Unraveling the Molecular and Cellular Pathogenesis of COVID-19-Associated Liver Injury

Abstract

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) continues to cause substantial morbidity and mortality. Most infections are mild; however, some patients experience severe and potentially fatal systemic inflammation, tissue damage, cytokine storm, and acute respiratory distress syndrome. Patients with chronic liver disease have been frequently affected, experiencing high morbidity and mortality. In addition, elevated liver enzymes may be a risk factor for disease progression, even in the absence of underlying liver disease. While the respiratory tract is a primary target of SARS-CoV-2, it has become evident that COVID-19 is a multisystemic infectious disease. The hepatobiliary system might be influenced during COVID-19 infection, ranging from a mild elevation of aminotransferases to the development of autoimmune hepatitis and secondary sclerosing cholangitis. Furthermore, the virus can promote existing chronic liver diseases to liver failure and activate the autoimmune liver disease. Whether the direct cytopathic effects of the virus, host reaction, hypoxia, drugs, vaccination, or all these risk factors cause liver injury has not been clarified to a large extent in COVID-19. This review article discussed the molecular and cellular mechanisms involved in the pathogenesis of SARS-CoV-2 virus-associated liver injury and highlighted the emerging role of liver sinusoidal epithelial cells (LSECs) in virus-related liver damage.

Keywords: COVID-19; SARS-CoV-2; autoimmune liver disease; chronic liver disease; liver injury; vaccination.

Figure 1

The life cycle of the SARS-CoV-2 virus. SARS-CoV-2 proteins bind to the ACE2 receptor. TMPRSS2 promotes viral uptake and fusion at the cellular and endosomal membranes. Following entry, the release and uncoating of the genomic RNA subject it to the immediate translation of the two large opening reading frames, ORF1a, and ORF1b. During the cellular life cycle, SARS-CoV-2 viruses express and replicate their genomic RNA to produce full-length copies that are incorporated into newly produced viral particles.

Figure 2

LSEC activation and cellular interaction during SARS-CoV-2 infection. SARS-CoV-2 infection stimulates a systemic release of IL-6 that induces LSECs through a trans-signaling pathway involving the sIL-6R and gp130. Activated LSECs acquired a procoagulant and proinflammatory phenotype, which express vWF, Factor VIII, CXCL1, and 2 and cell adhesion molecules, which eventually promote platelet and neutrophil recruitment in the liver. Additionally, LSECs express IL-6 and interact with hepatocytes, which respond to IL-6 through a classical signaling pathway involving the IL-6R. Hepatocytes play a critical role in the systemic response to SARS-CoV-2 via expressing fibrinogen and acute phase proteins.

Figure 3

Clinical outcomes of SARS-CoV-2-related immunopathology. COVID-19 patients with lymphopenia are susceptible to infections with the microbe, which promotes disease progression and increased severity. Furthermore, cytokine storms can trigger inflammatory-associated multiple organ dysfunction, including lung injury that can result in ARDS, liver injury with ALT, AST, GGT elevation, kidney injury with increased BUN and creatinine levels, and heart injury with increased creatinine kinase (CK) and lactate dehydrogenase (LDH) levels.