Metabolic and Clinical Heterogeneity in MASLD Risk Stratification: Independent Effects of Body Mass Index and Fib-4 on Cirrhosis, and Clinical Implications of Noninvasive Score Discordance in a Veteran Cohort

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease in the United States. Noninvasive fibrosis scores, particularly Fibrosis-4 (Fib-4) and the NAFLD fibrosis score (NFS), guide risk stratification, yet their independent contributions and potential discordance in clinical practice remain poorly characterized. This study examines whether body mass index (BMI) and Fib-4 independently predict cirrhosis, and whether discordance between Fib-4 and NFS identifies a high-risk phenotype. Methods Retrospective cross-sectional analysis of 80 veterans with MASLD followed at a single Veterans Affairs medical center (2015–2023). Multivariable logistic regression assessed independent associations of Fib-4 and BMI with cirrhosis. Prevalence and clinical predictors of Fib-4 vs. NFS discordance were quantified, and associations with cirrhosis or metabolic dysfunction-associated steatohepatitis (MASH) were tested. Results In multivariable analysis, Fib-4 (OR 2.17 per unit, 95% CI 1.14–4.13, p = 0.018) and BMI (OR 1.19 per kg/m², 95% CI 1.05–1.37, p = 0.007) were independent predictors of cirrhosis. Cirrhosis prevalence rose stepwise across BMI quartiles and obesity classes (0% in normal weight to 20% in obese class III). Discordance between Fib-4 and NFS occurred in 13/80 patients (16%), and discordant patients had > 5-fold higher prevalence of cirrhosis or MASH compared to concordant patients (33.3% vs. 6.3%, p = 0.009). Discordant patients were older, more often diabetic, thrombocytopenic, and at higher cardiovascular risk. Conclusion BMI and Fib-4 are independent, additive predictors of cirrhosis in MASLD. Noninvasive score discordance identifies a high-risk phenotype requiring escalation to elastography or hepatology referral. Integrated metabolic-fibrotic risk assessment incorporating BMI, Fib-4, NFS, and discordance status improves diagnostic accuracy and patient triage for emerging MASLD therapies.