Patient selection process
A total of 105 patients were included in this study, accounting for 52.8% of the patients receiving treatment for COVID-19 at Beijing Ditan Hospital, Capital Medical University from January 12, 2020 to March 17, 2020. Patient selection for inclusion in the analysis is shown in Figure 1.
Clinical characteristics at admission
The results of clinical characteristics at admission are presented in Table 1. The median age was 45.0 years (IQR: 33.5,59.5; range: 18 to 92) in the entire cohort, 41.0 years (IQR: 33.0,56.0) in mild cases (n=79) and 59.0 years (48.5,69.8) in severe cases (n=26) (p < 0.001). The male-female ration was 1:1 in mild cases and 2.2:1 in severe cases (p = 0.07). The time from symptom onset to hospital admission was 4.0 days in the mild cases vs. 7.0 days in severe cases (p = 0.005). The median hospital stay was 22 days in the entire cohort, 20 days in mild cases vs. 31.5 days in severe cases (p = 0.001).
A total of 89 out of 105 patients underwent abdominal ultrasound scans for fatty liver. Fatty liver was detected in 40.0% of the mild cases vs. 45.8% in severe cases (p = 0.64). One patient had extended history of heavy alcohol use (ethanol consumption at >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 were tested in 22 patients; the results showed positive anti-HCV but no HCV RNA in 1 patient. Among the 37 patients with fatty liver, 11 (29.7%) had elevated ALT; 6 (21.6%) were mild cases and 5 (13.5%) were severe cases. In 9 out of the 11 cases, ALT elevation was < 2 ×ULN (upper limit of normal reference range); the highest ALT level was 129.9 U/L. We did not perform statistical analysis due to the small sample size.
The analysis results of liver functions at admission are also presented in Table 1. Seventeen out of 105 patients (16.2%) elevated ALT. The median ALT level was 22.0 U/L in mild cases vs. 27.8 U/L in severe cases (p = 0.09). However, there was no difference in the distribution of ALT at different levels between the two groups (p = 0.48). The highest ALT was 357 U/L, which was appeared on a male mild group patient. AST, TBil, CHE, and ALB levels were available in 50 patients only. The median AST was 22.0 U/L in mild cases vs. 46.3 U/L in severe cases (p < 0.001). The rate of isolated AST elevation was higher at 63.6% in severe cases vs. 5.1% in mild cases (p < 0.001). AST was elevated at ≥2 × ULN in 1 severe cases. The median TBil was 10.0 μmol/L in mild cases vs. 10.6 μmol/L in severe cases (p = 0.53). Among the 50 patients with TBil, only 2 cases had elevated TBil (1 patient in every group, and both below 2 × ULN). CHE analysis did not show statistically significant difference between the two groups (p = 0.14). A total of 22 (30.0%) patients had elevated ALT or AST or TBil, including 14 (17.7%) mild cases and 8(30.8%) severe cases (p = 0.16). The median ALB was 42.0 g/L in mild cases vs. 37.2 g/L in severe cases (p = 0.012).
Analysis of liver function during hospitalization
We compared the differences of the overall distribution and the abnormal rates of liver function indexes at different cut-off values as 1, 2, or 3 × ULN, respectively, between the two groups (see Table 2. and Figure 2).One critically ill patient died within the study period. A total of 508 ALT measurements, 383 AST measurements, and 383 TBil measurements during hospitalization were available for analysis. The highest was 357 U/L for ALT, 156.3 U/L for AST, and 102.9 μmol/L for TBil. It was showed that the overall distribution of ALT, AST, and TBil were all significantly difference between mild and severe group (p<0.05 for all).
In the single index analysis, the percentage of the patients having only 1 abnormal index was 56.2% in the entire cohort, 51.9% in mild cases vs. 69.2% in severe cases (p = 0.17). Nineteen (18.1%) patients had elevated ALT, AST or TBil levels ≥ 2×ULN: 10 in severe cases and 9 in mild cases (p = 0.004).
In the combined analysis, ALT or AST associated with TBil and elevation of all 3 indices were more common in severe cases (p < 0.001 or p = 0.001). The proportion of elevated TBil with elevated AST was 9.3%, and TBil with ALT was 8.6% (p> 0.99). A total of 8 patients had elevation in all 3 indices: 7 in severe cases vs. only 1 in mild cases. One patient (in the severe group) had elevation of all 3 indices ≥ 2 × ULN. The percentage of the patients with both elevated ALT and AST was 12.7% in mild cases vs. 46.2% in severe cases (p = 0.001). Nine patients had ≥ 3 × ULN elevation of ALT, AST or TBil.
Cases were divided into 4 categories based on ALT at admission and during hospitalization: normal during the entire period, normal and then abnormal, abnormal and then normal, and abnormal during the entire period. The results are shown in Table 3. Overall, liver functions returned to normal range in 77 (73.4%) patients before discharge.
A total of 68 patients (64.8%) had normal ALT during the entire period: 12 (46.2%) in severe cases and 56 (70.9%) in mild cases (p = 0.03).
Twenty (19.0%) patients had normal ALT at admission but had elevated ALT during hospitalization: 9 (34.6%) in severe cases and 11 (13.9%) in mild cases (p = 0.007). Upon discharge from the hospital, ALT was still elevated in 10 mild cases (3 at > 2 × ULN) and in 2 severe cases (1 at > 2 × ULN, and 1 was died). Most of ALT elevation occurred between day 4 and day 17 of hospitalization, with a mean of 7.3 ± 3.0 days in severe cases vs. 10.7 ± 4.1 days in mild cases (p = 0.048). Excluding 1 patient with delayed detection for personal reasons, ALT assessment was conducted every 2.7 ± 0.6 days between admission and the onset of ALT elevations in mild cases vs. 2.6 ± 0.7 days in severe cases (p = 0.86).
ALT was elevated at admission but normalized during hospitalization in 9 (8.6%) patients; 7 patients (8.9%) in mild cases and 2 patients (7.7%) in severe cases (p > 0.99). ALT was elevated at admission and remained elevated during hospitalization in 8 (7.6%) patients: 5 (6.3%) in mild cases and 3 (11.5%) in severe cases (p = 0.41). ALT in the last test remained elevated in 5 patients.
Dynamic ALT change in a representative case with mild illness
A 45-year-old man has ALT > 7 × ULN (357 U/L) upon admission. He presented with cough, fever, and chills on January 24, 2020 and was admitted to the hospital on January 28, 2020 with a diagnosis of COVID-19. He denied heavy alcohol use and chronic liver disease. Abdominal ultrasound showed no fatty liver, and HBsAg and anti-HCV were negative. Treatments included antipyretic, nutritional support, recombinant human interferon α-2b, lopinavir ritonavir tablet, reduced glutathione and compound glycyrrhizin. During the treatment, ALT gradually returned to normal (Figure 3). After 2 consecutive negative test for SARS-CoV-2 (on February 10, 2020 and February 12, 2020), he was discharged.