Patient inclusion process diagram
A total of 105 patients were included in this study, accounting for 52.8% of the patients diagnosed for COVID-19 at Beijing Ditan Hospital, Capital Medical University from January 12, 2020 to March 17, 2020,as shown in Figure 1.
Ages of patients ranged between 18 and 92 years old, with a median age of 43.4 years for mild ill group and 58.2 years for severe ill group (p < 0.001). Among79 mild ill group cases, the ratio of male: female = 1:1. There were 26 severe ill cases, including 18 (69.2%) males and 8 (31.8%)females. The median number of illness days was 7.0 in severe illgroup, which was significantly longer than the 4.0 days observed in the mild group. The patients were hospitalized for a median of 22 days, and 31.5 days for severe ill group, which was significantly longer than 20 days for mild illgroup (refer to Table 1).
Baseline characteristic analysis of all patients
We analyzed the baseline data of 105patients (Table 1). A total of 89 patients underwent abdominal ultrasound scans for fatty liver, with an overall proportion approximately 41.6%. The rate was 40.0% of mild ill group and 45.8% of severe illgroup, with no statistically significant difference between the two groups (p = 0.62). Among 105 patients, only 1 patient had a long history of ethylalcohol content>40 g/day. All patients denied a history of chronic hepatitis B or chronic hepatitis C. HBsAg, anti-HCV, anti-HIV, and syphilis-specific antibodies detection during hospitalization was performed for 22 patients, but only 1 patient was anti-HCV positive without HCV RNA load.
The results of liver function indexes are shown in Table 1. ALT of all patients was measured of which 17 (16.2%) patients had abnormally elevated levels, with a median of 22.0 U/L for mild ill group and 27.8 U/L for severe ill group, with no statistically significant difference between them. One 45-year-old man had the highest ALT of 357 U/L among all patients. Unfortunately, only 50 patients were analyzed for AST, TBil, CHE, and ALB levels at admission. The results showed that the median of AST was 46.3 U/L for severe ill group which was significantly higher than 22U/L for mild ill group (p < 0.001). For TBil index, the median was 10.0μmol/L formild ill group and 10.6μmol/Lfor severe ill group, with no statistically significant difference between the two groups (p = 0.54).CHE analysis did not show statistically significant difference between the two groups (p = 0.14). The median for ALB index was 42.0 g/L for the mild ill group, which was slightly higher than that observed inthe severe ill group of 37.2 g/L (p = 0.012).
According to abdominal ultrasound diagnosis, 11 of 37 patients (29.7%) with fatty liver and elevated ALT. 6 (21.6%) weremild ill and 5 (13.5%) were severe ill. At least 9 of them were < 2 ×ULN (Upper limit of normal value) and the highest was 129.9 U/L. We did not perform the statistical analysis considering the sample bias.
Stratified Analysis of Baseline Liver Function Indexes
The stratified analysis results of the abnormal elevated liver function indexes are presented in Table 2.A total of 22 (30.0%) patients showed abnormality in ALT or AST or TBil, including 14 (17.7%) patients in mild ill group and 30.8% in severe ill group. There was no statistically significant difference between the two groups (p = 0.156).
For single ALT index, the proportions between the mild and severe ill group were not statistically difference in all stratified comparison(p>0.05).
Interestingly, for the single ASTindex, the two groups showed a significant difference. 7(63.6%) group cases experienced > 1 × ULN and 1 patient reached 87.7 U/L, while only 2 of the mild ill group cases (5.1%) had > 1 × ULN and no cases of ≥ 2 × ULN. A total of 50 patients were tested for TBil and only 2 patients of severe ill group had abnormalities, but all abnormalities were below 2 × ULN.
Stratified and Joint Analysisof Liver Function Indexes during Hospitalization
One critically ill patient died in this study, with a fatality rate < 1.0% in 105 patients. A total of 508 times ALT, 383 times AST, and 383 times TBil were collected, averaging 3.64-4.83 times for one patient during hospitalization.
Liver function indexes of all patients were observed dynamically according to the different combined models of ALT, AST, and TBil, as shown in Table 3.
