Graupera et al. BMC Public Health 2022, 22(1):1385 BMC Public Health https://doi.org/10.1186/s12889-022-13724-6 STUDY PROTOCOL Open Access LiverScreen project: study protocol for screening for liver fibrosis in the general population in European countries Isabel Graupera1,2,3,4†, Maja Thiele5†, Ann T. Ma1,2,4, Miquel Serra‑Burriel6, Judit Pich7, Núria Fabrellas2,4, Llorenç Caballeria8, Robert J. de Knegt9, Ivica Grgurevic10, Mathias Reichert11, Dominique Roulot12, Jörn M. Schattenberg13, Juan M. Pericas14,15, Paolo Angeli16, Emmanuel A. Tsochatzis17, Indra Neil Guha18, Montserrat Garcia‑Retortillo19, Rosa M. Morillas20, Rosario Hernández21, Jordi Hoyo21, Matilde Fuentes21, Anita Madir10, Adrià Juanola1,2,3,4, Anna Soria1,2,4, Marta Juan7, Marta Carol1,2,3,4, Alba Diaz22, Sönke Detlefsen23, Pere Toran8, Guillem Pera8, Céline Fournier24, Anne Llorca24, Phillip N. Newsome25, Michael Manns26, Harry J. de Koning27, Feliu Serra‑Burriel28, Fernando Cucchietti28, Anita Arslanow1,2,13, Marko Korenjak29, Laurens van Kleef9, Josep Lluis Falcó30, Patrick S. Kamath31, Tom H. Karlsen32, Laurent Castera33, Frank Lammert11,34,35, Aleksander Krag5, Pere Ginès1,2,3,4*   and for the LiverScreen Consortium investigators Abstract Background The development of liver cirrhosis is usually an asymptomatic process until late stages when com‑ plications 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, espe‑ cially 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 inves‑ tigate 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 † Isabel Graupera and Maja Thiele contributed equally to this work. *Supported by the LiverScreen Consortium and funded by the European Commission under the program H20/20 to investigate screening for liver fibrosis and its applicability in European countries (www.​liver​screen.​eu). *Correspondence: Pere Ginès pgines@clinic.cat Full list of author information is available at the end of the article © The Author(s) 2022, corrected publication 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Graupera et al. BMC Public Health 2022, 22(1):1385 Page 2 of 10 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 Clini​caltr​ials.​gov (NCT03​789825). Keywords Cirrhosis, Screening, Liver fibrosis, Chronic liver disease, NAFLD, NASH, Vibration-controlled transient elastography Background rely either on a blood test or on liver stiffness measure- tography (VCTE) (FibroScan®, Echosens, Paris), which Liver cirrhosis is the end stage of chronic liver diseases ment (LSM), using vibration-controlled transient elas- and is a major cause of morbidity and mortality world- wide. According to data from the Global Burden of Dis- is the most used and validated non-invasive tool for ease Study, cirrhosis is the ­11th cause of death globally staging chronic liver diseases [7–10]. VCTE is a point- and the ­7th and ­12th leading cause of disability-associated of-care technique that can be performed by nurses life years (DALY) in people aged 50-74 years and 25-49 after a short training period, and consequently a large years respectively [1]. It is also the second cause of years number of people can be assessed [11]. While VCTE of working life lost in Europe [2]. The main etiologies of is available in many liver centers, it is mostly not avail- cirrhosis are hepatitis B and C virus infection, increased able in primary care settings where the early detection alcohol consumption and non-alcoholic fatty liver dis- of liver fibrosis should in fact take place. This technique ease (NAFLD), the latter of which is often associated with is particularly suited for the early detection of chronic obesity and type 2 diabetes mellitus [3]. liver disease either in the general or in high-risk popu- The development of cirrhosis, regardless of its cause, lations, particularly in patients with obesity, diabetes or usually occurs very slowly over 2-3 decades, a period increased alcohol consumption [9]. Moreover, previous during which collagen relentlessly deposits within the data suggest that the strategy of liver fibrosis screening liver until the normal liver architecture is disrupted and using TE may be cost-effective [12] but require further portal hypertension develops. In general, patients are not validation. diagnosed during this period because fibrosis deposi- tion is an asymptomatic process [3]. As such, most cases of cirrhosis are diagnosed when patients develop com- Study Rationale and Hypothesis plications related to portal hypertension, liver failure or Different recommendations have been made by the sci- liver cancer. No global strategy exists for the early detec- entific community to assess liver fibrosis, especially in tion of cirrhosis before such decompensation or cancer at-risk populations, using non-invasive tools [10, 13, 14]. occurs. Nevertheless, the main factor predicting long- However, these recommendations are based on previous term outcomes in patients with chronic liver disease is studies that either had insufficient sample size, did not the existence of liver fibrosis [4, 5], which highlights the systematically confirm the diagnosis with a liver biopsy, importance of identifying the disease early. Although or were not specifically designed to assess the cost-effec- some studies have demonstrated the potential