Study design
We conducted a single-center, prospective study at the hospital, field hospital, and cohort ward of a tertiary care facility. From September 2021 through October 2022, data were collected.
Study population and data collection
We enrolled a total of 300 patients, age >18 years, who were admitted to the hospitel, field hospital, and cohort ward after RT-PCR testing confirmed the diagnosis of COVID-19 infection. For the hospitel and field hospital, symptomatic COVID-19 without pneumonia, and an absence of risk factors for severe disease were the inclusion criteria. Any of the following cohort wards qualified for symptomatic COVID-19 treatment: having severe illness risk factors or with mild pneumonia. Preexisting liver disease was defined as any previous documentation of chronic viral hepatitis or cirrhosis. Exclusion conditions were COVID-19 patients with pneumonia and hypoxia requiring an oxygen supplement, patients with moderate to severe pneumonia (infiltration > 20% of total lung), and pregnant or breast-feeding women.
On the first day of admission, blood tests (including liver function tests and hepatitis B and C) and chest X-rays were performed on patients whose COVID-19 severity was mild to moderate. Patients underwent a series of liver function tests on days 1, 5, and 10 of their stay. A chest X-ray was repeated on day 5 or if the patient’s condition worsened, whichever came first. The patients’ baseline demographic information, including sex, underlying condition, herbal usage prior to admission, and heavy alcohol intake, were recorded. In addition, pharmaceutical information for managing COVID-19 infection during hospitalization was recorded, along with the length of stay. After the year 2022, patients meeting the increasing severity step of admission criteria were reassigned to the cohort ward for pneumonia and the ICU for severe pneumonia. Patients who are asymptomatic or symptomatic without pneumonia or who have no risk factors for severe disease will therefore be treated at home (home isolation).
Definition of liver injury (LI)
Numerous studies have defined and categorized various definitions of LI, either by pattern (hepatocellular vs. cholestasis)8, using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria9, or by defining severe LI as an increase in both transaminase and bilirubin levels10. Prior research classified LI severity levels as mild (alanine aminotransferase (ALT) 2 times ULN), moderate (2–5 times ULN), or severe (> 5 times ULN)11.
Currently, there is no consensus or guideline on the classification of COVID-19-associated liver damage. We defined it as a rise of liver enzymes over the normal level. The severity was classified as “mild,” “moderate,” or “severe” based on aspartate aminotransferase (AST) and/or ALT levels that were more than the ULN but within 2 times the ULN, 2–5 times the ULN, and > 5 times the ULN, respectively. The diagnosis of LI was made within 10 days of admission.
Classification of COVID-19 severity
The Department of Medical Services in Thailand has established COVID-19 infection guidelines. They have continuously enhanced their therapeutic protocols. The severity of the disease has been classified so that proper treatment and medicines can be administered:
1. Asymptomatic COVID-19, symptomatic COVID-19 without pneumonia and without severe illness risk factors.
2. COVID-19 with symptoms and risk factors for severe disease or mild to moderate pneumonia in the absence of oxygen assistance.
3. COVID-19 infection with pneumonia and hypoxia (≤ 94% oxygen saturation at rest).
Risk factors for severe disease include any of the following:
1. Age ≥ 60 years.
2. Chronic obstructive lung disease, chronic renal disease stages 3–5, coronary artery disease, cerebrovascular disease, active cancer illness, diabetes mellitus, cirrhosis, and Child–Pugh classification B or C.
3. Obesity (BMI greater than 30 kg/m2 or body weight greater than 90 kg).
4. Immunocompromised host (on steroids or undergoing chemotherapy, or HIV infection with a CD4 cell count of ≤ 200 cells per microliter).
Sample size calculations and statistical analysis
According to the study conducted by Z. Fan et al., 37.2% of the 148 hospitalized COVID-19-infected individuals exhibited liver damage12. We calculated the sample size with a 20% error margin and entered it into the following calculation. A minimum sample size of 163 patients would be required to demonstrate the results.
![](data:image/png;base64,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)
n = sample size
Z = standard normal distribution (Z (0.975) = 1.95)
α = type 1 error rate (0.05)
P = sample proportion (0.372)
d = error component of interval estimate
To compare categorical variables, a chi-square test and an independent t-test or Mann–Whitney U test were utilized. The liver damage result is reported as the mean and standard deviation. ANOVA was used to compare the changes in AST and ALT levels between baseline and hospitalization. Using univariate and multivariate analyses, the risk of liver damage in COVID-19 infections was found. P-values below 0.05 were regarded as statistically significant.
Ethics approval and consent to participate
The protocol for this study was authorized by the Institutional Review Board of the Faculty of Medicine at Vajira Hospital (COA 177/2021) and was done in accordance with the Declaration of Helsinki of 1975. Before participating in the trial, all patients voluntarily provided consent based on their understanding of the procedure and informed consent was obtained from all subjects.