How Much Is Too Much? Dose-Dependent Gallstone Risk from Weight Loss and the Role of Serum Cholesterol: Evidence from NHANES 2017–2020

Abstract Background: Gallstone disease (GSD) affects 10%-20% of U.S. adults and is strongly linked to obesity. Paradoxically, rapid weight loss may increase GSD risk, yet its dose-response pattern and lipid-mediated mechanisms remain underexplored. Objective: To assess the association between 1-year percentage total weight loss (%TWL) and GSD risk, evaluate the mediating role of serum total cholesterol (TC), and compare risks across different weight-loss methods. Methods: Using NHANES 2017–2020 data, we included 5,980 adults aged ≥ 20 years. %TWL was calculated from self-reported weights. GSD was defined by physician-diagnosed self-report. Multivariable logistic regression examined %TWL (continuous and quartiles) and GSD, adjusting for demographics, lifestyle, and comorbidities. Mediation analysis evaluated TC's role. Weight-loss strategies were categorized and assessed separately. Subgroup analyses examined effect modification by age, sex, obesity, dyslipidemia, diabetes, and hypertension. Machine learning identified key GSD predictors. Results: %TWL was positively associated with GSD in a linear dose-response manner (P-trend < 0.001). Each 1% increase in %TWL raised GSD risk by 3% (OR = 1.03; 95% CI: 1.01–1.05), with > 20% weight loss linked to 2.60-fold higher risk (OR = 2.60; 95% CI: 1.55–4.24). TC mediated 2.81% of the association (P = 0.038). Weight-loss methods such as dieting or fat restriction showed increased GSD risk in unadjusted models but lost significance after adjustment. The association was stronger in middle-aged and hyperlipidemic individuals. %TWL, age, sex, race, and obesity emerged as top predictors in machine learning analysis. Conclusion: Rapid weight loss (%TWL) is independently and dose-dependently associated with GSD risk, partly mediated by cholesterol. Risk is driven by weight-loss magnitude rather than method, underscoring the need for lipid monitoring in high-risk patients during weight management.