Short summary

In Denmark approx. 500.000 persons have a damaging alcohol consumption level and 140.000 persons are dependent of alcohol. Alcohol overconsumption leads to a higher risk of liver disease. Today the symptoms of liver disease are often spotted too late in the development of the disease thus the possibilities for prevention and early treatment are limited.

Rationale

This prospective study aims to determine the presence of liver fibrosis in patients with alcohol overconsumption, investigate diagnostic and prognostic markers for diagnosing early fibrogenic disease by non-invasive and minimally invasive methods. The cohort consists of 450 patients with ongoing or prior chronic, excessive alcohol use. The non-invasive methods to be used are:

• Real-time quantitative shear wave elastography (a multi-dimensional method, which generate an atlas of the liver stiffness, so that the measurements can be made in the largest and stiffest area)
• Transient elastography (one-dimensional method)
• Protein Fingerprinting (blood samples analyzed for fibrosis markers)
• The Enhanced Liver Fibrosis test (an algorithm of three direct markers of fibrosis)
• M30 and M65 cytokine-18 based markers of apoptosis and necrosis

Liver biopsies are taken to ensure the correct diagnosis has been made.

This project is part of the GALAXY consortium (Gut-and-liver-axis in alcoholic liver fibrosis), which is exploring the role of the gut microbiome in alcoholic liver fibrosis to improve understanding, diagnosis, prevention and treatment of chronic liver disease. Additionally, the following projects are also a part of the GALAXY consortium: OP_80 and OP_239.

Description of the cohort

The patients are recruited in the area of Odense from general practice, municipal alcohol rehabilitation clinics and patients referred for liver investigations at OUH. Ads will be made in newspapers and on the Internet.

Data and biological material

The project includes data from baseline inclusion, one follow up visit 12 months or more from baseline and clinical outcome data from patient files. Data is up loaded to OPEN Projects. There are data from blood analysis, histology, questionnaires and imaging diagnostics. Data is linked to register data from The Receipt Register, The Register of Cause of Death and The Danish Cancer Registry. Besides blood and liver samples for standard analyses, blood, liver tissue, saliva, feces and urine samples are collected for biobanking.

Collaborating researchers and departments

Research Unit for Gastroenterology and Hepatology, Department of Medical Gastroenterology, OUH Odense University Hospital

• Postdoc Maja Thiele, MD
• Professor Aleksander Krag

Publications associated with the project

Lindvig KP, Hansen TL, Madsen BS, Kjaergaard M, Møller L, Detlefsen S, Krag A, Thiele M. Diagnostic accuracy of routine liver function tests to identify patients with significant and advanced alcohol-related liver fibrosis. Scand J Gastroenterol. 2021 Sep;56(9):1088-1095. doi: 10.1080/00365521.2021.1929450. Epub 2021 Aug 20. PMID: 34415817.

Israelsen M, Guerrero Misas M, Koutsoumourakis A, Huang Y, Thiele M, Hall A, Rasmussen D, Covelli C, Buzzetti E, Prat LI, Roccarina D, Detlefsen S, Luong TV, Quaglia A, Krag A, Jeffrey G, Pinzani M, Tsochatzis EA. Collagen proportionate area predicts clinical outcomes in patients with alcohol-related liver disease. Aliment Pharmacol Ther. 2020 Dec;52(11-12):1728-1739. doi: 10.1111/apt.16111. Epub 2020 Oct 12. PMID: 33044010.

Israelsen M, Juel HB, Detlefsen S, Madsen BS, Rasmussen DN, Larsen TR, Kjærgaard M, Fernandes Jensen MJ, Stender S, Hansen T, Krag A, Thiele M; GALAXY and MicrobLiver consortiak. Metabolic and Genetic Risk Factors Are the Strongest Predictors of Severity of Alcohol-Related Liver Fibrosis. Clin Gastroenterol Hepatol. 2020 Dec 4:S1542-3565(20)31628-1. doi: 10.1016/j.cgh.2020.11.038. Epub ahead of print. PMID: 33279778.

