Cytokine-Induced Liver Injury in Coronavirus

* and a, DOI: 10.1097/MEG.0000000000002034 1 DOI: Shivaram P. Singh , Shivaram P. c Cytokines play important roles in regulating host defense Cytokines play important roles in regulating Cytokines are cellu- and maintenance of homeostasis [5]. through cells on other their activity exert that products lar Their mechanisms [6]. paracrine and endocrine autocrine, they can control a host and activity is receptor-mediated dif- proliferation, such as cellular of biologic functions, responses [5,6]. activation and inflammatory ferentiation, Cytokines in viral infections Toll-like includes The artillery against invading viruses the RIG-I-like receptors Nod-like receptors and receptors, pattern recognition recep- which can identify specific [7], cytokine by attack an launch and surface viral the on tors a major role in inducing Cytokines play production [8]. activating by cells virus-infected of killing and apoptosis of site the to them recruiting and cells specific immune interferons (IFNs) Of the different cytokines, damage [9]. provide the most robust response against viral injury [10]. IFNs can induce the release of a number of proteins and IFN-induced peptides that have an antiviral action [11]. player in a key to be found has been chemokine CXCL10 mounting an antiviral response in several viral-mediated respiratory syndromes [12]. and cytokines Coronaviruses Many of the systemic manifestations in severe acute res- could be explained by an piratory syndrome (SARS) immune-mediated response rather than a direct viral a In animal models of murine hepatitis virus, injury [13]. disease manifestations corre- widely studied coronavirus, rather than viral replication lated with immune response, B-cells) mice T- and (lacking While immunodeficient [14]. the addition of virus-spe- do not develop demyelination, The timing T-cells causes demyelination to occur [15]. cific Cytokines , Fuad Z . Aloor

c,d,e Department of d Division of f , Negin Hajizadeh b,c * f, , Sonali Narain a Department of Medicine, Donald and Barbara Zucker School of c

Review Department of Medicine, Division of Rheumatology, Northwell Health, Department of Medicine, Division of Rheumatology, Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Copyright © 2020 Wolters b

Liver dysfunction manifesting as elevated aminotransferase levels has been a common feature of coronavirus of coronavirus has been a common feature as elevated aminotransferase levels Liver dysfunction manifesting it has been However, in COVID-19 infection is unclear. infection. The mechanism of liver injury disease-2019 (COVID-19) multiorgan storm-related cytokine and dysfunction immune virus, the of effects cytopathic direct of result a be to hypothesized of injury due to medications used in the management and idiosyncratic drug-induced liver injury damage, hypoxia-reperfusion of COVID-19 is cytokine storm, of liver injury in the setting the pathophysiology regarding hypothesis COVID-19. The favored we have review, In the current of cytokines. response leading to hyperproduction inflammatory an aberrant and unabated Eur J literature. reported liver injury based on the pathophysiologic mechanisms of cytokine-induced summarized the potential Hepatol XXX: 00–00 Gastroenterol Kluwer Health, Inc. All rights reserved. Copyright © 2020 Wolters Division of Pulmonary, Critical Care and Sleep Medicine, Department of and Sleep Medicine, Critical Care Division of Pulmonary, Department of Gastroenterology, S.C.B. Medical College, Cuttack, Department of Gastroenterology, Kluwer Health, Inc. All rights reserved. 0954-691X Copyright © 2020 Wolters Sanjaya K. Satapathy Introduction corona- syndrome, Despite being primarily a respiratory has been found to cause virus disease-2019 (COVID-19) In a study involv- significant multiorgan dysfunction [1,2]. more than half of the ing 5700 patients with COVID-19, levels patients presented with elevated aminotransferase infection of liver injury in COVID-19 mechanism The [3]. of direct cytopathic has been postulated to be a result imbalance and cytokine immune effects of the virus, hypoxia-reperfusion multiorgan damage, storm-related liver injury dysfunction and idiosyncratic drug-induced of COVID- due to medications used for the management review is to consolidate The focus of the current 19 [4]. as cytokine surge implications of our understanding of the reference to evidence a cause of hepatic injury with special in the context of COVID-19.

