key: cord-0741964-4fs724wn authors: Xu, Ling; Liu, Jia; Lu, Mengji; Yang, Dongliang; Zheng, Xin title: Liver injury during highly pathogenic human coronavirus infections date: 2020-03-30 journal: Liver Int DOI: 10.1111/liv.14435 sha: 6530c411cf3c1cdcfcc30219b4a8481fdbb5e955 doc_id: 741964 cord_uid: 4fs724wn The severe acute respiratory syndrome coronavirus 2 (SARS‐Cov‐2), the pathogen of 2019 novel coronavirus disease (COVID‐19), has posed a serious threat to global public health. The WHO has declared the outbreak of SARS‐CoV‐2 infection an international public health emergency. Lung lesions have been considered as the major damage caused by SARS‐CoV‐2 infection. However, liver injury has also been reported to occur during the course of the disease in severe cases. Similarly, previous studies have shown that liver damage was common in the patients infected by the other two highly pathogenic coronavirus – severe acute respiratory syndrome coronavirus (SARS‐CoV) and the Middle East respiratory syndrome coronavirus (MERS‐CoV), and associated with the severity of diseases. In this review, the characteristics and mechanism of liver injury caused by SARS‐CoV, MERS‐CoV as well as SARS‐CoV‐2 infection were summarized, which may provide help for further studies on the liver injury of COVID‐19. and mechanism of liver injury caused by SARS-CoV, MERS-CoV as well as SARS-CoV-2 infection were summarized, which may provide help for further studies on the liver injury of COVID-19. Severe acute respiratory syndrome (SARS) is an acute infectious disease caused by SARS-CoV. 5 shown that liver injury occurred in SARS patients, which was mainly manifested in the mild and moderate elevation of ALT and/ or AST during the early stage of the disease. Some patients had decreased serum albumin and increased serum bilirubin levels. [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] The severe cases were more likely to have severe liver injury compared to mild cases. 6, 10, 12 Studies have been performed to understand the mechanism of liver damage caused by SARS-CoV. Autopsy of SARS patients found large numbers of virus particles not only in the lungs but also in the parenchymal cells and vascular endothelium of other organs, including the liver. 19 ,20 SARS-CoV genome was also detected in hepatocytes by RT-PCR. 19, 20, 21 It is known that SARS-CoV uses angiotensin-converting enzyme 2 (ACE2) as the receptor for cell entry. 22 ACE2 was found to be abundantly expressed on endothelial cells of the liver, 23 which makes the liver a potential target for SARS-CoV. Liver biopsies in SARS patients showed a significant increase in mitotic cells, with eosinophilic bodies and balloon-like hepatocytes, suggesting that SARS-CoV may induce apoptosis of liver cells and thus cause liver injury. 18 Other studies showed that SARS-CoV-specific protein 7a can induce apoptosis in cell lines of different organs (including the lung, kidney and liver) through the caspase-dependent pathway, further confirming the possibility that SARS-CoV directly attacks liver tissue and causes liver injury. 24 Abnormal serum levels of cytokines and chemokines were found at the early stage of SARS-CoV infection in patients. Duan et al 12 reported that serum IL-1, IL-6 and IL-10 levels in patients with abnormal liver function were higher than those in patients with normal liver function, suggesting a possible correlation between liver damage and the inflammatory responses induced by SARS-CoV infection. Besides, SARS patients with HBV/HCV infection were more prone to develop liver damage and severe hepatitis, which is probably due to enhanced replication of hepatitis virus during SARS-CoV infection. 13 It is particularly worth noting that antibiotics (macrolides, quinolones), antivirals (ribavirin), steroids and other drugs used for the treatment of SARS patients may also result in liver damage. 7,25 Different from SARS-CoV, MERS-CoV was found to utilize dipeptidyl peptidase-4 (DPP-4) as its functional receptor for establishing infection in cells. 35 The expression level of DPP-4 in the liver is high, 36 Recent studies on COVID-19 have shown that the incidence of liver injury ranged from 14.8% to 53%, mainly indicated by abnormal ALT/AST levels accompanied by slightly elevated bilirubin levels. [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] The albumin is decreased in severe cases and the level of albumin is around 26.3-30.9 g/L. 46 The proportion of developing liver injury in severe COVID-19 patients was significantly higher than that in mild patients. [40] [41] [42] In death cases of COVID-19, the incidence of liver injury might reach as high as 58.06% 51 and 78%. 50 One study reported that serum ALT and AST levels increased up to 7590 U/L and 1445 U/L, respectively, in a severe COVID-19 patient. 46 limited. It has been shown that SARS-CoV-2 also uses ACE2 as its entry receptor as SARS-Cov does. 52 Chai et al 53 found that both liver cells and bile duct cells express ACE2. However, the ACE2 expression of bile duct cells is much higher than that of liver cells, but to a comparable level of alveolar type 2 cells in the lung. Bile duct epithelial cells are known to play important roles in liver regeneration and immune response. 54 These results suggested that the liver injury occurred in COVID-19 patients may be due to the damage to bile duct cells, but not liver cells by the virus infection. Besides, the inflammatory cytokine storm was observed in severe COVID-19 cases, 55 These drugs are all potential causes of liver injury during COVID-19, but not yet being evident. 49 Actually, a recent study reported that the liver injury observed in COVID-19 patients might be caused by lopinavir/litonavir, which is used as antivirals for the treatment of SARS-CoV-2 infection. 43 So far, there is a lack of reports that liver failure occurs in COVID-19 patients with chronic liver diseases, such as chronic hepatitis B or C. In this review, we summarized the reports of liver injury caused by SARS-CoV, MERS-CoV and SARS-CoV-2 infection ( This work is supported by the Fundamental Research Funds for the Central Universities (2020kfyXGYJ016 and 2020kfyXGYJ028). We thank Ms Delia Cosgrove for the language correction of this manuscript. The authors disclose no conflicts of interest. 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