未经评估:本研究的目的是研究非酒精性脂肪性肝病(NAFLD)风险个体的肝损伤与凝血平衡之间相互作用的决定因素。
UNASSIGNED:我们考虑了581名具有≥3种代谢改变的健康参与者进行临床和基因组评估,通过Fibroscan测量肝脏硬度(LSM)和受控衰减参数(CAP),Pro-C3,凝血平衡(血管性血友病因子[vWF],因子VIII/蛋白C比率[F8/PC]作为主要结果,D-二聚体作为凝血/纤维蛋白溶解激活的标志物)。
未经证实:肝纤维化指标(纤维化-4[FIB-4]和肝硬度测量[LSM]),但不是肝脏脂肪(CAP),与较高的F8/PC比率独立相关(p<0.01),触发D-二聚体形成(p=2E-21)。与肝损伤在确定促凝血状态中的因果作用保持一致,主要脂肪肝遗传风险变异体PNPLA3p.I148M与F8/PC比值独立相关(p=0.048).反之亦然,凝血平衡的主要决定因素是ABO基因座变异(p=1E-16),通过对vWF的影响(p=8E-26)。rs687289ABO和因子VLeiden均与较高的Pro-C3独立相关(p<0.025),ABO的作用由对vWF的影响介导(与Pro-C3相关的p=5E-10)。孟德尔随机化分析与促凝血失衡与纤维形成增加的因果关系一致(pro-C3的稳健MR-Eggerp=0.001),但没有纤维化(对于LSM;p=不显著)。
未经证实:在代谢功能障碍的个体中,肝损伤严重程度和PNPLA3p.I148M变异体可能与促凝状态相关.反之亦然,对ABO和其他影响凝血功能的基因的遗传性变异体的评估与促凝血失衡在纤维形成早期激活中的因果作用一致.
未经证实:在代谢改变有代谢性脂肪肝风险的个体中,有增加血液凝固(凝血)的趋势,但其病因及对肝病进展的影响尚不清楚.在这里,我们显示肝损伤的严重程度和代谢改变,但不是肝脏脂肪,是代谢性脂肪肝患者凝血功能增强的主要原因。通过使用遗传学方法,我们表明,由于脂毒性的肝脏炎症可能有利于增加凝血,这反过来会引发肝纤维化,引发导致进行性肝病的恶性循环。
UNASSIGNED: The aim of this study was to examine the determinants of the interplay between liver damage and the coagulation balance in individuals at risk of non-alcoholic fatty liver disease (NAFLD).
UNASSIGNED: We considered 581 healthy participants with ≥3 metabolic alterations undergoing clinical and genomic evaluation, measurement of liver stiffness (LSM) and controlled attenuation parameter (CAP) by Fibroscan, Pro-C3, coagulation balance (von Willebrand factor [vWF], factor VIII/protein C ratio [F8/PC] as the main outcome, D-dimer as marker of coagulation/fibrinolysis activation).
UNASSIGNED: Liver fibrosis indices (both Fibrosis-4 [FIB-4] and liver stiffness measurement [LSM]), but not liver fat (CAP), were independently associated with higher F8/PC ratio (p <0.01), triggering D-dimer formation (p = 2E-21). In keeping with a causal role of liver damage in determining a procoagulant status, the main fatty liver inherited risk variant PNPLA3 p.I148M was independently associated with the F8/PC ratio (p = 0.048). Vice versa, the main determinant of the coagulation balance was ABO locus variation (p = 1E-16), through the impact on vWF (p = 8E-26). Both rs687289 ABO and factor V Leiden were independently associated with higher Pro-C3 (p <0.025), with the effect of ABO being mediated by the impact on vWF (p = 5E-10 for association with Pro-C3). Mendelian randomisation analysis was consistent with a causal association of procoagulant imbalance with heightened fibrogenesis (p = 0.001 at robust MR-Egger for Pro-C3), but not with fibrosis (for LSM; p = not significant).
UNASSIGNED: In individuals with metabolic dysfunction, liver damage severity and possibly the PNPLA3 p.I148M variant were associated with procoagulant status. Vice versa, evaluation of inherited variants in ABO and other genes influencing coagulation was consistent with a causal role of procoagulant imbalance in activation of early stages of fibrogenesis.
UNASSIGNED: In individuals with metabolic alterations at risk of metabolic fatty liver disease, there is a tendency toward heightened blood coagulation (clotting), but the cause and the impact on the progression of liver disease remain unclear. Here we show that liver damage severity and metabolic alterations, but not hepatic fat, are mainly responsible for heightened coagulation in patients with metabolic fatty liver disease. By using genetic approaches, we showed that hepatic inflammation due to lipotoxicity may favour heightened coagulation, which in turn can trigger liver fibrosis, igniting a vicious cycle that leads to progressive liver disease.