SARS-CoV-2 induced liver injury: Incidence, risk factors, impact on COVID-19 severity and prognosis in different population groups

Abstract

Liver is unlikely the key organ driving mortality in coronavirus disease 2019 (COVID-19) however, liver function tests (LFTs) abnormalities are widely observed mostly in moderate and severe cases. According to this review, the overall prevalence of abnormal LFTs in COVID-19 patients ranges from 2.5% to 96.8% worldwide. The geographical variability in the prevalence of underlying diseases is the determinant for the observed discrepancies between East and West. Multifactorial mechanisms are implicated in COVID-19-induced liver injury. Among them, hypercytokinemia with “bystander hepatitis”, cytokine storm syndrome with subsequent oxidative stress and endotheliopathy, hypercoagulable state and immuno-thromboinflammation are the most determinant mechanisms leading to tissue injury. Liver hypoxia may also contribute under specific conditions, while direct hepatocyte injury is an emerging mechanism. Except for initially observed severe acute respiratory distress syndrome corona virus-2 (SARS-CoV-2) tropism for cholangiocytes, more recent cumulative data show SARS-CoV-2 virions within hepatocytes and sinusoidal endothelial cells using electron microscopy (EM). The best evidence for hepatocellular invasion by the virus is the identification of replicating SARS-CoV-2 RNA, S protein RNA and viral nucleocapsid protein within hepatocytes using in-situ hybridization and immunostaining with observed intrahepatic presence of SARS-CoV-2 by EM and by in-situ hybridization. New data mostly derived from imaging findings indicate possible long-term sequelae for the liver months after recovery, suggesting a post-COVID-19 persistent live injury.

Keywords: COVID-19, SARS-CoV-2, Liver injury, Cytokine storm, Endotheliopathy, Immuno-thromboinflammation, Direct hepatocyte injury

Core Tip: Following respiratory system, liver is the second most involved organ in coronavirus disease 2019 (COVID-19). Besides the well-observed cholangiocyte tropism, typical severe acute respiratory distress syndrome corona virus-2 (SARS-CoV-2) Lesions indicated by ultrastructural and histological evidence, identification of replicating SARS-CoV-2, S and nucleocapsid proteins RNAs within hepatocytes, as well as intrahepatic virus observation by electron microscopy and in-situ hybridization, converge to the conclusion that SARS-CoV-2 may also be hepatotropic. Most prevalent mechanisms of COVID-19-related liver injury are hypercytokinemia with “bystander hepatitis”, cytokine storm syndrome with subsequent oxidative stress, endotheliopathy and immuno-thromboinflammation. Depending on the grade of their abnormalities, increased serum aspartate aminotransferase, (mostly peak) alanine aminotransferase, alkaline phosphatase, total bilirubin, inflammatory markers (C-reactive protein, ferritin, interleukin-6, -10) and decreased albumin levels are independent discriminators of COVID-19 severity and mortality. Age, male gender, chronic liver disease, liver cirrhosis, obesity, diabetes, and non-alcoholic fatty liver disease are independent prognostic factors of unfavorable COVID-19 outcomes.