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Cytokine-Induced Liver Injury in Coronavirus

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Cytokine-Induced Liver Injury in Coronavirus Review Cytokine-induced liver injury in coronavirus disease-2019 (COVID-19): untangling the knots Prajna Anirvana, Sonali Narainb,c, Negin Hajizadehc,d,e, Fuad Z . Aloorc, Shivaram P. Singha,* and Sanjaya K. Satapathyf,* 01/15/2021 on BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= by https://journals.lww.com/eurojgh from Downloaded Liver dysfunction manifesting as elevated aminotransferase levels has been a common feature of coronavirus disease-2019 (COVID-19) infection. The mechanism of liver injury in COVID-19 infection is unclear. However, it has been Downloaded hypothesized to be a result of direct cytopathic effects of the virus, immune dysfunction and cytokine storm-related multiorgan damage, hypoxia-reperfusion injury and idiosyncratic drug-induced liver injury due to medications used in the management of from COVID-19. The favored hypothesis regarding the pathophysiology of liver injury in the setting of COVID-19 is cytokine storm, https://journals.lww.com/eurojgh an aberrant and unabated inflammatory response leading to hyperproduction of cytokines. In the current review, we have summarized the potential pathophysiologic mechanisms of cytokine-induced liver injury based on the reported literature. Eur J Gastroenterol Hepatol XXX: 00–00 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= Introduction Cytokines Despite being primarily a respiratory syndrome, corona- Cytokines play important roles in regulating host defense virus disease-2019 (COVID-19) has been found to cause and maintenance of homeostasis [5]. Cytokines are cellu- significant multiorgan dysfunction [1,2]. In a study involv- lar products that exert their activity on other cells through ing 5700 patients with COVID-19, more than half of the autocrine, paracrine and endocrine mechanisms [6]. Their patients presented with elevated aminotransferase levels activity is receptor-mediated and they can control a host [3]. The mechanism of liver injury in COVID-19 infection of biologic functions, such as cellular proliferation, dif- has been postulated to be a result of direct cytopathic ferentiation, activation and inflammatory responses [5,6]. effects of the virus, immune imbalance and cytokine storm-related multiorgan damage, hypoxia-reperfusion Cytokines in viral infections dysfunction and idiosyncratic drug-induced liver injury due to medications used for the management of COVID- The artillery against invading viruses includes Toll-like 19 [4]. The focus of the current review is to consolidate receptors, Nod-like receptors and the RIG-I-like receptors our understanding of the implications of cytokine surge as [7], which can identify specific pattern recognition recep- a cause of hepatic injury with special reference to evidence tors on the viral surface and launch an attack by cytokine in the context of COVID-19. production [8]. Cytokines play a major role in inducing apoptosis and killing of virus-infected cells by activating specific immune cells and recruiting them to the site of damage [9]. Of the different cytokines, interferons (IFNs) European Journal of Gastroenterology & Hepatology 2020, XXX:00–00 provide the most robust response against viral injury [10]. Keywords: coronavirus disease-2019, cytokine release syndrome, endotheliitis, liver injury, transaminitis IFNs can induce the release of a number of proteins and on peptides that have an antiviral action [11]. IFN-induced aDepartment of Gastroenterology, S.C.B. Medical College, Cuttack, 01/15/2021 India, bDepartment of Medicine, Division of Rheumatology, Northwell Health, chemokine CXCL10 has been found to be a key player in Manhasset, cDepartment of Medicine, Donald and Barbara Zucker School of mounting an antiviral response in several viral-mediated Medicine at Hofstra/Northwell, Northwell Health, Hempstead, dDepartment of respiratory syndromes [12]. Information Services, Institute of Health, Innovations and Outcomes Research, Feinstein Institutes for Medical Research, Northwell Health, New Hyde Park, eDivision of Pulmonary, Critical Care and Sleep Medicine, Department of Coronaviruses and cytokines Medicine, Northwell Health, Manhasset, New York, USA and fDivision of Hepatology at Sandra Atlas Bass Centre for Liver Diseases and Transplantation, Many of the systemic manifestations in severe acute res- Barbara and Zucker School of Medicine/Northwell Health, Manhasset, New piratory syndrome (SARS) could be explained by an York, USA immune-mediated response rather than a direct viral Correspondence to Sanjaya K. Satapathy, MBBS, MD, DM, Donald and Barbara injury [13]. In animal