reversibil- tive strategy in terms of health outcomes and treatment ity of liver fibrosis after treating the etiology, the actual costs in either general or at-risk population [15]. There- effectiveness of treatments decrease in late stages com- fore, we hypothesize that a screening program using a pared to early stages of fibrosis [6]. Emphasis should non-invasive method for the diagnosis of liver fibrosis therefore be put on early diagnosis of disease to maxi- may be useful in detecting asymptomatic subjects with mize its potential reversibility. advanced liver fibrosis. This early detection of disease Standard liver biochemical tests such as serum ami- would allow the implementation of treatment with the notransferases, or liver ultrasound, are not accurate aim of halting progression or even favoring regression of methods to detect fibrosis [3]. In recent years, several fibrosis, thus preventing the development of hard clinical non-invasive methods assessing the presence and sever- outcomes related to the liver disease, such as liver cirrho- ity of liver fibrosis have been developed. These methods sis, liver cancer, or liver-related death. Graupera et al. BMC Public Health 2022, 22(1):1385 Page 3 of 10 Study Aim ultrasound. The FibroScan examination at visit 2 will be This is a population-based study aimed at investigating performed with both probes (M and XL). Afterwards, a whether liver stiffness measurement using transient elas- liver biopsy will be offered to the patient for diagnosis tography is useful to identify subjects with asymptomatic and staging of liver disease when LSM is above 8 kPa or if significant chronic liver disease in the general population. chronic liver disease is suspected, as per standard of care. Following diagnosis and staging at the corresponding Study design university hospital, all patients will be offered standard This study is a single group screening study. It has of care treatment and follow-up. Patients with NAFLD been registered retrospectively on Clini​caltr​ials.​gov will be offered a lifestyle modification program con- (NCT03789825) the ­14th of November 2018. First patient sisting of diet and exercise targeting weight loss of 10% included was in May 2018. and controlling risk factors of liver disease progression. The present population-based study will include 30,000 Each center will offer the specific program according to subjects in eight European countries (Fig. 1). Eligible par- its own protocol. Patients with NAFLD participating in ticipants will be invited to attend at their primary care the present study can still be included in other studies centre or at a research facility where a nurse will perform related to NAFLD that evaluate pharmacological treat- visit 1. This visit will include a detailed interview, physi- ments. Such treatment received in the context of clini- cal examination, questionnaires related to alcohol con- cal trial or other pharmacological interventions will be sumption, quality of life and health status assessment, recorded. Patients with high alcohol consumption will venipuncture for liver biochemical tests assessment and be offered psychological assessment and counseling to biobanking, and VCTE to assess LSM and controlled stop drinking or, at least, reduce harmful alcohol use. attenuation parameter (CAP). If participants show a LSM Finally, patients diagnosed with chronic liver disease ≥ 8 kPa, unreliable or failed VCTE measurement [16] from other etiologies (autoimmune disease, viral hepa- and/or increased ALT levels (ALT ≥ 1.5 x upper limit of titis, Wilson disease, etc.), will be treated according to normal value), they will be referred to second visit in a guidelines [13, 17–20]. All participants with LSM by Liver Unit at the academic center for further evaluation VCTE < 8 kPa and ALT levels <1.5 ULN who present (visit 2). Otherwise, the study finishes after completion risk factors for chronic liver diseases such as increased of visit 1 (Fig. 2). Visit 2 will be completed by hepatolo- alcohol consumption or obesity will be counseled on gists within the 3 months following visit 1, according to lifestyle modifications by their primary care physician a standardized work-up for liver disease diagnosis and for management of such risk factors. evaluation. Visit 2 will include evaluation of the partici- Participants that fail to attend to visit 2 will be con- pant’s medical history, physical examination with com- tacted by their primary care physician or nurse and plete liver tests, FibroScan examination and abdominal referred again to the second visit. Participants will be Fig. 1 Countries included in the LiverScreen project Graupera et al. BMC Public Health 2022, 22(1):1385 Page 4 of 10 Fig. 2 Study flowchart. LSM, liver stiffness measurement; ULN, upper limit of normal asked to consent to be contacted in the future for a re- APRI score) in the general population and in the evaluation at 5 and 10 years after visit 1. Information subgroup of patients with risk factors for chronic regarding liver-related clinical outcomes (presence of cir- liver disease, at visit 1 and 2. rhosis, decompensated cirrhosis, liver cancer and liver- 3. Comparison of liver fibrosis diagnosis accuracy related death), cardiovascular events, and all causes of between