GPIHBP1 autoantibody positivity in patients with recurrent severe hypertriglyceridemia: frequency, phenotype, and derivation of an exploratory screening score

Background Autoimmune chylomicronemia syndrome can be caused by autoantibodies anti-glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1). We aimed to determine the prevalence of patients with raised GPIHBP1 autoantibodies (AAb+), describe their clinical, genetic, and biochemical characteristics in comparison with Multifactorial (MCS) and Familial Chylomicronemia Syndrome (FCS), and develop a clinical GPIHBP1 autoantibody-related autoimmune chylomicronemia syndrome (GACS) score. Methods We recruited 203 patients with recurrent severe hypertriglyceridemia. Triglyceride-related genetics and biochemical variables: lipids, apolipoproteins, LPL (lipoprotein lipase) activity and mass, and GPIHBP1 autoantibody levels were determined. Statistical analyses were performed to identify variables independently associated with acute pancreatitis, assess differences between MCS, AAb+ (autoantibody level ≥58 U/mL), and FCS, and develop the GACS score. Results Proportions of AAb+ (11.3%) and FCS (10.3%) were similar. AAb+ patients showed: higher GPIHBP1/LPL genetic variants ratio, acute (recurrent) pancreatitis, splenomegaly, history of extreme hypertriglyceridemia (eHTG; triglycerides ≥2000 mg/dL), autoimmune disease and higher chylomicron-triglycerides than MCS. Conversely, AAb+ cases had a lower proportion of alcohol consumption and lower LPL activity and mass than MCS. Raised GPIHBP1 autoantibodies were independently associated with acute pancreatitis. Autoimmune disease, acute pancreatitis, eHTG, and no alcohol consumption were independent predictors of AAb+, thereby defining the GACS score and a cut-off ≥2 to recommend autoantibodies measurement, after FCS exclusion. Conclusions In this multicenter referral cohort of patients with recurrent severe hypertriglyceridemia, GPIHBP1 autoantibody positivity is as prevalent and clinically severe as FCS. The proposed GACS score provides with a promising tool that, after independent validation, may help clinicians in their medical decisions.