ADAMTSL2 protein and a soluble biomarker signature identify significant and advanced #fibrosis in adults with #NAFLD

Using an aptamer-based profiling platform we identified an individual and panel of circulating proteins that non-invasively identify significant fibrosis at-risk NASH in 316 adults with NAFLD.

An 8-protein panel can distinguish NAFL/NASH fibrosis stage 0-1 from fibrosis stage 2-4 with an AUROC 0.87- 0.89.

The ADAMTSL2 protein alone can distinguish NAFL/NASH fibrosis stage 0-1 from fibrosis stage 2-4 with an AUROC 0.83-0.86.

Both the 8-protein panel and ADAMTSL2 showed superior performance to the NAFLD Fibrosis Score and Fibrosis-4 Score.


Abstract
Aims and Background
Identifying fibrosis in non-alcoholic fatty liver disease (NAFLD) is essential to predict liver-related outcomes and inform treatment decisions. A protein-based signature of fibrosis could serve as a valuable, non-invasive diagnostic tool. This study sought to identify circulating proteins associated with fibrosis in NAFLD.


Methods
We used aptamer-based proteomics to measure 4783 proteins in two cohorts (Cohort A and B). Targeted, quantitative assays coupling aptamer-based protein pull down and mass spectrometry (SPMS) validated the profiling results in a bariatric and NAFLD cohort (Cohort C and D, respectively). Generalized linear modelling-logistic regression assessed the candidate proteins to classify fibrosis.


Results
From the multiplex profiling, 16 proteins differed significantly by fibrosis in cohorts A (n=62) and B (n=98). Quantitative and robust SPMS assays were developed for 8 proteins and validated in Cohorts C (n=71) and D (n=84). The protein A disintegrin and metalloproteinase with thrombospondin motifs like 2 (ADAMTSL2) accurately distinguished NAFL/NASH with fibrosis stage 0-1 (F0-1) from at-risk NASH with fibrosis stage 2-4 with an AUROC of 0.83 and 0.86 in Cohorts C and D, respectively, and from NASH with significant fibrosis (F2-3) with an AUROC of 0.80 and 0.83 in Cohorts C and D, respectively. An 8-protein panel distinguished NAFL/NASH F0-1 from at-risk NASH (AUROC 0.90 and 0.87 in Cohort C and D, respectively) and NASH F2-3 (AUROC 0.89 and 0.83 in Cohorts C and D, respectively). The 8-protein panel and ADAMTSL2 protein had superior performance to the NAFLD fibrosis score and Fibrosis-4 score.


Conclusion
The ADAMTSL2 protein and an 8-protein soluble biomarker panel are highly associated with at-risk NASH and significant fibrosis with superior performance to standard of care fibrosis scores.

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