The heterogeneity of cirrhosis - systemically assessed endotypes described by fibrosis, apoptosis, and immunoregulatory-related biomarkers

Background: Given the heterogeneity of advanced chronic liver disease, assessing disease activity-related biomarkers could aid in classifying cirrhosis endotypes for better patient monitoring and treatment selection. Aim: To investigate cirrhosis endotypes described by disease activity biomarkers related to fibrogenesis, immune cell activity, apoptosis, and systemic inflammation. Methods: The study included plasma EDTA samples from 106 participants with mild, moderate, and severe liver cirrhosis undergoing hepatic venous pressure gradient (HVPG) measurements and 39 healthy control participants. The biomarkers nordicPRO[sbnd]C3™ (fibrogenesis), GDF-15, CK18 M30 (apoptosis), CRP (systemic inflammation), nordicCPa9-HNE™ (neutrophil activity), and nordicVICM™ (macrophage activity) were measured. Results: PRO[sbnd]C3, GDF-15, CK18 M30, and CRP increased with cirrhosis severity (p < 0.05-p < 0.0001) and the degree of portal hypertension (p < 0.05-p < 0.01). CPa9-HNE decreased from mild to moderate and mild to severe cirrhosis (p < 0.01–0.0001) and correlated with HVPG (r=-0.53, p < 0.0001). VICM decreased from mild to severe cirrhosis (p < 0.01). A heatmap clustered analysis revealed four potential cirrhosis endotypes, reflecting underlying biological processes. Conclusion: Assessing markers related to active fibrogenesis, apoptosis, immune cell activity, and systemic inflammation revealed distinct molecular patterns among patients with cirrhosis. These findings suggest the presence of potential disease endotypes that could inform future strategies for patient monitoring, treatment selection, and prognostic assessment in cirrhosis management.