Direct or Collateral Liver Damage in SARS-CoV-2–Infected Patients

Abstract

Liver injury can result from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with more than one-third of COVID-19 patients exhibiting elevated liver enzymes. Microvesicular steatosis, inflammation, vascular congestion, and thrombosis in the liver have been described in autopsy samples from COVID-19 patients. Several factors, including direct cytopathic effect of the virus, immune-mediated collateral damage, or an exacerbation of preexisting liver disease may contribute to liver pathology in COVID-19. Due to its immunological functions, the liver is an organ likely to participate in the viral response against SARS-CoV-2 and this may predispose it to injury. A better understanding of the mechanism contributing to liver injury is needed to develop and implement early measures to prevent serious liver damage in patients suffering from COVID-19. This review summarizes current reports of SARS-CoV-2 with an emphasis on how direct infection and subsequent severe inflammatory response may contribute to liver injury in patients with and without preexisting liver disease.

Keywords

liver - SARS-CoV-2 - COVID-19 - ACE2 - inflammasome

^* Contributed equally to this manuscript.

Publikationsverlauf

Artikel online veröffentlicht:
04. September 2020

• References

• 1 ProMED. Undiagnosed pneumonia - China. Available at: https://promedmail.org/promed-post/?id=6864153 . Accessed May 1, 2020
• 2 World Health Organization. WHO Coronavirus Disease (COVID-19) Dashboard. Available at: https://covid19.who.int . Accessed July 12, 2020
• 3 Centers for Disease Control and Prevention. Coronavirus (COVID-19). Available at: https://www.cdc.gov/coronavirus/2019-ncov/index.html . Accessed May 1, 2020
• 4 Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020; 323 (13) 1239-1242
• 5 McMichael TM, Currie DW, Clark S. , et al; Public Health–Seattle and King County, EvergreenHealth, and CDC COVID-19 Investigation Team. Epidemiology of COVID-19 in a long-term care facility in King County, Washington. N Engl J Med 2020; 382 (21) 2005-2011
• 6 Huang C, Wang Y, Li X. , et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395 (10223): 497-506
• 7 Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020; 395 (10229): 1033-1034
• 8 Siu KL, Yuen KS, Castaño-Rodriguez C. , et al. Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC. FASEB J 2019; 33 (08) 8865-8877
• 9 Chau TN, Lee KC, Yao H. , et al. SARS-associated viral hepatitis caused by a novel coronavirus: report of three cases. Hepatology 2004; 39 (02) 302-310
• 10 Ng DL, Al Hosani F, Keating MK. , et al. Clinicopathologic, immunohistochemical, and ultrastructural findings of a fatal case of Middle East respiratory syndrome coronavirus infection in the United Arab Emirates, April 2014. Am J Pathol 2016; 186 (03) 652-658
• 11 Amanat F, Krammer F. SARS-CoV-2 vaccines: status report. Immunity 2020; 52 (04) 583-589
• 12 Wang D, Hu B, Hu C. , et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020; 323 (11) 1061-1069
• 13 Zhang C, Shi L, Wang F-S. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol 2020; 5 (05) 428-430
• 14 Zhou P, Yang XL, Wang XG. , et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579 (7798): 270-273
• 15 Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020; 367 (6485): 1444-1448
• 16 Zhao Y, Zhao Z, Wang Y, Zhou Y, Ma Y, Zuo W. Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2. Am J Respir Crit Care Med 2020;
• 17 Kim D, Lee J-Y, Yang J-S, Kim JW, Kim VN, Chang H. The architecture of SARS-CoV-2 transcriptome. Cell 2020; 181 (04) 914-921.e10
• 18 Tai W, He L, Zhang X. , et al. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol Immunol 2020; 17 (06) 613-620
• 19 Ou X, Liu Y, Lei X. , et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun 2020; 11 (01) 1620
• 20 Hoffmann M, Kleine-Weber H, Schroeder S. , et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181 (02) 271-280.e8
• 21 Shang J, Wan Y, Luo C. , et al. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci U S A 2020; 117 (21) 11727-11734
