Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria.
Hepatology. 2022 Mar;75(3):610-622. doi: 10.1002/hep.32220. Epub 2021 Dec 20.
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.
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.
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.
肝纤维化是门脉高压（PH）的静态和主要（70%-80%）成分。我们通过基于动物肝胶原比例面积（CPA）与门脉压（PP）或患者 HVPG 的相关性的三维分析来研究 PH 的动态成分。
不同的动物模型（胆管结扎：n = 31，四氯化碳：n = 12，硫代乙酰胺：n = 12，胆碱缺乏高脂饮食：n = 12）和患有单一病因胆汁淤积性（原发性胆汁性胆管炎/原发性硬化性胆管炎：n = 16）、酒精相关性（n = 22）和代谢性（NASH：n = 19）肝病的患者接受了肝标本/活检的 CPA 定量。基于 CPA 与 PP/HVPG 的相关性，在预期 PP/HVPG 较低和较高的动物/患者亚组中确定了潜在的动态成分。使用肝硬度测量（LSM）代替 CPA 在患者队列（n = 245）中验证了 CPA 动态成分。CPA 与动物模型中的 PP（Rho = 0.531；p < 0.001）和患者中的 HVPG（Rho = 0.439；p < 0.001）显著相关。CPA 与 PP/HVPG 的相关性在不同的动物模型和患者病因之间存在差异。在模型中，高动力循环的严重程度和特定的纤维化模式（门脉纤维化：p = 0.02；间隔宽度：p = 0.03）与 PH 严重程度相关。在患者中，高动力循环（p = 0.04）、血管功能障碍/血管生成（VWF-Ag：p = 0.03；可溶性血管内皮生长因子受体 1：p = 0.03）和胆汁酸（p = 0.04）是 PH 的动态调节剂。LSM-HVPG 验证队列证实了这些因素，还表明白细胞介素 6（p = 0.008）和透明质酸（HA：p < 0.001）是 PH 的动态成分。
“静态”纤维化对 PH 严重程度的相对贡献因肝损伤类型而异。除了高动力循环外，增加的胆汁酸、VWF-Ag、白细胞介素 6 和 HA 似乎表明患者的 PH 具有明显的动态成分。
