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Multicenter analysis of clinical characteristics and outcome of COVID-19 patients with liver injury
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April 16 2020 Jnl of Hepatology - Xiaolong Qi, Chuan Liu, Zicheng Jiang, Ye Gu, Guo Zhang, Chuxiao Shao, Hongmei Yue, Zhenhuai Chen, Baoyi Ma, Dengxiang Liu, Lin Zhang, Jitao Wang, Dan Xu, Junqiang Lei, Xun Li, Huihong Huang, Yan Wang, Hongyan Liu, Jie Yang, Hongqiu Pan, Weiying Liu, Wenjuan Wang, Fujian Li, Shengqiang Zou, Hongguang Zhang, Jiahong Dong
To the Editor
The coronavirus disease 2019 (COVID-19) has become a global challenge since the December 2019.1
We read with interest the paper "Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study", in which 43 (43.4%) of 99 patients had differing degrees of liver function abnormality; One patient had severe liver function damage (alanine aminotransferase [ALT] 7590 U/L, aspartate aminotransferase [AST] 1445 U/L).1
For patients with COVID-19 in intensive care unit care, liver function was significantly worse than those in non-intensive care unit care.2 The similar features was further reported in a study of 138 hospitalized patients in Wuhan, China.3 On the basis of these clinical findings, liver injury in COVID-19 attracted widespread concern.4
There is no data yet focusing on the clinical characteristics and outcome of COVID-19 patients with liver injury.
In the multicenter cohort (COVID-LIVER-CHESS) of 9 designated hospitals in China, patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and without pre-existing liver-related comorbidities were consecutively enrolled from January 23, 2020 to February 18, 2020, with final follow-up on March 19, 2020. We defined liver injury as any parameter more than the upper limit of normal value of ALT (40 U/L), AST (40 U/L), and total bilirubin (TBil, 17.1 μmol/L) on admission. Also, we defined the degree of severity of COVID-19 (severe vs. nonsevere) at the time of admission.5
During hospitalization, most patients received antiviral treatment with interferon inhalation, lopinavir and ritonavir, combined with probiotics. Patients were discharged once the results of two real-time fluorescence polymerase-chain-reaction tests taken 24 hours apart were negative for SARS-CoV-2. This study was approved by ethics commissions, with a waiver of written informed consent.
Of the 70 consecutive patients with COVID-19 in 9 designated hospitals (The First Hospital of Lanzhou University, Lanzhou; Ankang Central Hospital, Ankang; The Sixth People's Hospital of Shenyang, Shenyang; Lishui Central Hospital, Lishui; The Affiliated Third Hospital of Jiangsu University, Zhenjiang; The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning; The People's Hospital of LinXia Hui Prefecture, Linxia; The People's Hospital of Baoding, Baoding; Xingtai People's Hospital, Xingtai, Figure 1A), the degree of severity of COVID-19 was nonsevere in 67 (95.71%) patients, and severe in 3 (4.29%) cases on admission. Of 3 patients with severe COVID-19, all were transferred to the intensive care unit due to progressive disease, and 1 died of acute respiratory distress syndrome. Thirty-two (45.71%) patients with COVID-19 were classfied with liver injury on admission, including elevated ALT (N=15 [21.43%], 42.00-72.70 U/L), AST (N=5 [7.14%]; 42.90-61.00 U/L), and TBil (N=25 [35.71%], 18.00-148.00 μmol/L). One of 3 patients with severe disease had an elevated ALT of 61 U/L on admission. The clinical characteristics and outcome were summarized in Table 1. Of 32 patients with liver injury, the median age were 41.00 (interquartile range [IQR], 27.50-50.00) years and 23 (71.88%) were male. Eight (25.00%) patients had comorbidities, including 6 (18.75%) hypertension, and 2 (6.25%) malignancy. Common symptoms were fever (22 [68.75%]), cough (24 [75.00%]), myalgia (6 [18.75%]), and diarrhea (5 [15.63%]). Leukopenia and lymphopenia occurred in 7 (21.88%) and 5 (15.63%) patients, respectively. There were elevated blood levels for C-reactive protein in 21 (65.63%) patients with liver injury (Table 1). Chest images showed abnormal findings including ground-glass opacity in the lungs of 31 (96.88%) patients. Notably, the time from illness onset to admission of COVID-19 patients was correlated with the risk of liver injury (Figure 1B). For those with liver injury, the time from onset to admission was significantly longer than that of cases without liver injury (8.00 [IQR, 5.00-10.00] vs 5.00 [IQR, 4.00-9.00]; P=0.037, Figure 1C). As for March 19, 2020, the hospital stay of 68 discharged patients with liver injury did not show statistical difference compared to those without liver injury (16.00 [IQR, 12.00-20.00] vs 15.00 [IQR, 10.00-22.50]; P=0.810, Figure 1D).
In the COVID-LIVER-CHESS study, we analyzed the clinical characteristics and outcome of multicenter patients with COVID-19 related liver injury for the first time, to our best knowledge. Notably, COVID-19 involves in not only respiratory system, but also digestive system.4, 5, 6
Diarrhea occurred in 42 (3.8%) of 1,099 patients in China,5and 43 (43.4%) of 99 patients had differing degrees of liver function abnormality.1
On the basis of an unbiased evaluation of cell type specific expression of angiotensin converting enzyme 2 (ACE2) using single cell RNA-seq data, it indicated that SARS-CoV-2 might directly bind to ACE2 positive cholangiocytes to dysregulate liver function.7, 8, 9
Liver pathological findings of COVID-19 showed moderate microvascular steatosis, and mild lobular and portal activity, which suggested that the injury could have been caused by either SARS-CoV-2 infection or drug-induced liver injury.10
In our study, a longer time from illness onset to admission resulted in the risk of liver injury in patients with COVID-19, which highlighted the urgent need of early detection of SARS-CoV-2 infection. Since patients in the study did not receive therapy including antiviral drugs, traditional Chinese medicine and nonsteroidal antiinflammatory drugs before admission, and 67 (95.71%) of 70 patients had a nonsevere disease, 32 (45.71%) patients with liver injury on admission were more likely to be caused by SARS-CoV-2 infection. Considering the side effect of antiviral drugs including lopinavir and ritonavir used during hospitalization, systemic inflammatory response and pneumonia-associated hypoxia in severe cases,2,4
liver injury in patients with COVID-19 might be aggravated. The further study on the mechanism of liver injury in COVID-19 remains needed. In addition, the hospital stay of patients with liver injury was not statistically different compared to that of cases without liver injury, which might result from mild liver injury on admission. Therefore, we recommend dynamic monitoring the liver function of patients with liver injury, especially those in intensive care unit care.
The study was limited by small sample size and lack of dynamic monitoring of liver function during hospitalization. A larger longitudinal cohort is needed to clarify the role of liver injury in the outcome of patients with SARS-CoV-2 infection. In summary, the multicenter analysis presents the clinical characteristics and outcome of COVID-19 patients with liver injury, which has important reference value to offer a better multi-system care.

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