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Abstract Details
Defining the serum proteomic signature of hepatic steatosis, inflammation, ballooning and fibrosis in non-alcoholic fatty liver disease
J Hepatol. 2023 Apr;78(4):693-703. doi: 10.1016/j.jhep.2022.11.029.Epub 2022 Dec 14.
1Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. Electronic address: arun.sanyal@vcuhealth.org.
2Clinical R&D, SomaLogic Inc., Boulder, CO, USA.
3Dept. of Pediatrics, Columbia University, New York, NY, USA.
4Division of Gastroenterology, Saint Louis University School of Medicine, St. Louis, MO, USA.
5Applied Modeling, SomaLogic, Inc., Boulder, CO, USA.
6Liver Institute Northwest, Seattle, WA, USA.
7Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA.
8Division of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA.
9Division of Gastroenterology and Hepatology, Duke University School of Medicine, Durham, NC, USA.
10NAFLD Research Center, University of California San Diego School of Medicine, San Diego, CA, USA.
11Division of Gastroenterology and Hepatology, University of California San Francisco School of Medicine, San Francisco, CA, USA.
12Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
13Dept. of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
14Business Development, SomaLogic Inc, Boulder, CO, USA.
15Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
Abstract
Background & aims: Despite recent progress, non-invasive tests for the diagnostic assessment and monitoring of non-alcoholic fatty liver disease (NAFLD) remain an unmet need. Herein, we aimed to identify diagnostic signatures of the key histological features of NAFLD.
Methods: Using modified-aptamer proteomics, we assayed 5,220 proteins in each of 2,852 single serum samples from 636 individuals with histologically confirmed NAFLD. We developed and validated dichotomized protein-phenotype models to identify clinically relevant severities of steatosis (grade 0 vs. 1-3), hepatocellular ballooning (0 vs. 1 or 2), lobular inflammation (0-1 vs. 2-3) and fibrosis (stages 0-1 vs. 2-4).
Results: The AUCs of the four protein models, based on 37 analytes (18 not previously linked to NAFLD), for the diagnosis of their respective components (at a clinically relevant severity) in training/paired validation sets were: fibrosis (AUC 0.92/0.85); steatosis (AUC 0.95/0.79), inflammation (AUC 0.83/0.72), and ballooning (AUC 0.87/0.83). An additional outcome, at-risk NASH, defined as steatohepatitis with NAFLD activity score ≥4 (with a score of at least 1 for each of its components) and fibrosis stage ≥2, was predicted by multiplying the outputs of each individual component model (AUC 0.93/0.85). We further evaluated their ability to detect change in histology following treatment with placebo, pioglitazone, vitamin E or obeticholic acid. Component model scores significantly improved in the active therapies vs. placebo, and differential effects of vitamin E, pioglitazone, and obeticholic acid were identified.
Conclusions: Serum protein scanning identified signatures corresponding to the key components of liver biopsy in NAFLD. The models developed were sufficiently sensitive to characterize the longitudinal change for three different drug interventions. These data support continued validation of these proteomic models to enable a "liquid biopsy"-based assessment of NAFLD.
Clinical trial number: Not applicable.
Impact and implications: An aptamer-based protein scan of serum proteins was performed to identify diagnostic signatures of the key histological features of non-alcoholic fatty liver disease (NAFLD), for which no approved non-invasive diagnostic tools are currently available. We also identified specific protein signatures related to the presence and severity of NAFLD and its histological components that were also sensitive to change over time. These are fundamental initial steps in establishing a serum proteome-based diagnostic signature of NASH and provide the rationale for using these signatures to test treatment response and to identify several novel targets for evaluation in the pathogenesis of NAFLD.