Unbiased clustering of 349 MASLD patients identified disease subgroups; multi-omics (spatial transcriptomics, scRNA-seq, immunohistochemistry) characterized a high-risk immune-driven subgroup, with validation in two independent cohorts (n=287 and n=272) over a 5-year follow-up.
One cluster had a 5-year cumulative incidence of liver-related events (LRE) of 24.0% (95% CI 14.8%–37.4%); elevated IgA ≥318 mg/dL was an independent predictor of LRE (HR 3.17, 95% CI 1.27–7.91; P=0.01), persisting after adjustment for advanced fibrosis.
Observational clustering design limits causal inference; IgA threshold (≥318 mg/dL) was derived from a single discovery cohort before external validation; gut permeability link is based on indirect markers (EndoCAb IgG, immunohistochemistry) rather than direct functional measures.
Consider measuring serum IgA in MASLD patients — a level ≥318 mg/dL may flag a high-risk subgroup warranting closer surveillance regardless of fibrosis stage. This IgA-driven phenotype also points to the gut-liver immune axis as a potential therapeutic target.
