P1117 Molecular and clinical characterization of metabolic associated steatotic liver disease in the setting of immune-mediated inflammatory diseases: a link with cancer risk in IBD?

Abstract

Abstract Background Growing evidence suggests an increased prevalence of metabolic associated steatotic liver disease (MASLD) in the context of immune-mediated inflammatory diseases (IMIDs). The risk of incident extrahepatic cancers is higher in MASLD. We aimed to clinically and mechanistically characterize IMID-MASLD patients compared to classic-MASLD, and its relation to cancer risk in IBD. Methods Ambidirectional, case‒control study including a prospective cohort of IMID patients (IBD, psoriasis, hidradenitis, and spondyloarthritis). MASLD and advanced-MASLD was established by the controlled attenuation parameter and transient elastography, respectively. Controls from the general population were age-, sex-, type 2 diabetes-, and BMI-matched in a 1:2 ratio. Liver biopsies were collected when significant liver fibrosis was suspected. Total RNA was obtained 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. Data on global cancer prevalence was retrospectively collected on a multicenter IBD cohort. Results 1435 IMID patients and 2918 controls were initially included. Advanced-MASLD prevalence was significantly higher among IMID patients than controls(p<0.0001). In multivariate analysis, concomitant IMID was an independent and the strongest predictor of advanced-MASLD (adjusted OR 2.587; < 0.001).Transcriptomic data was obtained in 109 patients and showed 87 significant genes differentially expressed between IMID- and classic-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 (figure 1). A comparable transcriptomic signature was observed in IBD-MASLD, involving genes as IGFBP2, PLEKHA4, or metallothioneins, all of them associated to pour prognosis in renal cell carcinoma (RCC). In the multicentre IBD cohort (n=1905; female 50.5%; mean age 50.7 years, mean follow up: 13.3 years) we observed a global cancer prevalence of 9.0%, with a higher-than-expected RCC prevalence (table 1). Whereas RCC represents 3.2% of all cancers in the general population, it accounts for 8.7% in our IBD cohort, in agreement with our molecular data. Conclusion Advanced MASLD has a disproportionately high prevalence in IMID populations. Both conditions can trigger a protumoral condition that can lead to an accelerated form of MASLD independent of classic metabolic pathways and a higher cancer risk, as is the case of RCC in the IBD population.