Fasting Hormonal and Inflammatory Profiles according to Liver Fibrosis Stages in Metabolic Dysfunction-Associated Steatotic Liver Disease

Endocrine mechanisms underlying progression of metabolic dysfunction-associated steatotic liver disease (MASLD) to advanced fibrosis remain unclear. We aimed to characterize fasting hepatokines, adipokines, gastrointestinal hormones, and inflammatory markers according to fibrosis stages in MASLD and explore their associations with glucose and lipid metabolism. In this cross-sectional study, 79 individuals with MASLD were grouped into no evidence of advanced fibrosis (no-AF; F0-F2) (n=51) and advanced fibrosis (AF; F3-F4) (n=28). Fasting plasma levels of hepatokines (ANGPTL3, ANGPTL4, ANGPTL6, and FGF-21), adipokines (leptin), gastrointestinal hormones (GLP-1, GIP, glucagon, and FGF-19), and inflammatory markers (TNF-α, IL-6, and MCP-1) were measured. Spearman correlations between hormones and indices of glucose and lipid metabolism were calculated and further adjusted for age, sex, and BMI. Median age (56[44-64] vs. 56[48-65] yr), sex (57 vs. 39% women), and BMI (33[27-37] vs. 34[31-38] kg/m ² ) were comparable between groups. Individuals with AF had lower ANGPTL6 (p=0.03) and higher IL-6 (p=0.02) and TNF-α (p<0.0001), whereas other hepatokines, leptin, and gastrointestinal hormones were similar between groups. Independently of age, sex, and BMI, ANGTL6 was positively associated with triglycerides (r=0.44, p<0.01). GIP and glucagon were strongly associated with hepatic and adipose tissue insulin resistance and reduced β-cell function (p≤0.003). Additionally, FGF-19 was negatively associated with hepatic insulin sensitivity (r=-0.26, p=0.02) and positively associated with insulin secretion (r=0.27, p=0.02). Overall, our results suggest that advanced fibrosis is characterized by selective reduction of ANGPTL6 and increased inflammatory markers rather than global endocrine alterations. Gastrointestinal hormones could be major contributors of impaired fasting glucose metabolism in MASLD.