Sex-Specific Determinants of Gallstone Disease: Integrating Metabolic, Behavioral, and Genetic Mechanisms

Gallstone disease is one of the most prevalent gastrointestinal disorders worldwide, with an increasing burden driven by population aging and metabolic risk.Gallstone is not a uniform condition but demonstrates marked sex-and age-specific differences in epidemiology, pathophysiology, and risk profiles.This review integrates current evidence on clinical, metabolic, behavioral, and genetic determinants of gallstones with a focus on sex-specific mechanisms.Epidemiological studies show a higher prevalence of gallstones in females, particularly during reproductive years, whereas male predominance emerges with aging.These differences are largely attributed to hormonal influences, especially estrogen-induced increases in biliary cholesterol secretion and gallbladder hypomotility.Metabolic factors-including obesity, insulin resistance, and metabolic dysfunction-associated steatotic liver disease-play central roles, with stronger associations observed in females.In contrast, visceral adiposity appears to be a more important determinant in males.Behavioral and lifestyle factors further modify gallstone risk in a sex-specific manner.Diets high in energy and low in fiber increase risk, whereas physical activity reduces it.Coffee consumption shows a protective association predominantly in females.Smoking and alcohol demonstrate heterogeneous effects, suggesting sex-dependent biological interactions.Genetic susceptibility contributes to inter-individual variability, with variants in genes regulating cholesterol transport, bile acid metabolism, and bilirubin conjugation implicated in gallstone formation.Geneenvironment and gene-sex interactions further modulate risk.Additionally, pregnancy and rapid weight loss, including after bariatric surgery, highlight the impact of hormonal and metabolic transitions.In conclusion, gallstones arise from a complex interplay of metabolic, behavioral, and genetic factors with significant sex-specific modulation.Incorporating sex-informed approaches into risk stratification and prevention strategies may improve outcomes and reduce the global burden of gallstones.