ADAMTSL2 protein and a soluble biomarker signature identify at-risk non-alcoholic steatohepatitis and fibrosis in adults with NAFLD
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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.
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Proteomics of patient serum identified a protein signature that distinguishes different fibrosis stages.
“Proteomics analysis of patient serum also identified a protein signature that effectively distinguished different stages of fibrosis (123).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [123]
Serum proteomics and metabolomics show considerable promise but are not yet widely implemented.
“Serum proteomics and metabolomics techniques that measure changes in large numbers of analytes (296, 297) show considerable promise but are not yet widely implemented.”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [297]
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- Authors
- Corey, K. E., Pitts, R., Lai, M., Loureiro, J., Masia, R., Osganian, S. A., Gustafson, J. L., Hutter, M. M., Gee, D. W., Meireles, O. R., Witkowski, E. R., Richards, S. M., Jacob, J., Finkel, N., Ngo, D., Wang, T. J., Gerszten, R. E., Ukomadu, C., & Jennings, L. L.
- Affiliations
- Harvard University (US)
- Beth Israel Deaconess Medical Center (US)
- Massachusetts General Hospital (US)
- Vanderbilt University (US)
- Corresponding author
- Corey, Kathleen E.
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2022-01
- Volume
- 76
- Issue
- 1
- Pages
- 25-33
- ISSN
- 0168-8278 (ISSN-L)
- PMC
- PMC8688231
- OpenAlex
- W3202721341
- Cited by
- 88
- References
- 41
- Citations by year
- 2026: 17 · 2025: 22 · 2024: 19 · 2023: 20 · 2022: 8 · 2021: 2
- FWCI
- 9.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Hepatology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Novartis Repository (Novartis) (submittedVersion)
- Funders
- Novartis
- National Institutes of Health (R01 DK114144, R01HL132320, R01HL133870)
- Bristol-Myers Squibb
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- ADAMTSL2, nonalcoholic steatohepatitis, liver fibrosis, non-alcoholic fatty liver disease, circulating proteins, aptamer-based proteomics, non-invasive diagnosis, fibrosis staging, NAFLD fibrosis score, Fibrosis-4 score, bariatric surgery, liver-related outcomes, prognostic factors
- MeSH terms
- ADAMTS Proteins, Adult, Biopsy, Female, Humans, Liver Cirrhosis, Male, Massachusetts, Middle Aged, Prospective Studies, ROC Curve, Cohort Studies, Biomarkers, Logistic Models, Case-Control Studies, Area Under Curve, Non-alcoholic Fatty Liver Disease
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