Combined Effects of Environmental and Lifestyle Exposures on Liver Health: The Mediating Role of Allostatic Load

Background: Liver disease is a growing global health burden. While individual environmental exposures like heavy metals (lead, cadmium, mercury) and behavioral factors such as smoking and alcohol use are known risk factors, their combined impact and the underlying physiological pathways are poorly understood. Allostatic load (AL), a measure of cumulative physiological stress, is a potential mediator or modifier in the relationship between these chronic exposures and liver disease. This study aimed to investigate the joint effects of heavy metals and behavioral exposures on liver health and to examine the mediating role of AL. Methods: This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) 2017–2018 cycle. We assessed blood concentrations of the environmental and lifestyle variables in relation to liver biomarkers and the Fatty Liver Index (FLI). Descriptive statistics were used to summarize participant characteristics. Multivariable linear regression and Bayesian Kernel Machine Regression–Causal Mediation Analysis (BKMR-CMA) were used to model combined, nonlinear effects of the exposure–outcome mixture and to evaluate the mediating role of AL. Results: Lead exposure was positively associated with higher AST (β = 0.65, p = 0.04) and GGT (β = 1.99, p = 0.05), while smoking increased GGT (β = 0.79, p = 0.03) and ALP (β = 0.78, p < 0.01). AL independently predicted higher FLI (β = 3.66, p < 0.001). Conclusions: This study highlights that liver health is influenced by the combined effects of environmental pollutants, behaviors, and cumulative biological stress. While lead exposure and smoking were independently linked to liver enzyme elevations, and AL to FLI, mediation by AL was limited, though trends suggest AL may still amplify chronic metabolic pathways leading to liver disease.