LiverScreen project: study protocol for screening for liver fibrosis in the general population in European countries
Authors: Graupera Isabel , Thiele Maja , Ma Ann T. , Serra-Burriel Miquel , Pich Judit , Fabrellas Núria , Caballeria Llorenç , de Knegt Robert J. , Grgurevic Ivica , Reichert Mathias , Roulot Dominique , Schattenberg Jörn M. , Pericas Juan M. , Angeli Paolo , Tsochatzis Emmanuel A. , Guha Indra Neil , Garcia-Retortillo Montserrat , Morillas Rosa M. , Hernández Rosario , Hoyo Jordi , Fuentes Matilde , Madir Anita , Juanola Adrià , Soria Anna , Juan Marta , Carol Marta , Diaz Alba , Detlefsen Sönke , Toran Pere , Pera Guillem , Fournier Céline , Llorca Anne , Newsome Phillip N. , Manns Michael , de Koning Harry J. , Serra-Burriel Feliu , Cucchietti Fernando , Arslanow Anita , Korenjak Marko , van Kleef Laurens , Falcó Josep Lluis , Kamath Patrick S. , Karlsen Tom H. , Castera Laurent , Lammert Frank , Krag Aleksander , Ginès Pere ,   for the LiverScreen Consortium investigators, Alvarez Marifé , Andersen Peter , Angeli Paolo , Ardèvol Alba , Arslanow Anita , Beggiato Luca , Abdesselam Zahia Ben , Bennett Lucy , Boutouria Bajiha , Brocca Alessandra , Broquetas M. Teresa , Caballeria Llorenc , Calvino Valeria , Camacho Judith , Capdevila Aura , Carol Marta , Castera Laurent , Cervera Marta , Cucchietti Fernando , de Fuentes Anna , de Knegt Rob , Detlefsen Sonke , Diaz Alba , Bande José Diéguez , Esnault Vanessa , Fabrellas Núria , Falco Josep lluis , Fernández Rosa , Fournier Celine , Fuentes Matilde , Galle Peter , García Edgar , García-Retortillo Montserrat , Garrido Esther , Ginès Pere , Medina Rosa Gordillo , Gratacós-Gines Jordi , Graupera Isabel , Grgurevic Ivica , Guha Indra Neil , Guix Eva , Harris Rebecca , Boluda Elena Hernández , Hernández-Ibañez Rosario , Hoyo Jordi , Ikram Arfan , Incicco Simone , Israelsen Mads , Juan Marta , Juanola Adria , Kaiser Ralf , Kamath Patrick S. , Karlsen Tom H. , Kjærgaard Maria , de Koning Harry J. , Korenjak Marko , Krag Aleksander , Hansen Johanne Kragh , Krawczyk Marcin , Lambert Irina , Lammert Frank , Laboulaye Philippe , Sørensen Simon Langkjær , Laserna-Jiménez Cristina , Pi Sonia Lazaro , Ledain Elsa , Levy Vincent , Londoño Vanessa , Loyer Guirec , Llorca Anne , Ma Ann T. , Madir Anita , Manns Michael , Marshall Denise , Martí M. Lluïsa , Martínez Sara , Sala Ricard Martínez , Font Roser Masa , Jensen Jane Møller , Morillas Rosa M. , Muñoz Laura , Nadal Ruth , Napoleone Laura , Navarrete J. M. , Newsome Phillip N. , Nielsen Vibeke , Pérez Martina , Pulido Juan Manuel Pericas , Piano Salvatore , Pich Judit , Escobet Judit Presas , Pose Elisa , Lindvig Katrine Prier , Reichert Matthias , Riba Carlota , Roulot Dominique , Rubio Ana Belén , Sánchez-Morata Maria , Schattenberg Jörn , Serra-Burriel Feliu , Serra-Burriel Miquel , Just Louise Skovborg , Sonneveld Milan , Soria Anna , Stern Christiane , Such Patricia , Thiele Maja , Toran Pere , Torrejón Antoni , Tonon Marta , Tsochatzis Emmanuel A. , van Kleef Laurens , van Wijngaarden Paulien , Velázquez Vanessa , Viu Ana , Weber Susanne Nicole , Wildsmith Tracey 
Published: July 2022

Abstract
Background
The development of liver cirrhosis is usually an asymptomatic process until late stages when complications occur. The potential reversibility of the disease is dependent on early diagnosis of liver fibrosis and timely targeted treatment. Recently, the use of non-invasive tools has been suggested for screening of liver fibrosis, especially in subjects with risk factors for chronic liver disease. Nevertheless, large population-based studies with cost-effectiveness analyses are still lacking to support the widespread use of such tools. The aim of this study is to investigate whether non-invasive liver stiffness measurement in the general population is useful to identify subjects with asymptomatic, advanced chronic liver disease.

Methods
This study aims to include 30,000 subjects from eight European countries. Subjects from the general population aged ≥ 40 years without known liver disease will be invited to participate in the study either through phone calls/letters or through their primary care center. In the first study visit, subjects will undergo bloodwork as well as hepatic fat quantification and liver stiffness measurement (LSM) by vibration-controlled transient elastography. If LSM is ≥ 8 kPa and/or if ALT levels are ≥1.5 x upper limit of normal, subjects will be referred to hospital for further evaluation and consideration of liver biopsy. The primary outcome is the percentage of subjects with LSM ≥ 8kPa. In addition, a health economic evaluation will be performed to assess the cost-effectiveness and budget impact of such an intervention. The project is funded by the European Commission H2020 program.

Discussion
This study comes at an especially important time, as the burden of chronic liver diseases is expected to increase in the coming years. There is consequently an urgent need to change our current approach, from diagnosing the disease late when the impact of interventions may be limited to diagnosing the disease earlier, when the patient is asymptomatic and free of complications, and the disease potentially reversible. Ultimately, the LiverScreen study will serve as a basis from which diagnostic pathways can be developed and adapted to the specific socio-economic and healthcare conditions in each country.

Trial registration
This study is registered on Clinicaltrials.gov (NCT03789825).