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

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  1   2 , Jeremy Magnanensi  3 , Yacine Hajji  3 , Alexandra Caron  3 , Zouher Majd  3 , Christian Rosenquist  3 , Dean W Hum  3 , Bart Staels  4 , Margery A Connelly  5 , Rohit Loomba  6 , Stephen A Harrison  7   8 , Vlad Ratziu  9 , Arun J Sanyal  10
Affiliations

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 et al. JHEP Rep. .

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.

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Conflict of interest statement

QMA: research support from LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) consortium funded by the Innovative Medicines Initiative Program of the European Union under Grant Agreement 777377 (this multistakeholder consortium includes industry partners and received funding from EFPIA); grants or contracts from AstraZeneca, Boehringer Ingelheim, and Intercept Pharmaceuticals; royalties or licenses from Elsevier Ltd.; consulting fees (on behalf of Newcastle University) from Alimentiv, Akero Therapeutics, Inc., AstraZeneca, Axcella Health, Inc., 89bio, Inc., Boehringer Ingelheim, Bristol Myers Squibb, Galmed Pharmaceuticals, Genfit S.A., Genentech, Gilead Sciences Inc., GlaxoSmithKline, Hanmi, HistoIndex Pte Ltd., Intercept Pharmaceuticals, Inventiva, Ionis, IQVIA, Janssen, Madrigal Pharmaceuticals, Medpace, Merck, NGM Biopharmaceuticals, Novartis Pharmaceuticals, Novo Nordisk, PathAI, Pfizer, Prosciento, Poxel S.A., Resolution Therapeutics, Roche, Ridgeline Therapeutics, RTI, Shionogi, and Terns Pharmaceuticals; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Fishawack, Integritas Communications, Kenes, Novo Nordisk, Madrigal Pharmaceuticals, Medscape, and Springer Healthcare; served on advisory boards or data safety monitoring boards (on behalf of Newcastle University) for Medpace (NorthSea Therapeutics B.V., DSMB). BS: consulting fees from Genfit S.A. MAC: Labcorp employee. RL: grants/funding support from the National Center for Advancing Translational Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung, and Blood Institute, Arrowhead Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galectin Therapeutics, Inc., Galmed Pharmaceuticals, Gilead Sciences, Inc., Hanmi, Intercept Pharmaceuticals, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Sonic Incytes, and Terns Pharmaceuticals; consulting fees from Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, CohBar, Inc., Eli Lilly, Galmed Pharmaceuticals, Gilead Sciences, Inc., Glympse Bio, HighTide Therapeutics, Ini Pharma, Intercept Pharmaceuticals, Intercept Pharmaceuticals, Ionis, Janssen, Madrigal Pharmaceuticals, Metacrine, NGM Biopharmaceuticals, Novartis Pharmaceuticals, Novo Nordisk, Merck, Pfizer, Sagimet Biosciences, Theratechnologies, Inc., 89bio, Inc., Terns Pharmaceuticals, and Viking Therapeutics; other financial interests: LipoNexus, Inc. (co-founder). SAH: grants or contracts from Akero Therapeutics, Alentis Therapeutics, Altimmune, B. Riley FBR, ChronWell, Corcept Therapeutics, Echosens, Axcella Health, Cirius Therapeutics, CiVi Biopharma, Cymabay Therapeutics, Inc., Enyo Pharma S.A., Galectin Therapeutics, Inc., Galmed Research & Development, Ltd., Genfit S.A., Gilead Sciences, Inc., Hepion Pharmaceuticals, Inc., Hepta Bio, HighTide Therapeutics, Inc, HistoIndex, Intercept Pharmaceuticals, Ionis, Madrigal Pharmaceuticals, Medpace, NGM Biopharmaceuticals, Inc., NeuroBo, NorthSea Therapeutics B.V., Novartis Pharmaceuticals, Novo Nordisk, Path AI, Perspectum, Poxel S.A., Sagimet Biosciences, Sonic Incytes, Terns Pharmaceuticals, and Viking Therapeutics; stock or stock options for Akero Therapeutics, ChronWell, Cirius Therapeutics, Galectin Therapeutics, Inc., Genfit S.A., Hepion Pharmaceuticals, Inc., HistoIndex Pte Ltd., Metacrine, NGM Biopharmaceuticals, Inc., NorthSea Therapeutics B.V. VR: grants or contracts from Intercept Pharmaceuticals, and Gilead Sciences, Inc.; consulting fees from Boehringer Ingelheim, Novo Nordisk, Poxel S.A., Enyo Pharma S.A., Madrigal Pharmaceuticals, Terns Pharmaceuticals, Intercept Pharmaceuticals, NGM Biopharmaceuticals Inc., and Pfizer. AJS: stock options in Genfit S.A., Tiziana, Indalo, Durect, Inversago, and Galmed Pharmaceuticals; consultant to AstraZeneca, Salix, Tobira, Takeda, Jannsen, Gilead Sciences, Inc., Terns Pharmaceuticals, Merck, Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Inc., Sagimet Biosciences, Valeant, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Hemoshear, Novartis Pharmaceuticals, Inventiva, Enyo, Akero Therapeutics, 89bio, Inc., Novo Nordisk, Pfizer, Amgen, Genentech, Regeneron, Alnylam, Hanmi, LG Chem, Histoindex, Thera Technologies, Intercept Pharmaceuticals, Target-RWE, Surrozen, Zydus, Path AI, Exhalenz, and Genfit S.A.; his institution has received grant support from Gilead Sciences, Inc., Salix, Tobira, Bristol Myers Squibb, Pfizer, Intercept Pharmaceuticals, Merck, AstraZeneca, Mallinckrodt, and Novartis Pharmaceuticals; royalties received from Elsevier and UpToDate. JM, YH, AC, ZM, CR, and DWH: stock or stock options from Genfit S.A. and serve as Genfit S.A. employees. Please refer to the accompanying ICMJE disclosure forms for further details.

