Nonlinear Association Between Metabolic Syndrome Severity and Advanced Fibrosis in Metabolic Dysfunction-Associated Steatotic Liver Disease.

BACKGROUND AND AIMS: Metabolic dysfunction drives hepatic progression in metabolic dysfunction-associated steatotic liver disease (MASLD), yet conventional binary metabolic syndrome (MetS) definitions may obscure dose-response risk of fibrosis. We evaluated the association between MetS severity and advanced fibrosis probability in a representative US MASLD cohort.

METHODS

Adults aged 20-74 years with ultrasound-defined MASLD in the Third National Health and Nutrition Examination Survey were analyzed. Exposure was the validated MetS severity Z-score (quartiles, percentile categories, and continuous percentile with restricted cubic splines). Outcome was the Nonalcoholic Fatty Liver Disease Fibrosis Score (NFS)-defined advanced fibrosis probability (intermediate-to-high: NFS ≥ -1.455; high: NFS > 0.676). Complex survey logistic regression estimated adjusted odds ratios (aORs).

RESULTS

Among 3036 participants, 29.6% had intermediate fibrosis probability and 5.2% had high advanced fibrosis probability. High fibrosis probability was most prevalent in non-Hispanic Black adults (8.0%) and least in Mexican Americans (2.6%; P value <.001). Approximately 2.5% of the low MetS severity group had a high probability of advanced fibrosis compared with 11.4% in the very high MetS severity group (P value <.001). Each one-quartile decrease in MetS severity was associated with 21% (aOR = 0.79; 95% confidence interval [CI]: 0.68-0.91) and 32% (aOR = 0.68; 95% CI: 0.48-0.96) lower odds of intermediate-to-high and high probability of advanced fibrosis, respectively. In dose-response analyses, advanced fibrosis risk rose modestly through midrange severities and accelerated beyond the 70th severity percentile, reaching aOR of 3.59 (95% CI: 2.74-4.70) at the 90th vs the 50th percentile.

CONCLUSION

MetS severity demonstrates a graded and nonlinear association with advanced fibrosis probability in MASLD. A continuous metabolic-burden measure may enhance upstream triage and risk stratification alongside existing noninvasive pathways.