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Covid-19: how a virus is turning the world upside down

BMJ 2020; 369 doi: (Published 03 April 2020) Cite this as: BMJ 2020;369:m1336

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Re: Covid-19: how a virus is turning the world upside down

Dear Editor

Clues to Understanding the Pathogenesis of Coronavirus Infection (COVID-19 and SARS-CoV)

The new coronavirus infection (COVID-19) has a case-fatality rate of around 3%, with higher rates in older persons with preexisting chronic disease. However, such rates depend on having reliable denominators, which are lacking in most parts of the world. Respiratory symptoms are most common, as in influenza and Severe Acute Respiratory Syndrome (SARS-CoV), but early features often include diarrhoea, nausea, vomiting and abdominal pain. [1] The tropism of SARS-CoV to the liver is accompanied by severe liver involvement; likewise, patients with severe COVID-19 appear to have high rates of liver dysfunction. [2]

Clues to the pathogenesis included histologic evidence of conspicuous mitoses with apoptosis and ballooning of hepatocytes in SARS-CoV, suggesting that damage is mediated by apoptosis. [3] These features can be due to vitamin A, a known cause of liver injury. [4] A second clue is that in COVID-19, which shares the same receptor with SARS, angiotensin-converting enzyme 2 (ACE2), single-cell RNA sequencing revealed a significant enrichment of ACE2 receptor expression in cholangiocytes (59.7% of cells) but less so in hepatocytes (2.6% of cells), [5] implicating intrahepatic bile duct damage in liver dysfunction.

We propose that infection-induced activation of the retinoid cascade triggers cell-mediated apoptotic hepatitis, leading to transient cholestatic liver dysfunction in which stored vitamin A compounds (retinyl esters and retinoic acid) enter the circulation via damaged bile ducts and hepatocytes, in turn causing acute lung injury and other organ damage via apoptosis, necrosis and acute neutrophilic infiltration. Increased retinoid may drive the early rise in neutrophil count but higher concentrations could induce massive apoptosis of neutrophils and lymphocytes, which could lower the functionality of the immune system and lead to secondary bacterial infection and sepsis.

Pre-existing liver disease, obesity and diabetes are all strongly associated with susceptibility to severe influenza A infection and with retinoid accumulation, and could similarly explain susceptibility to severe COVID-19 among older persons with co-morbidities. The severity of coronavirus infection and influenza may be influenced in a concentration-dependent fashion by retinyl esters and retinoic acid.

The model could be tested by determining retinoid concentrations in the blood and respiratory secretions of patients and controls. Subject to testing, the model suggests that advice to patients should include avoiding alcohol, other liver-damaging substances, and prescribed drugs that are metabolized in the liver.

Anthony R. Mawson, MA, DrPH *
Professor, Department of Epidemiology and Biostatistics
School of Public Health, College of Health Sciences
Jackson State University
Jackson, MS 39213
* Corresponding author

Ashley M. Croft, MA, MBBS, MSc, DTM&H, DMCC, FFPHM
Postgraduate Research Fellow
School of Pharmacy and Biomedical Sciences
University of Portsmouth
White Swan Road
Portsmouth, PO1 2DT
United Kingdom

Federico Gonzalez-Fernandez, MD, PhD
Associate Chief of Staff for Research & Development
GV (Sonny) Montgomery Veterans Affairs Medical Center
1500 E Woodrow Wilson Ave
Jackson, MS 39216


1. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020 Feb 7. doi: 10.1001/jama.2020.1585. [Epub ahead of print]

2. Zhang C, Shi L, Wang FS. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol 2020 Mar 4. pii: S2468-1253(20)30057-1. doi: 10.1016/S2468-1253(20)30057-1.

3. Chau TN, Lee KC, Yao H, Tsang TY, Chow TC, Yeung YC, Choi KW, Tso YK, Lau T, Lai ST, Lai CL. A detailed report on liver pathology in three cases of SARS-associated viral hepatitis. Hepatology 2004; 39(2):302-10.

4. Dan Z, Popov Y, Patsenker E, Preimel D, Liu C, et al. Hepatotoxicity of alcohol-induced polar retinol metabolites involves apoptosis via loss of mitochondrial membrane potential. FASEB J 2005; 19:845–847. doi: 10.1096/fj.04-2809fje.

5. Chai XQ, Hu LF, Zhang Y, et al. Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. Preprint. Posted online February 03, 2020. bioRxiv 931766. doi: 10.1101/2020.02.03.931766;

Competing interests: No competing interests

10 April 2020
Anthony R. Mawson
Ashley M. Croft (Postgraduate Research Fellow, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK), Federico Gonzalez-Fernando (Associate Chief of Staff for Research & Development GV (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS 39216, USA)
Department of Epidemiology and Biostatistics, School of Public Health, College of Health Sciences, Jackson State University
Jackson, Mississippi, USA