. 2023 Nov:134:107352.

doi: 10.1016/j.cct.2023.107352. Epub 2023 Oct 4.

Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS): Assessment & validation of imaging modality performance across the NAFLD spectrum in a prospectively recruited cohort study (the LITMUS imaging study): Study protocol

Michael Pavlides¹, Ferenc E Mózes², Salma Akhtar², Kristy Wonders³, Jeremy Cobbold⁴, Elizabeth M Tunnicliffe⁵, Michael Allison⁶, Edmund M Godfrey⁷, Guruprasad P Aithal⁸, Susan Francis⁹, Manuel Romero-Gomez¹⁰, Javier Castell¹¹, Isabel Fernandez-Lizaranzu¹¹, Rocio Aller¹², Rebeca Sigüenza González¹³, Salvador Agustin¹⁴, Juan M Pericàs¹⁴, Jerome Boursier¹⁵, Christophe Aube¹⁶, Vlad Ratziu¹⁷, Mathilde Wagner¹⁸, Salvatore Petta¹⁹, Michela Antonucci²⁰, Elisabetta Bugianesi²¹, Riccardo Faletti²², Luca Miele²³, Andreas Geier²⁴, Jörn M Schattenberg²⁵, Emrich Tilman²⁶, Mattias Ekstedt²⁷, Peter Lundberg²⁸, Annalisa Berzigotti²⁹, Adrian T Huber³⁰, George Papatheodoridis³¹, Hannele Yki-Järvinen³², Kimmo Porthan³², Moritz Jörg Schneider³³, Paul Hockings³³, Elizabeth Shumbayawonda³⁴, Rajarshi Banerjee³⁴, Kay Pepin³⁵, Mike Kalutkiewicz³⁵, Richard L Ehman³⁶, Aldo Trylesinksi³⁷, Harvey O Coxson³⁸; LITMUS Consortium Investigators; Miljen Martic³⁹, Carla Yunis⁴⁰, Theresa Tuthill⁴⁰, Patrick M Bossuyt⁴¹, Quentin M Anstee³, Stefan Neubauer⁵, Stephen Harrison²

Affiliations

¹ Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Translational Gastroenterology Unit, University of Oxford, Oxford, UK; Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust and the University of Oxford, Oxford, UK. Electronic address: Michael.pavlides@cardiov.ox.ac.uk.
² Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
³ Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
⁴ Translational Gastroenterology Unit, University of Oxford, Oxford, UK; Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust and the University of Oxford, Oxford, UK.
⁵ Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust and the University of Oxford, Oxford, UK.
⁶ Liver Unit, Department of Medicine, Cambridge NIHR Biomedical Research Centre, Cambridge University NHS Foundation Trust, UK.
⁷ Department of Radiology, Cambridge University NHS Foundation Trust, Cambridge, UK.
⁸ NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.
⁹ Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, UK.
¹⁰ Digestive Diseases Unit, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
¹¹ Radiodiagnosis Clinical Management Unit, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
¹² Department of Gastroenterology, Clinic University Hospital, Medical School, University of Valladolid, CIBERINFEC, Valladolid, Spain.
¹³ Department of Radiology, Clinic University Hospital, Medical School, University of Valladolid, Valladolid, Spain.
¹⁴ Liver Unit, Vall d'Hebron Institut de Recerca, Vall d'Hebron Barcelona Hospital, Centros de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
¹⁵ Centre Hospitalier Universitaire d'Angers, Angers, France; & Laboratoire HIFIH UPRES EA3859, Université d'Angers, Angers, France.
¹⁶ Department of Radiology, Centre Hospitalier Universitaire d'Angers, Angers, France; & Laboratoire HIFIH UPRES EA3859, Université d'Angers, Angers, France.
¹⁷ Sorbonne Université, Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France.
¹⁸ Radiology department, AP-HP.6, GH Pitié Salpêtrière - Charles Foix Sorbonne Université, Paris, France.
¹⁹ Section of Gastroenterology, PROMISE, University of Palermo, Italy.
²⁰ Section of Radiology - Di.Bi.Me.F., University of Palermo, Palermo, Italy.
²¹ Division of Gastroenterology, Department of Medical Sciences, University of Torino, Torino, Italy.
²² Department of Diagnostic and Interventional Radiology, University of Turin, Turin, Italy.
²³ Department of Translational Medicine and Surgery, Medical School, Università Cattolica del S. Cuore and Fondazione Pol. Gemelli IRCCS Hospital, Rome, Italy.
²⁴ Department of Hepatology, University of Würzburg, Würzburg, Germany.
²⁵ Metabolic Liver Research Program, I. Department of Medicine, University Medical Centre, Mainz, Germany.
²⁶ Department of Diagnostic and Interventional Radiology, University Medical Center of Johannes-Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany.
²⁷ Department of Health, Medicine and Caring Sciences, and Centre for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden.
²⁸ Department of Radiation Physics, and Centre for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden.
²⁹ Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.
³⁰ Department of Diagnostic, Interventional and Paediatric Radiology (DIPR), Bern University Hospital, University of Bern, Bern, Switzerland.
³¹ Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece.
³² Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
³³ Antaros Medical AB, Mölndal, Sweden.
³⁴ Perspectum Ltd, Oxford, UK.
³⁵ Resoundant Inc, Rochester, MN, USA.
³⁶ Department of Radiology, Mayo Clinic, Rochester, MN, USA.
³⁷ ADVANZPHARMA, Capital House, 1st Floor, 85 King William Street, London EC4N 7BL, United Kingdom.
³⁸ Boehringer Ingelheim Pharma GmbH & Co., KG, Germany.
³⁹ Novartis AG, Translational Medicine, Clinical and Precision Medicine Imaging, Basel, Switzerland.
⁴⁰ Clinical Development and Operations, Pfizer Inc., Lake Mary, FL, USA.
⁴¹ Department of Epidemiology & Data Science, Amsterdam Public Health, Amsterdam University Medical Centres, University of Amsterdam, the Netherlands.

