COVID-19 and the Liver: A 2021 Update

Catherine W. Spearman; Alessio Aghemo; Luca Valenti; Mark W. Sonderup


Liver International. 2021;41(9):1988-1998. 

In This Article

Pathophysiology of COVID-19

SARS-CoV-2 is a single, positive-stranded RNA virus that replicates using a virally encoded RNA-dependent RNA polymerase. It binds to target cells via a hidden receptor-binding domain of the Spike protein to the angiotensin-converting enzyme 2 (ACE-2), which acts as a functional receptor.[5,6] Cell entry requires priming of the Spike protein by a cellular serine protease, TMPRSS2. Other proteases and co-expression are also required.[7] Cell entry of the virus is pre-activated by a target cell proprotein convertase called furin, reducing its dependence on target cell proteases for cell entry. Furin is found in the lungs, the liver and small intestine and enables efficient cell entry, while evading immune surveillance and promoting transmission.[8]

Following entry into the host cell, injury occurs as a result of potential direct virus-mediated cell damage with dysregulation of renin-angiotensin-aldosterone system (RAAS) as a consequence of downregulation of ACE-2 related to viral entry leading to decreased cleavage of angiotensin I and II. Endothelial cell damage and thrombo-inflammation leads to both micro- and macrovascular thromboses.[9] Virus-induced immune dysregulation and hyperinflammation through inhibition of type-I interferon (IFN) signalling, T-cell lympho-depletion, upregulated proinflammatory cytokines (especially interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α), induces a hyperactive innate immune system with a resulting cytokine storm[4,10,11] (Figure 1).

Figure 1.

Mechanisms of liver injury in COVID-19

SARS-CoV-2 variants have now emerged in the United Kingdom (501Y.V1 or B.1.1.7)[12] and South Africa (501Y.V2 or B.1.351)[13,14] and share the spike N501Y substitution located in the viral spike protein receptor-binding domain for cell entry. Another variant from Brazil (501Y.V3 or P.1) also contains mutations (N501Y, E484K and K417T) in the receptor-binding domain of the spike protein,[15] and, recently, in India, the B.1.617 variant containing the mutations, E484Q and L452R, has been identified. SARS-CoV-2 variants are more transmissible[12,16] and may be associated with a higher morbidity and mortality.[17,18]