Among adults with biopsy-proven MASLD enrolled in the NASH CRN (n=2,395), this study examined genetic and metabolic risk factors associated with younger-onset MASLD cirrhosis, defined as cirrhosis presenting before age 50 (the lowest quartile of cirrhosis age).
One-quarter of MASLD cirrhosis patients presented before age 50; high genetic risk score (OR 2.33, 95% CI 1.26–4.23) and type 2 diabetes (OR 3.74, 95% CI 2.08–6.82) were independently associated with younger-onset cirrhosis, while the protective HSD17B13 variant was less common in younger-onset cases (24% vs. 34%, p=0.004).
The study is cross-sectional and relies on biopsy-proven MASLD from a clinical research network, which may not represent the broader MASLD population; the genetic risk score is limited to three genes (PNPLA3, TM6SF2, HSD17B13) and may miss other relevant variants.
Clinicians should screen younger MASLD patients (under 50) more proactively for cirrhosis if they have type 2 diabetes or a high genetic risk profile, as these factors are the strongest independent drivers of early-onset cirrhosis in this population.