disease-2019 (COVID-19): untangling the knots untangling (COVID-19): disease-2019 Prajna Anirvan Cytokine-induced liver injury in coronavirus in coronavirus injury liver Cytokine-induced Information Services, Institute of Health, Innovations and Outcomes Research, Information Services, Institute of Health, Innovations and Outcomes Research, Northwell Health, New Hyde Park, Feinstein Institutes for Medical Research, Medicine, Northwell Health, Manhasset, New York, USA and Medicine, Northwell Health, Manhasset, New York, India, Medicine at Hofstra/Northwell, Northwell Health, Hempstead, Hepatology at Sandra Atlas Bass Centre for Liver Diseases and Transplantation, Liver Diseases and Transplantation, for Hepatology at Sandra Atlas Bass Centre Barbara and Zucker School of Medicine/Northwell Health, Manhasset, New USA York, DM, Donald and Barbara MBBS, MD, to Sanjaya K. Satapathy, Correspondence Zucker School of Medicine at Hofstra/ Northwell Health, 400 Community Drive, 11030, USA Manhasset, New York +516 562 5010; 562 fax: +516 2688;Tel: e-mail: [email protected] Sanjaya K. Satapathy contributed equally to the Singh and Dr. Shivaram P. *Dr. writing of this article. Received 27 September 2020 Accepted 23 November 2020 e a European Journal of Gastroenterology & Hepatology 2020, XXX:00–00 Journal of Gastroenterology European syndrome, disease-2019, cytokine release coronavirus Keywords: transaminitis endotheliitis, liver injury, Manhasset,

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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 Cytokine storm or cytokine release syndrome (CRS) can be viral load, loss of lung function, lung injury and a fatal defined as an aberrant, exaggerated and unabated systemic outcome [38]. Upregulation of genes involved in apoptosis inflammatory response precipitated by infection, drugs or and p53 signaling have also been observed in COVID 19 as an allogenic response to foreign tissue resulting in the – a likely explanation of lymphopenia commonly encoun- overproduction of pro-inflammatory cytokines, leading to tered in these patients [39]. TNF-α-mediated apoptosis multiorgan dysfunction [25]. Cytokine storms have been of lymphocytes has been documented in several studies associated with a number of diseases, including the avian [40,41]. Lymphopenia, in turn, has been associated with H5N1 influenza virus infection [26]. Cytokine storm is poorer outcomes in COVID-19 patients [42]. CRP values usually heralded by local inflammation that spills over to ≥20 mg/L and a lymphocyte count <1.1 × 109/L have been the systemic circulation [6]. Local inflammation involves found to be independent risk factors for liver injury in vasodilatation, increased vascular permeability and recruit- COVID-19 [42]. Lymphopenia can cause an unrestrained ment of inflammatory mediators to the site of involvement expression of the immune response leading to organ dam- aimed at generating a host response. Dysregulation of this age [43]. This might be one mechanism of how lymphope- immune response causes increased production of cytokines nia in COVID-19 may upregulate inflammatory mediators and chemokines, which in turn, act as chemoattractants for such as IL-6, IL-2 and IFN-γ and not only cause pulmonary other inflammatory cells, resulting in exaggerated immune injury, but also involve extra-pulmonary organs such as response with consequent systemic manifestations [27]. the liver [44]. It is quite interesting to note that lymphope- IL-6, IL-10 and IFN-γ are the primary cytokines that are nia, despite being an effect of COVID-19-triggered apop- consistently found to be elevated in the serum of patients tosis, can perpetuate an exaggerated immune response. with CRS [28,29]. Moreover, the differential expression of Therefore, the cytokine storm represents the extremes of chemokines, such as CXCL9, CXCL10 and CXCL11, has immune system dysfunction and dysregulation that leads been found to regulate T-cell function and infiltration in to systemic complications and unfavorable outcomes. the periphery during inflammation [30]. In COVID-19, similar to MERS CoV and SARS CoV Clinical manifestations of cytokine storm infections, the key immune-mediated manifestation of end-organ damage is the acute respiratory distress syn- Cytokine storm can present as a spectrum of illness drome (ARDS), which is associated with high short-term ranging from mild flu-like symptoms to life-threatening

Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Cytokine-induced liver injury in coronavirus disease-2019 Anirvan et al. www.eurojgh.com 3 manifestations such as hyperpyrexia, shock requiring vas- mention that angiotensin converting enzyme 2 (ACE2)- opressor support, disseminated intravascular coagulation mediated entry of SARS CoV-2 leads to ACE2 receptor and multiorgan dysfunction [45]. Respiratory involve- shedding [57]. ACE2 downregulation has been linked to ment may progress to ARDS [45]. In addition, renal injury, vascular dysfunction through the induction of a state of cytopenias, coagulopathy and cardiac dysfunction may NO deficiency and oxidative stress [58]. Suppression of occur [45]. Neurological symptoms, ranging from mild superoxide production markedly alleviates influenza A confusion to seizures, may occur [46]. Cytokine storm can virus-induced lung injury and virus replication, irrespec- sometimes, in severe cases, resemble macrophage activa- tive of the infecting strain [59]. Preliminary studies sug- tion syndrome or hemophagocytic lymphohistiocytosis gest that alpha-lipoic acid treatment might be able to (HLH) with similar biochemical abnormalities [47]. improve the 30-day survival rate of patients with critically ill COVID-19, indicating a role of ROS generation in the pathophysiology of COVID-19 [60]. Pulmonary capillary Liver injury in the setting of cytokine storm leak syndrome secondary to SARS-CoV-2 virus infection Hepatic involvement in patients in critical care units with and development of noncardiogenic pulmonary edema sepsis or other insults resulting in cytokine surge usually has recently been documented [61]. Thus, increased vas- manifests either transaminitis, predominantly with AST cular permeability secondary to cytokine release, hypoper- elevation and uncommonly with mild hyperbilirubine- fusion, endothelial dysfunction, ROS generation and NO mia with or without alkaline phosphatase elevation. In a deficiency underlie the pathophysiology of liver dysfunc- study on 148 patients of COVID-19, more than one-third tion due to systemic effects of the cytokine storm. of patients admitted to the hospital were found to have the abnormal liver function, manifested chiefly as derange- Cytokine storm and renin-angiotensin-aldosterone system ments in alanine aminotransferase (ALT) (18.2%) and aspartate aminotransferase (AST) (21.6%), which was Involvement of the renin-angiotensin-aldosterone sys- associated with a longer duration of hospital stay [22]. In tem (RAAS) has been observed in the setting of hyper- addition, patients with abnormal liver function had higher cytokinemia [62]. TNF-α-mediated lung injury requires levels of procalcitonin and CRP [22]. Further research is the mediation of angiotensin II [63]. Angiotensin II has needed to understand the pathophysiology of cytokine-in- been linked to inflammation, tissue injury and oxidative duced hepatic injury in the light of the complex interplay stress [64]. Angiotensin II can induce inflammation via the between the offending cytokines, the systemic adverse angiotensin 1 receptor (AT1) [64]. ACE2 downregulation effects of cytokine release, the local injury affected and the has been linked to thrombosis through multiple mecha- hepatic response to such injury. nisms [65]. Loss of ACE 2 has been shown to shift the RAAS axis away from the anti-inflammatory angiotensin Liver injury due to systemic effects of cytokine release (1–7)/angiotensin (1–9) pathways and augment the proinflammatory angiotensin II–AT1 pathway with deleterious The liver is extremely sensitive to disturbances of systemic consequences [66]. Imbalance of the RAAS has also been homoeostasis and is affected through multiple mecha- linked to induction of thrombosis through the expression nisms, which include both vascular and immune-mediated of plasminogen activator inhibitor-1 [67], bradykinin pathways [48]. We describe here the major mechanisms accumulation [68] and angiotensin IV [69] and aldoster- of cytokine-induced systemic effects that contribute to one-mediated [70] impairment of fibrinolysis. The pres- hepatic injury. ence of local RAAS in the liver [71] and an imbalance between the various components of RAAS, including the Cytokine-induced vascular dysfunction, hypoperfusion canonical and noncanonical axes, may play a pivotal role and oxidative stress in hepatocyte inflammation and injury [72]. Cytokines are known to cause adhesion of immune cells to endothelial cells, thereby increasing vascular permea- Local effects of cytokine release bility [49]. TNF-α can induce endothelial dysfunction in The liver, although classically believed to be an immuno- pulmonary arteries in response to thrombin [50]. TNF- privileged site [73], is replete with inflammatory ticking α also impairs endothelium-dependent and nitric oxide bombs, comprising of a heterogeneous milieu of inflamma- (NO)-mediated vasodilation in various vascular beds as tory components [74,75]. Dysregulated cytokine release evidenced in experimental models [51]. Cytokines could can elicit an acute phase response in the hepatocytes [76]. also potentially lead to increased generation of reactive An overview of local injury in the liver and the hepatic oxygen species (ROS) which, in turn, may cause cellular response to such an injury is described below. injury and death [52]. This excess activation of cytokines causing endothelial dysfunction and ROS generation can Kupffer cells, endothelial dysfunction, hepatocyte damage result in vascular leakage and capillary leak syndrome and microthrombosis [53]. Capillary leak syndrome can, by itself, cause alveolar edema and hypoxia, and can produce edema in different In the liver, Kupffer cells, neutrophils, hepatocytes and organs, such as the brain, heart, liver and kidneys [54]. liver sinusoidal endothelial cells (LSECs) mediate the This is corroborated by studies demonstrating a reduction hepatic response to cytokine release [77]. Hepatocellular of microcirculatory blood flow in the liver to 50% of base- damage can trigger Kupffer cell activation [78]. Kupffer line during hypodynamic septic shock [55]. cells release cytokines, ROS and NO which induce LSEC NO deficiency in vascular endothelium may contribute and can perpetuate hepatocyte injury [77]. TNF-α can to the pathophysiology of COVID-19 [56]. It needs no directly stimulate hepatocytes to produce IL-6, which, in

Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 4 European Journal of Gastroenterology & Hepatology xxx 2020 • Volume XXX • Number XXX turn, increases caspase-3 and leads to hepatocellular apop- classically described in immunodeficiency syndromes, an tosis [79]. NO generated by activated neutrophils can lead acquired form induced by offending agents – viruses, bac- to peroxynitrite formation, a potent ROS that can cause teria and malignancies – has been increasingly described mitochondrial damage with consequent hepatocellular [93]. The pathophysiology of acquired HLH probably necrosis and apoptosis [77]. This interplay between sinu- involves suppression of T-cell function by viral infections soidal endothelial cells, hepatic macrophages and leuko- [94]. Hepatic injury in HLH is mainly due to cytokine cytes leads to a redistribution of intrahepatic blood flow storm, which results due to impaired natural killer/cyto- causing decreased sinusoidal perfusion [80]. Endothelial toxic T lymphocyte function [95]. Macrophage-derived dysfunction, neutrophil invasion and microthrombi for- IL-2, IFN-γ and TNF-α have been found to produce mation further enhance liver tissue ischemia and damage porto-sinusoidal inflammation that leads to transamini- [77]. Liver biopsy specimen of a patient with COVID-19 tis, sinusoidal dilatation and congestion and Kupffer cell revealed microvesicular steatosis along with lobular and hyperplasia [95]. Interestingly, it has been postulated based portal activity, probably implying viral-mediated injury or on robust evidence that severe COVID-19-associated a possibility of drug-induced liver injury [81]. However, pneumonia patients may exhibit several features of sys- in a study carried out by Liu et al. [82], autopsy of the temic hyperinflammation designated as secondary HLH liver of COVID-19 patients revealed hepatomegaly with [96]. The inflammatory response in COVID-19 pneumo- hepatocyte degeneration accompanied by lobular focal nia is significant, but does not seem to be as pronounced necrosis and neutrophil infiltration, portal infiltration of as that found in HLH. Nevertheless, data suggest that sec- lymphocytes and monocytes, and congestion of hepatic ondary HLH may play a crucial role in the pathogenesis sinuses with microthrombosis. In another autopsy case of severe COVID-19. A recent study showed that hemo- series, thrombosis was found in multiple organs and was phagocytosis is a common finding in the bone marrow of present even after anticoagulation in some cases with deceased patients with severe COVID-19 [97]. the liver showing accumulation of platelet-fibrin micro- The laboratory profile of severe COVID-19 pneumonia thrombi in the hepatic sinusoids [83]. Recent consensus patients have revealed highly elevated CRP and ferritin statements on the treatment of coagulation dysfunction levels, which are central to the diagnosis of HLH [98]. in COVID-19 [84] have highlighted the microvascular The presence of abnormal liver function tests and coagu- damage due to intense inflammation occurring in differ- lopathy may imply the diagnosis of secondary HLH in a ent organs. This manifests as extensive microthrombosis subset of COVID-19 patients [99]. Elevation of particu- in the pulmonary circulation [85] and could possibly, in lar cytokines, such as IL-1β, IL-2, IL-6, TNF and CCL2, our opinion, involve other organs, such as the liver. ACE2 has been observed in COVID-19 patients which is similar receptors, through which SARS-CoV-2 gains access to the to that in secondary HLH [100]. The pathophysiology of host cell, are also expressed by endothelial cells [86]. Viral cytokine-induced liver dysfunction is illustrated in Fig. 1. elements are indeed present within endothelial cells with evidence of endothelial and inflammatory cell death [2]. Pattern of liver injury in cytokine storm These findings suggest that SARS-CoV-2 infection induces endotheliitis in several organs as a direct consequence Hypercytokinemia-induced liver injury can be either of viral involvement and aberrant host inflammatory hypoxic/hepatocellular injury manifesting as transaminitis response. Histopathological data on the liver in patients or cholestatic injury presenting with hyperbilirubinemia. with COVID-19 are emerging [87], and the occurrence Sepsis is an important promoter of liver injury causing of hepatic microthrombosis could be a potential mecha- both hyperbilirubinemia and hypoxic hepatitis [101,102]. nism of liver injury. In fact, there is now emerging evi- A recent clinical trial involving 312 patients with sep- dence to support anticoagulation as a treatment strategy sis reported 20% prevalence of acute liver failure [103]. for COVID-19 [88]. Patients with chemotherapy induced cytokine storm and Visualization of hepatobiliary excretory function those with acquired HLH also develop transaminitis and in experimental models of sepsis, where high levels of hyperbilirubinemia [104–106]. To differentiate between cytokines were generated, revealed severe impairment the terms ‘liver dysfunction’ and ‘liver failure’, the use of hepatocellular transport, specifically at the canalicu- of organ dysfunction scores have been advocated [107]. lar pole [89]. Release of pro-inflammatory cytokines by There is no single marker or a combination of markers Kupffer cells could lead to downregulation of transporters that reflects the entire spectrum of hepatic dysfunction or involved in bile flow [90]. In the setting of COVID-19, could predict a mortality rate of over 50% [108]. Skeletal however, the cholestatic pattern of liver injury is uncom- muscles, heart, lung, brain, kidney and other organs may mon [91]. Most patients present with elevated ami- release AST, and so serum ALT may better reflect hepatic notransferase levels with a predominant AST elevation dysfunction [109]. However, it is generally accepted that [3]. As such, liver injury related to COVID-19 although during liver injury, hepatocellular permeability is increased akin to sepsis with significant proinflammatory cytokine with consequent release of AST and ALT into the plasma production may have alternate explanations. [109]. Metanalytic studies have shown that liver dysfunc- Acquired hemophagocytic lymphohistiocytosis and liver tion in COVID-19 is not uncommon [110]. In a study by Chen et al., out of 99 cases diagnosed with COVID-19, injury 43.4% had increased serum levels of ALT and AST [111]. HLH is a catastrophic hyperinflammatory syndrome In another study from Wuhan, among 305 patients with occurring in genetically susceptible individuals resulting COVID-19, 39.1% had transaminitis or hyperbilirubine- from an exaggerated immune response [92]. Although mia at admission [112]. The mean levels of serum ALT,