PMID: 37802221
DOI: 10.1016/j.cct.2023.107352

Free article

Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS): Assessment & validation of imaging modality performance across the NAFLD spectrum in a prospectively recruited cohort study (the LITMUS imaging study): Study protocol

Michael Pavlides et al. Contemp Clin Trials. 2023 Nov.

Free article

. 2023 Nov:134:107352.

doi: 10.1016/j.cct.2023.107352. Epub 2023 Oct 4.

Authors

Affiliations

¹ Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Translational Gastroenterology Unit, University of Oxford, Oxford, UK; Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust and the University of Oxford, Oxford, UK. Electronic address: Michael.pavlides@cardiov.ox.ac.uk.
² Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
³ Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
⁴ Translational Gastroenterology Unit, University of Oxford, Oxford, UK; Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust and the University of Oxford, Oxford, UK.
⁵ Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust and the University of Oxford, Oxford, UK.
⁶ Liver Unit, Department of Medicine, Cambridge NIHR Biomedical Research Centre, Cambridge University NHS Foundation Trust, UK.
⁷ Department of Radiology, Cambridge University NHS Foundation Trust, Cambridge, UK.
⁸ NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.
⁹ Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, UK.
¹⁰ Digestive Diseases Unit, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
¹¹ Radiodiagnosis Clinical Management Unit, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
¹² Department of Gastroenterology, Clinic University Hospital, Medical School, University of Valladolid, CIBERINFEC, Valladolid, Spain.
¹³ Department of Radiology, Clinic University Hospital, Medical School, University of Valladolid, Valladolid, Spain.
¹⁴ Liver Unit, Vall d'Hebron Institut de Recerca, Vall d'Hebron Barcelona Hospital, Centros de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
¹⁵ Centre Hospitalier Universitaire d'Angers, Angers, France; & Laboratoire HIFIH UPRES EA3859, Université d'Angers, Angers, France.
¹⁶ Department of Radiology, Centre Hospitalier Universitaire d'Angers, Angers, France; & Laboratoire HIFIH UPRES EA3859, Université d'Angers, Angers, France.
¹⁷ Sorbonne Université, Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France.
¹⁸ Radiology department, AP-HP.6, GH Pitié Salpêtrière - Charles Foix Sorbonne Université, Paris, France.
¹⁹ Section of Gastroenterology, PROMISE, University of Palermo, Italy.
²⁰ Section of Radiology - Di.Bi.Me.F., University of Palermo, Palermo, Italy.
²¹ Division of Gastroenterology, Department of Medical Sciences, University of Torino, Torino, Italy.
²² Department of Diagnostic and Interventional Radiology, University of Turin, Turin, Italy.
²³ Department of Translational Medicine and Surgery, Medical School, Università Cattolica del S. Cuore and Fondazione Pol. Gemelli IRCCS Hospital, Rome, Italy.
²⁴ Department of Hepatology, University of Würzburg, Würzburg, Germany.
²⁵ Metabolic Liver Research Program, I. Department of Medicine, University Medical Centre, Mainz, Germany.
²⁶ Department of Diagnostic and Interventional Radiology, University Medical Center of Johannes-Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany.
²⁷ Department of Health, Medicine and Caring Sciences, and Centre for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden.
²⁸ Department of Radiation Physics, and Centre for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden.
²⁹ Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.
³⁰ Department of Diagnostic, Interventional and Paediatric Radiology (DIPR), Bern University Hospital, University of Bern, Bern, Switzerland.
³¹ Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece.
³² Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
³³ Antaros Medical AB, Mölndal, Sweden.
³⁴ Perspectum Ltd, Oxford, UK.
³⁵ Resoundant Inc, Rochester, MN, USA.
³⁶ Department of Radiology, Mayo Clinic, Rochester, MN, USA.
³⁷ ADVANZPHARMA, Capital House, 1st Floor, 85 King William Street, London EC4N 7BL, United Kingdom.
³⁸ Boehringer Ingelheim Pharma GmbH & Co., KG, Germany.
³⁹ Novartis AG, Translational Medicine, Clinical and Precision Medicine Imaging, Basel, Switzerland.
⁴⁰ Clinical Development and Operations, Pfizer Inc., Lake Mary, FL, USA.
⁴¹ Department of Epidemiology & Data Science, Amsterdam Public Health, Amsterdam University Medical Centres, University of Amsterdam, the Netherlands.