Van Espen L, Bak EG, Beller L, Close L, Deboutte W, Juel HB, Nielsen T, Sinar D, De Coninck L, Frithioff-Bøjsøe C, Fonvig CE, Jacobsen S, Kjærgaard M, Thiele M, Fullam A, Kuhn M, Holm JC, Bork P, Krag A, Hansen T, Arumugam M, Matthijnssens J. A Previously Undescribed Highly Prevalent Phage Identified in a Danish Enteric Virome Catalog. mSystems. 2021 Oct 26;6(5):e0038221. doi: 10.1128/mSystems.00382-21. Epub 2021 Oct 19. PMID: 34665009; PMCID: PMC8525569.

Lackner C, Stauber RE, Davies S, Denk H, Dienes HP, Gnemmi V, Guido M, Miquel R, Paradis V, Schirmacher P, Terracciano L, Berghold A, Pregartner G, Binder L, Douschan P, Rainer F, Sygulla S, Jager M, Rautou PE, Bumbu A, Horhat A, Rusu I, Stefanescu H, Detlefsen S, Krag A, Thiele M, Cortez-Pinto H, Moreno C, Gouw ASH, Tiniakos DG. Development and prognostic relevance of a histologic grading and staging system for alcohol-related liver disease. J Hepatol. 2021 Oct;75(4):810-819. doi: 10.1016/j.jhep.2021.05.029. Epub 2021 Jun 11. PMID: 34126105.

Madsen, B. S., Thiele, M., Detlefsen, S., Kjaergaard, M., Møller, L. S., Trebicka, J., Nielsen, M. J., Gudmann, N. S., Leeming, D. J., Karsdal, M. A., & Krag, A. (2021). PRO-C3 and ADAPT algorithm accurately identify patients with advanced fibrosis due to alcohol-related liver disease. Alimentary Pharmacology & Therapeutics, 54(5), 699-708. https://doi.org/10.1111/apt.16513

Papatheodoridi M, Hiriart JB, Lupsor-Platon M, Bronte F, Boursier J, Elshaarawy O, Marra F, Thiele M, Markakis G, Payance A, Brodkin E, Castera L, Papatheodoridis G, Krag A, Arena U, Mueller S, Cales P, Calvaruso V, de Ledinghen V, Pinzani M, Tsochatzis EA. Refining the Baveno VI elastography criteria for the definition of compensated advanced chronic liver disease. J Hepatol. 2021 May;74(5):1109-1116. doi: 10.1016/j.jhep.2020.11.050. Epub 2020 Dec 9. PMID: 33307138.

Rasmussen DN, Thiele M, Johansen S, Kjærgaard M, Lindvig KP, Israelsen M, Antonsen S, Detlefsen S, Krag A; GALAXY; MicrobLiver consortia. Prognostic performance of 7 biomarkers compared to liver biopsy in early alcohol-related liver disease. J Hepatol. 2021 Nov;75(5):1017-1025. doi: 10.1016/j.jhep.2021.05.037. Epub 2021 Jun 10. PMID: 34118335; PMCID: PMC8522804.

Thiele M, Johansen S, Gudmann NS, Madsen B, Kjaergaard M, Nielsen MJ, Leeming DJ, Jacobsen S, Bendtsen F, Møller S, Detlefsen S, Karsdal M, Krag A; GALAXY Consortium. Progressive alcohol-related liver fibrosis is characterised by imbalanced collagen formation and degradation. Aliment Pharmacol Ther. 2021 Oct;54(8):1070-1080. doi: 10.1111/apt.16567. Epub 2021 Aug 24. PMID: 34428307.

Torp N, Israelsen M, Madsen B, Lutz P, Jansen C, Strassburg C, Mortensen C, Knudsen AW, Sorensen GL, Holmskov U, Schlosser A, Thiele M, Trebicka J, Krag A. Level of MFAP4 in ascites independently predicts 1-year transplant-free survival in patients with cirrhosis. JHEP Rep. 2021 Mar 29;3(3):100287. doi: 10.1016/j.jhepr.2021.100287. Erratum in: JHEP Rep. 2021 Aug 27;3(5):100353. PMID: 34041469; PMCID: PMC8141937.