ADAMTSL2 protein and a soluble biomarker signature identify at-risk non-alcoholic steatohepatitis and fibrosis in adults with NAFLD

Kathleen E. Corey, Rebecca Pitts, Michelle Lai, Joseph Loureiro, Ricard Masia, Stephanie A. Osganian, Jenna L. Gustafson, Matthew M. Hutter, Denise W. Gee, Ozanan R. Meireles, Elan R. Witkowski, Shola M. Richards, Jaison Jacob, Nancy Finkel, Debby Ngo, Thomas J. Wang, Robert E. Gerszten, Chinweike Ukomadu, Lori L. Jennings

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background & Aims: Identifying fibrosis in non-alcoholic fatty liver disease (NAFLD) is essential to predict liver-related outcomes and guide 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 4,783 proteins in 2 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 modeling-logistic regression assessed the ability of 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 A disintegrin and metalloproteinase with thrombospondin motifs like 2 (ADAMTSL2) protein accurately distinguished non-alcoholic fatty liver (NAFL)/non-alcoholic steatohepatitis (NASH) with fibrosis stage 0-1 (F0-1) from at-risk NASH with fibrosis stage 2-4, with AUROCs of 0.83 and 0.86 in Cohorts C and D, respectively, and from NASH with significant fibrosis (F2-3), with AUROCs 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 (AUROCs 0.90 and 0.87 in Cohort C and D, respectively) and NASH F2-3 (AUROCs 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; they exhibited superior diagnostic performance compared to standard of care fibrosis scores. Lay Summary: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of liver disease worldwide. Diagnosing NAFLD and identifying fibrosis (scarring of the liver) currently requires a liver biopsy. Our study identified novel proteins found in the blood which may identify fibrosis without the need for a liver biopsy.

Original languageEnglish (US)
Pages (from-to)25-33
Number of pages9
JournalJournal of Hepatology
Volume76
Issue number1
DOIs
StatePublished - Jan 2022
Externally publishedYes

Keywords

  • ADAMTSL2
  • biomarker
  • fibrosis
  • non-alcoholic fatty liver disease
  • non-alcoholic steatohepatitis
  • proteomics

ASJC Scopus subject areas

  • Hepatology

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