SARS-CoV-2 related liver impairment – perception may not be the reality
Authors: Cyriac Abby Philips, Rizwan Ahamed, Philip Augustine
Journal: Journal of Hepatology (2020)

SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19Journal of HepatologyVol. 73Issue 4PreviewLiver enzyme abnormalities are common in patients with coronavirus disease 2019 (COVID-19). Whether or not severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to liver damage per se remains unknown. Herein, we reported the clinical characteristics and liver pathological manifestations of COVID-19 patients with liver enzyme abnormalities. Full-Text PDF Reply to: Correspondence relating to "SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19"Journal of HepatologyVol. 73Issue 4PreviewWe appreciate the thoughtful comments on our paper. Our study focused on coronavirus disease 2019 (COVID-19)-related liver enzyme abnormalities, rather than acute liver injury. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could infect the liver, it is not a hepatotropic virus that induces pronounced hepatitis. In keeping with this, abnormal liver function tests during the course of COVID-19 are common and primarily limited to aminotransferases, while clinically severe acute liver injury is rare. Full-Text PDF The catastrophic emergence of COVID-19 has led to large volumes of research from epicentres of infection, with some focusing on COVID-19-related liver impairment. In this regard, the study by Wang et al. published in the Journal intrigued us.1Wang Y. Liu S. Liu H. Li W. Lin F. Jiang L. et al.SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19.J Hepatol. 2020; 72: 807-816Abstract Full Text Full Text PDF Scopus (455) Google Scholar The authors associate very minimal elevations in alanine (ALT) and aspartate aminotransferase (AST; ALT >AST) to disease severity and demonstrate 'specific' COVID-19-related cytopathic changes and virus-like particles on post-mortem liver histopathology (n = 2). They found that severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) caused massive apoptosis and binucleation of hepatocytes, resulting in liver enzyme abnormality and synthetic liver dysfunction, the latter in the form of hypoalbuminemia. Their painstaking work is commendable, but their assessment of clinical and investigational events may not reflect the reality. It is recommended that the ideal cut-off for diagnosing acute hepatic injury is 200 U/L and 300 U/L for AST and ALT, respectively.2Dufour D.R. Lott J.A. Nolte F.S. Gretch D.R. Koff R.S. Seeff L.B. Diagnosis and monitoring of hepatic injury. II. Recommendations for use of laboratory tests in screening, diagnosis, and monitoring.Clin Chem. 2000; 46: 2050-2068Crossref PubMed Scopus (329) Google Scholar The degree of elevation in AST and ALT in the current study can only be considered an 'altered' liver test, not akin to acute hepatic injury. In hepatic impairment, there must be very clear evidence for metabolic (hypoglycaemia, hyperammonemia), secretory (hyperbilirubinemia) and synthetic (hypoalbuminemia, raised prothrombin time) dysfunction. Except for a mild rise in ALT and hypoalbuminemia, significant liver dysfunction is elusive in the current study. Importantly, hypoalbuminemia, in the absence of other significant liver test abnormalities, virtually rules out the hepatic origin of this abnormality. Acute liver injury is best identified by international normalized ratio >2.0, which was conspicuously absent in the current study.3Koch D.G. Speiser J.L. Durkalski V. Fontana R.J. Davern T. McGuire B. et al.The natural history of severe acute liver injury.Am J Gastroenterol. 2017; 112: 1389-1396Crossref PubMed Scopus (90) Google Scholar The liver biopsy findings of hepatocyte apoptosis, binuclear or occasional multinuclear syncytial hepatocytes, in the absence of viral inclusions and presence of moderate steatosis, with mild focal lobular or portal inflammation are non-specific findings that may not be related to viral cytopathy. These findings can undoubtfully be seen in sepsis and multi-organ dysfunction associated with critical illness (moderate to severe apoptosis, steatosis, lobular and portal inflammation), aging, drug-induced liver injury and fatty liver disease (binucleation or polyploidy– a feature of liver cell renewal and not injury).4Koskinas J. Gomatos I.P. Tiniakos D.G. Memos N. Boutsikou M. Garatzioti A. et al.Liver histology in ICU patients dying from sepsis: a clinicopathological study.World J Gastroenterol. 