SARS-CoV-2 infection and liver involvement

Abstract

The COVID-19 pandemic is the largest public health challenge in living memory. Patients with underlying liver disease have been disproportionately affected, experiencing high morbidity and mortality. In addition, elevated liver enzymes appear to be a risk factor for disease progression, even in the absence of underlying liver disease. Nevertheless, the mechanism of liver injury in SARS-CoV-2 infection remains largely unknown. This review aims to provide an overview of the mechanisms by which SARS-CoV-2 induces liver injury, and the impact of COVID-19 on cirrhosis, alcohol-related liver disease, autoimmune liver disease, non-alcoholic fatty liver disease, hepatitis B and C virus infection, liver-transplant recipients and patients with hepatocellular carcinoma. Finally, emerging data on vaccination in liver diseases is discussed, to help inform public health policy.

Keywords: Alcohol-related liver disease; Autoimmune liver disease; COVID-19; Chronic liver disease; Cirrhosis; Hepatitis B virus infection; Liver injury; Non-alcoholic fatty liver disease; SARS-CoV-2; Vaccination.

Fig. 1

Covid-19 is associated with increased liver damage. SARS-CoV-2 infection in the lungs triggers ischemic/hypoxic damage as a result of pneumonia. In some patients, the antiviral response is disproportionate and results in over-activation of immune cells and consequent hyper-production of cytokines (cytokine storm). High levels of circulating cytokines, in particular IL-6, are associated with development of liver injury, which is exacerbated by direct cytotoxic effect of SARS-CoV-2 on the liver and by the hepatotoxicity associated with approved drugs for therapy against COVID-19

Fig. 2

Patients with cirrhosis are at greater risk of developing acute hepatic decompensation upon SARS-CoV-2 infection, since they display weaker response to the vaccine resulting in lower levels of circulating antibodies against SARS-CoV-2 and also have increased expression of ACE2 on the hepatocyte membrane. ACE2 is not typically expressed on the surface of healthy hepatocytes but has elevated expression in cirrhosis permitting entry of SARS-CoV-2 into the cell. Cirrhosis is also associated with low-levels of circulating gut-derived bacterial products, which predispose to systemic inflammation and upregulation of inflammasome pathways. This results in sensitisation of hepatocytes to SARS-CoV-2 infection and subsequent pro-inflammatory cell death and immune responses

Fig. 3

Upregulation of hepatocyte inflammasome signalling in cirrhosis predisposes to exacerbated cell death following SARS-CoV-2 infection. In cirrhosis (right panel) bacterial products (such as lipopolysaccharide) bind and activate Caspases-4/5 leading to cleavage of the dimeric protein Gasdermin-D (GSDMD). GSDMD N-terminal migrates to the plasma membrane, forming pores that allow the unregulated passage of damage-associated molecular patterns and electrolytes. K⁺ efflux and mitochondrial damage are also triggers of NLRP3 assembly, which in turns activates caspase-1 and leads to processing of pro-IL1β. Upon SARS-Cov-2 infection, viral proteins react with the already assembled NLRP3, leading to activation of downstream pathways. By contrast, in healthy liver (left panel), absence of ACE2 receptor delays the entry of SARS-CoV-2 into the cells. NLRP3 is present, but inactive, thus slowing the progress towards activation of pro-inflammatory caspases and processing of GSDMD and pro-IL1β

Fig. 4

Risk of severe Covid-19 and overall mortality considering the weighted value of published studies, adjusted for the number of patients included. Risk of severe COVID-19 was a composite endpoint of need for hospitalization, ICU or ventilation for each aetiology and risk of liver injury in Child–Pugh class