VCTE, fibrosis scores and liver biopsy death will be collected. Patient assessment will be per- in the general population and in the subgroup of formed through clinical records (via health care registries patients with risk factors for chronic liver diseases, or health insurance systems) or telephone contact. No in patients with a liver biopsy available at visit 2. further visits will be performed. These clinical outcomes 4. Percentage of subjects with controlled attenuation will be used to inform the cost-effectiveness analysis of parameter (CAP) ≥ 250 dB/m, either with M or XL the liver fibrosis screening program. probe, in the general population and in the sub- group of patients with risk factors for chronic liver Primary outcome measure diseases at visit 1 and/or 2. Percentage of subjects with LSM by VCTE ≥ 8 kPa at 5. Comparison of liver steatosis diagnosis accuracy any visit, either with the M or XL probe, in the general between CAP and steatosis scores (including fatty population. liver index (FLI), hepatic steatosis index (HSI), lipid accumulation product (LAP), index of NASH Secondary outcome measures (ION) and NAFLD-liver fat score (NAFLD-LFS)) in the general population and in the subgroup of 1. Percentage of subjects with LSM by VCTE ≥ 8 kPa patients with risk factors for chronic liver diseases in the subgroup of patients with risk factors for at visit 1 and 2. chronic liver diseases at visit 1 and/or 2. 6. Comparison of liver steatosis diagnosis accuracy 2. Comparison of liver fibrosis diagnosis accu- between CAP, steatosis scores (including FLI, HSI, racy between VCTE and fibrosis scores (includ- LAP, ION and NAFLD-LFS) and liver biopsy in the ing NAFLD fibrosis score, FIB-4, Forns index and general population and in the subgroup of patients Graupera et al. BMC Public Health 2022, 22(1):1385 Page 5 of 10 with risk factors for chronic liver diseases, in care centres, or; 3/ zip code registry. In the first sce- patients with liver biopsy available at visit 2. nario, general practitioners and primary care nurses 7. Comparison of liver steatosis diagnosis accuracy will randomly invite walk-in subjects of their respective between CAP and abdominal ultrasound in the primary care centres to participate in the study. In the general population and in the subgroup of patients second and third scenarios, subjects will be randomly with risk factors for chronic liver diseases, in invited to participate through phone calls or postal let- patients with abdominal ultrasound available at ters. In the third scenario, subjects will be electroni- visit 2. cally invited to participate based on random drawing of 8. Comparison of values obtained with M and XL social security numbers. Once subjects accept to par- probes in the assessment of LSM and CAP using ticipate in the study, they will be given an appointment VCTE at visit 2. at the primary care center or research facility where 9. Cost-effectiveness and budgetary impact of a liver they will be informed about the details of the study and fibrosis screening program for liver fibrosis detec- enrolled if they meet the inclusion/exclusion criteria tion in the general population and in the subpopu- outlined below. lation with risk factors for chronic liver diseases. Direct and indirect cost savings of early detection Inclusion criteria of liver fibrosis in subjects with risk factors for chronic liver diseases. 10. Percentage of measurement failure during VCTE 1. Age ≥ 40 years. examination at visit 1 and 2. 2. Able to give informed consent. 11. Percentage of patients with procedure-related adverse events (adverse events related to VCTE Exclusion criteria Patients meeting 1 or more of the fol- and/or liver biopsy) and serious adverse events lowing criteria cannot be selected: during the duration of the study. 12. Detection of common genetic variants, single nucleotide polymorphisms (SNPs), in patients with 1. Previously known chronic liver disease (including and without significant hepatic fibrosis or chronic cholestasis). Patients with already known liver stea- liver diseases, including genome-wide association tosis but no diagnosis of liver fibrosis or cirrhosis can studies (GWAS) and whole-genome sequencing be included. (WGS) in blood samples. 2. Subjects with mental incapacity, language barrier, 13. Incidence of cirrhosis, liver cancer, and liver-related insufficient social support or any other reason con- death and all-cause of mortality in patients with sidered by the investigator precluding adequate significant fibrosis and/or severe steatosis after 5 understanding or cooperation in the study. and 10 years from the first evaluation. 