Elevated circulating activin A is associated with disease severity in advanced steatotic liver disease (SLD)

Abstract Background Steatotic liver disease (SLD) is a major contributor to the global burden of chronic liver disease and is linked to liver fibrosis. Emerging evidence implicates activin A in this process, but its role remains unclear due to conflicting findings. This cross-sectional study examines circulating levels of activin A and its endogenous inhibitor follistatin in individuals with metabolic dysfunction and evaluates their associations with clinical indicators of steatosis and fibrosis. Methods Plasma activin A and follistatin were measured with ELISA in 309 participants with type 2 diabetes (T2D) with or without SLD and in 97 participants with SLD-related cirrhosis. Hepatic fat was assessed using 1 H-MRS-PDFF or MRI-PDFF, or if unavailable, controlled attenuation parameter (CAP). Liver stiffness was measured with vibration-controlled transient elastography (VCTE). Results In the diabetes cohort, participants with steatosis and fibrosis had higher activin A concentrations than participants with neither steatosis nor fibrosis (0.400 ng/mL vs. 0.285 ng/mL, P = 0.036). In the cirrhosis cohort, activin A correlated strongly with liver stiffness (ρ = 0.696, P < 0.001). Participants with VCTE suggestive of compensated advanced chronic liver disease (cACLD) and clinically significant portal hypertension (CSPH) exhibited significantly higher activin A concentrations than participants without (0.546 vs. 0.307 ng/mL, P < 0.001 and 0.624 vs. 0.396 ng/mL, P < 0.001, respectively). In this study, neither follistatin nor the activin A-to-follistatin ratio​ was associated with steatosis or fibrosis. Conclusions Activin A was associated with liver stiffness and was higher in participants with SLD-related cirrhosis.