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk, Pfizer, Poxel, ProSciento, Raptor Pharma, Servier, Viking Therapeutics; and has received speaker fees from Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit, Gilead, Integritas Communications, MedScape. SAH has received research grants from Akero, Altimmune, Axcella-Cirius, CiVi Biopharma, Cymabay, Galectin, Genfit, Gilead Sciences, Hepion Pharmaceuticals, Hightide Therapeutics, Intercept, Madrigal, Metacrine, NGM Bio, Northsea Therapeutics, Novartis, Novo Nordisk, Poxel, Sagimet, and Viking; and has received consulting fees from Akero, Altimmune, Alentis, Arrowhead, Axcella, Echosens, Enyo, Foresite Labs, Galectin, Genfit, Gilead Sciences, Hepion, Hightide, HistoIndex, Intercept, Kowa, Madrigal, Metacrine, NeuroBo, NGM, Northsea, Novartis, Novo Nordisk, Poxel, Perspectum, Sagimet, Terns, and Viking. MP is a shareholder of Perspectum. All other authors declared no competing interests.