Department of Population and Quantitative Health Sciences
Amino Acids, Peptides, and Proteins | Biological Factors | Diagnosis | Digestive System Diseases | Hepatology
BACKGROUND and AIMS: Given the lack of effective therapies and high mortality in acute alcohol-associated hepatitis (AH), it is important to develop rationally-designed biomarkers for effective disease management. Complement, a critical component of the innate immune system, contributes to uncontrolled inflammatory responses leading to liver injury, but is also involved in hepatic regeneration. Here we investigated if a panel of complement proteins and activation products would provide useful biomarkers for severity of AH and aid in predicting 90 days mortality.
APPROACH and RESULTS: Plasma samples collected at time of diagnosis from 254 patients with moderate and severe AH recruited from four medical centers and 31 healthy individuals were used to quantify complement proteins by ELISA and Luminex arrays. Components of the classical and lectin pathways, including complement factors C2, C4b and C4d, as well as complement factor I (CFI) and C5, were reduced in AH patients compared to healthy individuals. In contrast, components of the alternative pathway, including complement factor Ba (CFBa) and factor D (CFD), were increased. Markers of complement activation were also differentially evident, with C5a increased and the soluble terminal complement complex (sC5b9) decreased in AH. Mannose binding lectin (MBL), C4b, CFI, C5 and sC5b9 were negatively correlated with model for end-stage liver disease (MELD) score, while CFBa and CFD were positively associated with disease severity. Lower CFI and sC5b9 were associated with increased 90-day mortality in AH.
CONCLUSIONS: Taken together, these data indicate that AH is associated with a profound disruption of complement. Inclusion of complement, especially CFI and sC5b9, along with other laboratory indicators, could improve diagnostic and prognostic indications of disease severity and risk of mortality for AH patients.
alcohol-associated hepatitis, complement pathway, severity, mortality, nomogram
Rights and Permissions
© 2020 American Association for the Study of Liver Diseases. This is a PDF file of an accepted manuscript that has been accepted for publication and posted with a 12-month embargo as allowed by the publisher’s author rights policy at https://authorservices.wiley.com/author-resources/Journal-Authors/licensing/self-archiving.html. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
DOI of Published Version
Fan X, McCullough RL, Huang E, Bellar A, Kim A, Poulsen KL, McClain CJ, Mitchell M, McCullough AJ, Radaeva S, Barton B, Szabo G, Dasarathy S, Rotroff DM, Nagy LE. Diagnostic and Prognostic Significance of Complement in Patients with Alcohol-associated Hepatitis. Hepatology. 2020 Jun 17. doi: 10.1002/hep.31419. Epub ahead of print. PMID: 32557728. Link to article on publisher's site
Hepatology (Baltimore, Md.)
Fan X, McCullough RL, Huang E, Bellar A, Kim A, Poulsen KL, McClain CJ, Mitchell M, McCullough AJ, Radaeva S, Barton BA, Szabo G, Dasarathy S, Rotroff DM, Nagy LE. (2020). Diagnostic and Prognostic Significance of Complement in Patients with Alcohol-associated Hepatitis. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1002/hep.31419. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1715