• 22 Wang Q, Zhang Y, Wu L. , et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell 2020; 181 (04) 894-904.e9
• 23 Shang J, Ye G, Shi K. , et al. Structural basis of receptor recognition by SARS-CoV-2. Nature 2020; 581 (7807): 221-224
• 24 Recalcati S. Cutaneous manifestations in COVID-19: a first perspective. J Eur Acad Dermatol Venereol 2020; 34 (05) e212-e213
• 25 Castaño-Rodriguez C, Honrubia JM, Gutiérrez-Álvarez J. , et al. Role of severe acute respiratory syndrome coronavirus viroporins E, 3a, and 8a in replication and pathogenesis. MBio 2018; 9 (03) e02325-e17
• 26 Yang X, Yu Y, Xu J. , et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020; 8 (05) 475-481
• 27 Meduri GU, Kohler G, Headley S, Tolley E, Stentz F, Postlethwaite A. Inflammatory cytokines in the BAL of patients with ARDS. Persistent elevation over time predicts poor outcome. Chest 1995; 108 (05) 1303-1314
• 28 Dolinay T, Kim YS, Howrylak J. , et al. Inflammasome-regulated cytokines are critical mediators of acute lung injury. Am J Respir Crit Care Med 2012; 185 (11) 1225-1234
• 29 Chen IY, Moriyama M, Chang M-F, Ichinohe T. Severe acute respiratory syndrome coronavirus viroporin 3a activates the NLRP3 inflammasome. Front Microbiol 2019; 10: 50
• 30 Fung S-Y, Yuen K-S, Ye Z-W, Chan C-P, Jin D-Y. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses. Emerg Microbes Infect 2020; 9 (01) 558-570
• 31 Jose RJ, Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir Med 2020; 8 (06) e46-e47
• 32 Yang Z, Du J, Chen G. , et al. Coronavirus MHV-A59 infects the lung and causes severe pneumonia in C57BL/6 mice. Virol Sin 2014; 29 (06) 393-402
• 33 Zalinger ZB, Elliott R, Weiss SR. Role of the inflammasome-related cytokines IL-1 and IL-18 during infection with murine coronavirus. J Neurovirol 2017; 23 (06) 845-854
• 34 Lin SH, Fu J, Wang CJ. , et al. Inflammation elevated IL-33 originating from the lung mediates inflammation in acute lung injury. Clin Immunol 2016; 173: 32-43
• 35 Chakraborty D, Zenker S, Rossaint J. , et al. Alarmin S100A8 activates alveolar epithelial cells in the context of acute lung injury in a TLR4-dependent manner. Front Immunol 2017; 8: 1493
• 36 Sun S, Sursal T, Adibnia Y. , et al. Mitochondrial DAMPs increase endothelial permeability through neutrophil dependent and independent pathways. PLoS One 2013; 8 (03) e59989
• 37 Heymann F, Tacke F. Immunology in the liver--from homeostasis to disease. Nat Rev Gastroenterol Hepatol 2016; 13 (02) 88-110
• 38 Qi F, Qian S, Zhang S, Zhang Z. Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses. Biochem Biophys Res Commun 2020; 526 (01) 135-140
• 39 Paizis G, Tikellis C, Cooper ME. , et al. Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2. Gut 2005; 54 (12) 1790-1796
• 40 Chen N, Zhou M, Dong X. , et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395 (10223): 507-513
• 41 Zippi M, Fiorino S, Occhigrossi G, Hong W. Hypertransaminasemia in the course of infection with SARS-CoV-2: incidence and pathogenetic hypothesis. World J Clin Cases 2020; 8 (08) 1385-1390
• 42 Barton LM, Duval EJ, Stroberg E, Ghosh S, Mukhopadhyay S. COVID-19 autopsies, Oklahoma, USA. Am J Clin Pathol 2020; 153 (06) 725-733
• 43 Tian S, Xiong Y, Liu H. , et al. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Mod Pathol 2020; 33 (06) 1007-1014
• 44 Hanley B, Lucas SB, Youd E, Swift B, Osborn M. Autopsy in suspected COVID-19 cases. J Clin Pathol 2020; 73 (05) 239-242
• 45 Chai X, Hu L, Zhang Y. , et al. Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. bioRxiv 2020;
• 46 Zhao B, Ni C, Gao R. , et al. Recapitulation of SARS-CoV-2 infection and cholangiocyte damage with human liver ductal organoids. Protein Cell 2020; (Epub ahead of print)
• 47 Lax SF, Skok K, Zechner P. , et al. Pulmonary arterial thrombosis in COVID-19 with fatal outcome: results from a prospective, single-center, clinicopathologic case series. Ann Intern Med 2020; (Epub ahead of print)
• 48 Zhang Y, Zheng L, Liu L, Zhao M, Xiao J, Zhao Q. Liver impairment in COVID-19 patients: a retrospective analysis of 115 cases from a single centre in Wuhan city, China. Liver Int 2020; (Epub ahead of print)