3. Subjects with a history of current malignancy includ- 14. Incidence of cardiovascular events in patients with ing solid tumors and hematologic disorders. significant fibrosis and/or severe steatosis after 5 4. Subjects with significant extrahepatic disease that and 10 years from the first evaluation. may impair short-term prognosis (including conges- tive heart failure New York Heart Association Grade IV, chronic obstructive pulmonary disease (COPD) Recruitment and enrollment of participants GOLD > 3). This is a European multicentre clinical research study 5. Subjects with kidney disease (serum creatinine > 3 undertaken in the general population without known mg/dL or undergoing renal replacement therapy). liver disease. Participating countries are Denmark, United Kingdom, France, Germany, Netherlands, Italy, Croatia and Spain. LiverScreen recruiting sites (primary care centres and university hospitals) are described in Premature withdrawal Additional File 1. A subject is free to withdraw from the study at any Subjects aged 40 years and older, without known liver time. In addition, the investigator may decide, for rea- disease, from the general population will be eligible for sons of medical prudence, to remove the subject from the study. Eligible patients will be identified following the study. The date and reasons for stopping the study EU general data protection regulation (GDPR-2018) will be clearly stated on the subject’s case report form and will be contacted either by: 1/ general practitioners and source document. or primary care nurses; 2/ electronic records at primary Graupera et al. BMC Public Health 2022, 22(1):1385 Page 6 of 10 Measurements and investigation procedures to literature [8, 10]: NFS ≥ 0.676, Forns index ≥ 6.9, Measurements and investigations will follow the study FIB-4 ≥ 2.67, APRI ≥ 1.50. plan outlined in Table 1. c) Liver biopsy. In patients with a liver biopsy available, Liver fibrosis will be estimated by three different liver fibrosis will be assessed and defined according methods: LSM, liver fibrosis scores and liver biopsy. to SAF/NASH CRN Score [21] and analyzed by two central readers. Discrepancies between two readers a) LSM will be performed in all patients using VCTE. will be re-assessed and discussed until consensus. LSM will be performed with M or XL probe follow- Liver steatosis will be estimated using four differ- the Fibroscan®. LSM will be repeated at visit 2 in ing the Automatic Probe Selection tool available on ent methods, CAP, abdominal ultrasound, liver steatosis those patients referred to the university hospital. Sig- scores and liver biopsy. nificant liver fibrosis by VCTE will be defined by a LSM ≥ 8.0 kPa with either M or XL probe. a) Liver steatosis measured by transient elastography. b) Fibrosis scores/serum biomarkers: Four different CAP using VCTE with either M or XL probe will be established liver fibrosis scores using different blood measured at the time of LSM. Liver steatosis will be tests will be determined at visit 1: NAFLD fibro- diagnosed when the value of CAP ≥ 250 dB/m [22]. sis score (NFS), Forns Index, Fibrosis-4 (FIB-4) and b) Liver steatosis measured by abdominal ultrasound. AST to Platelet Ratio Index (APRI). Significant liver Patients referred to visit 2 will be evaluated by the fibrosis will be defined when the values of the differ- hepatologist, and an abdominal ultrasound will be ent scores are above the following cut-offs, according performed. Liver steatosis assessed by ultrasound will be graded semiquantitatively (mild, moderate and severe) [23]. c) Liver steatosis measured by steatosis scores. Five dif- Table 1 Study procedures ferent liver steatosis scores using different blood tests STUDY PROCEDURES VISIT 1 VISIT 2 will be determined, including FLI, HSI, LAP, ION, NAFLD- LFS, and compared to CAP values. Signifi- Informed consent X cant liver steatosis will be defined when the values of Inclusion/exclusion criteria X the different scores are above the following cut-offs, Medical/surgical history X X according to literature [24]: FLI ≥ 60, HSI > 36, LAP Vital signs X X ≥ 80, ION ≥ 22, NAFLD-LFS ≥ -0.640. Physical examination X X d) Liver steatosis measured by liver biopsy. In patients Concomitant medication X X with a liver biopsy available, liver steatosis will be Alcohol consumption questionnaire (AUDIT) X X assessed in histological samples and defined accord- Quality of life questionnaires (EuroQoL 5d-3) X ing to SAF/NASH CRN Score [21] and analyzed by Health survey (SF-12) X two central readers. LABORATORY ASSESSMENTS HCV/HBV serologies X ALT/AST levels X X GGT/AP levels X X Sample size calculation Haematology X The sample size for the LiverScreen project has been Biochemistry X computed to answer the questions of 1/ the usefulness Coagulation X of TE as a screening method to detect significant liver Leucocyte and CRP X fibrosis among the European general population ≥ 40 Antibodies for autoimmune and celiac diseases X years, and 2/ the differences (if any) in the 5-year inci- Biochemistry: TSH, ceruloplasmin, α1AT, bilirubin X dence of liver clinical outcomes (or cardiovascular events BIOBANK or mortality) between those with and without significant Blood samples: plasma, serum, DNA. X liver fibrosis (LSM ≥ 8 kPa). Because the gold standard VC TRANSIENT ELASTOGRAPHY X X for the staging of liver fibrosis remains liver biopsy, the ABDOMINAL ULTRASOUND X sample size calculation of the study considers the final LIVER BIOPSY X number of liver biopsies needed to evaluate the concord- AE assessment X X ance between liver biopsy and VCTE. For an estimated prevalence of LSM ≥ 8 kPa of around 3%, assuming a 5% AE adverse event, AP alkaline phosphatase, α1AT α1-antitrypsin, CRP C-reactive protein, HBV hepatitis B virus, HCV hepatitis C virus, TSH thyroid stimulating of bilateral alpha error and a statistical power of 95%, a hormone sample size of 28,887 subjects would