LAUSR

BACKGROUND & AIMS Liver fibrosis is the static and main (70-80%) component of portal hypertension (PH). We investigated dynamic components of PH by a 3-dimensional analysis based on correlation of hepatic collagen proportionate area (CPA) with portal pressure (PP) in animals or hepatic venous pressure gradient (HVPG) in patients. METHODS Different animal models (BDL: n=31, CCl4: n=12, TAA: n=12, CDHFD: n=12) and patients with a confirmed single etiology of cholestatic (PBC/PSC: n=16), alcohol related (ALD: 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. RESULTS 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; sVEGFR1: 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. CONCLUSION 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.