Early-pregnancy ALT, AST, and GGT in relation to gestational diabetes: a GGT-focused association pattern

To explore the associations of early-pregnancy alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transferase (GGT) with gestational diabetes mellitus (GDM) risk, and to examine the statistical interdependencies among these enzymes in relation to GDM.

This retrospective cohort included 9,077 singleton pregnancies. Multivariate logistic regression was used to examine the associations of ALT, AST, and GGT with GDM. Statistical mediation models (PROCESS Macro Model 4) assessed whether the association of ln-ALT and ln-AST with GDM could be statistically accounted for by ln-GGT. Stratified analyses by ln-ALT quartiles examined whether the negative association of ln-AST (observed after adjustment for other enzymes) varied across levels of hepatocellular injury. Moderated mediation analysis (PROCESS Macro Model 58) examined whether age, pre-pregnancy BMI, or gestational age at sampling modified the observed associations. All models were adjusted for prespecified covariates.

In regression analyses, ln-GGT showed the strongest association with GDM (aOR 1.514-1.640, all P < 0.001). ln-ALT was associated with GDM in the single-enzyme model (P = 0.016) but was attenuated after ln-GGT adjustment (P = 0.801). ln-AST showed no association in the single-enzyme model (P = 0.982) but demonstrated a negative association after co-adjustment (aOR 0.494-0.738, P < 0.05). Mediation analysis indicated that the association of ln-ALT with GDM was largely accounted for by ln-GGT (indirect effect β=0.1754, 95% CI 0.0986-0.2527). ln-AST demonstrated contrasting statistical associations: a positive indirect component via ln-GGT (indirect effect β=0.2797, 95% CI 0.1770-0.3815) and a negative direct association (β=-0.3041, P = 0.037). Stratification by ln-ALT quartiles showed that the negative association of ln-AST was statistically significant only in quartiles 3-4. BMI positively, and gestational age negatively, modified the associations between ALT/AST and GGT (all P < 0.001).

Early-pregnancy hepatic enzymes and GDM exhibit a GGT-focused interdependent association pattern: the association of ALT with GDM is largely accounted for by GGT, whereas AST demonstrates contrasting statistical associations-a positive indirect component via GGT and a negative direct association. This descriptive framework offers one potential statistical account for heterogeneous observational findings; prospective and experimental studies are needed to validate these patterns.