be required. If 3% Graupera et al. BMC Public Health 2022, 22(1):1385 Page 7 of 10 of the study population have altered VCTE and only 50% an intervention, both of which will be carried out accord- of them agree to have a liver biopsy performed, we will ing to the Consolidated Health Economics Evaluation have around 450-500 available liver biopsies. Considering Reporting Standards 2022 (CHEERS) [25]. all these factors, the sample size of the study will be of The first one will be an empirical Markov-chain model, 30,000 subjects. where included population will be classified in each node of the model (depending on the endpoint), and transition Statistical analyses probabilities will be obtained from validated liver-dis- Categorical parameters will be presented by means of ease progression model. Probabilistic sensitivity analysis frequencies (%). Continuous parameters will be summa- will be carried out to assess the inherent uncertainty of rized by mean ± standard deviation or median and inter- the model. For the budget impact model, costing based quartile range, where appropriate. All patients having a on resource utilization will be modeled to evaluate the VCTE examination with valid measurements [8] will be viability of such a screening intervention onto national included in the analysis population. Subjects excluded health services. The results of the model will be much from the analysis will be compared to those having a more context-specific as they will depend upon NHS VCTE examination with valid measurements using the silos. The goal of the health economic evaluation is to Chi squared test and t-test for categorical or continuous help in the design of a cost-effective screening inter- characteristics respectively. Prevalence and its 95% con- vention that minimizes its budget impact to healthcare fidence intervals (95%CI) of LSM ≥ 8 kPa will be com- providers. puted overall (primary endpoint) and in the subgroup During follow-up at 5 and 10 years for clinical events, of patients with risk factors. Analogously, prevalence of the Markov-chain model will be updated, and transition CAP ≥ 250 dB/m and its 95%CI will be computed, over- probabilities will be estimated from the 5-year follow- all and among patients with risk factors. Concordance up. Due to the multicentre nature of the study, rather between variables (LSM, fibrosis scores, CAP, steatosis than collecting cost data, comparable resource utiliza- scores, liver biopsy) will be computed. Scatter plots and tion across hospitals will be used as the unit of account, Pearson’ r linear correlation coefficients will be used to such as number of visits to the emergency room, admis- explore the relationship between continuous variables, sions and length of stay. The model will be later cali- including LSM and fibrosis scores values. Receiver oper- brated and adjusted for each of the participant countries, ating characteristic (ROC) curves, using LSM ≥ 8 kPa as as incidence, prevalence and costs may vary depending the gold standard for fibrosis, will be computed for the on country characteristics. The comparative effective- different continuous fibrosis scores. Sensitivity, speci- ness endpoints to be modelled will include: self-reported ficity, predictive values and likelihood ratios will be EuroQoL 5d-3L, liver progression and mortality. performed using LSM ≥ 8 kPa as the gold standard for fibrosis for different fibrosis categorized scores. Com- Risks and disadvantages for patients parison of values obtained with M and XL probes in the As in any screening study, the principal individual risk assessment of LSM and CAP will be performed both, for participants will be the potential overdiagnosis of a using the continuous forms of the variables with t tests chronic disease, which may lead to anxiety and unnec- (or non-parametric tests in the case these variables vio- essary investigations and hospital visits. The exhaustive late the necessary assumptions), and using the categori- evaluation at the second study visit will assess for the cal variables using the 8 kPa and 250 dB/m2 cut-offs with presence or absence of chronic liver disease, and there- Chi squared test. In addition, multivariate linear regres- fore reduce this risk of overdiagnosis. Another potential sion models and multivariate logistic regression models risk is that associated to liver biopsy. Liver biopsy will be will be computed with LSM (or CAP) as the dependent performed as a standard of care work-up in patients with variable (continuous for linear model and categorical for chronic liver disease suspected as a result of the imaging, logistic mode) to assess the effect of the M or XL and blood tests and/or VCTE evaluation. Liver biopsy is con- potential interaction with the probe size. The relative fre- sidered a safe procedure when used for diagnosing pur- quency of adverse events to the study procedures will be poses of non-malignant liver disorders. Adverse events reported in percent. associated with liver biopsy are pain at the puncture site, intraabdominal bleeding, perforation of the gallbladder Health economic evaluation or bile peritonitis [26]. The most frequent of these com- A health economic evaluation of the study will be per- plications is intraabdominal bleeding, which occurs in