Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy.

ABSTRACT Background and Aims COVID-19 is associated with liver injury and elevated IL-6. We hypothesized that IL-6 trans-signaling in liver sinusoidal endothelial cells (LSECs) leads to endotheliopathy (a proinflammatory and procoagulant state) and liver injury in COVID-19. Methods Coagulopathy, endotheliopathy, and ALT were retrospectively analyzed in a subset (n=68), followed by a larger cohort(n=3,780) of COVID-19 patients. Liver histology from 43 COVID-19 patients was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism. Results Factor VIII, fibrinogen, D-dimer, vWF activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in COVID-19 patients with liver injury (elevated ALT). IL-6 positively correlated with vWF antigen(P=0.02), factor VIII activity(P=0.02), and D-dimer(P Conclusion COVID-19 is associated with coagulopathy and endotheliopathy in the liver endothelium driven by IL-6 trans-signaling, a possible mechanism of liver injury. Lay Summary Patients with SARS-CoV-2 infection often have liver injury, but why this occurs remains unknown. High levels of interleukin-6 (IL-6) and its circulating receptor, which form a complex to induce inflammatory signals, have been observed in COVID-19 patients. This paper demonstrates that the IL-6 signaling complex causes harmful changes to liver sinusoidal endothelial cells and may promote blood clotting and contribute to liver injury.