Impact of age on NIS2+™ and other non-invasive blood tests for the evaluation of liver disease and detection of at-risk MASH

Quentin M Anstee; Jeremy Magnanensi; Yacine Hajji; Alexandra Caron; Zouher Majd; Christian Rosenquist; Dean W Hum; Bart Staels; Margery A Connelly; Rohit Loomba; Stephen A Harrison; Vlad Ratziu; Arun J Sanyal

doi:10.1016/j.jhepr.2024.101011

Impact of age on NIS2+™ and other non-invasive blood tests for the evaluation of liver disease and detection of at-risk MASH

JHEP Rep. 2024 Jan 19;6(4):101011. doi: 10.1016/j.jhepr.2024.101011. eCollection 2024 Apr.

Authors

Quentin M Anstee^{1

2}, Jeremy Magnanensi³, Yacine Hajji³, Alexandra Caron³, Zouher Majd³, Christian Rosenquist³, Dean W Hum³, Bart Staels⁴, Margery A Connelly⁵, Rohit Loomba⁶, Stephen A Harrison^{7

8}, Vlad Ratziu⁹, Arun J Sanyal¹⁰

Affiliations

¹ Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
² Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.
³ Genfit S.A., Loos, France.
⁴ Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, Lille, France.
⁵ Labcorp, Morrisville, NC, US.
⁶ NAFLD Research Center, Division of Gastroenterology, University of California at San Diego, La Jolla, CA, US.
⁷ Summit Clinical Research, San Antonio, TX, US.
⁸ Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
⁹ Sorbonne Université, Institute for Cardiometabolism and Nutrition, Hôpital Pitié-Salpêtrière, Paris, France.
¹⁰ Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, US.

Abstract

Background & aims: Robust performance of non-invasive tests (NITs) across ages is critical to assess liver disease among patients with metabolic dysfunction-associated liver disease (MASLD). We evaluated the impact of age on the performance of NIS2+™ vs. other NITs.

Methods: An analysis cohort (N = 1,926) with biopsy-proven MASLD was selected among individuals screened for the phase III RESOLVE-IT clinical trial and divided into ≤45, 46-55, 56-64, and ≥65 years groups. To avoid potential confounding effects, a well-balanced cohort (n = 708; n = 177/age group) was obtained by applying a propensity score-matching algorithm to the analysis cohort. Baseline values of biomarkers and NITs were compared across age groups using one-way ANOVA, and the impact of age and histology were compared through three-way ANOVA. The impact of age on NIT performance for the detection of at-risk metabolic dysfunction-associated steatohepatitis (MASH; MASLD activity score [MAS] ≥4 and fibrosis stage [F] ≥2) was also evaluated.

Results: Age did not affect the distributions of NIS2+™ and APRI (aspartate aminotransferase-to-platelet ratio index), but significantly (p <0.0001) impacted those of NFS (NAFLD fibrosis score), FIB-4 (Fibrosis-4 index), and Enhanced Liver Fibrosis (ELF™) score. NIS2+™ was the only NIT on which fibrosis and MAS exerted a moderate to large effect. While the impact of fibrosis on APRI was moderate, that of MAS was low. The impact of age on FIB-4 and NFS was larger than that of fibrosis. NIS2+™ exhibited the highest AUROC values for detecting at-risk MASH across age groups, with stable performances irrespective of cut-offs.

Conclusions: NIS2+™ was not significantly impacted by age and was sensitive to both fibrosis and MAS grade, demonstrating a robust performance to rule in/out at-risk MASH with fixed cut-offs.

Impact and implications: While metabolic dysfunction-associated steatotic liver disease (MASLD) can affect individuals of all ages, patient age could represent an important confounding factor when interpreting non-invasive test (NIT) results, highlighting the need for reliable and efficient NITs that are not impacted by age and that could be interpreted with fixed cut-offs, irrespective of patient age. We report the impact of age on different well-established NITs - among those tested, only two panels, NIS2+™ and APRI, were not impacted by age and can be used and interpreted independently of patient age. NIS2+™ was also sensitive to both fibrosis and MAS, further confirming its efficiency for the detection of the composite endpoint of at-risk MASH and its potential as a valuable candidate for large-scale implementation in clinical practice and clinical trials.

Keywords: MASH; MASLD; NAFLD; NASH; NIS2+™; NITs; Non-invasive blood-based tests; age; at-risk MASH; fibrosis; metabolic dysfunction-associated liver disease; metabolic dysfunction-associated steatohepatitis.