Age as a Confounding Factor for the Accurate Non-Invasive Diagnosis of Advanced NAFLD Fibrosis

Stuart McPherson, Tim Hardy, Jean-Francois Dufour, Salvatore Petta, Manuel Romero-Gomez, Mike Allison, Claudia P Oliveira, Sven Francque, Luc Van Gaal, Jörn M Schattenberg, Dina Tiniakos, Alastair Burt, Elisabetta Bugianesi, Vlad Ratziu, Christopher P Day, Quentin M Anstee, Stuart McPherson, Tim Hardy, Jean-Francois Dufour, Salvatore Petta, Manuel Romero-Gomez, Mike Allison, Claudia P Oliveira, Sven Francque, Luc Van Gaal, Jörn M Schattenberg, Dina Tiniakos, Alastair Burt, Elisabetta Bugianesi, Vlad Ratziu, Christopher P Day, Quentin M Anstee

Abstract

Objectives: Non-invasive fibrosis scores are widely used to identify/exclude advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). However, these scores were principally developed and validated in patients aged between 35 and 65 years of age. The objective of this study was to assess the effect of age on the performance of non-invasive fibrosis tests in NAFLD.

Methods: Patients were recruited from European specialist hepatology clinics. The cohort was divided into five age-based groups: ≤35 (n=74), 36-45 (n=96), 46-55 (n=197), 56-64 (n=191), and ≥65 years (n=76), and the performance of the aspartate aminotransferase (AST)/alanine transaminase (ALT) ratio, fibrosis 4 (FIB-4), and NAFLD fibrosis score (NFS) for advanced fibrosis (stage F3-F4) for each group was assessed using liver biopsy as the standard.

Results: Six hundred and thirty-four patients were included. The diagnostic accuracy of the AST/ALT ratio was lower than NFS and FIB-4 in all the age groups. The AST/ALT ratio, NFS, and FIB-4 score performed poorly for a diagnosis of advanced fibrosis in those aged ≤35 years (area under the receiver operating characteristic curves (AUROCs 0.52, 0.52, and 0.60, respectively). For all groups >35 years, AUROCs for advanced fibrosis were similar for the NFS and FIB-4 score (range 0.77-0.84). However, the specificity for advanced fibrosis using the FIB-4 and NFS declined with age, becoming unacceptably low in those aged ≥65 years (35% for FIB-4 and 20% for NFS). New cutoffs were derived (and validated) for those aged ≥65 years, which improved specificity to 70% without adversely affecting sensitivity (FIB-4 2.0, sensitivity 77%; NFS 0.12, sensitivity 80%).

Conclusions: The NFS and FIB-4 scores have similar accuracy for advanced fibrosis in patients aged >35 years. However, the specificity for advanced fibrosis is unacceptably low in patients aged ≥65 years, resulting in a high false positive rate. New thresholds for use in patients aged ≥65 years are proposed to address this issue.

Conflict of interest statement

Guarantor of the article: Stuart McPherson, BSc, MBChB, MD, FRCP.

Specific author contributions: Design of study, data collection, analysis, writing manuscript and approval of final manuscript: S.M. and Q.M.A. Data collection, review of manuscript for important intellectual content, and approved final manuscript: T.H., J.-F.D., S.P., M.R.-G., M.A., C.P.O., S.F., L.V.G., J.M.S., D.T., A.B., E.B., V.R., and C.P.D.

Financial support: Q.M.A. is the recipient of a Clinical Senior Lectureship Award from the Higher Education Funding Council for England (HEFCE).

Potential competing interests: None.

Figures

Figure 1
Figure 1
Plots of sensitivity and specificity against age for existing diagnostic cutoffs for advanced fibrosis for: (a) aspartate aminotransferase (AST)/alanine transaminase (ALT) ratio (0.8); (b) non-alcoholic fatty liver disease fibrosis score (NFS) (−1.445); (c) fibrosis 4 (FIB-4) score (1.3). These show a reduction in sensitivity and an increase in specificity with age.
Figure 2
Figure 2
Relationship between serum alanine transaminase (ALT) level and age in patients with (a) stage F0–F1 fibrosis and (b) stage F2–F4 fibrosis. Relationship between serum aspartate aminotransferase (AST) level and age in patients with (c) stage F0–F1 fibrosis and (d) stage F2–F4 fibrosis. A full color version of this figure is available at the American Journal of Gastroenterology journal online.
Figure 3
Figure 3
Plots of sensitivity and specificity against age for new diagnostic cutoffs for advanced fibrosis for: (a) fibrosis 4 (FIB-4) score (2.0); (b) non-alcoholic fatty liver disease fibrosis score (NFS) (0.12). Age range for which proposed thresholds are optimized is highlighted by red box. These show better specificity than current cutoffs without an adverse effect on sensitivity. A full color version of this figure is available at the American Journal of Gastroenterology journal online.
Figure 4
Figure 4
Proposed algorithm for the use of the (a) non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) and (b) fibrosis 4 (FIB-4) score to help diagnose or exclude advanced fibrosis patients using the age specific cutoffs. The NFS and FIB-4 scores are not suitable for patients aged <35 years. Existing thresholds as previously published should be used for those aged 35–65 years. The new lower thresholds derived and validated in the current paper are recommended for those aged ≥65 years. Existing upper cutoffs remain the same for those aged ≥65 years. A full color version of this figure is available at the American Journal of Gastroenterology journal online.

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