At the single index analysis, the highest ALT was 357 U/L, AST was 156.3 U/L, and TBil was 102.9 μmol/L. 56.2% of 105 patients had abnormality with single index, and rate was up to 69.2% in severe ill group, significantly higher than that of 51.9% inmild ill group (p < 0.001); ALT and AST abnormalities occurred in 48.0% of severe ill group patients, compared to 13.9% of mild ill group. However, 19 (18.1%) patients showed ALT, AST and TBil levels ≥ 2 × ULN, of which 10 patients were from the severe ill group cases, significantly higher than mild ill group cases. 9 patients showed any index≥ 3 × ULN. The proportion of elevated TBil with elevated AST was higher than with elevated ALT.
In the combined indexes analysis, ALT or AST associated with TBil and 3 indexes elevations together were more common in severe ill group patients (p < 0.001); However, only 8 patients numerically were seen with an increase in the 3 indexes together, 7 of whom were severe ill group cases. Furthermore, ALT, AST, and TBil levels ≥ 2 × ULN were observed in only 1 critically ill patient.
These results suggest that during the course of COVID-19, liver function abnormalities are generally mild, and moderate and severe liver injury is very low.
Patterns analysis of liver function indexes during hospitalization
We divided all patients into 4 kinds of patterns based on the ALT index of baseline and hospitalization: Continuous normal, normal and then abnormal, abnormal and then normal,continuous abnormal. The results are shown in Table 4.
In total, 68 patients (64.7%) had normal ALT during the course of COVID-19, 12 patients (46.2%) were severe ill group cases and 56 patients (70.9%) were mild ill group cases, which was significantly higher than that of the former (p = 0.022).
Twenty (19.0%) patients had normal ALT at admission but had abnormalities during hospitalization of which 9 (34.6%) patients were severe ill group cases and 11 (13.9%) patients were mild ill group cases(p = 0.009). By the time the last test was done before discharge, 10 mild ill group patients still had ALT abnormalities, 3 of which were > 2 × ULN. Most of ALT elevations occurred between day 4 and day 17 of hospitalization, with a mean of 7.3 ± 3.0 days for severe illgroup and 10.7 ± 4.1 days for mild ill group, with significant differences between the two groups (p = 0.048); Excluding 1 patient who delayed detection for personal reasons, ALT assessments were performed every 2.7 ± 0.6 days between admission and the onset of ALT elevations in mild ill group,and 2.6 ± 0.7 days in severe ill group. There was no significant difference between the two groups (p = 0.86), suggesting that the finding of ALT elevations was not related to delayed detection in mild illgroup.
Nine patients (8.6%) had elevated ALT at admission but continued to decline until recovery during the subsequent treatment period; 7 patients (8.9%) were mild ill group cases and 2 patients (8.0%) were severe ill group cases, with no statistically significant difference between the two groups (p > 0.99).
Eightpatients (7.6%) had abnormal ALT at admission, followed by continuous abnormality or fluctuation in normal/abnormal state; 5 patients (6.3%) were mild ill group cases and 3 patients (11.5%) were severe ill group cases. At the last test in these patients, 5 patients still failed to show normalized ALT, suggesting that they should be analyzed for other causes of transaminase elevations.
An observation on the dynamic Change of ALT in a mild ill patient
We also focused on the outcome of one mild ill patient with baseline ALT > 7 × ULN. A 45-year-old male patient, who denied a long history of heavy alcohol use and chronic liver disease, presented with cough, fever, and chills on Jan. 24, 2020 and was admitted to the hospital on Jan. 28, 2020 with a diagnosis of COVID-19. After admission, ALT 357 U/L was found. Abdominal ultrasound showed no fatty liver, and HBsAg and anti-HCV were negative. Antipyretic, nutritional support, recombinant human interferon α-2b, lopinavir ritonavir tablet and reduced glutathione, compound glycyrrhizin were administered. During the treatment, the patient's ALT gradually returned to normal (as shown in Figure 2), and the patient's sputum samples were serially negative for SARS-CoV-2 on Feb.10, 2020 and Feb,12,2020, and he was discharged.