1Director, Stravitz-Sanyal Institute of Liver Disease and Metabolic Health, VCU School of Medicine and Chair, Division of Gastroenterology, Hepatology and Nutrition in the Department of Internal Medicine at VCU School of Medicine, Richmond, VA, USA.
2Echosens, Paris, France.
3Inova Fairfax Medical Campus, Falls Church, VA, USA.
4Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
5National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK & Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
6Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
7Department of Gastroenterology, School of Medicine, Recep Tayyip Erdogan University, Rize, Turkey; Liver Research Unit, Institute of Gastroenterology, Marmara University, Istanbul, Turkey.
8Hepatology and Gastroenterology Department, Haut-Lévêque University Hospital, Pessac, France.
9Hepato-gastroenterology & Digestive Oncology Department, Grenoble-Alpes University Hospital, Grenoble, France.
10NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, China; Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China.
11Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
12Toronto Liver Centre, Toronto, ON, Canada.
13Gilead Sciences, Inc., Foster City, CA, USA; The Liver Company, Palo Alto, CA, USA.
14HIFIH Laboratory, UPRES EA3859, SFR 4208, Angers University, Angers, France.
15Echosens, Paris, France. Electronic address: firstname.lastname@example.org.
16HIFIH Laboratory, UPRES EA3859, SFR 4208, Angers University, Angers, France; Hepato-Gastroenterology Department, Angers University Hospital, Angers, France.
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.