The Association Between Bilirubin and Vestibular Dysfunction in U.S. in Middle-Aged and Elderly People Insights from NHANES 1999 – 2004 and Mendelian Randomization Analysis

Abstract

Background Vestibular dysfunction represents a significant public health burden, and the association with the endogenous antioxidant bilirubin remains controversial. This study aimed to systematically evaluate the association and potential causal mechanisms between serum total bilirubin (STB) and vestibular dysfunction by integrating observational research with causal inference methods. Methods Cross-sectional data from NHANES (1999-2004) were analyzed using weighted multivariable logistic regression and restricted cubic splines to examine the association between serum total bilirubin (STB) quartiles and vestibular dysfunction (assessed by Romberg test failure). Bidirectional two-sample Mendelian randomization (MR) was further employed to assess causality using genetic instruments. Results Among 4,500 participants, a multivariable-adjusted model revealed a significant inverse association between moderate STB concentrations (Q2: 10.27–11.97 μmol/L) and vestibular dysfunction (OR = 0.71, P = 0.018). A nonlinear dose-response relationship was observed (P-nonlinear = 0.002). Age significantly modified the effect, with protection in participants <60 years (OR = 0.97, P = 0.006) but risk in those ≥60 (OR = 1.03, P = 0.016). Genetically elevated direct bilirubin reduced overall vestibular dysfunction risk (OR = 0.84, P < 0.001), most notably for Ménière’s disease (OR = 0.76, P = 0.007). Sensitivity analyses supported result robustness (no heterogeneity or pleiotropy detected). Conclusion Moderate STB concentrations may reduce vestibular dysfunction risk. This protective effect is causally mediated by bilirubin in individuals under 60, suggesting bilirubin homeostasis could be a novel target for prevention. The reversed association in older adults warrants further investigation.