Liver Disease and Coronavirus Disease 2019: From Pathogenesis to Clinical Care

Abstract

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus that emerged in late 2019, is posing an unprecedented challenge to global health. Coronavirus disease 2019 (COVID-19), the clinical disease caused by SARS-CoV-2, has a variable presentation ranging from asymptomatic infection to life-threatening acute respiratory distress syndrome and multiorgan failure. Liver involvement is common during COVID-19 and exhibits a spectrum of clinical manifestations from asymptomatic elevations of liver function tests to hepatic decompensation. The presence of abnormal liver tests has been associated with a more severe presentation of COVID-19 disease and overall mortality. Although SARS-CoV-2 RNA has been detected in the liver of patients with COVID-19, it remains unclear whether SARS-CoV-2 productively infects and replicates in liver cells and has a direct liver-pathogenic effect. The cause of liver injury in COVID-19 can be attributed to multiple factors, including virus-induced systemic inflammation, hypoxia, hepatic congestion, and drug-induced liver disease. Among patients with cirrhosis, COVID-19 has been associated with hepatic decompensation and liver-related mortality. Additionally, COVID-19's impact on health care resources can adversely affect delivery of care and outcomes of patients with chronic liver disease. Understanding the underlying mechanisms of liver injury during COVID-19 will be important in the management of patients with COVID-19, especially those with advanced liver disease. This review summarizes our current knowledge of SARS-CoV-2 virus-host interactions in the liver as well the clinical impact of liver disease in COVID-19.

FIG. 1

Model of the SARS‐CoV‐2 life cycle in infected host cells of human patients. Following binding to the ACE2 receptor and the coreceptor (1) neuropilin‐1 (NRP1) and priming by (2) TMPRSS2, SARS‐CoV‐2 enters the host cell, where (3) the viral RNA is released into the cytoplasm. ORFs 1a and 1ab are then directly translated into (4) large polyproteins, which, following (5) proteolytic cleavage, form the replication complex. (6) A negative‐sense viral RNA is synthesized and used as template to form the positive‐sense viral genome and the individual mRNAs. (7) The nucleocapsid protein is translated in the cytoplasm, whereas spike, membrane, and envelope proteins are translated in the ER and transported to the Golgi. Viral particles containing RNA‐nucleocapsid complexes, spike, and envelope proteins (8) assemble at the ERGIC and (9) are subsequently released from the host cells. Current treatment options target different stages of the viral life cycle. Virus entry can be blocked by the recently FDA‐approved therapy with convalescent patient sera. Proteolysis of the viral polyproteins is inhibited by the HIV‐protease inhibitors lopinavir/ritonavir, whereas replication can be targeted by the nucleotide‐analogue remdesivir. Targets and compounds for antiviral therapy are marked in blue. Abbreviations: ERGIC, ER‐Golgi‐intermediate‐complex; pp, polyprotein.

FIG. 2

Expression of SARS‐CoV‐2 cell entry factors ACE2 and TMPRSS2 in the human liver assessed by single‐cell RNA sequencing (RNASeq) and immunohistochemistry. (A) Expression t‐distributed stochastic neighbor embedding (t‐SNE) maps of ACE2 and TMPRSS2 in the nondiseased human liver. The color bar indicates log2 normalized expression (n = 10,372 cells) retrieved by data processing from the human liver cell atlas.^{( 16 )} The y‐axis shows log 2 normalized expression. (B) Violin plots of scaled gene expression data of ACE2 and TMPRSS2 in liver cell subsets of patients with and without cirrhosis from https://www.livercellatlas.mvm.ed.ac.uk/.^{( 73 )} (C) Immunohistochemistry staining of ACE2 and TMPRSS2 of nondiseased livers showing protein expression in cholangiocytes (arrows) and hepatocytes (arrowheads). Data and images from https://www.proteinatlas.org/.^{( 74 )} Abbreviations: EPCAM, epithelial cell adhesion module; ILC, innate lymphoid cell; NK, natural killer cell; NKT, natural killer T cell; NP, mononuclear phagocytic cell; pDC, plasmacytoid dendritic cell.

FIG. 3

COVID‐19–related liver injury and mortality in patients who were hospitalized with and without chronic liver disease (CLD). Patients without CLD usually present with AST elevation, which correlates with ICU admission and mortality. Among patients with CLD, NAFLD has the highest risk of severe illness, ICU admission, and need for mechanical ventilation.^{( 54}, ^{56 )} Patients with cirrhosis are at risk for decompensation, and patients who are decompensated have a high risk of acute‐on‐chronic liver failure (ACLF) and mortality.^{( 46}, ⁴⁷, ⁴⁸, ^{49 )} Abbreviations: CTP, Child‐Turcotte‐Pugh; ICU, intensive care unit.

FIG. 4

Current understanding of mechanisms of liver injury in COVID‐19. Following SARS‐CoV‐2 infection of lung epithelial cells, immune cells such as T cells, macrophages, and neutrophils are recruited to the site of infection and cause local inflammation. In severe cases, local inflammation can spill over to global circulation, inducing a massive release of cytokines that can affect other organs, including the liver. Additionally, SARS‐CoV‐2 can potentially induce local inflammation in the liver, either by activating liver‐resident immune cells or by directly infecting hepatocytes and other liver cells. Mostly, COVID‐19 only results in raised aminotransferases and in some cases mild hypoalbuminemia, but in the most severe cases, it can lead to liver decompensation, which can result in potentially fatal ACLF.^{( 22}, ³⁶, ⁴⁷, ^{75 )} Abbreviations: ACLF, acute‐on‐chronic liver failure; DAMP, damage‐associated molecular pattern; IFN, interferon; PAMP, pathogen‐associated molecular pattern; TPO, thrombopoietin.