2008; 14: 1389-1393Crossref PubMed Scopus (80) Google Scholar, 5Wang M.J. Chen F. Lau J.T.Y. Hu Y.P. Hepatocyte polyploidization and its association with pathophysiological processes.Cell Death Dis. 2017; 8: e2805Crossref PubMed Scopus (78) Google Scholar, 6Hsu S.H. Duncan A.W. Pathological polyploidy in liver disease.Hepatology. 2015; 62: 968-970Crossref PubMed Scopus (11) Google Scholar The liver biopsy does not correlate with increased gamma-glutamyltransferase, which could have been secondary to the systemic illness or drug toxicity. CD68+ cellular infiltration of the hepatic sinusoids (a marker of macrophage activation) can be noted in any acute or chronic systemic inflammatory state affecting the liver, including non-alcoholic fatty liver disease (NAFLD).7Dou L. Shi X. He X. Gao Y. Macrophage phenotype and function in liver disorder.Front Immunol. 2020; 10: 3112Crossref PubMed Scopus (108) Google Scholar Finally, the 'spiked' inclusions and their degenerate components may not be of viral origin since confirmatory PCR testing for viral nucleic acids was not performed. Such 'corona-like' particles could be intrahepatic cholesterol crystals, lamellations, or 'crown-like' structures seen in patients with NAFLD. In the latter, Kupffer cells surround and engulf remnant lipid droplets (themselves granular or spiky cytoplasmic inclusions) of apoptotic hepatocytes. Moreover, associating mitochondrial changes to SARS-CoV-2 infection of hepatocytes could be erroneous. Electron microscopic changes of liver mitochondria in the form of enlarged mitochondria, intramitochondrial crystalline inclusions, mitochondrial matrix granules, vesicles containing electron-dense material in peribiliary Golgi-zone and electron-dense material accumulation in the space of Disse are notable in steatotic livers and drug-induced liver injury.8Ioannou G.N. Haigh W.G. Thorning D. Savard C. Hepatic cholesterol crystals, and crown-like structures distinguish NASH from simple steatosis.J Lipid Res. 2013; 54: 1326-1334Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar,9Pessayre D. Fromenty B. Berson A. Robin M.A. Lettéron P. Moreau R. et al.Central role of mitochondria in drug-induced liver injury.Drug Metab Rev. 2012; 44: 34-87Crossref PubMed Scopus (224) Google Scholar In non-hepatotropic viral infection, such as cytomegalovirus-hepatitis, the liver involvement occurs as part of the disseminated systemic disease or secondary organ dysfunction that could be true for the SARS-CoV-2.10Gupta E. Ballani N. Kumar M. Sarin S.K. Role of non-hepatotropic viruses in acute sporadic viral hepatitis and acute-on-chronic liver failure in adults.Indian J Gastroenterol. 2015; 34: 448-452Crossref PubMed Scopus (24) Google Scholar To conclude, even though intriguing, the study by Wang et al. might have arrived at unfounded conclusions regarding SARS-CoV-2-related liver injury. Hepatic impairment is not confirmed, and multiple viral cytopathic effects described on liver histology may be misleading in the presence of multiple comorbidities. 'COVID-19 induced liver injury' may be illusory. Current research has not confirmed direct SARS-CoV-2-related liver injury, and the features described may only indicate hepatic involvement in a severe systemic inflammatory disease. The authors received no financial support to produce this manuscript. CAP and RA designed the study; PA critically revised the manuscript; all authors approved the final version. CAP received advisory and consulting fees from Cipla® (India) Ltd. RA and PA have nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details. Download .pdf (.24 MB) Help with pdf files disclosures.pdf