Liver cirrhosis is the 13th leading cause of years of life lost worldwide and the 7th in Denmark. It causes 1.2 million deaths annually and is one of the leading causes of hospital admissions. Cirrhosis represents a major worldwide health issue due to the high mortality rate in combination with a significant economic burden of the disease on health care systems and advanced social burden on patients and relatives.
Cirrhosis is the final consequence of liver disease, which may be caused by several etiological factors including alcohol, type 2 diabetes mellitus (T2DM), the metabolic syndrome (MetS), obesity or a combination of these factors. These factors are very common worldwide and chronic liver disease is therefore highly prevalent. The global prevalence of non-alcoholic fatty liver disease (NAFLD) is estimated to be 25.2%, and alcohol causes more than 50% of all deaths due to cirrhosis. It is expected that the overall burden of liver disease will increase due to the obesity epidemic and continued high rates of harmful alcohol drinking.
Liver fibrogenesis occurs over decades, but the disease is rarely diagnosed in the pre-cirrhotic stage or in compensated cirrhosis because it remains asymptomatic. Currently, 75% of patients are diagnosed with a decompensating event, most commonly ascites. At this stage of disease, the median survival is only three years.
Timely diagnosis would allow for identification of the etiological factors driving the fibrogenesis and allow specific targeted interventions and timely institution of preventive measures.
The gold standard for diagnosing non-alcoholic steatohepatitis (NASH), that can lead to liver fibrosis, and staging of liver fibrosis is liver biopsy, but liver biopsies have major limitations such as invasiveness, high costs and sampling variability. Given the high prevalence of ALD and NAFLD worldwide, liver biopsies cannot be proposed to all patients. As a consequence there has been a growing interest for alternative non-invasive strategies. Non-invasive methods rely on two approaches: Imaging techniques and serum biomarkers. The reference non-invasive method is transient elastography (TE; FibroScan). TE is based on the physical properties of the liver and measures liver stiffness to evaluate the amount of fibrosis in the liver. We have recently showed that liver stiffness correlates highly with liver fibrosis and has excellent accuracy for the diagnosis of significant alcoholic fibrosis and cirrhosis. Serum biomarkers can be divided in direct and indirect markers. The widely used "liver blood tests" - or indirect markers of liver fibrosis - reflect the liver function, hepatic inflammation, cholestasis or cholangiocyte damage. Direct markers of liver fibrosis reflects the extracellular matrix (ECM) generation and includes the Enhanced Liver Fibrosis test and neoepitope markers of ECM turnover. Elastography is probably superior to serum markers for detecting significant fibrosis and cirrhosis but combining elastography with indirect and/or direct serum markers may increase diagnostic accuracy and is recommended in European guidelines.
Current guidelines provide conflicting recommendations on screening in diabetic patients due to lack of data. An ALD and NAFLD screening program may be in accordance with Wilson and Jungners ten principles of early disease detection. Secondary prevention of ALD and NAFLD would require an assessment of benefit, harms and costs of a screening program of at-risk patients.
The identification of patients in early stages of chronic liver diseases faces two major challenges: (1) Is there a reliable methods for early diagnosis? (2) Can this method be used for screening in at-risk populations and (3) if so; does this improve the patients' prognosis?
We aim to evaluate the aptitude of TE as a screening tool for advanced liver fibrosis based on analyses of benefit, harm, detection rate, technical applicability and prognostic potential. We will use an 8.0 kPa cut-off value to rule out advanced fibrosis.
The objectives of this study are therefore: (1) to screen 3000 patients at risk of ALD or NAFLD and 1000 randomly selected participants from the general population for advanced fibrosis with TE; (2) to investigate benefits and harms of screening for advanced fibrosis in a population-level screening programme, compared to unscreened control cohorts from the Inter99 study and the Copenhagen and Odense alcohol rehabilitation cohorts; (3) in patients with a positive screening test, to investigate the accuracy, prognostic potential and applicability of imaging and serum non-invasive markers to diagnose advanced fibrosis, using liver biopsy as reference.
Data and biological material
The biobank will contain material from study participants from visit 0, 1 and 2. The material at visit 0 and 2 is 110 ml. blood, 9 ml. urine, 2 ml. saliva and 20 grams of feces. The material from visit 1 is 110 ml blood and 10 mm x 0.4 mm liver tissue.
