Inherited Genetic Risk of Liver Fibrosis in Lean Versus Nonlean Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

INTRODUCTION: Previous studies have revealed conflicting results regarding liver fibrosis risk in lean metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to compare the risk of significant fibrosis in lean versus nonlean MASLD and identify fibrosis-associated factors in lean MASLD. METHODS: The study was a cross-sectional analysis of prospectively enrolled adults with MASLD. Individuals with lean MASLD were age- and sex-matched with nonlean MASLD. Fibrosis assessment included vibration-controlled transient elastography, magnetic resonance elastography and liver biopsy. A genetic risk score (GRS), summating the effect alleles of PNPLA3 and TM6SF2 minus the protective HSD17B13 genotype, was estimated to consider inherited genetic risk across BMI categories. Results were validated in an external Latin American cohort. RESULTS: The mean ( ± $$ \pm $$ SD) age of 312 included participants with MASLD was 58.3  ± $$ \pm $$  11.6 years and 69.2% were female. 44 (14.1%) individuals were lean, 90 (28.9%) were overweight, 90 (28.9%) had class I obesity and 88 (28.1%) had class II or greater obesity. The prevalence of significant fibrosis was 27.3% in lean and 31.1% in nonlean (p = 0.653). Individuals with a high GRS had a higher prevalence of significant fibrosis compared to patients with low GRS (36.5% vs. 25.2%, p = 0.043) and the prevalence of significant fibrosis was similar in lean and nonlean patients with high GRS (31.3% vs. 37.1%, p = 0.645). The Latin American cohort exhibited similar results. CONCLUSIONS: The prevalence of significant fibrosis and the effect of GRS were similar in lean and nonlean MASLD, highlighting that lean MASLD patients may have a comparable risk to overweight and obese MASLD.