Figures

None
Graphical abstract
Fig. 1
Fig. 1
ROC curves and AUROC values (95% CIs) of NITs for the detection of subpopulations characterized by age or intended histologic endpoints. Matched cohort, N = 708. ALT, alanine aminotransferase; APRI, aspartate aminotransferase-to-platelet ratio index; ELF™, Enhanced Liver Fibrosis; FIB-4, Fibrosis-4; NAFLD, non-alcoholic fatty liver disease; NFS, NAFLD fibrosis score; NIT, non-invasive test.
Fig. 2
Fig. 2
NIT scores distributions by age and at-risk MASH status. ∗y-axis on a log10 scale for improved representations. Matched cohort, n = 708. At-risk MASH was defined as MASH with MAS ≥4 and F ≥2. ALT, alanine aminotransferase; APRI, aspartate aminotransferase-to-platelet ratio index; ELF™, Enhanced Liver Fibrosis; FIB-4, Fibrosis-4; MAS, MASLD activity score; MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated liver disease; NAFLD, non-alcoholic fatty liver disease; NFS, NAFLD fibrosis score; NIT, non-invasive test.
Fig. 3
Fig. 3
Differences in clinical performance (sensitivity and specificity) for the detection of at-risk MASH between ≤45 and ≥65 years age groups by cut-off. Matched cohort, n = 708. At-risk MASH was defined as MASH with MAS ≥4 and F ≥2. APRI, aspartate aminotransferase-to-platelet ratio index; ALT, alanine aminotransferase; APRI, aspartate aminotransferase-to-platelet ratio index; ELF™, Enhanced Liver Fibrosis; FIB-4, Fibrosis-4; MAS, MASLD activity score; MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated liver disease; NAFLD, non-alcoholic fatty liver disease; NFS, NAFLD fibrosis score.
Fig. 4
Fig. 4
AUROC values for at-risk MASH detection across age groups. Matched cohort, n = 708. At-risk MASH was defined as MASH with MAS ≥4 and F ≥2. ALT, alanine aminotransferase; APRI, aspartate aminotransferase-to-platelet ratio index; ELF™, Enhanced Liver Fibrosis; FIB-4, Fibrosis-4; MAS, MASLD activity score; MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated liver disease; NAFLD, non-alcoholic fatty liver disease; NFS, NAFLD fibrosis score.
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