Fibrosis and liver inflammation are key regulators of α1-acid glycoprotein fucosylation

Background and Aims: There is an urgent need for new high-quality markers in the early detection of hepatocellular carcinoma (HCC). Astroem et al. suggested that S2-bound α1-acid glycoprotein (AGP) might be a promising marker. Consequently, we evaluated S2-bound AGP for a predictive advantage in the early detection of HCC. Methods: In a retrospective case-control study of patients chronically infected with hepatitis C virus (HCV) and treated with direct-acting antiviral agents (n=93), we measured S2-bound AGP using the HepaCheC ELISA kit (Glycobond AB, Linkoeping, SE) at treatment start, end of treatment and follow-up (maximum: 78 months). Patients were retrospectively propensity score matched (1:2). 31 patients chronically infected with HCV developed HCC after sustained virological response while 62 did not. In addition, samples of HBV, MASLD and HCC from different etiologies patients were measured. Results: S2-bound AGP elevation in HCC patients was confirmed. However, we did not observe a predictive advantage of S2-bound AGP in early detection of HCC during treatment and follow-up. Interestingly, S2-bound AGP levels correlated with aspartate aminotransferase (ρ=0.56, p=9.5x10-15) and liver elastography (ρ=0.67, p=2.2x10-16). Of note, S2-bound AGP decreased in patients chronically infected with HCV after treatment-induced clearance of HCV. Conclusion: Fibrosis and liver inflammation are key regulators in the fucosylation of AGP. The potential role of S2-bound AGP as a novel tumor marker requires further investigation. ### Competing Interest Statement MC reports personal fees from Abbvie, personal fees from Falk Foundation, personal fees from Gilead, personal fees from GlaxoSmithKline, personal fees from Jansen-Cilag, personal fees from Merck/MSD, personal fees from Novartis, personal fees from Roche, personal fees from Spring Bank Pharmaceuticals, and personal fees from Swedish Orphan Biovitrum, outside the submitted work HW reports grants/research support and personal fees from Abbvie, Biotest AG and Gilead. He received personal fees from Aligos Therapeutics, Altimmune, Astra Zeneca, Bristol-Myers-Squibb, BTG Pharmaceuticals, Dicerna Pharmaceuticals, Enanta Pharmaceuticals, Dr. Falk Pharma, Falk Foundation, Intercept Pharmaceuticals, Janssen, Merck KGaA, MSD Sharp & Dohme GmbH, MYR GmbH, Norgine, Novartis, Pfizer Pharma GmbH, Roche and Vir Biotechnology, outside the submitted work. PS has received speaker fees from Merk Sharp & Dohme, Eisai, Roche and Albireo. IR and PP are unpaid board members of Glycobond AB. LK, JT, BB, CO and RZ have nothing to disclose. ### Funding Statement This project is part of project A5 in the Collaborative Research Center 900 - Microbial Persistence and its Control. The Swedish Cancer Society supported PS. The project was partly financed by grants from Glycobond AB. CO was supported by a grant from the KlinStrucMed program of Hannover Medical School, funded by the Else Kroener-Fresenius Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This article does not contain any studies with animals performed by any of the authors. The study protocol conformed to the ethical guidelines of the Declaration of Helsinki and the ethics committee of Hannover Medical School approved this study a priori (No. 9474\_BO\_K_2020). Informed consent was obtained from all individual participants included in the study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors