Using the ELF test, FIB-4 and NAFLD fibrosis score to screen the population for liver disease

Abstract

There is a need for accurate population screening biomarkers for alcohol-related and non-alcoholic fatty liver disease (ALD, NAFLD). We evaluated the Enhanced Liver Fibrosis (ELF) test compared to FIB-4 and NAFLD fibrosis score (NFS) using transient elastography (TE) as fibrosis screening reference. We prospectively included participants from the general population, and people at risk of ALD or NAFLD. Screening positive participants (TE ≥8kPa) were offered a liver biopsy. We measured concomitant ELF, FIB-4, and NFS using validated cut-offs: ≥9.8, ≥1.3, ≥-1.45, respectively. We included 3,378 participants (1,973 general population, 953at risk of ALD, 452at risk of NAFLD), with a median age of 57 years (IQR: 51-63). Two hundred-and-forty-two were screening positive (3.4% in general population, 12% in ALD, 14% in NAFLD). Most participants with TE <8kPa also had ELF <9.8 (88%) despite a poor overall correlation between ELF and TE (Spearman´s rho=0.207). ELF had 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 8% false positives, 4% false negatives and 88% correctly classified. We performed a liver biopsy in 155/242 (64%) screening positives, of those 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) versus 0.73 (0.64-0.81) and 0.66 (0.57-0.76). 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. 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. Clinicaltrials.gov number NCT03308916.