Short summary

Liver-Screen is a multicenter European study to assess the prevalence of significant liver fibrosis using transient elastography (TE using FibroScan) in the general population. The study will include 20,000 subjects above 40 years of age who have no previously known chronic liver disease. All subjects will be investigated with TE, which is an ultrasound-based, non-invasive liver fibrosis marker. Participant with elevated liver stiffness >8 kPa measured by TE will be offered liver biopsy.

Rationale

Liver cirrhosis is a major cause of death worldwide and accounts for a large number of hospitalizations and high resource utilization. In 2015, approximately 2 million people died in the world due to cirrhosis or hepatocellular carcinoma (which usually occurs with underlying cirrhosis), 3.7% of all deaths occurring that particular year. This death rate is higher than that of malaria, colorectal cancer, or breast cancer. Main causes of cirrhosis are hepatitis B and C virus infection, increased alcohol consumption, and non-alcoholic fatty liver disease (NAFLD), the latter often associated with obesity and type-2 diabetes mellitus. Currently, most cases of cirrhosis are diagnosed when patients develop complications related to portal hypertension, liver failure, or liver cancer. There are no strategies for early detection of cirrhosis before decompensation or cancer occurs. This is important because therapies are less effective in late stages compared to early stages.

Development of cirrhosis, whatever the cause is, occurs very slowly over a period of 2-3 decades. In general, patients are not diagnosed during this period of time because the disease is asymptomatic and patients do not seek medical attention2. The main factor predicting long-term outcome of patients with chronic liver disease in early stages is the existence of liver fibrosis4-6. Interestingly, standard liver tests used to evaluate liver function, such as serum aminotransferase activities or liver ultrasound, are not accurate methods to detect fibrosis. In recent years, several non-invasive methods assessing the presence and severity of liver fibrosis have been developed. These methods rely either on a blood test or on liver stiffness measurement (LSM), using transient elastography (TE) (FibroScan), which is the most commonly used and validated tool for staging chronic liver diseases6-8. TE is a widely available point-of-care technique that can be performed by nurses after a short training period. This technique thus seems particularly suited for the early detection of chronic liver diseases either in the general population or in high-risk populations, particularly in patients with obesity and/or diabetes or excessive alcohol consumption8. Whether a screening strategy with non-invasive methods including TE or serum biomarkers in general population is a cost-effective strategy in terms of health outcomes and treatment costs is not known.

Therefore, we hypothesize that a screening program with a non-invasive method for diagnosis of liver fibrosis may be useful in detecting subjects with advanced liver fibrosis. This would allow the implementation of treatment to halt progression or even favor regression of fibrosis, thus preventing the development of hard clinical outcomes related to the liver disease, such as liver cirrhosis, liver cancer, or liver-related death.

This is a population-based study aimed at investigating whether liver stiffness measurement using transient elastography, a simple and widely available non-invasive method for detecting liver fibrosis, is useful to identify subjects with pre-symptomatic significant chronic liver disease among general population.

In a second stage, we will evaluate the incidence of liver-related and cardiovascular-related outcomes after 5 and 10 years of follow-up in patients with and without liver fibrosis as diagnosed by TE.

Description of the cohort

The cohort will consist of 20,000 participants from the general population, recruited by random drawing from centers in Denmark, Spain, France, Italy, England, the Netherlands and Germany.

Data and biological material

Inclusion Criteria

Patients included into the study must meet all the following criteria:

1) Age above 40 years

2) Able to give informed consent

Exclusion Criteria

Patients meeting 1 or more of the following criteria cannot be selected:

1) Previously known chronic liver disease (including cholestasis). Patients with already known liver steatosis but no diagnosis of liver fibrosis or cirrhosis can be included

2) Subjects with mental incapacity, language barrier, insufficient social support or any other reason considered by the investigator precluding adequate understanding or cooperation in the study

3) Subjects with a history of current malignancy including solid tumors and hematologic disorders

4) Subjects with significant extrahepatic disease that may impair short-term prognosis (including congestive heart failure New York Heart Association Grade IV, COPD GOLD over3)

5) Subjects with kidney disease (serum creatinine over 3mg/dL or under renal replacement therapy)

Subjects will attend a primary care center where a study nurse under the supervision of a physician will perform a first visit (VISIT 1). This visit will entail evaluation of the patient's medical history and a physical examination with general blood tests, LSM and CAP using TE and questionnaires related to alcohol consumption (AUDIT, see Appendix 6), quality of life (EuroQoL 5d-3, see Appendix 4) and health status (SF-12, see Appendix 5). Blood samples will be taken for biobanking storage.

According to the results of the LSM and liver tests performed at visit 1, two different groups will emerge:

• Screened group A (SG-A): High-risk group for liver fibrosis, defined by those patients with LSM over 8 kPa obtained with either M or XL probe or with ALT over 1.5 x upper limits of normal value.
• Screened group B (SG-B): Low-risk group for liver fibrosis, defined by LSM < 8 kPa and normal ALT or <1.5 x upper limit of normal value.

Subjects with presumed liver fibrosis (increased LSM or abnormal ALT values) (SG-A) will be subsequently evaluated in a second visit with-in the next 3 months (VISIT 2) at the University Hospital. The second visit will be performed by hepatologists according to a standardized work-up that includes evaluation of the patient's medical history, physical examination with complete liver tests, TE and abdominal ultrasound. Afterwards, a liver biopsy will be proposed to the patient for confirmation and staging of liver disease or if NAFLD or Alcoholic liver disease is suspected, as standard of care management.

Biobank material: Plasma and serum from inclusion visit 1

Questionnaires: SF-12, AUDIT, EuroQoL 5d-3

No register data

Outcome data collected from patient files, 5 and 10 years after study inclusion.

Collaborating researchers and departments

Hospital Clinic de Barcelona Spain

• Pere Ginès
• Isabel Graupera
• Marta Aldea

Hôpital Beaujon, Clichy France

• Laurent Castera, 

Saarland University Medical Centre Germany

• Frank Lammert

University Hospital Mainz Germany

• Peter Galle

Hôpital Avicenne, Bobigny France

• Dominique Roulot

University of Padova Italy

• Paolo Angeli

USR Metropolitan Nord CatSalut Spain

• Llorenç Caballeria
• Guillem Pera
• Pere Torán, 

Odense University Hospital Denmark

• Aleksander Krag
• Maja Thiele

University of Nottingham United Kingdom of GB

• I. Neil Guha

Erasmus Medical Center Rotterdam The Netherlands

• Sarwa Darwish Murad

University of Barcelona Spain

• Núria Fabrellas

CRES, University Pompeu Fabra Spain

• Miquel Serra

Hospital Germans Trias i Pujol Spain

• Rosa M Morillas

Publications associated with the project

Serra-Burriel, M., Graupera, I., Torán, P., Thiele, M., Roulot, D., Wong, V.W-S., Guha, I.N., Fabrellas, N., Arslanow, A., Expósito, C., Hernández, R., Wong, G.L-H., Harman, D., Murad, S.D., Krag, A., Pera, G., Angeli, P., Galle, P., Guruprasad, A., Caballeria, L., Castera, L., Ginès, P., Lammert, F., on behalf of the investigators of the LiverScreen Consortium, Transient elastography for screening of liver fibrosis: costeffectiveness analysis from six prospective cohorts in Europe and Asia, Journal of Hepatology (2019), doi: https://doi.org/10.1016/j.jhep.2019.08.019