The many faces of coronavirus disease 2019: COVID-19 and the liver

Abstract

The coronavirus disease 2019 (COVID-19) continues to pose unprecedented challenges to patients, physicians, and healthcare setups alike. Its numerous clinical ramifications remain unabated, with increasing medical literature establishing its involvement in the onset and perpetuation of a myriad of extrapulmonary manifestations. Of these extrapulmonary manifestations, hepatic impairment has been extensively reported by researchers and clinicians. While hepatic impairment is noted to be an established possible sequel of a COVID-19 infection, its pathophysiological basis remains unclear [1,2]. In order to devise effective, all-encompassing management protocols, it is imperative to thoroughly elucidate the pathophysiology and clinical manifestations of COVID-19 plays in causing liver injury. Herein, we aim to review the literature to date on hepatic manifestations of COVID-19 in patients with no pre-existing liver disease, patients with chronic liver disease and patients with liver transplantation. Viral tropism heavily depends on the presence of virus-specific receptors at the membrane of a host cell [3]. For SARS-CoV-2, this is mediated by the virus’ spike (S) protein interacting with the ACE-2 and TMPRSS-2 receptors, ultimately resulting in an endocytic cell-entry pathway [3]. Pertinently, the SARS-CoV-2 RNA has been found in extrapulmonary organs such as the liver. However, the cellular sites of replication have yet to be elucidated. The liver injury seen in COVID-19 patients is generally mild, even in the setting of pre-existing liver conditions and in severe COVID-19. The major concern, however, stems from the liver’s pivotal role in drug metabolism and core endogenous processes such as coagulation, osmotic pressure maintenance, and acute phase reactant production. Understanding the mechanisms by which SARS-CoV-2 could gain entry into a hepatocyte could therefore prove beneficial for the development of therapeutic targets and management strategies. There are three proposed mechanisms which have been found to cause liver damage COVID-19 patients. The first mechanism is through a direct effect of the virus. ACE-2 receptor expression is a major determinant of a cell’s susceptibility to SARS-CoV-2 infection [2,4]. The ACE-2 receptors are ubiquitous throughout the body, particularly in type II pneumocytes and the hepatobiliary system [2]. A recent RNA sequencing study found similar levels of ACE-2 expression in cholangiocytes when compared to those in lung alveoli, the primary infection site for COVID-19 [5]. ACE-2 receptors were found to be expressed in 59.7% of cholangiocytes, a proportion similar to that in type II pneumocytes. This insinuates the vulnerability of cholangiocytes to SARS-CoV-2 [2,4,5]. A potential deleterious cytopathic effect of SARS-CoV-2 is biliary tree dysfunction and imminent liver dysfunction [4]. This notion has also been corroborated by the elevated levels of gamma-glutamyl transferase (GGT) observed in several SARS-CoV-2 case series [2]. In healthy hepatocytes, the ACE-2 receptor levels were significantly lower, at 2.6% [5]. However, these levels were elevated in specific circumstances. Firstly, fibrosis and cirrhosis increase ACE-2 receptor expression, supporting the results from previous studies that indicated a higher risk for SARS-CoV-2 hepatocellular tropism in patients with underlying liver injury [3]. Similarly, hypoxia is another circumstance in which ACE-2 expression is upregulated in hepatocytes. This serves as a potential explanation for the dissemination of extrapulmonary manifestations in patients who develop more severe hypoxic COVID-19 symptoms such as ARDS. The possible mechanisms by which COVID-19 causes liver injury are delineated in Fig. 1. The pathway for viral entry into hepatocyte cell lines might also utilize the PIKfyve-TCP2 endocytic pathway present in the liver and gallbladder at similar levels to the lungs [3]. Other studies have showed that preincubation of the beta-coronavirus’ S protein with trypsin enhanced the affinity for its receptor on the host cell surface. Trypsin, among other proteases, is expressed in the hepatic epithelial cells as they are crucial for remodeling the extracellular matrix. This enhanced affinity for the S protein in the presence of trypsin may be enough to compensate for the lower levels of ACE-2 expression in healthy hepatocytes. An important distinction needs to be made, however, between viral entry into a cell and viral replication—and consequently proliferation—within the cell. Notably, SARS-CoV-2 was able to replicate in the hepatocyte cell line as well as overexpress proinflammatory cytokines that perpetuate underlying hepatic damage [6]. The endocytic pathway is elucidated by Fig. 2 below. SARS-CoV-2 tropism might occur by infecting monocyte-derived macrophages. Since monocyte-derived macrophages are known to express ACE-2 receptors, it is not surprising that lung alveolar macrophages stained positive in immunohistochemical detection of SARSCoV-2 [3]. However, the specialized hepatic tissue macrophages, Kupffer cells, did not stain; this was despite the fact that Kupffer cells proliferated in the setting of a COVID-19 infection [3]. It was subsequently discovered that Kupffer cells do not express ACE-2 receptors, at least in healthy human livers, from which these RNA sequences were analysed. Reliable comparison calls for similar quantification in COVID-19 patients with underlying liver conditions. When the liver is injured, monocyte-derived macrophages extravasate into the liver. If these immune cells were infected with SARS-CoV-2, they could potentially be carriers to ACE-2 receptor-expressing hepatocytes. The second mechanism of liver damage is through a dysregulated immune response. Severe COVID-19 patients have an increased activation of inflammatory markers [2–4]. This occurs due to upregulated innate immune response with T-cell lymphopenia [3]. These mechanisms could lead to a cytokine storm, which in turn could lead to pulmonary and extrapulmonary injuries including hepatic inflammation and injury [2]. The overactivation of the immune response leads to an activation of cytotoxic (CD8) T-cells that survey the body and induce