Pathophysiological Mechanisms of Liver Injury in COVID-19

Alexander D. Nardo; Mathias Schneeweiss-Gleixner; May Bakail; Emmanuel D. Dixon; Sigurd F. Lax; Michael Trauner

Disclosures

Liver International. 2021;41(1):20-32. 

In This Article

The Gut-liver Axis as the Potential Route for SARS-CoV-2 Hepatic Infection

Since SARS-CoV-2 infection affects also the gastrointestinal (GI) tract,[158] a significant proportion of COVID-19 patients experience gastrointestinal symptoms, including diarrhea (2%-35.6%), nausea (1%-17.3%) and vomiting (1%-6.4%).[158] Notably, both SARS-CoV-2 RNA and viable virions have been identified in stool samples of infected patients and post-mortem.[24,159–162] Hepatic and gastrointestinal manifestations appear more frequently in severe forms of COVID-19 infections.[3–5,163–165] Interestingly, a recent study by Jin and colleagues showed that individuals with pre-existing liver diseases are more susceptible to develop an intestinal phenotype upon SARS-CoV-2 infection.[163] SARS-CoV-2 is potentially able to infect cells of the gastrointestinal tract, since ileal and colonic enterocytes co-express ACE2 and TMPRSS2, the central proteins for viral attachment.[166–168] Recently, viral nucleocapsid protein could be demonstrated within enterocytes by immunohistochemistry.[24] The Human Protein Atlas database further corroborates these observations, with intestinal cells exhibiting the highest pattern of ACE2 expression across the whole human cell type repertoire (data available at https://www.proteinatlas.org/ENSG00000130234-ACE2/tissue ). Moreover, human intestinal organoids have been shown to be permissive to SARS-CoV and SARS-CoV-2 infection.[169] Direct gastrointestinal infection has been reported also by biopsy-proven RNA and nucleocapsid protein detection in gastric, duodenal and rectal epithelia.[160] Interestingly, gastrointestinal symptoms may appear before or even in the absence of manifestations in the respiratory tract.[165] This suggests that the GI tract might be a primary site of COVID-19 infection, and therefore that oral-fecal transmission could be an alternative route of infection for SARS-CoV-2 (this has been extensively reviewed).[162,170]

We would like to propose the following putative way of SARS-CoV-2 infection through the hepatobiliary system. COVID-19 intestinal infection might impair the intestinal epithelial and vascular barriers, eventually leading to hepatic translocation of the virus through the portal vein. Hepatic infection might therefore start in hepatocytes, which express the required receptor binding proteins and are in direct contact with the portal circulation. Subsequently, SARS-CoV-2 virions exiting infected hepatocytes by transcytotic vesicular pathways could reach the bile, which has tested positive in some studies,[76] although this remains controversial.[49] As a result, cholangiocytes might also get in contact with and infected by SARS-CoV-2. Since the biliary tract provides a direct link between liver and gut, SARS-CoV-2 may thereby reach and infect the intestine via bile, causing in turn a second wave of infection.

Thus, the here proposed speculative mechanism could generate a vicious circle, which increases the chances of survival for the virus and might explain the worse overall outcome in patients manifesting hepatic and intestinal symptoms upon SARS-CoV-2 infection. On the other hand, COVID-19 with fatal outcome seems to be associated with severe damage of lung tissue, whereas the intestines are only mildly altered, most commonly by focal ischaemic changes in the intestinal mucosa.[24] Whether biliary tropism and requirement of bile/bile acids for viral attachment and entry into cholangiocytes and enterocytes[171,172] also play a role for SARS-CoV-2 remains to be determined. Given the functional and physiological similarities between bile ducts and ducts of the exocrine pancreas, and the observations concerning a potential pancreatic involvement in COVID-19 infection,[49,173,174] the research of a common mechanism allowing infection of the two tissues might help in uncovering further determinants of SARS-CoV-2 tropism.

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