Elevated serum aspartate aminotransferase level identifies patients with coronavirus disease 2019 and predicts the length of hospital stay

Abstract Background Coronavirus disease 2019 (COVID‐19) has become a worldwide public health emergency. This study aimed to investigate the clinical significance of liver blood tests in COVID‐19 patients. Methods The analysis included clinical data of 23 patients with suspected COVID‐19 and 66 patients with confirmed COVID‐19 from January 25 to February 20, 2020. The relationship between liver blood test results, liver condition (HBsAb positive, HBcAb positive, and fatty liver disease), and duration of hospital stay among COVID‐19 patients was analyzed. Results The median hospital stay of COVID‐19 patients was 6 days. Serum albumin (Alb) level was lower in patients with COVID‐19 confirmed on admission than in patients with suspected COVID‐19 (40.08 g/L vs 42.50 g/L, P = .016), while the level of aspartate aminotransferase (AST) was higher (23 U/L vs 18 U/L, P = .005). Abnormal results of liver blood tests in patients with COVID‐19 included increased levels of alanine transaminase (ALT) (21.2%, 14 patients), AST (15.2%, 10 patients), and gamma‐glutamyl transpeptidase (GGT) (22.7%, 15 patients). After 5‐10 days of treatment, levels of Alb and AST in COVID‐19 patients were significantly decreased (P < .001 and P = .027, respectively). Abnormal levels of Alb and AST in patients with COVID‐19 were not associated with the liver condition (all P > .05). In addition, only levels of AST were positively correlated with the duration of hospital stay (r = .334, P = .007). Conclusion Abnormal results of the liver blood test were found in COVID‐19 patients. The COVID‐19 patients on admission with the higher levels of AST might have longer hospital stays.


| INTRODUC TI ON
Several cases of pneumonia of an unknown etiology were detected in Wuhan, Hubei Province, China, in December 2019, and currently, an increasing number of countries face the challenge of the ensuing pandemic. There are more than 1 353 361 confirmed cases of the disease in more than 200 countries, and the number of deaths exceeds 79 235 as of April 8, 2020. 1 On February 11, 2020, the disease was named COVID-19, and the responsible virus was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 2,3 COVID-19 is highly contagious, and adults and children of all ages and both sexes are generally susceptible to infection by SARS-CoV-2. The virus is mostly transmitted through respiratory droplets and contact from person to person. 4 The incubation period in the majority of patients is no longer than 14 days, and in most of them ranges from 3 to 7 days. The common clinical symptoms of COVID-19 are fever, dry cough, fatigue, and dyspnea. In some cases, gastrointestinal symptoms such as diarrhea may be present. 5 Most of the patients have a mild course of the disease and good prognosis, while in a small fraction of cases, the progression of the disease can lead to multiple organ dysfunction and even death.
During the outbreak of the severe acute respiratory syndrome (SARS) in 2003, caused by SARS-CoV, it was found that most patients had liver damage, and the virus was identified in the liver tissue. The genomic sequence similarity between SARS-CoV-2 and SARS-CoV is 82%, 6 raising the possibility that abnormalities in liver function might also be present in COVID-19 patients. In fact, liver damage in these patients has been reported in some studies. [6][7][8] Alanine transaminase (ALT) and aspartate aminotransferase (AST) levels were elevated in 20% of COVID-19 patients, 9 and the increase was more apparent in critically ill patients. However, the mechanism underlying this association remains unclear. It has been documented that, in a manner similar to SARS-CoV, SARS-CoV-2 invades cells mainly through angiotensin-converting enzyme 2 (ACE2). It is important that ACE2 is expressed not only in the lungs but also in bile duct cells of the liver. 10 Drug-induced liver injury, liver hypoxia, and immune-inflammatory reaction may also be involved in liver injury.
Although abnormalities in liver blood tests in COVID-19 patients have been reported, it is unknown whether they are related to the condition of the liver, such as hepatitis B virus infection or fatty liver. Based on the above information, the data of 23 suspected and 66 confirmed cases were collected to further explore the association between liver injury and COVID-19. The data were analyzed to assess the differences in liver blood test results between patients with confirmed and suspected COVID-19, evaluate liver state function, and establish the presence of a correlation between liver indexes and the length of hospital stay.

| Participants
A total of 89 cases were enrolled in the study, including 23 suspected and 66 confirmed patients with COVID-19. All these participants were admitted to the Huai'an Fourth People's Hospital from January 25 to February 20, 2020. A throat swab positive for SARS-CoV-2 was classified as confirmed patients with COVID-19. During the same period, COVID-19 was suspected in 23 patients who were admitted to this hospital. Suspected cases were identified as having fever or respiratory symptoms, and a history of exposure to a source of transmission within the past 14 days. The suspected patients were discharged from the hospital once the results of two RT-PCR tests taken 24 hours apart were negative. The study was approved by the

| Data collection
Epidemiological data were collected through brief interviews with each patient. The radiologic assessment included the chest com-  SPSS 23.0 software was used for data processing and analysis. The counting data were represented by the number of cases (percentage). The continuous data were non-normally distributed and represented by the median (interquartile range). The chi-square test was used for intergroup comparison. Rank sum test was used for nonparametric data, and binary logistic regression analysis was used for categorical data. P < .05 was considered statistically significant.