• 49 Zhang W, Li C, Liu B. , et al. Pioglitazone upregulates hepatic angiotensin converting enzyme 2 expression in rats with steatohepatitis. Ann Hepatol 2013; 12 (06) 892-900
• 50 Ding Y, He L, Zhang Q. , et al. Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways. J Pathol 2004; 203 (02) 622-630
• 51 Wang Y, Liu S, Liu H. , et al. SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19. J Hepatol 2020; S0168-8278 (20) 30294-4
• 52 Maini MK, Boni C, Lee CK. , et al. The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med 2000; 191 (08) 1269-1280
• 53 Xu J, Zhao S, Teng T. , et al. Systematic comparison of two animal-to-human transmitted human coronaviruses: SARS-CoV-2 and SARS-CoV. Viruses 2020; 12 (02) 244
• 54 Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 2017; 39 (05) 529-539
• 55 Chan HL, Kwan AC, To KF. , et al. Clinical significance of hepatic derangement in severe acute respiratory syndrome. World J Gastroenterol 2005; 11 (14) 2148-2153
• 56 Dizier S, Forel J-M, Ayzac L. , et al; ACURASYS Study Investigators, PROSEVA Study Group. Early hepatic dysfunction is associated with a worse outcome in patients presenting with acute respiratory distress syndrome: a post-hoc analysis of the ACURASYS and PROSEVA studies. PLoS One 2015; 10 (12) e0144278
• 57 Duan ZP, Chen Y, Zhang J. , et al. [Clinical characteristics and mechanism of liver injury in patients with severe acute respiratory syndrome]. Zhonghua Gan Zang Bing Za Zhi 2003; 11 (08) 493-496
• 58 Wu C, Chen X, Cai Y. , et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020; (Epub ahead of print)
• 59 Tu W, Satoi S, Zhang Z. , et al. Hepatocellular dysfunction induced by nitric oxide production in hepatocytes isolated from rats with sepsis. Shock 2003; 19 (04) 373-377
• 60 Sproston NR, Ashworth JJ. Role of C-reactive protein at sites of inflammation and infection. Front Immunol 2018; 9: 754
• 61 Yang F, Shi S, Zhu J, Shi J, Dai K, Chen X. Analysis of 92 deceased patients with COVID-19. J Med Virol 2020; 15 (Apr):
• 62 Jin X, Lian JS, Hu JH. , et al. Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms. Gut 2020; 69 (06) 1002-1009
• 63 Wu J, Liu J, Zhao X. , et al. Clinical characteristics of imported cases of COVID-19 in Jiangsu Province: a multicenter descriptive study. Clin Infect Dis 2020; (Epub ahead of print)
• 64 Li X, Wang L, Yan S. , et al. Clinical characteristics of 25 death cases with COVID-19: A retrospective review of medical records in a single medical center, Wuhan, China. Int J Infect Dis 2020; 94: 128-132
• 65 Wang Y, Zhu F, Wang C. , et al. The risk of children hospitalized with severe COVID-19 in Wuhan. Pediatr Infect Dis J 2020; 39 (07) e91-e94
• 66 Xie H, Zhao J, Lian N, Lin S, Xie Q, Zhuo H. Clinical characteristics of non-ICU hospitalized patients with coronavirus disease 2019 and liver injury: a retrospective study. Liver Int 2020; 40 (06) 1321-1326
• 67 Lei F, Liu YM, Zhou F. , et al. Longitudinal association between markers of liver injury and mortality in COVID-19 in China. Hepatology 2020; (Epub ahead of print)
• 68 Fan Z, Chen L, Li J. , et al. Clinical features of COVID-19-related liver damage. Clin Gastroenterol Hepatol 2020; 18 (07) 1561-1566
• 69 Cai Q, Huang D, Yu H. , et al. COVID-19: abnormal liver function tests. J Hepatol 2020; S0168-8278(20)30218-X
• 70 Wang X, Fang X, Cai Z. , et al. Comorbid chronic diseases and acute organ injuries are strongly correlated with disease severity and mortality among COVID-19 patients: a systemic review and meta-analysis. Research (Wash D C) 2020; 2020: 2402961
• 71 Ji D, Qin E, Xu J. , et al. Non-alcoholic fatty liver diseases in patients with COVID-19: a retrospective study. J Hepatol 2020; S0168-8278(20)30206-3
• 72 Singh S, Khan A. Clinical characteristics and outcomes of COVID-19 among patients with pre-existing liver disease in United States: a multi-center research network study. Gastroenterology 2020; (Epub ahead of print)
• 73 Zhu L, She Z-G, Cheng X. , et al. Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes. Cell Metab 2020; 31 (06) 1068-1077.e3