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Background and Aims  Liver fibrosis is the static and main (70%‐80%) component of portal hypertension (PH). We investigated dynamic components of PH by a three‐dimensional analysis based on correlation of hepatic collagen proportionate area (CPA) with portal pressure (PP) in animals or HVPG in patients.    Approach and Results  Different animal models (bile duct ligation:  n  = 31, carbon tetrachloride:  n  = 12, thioacetamide:  n  = 12, choline‐deficient high‐fat diet:  n  = 12) and patients with a confirmed single etiology of cholestatic (primary biliary cholangitis/primary sclerosing cholangitis:  n  = 16), alcohol‐associated ( n  = 22), and metabolic (NASH:  n  = 19) liver disease underwent CPA quantification on liver specimens/biopsies. Based on CPA‐to‐PP/HVPG correlation, potential dynamic components were identified in subgroups of animals/patients with lower‐than‐expected and higher‐than‐expected PP/HVPG. Dynamic PH components were validated in a patient cohort ( n  = 245) using liver stiffness measurement (LSM) instead of CPA. CPA significantly correlated with PP in animal models (Rho = 0.531;  p  < 0.001) and HVPG in patients (Rho = 0.439;  p  < 0.001). Correlation of CPA with PP/HVPG varied across different animal models and etiologies in patients. In models, severity of hyperdynamic circulation and specific fibrosis pattern (portal fibrosis:  p  = 0.02; septa width:  p  = 0.03) were associated with PH severity. In patients, hyperdynamic circulation ( p  = 0.04), vascular dysfunction/angiogenesis (VWF‐Ag:  p  = 0.03; soluble vascular endothelial growth factor receptor 1:  p  = 0.03), and bile acids ( p  = 0.04) were dynamic modulators of PH. The LSM‐HVPG validation cohort confirmed these and also indicated IL‐6 ( p  = 0.008) and hyaluronic acid (HA:  p  < 0.001) as dynamic PH components.    Conclusions  The relative contribution of “static” fibrosis on PH severity varies by type of liver injury. Next to hyperdynamic circulation, increased bile acids, VWF‐Ag, IL‐6, and HA seem to indicate a pronounced dynamic component of PH in patients.

Distinct structural and dynamic components of portal hypertension in different animal models and human liver disease etiologies