Author information
1Centre for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Denmark; Department of Clinical Research, University of Southern Denmark, Denmark.
2Centre for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Denmark.
3Danish Center for Healthcare Improvements, Aalborg University, Denmark.
4Department of Clinical Research, University of Southern Denmark, Denmark; Department of Clinical Biochemistry, Odense University Hospital, Denmark.
5Centre for Quantum Mathematics, Department of Mathematics and Computer Science, University of Southern Denmark, Denmark.
6Department of Clinical Research, University of Southern Denmark, Denmark; Department of Pathology, Odense University Hospital, Denmark.
7Department of Clinical Biochemistry, Odense University Hospital, Denmark.
8Centre for Quantum Mathematics, Department of Mathematics and Computer Science, University of Southern Denmark, Denmark; Danish Institute of Advanced Study (DIAS), University of Southern Denmark, Denmark.
9Liver Unit Hospital Clínic, Institut D´investigacions Biomédiques August Pi I Sunyer (IDIBAPS), Spain; Centro de Investigación En Red de Enfermedades Hepáticas Y Digestivas (CIBEREHD) Barcelona; Faculty of Medicine and Health Sciences, University of Barcelona, Spain.
10Centre for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Denmark; Department of Clinical Research, University of Southern Denmark, Denmark. Electronic address: maja.thiele@rsyd.dk.
11Centre for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Denmark; Department of Clinical Research, University of Southern Denmark, Denmark; Danish Institute of Advanced Study (DIAS), University of Southern Denmark, Denmark.
Abstract
Background & aims: There is a need for accurate biomarkers of fibrosis for population screening of alcohol-related and non-alcoholic fatty liver disease (ALD, NAFLD). We compared the performance of the enhanced liver fibrosis (ELF) test to the fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS), using transient elastography as the reference standard.
Methods: We prospectively included participants from the general population, and people at risk of ALD or NAFLD. Screening positive participants (TE ≥8 kPa) were offered a liver biopsy. We measured concomitant ELF, FIB-4, and NFS using validated cut-offs: ≥9.8, ≥1.3, ≥-1.45, respectively.
Results: We included 3,378 participants (1,973 general population, 953 at risk of ALD, 452 at risk of NAFLD), with a median age of 57 years (IQR: 51-63). Two hundred-and-forty-two were screening positive (3.4% in the general population, 12%/14% who were at-risk of ALD/NAFLD, respectively). Most participants with TE <8 kPa also had ELF <9.8 (88%) despite a poor overall correlation between ELF and TE (Spearman´s rho = 0.207). ELF was associated with significantly fewer false positives (11%) than FIB-4 and NFS (35% and 45%), while retaining a low rate of false negatives (<8%). A screening strategy of FIB-4 followed by ELF in indeterminate cases resulted in false positives in 8%, false negatives in 4% and the correct classification in 88% of cases. We performed a liver biopsy in 155/242 (64%) patients who screened positive, of whom 54 (35%) had advanced fibrosis (≥F3). ELF diagnosed advanced fibrosis with significantly better diagnostic accuracy than FIB-4 and NFS: AUROC 0.85 (95% CI 0.79-0.92) vs. 0.73 (0.64-0.81) and 0.66 (0.57-0.76), respectively.
Conclusion: The ELF test alone or combined with FIB-4 for liver fibrosis screening in the general population and at-risk groups reduces the number of futile referrals compared to FIB-4 and NFS, without overlooking true cases.
Impact and implications: We need referral pathways that are efficient at detecting advanced fibrosis from alcohol-related and non-alcoholic fatty liver disease in the population, but without causing futile referrals or excessive use of resources. This study indicates that a sequential test strategy of FIB-4 followed by the ELF test in indeterminate cases leads to few patients referred for confirmatory liver stiffness measurement, while retaining a high rate of detected cases, and at low direct costs. This two-step referral pathway could be used by primary care for mass, targeted, or opportunistic screening for liver fibrosis in the population.
Clinical trial number: Clinicaltrials.gov number NCT03308916.