COVID-19 and liver disease: mechanistic and clinical perspectives

Abstract

Our understanding of the hepatic consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its resultant coronavirus disease 2019 (COVID-19) has evolved rapidly since the onset of the pandemic. In this Review, we discuss the hepatotropism of SARS-CoV-2, including the differential expression of viral receptors on liver cell types, and we describe the liver histology features present in patients with COVID-19. We also provide an overview of the pattern and relevance of abnormal liver biochemistry during COVID-19 and present the possible underlying direct and indirect mechanisms for liver injury. Furthermore, large international cohorts have been able to characterize the disease course of COVID-19 in patients with pre-existing chronic liver disease. Patients with cirrhosis have particularly high rates of hepatic decompensation and death following SARS-CoV-2 infection and we outline hypotheses to explain these findings, including the possible role of cirrhosis-associated immune dysfunction. This finding contrasts with outcome data in pharmacologically immunosuppressed patients after liver transplantation who seem to have comparatively better outcomes from COVID-19 than those with advanced liver disease. Finally, we discuss the approach to SARS-CoV-2 vaccination in patients with cirrhosis and after liver transplantation and predict how changes in social behaviours and clinical care pathways during the pandemic might lead to increased liver disease incidence and severity.

Fig. 1. Hepatotropism of SARS-CoV-2.

Understanding the hepatotropic effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has required a combination of experimental and clinical models. Hepatoma cell lines in vitro have been shown to support the entire life cycle of SARS-CoV-2 (part a, which shows a Huh-7 cell with widespread intracellular spike protein staining magenta). In vitro cell models have also demonstrated the role of accessory receptors such as high-density lipoprotein receptor scavenger receptor B type 1 (SR-B1) alongside ACE2 for cell entry. In addition, both biliary and hepatocyte organoid models have been shown to express necessary viral entry receptors and recapitulate SARS-CoV-2 infection (part b). Although there is some variability between gene expression studies regarding the distribution of ACE2 on liver cell types, cholangiocytes seem to have the greatest receptor concentration followed by hepatocytes (part c); there is also ACE2 upregulation in the parenchyma of cirrhotic livers. Lastly, histological examination of livers from patients with fatal respiratory coronavirus disease 2019 (COVID-19) have shown a range of microscopic changes such as widespread vascular abnormalities, steatosis and mitochondrial abnormalities (part d). The evidence for direct hepatocyte infection remains inconclusive. TMPRSS2, transmembrane serine protease 2. Part a microscopy image courtesy of S. Davies, University of Birmingham. Part c adapted with permission from ref., Wiley.

Fig. 2. Mortality following SARS-CoV-2 infection according to baseline liver disease stage and level of medical support.

Rates of mortality in patients with chronic liver disease (CLD) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection following hospitalization, admission to intensive care unit (ICU) and invasive ventilation separated by liver disease stage. CP, Child–Pugh. Adapted from ref., CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).

Fig. 3. Possible mechanisms for adverse COVID-19 outcomes in patients with cirrhosis.

Patients with cirrhosis have a high risk of mortality from respiratory failure following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This risk might occur through multiple converging pathways, including contributions from cirrhosis-associated immune dysfunction, acute hepatic decompensation and a systemic inflammatory response. Cirrhosis-associated immune dysfunction could also lead to defective immune responses following future SARS-CoV-2 vaccination. ACLF, acute-on-chronic liver failure; COVID-19, coronavirus disease 2019.

Fig. 4. Trends in liver disease risk factors and management and possible future effect on liver disease incidence and severity.

Trends over time in liver disease risk factors and hepatology care provision in relation to the onset of the coronavirus disease 2019 (COVID-19) pandemic and the cumulative short-term, medium-term and long-term effects this pandemic might have on liver health. HCC, hepatocellular carcinoma; IP, inpatient; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; UGI, upper gastrointestinal; USS, ultrasound scan.

Fig. 5. UK Liver transplant activity before and during COVID-19 pandemic.

United Kingdom National Health Service Blood and Transplant service data on liver transplant activity before and during the coronavirus disease 2019 (COVID-19) pandemic. The data for Fig. 5 that support the plots within this paper are available from the NHS Blood and Transplant Organ Donation and Transplantation Reports and the Coronavirus (COVID-19) in the UK website. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.