Questionaires: Food questionaires, Quality of life, AUDIT, Consequences of screening
We will assess clinical outcomes 1, 5 and 10 years after inclusion. Clinical outcomes will be investigated from patient files and national registers (CPR registry, Landspatientregisteret, Cancerregisteret, Dødsårsagsregisteret, Den Nationale Receptdatabase, receptudstedelser i Fælles medicinkort (FMK) og i Sundhedsdatastyrelsens blodprøveregister).
We define clinical outcomes as:
- All cause mortality
- Disease specific mortality: liver related and cardio-vascular
- All cause hospitalizations
- Disease specific hospitalizations: liver related and cardio-vascular
- Progression to liver-related complications:
- Hepatic encephalopathy, covert or overt
- Spontaneous bacterial peritonitis
- Variceal bleeding
- Hepatocellular carcinoma
- MELD-Na score more than 15
We will also address progression of liver disease by evidence of clinically significant portal hypertension.
Collaborating researchers and departments
Department of Gastroenterology and hepathology, Odense University Hospital
- Aleksander Krag, MD, PhD, professor of Hepatology
- Maja Thiele, MD, PhD, associate professor
- Linda Møller, MD, PhD, postdoctoral fellow
- Ditlev Rasmussen, MD, PhD student
- Bjørn Stæhr Madsen, MD, PhD student
- Camilla Dalby Hansen, MD-PhD student
- Suganya Ganesalingam, MD, PhD student
- Mads Israelsen, MD, PhD student
- Katrine Thorhauge, pregraduate research fellow
- Thor Lars Hansen, pregraduate research fellow
Unit for Clinical Alcohol Research, Institute for Clinical Research, University of Southern Denmark
- Anette Søgaard Nielsen, MD, PhD, associate professor of psychiatry
Emergency Department (FAM), Odense University Hospital
- Annmarie Touborg Lassen, MD, PhD and professor of emergency medicine
Department of endocrinology, Odense University hospital
- Henning Beck Nielsen, MD, professor of endocrinology
- Kurt Højlund, MD, professor of endocrinology
Department of Clinical Biochemistry and Pharmacology, Odense University Hospital
- Lars Melholt, professor of clinical biochemistry
Department of Pathology, Odense University Hospital
- Sönke Detlefsen, MD, associate professor
Department of Clinical Biochemistry, Odense University Hospital Svendborg
- Steen Antonsen, chief consultant
Department of Internal Medicine, Esbjerg University Hospital of South-West Jutland
- Mette Munk Lauridsen, MD, PhD, postdoctoral fellow
- Torben Knudsen, MD, chief consultant
The Copenhagen Alcohol Cohort, National Institute of Public Health, University of Southern Denmark
The Inter99 study, NNF Center for Metabolic Research, University of Copenhagen
The LiverScreen study, Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Spain
Nordic Bioscience A/S, Denmark
- Morten Karsdal, professor, CEO
VLV Bio, Peviva AB, Sweden
- Richard Hermann, managing director
Manatee APS, Denmark
Siemens Healthcare A/S, Denmark
Department of Pathology, University Paris-Diderot, France
- Pierre Bedossa, professor
The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and University College London Institute for Liver and Digestive Health, London, UK
- Emmanuel Tsochatzis, MD, associate professor
Novo Nordisk Center for Proteine Research and Max Planck Institute of Biochemistry, Department of Proteomics and Signal Transduction, München, Germany
Steno Diabetes Center, Gentofte, Denmark
Novo Nordisk Center for Basic Metabolic Research, University of Copenhagen
- Torben Hansen, MD, PhD, professor
Department of Biochemistry and Molecular Biology, University of Southern Denmark
- Susanne Mandrup, professor
Biomedical Research Foundation, Academy of Athens, Greece
European Molecular Biology Laboratory, EMBL, University of Heidelberg, Germany
- Michael Kuhn, postdoctoral fellow
Department for Visceral Surgery and Medicine, University Hospital Bern, Switzerland
Laboratory for Fibrosis and Portal Hypertension, Department of Internal Medicine 1, University of Bonn, Germany
- Jonel Trebicka, adjunct professor
Department of Health Management and Health Economics, University of Oslo, Norway
- Hans Melberg, associate professor
Department of Health Economics, Universitet Pompeu Fabra, Barcelona, Spain
NNF Center for Proteine Research, Disease Systems Biology Program
- Lars Juhl Jensen, professor
NNF Center for Basic Metabolic Research, University of Copenhagen
- Manimozhian Arumugam, associate professor