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. 2023 Feb;78(2):247-259.
doi: 10.1016/j.jhep.2022.10.034. Epub 2022 Nov 12.

Enhanced diagnosis of advanced fibrosis and cirrhosis in individuals with NAFLD using FibroScan-based Agile scores

Arun J Sanyal  1 , Julie Foucquier  2 , Zobair M Younossi  3 , Stephen A Harrison  4 , Philip N Newsome  5 , Wah-Kheong Chan  6 , Yusuf Yilmaz  7 , Victor De Ledinghen  8 , Charlotte Costentin  9 , Ming-Hua Zheng  10 , Vincent Wai-Sun Wong  11 , Magdy Elkhashab  12 , Ryan S Huss  13 , Robert P Myers  13 , Marine Roux  14 , Aymeric Labourdette  2 , Marie Destro  2 , Céline Fournier-Poizat  15 , Véronique Miette  2 , Laurent Sandrin  2 , Jérôme Boursier  16
Affiliations

Enhanced diagnosis of advanced fibrosis and cirrhosis in individuals with NAFLD using FibroScan-based Agile scores

Arun J Sanyal et al. J Hepatol. 2023 Feb.

Abstract

Background & aims: Currently available non-invasive tests, including fibrosis-4 index (FIB-4) and liver stiffness measurement (LSM by VCTE), are highly effective at excluding advanced fibrosis (AF) (F ≥3) or cirrhosis in people with non-alcoholic fatty liver disease (NAFLD), but only have moderate ability to rule-in these conditions. Our objective was to develop and validate two new scores (Agile 4 and Agile 3+) to identify cirrhosis or AF, respectively, with optimized positive predictive value and fewer indeterminate results, in individuals with NAFLD attending liver clinics.

Methods: This international study included seven adult cohorts with suspected NAFLD who underwent liver biopsy, LSM and blood sampling during routine clinical practice or screening for trials. The population was randomly divided into a training set and an internal validation set, on which the best-fitting logistic regression model was built, and performance and goodness of fit were assessed, respectively. Furthermore, both scores were externally validated on two large cohorts. Cut-offs for high sensitivity and specificity were derived in the training set to rule-out and rule-in cirrhosis or AF and then tested in the validation set and compared to FIB-4 and LSM.

Results: Each score combined LSM, AST/ALT ratio, platelets, sex and diabetes status, as well as age for Agile 3+. Calibration plots for Agile 4 and Agile 3+ indicated satisfactory to excellent goodness of fit. Agile 4 and Agile 3+ outperformed FIB-4 and LSM in terms of AUROC, percentage of patients with indeterminate results and positive predictive value to rule-in cirrhosis or AF.

Conclusions: The two novel non-invasive scores improve identification of cirrhosis or AF among individuals with NAFLD attending liver clinics and reduce the need for liver biopsy in this population.

Impact and implications: Non-invasive tests currently used to identify patients with advanced fibrosis or cirrhosis, such as fibrosis-4 index and liver stiffness measurement by vibration-controlled transient elastography, have high negative predictive values but high false positive rates, while results are indeterminate for a large number of cases. This study provides scores that will help the clinician diagnose advanced fibrosis or cirrhosis. These new easy-to-implement scores will help liver specialists to better identify (1) patients who need more intensive follow-up, (2) patients who should be referred for inclusion in therapeutic trials, and (3) which patients should be treated with pharmacological agents when effective therapies are approved.

Keywords: Advanced fibrosis; Cirrhosis; Non-Alcoholic Fatty Liver Disease; Non-invasive test; VCTE; Vibration-Controlled Transient Elastography.

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Conflict of interest statement

