Author information
1Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
2Department of Epidemiology and Data Science, Amsterdam Public Health, Amsterdam UMC, University of Amsterdam, Netherlands.
3School of Medicine, The University of Jordan, Amman, Jordan.
4Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna, Austria.
5Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
6Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
7Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Netherlands.
8Laboratoire HIFIH, UPRES EA 3859, SFR ICAT 4208, Université d'Angers, Angers, France; Service d'Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d'Angers, Angers, France.
9Service d'Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d'Angers, Angers, France.
10Hepatology Center, Saiseikai Suita Hospital, Osaka, Japan.
11Department of Medical Sciences, University of Turin, Torino, Italy.
12All India Institute of Medical Sciences, New Delhi, India.
13Department of Medical Imaging, Iuliu Ha?ieganu University of Medicine and Pharmacy, Regional Institute of Gastroenterology and Hepatology "Prof. Dr. Octavian Fodor", Cluj-Napoca, Romania.
14Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
15Translational Gastroenterology Unit, University of Oxford, Oxford, UK; Oxford National Institute for Health and Care Research (NIHR) Biomedical Research Centre, Oxford University Hospitals National Health Service (NHS) Foundation Trust, University of Oxford, Oxford, UK.
16Department of Oncology, Gastroenterology, Hepatology, Pulmonology and Infectious Diseases, University Hospital Leipzig, Leipzig, Germany.
17Division of Gastroenterology and Hepatology and Division of Infectious Diseases, McGill University Health Centre, Montreal, QC, Canada.
18Sheila Sherlock Liver Unit, Royal Free London NHS Foundation Trust, London, UK; Institute for Liver and Digestive Health, University College London, London, UK.
19Sheila Sherlock Liver Unit, Royal Free London NHS Foundation Trust, London, UK; Institute for Liver and Digestive Health, University College London, London, UK; Department of Translational Medicine and Surgery, Università Cattolica Del Sacro Cuore, Rome, Italy.
20Department of Gastroenterology and Hepatology, School of Medicine, Yokohama City University, Yokohama, Japan.
21Division of Liver and Pancreatic diseases, Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
22Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
23Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Touon, Japan.
24Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
25MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Wenzhou Key Laboratory of Hepatology, Wenzhou, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China.
26Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital, University of Sydney, Sydney, NSW, Australia.
27Section of Gastroenterology and Hepatology, PROMISE, Palermo, Italy.
28Gastroenterology Hepatology and Transplantation Unit, ASST Papa Giovanni XXIII, Bergamo, Italy.
29Hepatology Unit, Ospedale San Giuseppe, University of Milan, Milan, Italy.
30NIHR Nottingham Biomedical Research Centre and Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK.
31Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea.
32Department of Health, Medical and Caring Sciences, Linköping University, Linköping, Sweden.
33Department of Diagnostic and Interventional Radiology, Saint-Eloi Hospital and Institut Desbrest d'Epidémiologie et de Santé Publique, IDESP UMR UA11 INSERM, University Hospital of Montpellier, Montpellier, France.
34Centre d'Investigation de la Fibrose Hépatique, Hôpital Haut-Lévêque, Bordeaux University Hospital, Pessac, France; INSERM1312, Bordeaux University, Bordeaux, France.
35Department for Visceral Medicine and Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Biomedical Research, University of Bern, Bern, Switzerland.
36Department of Biomedical Research, University of Bern, Bern, Switzerland; Graduate School for Health Sciences, University of Bern, Bern, Switzerland.
37Houston Research Institute, Houston Methodist Hospital, Houston, TX, USA.
38Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
39Echosens, Paris, France.
40Division of Hepatology, University Hospital Würzburg, Würzburg, Germany.
41Novartis Institutes for BioMedical Research, Basel, Switzerland.
42Digital Sciences and Translational Imaging, Pfizer, Cambridge, MA, USA.
43Translational and Clinical Research Institute, 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.
44Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Translational Gastroenterology Unit, University of Oxford, Oxford, UK; Oxford National Institute for Health and Care Research (NIHR) Biomedical Research Centre, Oxford University Hospitals National Health Service (NHS) Foundation Trust, University of Oxford, Oxford, UK. Electronic address: michael.pavlides@cardiov.ox.ac.uk.
Abstract
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.