Valenti Luca, Tripodi Armando, La Mura Vincenzo, Pelusi Serena, Bianco Cristiana, Scalambrino Erica, Margarita Sara, Malvestiti Francesco, Ronzoni Luisa, Clerici Marigrazia, D'Ambrosio Roberta, Fraquelli Mirella, Carpani Rossana, Prati Daniele, Peyvandi Flora
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Precision Medicine Lab, Biological Resource Center, Department of Transfusion Medicine, Milan, Italy.
Università Degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy.
JHEP Rep. 2022 Sep 25;4(12):100598. doi: 10.1016/j.jhepr.2022.100598. eCollection 2022 Dec.
BACKGROUND & AIMS: 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).
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).
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 ( <0.01), triggering D-dimer formation ( = 2E-21). In keeping with a causal role of liver damage in determining a procoagulant status, the main fatty liver inherited risk variant p.I148M was independently associated with the F8/PC ratio ( = 0.048). , the main determinant of the coagulation balance was locus variation ( = 1E-16), through the impact on vWF ( = 8E-26). Both rs687289 and factor V Leiden were independently associated with higher Pro-C3 ( <0.025), with the effect of being mediated by the impact on vWF ( = 5E-10 for association with Pro-C3). Mendelian randomisation analysis was consistent with a causal association of procoagulant imbalance with heightened fibrogenesis ( = 0.001 at robust MR-Egger for Pro-C3), but not with fibrosis (for LSM; = not significant).
In individuals with metabolic dysfunction, liver damage severity and possibly the p.I148M variant were associated with procoagulant status. , evaluation of inherited variants in and other genes influencing coagulation was consistent with a causal role of procoagulant imbalance in activation of early stages of fibrogenesis.
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.
本研究旨在探讨非酒精性脂肪性肝病（NAFLD）风险个体中肝损伤与凝血平衡之间相互作用的决定因素。
我们纳入了581名有≥3种代谢改变的健康参与者，对其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），检测前C3、凝血平衡（以血管性血友病因子[vWF]、因子VIII/蛋白C比值[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）。
肝纤维化指标（包括Fibrosis - 4 [FIB - 4]和肝脏硬度测量值[LSM]），而非肝脂肪（CAP），与较高的F8/PC比值独立相关（<0.01），并引发D - 二聚体形成（= 2E - 21）。与肝损伤在决定促凝状态中的因果作用一致，主要的脂肪肝遗传风险变异p.I148M与F8/PC比值独立相关（= 0.048）。此外，凝血平衡的主要决定因素是基因座变异（= 1E - 16），通过对vWF的影响（= 8E - 26）。rs687289和因子V莱顿均与较高的前C3独立相关（<0.025），其作用通过对vWF的影响介导（与前C3的关联= 5E - 10）。孟德尔随机化分析与促凝失衡与纤维生成增加的因果关联一致（前C3在稳健的MR - Egger分析中= 0.001），但与纤维化无关（对于LSM；=不显著）。
在代谢功能障碍个体中，肝损伤严重程度以及可能的p.I148M变异与促凝状态相关。此外，对基因及其他影响凝血的基因中遗传变异的评估与促凝失衡在纤维生成早期激活中的因果作用一致。
在有代谢性脂肪肝病风险的代谢改变个体中，存在血液凝固（凝血）增强的趋势，但原因及对肝病进展的影响仍不清楚。在此我们表明，肝损伤严重程度和代谢改变，而非肝脂肪，是代谢性脂肪肝病患者凝血增强的主要原因。通过使用遗传方法，我们表明脂毒性引起的肝脏炎症可能有利于凝血增强，进而可引发肝纤维化，引发恶性循环导致进行性肝病。
