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

McConnell, Matthew; Kawaguchi, Nao; Kondo, Reiichiro; Sonzogni, Aurelio; Licini, Lisa; Valle, Clarissa; Bonaffini, Pietro Andrea; Sironi, Sandro; Alessio, Maria Grazia; Previtali, Giulia; Seghezzi, Michela; Zhang, Xuchen; Lee, Alfred Ian; Pine, Alexander B; Chun, Hyung J.; Zhang, Xinbo; Fernández‐Hernando, Carlos; Qing, Hua; Wang, Andrew; Price, Christina; Sun, Zhaoli; Utsumi, Teruo; Hwa, John; Strazzabosco, Mario; Iwakiri, Yasuko

doi:10.1016/j.jhep.2021.04.050

Cited by 82 publications

(119 citation statements)

References 44 publications

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“…13,21 Another potential cause of liver injury is a hypercoagulable state, which also has been associated with COVID-19. Studies have shown increased markers for endothelial cell and platelet activation in patients with severe disease, potentially resulting in microthrombi [22][23][24] that could affect liver blood flow. We initially defined the hypercoagulable state as increased D-dimer and fibrinogen levels, however, because these tests also correlated significantly, we defined it solely as a D-dimer level of 5 mg/L or higher throughout hospitalization.…”

Section: Discussionmentioning

confidence: 99%

Significant Liver Injury During Hospitalization for COVID-19 Is Not Associated With Liver Insufficiency or Death

Chew

Tang

Radcliffe

et al. 2021

Clinical Gastroenterology and Hepatology

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Background and Aims COVID-19 is associated with hepatocellular liver injury of uncertain significance. We aimed to determine whether development of significant liver injury during hospitalization is related to concomitant medications or processes common in COVID-19 (e.g. ischemia, hyperinflammatory or hypercoagulable states) and to determine whether it can result in liver failure and death. Methods 834 consecutive patients hospitalized with COVID-19 were included. Clinical, medication and laboratory data were obtained at admission and throughout hospitalization using an identified database. Significant liver injury was defined as an AST≥ 5X ULN; ischemia was defined as vasopressor use for a minimum of 2 consecutive days; hyper-inflammatory state as hs-CRP ≥100mg/L and hypercoagulability as D-dimer ≥5mg/L, any time during hospitalization. Results 105 (12.6%) patients developed significant liver injury. Compared to those without significant liver injury, ischemia [OR 4.3 (2.5-7.4, p <0.0001)] and tocilizumab use [OR 3.6 (1.9-7.0, p=0.0001)] were independent predictors of significant liver injury. While AST correlated closely with ALT (R=0.89) throughout hospitalization, AST did not correlate with INR (R= 0.10) or with bilirubin (R=0.09). Death during hospitalization occurred in 136 (16.3%) patients. Multivariate logistic regression showed that significant liver injury was not associated with death [OR 1.4 (0.8-2.6, p=0.2)], while ischemic [OR 2.4 (1.4-4.0, p=0.001)] hypercoagulable [OR 1.7 (1.1-2.6, p=0.02)], and hyperinflammatory [OR 1.9 (1.2-3.1, p=0.02)] disease states were significant predictors of death. Conclusions Liver test abnormalities known to be associated with COVID-19 are secondary to other insults, mostly ischemia or drug-induced liver injury, and do not lead to liver insufficiency or death.

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Section: Discussionmentioning

confidence: 99%

Significant Liver Injury During Hospitalization for COVID-19 Is Not Associated With Liver Insufficiency or Death

Chew

Tang

Radcliffe

et al. 2021

Clinical Gastroenterology and Hepatology

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“…Coagulopathy and liver endotheliopathy have been suggested to be at least partially driven by interleukin (IL)-6 trans-signaling, which would lead to the expression of procoagulant (such as factor VIII or von Willebrand factor) and proinflammatory factors as well as increased platelet attachment in liver sinusoidal endothelial cells. Interestingly, these effects were blocked by soluble gp130, which acts as an IL-6 trans-signaling inhibitor, and the janus kinase inhibitor ruxolitinib, providing support for these therapeutic approaches[ 22 ]. Histopathologic features suggestive of some level of cytopathic injury, however, have been also observed in liver biopsies[ 23 ].…”

