Clinical and genetic determinants of the fatty liver-coagulation balance interplay in individuals with metabolic dysfunction.

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).

METHODS

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).

RESULTS

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).

CONCLUSIONS

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.

LAY SUMMARY

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.