1 National Institute for Health Research Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, UK; Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. Electronic address: email@example.com.
2 R&D Department, Echosens, Paris, France.
3 National Institute for Health Research Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, UK; Test Evaluation Research Group, Institute of Applied Health Research, University of Birmingham, Birmingham, UK.
4 Brooke Army Medical Center, Fort Sam Houston, TX, USA; Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
5 Department of Hepato-Gastroenterology, Angers University Hospital, Angers, France; HIFIH Laboratory UPRES EA3859, SFR4208, Angers University, Angers, France.
6 Gastroenterology and Hepatology Unit, Gastrointestinal Endoscopy Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
7 Liver Research Unit, Institute of Gastroenterology, Marmara University, Istanbul, Turkey; Department of Gastroenterology, School of Medicine, Marmara University, Istanbul, Turkey.
8 Department of Nutrition, Hôpital Européen Georges-Pompidou (APHP), University of Paris, Paris, France.
9 NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou, China.
10 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
11 Department of Medicine, Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
12 UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK.
13 Institute of Cellular Medicine-Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK.
14 Institute of Translational and Stratified Medicine, University of Plymouth, Plymouth, UK.
15 NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.
16 NIHR Oxford Biomedical Research Centre and Oxford Liver Unit, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.
17 Pathology Department, Hôpital Beaujon, APHP, Clichy, France.
18 Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK; Liverpat, Paris, France.
19 Medical Affairs Department, Echosens, Paris, France.
20 Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
BACKGROUND: The burden of non-alcoholic fatty liver disease (NAFLD) is increasing globally, and a major priority is to identify patients with non-alcoholic steatohepatitis (NASH) who are at greater risk of progression to cirrhosis, and who will be candidates for clinical trials and emerging new pharmacotherapies. We aimed to develop a score to identify patients with NASH, elevated NAFLD activity score (NAS≥4), and advanced fibrosis (stage 2 or higher [F≥2]).
METHODS: This prospective study included a derivation cohort before validation in multiple international cohorts. The derivation cohort was a cross-sectional, multicentre study of patients aged 18 years or older, scheduled to have a liver biopsy for suspicion of NAFLD at seven tertiary care liver centres in England. This was a prespecified secondary outcome of a study for which the primary endpoints have already been reported. Liver stiffness measurement (LSM) by vibration-controlled transient elastography and controlled attenuation parameter (CAP) measured by FibroScan device were combined with aspartate aminotransferase (AST), alanine aminotransferase (ALT), or AST:ALT ratio. To identify those patients with NASH, an elevated NAS, and significant fibrosis, the best fitting multivariable logistic regression model was identified and internally validated using boot-strapping. Score calibration and discrimination performance were determined in both the derivation dataset in England, and seven independent international (France, USA, China, Malaysia, Turkey) histologically confirmed cohorts of patients with NAFLD (external validation cohorts). This study is registered with ClinicalTrials.gov, number NCT01985009.
FINDINGS: Between March 20, 2014, and Jan 17, 2017, 350 patients with suspected NAFLD attending liver clinics in England were prospectively enrolled in the derivation cohort. The most predictive model combined LSM, CAP, and AST, and was designated FAST (FibroScan-AST). Performance was satisfactory in the derivation dataset (C-statistic 0·80, 95% CI 0·76-0·85) and was well calibrated. In external validation cohorts, calibration of the score was satisfactory and discrimination was good across the full range of validation cohorts (C-statistic range 0·74-0·95, 0·85; 95% CI 0·83-0·87 in the pooled external validation patients' cohort; n=1026). Cutoff was 0·35 for sensitivity of 0·90 or greater and 0·67 for specificity of 0·90 or greater in the derivation cohort, leading to a positive predictive value (PPV) of 0·83 (84/101) and a negative predictive value (NPV) of 0·85 (93/110). In the external validation cohorts, PPV ranged from 0·33 to 0·81 and NPV from 0·73 to 1·0.
INTERPRETATION: The FAST score provides an efficient way to non-invasively identify patients at risk of progressive NASH for clinical trials or treatments when they become available, and thereby reduce unnecessary liver biopsy in patients unlikely to have significant disease.
FUNDING: Echosens and UK National Institute for Health Research.