Fig. 1. The figure illustrates the pathophysiologic mechanisms of liver injury in COVID-19.

AST and bilirubin were also significantly higher in patients Acknowledgements with more severe disease [113]. In a meta-analysis of 20 S.K.S. and S.P.S. conceptualized, wrote, reviewed and retrospective studies, higher serum levels of AST and ALT edited the article. P.A. prepared the original draft. S.N., were found to be associated with a significant increase in N.H. and F.Z. reviewed and edited the article. F.Z. is the severity of COVID-19 infection [114]. Additionally, responsible for figure illustration. All authors participated AST-dominant aminotransferase elevation has been found in providing important intellectual inputs, participated in to be common in COVID-19, mirrors disease severity and critical revision of the article and approved the final ver- appears to reflect true hepatic injury [115]. sion of the manuscript. This work was partially supported by a grant from the Kalinga Gastroenterology Foundation, Conclusion Cuttack, India. The pathogenesis of cytokine-mediated liver injury in the setting of COVID-19 is poorly understood, but sev- Conflicts of interest eral intriguing observations point towards the complex S.K.S. has served as a speaker for Intercept, Alexion, pathophysiological process mediated by inflammation, Dova, as an advisory board member for Gilead, Intercept, altered coagulation and RAAS activation culminating Bayer, and has received research funding from Gilead, in microvascular insult, hepatocyte damage and per- Biotest, Genfit, Conatus, Intercept, Shire, Exact Sciences, petuation of inflammation. Although transaminitis has Eananta, Dova, Bayer. S.K.S. is an employee of Northwell been reported in more than half of the patients, hyper- Health. For the remaining authors, there are no conflicts bilirubinemia and elevated alkaline phosphatase are of interest. uncommon. Liver injury probably is, perhaps, a part of dysregulated immune response in COVID-19 [116]. References Therapeutic strategies should target the immune system, RAAS and coagulation pathways synergistically. A crit- 1 Zaim S, Chong JH, Sankaranarayanan V, Harky A. COVID-19 and multi-organ response. Curr Probl Cardiol 2020; 45:100618. ical appraisal of hepatic injury in the setting of CRSs 2 Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, would be crucial to our understanding of liver dysfunc- Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in tion in COVID-19. COVID-19. Lancet 2020; 395:1417–1418.

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