Pathophysiological Mechanisms of Liver Injury in COVID-19

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

Disclosures

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

In This Article

SARS-CoV-2 and Hepatic Steatosis

Microvesicular and macrovesicular steatosis have been observed in liver autopsies of COVID-19 patients who presented with SARS-CoV-2 infection as the only risk factor for liver injury, and in some cases, SARS-CoV-2 hepatocellular infection has been proven.[40,49] Importantly, hepatic lipid accumulation as a result of SARS-CoV-2 infection must be differentiated from pre-existing NAFLD, which has been shown to increase the risk for poor outcome in COVID-19 patients.[50] Deregulated in host lipid metabolism and mitochondrial activity as a result of potential direct SARS-CoV-2 cytopathic effects and/or immunopathology induced by cytokine storm, as well as drug side effects (eg corticosteroids) may be important contributors to the development of hepatic steatosis in COVID-19 (Figure 2).

Microvesicular steatosis is typically caused by genetic or acquired mitochondrial β-oxidation defects.[94] Preliminary observations suggest that SARSR-CoV-2 affects mitochondrial activity.[95] Furthermore, Wang et al also identified mitochondrial crista abnormalities in liver specimen of COVID-19 patients.[40] Interestingly, impaired mitochondrial activity has also been implicated in the pathogenesis of NAFLD/NASH.[96] Thus, SARS-CoV-2 infection might even worsen the metabolic state and aggravate pre-existing NAFLD by these mechanisms.

Endoplasmic reticulum (ER) stress is known to induce de novo lipogenesis in hepatocytes.[97] Several studies have implicated SARS-CoV infection in the induction of ER stress. For instance, significant up-regulation of ER stress markers glucose-regulated protein 78 (GRP78) and GRP94 has been observed upon SARS-CoV infection in several cell lines.[98–100] The coronavirus S protein seems to be a major burden for the host ER and might play a key role in ER stress induction.[98,99] Rearrangement of intracellular membranes by extensive depletion of lipid components from the ER during SARS-CoV-2 infection may also contribute to ER stress.[20] Moreover, the ER stress-related PERK-eIF2-α pathway is over-activated upon SARS-CoV infection in vitro.[101] Finally, electron microscopy examinations, which proved SARS-CoV-2 hepatocellular infection, reported a pathological ER dilatation in infected hepatocytes,[40] which most probably will cause ER stress. Collectively, these data could indicate that SARS-CoV-2, as other coronaviruses, induces ER stress upon infection, and that the ER stress-induced de novo lipogenesis could also contribute to the development of steatosis in COVID-19 patients (Figure 2).

De novo lipogenesis is also induced by the mammalian target of rapamycin (mTOR),[102] which is also the cardinal regulator of autophagy.[103] SARS-CoV has been previously shown to hijack the autophagy pathway through processes that rely on the viral non-structural protein 6 (nsp6), highly conserved in SARS-CoV-2.[104–106] Furthermore, mTOR hyper-activation has been observed in MERS-CoV-infected HuH7 cells, and inhibition of mTOR signalling pathway by rapamycin inhibits viral replication.[107] Given the recent observations that SARS-CoV-2 infection restricts autophagy,[108] it is tempting to speculate that SARS-CoV-2, SARS-CoV and MERS-CoV share a similar mTOR-dependent mechanism of infection. Furthermore, significantly increased mTOR activity has been revealed upon IL-6 stimulation.[109] Thus, SARS-CoV-2 infection could lead to a hyper-activation of hepatic mTOR signalling, via direct infection of hepatic cells, or indirect, cytokine storm-related systemic IL-6-dependent effects, which could contribute to the steatotic phenotype in livers of COVID-19 patients (Figure 2).

Although disadvantageous for the host, induction of host lipogenesis might be crucial for SARS-CoV-2 life cycle. Indeed, enhanced de novo lipogenesis could supply the virus with sufficient amounts of lipids to generate the vesicular systems required for viral replication and exocytosis. mTOR-mediated promotion of protein synthesis[110,111] and inhibition of autophagolysosome formation[112,113] may further favour viral replication while preventing viral degradation and ignition of an adequate immune response. Since insulin and glucose signalling positively regulate mTOR activity in the liver,[114,115] constitutive mTOR over-activation in obese and diabetic patients[116–118] could at least in part explain their higher risk for worse outcome of COVID-19 (Figure 2).

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