SARS-CoV-2-mediated liver injury: pathophysiology and mechanisms of disease

Abstract

Background: SARS-CoV-2-induced severe inflammatory response can be associated with severe medical consequences leading to multi-organ failure, including the liver. The main mechanism behind this assault is the aggressive cytokine storm that induces cytotoxicity in various organs. Of interest, hepatic stellate cells (HSC) respond acutely to liver injury through several molecular mechanisms, hence furthering the perpetuation of the cytokine storm and its resultant tissue damage. In addition, hepatocytes undergo apoptosis or necrosis resulting in the release of pro-inflammatory and pro-fibrogenic mediators that lead to chronic liver inflammation.

Aims: The aim of this review is to summarize available data on SARS-CoV-2-induced liver inflammation in addition to evaluate the potential effect of anti-inflammatory drugs in attenuating SARS-CoV-2-induced liver inflammation.

Methods: Thorough PubMed search was done to gather and summarize published data on SARS-CoV-2-induced liver inflammation. Additionally, various anti-inflammatory potential treatments were also documented.

Results: Published data documented SARS-CoV-2 infection of liver tissues and is prominent in most liver cells. Also, histological analysis showed various features of tissues damage, e.g., hepatocellular necrosis, mitosis, cellular infiltration, and fatty degeneration in addition to microvesicular steatosis and inflammation. Finally, the efficacy of the different drugs used to treat SARS-CoV-2-induced liver injury, in particular the anti-inflammatory remedies, are likely to have some beneficial effect to treat liver injury in COVID-19.

Conclusion: SARS-CoV-2-induced liver inflammation is a serious condition, and drugs with potent anti-inflammatory effect can play a major role in preventing irreversible liver damage in COVID-19.

Keywords: ACE 2 receptors; Acute liver failure; Ang2; COVID-19; Chronic liver failure; Cytokine storm; Hepatic stellate cells; Inflammation.

Fig. 1

Mechanism of COVID-19-induced liver injury. (1) SARS-CoV-2 virus enters the host cell through binding to angiotensin converting enzyme 2 (ACE2) and TMPRSS receptors that are abundant in the liver. Once in the cytoplasm, SARS-CoV-2 releases its genomic RNA and starts replicating inside the host cell. (2) Upon viral entry, Kupffer cells serve as the first gate against inflammatory stimuli in the portal circulation and produce inflammatory cytokines in the sinusoidal lumen. (3) The endocytosis of SARS-CoV-2 and ACE2 triggers an increase of serum angiotensin II, which acts as a vasoconstrictor and pro-inflammatory cytokine. (4) Increased inflammatory markers include increased levels of ACE2 which is characterized by high C-reactive protein, lactate dehydrogenase, IL-6, and ferritin levels, C5a and C3a which increase production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor-α (TNF- α), and C5b-9 which stimulates release of IL-6. (5) Hepatic stellate cells in the Space of Disse respond to this inflammatory stimulus originating in the sinusoids and lose their lipid-rich granules. Furthermore, they secrete pro-inflammatory cytokines such as IL-1β and IL-18, which further contribute to the cytokine storm. (6) The cytokine storm induces liver damage and injury including portal fibrosis, ballooned cells, acidophilic bodies, microvascular steatosis, lobular inflammation, vascular derangement, etc. (Created with BioRender.com) expression (3) as well as induction of a set of pro-inflammatory factors (4). Mechanisms involved in reducing the inflammatory processes are shown in red arrows