formed to assess the cost-effectiveness and budget impact 2.2 out of 1,000 biopsies. In the current study, all liver of the screening approach. Two models will be performed biopsies will be performed by experienced medical staff to assess the cost-effectiveness and budget impact of such at each participating university hospital. There is no Graupera et al. BMC Public Health 2022, 22(1):1385 Page 8 of 10 expected risk or discomfort related to VCTE or abdomi- Abbreviations APRI AST to platelet ratio index nal ultrasonography. CAP Controlled attenuation parameter DALY Disability-associated life years FIB-4 Fibrosis-4 Ethics FLI Fatty liver index Currently there are no known effective drugs to treat liver HSI Hepatic steatosis index ION Index of NASH fibrosis. However, treatment of the etiological factors of LAP Lipid accumulation product chronic liver diseases can induce fibrosis regression [6]. LSM Liver stiffness measurement Detection of liver fibrosis will lead to implementation of NAFLD Non-alcoholic fatty liver disease NAFLD-LFS NAFLD-liver fat score effective treatment in chronic viral hepatitis (B and C) NFS NAFLD fibrosis score and referral to withdrawal programs for alcohol-related NASH Non-alcoholic steatohepatitis liver disease. Lifestyle modification interventions can be VCTE Vibration-controlled transient elastography implemented in patients with chronic liver disease due to alcohol-related liver disease and NAFLD, the most Supplementary Information frequent etiologies in Europe. Patients with risk factors The online version contains supplementary material available at https://​doi.​ org/​10.​1186/​s12889-​022-​13724-6. for chronic liver disease but without fibrosis will also be counseled to change detrimental lifestyle habits in order Additional file 1. LiverScreen Project recruiting centers. to avoid disease development in the future. We believe Additional file 2. Safety assessment, Data collection and processing, that the benefits of participating in this observational Quality control and regulatory considerations. clinical study outweigh the risks mentioned in previous Additional file 3. Participant information sheet. sections, and we believe it to be ethically safe. Informed consent is obtained from all participants. Acknowledgements The LiverScreen Consortium includes: Marifé Alvarez, Peter Andersen, Paolo Angeli, Alba Ardèvol, Anita Arslanow, Discussion Luca Beggiato, Zahia Ben Abdesselam, Lucy Bennett, Bajiha Boutouria , The present study, an investigator-initiated study held by Alessandra Brocca, M Teresa Broquetas, Llorenc Caballeria, Valeria Calvino, the LiverScreen consortium and funded by the European Judith Camacho, Aura Capdevila, Marta Carol, Laurent Castera, Marta Cervera, Fernando Cucchietti, Anna de Fuentes, Rob de Knegt, Sonke Detlefsen, Alba Commission H2020 program, aims to investigate the use Diaz, José Diéguez Bande, Vanessa Esnault, Núria Fabrellas, Josep lluis Falco, of a screening program with a non-invasive test for liver Rosa Fernández, Celine Fournier, Matilde Fuentes, Peter Galle, Edgar García, fibrosis in the European general population. This study Montserrat García-Retortillo, Esther Garrido, Pere Ginès, Rosa Gordillo Medina, Jordi Gratacós-Gines, Isabel Graupera, Ivica Grgurevic, Indra Neil Guha, Eva comes at an especially important time, as the burden of Guix, Rebecca Harris, Elena Hernández Boluda, Rosario Hernández-Ibañez, Jordi chronic liver diseases is expected to increase in com- Hoyo, Arfan Ikram, Simone Incicco, Mads Israelsen, Marta Juan, Adria Juanola, ing years [2]. There is thus an urgent need to change the Ralf Kaiser, Patrick S Kamath, Tom H Karlsen, Maria Kjærgaard, Harry J de Koning, Marko Korenjak, Aleksander Krag, Johanne Kragh Hansen, Marcin Krawczyk, current approach, from diagnosing liver diseases late, Irina Lambert, Frank Lammert, Philippe Laboulaye, Simon Langkjær Sørensen, when the impact of interventions is limited, to diagnos- Cristina Laserna-Jiménez, Sonia Lazaro Pi, Elsa Ledain, Vincent Levy, Vanessa ing the disease earlier, when complications have not yet Londoño, Guirec Loyer, Anne Llorca, Ann T. Ma, Anita Madir, Michael Manns, Denise Marshall, M. Lluïsa Martí, Sara Martínez, Ricard Martínez Sala, Roser Masa occurred [2, 14]. This change would facilitate the applica- Font, Jane Møller Jensen, Rosa M Morillas, Laura Muñoz, Ruth Nadal, Laura tion of specific therapies that may halt the progression of Napoleone, JM Navarrete, Phillip N Newsome, Vibeke Nielsen, Martina Pérez, fibrosis in some patients and prevent them from reach- Juan Manuel Pericas Pulido, Salvatore Piano, Judit Pich, Judit Presas Escobet, Elisa Pose, Katrine Prier Lindvig, Matthias Reichert, Carlota Riba, Dominique ing the stage of decompensated cirrhosis or developing Roulot, Ana Belén Rubio, Maria Sánchez-Morata, Jörn Schattenberg, Feliu Serra- liver cancer. The current study will specifically aim to Burriel, Miquel Serra-Burriel, Louise Skovborg Just, Milan Sonneveld, Anna Soria, answer questions regarding diagnostic accuracy and cost- Christiane Stern, Patricia Such, Maja Thiele, Pere Toran, Antoni Torrejón, Marta Tonon, Emmanuel A Tsochatzis, Laurens van Kleef, Paulien van Wijngaarden, effectiveness of non-invasive tests in the diagnosis of liver Vanessa Velázquez, Ana