models of murine hepatitis virus, a Zucker School of Medicine at Hofstra/ Northwell Health, 400 Community Drive, Manhasset, New York 11030, USA widely studied coronavirus, disease manifestations corre- Tel: +516 562 5010; fax: +516 562 2688; e-mail: [email protected] lated with immune response, rather than viral replication *Dr. Shivaram P. Singh and Dr. Sanjaya K. Satapathy contributed equally to the [14]. While immunodeficient (lacking T- and B-cells) mice LWW writing of this article. do not develop demyelination, the addition of virus-spe- Received 27 September 2020 Accepted 23 November 2020 cific T-cells causes demyelination to occur [15]. The timing 0954-691X Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MEG.0000000000002034 1 Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 2 European Journal of Gastroenterology & Hepatology xxx 2020 • Volume XXX • Number XXX of elevations in inflammatory cytokines and CRP corre- mortality [31]. The presence of increased levels of IL-1 lated with progression of pulmonary infiltrates of SARS beta (IL-1ß), IFN-γ and CXCL10 in COVID-19 patients patients [16]. In Middle Eastern respiratory syndrome implicate a potential T-helper-1 (Th1) cell-mediated (MERS) patients too, increase in serum levels of CXCL10 response [32]. When initial immune responses fail to con- correlated with disease severity [17]. trol viral replication, the virus may induce target cells to The role of cytokines as potentially important mediators release overwhelming amounts of cytokines and thus lead of the pathophysiology of COVID-19 has been established to pathological lesions [33]. In a randomized study com- with the demonstration that proinflammatory cytokines paring the neutralizing antibody Ly-Cov555 to placebo, and chemokines – tumor necrosis factor-alfa (TNFα) and the persistence of a high viral load at Day 7 was associated IFN-gamma (IFNγ), CXCL10 and CXCL8 – were higher with more severe forms of COVID-19, which is consist- in the plasma of COVID-19 patients compared to healthy ent with this assertion [34]. In patients of COVID-19 with controls [18]. Circulating concentrations of CXCL10, comorbidities, such as diabetes mellitus and factors like CCL2 and TNFα were also found to be significantly higher reduced T-cell function, diminished viral clearance and a in patients requiring admission to intensive care units [18]. state of chronic inflammation ultimately culminate in the Inflammatory markers such as C-reactive protein (CRP), genesis of a cytokine storm [35]. lactate dehydrogenase (LDH) and procalcitonin have been Activated T-cells release IFN and TNF-α, which, in found to be frequently elevated in COVID-19 patients turn, cause activation of macrophages and dendritic cells. [19]. Many of the early studies from China and Italy have These cells produce large amounts of IL-6 which, in a kind reported that elevated ferritin, CRP, LDH, interleukin 6 (IL- of vicious cycle, perpetuates the inappropriate immune 6) and D-dimer correlated with severe illness and increased response. In the early phase, TNF-α, IL-1ß, IL-8 and mono- mortality [20]. In a retrospective cohort study, severe acute cyte chemoattractant protein-1 appear which is followed liver injury was found to be significantly associated with by a sustained increase in IL-6 [6]. IL-6 contributes to elevated inflammatory markers including ferritin and IL-6 the characteristic symptoms of cytokine storm-increased [21]. In another retrospective, single-center study of 148 vascular permeability and coagulopathy [29]. Thus, the patients with COVID-19 from China, higher levels of pro- surge of massive amounts of pro-inflammatory cytokines calcitonin and CRP were found in patients presenting with [IFNs, ILs, TNFα and Transforming Growth Factor β abnormal liver function tests [22]. This appears quite sim- (TGFβ)] and chemokines such as CXCL10, CXCL8 and ilar to studies in SARS and MERS where IL, TNF-α and CCL5 generates and sustains the aberrant systemic inflam- endotoxins were higher in patients with liver injury com- matory response [18]. These events may be followed by pared to those with preserved liver function, [23,24] indi- an anti-inflammatory response in which there is a rise in cating that in addition to the association of cytokine storm IL-10 with concurrent downregulation of neutrophil and with disease outcomes, cytokine release could possibly also lymphocyte function – an event termed ‘immunoparalysis’ induce and propagate hepatic dysfunction. [36]. Although apparently favorable, immunoparalysis is associated with poor prognosis [37]. In COVID-19, continuously high levels of CXCL10 Cytokine release syndrome- pathophysiology and CCL7 were found to be associated with increased
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