PMID: 37802221
DOI: 10.1016/j.cct.2023.107352

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome with global prevalence reaching epidemic levels. Despite the high disease burden in the population only a small proportion of those with NAFLD will develop progressive liver disease, for which there is currently no approved pharmacotherapy. Identifying those who are at risk of progressive NAFLD currently requires a liver biopsy which is problematic. Firstly, liver biopsy is invasive and therefore not appropriate for use in a condition like NAFLD that affects a large proportion of the population. Secondly, biopsy is limited by sampling and observer dependent variability which can lead to misclassification of disease severity. Non-invasive biomarkers are therefore needed to replace liver biopsy in the assessment of NAFLD. Our study addresses this unmet need. The LITMUS Imaging Study is a prospectively recruited multi-centre cohort study evaluating magnetic resonance imaging and elastography, and ultrasound elastography against liver histology as the reference standard. Imaging biomarkers and biopsy are acquired within a 100-day window. The study employs standardised processes for imaging data collection and analysis as well as a real time central monitoring and quality control process for all the data submitted for analysis. It is anticipated that the high-quality data generated from this study will underpin changes in clinical practice for the benefit of people with NAFLD. Study Registration: clinicaltrials.gov: NCT05479721.

Keywords: 2D shear wave elastography; 2DSWE; DeMILI; Diffusion weighted imaging; Fibro-MRI; Iron corrected T1; Liver Multiscan; Magnetic resonance elastography; NASH-MRI; PDFF; Proton density fat fraction; R2*; T1 mapping; T2*; VCTE; liver stiffness; pSWE; point shear wave elastography; ultrasound elastography; vibration controlled transient elastography.

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Conflict of interest statement

