Cryptogenic steatotic liver disease: a lean phenotype associated with increased liver-related mortality

BACKGROUND: Cryptogenic steatotic liver disease (SLD) remains undefined. OBJECTIVE: We investigated the clinical features and outcomes of cryptogenic SLD, operationalised as lean SLD without recorded cardiometabolic risk factors (CMRFs). DESIGN: Clinical characteristics were evaluated in the UK Biobank (UKB) magnetic resonance proton density fat fraction (MR-PDFF) cohort (SLD defined as PDFF ≥5%). Findings were assessed in a hepatic steatosis index-based UKB cohort and externally validated in three cross-sectional cohorts, including the National Health and Nutrition Examination Survey and Korean National Health Insurance Service (KNHIS) cohorts. Outcomes were examined using Cox regression in two longitudinal cohorts: the UKB hepatic steatosis index cohort and the KNHIS cohort. RESULTS: Among 30 847 MR-PDFF participants, 1195 (3.4%) had non-obese SLD (body mass index <25 kg/m²); 13.7% had cryptogenic SLD and 86.3% had lean metabolic dysfunction-associated SLD. Cryptogenic SLD showed less favourable metabolic and liver-related profiles than non-SLD/no CMRF across cohorts. In cohort-specific analyses, cryptogenic SLD exhibited higher contrast-enhanced T1-weighted image values and an increased prevalence of PNPLA3 and TM6SF2 risk variants in the UKB MR-PDFF cohort. Higher fibrosis rates were observed in the magnetic resonance elastography cohort. In longitudinal analyses, cryptogenic SLD was associated with liver-related death in KNHIS (HR 2.5, 95% CI 1.4 to 4.3). A similar but imprecise association was observed in the UKB hepatic steatosis index cohort (HR 13.2, 95% CI 1.9 to 92.4). The KNHIS association persisted after stricter alcohol exclusion. CONCLUSION: Operationally defined cryptogenic SLD accounted for a substantial proportion of lean SLD. Despite no recorded CMRFs, this phenotype was associated with liver injury markers and liver-related mortality.