Jachs Mathias, Hartl Lukas, Simbrunner Benedikt, Bauer David, Paternostro Rafael, Scheiner Bernhard, Schwabl Philipp, Stättermayer Albert F, Pinter Matthias, Eigenbauer Ernst, Quehenberger Peter, Trauner Michael, Reiberger Thomas, Mandorfer Mattias
Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria.
Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria.
Clin Gastroenterol Hepatol. 2022 Jun;20(6):1362-1373.e6. doi: 10.1016/j.cgh.2021.07.012. Epub 2021 Jul 10.
BACKGROUND & AIMS: Nonselective beta blockers (NSBBs) exert beneficial effects beyond lowering hepatic venous pressure gradient (HVPG), which may be particularly relevant in patients with decompensated cirrhosis (DC), in whom bacterial translocation and bacterial-induced systemic inflammation drive the development of complications such as acute-on-chronic liver failure (ACLF). We evaluated whether NSBB-related changes in von Willebrand factor (VWF) may serve as a biomarker for these effects.
In this retrospective analysis, 159 prospectively characterized patients with clinically stable DC (ie, without acute decompensation) who underwent paired HVPG/VWF assessments before/on NSBB therapy were classified as 'VWF-responders' (as defined by a ≥5% decrease in VWF) versus 'VWF-non-responders.'
There were no major differences in baseline characteristics between VWF-responders (61%) and VWF-non-responders. VWF-responders showed more pronounced decreases in inflammation (procalcitonin), whereas rates of HVPG-response were similar. In line, NSBB-related changes in VWF correlated with the dynamics of bacterial translocation/inflammation (lipopolysaccharide-binding protein, C-reactive protein, and procalcitonin), rather than those of HVPG. Interestingly, VWF-responders also showed less pronounced NSBB-related decreases in mean arterial pressure, suggesting an amelioration of systemic vasodilatation. Finally, VWF-response was associated with decreased risks of further decompensation (adjusted hazard ratio [aHR], 0.555; 95% confidence interval [CI], 0.337-0.912; P = .020), ACLF (aHR, 0.302; 95% CI, 0.126-0.721; P = .007), and liver-related death (aHR, 0.332; 95% CI, 0.179-0.616; P < .001) in Cox regression models adjusted for prognostic factors including changes in HVPG.
Decreases in VWF upon NSBB therapy reflect their anti-inflammatory activity, are accompanied by less pronounced adverse effects on systemic hemodynamics, and are independently associated with a decreased risk of further decompensation, ACLF, and death. VWF-response may discriminate between decompensated patients who benefit from NSBB treatment and have a favorable prognosis versus patients with poor outcomes.
非选择性β受体阻滞剂（NSBBs）除了能降低肝静脉压力梯度（HVPG）外，还具有其他有益作用，这对于失代偿期肝硬化（DC）患者可能尤为重要，因为在这些患者中，细菌易位和细菌诱导的全身炎症会促使诸如慢加急性肝衰竭（ACLF）等并发症的发生。我们评估了NSBBs治疗引起的血管性血友病因子（VWF）变化是否可作为这些作用的生物标志物。
在这项回顾性分析中，159例临床稳定的DC患者（即无急性失代偿）在接受NSBB治疗前/治疗时进行了配对的HVPG/VWF评估，根据VWF是否降低≥5%分为“VWF反应者”和“VWF无反应者”。
“VWF反应者”（61%）和“VWF无反应者”的基线特征无显著差异。“VWF反应者”的炎症指标（降钙素原）下降更为明显，而HVPG反应率相似。同样，NSBB治疗引起的VWF变化与细菌易位/炎症（脂多糖结合蛋白、C反应蛋白和降钙素原）的动态变化相关，而非与HVPG的变化相关。有趣的是，“VWF反应者”NSBB治疗引起的平均动脉压下降也不明显，提示全身血管扩张有所改善。最后，在调整了包括HVPG变化等预后因素的Cox回归模型中，VWF反应与进一步失代偿风险降低（调整后风险比[aHR]，0.555；95%置信区间[CI]，0.337 - 0.912；P = 0.020）、ACLF风险降低（aHR，0.302；CI，0.126 - 0.721；P = 0.007）以及肝脏相关死亡风险降低（aHR，0.332；CI，0.179 - 0.616；P < 0.001）相关。
NSBB治疗后VWF的降低反映了其抗炎活性，对全身血流动力学的不良影响较小，并与进一步失代偿、ACLF和死亡风险降低独立相关。VWF反应可能有助于区分从NSBB治疗中获益且预后良好与预后不良的失代偿患者。
