SARS-associated viral hepatitis caused by a novel coronavirus: report of three cases

Abstract

Liver impairment is commonly reported in up to 60% of patients who suffer from severe acute respiratory syndrome (SARS). Here we report the clinical course and liver pathology in three SARS patients with liver impairment. Three patients who fulfilled the World Health Organization case definition of probable SARS and developed marked elevation of alanine aminotransferase were included. Percutaneous liver biopsies were performed. Liver specimens were examined by light and electron microscopy, and immunohistochemistry. Reverse-transcriptase polymerase chain reaction (RT-PCR) using enhanced real-time PCR was applied to look for evidence of SARS-associated coronavirus infection. Marked accumulation of cells in mitosis was observed in two patients and apoptosis was observed in all three patients. Other common pathologic features included ballooning of hepatocytes and mild to moderate lobular lymphocytic infiltration. No eosinophilic infiltration, granuloma, cholestasis, fibrosis, or fibrin deposition was noted. Immunohistochemical studies revealed 0.5% to 11.4% of nuclei were positive for proliferative antigen Ki-67. RT-PCR showed evidence of SARS-associated coronavirus in the liver tissues, but not in the sera of all 3 patients. However, electron microscopy could not identify viral particles. No giant mitochondria, micro- or macro-vesicular steatosis was observed. In conclusion, hepatic impairment in patients with SARS is due to SARS-associated coronavirus infection of the liver. The prominence of mitotic activity of hepatocytes is unique and may be due to a hyperproliferative state with or without disruption of cell cycle by the coronavirus. With better knowledge of pathogenesis, specific therapy may be targeted to reduce viral replication and modify the disease course.

Figure 1

Temperature, ALT level, white blood cell counts, and treatment of patients 1 (A), 2 (B), and 3 (C).

Figure 2

(A) Histologic section of the liver showing mild portal lymphocytic infiltration and relatively sparse lobular inflammation in patient 1 (Hematoxyline & Eosin ×100). (B) Prominent balloon degeneration of hepatocytes with focal collection of acidophilic bodies (arrow) in patient 1 (Hematoxyline & Eosin ×400). (C) Mild portal inflammation in patient 2 (Hematoxyline & Eosin ×200). (D) Lobular activity with focal neutrophilic infiltration in patient 3 (Hematoxyline & Eosin, ×400).

Figure 3

Extremely brisk mitotic activities (arrows) among the hepatocytes in patient 1 (Hematoxyline & Eosin ×400).

Figure 4

Immunohistochemical staining for Ki‐67 showing marked increase in hepatocyte labeling in patient 1 (×100; inset ×400).

Figure 5

(A) Liver tissues of all three patients showing positive results for SARS‐CoV obtained with real‐time PCR as detected by the ABI Prism 7700 Sequence Detector. (B) Sera of all three patients showing negative results for SARS‐CoV obtained with real‐time PCR as detected by the ABI Prism 7700 Sequence Detector.

Figure 6

(A) In patient 2, mitochondria are largely normal ultrastructurally, with occasional ones appearing elongated (Transmission electron microscopy [TEM] ×3000; inset ×35000). (B) Electron microscopy showing a hepatocyte in mitosis with disappearance of nuclear membrane and spindle formation (arrow) in patient 3 (TEM ×5000).