Cross-sectional association between gallstone disease and nonalcoholic fatty liver disease: Exploring the mediating roles of hematological and biochemical markers

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder worldwide and is closely associated with metabolic comorbidities. Gallstone disease (GSD), another prevalent hepatobiliary condition, frequently coexists with NAFLD; however, their relationship and underlying mediating mechanisms remain unclear. This study aimed to investigate the association between a history of GSD and NAFLD using data from National Health and Nutrition Examination Survey 2017-March 2020. Restricted cubic spline models were employed to assess the linearity of this association, stratified analyses were conducted to evaluate the effect of cholecystectomy and sex, and least absolute shrinkage and selection operator regression combined with mediation analysis was used to screen for hematological and biochemical mediators. Among 3401 participants, 324 had GSD. Compared with those without GSD, affected individuals were older, more likely to be female, and had a higher prevalence of metabolic comorbidities. They also exhibited lower levels of albumin and iron, but higher levels of alkaline phosphatase (ALP), lactate dehydrogenase, white blood cell count (WBC), neutrophils, platelet count, red cell distribution width, and high-sensitivity C-reactive protein, along with reduced red blood cell count, hemoglobin, and hematocrit. The prevalence of NAFLD was significantly higher among participants with GSD (70.37% vs 53.85%). Multivariable logistic regression confirmed an independent association between GSD and NAFLD (odds ratio = 1.747, 95% confidence interval: 1.334–2.302). Restricted cubic spline analysis demonstrated a linear relationship, and the results were not materially modified by cholecystectomy or sex. Mediation analysis indicated that ALP, alanine aminotransferase (ALT), uric acid, and WBC significantly mediated the association, accounting for 6.08%, 19.54%, 11.37%, and 5.52% of the effect, respectively. GSD is independently associated with NAFLD, and this relationship is partly mediated by hematological and biochemical markers (ALP, alanine transaminase, uric acid, and WBC), suggesting shared metabolic and hepatobiliary pathways between the 2 conditions.