Biopsy-Proven SLD Subtypes Show Distinct Fibrosis Patterns

Key Takeaways

• During a median 43.8 months of follow-up, MetALD and ALD were associated with higher all-cause mortality and liver-related event risk than non-SLD.
• Among participants with at least F3 fibrosis, ALD carried higher mortality and liver-related event risk than MASLD.
• AI-based quantitative fibrosis analysis of 88 biopsies showed greater periportal and zone 2 collagen density in MetALD and ALD than MASLD despite similar conventional fibrosis stages.

In a multicenter prospective cohort of 2,551 individuals with biopsy-proven steatotic liver disease or non-SLD controls, MetALD and ALD were associated with higher mortality and liver-related event risk than non-SLD.

Investigators assembled the cohort from multiple centers between 2010 and 2023, enrolling biopsy-proven MASLD, MetALD, ALD, and non-SLD controls. The full analysis included 2,551 individuals and focused on subtype comparisons rather than a single steatotic liver disease category. Outcomes included all-cause mortality, liver-related events, cardiovascular disease, and extrahepatic malignancies.

Over a median 43.8 months, the cohort recorded 166 deaths and 162 liver-related events. Versus non-SLD, adjusted mortality risk was higher with MetALD, ASHR 3.05, 95% CI 1.08-8.58, and with ALD, ASHR 5.80, 95% CI 2.26-14.87. Adjusted liver-related event risk also rose for MetALD, ASHR 6.13, 95% CI 1.33-28.20, and for ALD, ASHR 10.96, 95% CI 2.55-47.14. Among participants with at least F3 fibrosis, ALD carried higher mortality and liver-related event risks than MASLD, indicating further divergence in advanced fibrosis.

A separate AI-based quantitative fibrosis analysis used second harmonic generation imaging on 88 liver biopsies from 28 MASLD, 30 MetALD, and 30 ALD cases. That subset allowed comparison of collagen distribution across subtypes with similar conventional fibrosis stage assignments. MetALD and ALD showed greater collagen density in periportal and zone 2 regions than MASLD despite those comparable routine stages.

Taken together, the prospective data linked biopsy-defined subtype assignment with different outcome profiles over the observed follow-up period. MetALD and ALD were associated with higher mortality and liver-related risk than non-SLD controls, while the imaging subset showed parallel collagen pattern differences.