SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19

Abstract

Background & aims: Liver enzyme abnormalities are common in patients with coronavirus disease 2019 (COVID-19). Whether or not severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to liver damage per se remains unknown. Herein, we reported the clinical characteristics and liver pathological manifestations of COVID-19 patients with liver enzyme abnormalities.

Methods: We analyzed 156 patients diagnosed with COVID-19 from 2 designated centers in China and compared clinical features between patients with or without elevated aminotransferases. Postmortem liver biopsies were obtained from 2 cases who had elevated aminotransferases. We investigated the patterns of liver impairment by electron microscopy, immunohistochemistry, TUNEL assay and pathological studies.

Results: Sixty-four out of 156 (41.0%) patients with COVID-19 had elevated aminotransferases. The median levels of alanine aminotransferase were 50 U/L vs. 19 U/L, respectively, aspartate aminotransferase were 45.5 U/L vs. 24 U/L, respectively in abnormal and normal aminotransferase groups. Liver enzyme abnormalities were associated with disease severity, as well as a series of laboratory tests including higher alveolar-arterial oxygen partial pressure difference, higher gamma-glutamyltransferase, lower albumin, decreased CD4+ T cells and B lymphocytes. Ultrastructural examination identified typical coronavirus particles, characterized by spike structures, in the cytoplasm of hepatocytes in 2 COVID-19 cases. SARS-CoV-2-infected hepatocytes displayed conspicuous mitochondrial swelling, endoplasmic reticulum dilatation and glycogen granule decrease. Histologically, massive hepatic apoptosis and some binuclear hepatocytes were observed. Taken together, both ultrastructural and histological evidence indicated a typical lesion of viral infection. Immunohistochemical results showed scarce CD4+ and CD8+ lymphocytes. No obvious eosinophil infiltration, cholestasis, fibrin deposition, granuloma, massive central necrosis, or interface hepatitis were observed.

Conclusions: SARS-CoV-2 infection in the liver directly contributes to hepatic impairment in patients with COVID-19. Hence, a surveillance of viral clearance in liver and long-term outcome of COVID-19 is required.

Lay summary: Liver enzyme abnormalities are common in patients with coronavirus disease 2019 (COVID-19). We reported the clinical characteristics and liver pathological manifestations of COVID-19 patients with elevated liver enzymes. Our findings suggested that SARS-CoV-2 infection of the liver is a crucial factor contributing to hepatic impairment in patients with COVID-19.

Keywords: COVID-19; Cytopathy; Liver enzyme abnormality; SARS-CoV-2 infection; Transaminase.

Graphical abstract

Fig. 1

Postmortem biopsy specimens from case 1. (A) Lung tissue showing diffuse alveolar damage, desquamation and hyaline membrane, and multinucleated syncytial pneumocytes, as well as interstitial mononuclear infiltrates (H&E staining, original magnification ×200, up-right region original magnification ×400). (B) Liver tissue showing substantial apoptotic hepatocytes, prominent binuclear hepatocytes, and mild to moderate steatosis. (H&E staining, original magnification ×200, up-right region original magnification ×400). (C) Immunohistochemistry of liver tissue revealing activated CD68+ cells (original magnification ×200), (D) scattered CD4+ cells and (E) CD8+ cells in lobular and portal areas (original magnification ×400). (F) Nuclear proliferative antigen Ki-67 was positive in a few mononuclear cells and hepatocytes (original magnification ×400). TUNEL staining (green) showing apoptotic cells in control liver tissue (G–I) and in COVID-19 liver tissue (J–L). DAPI (blue) was applied to visualize nuclei. (M) Ultrastructural examination identifying amounts of typical coronavirus particles (arrow) with size of 60–120 nm in cytoplasm of hepatocytes. Ultrastructural impairment manifesting conspicuous mitochondria (marked as M) swelling and glycogen granule decrease (original magnification ×15,000). COVID-19, coronavirus disease 2019.

Fig. 2

Postmortem biopsy specimens from case 2. (A) Lung tissue showing late phase diffuse alveolar damage, with cellular and fibrinous exudation, hemorrhage, and foamy cells in alveolar spaces (H&E staining, original magnification ×400). (B) Liver tissue revealing abundant apoptotic hepatocytes, plenty of binuclear cells, and mild to moderate micro- and macrovesicular steatosis (H&E staining, original magnification ×200). (C) Immunohistochemistry for liver tissue revealing numerous activated CD68+ Kupffer cells (original magnification ×200), (D) scattered CD4+ and (E) CD8+ cells in lobules (original magnification ×400). (F) A few Ki67 positive proliferative hepatocytes and Kupffer cells (original magnification ×400). (G–I) TUNEL assay displaying apoptotic hepatocytes (green). (J) Electron microscopy showing numerous coronavirus particles (arrow) in cytoplasm of hepatocytes. The pattern of cell damage including decreased glycogen granules and canalicular (marked as C) impairment with shedding of microvilli (original magnification ×12,000).