TY - JOUR

T1 - Prognostic performance of 7 biomarkers compared to liver biopsy in early alcohol-related liver disease

AU - Rasmussen, Ditlev Nytoft

AU - Thiele, Maja

AU - Johansen, Stine

AU - Kjærgaard, Maria

AU - Lindvig, Katrine Prier

AU - Israelsen, Mads

AU - Antonsen, Steen

AU - Detlefsen, Sönke

AU - Krag, Aleksander

AU - Anastasiadou, Ema

AU - Arumugam, Manimozhian

AU - Bork, Peer

AU - Hansen, Torben

AU - Hartoft, Christina

AU - Israelsen, Hans

AU - Karsdal, Morten

AU - Legido-Quigley, Cristina

AU - Melberg, Hans Olav

AU - Trebicka, Jonel

AU - Mann, Mathias

AU - Matthijnssens, Jelle

AU - MicrobLiver consortia

N1 - Funding Information: This project received funding through the GALAXY project from the European Union's Horizon 2020 Framework Programme for Research and Innovation, Grant Agreement number 668031, through the MicrobLiver project from the Novo Nordic Foundation Challenge Programme, grant number NNF15OC0016692, and from the Research Foundations at University of Southern Denmark, Odense University Hospital and Region of Southern Denmark. Siemens Healthcare A/S (Ballerup, Denmark) provided the assays used for measuring the enhanced liver fibrosis test, and partly funded the salary for collecting outcome data without restrictions. The Toyota Foundation and The AP Moeller Foundation granted funds to purchase the FibroScan and Aixplorer systems. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Funding Information: This project received funding through the GALAXY project from the European Union’s Horizon 2020 Framework Programme for Research and Innovation , Grant Agreement number 668031 , through the MicrobLiver project from the Novo Nordic Foundation Challenge Programme, grant number NNF15OC0016692 , and from the Research Foundations at University of Southern Denmark , Odense University Hospital and Region of Southern Denmark . Siemens Healthcare A/S (Ballerup, Denmark) provided the assays used for measuring the enhanced liver fibrosis test, and partly funded the salary for collecting outcome data without restrictions. The Toyota Foundation and The AP Moeller Foundation granted funds to purchase the FibroScan and Aixplorer systems. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: © 2021 The Authors

PY - 2021

Y1 - 2021

N2 - Background & Aims: Alcohol is the most common cause of liver-related mortality and morbidity. We therefore aimed to assess and compare the prognostic performance of elastography and blood-based markers to predict time to the first liver-related event, severe infection, and all-cause mortality in patients with a history of excess drinking. Methods: We performed a prospective cohort study in patients with early, compensated alcohol-related liver disease. At baseline, we obtained a liver biopsy, transient elastography (TE), 2-dimensional shear-wave elastography (2D-SWE), enhanced liver fibrosis test (ELF), FibroTest, fibrosis-4 index (FIB-4), non-alcoholic fatty liver fibrosis score (NFS) and Forns index. We compared C-statistics and time-dependent AUC for prognostication. We used validated cut-off points to create 3 risk groups for each test: low, intermediate and high risk. Results: We followed 462 patients for a median of 49 months (IQR 31–70). Median age was 57 years, 76% were males, 20% had advanced fibrosis. Eighty-four patients (18%) developed a liver-related event after a median of 18 months (7-34). TE had the highest prognostic accuracy, with a C-statistic of 0.876, and time-dependent AUC at 5 years of 0.889, comparable to 2D-SWE and ELF. TE, ELF and 2D-SWE outperformed FibroTest, FIB4, NFS, Forns index and biopsy-verified fibrosis stage. Compared to patients with TE <10 kPa, the hazard ratios for liver-related events for TE 10–15 kPa were 8.1 (3.2–20.4), and 27.9 (13.8–56.8) for TE >15 kPa. Periods of excessive drinking during follow-up increased the risk of progressing to liver-related events, except for patients in the low-risk groups. Conclusion: TE, ELF and 2D-SWE are highly accurate prognostic markers in patients with alcohol-related liver disease. Easy-to-use cut-offs can distinguish between substantially different risk profiles. Lay summary: Alcohol is the leading cause of death and illness due to liver disease. In this study, we assessed the ability of biomarkers to predict the risk of developing symptomatic liver disease in patients with early stages of alcohol-related liver disease. We found that several tests accurately predicted the risk of liver-related events such as ascites, esophageal varices and hepatic encephalopathy during an average follow-up of 4.1 years. Liver stiffness measurements by ultrasound elastography and the enhanced liver fibrosis test performed best. By using them, we were able to stratify patients into 3 groups with significantly different risks.

AB - Background & Aims: Alcohol is the most common cause of liver-related mortality and morbidity. We therefore aimed to assess and compare the prognostic performance of elastography and blood-based markers to predict time to the first liver-related event, severe infection, and all-cause mortality in patients with a history of excess drinking. Methods: We performed a prospective cohort study in patients with early, compensated alcohol-related liver disease. At baseline, we obtained a liver biopsy, transient elastography (TE), 2-dimensional shear-wave elastography (2D-SWE), enhanced liver fibrosis test (ELF), FibroTest, fibrosis-4 index (FIB-4), non-alcoholic fatty liver fibrosis score (NFS) and Forns index. We compared C-statistics and time-dependent AUC for prognostication. We used validated cut-off points to create 3 risk groups for each test: low, intermediate and high risk. Results: We followed 462 patients for a median of 49 months (IQR 31–70). Median age was 57 years, 76% were males, 20% had advanced fibrosis. Eighty-four patients (18%) developed a liver-related event after a median of 18 months (7-34). TE had the highest prognostic accuracy, with a C-statistic of 0.876, and time-dependent AUC at 5 years of 0.889, comparable to 2D-SWE and ELF. TE, ELF and 2D-SWE outperformed FibroTest, FIB4, NFS, Forns index and biopsy-verified fibrosis stage. Compared to patients with TE <10 kPa, the hazard ratios for liver-related events for TE 10–15 kPa were 8.1 (3.2–20.4), and 27.9 (13.8–56.8) for TE >15 kPa. Periods of excessive drinking during follow-up increased the risk of progressing to liver-related events, except for patients in the low-risk groups. Conclusion: TE, ELF and 2D-SWE are highly accurate prognostic markers in patients with alcohol-related liver disease. Easy-to-use cut-offs can distinguish between substantially different risk profiles. Lay summary: Alcohol is the leading cause of death and illness due to liver disease. In this study, we assessed the ability of biomarkers to predict the risk of developing symptomatic liver disease in patients with early stages of alcohol-related liver disease. We found that several tests accurately predicted the risk of liver-related events such as ascites, esophageal varices and hepatic encephalopathy during an average follow-up of 4.1 years. Liver stiffness measurements by ultrasound elastography and the enhanced liver fibrosis test performed best. By using them, we were able to stratify patients into 3 groups with significantly different risks.

KW - Alcoholic liver disease

KW - Decompensation

KW - Liver stiffness

KW - Mortality

KW - Prognosis

U2 - 10.1016/j.jhep.2021.05.037

DO - 10.1016/j.jhep.2021.05.037

M3 - Journal article

C2 - 34118335

AN - SCOPUS:85111750413

VL - 75

SP - 1017

EP - 1025

JO - Journal of Hepatology, Supplement

JF - Journal of Hepatology, Supplement

SN - 0169-5185

IS - 5

ER -