, Department of Precision Medicine, University of Campania 'L. Vanvitelli' ,Naples, Italy
Liver injury in Coronavirus Disease 2019: a consequence or a cause?
To the editor- I read with interest the article by Zhang, et al.  describing potential role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mediated inflammation on liver injury. In fact, abnormal liver function tests are commonly seen in patients with coronavirus disease 2019 (COVID 19) . The mechanism of such alteration have been addressed to multiple factors such as virus induced inflammation, side effects of antivirals such as lopinavir/ritonavir or thrombotic microangiopathy, immune dysregulation and hepatic ischemia due to hypoxia and MOF . Liver dysfunction in COVID -19 patients was associated with higher risk of progressing to a severe disease with high levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin and low levels of albumin associated with greater risk for mortality [2,4,5]. Whether SARS-CoV-2 has a direct hepatotoxic effect remains unknown as to no study with a large number of patients have assessed direct cytopathic effect of this virus. Other coronaviruses were demonstrated to have hepatotropism in murine model [6,7], and evidence of SARS-COV was discovered in liver tissue of three patients . Although little is known about possible hepatotropism of the novel coronavirus SARS-CoV-2, a case report of two patients evidenced direct virus liver damage . In fact, TMPRSS2 mRNA expression, a cell surface transmembrane protein serine 2, which was found to have a role in virus entry in the host cells  was also found in a subset of hepatocytes and cholangiocytes .
Tsutsumi et al. found correlation between high levels of ALT and D-dimer, as well as inflammatory markers suggesting that abnormal liver function could be prompted by microvascular thrombosis in a contest of systemic inflammation .
In fact, liver dysfunction was found to correlate with pulmonary embolism in non COVID-19 patients , possibly as a consequence of embolism and not a risk for developing it as suggested by Heit, et al. whose findings suggested low risk of pulmonary embolism in chronic liver disease patients .
In contrast, hepatotropic viruses such as Hepatitis C and Cytomegalovirus, were linked to increased risk for developing pulmonary embolism [15,16].
Whether in case COVID-19 disease this liver injury is only a consequence of inflammation and microvascular thrombosis or whether the virus plays an additional direct toxic effect on hepatocytes and as a consequence resulting in an increased risk for developing thrombosis/embolic events, it remains unclear.
And as Zhang, et al. and other researchers gave several answers to the questions of the virus possible liver toxicity mechanism and leaving other questions unanswered, maybe they will inspire other researchers to add missing pieces to the puzzle of knowledge of this mysterious novel coronavirus SARS-CoV-2.
1. Zhang D, Zhu Z, Bi J, et al Clinical Characteristics and Risk Factors in Coronavirus Disease 2019 Patients with Liver Injury. Med Sci Monit. 2020 Dec 19;26:e928849. doi: 10.12659/MSM.928849.
2.Cai Q, Huang D, Yu H, et al. COVID-19: Abnormal liver function tests. J Hepatol. 2020 Sep;73(3):566-574. doi: 10.1016/j.jhep.2020.04.006.
3.Bertolini A, van de Peppel IP, Bodewes FAJA, et al. Abnormal Liver Function Tests in Patients With COVID-19: Relevance and Potential Pathogenesis. Hepatology. 2020 Nov;72(5):1864-1872. doi: 10.1002/hep.31480.
4. Parohan M, Yaghoubi S, Seraji A. Liver injury is associated with severe coronavirus disease 2019 (COVID-19) infection: A systematic review and meta-analysis of retrospective studies. Hepatol Res. 2020 Aug;50(8):924-935. doi: 10.1111/hepr.13510.
5. Lei F, Liu YM, Zhou F, et al. Longitudinal Association Between Markers of Liver Injury and Mortality in COVID-19 in China. Hepatology. 2020 Aug;72(2):389-398. doi: 10.1002/hep.31301.
6. Zhang R, Li Y, Cowley TJ, Steinbrenner AD, Phillips JM, Yount BL, Baric RS, Weiss SR. The nsp1, nsp13, and M proteins contribute to the hepatotropism of murine coronavirus JHM.WU. J Virol. 2015 Apr;89(7):3598-609. doi: 10.1128/JVI.03535-14.
7. Navas S, Weiss SR. Murine coronavirus-induced hepatitis: JHM genetic background eliminates A59 spike-determined hepatotropism. J Virol. 2003;77(8):4972-4978. doi:10.1128/jvi.77.8.4972-4978.2003.
8.Chau TN, Lee KC, Yao H, et al. SARS-associated viral hepatitis caused by a novel coronavirus: report of three cases. Hepatology. 2004 Feb;39(2):302-10. doi: 10.1002/hep.20111.
9. Fiel MI, El Jamal SM, Paniz-Mondolfi A, et al. Findings of Severe Hepatic Severe Acute Respiratory Syndrome Coronavirus-2 Infection. Cell Mol Gastroenterol Hepatol. 2020 Sep 28:S2352-345X(20)30158-2. doi: 10.1016/j.jcmgh.2020.09.015.
10. N. Iwata-Yoshikawa et al, TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection. J. Virol. 93, 1–15 (2019)
11.Pirola CJ, Sookoian S. SARS‐CoV‐2 virus and liver expression of host receptors: putative mechanisms of liver involvement in COVID‐19. Liver Int 2020 Apr 30. https://doi.org/10.1111/liv.14500.
12. Tsutsumi T, Saito M, Nagai H, et al. Association of coagulopathy with liver dysfunction in patients with COVID-19. Hepatol Res. 2020 Oct 12:10.1111/hepr.13577. doi: 10.1111/hepr.13577.
13. Aslan S, Meral M, Akgun M, Acemoglu H, Ucar EY, Gorguner M, Mirici A. Liver dysfunction in patients with acute pulmonary embolism. Hepatol Res. 2007 Mar;37(3):205-13. doi: 10.1111/j.1872-034X.2007.00014.x.
14. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton LJ. Risk Factors for Deep Vein Thrombosis and Pulmonary Embolism: A Population-Based Case-Control Study. Arch Intern Med. 2000;160(6):809–815. doi:10.1001/archinte.160.6.809.
15. Wang CC, Chang CT, Lin CL, Lin IC, Kao CH. Hepatitis C Virus Infection Associated With an Increased Risk of Deep Vein Thrombosis: A Population-Based Cohort Study. Medicine (Baltimore). 2015 Sep;94(38):e1585. doi: 10.1097/MD.0000000000001585.
16. Galli L, Gerdes VE, Guasti L, Squizzato A. Thrombosis Associated with Viral Hepatitis. J Clin Transl Hepatol. 2014;2(4):234-239. doi:10.14218/JCTH.2014.00031
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