Histopathological impact of SARS-CoV-2 on the liver: Cellular damage and long-term complications

Abstract

Coronavirus disease 2019 (COVID-19), caused by the highly pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), primarily impacts the respiratory tract and can lead to severe outcomes such as acute respiratory distress syndrome, multiple organ failure, and death. Despite extensive studies on the pathogenicity of SARS-CoV-2, its impact on the hepatobiliary system remains unclear. While liver injury is commonly indicated by reduced albumin and elevated bilirubin and transaminase levels, the exact source of this damage is not fully understood. Proposed mechanisms for injury include direct cytotoxicity, collateral damage from inflammation, drug-induced liver injury, and ischemia/hypoxia. However, evidence often relies on blood tests with liver enzyme abnormalities. In this comprehensive review, we focused solely on the different histopathological manifestations of liver injury in COVID-19 patients, drawing from liver biopsies, complete autopsies, and in vitro liver analyses. We present evidence of the direct impact of SARS-CoV-2 on the liver, substantiated by in vitro observations of viral entry mechanisms and the actual presence of viral particles in liver samples resulting in a variety of cellular changes, including mitochondrial swelling, endoplasmic reticulum dilatation, and hepatocyte apoptosis. Additionally, we describe the diverse liver pathology observed during COVID-19 infection, encompassing necrosis, steatosis, cholestasis, and lobular inflammation. We also discuss the emergence of long-term complications, notably COVID-19-related secondary sclerosing cholangitis. Recognizing the histopathological liver changes occurring during COVID-19 infection is pivotal for improving patient recovery and guiding decision-making.

Keywords: Liver, SARS-CoV-2, COVID-19, Angiotensin-converting enzyme 2, Histopathology, Liver biopsies, Liver autopsy, In vitro

Core Tip: Severe acute respiratory syndrome coronavirus 2 infection is linked to significant liver injury, emerging from the facilitated entry of the virus into liver cells, including cholangiocytes and endothelial cells, due to increased receptor expression. This invasion triggers critical cellular alterations such as mitochondrial swelling, endoplasmic reticulum dilation, and hepatocyte apoptosis. Confirmed by biopsy or autopsy, the presence of viral particles in liver tissues correlates with extensive histological damage, characterized by necrosis, steatosis, cholestasis, and inflammation. Such findings highlight the acute hepatic impact of coronavirus disease 2019 (COVID-19) and signal the risk of severe long-term complications, such as COVID-19-associated sclerosing cholangitis, emphasizing the profound and enduring effect of the virus on liver health.