Declaration of Competing Interest FEM, SA, KW, JC, MA, EMG, SF, MRG, JC, IFL, RA, RSG, JMP, JB, VR, MW, SP, MA, RF, LM, ET, ME, PL, ATH, GP, HYJ, KP and PMB declare no conflicts of interest. MP is a shareholder in Perspectum Ltd. EMT is a shareholder in Perspectum Ltd. SA is currently employed by Boehringer Ingelheim (but was not during his participation in the project). GPA has served as a consultant and an advisory board member for Pfizer Inc., Inventiva Pharma, GlaxoSmithKline and KaNDy Therapeutics; he has been a consultant to BerGenBio ASA, Median Technologies, FRACTYL, Amryt Pharmaceuticals and AstraZeneca; and has given presentations on behalf of Roche Diagnostics and Medscape all through the University of Nottingham contract. CA declares the following potential conflicts of interest: Hologic: Support of study and expert; Guerbet: Member of board, PI of study; Siemens: Expert. EB has served as a consultant or advisory board member for Boehringer Ingelheim, Gilead Sciences, Intercept, Merck, Novo Nordisk, Pfizer, ProSciento; and a speaker for Gilead Sciences, Intercept, Merck, Novo Nordisk, Pfizer. She has also received a research grant from Gilead Sciences for fatty liver research. AG served as a speaker and consultant for AbbVie, Alexion, AstraZeneca, Bayer, BMS, CSL Behring, Eisai, Falk, Gilead, Heel, Intercept, Ipsen, Merz, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, Sequana; received research funding from Intercept, Falk, Novartis. JMS reports consultancy for BMS, Boehringer Ingelheim, Echosens, Genfit, Gilead Sciences, Intercept Pharmaceuticals, Madrigal, Novartis, Pfizer, Roche, Sanofi; received research funding from Gilead Sciences and was on the speaker's bureau for Falk Foundation MSD Sharp & Dohme GmbH. MJS and PH are employed by Antaros Medical AB, Mölndal, Sweden. ES is employed by Perspectum Ltd., Oxford, UK. RB is a shareholder and employed (CEO) by Perspectum Ltd., Oxford, UK. KP and MK are employed by Resoundant Inc., Rochester, MN, USA. RLE and the Mayo Clinic have intellectual property rights and a financial interest in magnetic resonance elastography technology. AT is employed by ADVANZPHARMA, Capital House, 1st Floor, 85 King William Street, London, EC4N 7BL, United Kingdom. HC is employed by Boehringer Ingelheim Pharma GmbH & Co. MM is employed by Novartis AG, Basel, Switzerland. CY is employed by Pfizer Inc., Lake Mary, FL, USA. TT was employed by Pfizer at the time of her involvement with the project. QMA is coordinator of the EU IMI-2 LITMUS consortium, which is funded by the EU Horizon 2020 programme and EFPIA. This multistakeholder consortium includes industry partners. QMA has received research grant funding from AstraZeneca, Boehringer Ingelheim, and Intercept Pharmaceuticals, Inc.; has served as a consultant on behalf of Newcastle University for Alimentiv, Akero, AstraZeneca, Axcella, 89bio, Boehringer Ingelheim, Bristol Myers Squibb, Galmed, Genfit, Genentech, Gilead, GSK, Hanmi, HistoIndex, Intercept Pharmaceuticals, Inc., Inventiva, Ionis, IQVIA, Janssen, Madrigal, Medpace, Merck, NGM Bio, Novartis, Novo Nordisk, PathAI, Pfizer, Poxel, Resolution Therapeutics, Roche, Ridgeline Therapeutics, RTI, Shionogi, and Terns; has served as a speaker for Fishawack, Integritas Communications, Kenes, Novo Nordisk, Madrigal, Medscape, and Springer Healthcare; and receives royalties from Elsevier Ltd. SN is a shareholder in Perspectum Ltd. SAH has research grants from Akero, Altimmune, Axcella-Cirius, CiVi Biopharma, Cymabay, Galectin, Genfit, Gilead Sciences, Hepion Pharmaceuticals, Hightide Therapeutics, Intercept, Madrigal, Metacrine, NGM Bio, Northsea Therapeutics, Novartis, Novo Nordisk, Poxel, Sagimet, Viking. He has received consulting fees from Akero, Altimmune, Alentis, Arrowhead, Axcella, Echosens, Enyo, Foresite Labs, Galectin, Genfit, Gilead Sciences, Hepion, HIghtide, HistoIndex, Intercept, Kowa, Madrigal, Metacrine, NeuroBo, NGM, Northsea, Novartis, Novo Nordisk, Poxel, Perspectum, Sagimet, Terns, and Viking.

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Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS): Assessment & validation of imaging modality performance across the NAFLD spectrum in a prospectively recruited cohort study (the LITMUS imaging study): Study protocol

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Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS): Assessment & validation of imaging modality performance across the NAFLD spectrum in a prospectively recruited cohort study (the LITMUS imaging study): Study protocol

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