Viu, Susanne Nicole Weber, Tracey Wildsmith fibrosis in a low prevalence setting. Ultimately, the Liver- We acknowledge the help of Nicki van Berckel and Beatriz Márquez in the Screen study will serve as a basis from which diagnostic preparation of the manuscript. pathways can be developed and adapted to each country. Authors’ contributions IG, MT, MS, JP, NF, GP, LC, FL, AK, NG, ET, PG conceptualised the project. All authors were involved with generation of the protocol. IG, MT, ATM, MS, GP Study Status and JP wrote the first draft of the manuscript. All authors listed (IG, MT, AM, The study started enrolling participants in May 2018. As MS, JP, NF, LC, RK, IG, MR, DR, JS, JP, PA, ET, IG, MG, RM, RH, JH, MF, AM, AJ, AS, MJ, MC, AD, SD, PT, CF, AL, PN, MM, HK, FS, FC, AA, MK, LK, JF, PK, TK, LC, FL, of March 2022, 14,539 subjects have been enrolled. The AK, PG) have been implicated in the development of the ongoing project last subjects are expected to be enrolled in June 2023. described in the protocol including patients. All authors (IG, MT, AM, MS, JP, Follow-up of patients in the longitudinal study will end NF, LC, RK, IG, MR, DR, JS, JP, PA, ET, IG, MG, RM, RH, JH, MF, AM, AJ, AS, MJ, MC, AD, SD, PT, CF, AL, PN, MM, HK, FS, FC, AA, MK, LK, JF, PK, TK, LC, FL, AK, PG) were 10 years after visit 1, up until June 2033. involved in editing and approving the manuscript. The corresponding author Graupera et al. BMC Public Health 2022, 22(1):1385 Page 9 of 10 attests that all listed authors meet authorship criteria and that no others meeting JMP reports having received consulting fees from Boehringer Ingelheim and the criteria have been omitted. IG, MT, MS, and AK act as guarantors. Novo Nordisk. He has received speaking fees from Gilead, and travel expenses from Gilead, Rubió, Pfizer, Astellas, MSD, CUBICIN, and Novo Nordisk. He has Funding received educational and research support from Gilead, Pfizer, Astellas, Accel‑ This study is funded by the European Commission H20/20 program, under erate, Novartis, Abbvie, ViiV, and MSD. Funds from European Commission/ the call SC1-BHC-30-2019 named “Towards risk-based screening strategies EFPIA IMI2 853966-2, IMI2 777377, H2020 847989, and ISCIII PI19/01898 for non-communicable diseases”, Project number: 847989. The funding body EAT: Consulting fees from Gilead, Intercept, Pfizer and Orphalan. played no role in the design of the study, collection, analysis, and interpreta‑ JMS: Consultancy: Boehringer Ingelheim, BMS, Echosens, Genfit, Gilead Sci‑ tion of data, nor in writing the manuscript. ences, Intercept Pharmaceuticals, Madrigal, Novartis, Novo Nordisk, Nordic Bio‑ PG and members of his group have been supported by AGAUR 2017SGR- science, Pfizer, Roche, Sanofi, Siemens Healthcare GmbH. Research Funding: 01281. CIBEREHD (Centro de Investigacion Biomedica en Enfermedades Gilead Sciences, Boehringer Ingelheim, Siemens Healthcare GmbH. Speakers Hepaticas y Digestivas), and PI18/01330- PI18/00662 – PI18/00862 from the Bureau: Falk Foundation MSD Sharp & Dohme GmbH. Fundación de Investigación Sanitaria and cofunded by Instituto Carlos III RMM: Speaker: Gilead, Abbvie, Intercept; Consultant: Intercept, AbbVie. (ISCIII)-Subdirección General de Evaluación and the European Regional Devel‑ HJdK reports speakers’ fee from MSD on lung cancer screening symposium. opment Fund. Also supported in part by a grant from Gilead’s Investigator AK has served as speaker for Norgine, Siemens and Nordic Bioscience and partici‑ sponsored research program: study number IN-ES-989-5309. pated in advisory boards for Norgine and Siemens, all outside the submitted work. All other authors have declared no conflicts. Availability of data and materials Not applicable. Author details 1 For more details regarding Safety assessment, Data collection and processing, Liver Unit Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain. 2 Quality control and Regulatory considerations see Additional File 2. Institut D’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain. 3 Centro de Investigación En Red de Enfermedades Hepáticas Y Digesti‑ vas (Ciberehd), Barcelona, Spain. 4 Faculty of Medicine and Health Sciences, Uni‑ Declarations versity of Barcelona, Barcelona, Spain. 5 Centre for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, and Institute Ethics approval and consent to participate for Clinical Research, University of Southern Denmark Odense, Odense, Den‑ This study was approved by the research and ethics board of each participat‑ mark. 6 Epidemiology, Statistics, and Prevention Institute, University of Zurich, ing site, protocol version 1.1 9 January 2018: Comitè d’Ètica d’Investigació Zurich, Switzerland. 7 Clinical Trial Unit, Hospital Clínic, 08036 Barcelona, Spain. Clínica del Hospital Clínic de Barcelona (Spain), Comité de Ética de la Investi‑ 8 Unitat de Suport a la Recerca Metropolitana Nord, Fundació Institut Universi‑ gación del Hospital Universitari Germans Trias i Pujol (Spain), Comité de Ética tari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), de la Investigación Parc de Salut Mar (Spain), Comité de Ética de Investigación Metropolitana Nord, IDIAP Jordi Gol, ICS Institut Català de la Salut, Barcelona, del Hospital Universitari Vall d’Hebron (Spain), Comitè d’Ètica d’Investigació Spain. 