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

The Spectrum of Liver Involvement in COVID-19

COVID-19 associated liver injury is defined as any liver damage occurring during disease course and treatment of COVID-19 patients, with or without pre-existing liver disease.[4,34–39] This includes a broad spectrum of potential pathomechanisms including direct cytotoxicity from active viral replication of SARS-CoV-2 in the liver,[40,41] immune-mediated liver damage due to the severe inflammatory response/systemic inflammatory response syndrome (SIRS) in COVID-19,[42] hypoxic changes induced by respiratory failure, vascular changes due to coagulopathy, endothelitis or cardiac congestion from right heart failure, drug-induced liver injury and exacerbation of underlying liver disease (Figure 2). The incidence of elevated liver transaminases (ALT and AST) in COVID-19 patients ranges from 2.5% to 76.3%.[35,38,43,44] In a recent meta-analysis, the pooled rate for AST and ALT outside the reference range was 20%-22.5% and 14.6%-20.1% respectively.[35,45] These abnormalities can be accompanied by slightly increased total bilirubin levels in up to 35% of cases.[35,38,43,44] While elevations of cholestatic liver enzymes [alkaline phosphatase (ALP) and gamma glutamyl transferase (γGT)] were initially considered rather rare,[4,22,23,46] recent systemic reviews highlight elevations of ALP and γGT in 6.1% and 21.1% of COVID-19 patients respectively.[35,45] Moreover, a biphasic pattern with initial transaminase elevations followed by cholestatic liver enzymes has been reported, which could reflect SIRS-induced cholestasis at the hepatocellular/canalicular level or more severe bile duct injury in the later stage of the disease.[47] Although COVID-19-associated liver injury has been reported to be mild, it may affect a significant proportion of patients, especially those with a more severe disease course. In the light of the central role of the liver for the production of albumin, acute phase reactants and coagulation factors, hepatic dysfunction may impact on the multisystem manifestations of COVID-19 such as ARDS, coagulopathy and multiorgan failure.[2–7,48] Moreover, the liver is the primary metabolic and detoxifying organ in the human organism, and even a moderate loss of hepatic function could alter the safety profile and therapeutic efficacy of antiviral drugs metabolized in the liver. Hence, it is crucial to understand the causes of COVID-19-associated liver injury in more detail.

Figure 2.

Proposed pathophysiology for liver injury upon SARS-CoV-2 infection. COVID-19-associated hepatocellular damage is mainly characterized by moderate steatosis, lobular and portal inflammation, apoptotic/necrotic foci and elevation of plasma ALT and AST (upper left panel). Preliminary observations suggest that the injury might be caused by hepatocellular infection with direct cytopathic effects of SARS-CoV-2, which could induce mitochondrial dysfunction and ER stress contributing to steatosis. Furthermore, SARS-CoV-2 infection might also activate mTOR, which eventually inhibits autophagy (as a mechanism of viral degradation) and facilitates viral escape from the immune system. In addition, cytokine storm, hypoxic conditions due to ARDS and drug-induced liver injury (DILI) may contribute. COVID-19-associated cholangiocellular injury has also been observed and is mainly characterized by bile duct proliferation, occasionally bile plug formation and elevation of plasma γGT and ALP (lower left panel). From a hepatological perspective, COVID-19-positive patients may be divided into three categories: patients without pre-existing chronic liver disease, patients with early stage chronic liver disease and patients with advanced chronic liver disease/cirrhosis. COVID-19-associated liver injury may have a more severe outcome in patients with pre-existing liver disease, such as non-alcoholic fatty liver disease (NAFLD) and associated metabolic comorbidity. Moreover, COVID-19 may induce hepatic decompensation with increased mortality in cirrhotic patients (right panel)

So far, systematic information on underlying histopathological alterations is scarce. Hepatic steatosis (in part microvesicular) and Kupffer cell activation appear to be commonly encountered in livers of SARS-CoV-2-infected deceased, together with vascular alterations including derangement of intrahepatic portal vein branches, usually mild lobular and portal inflammation, ductular proliferation and liver cell necrosis.[40,46,49–51] Of note, examination of liver biopsies from a cohort of 48 deceased COVID-19 patients revealed extensive luminal thrombosis at the portal and sinusoidal level, together with portal fibrosis accompanied by significant pericyte activation.[51]

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