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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

Mózes FE 1 , Lee JA 2 , Vali Y 2 , Alzoubi O 3 , Staufer K 4 , Trauner M 5 Show all authors , Paternostro R 5 , Stauber RE 6 , Holleboom AG 7 , van Dijk AM 7 , Mak AL 7 , Boursier J 8 , de Saint Loup M 9 , Shima T 10 , Bugianesi E 11 , Gaia S 11 , Armandi A 11 , Shalimar 12 , Lupșor-Platon M 13 , Wong VW 14 , Li G 14 , Wong GL 14 , Cobbold J 15 , Karlas T 16 , Wiegand J 16 , Sebastiani G 17 , Tsochatzis E 18 , Liguori A 19 , Yoneda M 20 , Nakajima A 20 , Hagström H 21 , Akbari C 22 , Hirooka M 23 , Chan WK 24 , Mahadeva S 24 , Rajaram R 24 , Zheng MH 25 , George J 26 , Eslam M 26 , Petta S 27 , Pennisi G 27 , Viganò M 28 , Ridolfo S 29 , Aithal GP 30 , Palaniyappan N 30 , Lee DH 31 , Ekstedt M 32 , Nasr P 32 , Cassinotto C 33 , de Lédinghen V 34 , Berzigotti A 35 , Mendoza YP 36 , Noureddin M 37 , Truong E 38 , Fournier-Poizat C 39 , Geier A 40 , Martic M 41 , Tuthill T 42 , Anstee QM 43 , Harrison SA 1 , Bossuyt PM 2 , Pavlides M 44 , LITMUS investigators

Affiliations 

  • 1 Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
  • 2 Department of Epidemiology and Data Science, Amsterdam Public Health, Amsterdam UMC, University of Amsterdam, Netherlands
  • 3 School of Medicine, The University of Jordan, Amman, Jordan
  • 4 Division 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
  • 5 Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
  • 6 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
  • 7 Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Netherlands
  • 8 Laboratoire 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
  • 9 Service d'Hépato-Gastroentérologie et Oncologie Digestive, Centre Hospitalier Universitaire d'Angers, Angers, France
  • 10 Hepatology Center, Saiseikai Suita Hospital, Osaka, Japan
  • 11 Department of Medical Sciences, University of Turin, Torino, Italy
  • 12 All India Institute of Medical Sciences, New Delhi, India
  • 13 Department of Medical Imaging, Iuliu Hațieganu University of Medicine and Pharmacy, Regional Institute of Gastroenterology and Hepatology "Prof. Dr. Octavian Fodor", Cluj-Napoca, Romania
  • 14 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
  • 15 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
  • 16 Department of Oncology, Gastroenterology, Hepatology, Pulmonology and Infectious Diseases, University Hospital Leipzig, Leipzig, Germany
  • 17 Division of Gastroenterology and Hepatology and Division of Infectious Diseases, McGill University Health Centre, Montreal, QC, Canada
  • 18 Sheila Sherlock Liver Unit, Royal Free London NHS Foundation Trust, London, UK; Institute for Liver and Digestive Health, University College London, London, UK
  • 19 Sheila 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
  • 20 Department of Gastroenterology and Hepatology, School of Medicine, Yokohama City University, Yokohama, Japan
  • 21 Division of Liver and Pancreatic diseases, Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
  • 22 Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
  • 23 Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Touon, Japan
  • 24 Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 25 MAFLD 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
  • 26 Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital, University of Sydney, Sydney, NSW, Australia
  • 27 Section of Gastroenterology and Hepatology, PROMISE, Palermo, Italy
  • 28 Gastroenterology Hepatology and Transplantation Unit, ASST Papa Giovanni XXIII, Bergamo, Italy
  • 29 Hepatology Unit, Ospedale San Giuseppe, University of Milan, Milan, Italy
  • 30 NIHR Nottingham Biomedical Research Centre and Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK
  • 31 Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
  • 32 Department of Health, Medical and Caring Sciences, Linköping University, Linköping, Sweden
  • 33 Department 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
  • 34 Centre d'Investigation de la Fibrose Hépatique, Hôpital Haut-Lévêque, Bordeaux University Hospital, Pessac, France; INSERM1312, Bordeaux University, Bordeaux, France
  • 35 Department for Visceral Medicine and Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Biomedical Research, University of Bern, Bern, Switzerland
  • 36 Department of Biomedical Research, University of Bern, Bern, Switzerland; Graduate School for Health Sciences, University of Bern, Bern, Switzerland
  • 37 Houston Research Institute, Houston Methodist Hospital, Houston, TX, USA
  • 38 Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
  • 39 Echosens, Paris, France
  • 40 Division of Hepatology, University Hospital Würzburg, Würzburg, Germany
  • 41 Novartis Institutes for BioMedical Research, Basel, Switzerland
  • 42 Digital Sciences and Translational Imaging, Pfizer, Cambridge, MA, USA
  • 43 Translational 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
  • 44 Oxford 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
Lancet Gastroenterol Hepatol, 2023 Aug;8(8):704-713.
PMID: 37290471 DOI: 10.1016/S2468-1253(23)00141-3

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: 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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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