Section: Covid-19 and The Livermentioning

confidence: 99%

Coronavirus disease 2019 in liver transplant patients: Clinical and therapeutic aspects

Loinaz¹,

Marcacuzco²,

Fernández‐Ruiz³

2021

WJH

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The coronavirus disease 2019 (COVID-19) pandemic has profoundly impacted liver transplant (LT) activity across the world, with notable decreases in the number of donations and procedures in most Western countries, in particular throughout the first wave. The cumulative incidence of COVID-19 in LT recipients (with estimates ranging from 0.34% to 1.56%) appears to be at least comparable to that observed for the general population. Clinical and radiological features at presentation are also similar to non-transplant patients. The risk of death among LT recipients requiring hospital admission is high (from 12% to 19%), although some authors have suggested that overall mortality may be actually lower compared to the general non-transplant population. It is likely that these poor outcomes may be mainly influenced by the older age and higher comorbidity burden of LT recipients, rather than by the transplant status itself. In fact, it has been hypothesized that post-transplant immunosuppression would exert a protective role, with special focus on tacrolimus-containing regimens. There is scarce evidence to guide the optimal management of post-transplant COVID-19 and the use of antiviral or immunomodulatory therapies, although both clinical practice and guidelines support the dose reduction or withdrawal of anti-proliferative agents such as mofetil mycophenolate. Preliminary reports suggest that the antibody response to messenger RNA vaccines is significantly impaired as compared to non-immunocompromised individuals, in line with other transplant populations. Finally, it is foreseeable that the future will be conditioned by the emerging variants of severe acute respiratory syndrome coronavirus 2 with increased transmissibility among LT recipients.

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“…It is noteworthy that COVID-19 thrombosis and severe illness are more frequent in patients with metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). 7,8 In the cohort of patients from the study by McConnell, Kawaguichi et al, 14 there was a high prevalence of steatosis, and it is also possible that, in the context of systemic inflammation, liver steatosis rather than endotheliopathy, or the combination of the 2 elements, may favor liver neutrophil infiltration. Furthermore, IL-6 is only one of several cytokines which participate in the pathogenesis of COVID-19, 20 and the role of other cytokines or liver cells (e.g.…”

mentioning

confidence: 99%

“…12 Interleukin (IL)-6 has been postulated as a key proinflammatory cytokine in COVID-19 pathogenesis and IL-6 inhibition may improve outcomes and survival of patients with severe disease. 13 In this issue of Journal of Hepatology, McConnell, Kawaguchi et al 14 investigated the role of IL-6 signaling in the induction of a pro-coagulatory and proinflammatory phenotype in liver sinusoidal endothelial cells (LSECs), also called endotheliopathy by some authors. 15 IL-6 is a cytokine produced by macrophages, endothelial cells, T cells and fibroblasts upon stimulation of Toll-like receptor 4, IL-1 or tumor necrosis factor-a.…”

mentioning

confidence: 99%

“…17 Previous studies have shown that IL-6 not only promotes the acute phase response but also liver regeneration, tumorigenesis and modulation of glucose metabolism. 16 Aiming to understand the pathogenesis of COVID-19-related liver injury, McConnell, Kawaguchi et al 14 first showed that, in COVID-19 patients, the most common liver pathological features were liver congestion (98%), steatosis (47%), sinusoidal erythrocyte aggregation (44%) and neutrophil infiltration (> − 2x that in control livers). Among COVID-19 patients, patients with higher alanine aminotransferase (ALT > − 3x) had higher plasma levels of IL-6 and procoagulation factors, and more importantly, the liver histopathological analysis showed significantly higher intralobular neutrophil infiltration (2x that of patients with lower ALT) as well as trends toward a higher prevalence of steatosis and sinusoidal erythrocyte aggregation.…”

mentioning

confidence: 99%

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Unraveling the role of liver sinusoidal endothelial cells in COVID-19 liver injury

Saviano

Baumert

2021

Journal of Hepatology

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

Cited by 82 publications

References 44 publications

Significant Liver Injury During Hospitalization for COVID-19 Is Not Associated With Liver Insufficiency or Death

Significant Liver Injury During Hospitalization for COVID-19 Is Not Associated With Liver Insufficiency or Death

Coronavirus disease 2019 in liver transplant patients: Clinical and therapeutic aspects

Unraveling the role of liver sinusoidal endothelial cells in COVID-19 liver injury

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