As of March 10, 2023, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected nearly 676 million people worldwide, resulting in over 6.88 million deaths[18]. As research into the disease has progressed, it has become clear that in addition to attacking the lungs and causing varying degrees of respiratory symptoms, the virus can also involve multiple extra-pulmonary organs and cause systemic multi-organ damage. This phenomenon is more frequent in severely and critically ill patients and is associated with longer hospital stays and an increased risk of death[2, 19, 20]. Abnormal liver function is one of the most common extrapulmonary complications in patients with COVID-19. Not only are the abnormal levels of serum transaminase more common than other liver function indicators but also more related to the severity and prognosis of the disease[21].
Relevant clinical studies have shown that the occurrence of COVID-2019-associated liver injury may be influenced by a number of factors, and thus we expected to use relevant clinical indicators to predict the occurrence of liver function abnormalities in patients with COVID-2019. In this study, we screened important factors related to the occurrence of the COVID-2019 associated abnormal liver function with LASSO regression analysis. Next, the 14 variables obtained were included in the logistic regression model. Ultimately Gender, Liver disease, fungi, Azvudine, Paxlovid, Epinephrine, CRP max, and oxygenation index day 5 were identified and used to plot the nomogram of the model. The model was evaluated for discrimination and calibration in terms of the probability of abnormal liver function using the C-index and calibration plots, respectively, and the model proved to have good performance. The best-constructed prediction model was then validated in a validation dataset and the resulting AUC values suggest that the model is generalizable and provides benefit to clinical practice.
In this study, male patients (60.45%) had a higher probability of developing liver dysfunction than female patients (48.48%), which has been reported in many previous clinical studies[5, 13, 14, 22]. Pre-existing underlying liver disease (e.g. non-alcoholic fatty liver[23, 24], cirrhosis[25-27], chronic viral hepatitis[14]) is also a risk factor for hepatic insufficiency in patients with COVID-19, which may lead to an increased risk of progression to severe disease in these patients following COVID-19 infection[28], therefore they need to be monitored and evaluated more closely for liver function to avoid exacerbation of pre-existing liver disease. However, it is only clear that co-morbid liver disease increases the susceptibility of patients to SARS-CoV-2 infection and results in a worse clinical outcome, and further research is needed to determine how the underlying liver disease affects the course of COVID-19 and whether neo-coronavirus infection may exacerbate the extent of existing liver tissue damage in patients. The systemic inflammatory response caused by SARS-CoV-2 infection may contribute to liver injury in patients with severe COVID-19. Patients with COVID-19 have elevated infection-related markers such as CRP, PCT, sedimentation (ESR), and inflammatory factors such as TNFα and IL-6[29-31]. Immune-mediated cytokine storms cause the release of large amounts of pro-inflammatory cytokines, which can exacerbate the nonspecific immune inflammatory response in the liver and lead to secondary liver injury[2, 32].
We also observed that COVID-19 patients in the ICU were at risk of co-infection, with gastrointestinal infections being the most frequent (10.49%), a higher proportion than in the general ward[33]. The pathogens of co-infection are diverse, with studies showing that the most common co-bacterial infections are Mycoplasma pneumoniae, Pseudomonas aeruginosa, and Haemophilus influenza, while the most common co-fungal infections are Candida albicans and Aspergillus[34]. The use of more antibiotics or antifungal agents implies a higher risk of liver damage, suggesting the need for a more comprehensive and integrated assessment and a more cautious dosing strategy[35]. Patients with severe COVID-19 usually present clinical manifestations including acute respiratory distress syndrome, respiratory failure, acute heart failure, and septic shock[29]. As the liver has a high demand for oxygen, it is more susceptible to decreased arterial oxygen saturation and inadequate hepatic perfusion resulting in hepatic ischemia-reperfusion injury and hepatocellular hypoxia. At the same time, hypoxia-induced oxidative stress promotes the release of several inflammatory factors, which further exacerbates hepatic cell death[36]. Therefore, the use of vascular drugs and monitoring of oxygenation indicators in such patients are important predictors of the development of liver injury.
Finally, we focused on COVID-19 treatment drug induced liver injury. As Azvudine and Paxlovid are mainly recommended for use in adult patients with mild to moderate SARS-CoV 2 infection in the first 5 days and accompanied by high-risk factors for progression to severe illness[37-41], their usage rates in this study were relatively low [Azvudine (19%), Paxlovid (18%)], but we still observed that the use of the above two drugs increased the incidence of serum transaminase abnormalities. Due to the side effects of liver damage caused by Azvudine and Paxlovid, and limited research on their use in patients with severe COVID-19, it is currently clear that the use of these drugs is not recommended in patients with existing severe liver dysfunction[42].
On December 15, 2022, China's strategy for COVID-19 transferred from zero tolerance to the prevention of severe COVID-19. However, after policy changes, there was still a rapid increase in the number of infections and hospitalizations, which posed challenges to hospitals and medical workers. Referring to a large number of existing Observational study, we have listed many risk factors for liver injury in COVID-19 patients. Based on the patients admitted to the ICU in a major hospital in Tianjin after December 2022, we have constructed a prediction model for liver dysfunction, which may help clinicians to identify those patients with abnormal liver function early and reduce their progression to severe liver through timely interventions injury or even liver failure through timely intervention, with the aim of improving patient prognosis.
This study has some limitations. First, as a retrospective single-center study and with a relatively small number of patients included in the study, some bias is inevitable. The validity of the model may also need to be assessed in a completely new dataset, such as patients from different health systems or countries. Second, to ensure the generalizability of the model, we used elevated serum aminotransferases, which are most commonly manifested in COVID-19 patients with abnormal liver function, as an evaluation indicator. This may result in the omission of some patients whose main manifestations are abnormalities in other indicators (such as ALP, GGT, TBil, ALB, etc.), and this model needs further improvement to increase its practicality. Despite these shortcomings, we have successfully established a highly accurate prediction model for abnormal liver function in patients with COVID-19 in ICU.