ArticleJournal of hepatology2021
Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy.
Article in Journal of hepatology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers, 3 of them syntheses that pooled it.
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Who cites it
64 citing papers in PubMed, 3 syntheses or guidelines pooled it, 99 citations in OpenAlex.
- The immunopathological spectrum of COVID-19: from cytokine storm to autoimmunity-a systematic review.Frontiers in medicine · 2026Pooled it
- Organokines in COVID-19: A Systematic Review.Cells · 2023Pooled it
- Tissue factor in COVID-19-associated coagulopathy.Thrombosis research · 2022Pooled it
- Identification of Prognostic Factors and Regulatory Pathways in Porto-Sinusoidal Vascular Disorder.Liver international : official journal of the International Association for the Study of the Liver · 2026Article
- Identifying MASLD Patients with MASH or Significant Fibrosis: The Role of Lower ALT Thresholds.Journal of clinical medicine · 2026Article
- Platelet-derived S100A9 contributes to endotheliopathy in alcohol-associated hepatitis.JCI insight · 2026Article
- Hepatic Mechanisms and Therapeutic Target Underpinning Hypercoagulation in Obesity: Insights From Genetic and Transcriptomic Analyses.Exploration (Beijing, China) · 2026Article
- Unbiased characterization of COVID-19 endotypes leads to prognostication of high-risk individuals using routine blood tests.Communications medicine · 2026Article
- Giant Abdominal Haematoma and Rapid Multidrug-Resistant Infection After Low-Molecular-Weight Heparin in a Patient With COVID-19 and Rheumatoid Arthritis.Infection and drug resistance · 2026Article
- COVID-19 Infection, Drugs, and Liver Injury.Journal of clinical medicine · 2025Review
- Review
- Hematological Markers in Thromboembolic Events: A Comparative Study of COVID-19 and Non-COVID-19 Hospitalized Patients.Journal of clinical medicine · 2025Article
- Neuropilin-1 as a Neuroinflammatory Entry Factor for SARS-CoV-2 Is Attenuated in Vaccinated COVID-19 Patients: A Case-Control Study.Health science reports · 2025Article
- Assessing the consistency of FIB-4, APRI, and GPR in evaluating significant liver fibrosis and cirrhosis in COVID-19 patients with concurrent liver diseases.BMC gastroenterology · 2025Article
- mTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS.Journal of translational medicine · 2025Review
- Angiotensin-converting enzyme 2 and hepatic SARS-CoV-2 infection: Regulation, association, and therapeutic implications.World journal of gastroenterology · 2025Article
- Toxicities Associated with Systemic Administration of Interleukin-6 in Wistar Albino Rats.Journal of experimental pharmacology · 2025Article
- Challenging the notion of endothelial infection by SARS-CoV-2: insights from the current scientific evidence.Frontiers in immunology · 2025Article
- The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases.Experimental hematology & oncology · 2024Review
- How the immune response to the structural proteins of SARS-CoV-2 affects the retinal vascular endothelial cells: an immune thrombotic and/or endotheliopathy process with in silico modeling.Immunologic research · 2024Article
4 more citing papers are in PubMed but not listed here.
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Authors and funding
25 authors at 4 institutions in 3 countries.
Funding
Abstract
BACKGROUND AND
aimsCOVID-19 is associated with liver injury and elevated interleukin-6 (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.
methodsCoagulopathy, endotheliopathy, and alanine aminotransferase (ALT) were retrospectively analyzed in a subset (n = 68), followed by a larger cohort (n = 3,780) of patients with COVID-19. Liver histology from 43 patients with COVID-19 was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism.
resultsFactor VIII, fibrinogen, D-dimer, von Willebrand factor (vWF) activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in patients with COVID-19 and liver injury (elevated ALT). IL-6 positively correlated with vWF antigen (p = 0.02), factor VIII activity (p = 0.02), and D-dimer (p <0.0001). On liver histology, patients with COVID-19 and elevated ALT had significantly increased vWF and platelet staining, supporting a link between liver injury, coagulopathy, and endotheliopathy. Intralobular neutrophils positively correlated with platelet (p <0.0001) and vWF (p <0.01) staining, and IL-6 levels positively correlated with vWF staining (p <0.01). IL-6 trans-signaling leads to increased expression of procoagulant (factor VIII, vWF) and proinflammatory factors, increased cell surface vWF (p <0.01), and increased platelet attachment in LSECs. These effects were blocked by soluble glycoprotein 130 (IL-6 trans-signaling inhibitor), the JAK inhibitor ruxolitinib, and STAT1/3 small-interfering RNA knockdown. Hepatocyte fibrinogen expression was increased by the supernatant of LSECs subjected to IL-6 trans-signaling.
conclusionIL-6 trans-signaling drives the coagulopathy and hepatic endotheliopathy associated with COVID-19 and could be a possible mechanism behind liver injury in these patients. LAY SUMMARY: Patients with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 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 patients with COVID-19. 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.
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