key: cord-0830162-5c6fzdjm authors: Huang, Haijun; Chen, Shanshan; Li, Hong; Zhou, Xian‐Long; Dai, Yining; Jia, Wu; Zhang, Jun; Shao, Lina; Yan, Rong; Wang, Mingshan; Wang, Jiafeng; Tu, Yuexing; Ge, Minghua title: The association between markers of liver injury and clinical outcomes in patients with COVID‐19 in Wuhan date: 2020-07-22 journal: Aliment Pharmacol Ther DOI: 10.1111/apt.15962 sha: e27551c49124276cbf4758cd2391222c9d35312d doc_id: 830162 cord_uid: 5c6fzdjm BACKGROUND: The outbreak of coronavirus disease 2019 (COVID‐19) is a critical challenge for public health. The effect of COVID‐19 on liver injury has not been fully presented. AIMS: To evaluate the dynamic changes in liver function and the relationship between liver function damage and prognosis in patients with COVID‐19. METHODS: Retrospective analysis of clinical data of 675 patients with COVID‐19 in Zhongnan Hospital of Wuhan University from January 3 to March 8, 2020. Patients were classified as normal, abnormal liver function and liver injury. RESULTS: Of 675 patients, 253 (37.5%) had abnormal liver function during hospitalisation, and 52 (7.7%) had liver injury. The dynamic changes of ALT and AST levels were more significant in patients with liver injury and in those who died. AST >3‐fold ULN had the highest risk of death and mechanical ventilation. Compared to patients with normal AST levels, mortality and risk of mechanical ventilation significantly increased 19.27‐fold (95% confidence interval [CI], 4.89‐75.97; P < 0.0001) and 116.72‐fold (95% CI, 31.58‐431.46; P < 0.0001), respectively, in patients with AST above 3‐fold ULN. Increased leucocytes, decreased lymphocytes and female sex were independently associated with liver injury. CONCLUSIONS: The dynamic changes in liver function may have a significant correlation with the severity and prognosis of COVID‐19. Increased index of liver injury was closely related to mortality and need for mechanical ventilation. Therefore, these indicators should be closely monitored during hospitalisation. In December 2019, unexplained pneumonia cases emerged in Wuhan, Hubei Province, China, 1,2 which spread rapidly throughout the country and became a public health emergency of international concern. On January 7, a novel coronavirus was detected in a swab sample of a patient by the China Center for Disease Control and Prevention (CDC). The disease was subsequently named the novel coronavirus disease 2019 (2019-nCoV). 3 The pathogen of COVID-19 pneumonia is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 1,4 which mainly causes respiratory, intestinal, liver and nervous system diseases. 5, 6 A study showed that more than 50% of patients with COVID-19 have different degrees of liver injury. 7 Some studies have reported the clinical characteristics of patients with coronavirus disease 2019 (COVID- 19) , including some factors that may lead to COVID-19-related liver damage and the relationship between liver function damage and disease prognosis. 1, 3, [8] [9] [10] [11] In these studies, different degrees of elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were reported. 1, 3, 8, 12 However, the effect of COVID-19 on liver injury has not been fully presented. Liver injury is related to the severity and mortality of COVID-19. 13- 16 Cai et al systematically described the clinical characteristics of COVID-19 patients with liver injury and revealed that liver injury was related to disease severity. 14 In addition, a study reported that liver injury was related to death in patients with COVID-19, and mortality was related to an increase in liver enzyme levels. 13 However, mechanical ventilation, which is the main auxiliary treatment for critical patients and an important clinical outcome of COVID-19, was not involved. On the other hand, dynamic changes in liver functions may indicate a certain relationship between liver injury and mortality. There were few studies on the dynamic changes of liver functions in COVID-19-related liver injury. 13, 17 Nevertheless, the dynamic changes in liver function based on fatal and nonfatal individuals have never been reported. Moreover, there is little research on what abnormalities occur at what time and how those may relate to clinical outcomes. Therefore, we retrospectively analysed the clinical characteristics and dynamic changes in liver function based on different liver function levels at admission and different prognosis, in the purpose of finding out risk factors related to liver injury, and associations between markers of liver injury and clinical outcomes in COVID-19, including mortality and mechanical ventilation. From January 3 to March 8, 2020, the medical records of in-patients diagnosed with COVID-19 were analysed retrospectively at Zhongnan Hospital of Wuhan University. Information on epidemiological, demographic, clinical symptoms or physical signs and comorbidities was extracted from the electronic medical records. According to the diagnosis and treatment standard of COVID-19 18 issued by the National Health Committee, the disease severity was divided into three groups: mild, severe and critical. Patients with mild type might have fever and respiratory symptoms, and pneumonia was revealed by imaging. Severe COVID-19 was defined when the patients met any of the following criteria: (a) respiratory distress (≥30 breaths/min); (b) resting oxygen saturation ≤93%; and (c) arterial blood oxygen partial pressure (PaO2)/FiO2 ≤300 mm Hg. In the critical group, at least one of the following three diagnostic criteria Fisher's exact test. Dynamic changes in liver function based on different liver function levels at admission and different prognosis were presented using locally weighted scatterplot smoothing (LOESS). The mixed-effect Cox proportional