Clinical and molecular characterization of steatotic liver disease in the setting of immune-mediated inflammatory diseases

Abstract

Background and aimsGrowing evidence suggest an increased prevalence of metabolic associated steatotic liver disease (MASLD) in the context of immune-mediated inflammatory diseases (IMIDs). We aimed to characterize clinically and mechanistically a prospective cohort of steatotic liver disease (SLD) in IMID patients compared to controls. MethodsCross-sectional, case‒control study including a subset of IMID patients. Controls from the general population were age-, sex-, type 2 diabetes-, and BMI-matched at a 1:2 ratio. SLD was established using controlled attenuation parameter. Liver biopsies were obtained when significant liver fibrosis was suspected. Total RNA was extracted from freshly frozen cases and analyzed by RNA-seq. Differential gene expression was performed with ‘limma-voom’. Gene set enrichment analysis was performed using the fgsea R package with a preranked “limma t-statistic” gene list. Results1456 IMID patients and 2945 controls were included. Advanced-SLD (LSM ≥9.7 kPa) (13.46% vs. 3.79%; p<0.001) and advanced-MASLD (12.8% vs. 2.8%; p<0.001) prevalence were significantly higher among IMID patients than controls. In multivariate analysis, concomitant IMID was an independent and the strongest predictor of advanced-SLD (Adjusted OR 3.318 [2.225-4.947]; p < 0.001). Transcriptomic data was obtained in 109 patients and showed 87 significant genes differentially expressed between IMID-MASLD and control-MASLD. IMID-MASLD cases displayed an enriched expression of genes implicated in pro-tumoral activities or the control of the cell cycle concomitant with a negative expression of genes related to metabolism. ConclusionsThe prevalence of advanced SLD and MASLD is disproportionately elevated in IMID cohorts. Our findings suggest that IMIDs may catalyse a distinct MASLD pathway, divergent from classical metabolic routes, highlighting the need for tailored clinical management strategies. Impact and implicationsThe prevalence of advanced fibrosis SLD is increased in patients with immune-mediated inflammatory diseases, independent of classic metabolic risk factors or high-risk alcohol consumption. The transcriptomic analysis reveals a unique gene expression signature associated with cellular activities that can be compatible with a liver condition leading to an accelerated and aggressive form of SLD. Our findings underscore the importance of heightened screening for advanced liver disease risk across various medical disciplines overseeing IMID patients.