Pathophysiological Mechanisms of Liver Injury in COVID-19

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


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

In This Article

Abstract and Introduction


The recent outbreak of coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has resulted in a world-wide pandemic. Disseminated lung injury with the development of acute respiratory distress syndrome (ARDS) is the main cause of mortality in COVID-19. Although liver failure does not seem to occur in the absence of pre-existing liver disease, hepatic involvement in COVID-19 may correlate with overall disease severity and serve as a prognostic factor for the development of ARDS. The spectrum of liver injury in COVID-19 may range from direct infection by SARS-CoV-2, indirect involvement by systemic inflammation, hypoxic changes, iatrogenic causes such as drugs and ventilation to exacerbation of underlying liver disease. This concise review discusses the potential pathophysiological mechanisms for SARS-CoV-2 hepatic tropism as well as acute and possibly long-term liver injury in COVID-19.


Since December 2019, the outbreak of coronavirus disease 2019 (COVID-19), caused by the novel Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV) 2 (SARS-CoV-2), has led within a few months to a major global health and economic crisis. As of October 2020, more than 40 million confirmed cases have been reported worldwide, with nearly 1 million deaths, affecting 189 countries.[1] The respiratory tract is considered the main target of SARS-CoV-2 infection and a small subset of infected individuals becomes severely ill and may develop acute respiratory distress syndrome (ARDS) with potentially fatal outcome.[2] More recently, systemic features of the disease with the involvement of organs outside the respiratory tract, including the liver and gastrointestinal tract are receiving increasing attention, indicating that COVID-19 may be considered as a systemic infectious and inflammatory disease.[3–7] Although closely related to other Corona virus (CoV) family members SARS-CoV and MERS-CoV (Middle East Respiratory Syndrome CoV), infections with the new SARS-CoV-2 exhibit a different pathological pattern and the mechanistic link between CoVs-induced molecular pathophysiological changes and clinical manifestations remains incompletely understood.

Coronaviridae family members, including SARS-CoV-2, SARS-CoV and MERS-CoV, are enveloped viruses, characterized by a positive single-stranded RNA genome of about 30Kb.[8–10] The angiotensin-converting enzyme 2 (ACE2) has been established as the main viral receptor for SARS-CoV and SARS-CoV-2[11,12] (Figure 1). Following attachment to the host cell and viral S protein priming by the host transmembrane serine protease 2 (TMPRSS2),[13] SARS-CoV is internalized by endocytosis and the viral genome is released from the endosome.[14,15] In the cytosol, the viral RNA is translated into two polyproteins, pp1a and pp1ab, that are further processed to produce 16 non-structural proteins (nsp1 to nsp16),[16] the building blocks of the viral replicase–transcriptase complex (RTC).[17,18] The full viral genome is then replicated in RTC-containing vesicles.[19,20] In parallel, a set of specific sub-genomic mRNA is generated[14] for the production of SARS-CoV structural and accessory proteins, which assemble to form the nucleocapsid and viral envelope at the ER–Golgi intermediate compartment, allowing the subsequent release of mature virions[21] (Figure 1).

Figure 1.

SARS-CoV-2 life cycle in host cells. SARS-CoV-2 attachment to host cells in liver (eg hepatocytes) may be mediated by the interaction of Spike (S) protein with ACE2. S protein is cleaved by the transmembrane serine protease 2 (TMPRSS2), allowing the cellular entry of the virus. Once uncoated, the viral genome ((+) vgRNA) is released and translated by the ribosome into pp1a and pp1ab (not shown), that are further cleaved into 16 non-structural proteins (nsps). Following the viral replication/transcription complex (vRTC) assembly, nsp6 (in red) induces autophagosome formation, where viral replication might take place (purple dashed lines). Viral replication might also occur in double-membrane vesicles (DMV) (black dashed lines). nsp6-mediated inhibition of autophagosome/lysosome expansion might prevent viral degradation (purple dashed inhibitory line). Newly synthesized viral structural and accessory proteins assemble to form the nucleocapsid and viral envelope at the ER–Golgi intermediate compartment (lower right). Mature virions are then released through the exploitation of the host vesicular system (upper right). DMV and autophagosomes might also be used by the virus for exocytosis and release of mature virions (black dashed lines)

Although COVID-19 primarily affects the respiratory system, emerging evidence highlights the impact of this viral infection on other organ systems.[3–5,22,23] The ubiquitous distribution of the main viral entry receptor ACE2 may explain how SARS-CoV-2 is able to cause a widespread disease characterized by systemic organ involvement including the intestines,[24] heart, kidneys, pancreas, liver, muscular and nervous system.[11,25–28] In contrast to SARS-CoV-2-induced lung and myocardial injury, the clinical significance of liver involvement has been controversially debated from the very beginning of the COVID-19 pandemic.[22,28–33] However, the scientific progress over the last months has shed more light on several key questions concerning COVID-19-associated liver injury. In this review, we will highlight molecular evidence pointing towards a putative hepatic tropism of SARS-CoV-2, and further review pathophysiological mechanisms that could explain the hepatic phenotypes associated with COVID-19.