risk regression model was used to study the relationship between liver enzyme level and mortality and mechanical ventilation. The mixed-effect Cox model was adjusted for gender, age, smoking, chronic liver disease and comorbidities (including hypertension, diabetes mellitus, coronary heart disease and chronic obstructive pulmonary disease). To explore the factors associated with COVID-19-related liver injury, logistic regression analysis was performed. The variables with P < 0.1 in a univariate analysis were then included in a forward stepwise regression model. A twosided P of less than 0.05 was considered statistically significant. Table 1 . Among the 675 patients, 370 (54.8%) patients had normal liver function, 253 (37.5%) patients had abnormal liver function and 52 (7.7%) patients had liver injury. In patients with liver injury, the median age was 51.50 (35.75-60.25), and the ratio of males to females was 4:1. The body mass index (BMI) of patients with liver injury was 24.66 (23.14-26.37), which was higher than that of patients with normal and abnormal liver function. The incidences of hypertension, diabetes mellitus (DM), coronary heart disease (CHD) and chronic obstructive pulmonary disease (COPD) were 12 (23.08%), 6 (11.54%), 6 (11.54%) and 1 (1.92%), respectively, in these patients with liver injury. Among 52 patients with liver injury, 42 (80.77%) patients had fever, and 20 (38.46%) had dyspnoea, which were significantly higher than those of patients without liver injury (P < 0.001). Twenty-eight (53.85%) patients with liver injury were in the mild group, 8 (15.38%) patients were in the severe group and 16 (30.77%) patients were in the critical group. The median values of ALT, AST and TBIL were 105.00 (49.25-159.50), 58.50 (45.00-90.50) and 12.55 (9.50-17.67), respectively, which were much higher than those of patients with normal and abnormal liver function (P < 0.001 for all). The number of lymphocytes in patients with liver injury was 1.08 (0.58-1.63), which was significantly lower than that in patients without liver injury. Figure 3C depicted that the fluctuation in TBIL levels was mild and normal in the nonfatal group, and the TBIL levels increased much more slowly than the ALT and AST in the fatal group. Nevertheless, TBIL continued to rise slowly until it surpassed the ULN at the third week. Kaplan-Meier survival curves were used to evaluate the survival probability and mechanical ventilation-free survival probability during hospitalisation in patients of COVID-19 with different levels of ALT, AST and TBIL. Among these indexes of liver function, AST over 3-fold ULN had the highest risks of death and mechanical ventilation. In addition, abnormal levels of ALT and TBIL were also significantly associated with the risk of death and mechanical ventilation (Figures 4 and 5) . The relationship between impaired liver function, mortality and mechanical ventilation was evaluated by a mixed-effect Cox model adjusted for age, gender, smoking, chronic liver disease and comorbidities, with the hazard ratios of ALT, AST and TBIL to mortality and the risk of mechanical ventilation showed in Logistic regression analysis of the influencing factors of liver injury, such as epidemiological and clinical characteristics, and laboratory variables was performed to select the predictor parameters of COVID-19 patients. Factors significantly associated with liver injury were increased leucocytes, decreased lymphocytes and female (Table 3 ). In this study, we retrospectively and systematically analysed the There were few studies on the dynamic changes of liver functions in COVID-19-related liver injury. 13, 17 One study had suggested that the dynamic changes in liver enzyme levels in severe patients were more significant, and AST was the parameter most correlated with mortality. 13 Another study indicated that the pattern of liver biochemical was consistent with the damage of hepatocytes, especially AST. The correlation between AST and ALT was very strong on admission and throughout the hospitalisation. This suggested that liver injury was the predominant source of aminotransferase elevation. 17 It is in agreement with our findings. In our study, the dynamic changes of ALT and AST levels were more significant in patients with liver injury and in the fatal group. Moreover, AST over 3-fold ULN had the highest risks of death and mechanical ventilation. In the group of patients with liver injury, ALT and AST levels disease. The sight increase of AST levels in the early stage of disease may be related to immune-mediated inflammation in the liver. 13 On the other hand, a multicentre study has reported that the incidence of increased TBIL in COVID-19 was 10%. 12 In our study, level of TBIL increased only in the later stage of Increased leucocytes and decreased lymphocytes were proved to be risk factors for liver injury. [21] [22] [23] This occurred because of inflammatory response having some effect on the occurrence of COVID-19-related liver injury. 23 A study has showed that lymphopenia may be a key factor related to disease severity and mortality, 24 and this is consistent with the conclusion of our research. The study has several limitations. Firstly, this is a retrospective study. The data are not able to assess the causality of COVID-19related liver injury and poor clinical outcomes. Secondly, some cases did not have enough clinical data on past liver injury. Thirdly, the sample size of this study is small. A large cohort study is needed to clarify the association of dynamic changes in liver function and clinical outcomes. In conclusion, the dynamic changes in the markers of liver injury have a significant correlation with severity and prognosis of COVID-19. 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