9 Department of Gastroenterology and Hepatology, Erasmus MC Uni‑ IDIAP Jordi Gol (Barcelona), Ethics Board of the University Hospital Dubrava versity Medical Centre, Rotterdam, the Netherlands. 10 Department of Gastro‑ (Croatia), Comité de Protection des Personnes Sud Méditerranée V (France), enterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, Comitato Etico per la Sperimentazione Clinica Della Provincicia di Padova University of Zagreb School of Medicine and Faculty of Pharmacy and Bio‑ (Italy), London-Riverside Research Ethics Committee, NHS Health Research chemistry, Zagreb, Croatia. 11 Department of Medicine II, Saarland University Authority (UK), East Midlands-Derby Research Ethics Committee, NHS Health Medical Center, Homburg, Germany. 12 Unité d’Hépatologie, Hôpital Avicenne, Research Authority (UK), Ethik-Kommission bei der Landersärztekammer AP-HP, Université Paris 13, Bobigny, France. 13 Metabolic Liver Research Program, Rheinland-Pfalz, Mainz (Germany), Ethikommission der Ärztekammer des Saar‑ Department of Internal Medicine I, University Medical Centre of the Johannes landes, Saarbrücken (Germany). For Odense Universitetshospital, Denmark, an Gutenberg, Mainz, Germany. 14 Liver Unit, Department of Internal Medicine, amendment was made to an ongoing protocol that recruited similar patients Hospital Universitari Vall d´Hebron, Vall d’Hebron Institut de Recerca (VHIR) and collected the same data as the current project (ethics committee for the , Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain. 15 Universi‑ Region of Southern Denmark, protocol ID S-20170087). For Erasmus University tat Autònoma de Barcelona, Barcelona, Spain. 16 Unit of Internal Medicine Medical Center Rotterdam, the need for approval of the protocol was waived and Hepatology (UIMH), Department of Medicine (DIMED), University-Teaching due to the fact the center already has multiple studies in progress in “healthy Hospital of Padova, Padua, Italy. 17 UCL Institute for Liver and Digestive Health, volunteers” in a special research center called ERGO (Erasmus Rotterdam Royal Free Hospital, University College of London (UCL), London, UK. 18 NIHR GezondheidsOnderzoek) approved by the Ministry of Health, Welfare and Nottingham Biomedical Research University Mainz Centre, Nottingham Uni‑ Sport as of December 19, 2016 and as such considered “population screening”. versity Hospitals NHS Trust and the University of Nottingham, Nottingham, UK. Any changes in the master version of the protocol will be reviewed and 19 Liver Section, Gastroenterology Department, Hospital del Mar, Department approved by all partners and a protocol amendment will be evaluated and of Medicine, IMIM, Barcelona, Spain. 20 Liver Unit, Hospital Germans Trias i Pujol, approved by each of the Ethics Committee before implemented. IGTP, Badalona, Spain. 21 Institut Catala de la Salut (ICS). BCN. Ambit d’Atencio Signed informed consent is obtained from all participants. Primaria, Barcelona, Spain. 22 Department of Pathology. Centre of Biomedical Diagnosis. Hospital Cínic, Barcelona, Spain. 23 Department of Pathology, Odense Consent for publication University Hospital (OUH), University of Southern Denmark, Odense, Denmark. Not applicable. The main results of the project will be by the LiverScreen 24 Echosens, Paris, France. 25 National Institute for Health Research Biomedical Consortium. Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, UK. 26 Health Sciences, Hanno‑ Competing interests ver Medical School MHH, Hannover, Germany. 27 Department of Public Health, PG declares he has received Investigator Initiated Research funding from: Erasmus University Medical Center, Rotterdam, the Netherlands. 28 Barcelona Gilead, Grifols and Mallinckrodt Pharmaceuticals. He has participated on advi‑ Super Computing Center (BSC), Barcelona, Spain. 29 European Liver Patients’ sory boards or consultancy for: Gilead, Grifols, Mallinckrodt, Novartis, Martin Association, Brussels, Belgium. 30 Genesis Biomed, Barcelona, Spain. 31 Division Pharmaceuticals, and Ferring. of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Sci‑ LC: Consultancy for Allergan, Alexion, Echosens, Gilead, Intercept, MSD, Novo ence, Rochester, Minnesota, USA. 32 Oslo University hospital, Oslo, Norway. Nordisk, and Pfizer. Speaker bureau for Abbvie, Echosens, Gilead, Intercept, 33 Department of Hepatology, Hôpital Beaujon, Assistance Publique‑Hôpitaux and Novo Nordisk. Research grant from Gilead. de Paris, Clichy, Université de Paris, Paris, France. 34 Institute for Occupational IG: Speaking fees from Gilead, Abbvie, Intercept. Medicine and Public Health, Saarland University, Homburg, Germany. 35 Han‑ MT: Speaking fees from Siemens, Echosens, Norgine; consultancy fee from GE nover Medical School (MHH), Hannover, Germany. Healthcare. RJK has received Investigator Initiated Research funding from: Gilead, has worked on advisory boards for: AbbVie, BMS, Gilead, Merck, has spoken for AbbVie, Echosens, Gilead, Philips. Graupera et al. BMC Public Health 2022, 22(1):1385 Page 10 of 10 Received: 16 June 2022 Accepted: 1 July 2022 Gastroenterology. 2005;128:343–50. https://​doi.​org/​10.​1053/j.​gastro.​2004.​ Published: 19 July 2022 11.​018. 17. 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