AJS reports consultancy fees from Intercept, Gilead, Novo Nordisk, Eli Lilly, Boehringer Ingelhiem, Alnylam. Regeneron, Amgen, Genentech, Merck, Pfizer, Malinckrodt, 89Bio, Rivus, Bristol Myers Squibb, Hanmi, Labcorp, Novartis, Histoindex, NGM Bio, Hemoshear, Astra Zeneca; stock/stock options from Sanyal Bio, Exhalenz, Genfit, Inversago, Tiziana, Durect; royalties from Elesvier. ZMY report consultancy fees from Bristol Myers Squibb, Gilead, Intercept, Novo Nordisk, Novartis, Terns, Merck, Quest, Siemens and Madrigal.SAH reports grants from Akero Therapeutics, Inc., Axcella Health, Inc., Cirius Therapeutics, Inc., CiVi Biopharma Inc., Cymabay Therapeutics, Inc., Enyo Pharma S.A, Galectin Therapeutics, Inc., Galmed Research & Dev. LTD., Genfit Corp, Gilead Sciences, Inc., Hepion Pharmaceuticals, Inc., Hightide Therapeutics, Inc., Intercept Pharmaceuticals Inc., Madrigal Pharmaceuticals, Inc., Metacrine Inc., NGM Biopharmaceuticals Inc., Northsea Therapeutics B.V, Novartis Pharmaceuticals Corp, Novo Nordisk, Poxel, Sagimet Biosciences, Viking Therapeutics, Inc.; consultancy fees from AgomAB, Akero Therapeutics, Inc., Alentis Therapeutics AG, Alimentiv, Inc., Altimmune, Axcella Health, Inc., Boston Pharmaceuticals, B Riley FBR Inc., BVF Partners LP, Cohbar, Inc. Canfite, Corcept Therapeutics, Inc, Cymabay Therapeutics, Inc., Echosens North America Inc., Enyo Pharma S.A, Fibronostics, Foresite Labs, LLC, Fortress Biotech, Inc., Galectin Therapeutics, Inc., Genfit Corp, GNS, Hepion Pharmaceuticals Inc., Hightide Therapeutics, Inc., HistoIndex PTE LTD, Inipharm, Intercept Pharmaceuticals, Inc., Ionis, Kowa Research Institute, Inc., Madrigal Pharmaceuticals, Inc., Medpace, Inc. Metacrine Inc. Inc., Microba, NMG BIOPHARMACEUTICALS INC., Northsea Therapeutics B.V, Novo Nordisk, Nutrasource, Perspectum Diagnostics, Piper Sandler, Poxel, Prometic Pharma SMT LTD Pharma SMT LTD, Ridgeline, Sagimet Biosciences, Sonic Incytes Medical Corp, Terns Inc., Viking Therapeutics, Inc.; and stock/stock options from Akero Therapeutics, Inc., Chronwell Inc., Cirius Therapeutics, Inc, Galectin Therapeutics, Inc., Genfit Corp, Hepion Pharmaceuticals Inc., HistoIndex PTE LTD, Metacrine Inc., NGM BIOPHARMACEUTICALS INC., Northsea Therapeutics B.V, Sonic Incytes Medical Corp.PNN reports consultancy fees from Boehringer Ingelheim, Novo Nordisk, Intercept, Gilead, Poxel Pharmaceuticals. WKC reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Viatris, Hisky Medical. YY reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novo Nordisk, Echosens, Bilim _Ilaç.. VDL reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Echosens, Hologic. CC reports no conflict of interest. MHZ reports no conflict of interest.VWSW reports grants from Gilead Sciences; consultancy fees from Abbott, AbbVie, Echosens, Gilead Sciences, Novo Nordisk; stock/stock options from Illuminatio Medical Technology Limited.ME reports Altimune, Assembly, Arbutus, BMS, Boehringer, Enliven; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie. RSH reports stock/stock options from Gilead Sciences,Inc. and being a prior employee of Gilead Sciences, Inc.RPM reports stock/stock options from Gilead Sciences, Inc., The Liver Company, Inc. and being formerly employed by Gilead Sciences, Inc. and currently employed by The Liver Company, Inc.MR reports no conflict of interest.JB reports support for the present manuscript from Echosens; grants from Intercept, Inventiva, Siemens; consultancy fees from Echosens, Intercept, Siemens. JF, AL, MD, CFP, VM and LS are full time employee of Echosens.

Please refer to the accompanying ICMJE disclosure forms for further details.

Figures

Fig. 1.
Fig. 1.. Decision curves of FIB-4, LSM and Agile 4 for the diagnosis of cirrhosis.
(A) In the NASH CRN and (B) the French NAFLD cohorts and FIB-4, LSM and Agile 3+ for the diagnosis of advanced fibrosis (C) in the NASH CRN and (D) the French NAFLD cohorts. Decision curves analysis detailed in supplementary methods. FIB-4, fibrosis-4 index; LSM, liver stiffness measurement; NAFLD, non-alcoholic fatty liver disease; NASH CRN, Non-alcoholic Steatohepatitis Clinical Research Network.
Fig. 2.
Fig. 2.. Sensitivity, specificity, adjusted PPV and adjusted NPV of Agile 4 for the diagnosis of cirrhosis and Agile 3+ for the diagnosis of advanced fibrosis in the training set.
(A) Agile 4 for the diagnosis of cirrhosis; (B) Agile 3+ for the diagnosis of advanced fibrosis. NPV, negative predictive value; PPV, positive predictive value.
Fig. 3.
Fig. 3.. Percentage of patients in rule-out (<85% sensitivity cut-off), indeterminate and rule-in zones (≥90% specificity cut-off) for the diagnosis of cirrhosis with FIB-4, LSM and Agile 4.
(A) Training set (n = 1,434), (B) Internal validation set (n = 700), (C) NASH CRN cohort (n = 585), (D) French NAFLD cohort (n = 1,042). On each bar, the solid and transparent parts represent the percentage of patients with and without cirrhosis according to LB, respectively. FIB-4, fibrosis-4 index; LB, liver biopsy; LSM, liver stiffness measurement; NAFLD, non-alcoholic fatty liver disease; NASH CRN, Non-alcoholic Steatohepatitis Clinical Research Network.
Fig. 4.
Fig. 4.. Percentage of patients in rule-out (<85% sensitivity cut-off), indeterminate and rule-in zones (≥90% specificity cut-off) for the diagnosis of advanced fibrosis with FIB-4, LSM and Agile 3+.
(A) Training set (n = 1,434), (B) Internal validation set (n = 700), (C) NASH CRN cohort (n = 585), (D) French NAFLD cohort (n = 1,042). On each bar, the solid and transparent parts represent the percentage with and without AF according to LB, respectively. FIB-4, fibrosis-4 index; LB, liver biopsy; LSM, liver stiffness measurement; NAFLD, non-alcoholic fatty liver disease; NASH CRN, Non-alcoholic Steatohepatitis Clinical Research Network.
Fig. 5.
Fig. 5.. Sensitivity analysis assessing the impact of disease prevalence on PPV and NPV.
For Agile 4, the prevalence of cirrhosis was varied from 0.02 to 0.25 for (A) the cut-off of 0.251 (sensitivity = 0.79, specificity = 0.83) and (B) the cut-off of 0.565 (sensitivity = 0.53, specificity = 0.96) to evaluate their impact on NPV and PPV. For Agile 3+, the prevalence of advanced fibrosis was varied from 0.05 to 0.55 for (C) the cut-off of 0.451 (sensitivity = 0.87, specificity = 0.76) and (D) the cut-off of 0.679 (sensitivity = 0.69, specificity = 0.91). NPV, negative predictive value; PPV, positive predictive value.
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