| Results of liver blood tests in suspected and confirmed COVID-19 patients
The suspected patients were considered to represent controls, and the data were compared with those of COVID-19 patients ( Table 2).
The suspected and confirmed COVID-19 patients had similar clinical symptoms and imaging findings. Moreover, there was no significant difference between the two groups in sex, age, BMI, and disease duration. Serum Alb level was significantly decreased in COVID-19 patients than in suspects (40.08 g/L vs 42.50 g/L, P = .016), while the level of AST was higher (23 U/L vs 18 U/L, P = .005). Other liver blood tests did not differ significantly between the two groups.

| Abnormal liver blood tests in suspected and confirmed COVID-19 patients
Patients with suspected COVID-19 had serum Alb concentration within the normal reference range. However, Alb levels were decreased in 10 (15.2%) patients with confirmed COVID-19. In addition, ALT level was increased in 14 (21.2%) patients with confirmed COVID-19, AST level was increased in 10 (15.2%), and GGT level was increased in 15 (22.7%) patients with confirmed COVID-19. In comparison with patients with suspected COVID-19, patients with confirmed COVID-19 had lower Alb levels (40.08 g/L vs 42.5 g/L, P = .016) and higher AST levels (23 U/L vs 18 U/L, P = .005). There was no significant difference in TB, GGT, ALP, and PT between the two groups. These findings indicate that that Alb and AST levels may help to identify and monitor patients with confirmed COVID-19 (Table 3).

| Changes in liver blood test results in COVID-19 patients after 5-10 days of treatment
The measurement of liver function indices was repeated 5-10 days after the admission of COVID-19 patients to the hospital. In comparison with the results obtained at admission, the levels of Alb and AST were decreased (P < .001 and P < .027, respectively). However, the treatment did not affect the levels of TB, GGT, and ALP, and the value of PT (Table 4).

| Correlation between indices of liver function and the length of hospital stay in COVID-19 patients
Analysis of the association between the results of blood liver tests and duration of hospitalization in patients with COVID-19 demonstrated that a significant positive correlation was present only for serum level of AST (r = .334, P < .007). The six other measured indicators of liver function did not correlate with the length of hospital stay (Table 5).

| D ISCUSS I ON
COVID-19 has become a pandemic, affecting more than 1.3 million patients worldwide. Moreover, the prognosis of elderly patients and patients with chronic underlying diseases is poor. 12 Recent studies have documented that SARS-CoV-2 can be detected in fecal samples, and some patients with COVID-19 are positive for the anal swab test. 10,13 The overall occurrence of diarrhea in COVID-19 was 5.8% (145/2506). 5 These findings indicate that SARS-CoV-2 may affect the digestive system.
Abnormal results of liver tests have been reported in COVID- 19 patients, but the studied indicators were mostly limited to ALT and AST levels.   Given the above findings, we tend to hypothesize that the increase in AST may be the consequence of the COVID-19 disease itself rather than other concomitant liver diseases. Additionally, the positive rates of HBsAb and HBcAb among the suspected and confirmed COVID-19 patients have been analyzed, but no significant difference was found between these two groups. This result suggests that the injection of the hepatitis B vaccine or having been previously infected with the hepatitis B virus has no effect on the COVID-19 infection. Although some studies have suggested that HBV infection is a risk factor for severe COVID-19, 9 such a possibility needs to be confirmed in further studies involving larger numbers of patients.
Certain limitations of the current study should be acknowledged.
First, the number of included patients is relatively small due to a limited number of cases in our city. Moreover, also a small number of suspected COVID-19 patients were included in the analysis because TA B L E 4 Changes in liver blood tests within 5-10 days after treatment Second, among the cases included in this study, only 2 were severe, and there was no incidence of death. Therefore, the evaluation of the correlation between blood liver test and the severity of the disease and mortality was not possible. Third, the abnormal indices obtained in the blood liver test performed on admission could be caused by medications taken by the patient before the admission.
In conclusion, the performed analysis suggests that abnormal results of the liver blood test are common in COVID-19 patients. The serum level of AST measured on admission may be helpful to identify patients with COVID-19 and predict the length of their hospital stay.

ACK N OWLED G M ENTS
None.

CO N FLI C T O F I NTE R E S T
The authors declare no competing interests.

AUTH O R CO NTR I B UTI O N
Honggang Wang and Xiaozhong Yang designed the study. Xuexiang

E TH I C A L A PPROVA L A N D CO N S E NT TO PA RTI CI PATE
The study was approved by the ethical review committee of