Alcoholic-related liver disease cause the most liver-related deaths worldwide. Many of these people develop a severe form of disease called alcohol associated hepatitis (AH), which is often life threatening, even with hospitalization and treatment. Understanding the progression and molecular nature of AH is important to help design new treatments and interventions to help AH patients. Using proteomics tools based on mass spectrometry to provide a deep and broad analysis of the proteins in AH patients’ blood plasma enabled us to detect large scale changes.
Deep proteome analysis of blood plasma of AH patients led to the identification of significant fundamental changes across a majority of proteins detected when compared to normal blood plasma. This dysregulation represents an inability of normal protein expression and hence function in these patients. Markers of disease initiation and severity were also identified when comparing across normal and other liver conditions and mild versus severe AH. AH blood signatures were also linked to the defective function of genetic regulators in the liver. This provides a link to liver function dysregulation and systemic blood protein function in AH patients.
The advanced analytical capabilities found at EMSL, the Environmental Molecular Sciences Laboratory, a Department of Energy (DOE) Office of Science user facility at Pacific Northwest National Laboratory (PNNL), were applied to the blood plasma analysis of AH patients, to characterize the broad impact of AH liver dysfunction. The relevant comparisons across patients helped identify markers of disease severity and progression. Linking genetic signatures in liver to plasma protein expression and function also provided insight into how AH liver disease proliferates systemically throughout the blood. This study provides a strong foundation of data for researchers to investigate specific markers and targets for intervention and as markers of prognosis. Further work needs to be done to understand how current treatments affect these blood signatures, and which ones will be most likely to indicate efficacy of treatment.
Jon Jacobs, Pacific Northwest National Laboratory, firstname.lastname@example.org
Supported by the National Institutes of Health (NIH) through National Institute of Alcohol Abuse and Alcoholism (NIAAA) grants for the Southern California Alcoholic Hepatitis Consortium and the InTeam Alcoholic Hepatitis Consortium. Analysis was supported by NIAAA. Parts of this research were also supported by NIH National Institute of General Medical Sciences and NIH NIAAA.
Published: February 17, 2023
Josepmaria A., K. Kedia, M.A. Gritsenko, A. Clemente-Sanchez, A. Asghar, J.M. Herranz, Z. Liu, S.R. Atkinson, R.D. Smith, T.M. Norden-Krichmar, L.Z. Day, A. Stolz, J.A. Tayek, R. Bataller, T.R. Morgan, and J.M. Jacobs. Integrated Transcriptomic and Proteomic Analysis Identifies Plasma Biomarkers of Hepatocellular Failure in Alcohol-Associated Hepatitis, The American Journal of Pathology, 192(12), 1658–1669. [DOI: https://doi.org/10.1016/j.ajpath.2022.08.009].