Perioperative Dynamics of Autoantibodies Against Neurotransmitter Receptors in Liver Surgery: A Secondary Analysis of the PHYDELIO Trial

BackgroundPostoperative delirium (POD) is a common neurocognitive complication following major surgery, particularly in older adults and those undergoing liver resections. Neuroinflammatory mechanisms are considered central to its pathophysiology, yet molecular mediators remain poorly defined. Autoantibodies (aABs) targeting G protein-coupled receptors (GPCRs)--especially those relevant to neurotransmission--may contribute to POD by disrupting neuroimmune homeostasis. This study explored the perioperative dynamics of GPCR-specific aABs and their association with POD incidence. MethodsIn this secondary analysis of the PHYDELIO randomized controlled trial (ISRCTN18978802), we evaluated serum aAB levels targeting five GPCRs (M3R, M4R, {beta}2AR, D2R, and 5-HT2AR) in 142 patients undergoing liver surgery. Samples were collected preoperatively and on postoperative days 1, 2, and 7. POD was diagnosed using a comprehensive clinical assessment integrating validated screening tools and chart reviews. Repeated-measures ANOVAs examined time x group interactions, with additional post hoc and nonparametric tests applied as appropriate. ResultsSerum levels of four GPCR aABs (M3R, M4R, D2R, and 5-HT2AR) declined significantly following surgery and returned near baseline by day 7. {beta}2AR aAB levels remained stable. Patients who developed POD (45.8%) exhibited consistently lower aAB levels, reaching statistical significance for M3R (p = .029). No significant time x delirium interaction was found for any antibody. DiscussionMajor abdominal surgery transiently alters GPCR aAB levels, suggesting perioperative immune modulation or adsorption to tissue following disrupted barriers. Lower M3R aAB concentrations were associated with POD, aligning with proposed cholinergic involvement in its pathogenesis. While only M3R-specific effects reached significance, the consistent trend across aABs supports further investigation into their role as biomarkers or mediators of POD. Future studies should assess their functional activity and potential utility in risk stratification and therapeutic targeting.