key: cord-1016207-ujc6p956
authors: Gao, Feng; Zheng, Kenneth I.; Fan, Yu-Chen; Targher, Giovanni; Byrne, Christopher D.; Zheng, Ming-Hua
title: ACE2: A Linkage for the Interplay Between COVID-19 and Decompensated Cirrhosis
date: 2020-07-16
journal: Am J Gastroenterol
DOI: 10.14309/ajg.0000000000000780
sha: da5f6eda5c126cb1293999c84c96bde2a65b94c5
doc_id: 1016207
cord_uid: ujc6p956

nan

We read with interest the article "Clinical Characteristics of COVID-19 Patients With Digestive Symptoms" in The American Journal of Gastroenterology (1) . In the article, the authors reported that patients with digestive symptoms were more likely to suffer liver injury because of the upregulation of angiotensin-converting enzyme 2 (ACE-2) expression in the liver tissue. Liver cirrhosis is one of the most common digestive diseases in health care. Recent evidence indicates that cirrhosis significantly increases hepatic ACE2 expression (2) . We reviewed the available literature (published in PubMed, EMBASE, and Web of Science up to April 30, 2020) and hypothesized that patients with cirrhotic may be vulnerable to the serious clinical consequences of severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2) infection.

ACE2 is a membrane-bound enzyme expressed in many organs (including the liver) that is thought to be involved in the SARS-CoV-2 infection. The mechanism of the SARS-CoV-2 infection involves a viral coat protein termed SPIKE (S protein) acting as a receptor-binding region that binds to the extracellular domain of ACE2 to gain cell entry. Liver impairment is relatively common among patients with coronavirus disease 2019 (COVID-19), and ACE2-expressing liver cells are potential targets for the SARS-CoV-2 infection. Studies have demonstrated that cirrhosis significantly increases hepatic ACE2 expression (2) . In normal human livers, ACE2 staining was minimal and confined to the bile duct cells, vascular endothelium, and perivenular hepatocytes (2). By contrast, in cirrhotic livers, ACE2 was detected in most hepatocytes within cirrhotic nodules, as well as bile duct cells and vascular endothelial cells (2) . Upregulation of hepatic ACE2 allows more SARS-CoV-2 entry into cells and may cause greater virulence of SARS-CoV-2 in the liver. Therefore, compared with healthy individuals, patients with cirrhosis and COVID-19 may have a greater severity of hepatic dysfunction and even a higher risk of progression to liver failure.

ACE2 internalization by SARS-CoV-2 potentially results in the loss of ACE2 activity at the cell surface and voids a key pathway of angiotensin (Ang)-II metabolism and Ang-(1-7) generation (3). A recent study reported higher plasma levels of Ang II in patients with COVID-19 than in healthy controls that would be consistent with lower ACE2 activity (4). Ang II is the key effector peptide in renin-angiotensin system, which mediates vasoconstriction, sustains renal sodium retention, and promotes hepatic fibrogenesis. The important role of ACE2 is likely to balance the renin-angiotensin system status by degrading Ang II and generating Ang- (1-7) . Experimentally, Ang-(1-7) inhibits liver fibrogenesis and exerts natriuretic and portal hypotensive effects (5) . Therefore, in patients with cirrhotic, the reduction in ACE2 by SARS-CoV-2-induced internalization would be predicted to aggravate liver fibrosis and portal hypertension, and exacerbate disease severity acutely and, perhaps, even in the long term. Besides, cell surface reduction of ACE2 contributes to widespread inflammation associated with COVID-19 (3).

In summary, we speculate that COVID-19 infection may specifically affect patients with decompensated cirrhosis, because these patients may overexpress the ACE2 enzyme, leading to higher levels of SARS-CoV-2 infection in a group of patients who are already at a greater risk of microbial infection. 

Clinical Characteristics of COVID-19 patients with digestive symptoms in Hubei, China: A descriptive, cross-sectional, multicenter study

Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2

COVID-19, ACE2 and the cardiovascular consequences

The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients

Pathways of hepatic and renal damage through non-classical activation of the renin-angiotensin system in chronic liver disease