Liver injury in COVID-19 – The culprit may not be COVID-19!

We read the study by Ding et al with great interest. We congratulate the authors on conducting this large, multicentric study. They have demonstrated that raised levels of aspartate aminotransaminase and direct bilirubin at admission can be used as independent predictors of mortality in patients with coronavirus disease 2019 (COVID-19). They developed a prognostic model with a nomogram that can be used to predict the overall survival probability in patients with COVID-19. Importantly, they have reported that chronic HBV infection is not associated with an increased risk of lethal outcomes in patients with COVID-19. Previous studies have revealed that liver abnormalities occur more frequently in patients with severe COVID-19 and this has been consequential in establishing the association between various liver function abnormalities and their effect on mortality in COVID-19. This is due to the multiplier effect of multiple organ dysfunction, cytokine storm, drug effects and hypoxic liver injury, rather than the direct cytopathic effect of the SARS-CoV-2. Kulkarni et al. performed a meta-analysis of 20,874 patients and reported that 3.6% of patients had chronic liver disease (CLD). The odds of developing severe COVID-19 in patients with CLD was 0.81 (95% CI 0.31–2.09; p = 0.67) compared to non-CLD patients. COVID-19 patients with elevated liver chemistries had higher risk of mortality (odds ratio [OR] 3.46 [2.42–4.95, p <0.001]) and severe disease (OR 2.87 [95% CI 2.29–3.6, p <0.001]) compared to patients without elevated liver chemistries. In this study, around 61.8% patients had some abnormal liver chemistry during the course of hospitalization. However, there are some important issues that have not been addressed in the paper.

The study fails to identify underlying CLD as a predictor of worse outcome, possibly due to the small number of patients in the study. Also, the severity of liver disease in terms of various scoring systems has not been corelated with the outcomes. Only 11 individuals had compensated cirrhosis and 3 had decompensated cirrhosis. Standard severity scoring systems like Child-Pugh and model for end-stage liver disease for cirrhosis and Maddrey’s discriminant function for alcoholic hepatitis have not been described and correlated with survival.^,

Although most patients developed some transaminitis during admission, there were several confounding factors that blur the direct association of liver dysfunction attributable to COVID-19. Cai et al. reported use of drugs, systemic inflammation, secondary sepsis, polypharmacy, shock and hypoxia as contributors to liver injury in COVID-19. The presence of hypoxic injury is also a contributor to liver injury and has not been described in this study. It is evident from the description that the hospitalized patients in this cohort were sick, with most requiring high flow oxygen or invasive ventilation which could have contributed independently to liver injury. Also, the use of various medications during the hospital course should be included in the analysis. The use of hepatotoxic drugs like lopinavir and ritonavir have been shown to be associated with liver injury. Alcohol abuse or use of Chinese herbal medication before admission should also be determined and adjusted for in multivariate analysis as that can be a potential contributor to liver injury. The large number of drugs used in clinical trials and variable management of such patients based on evolving evidence also makes comparisons of cohorts difficult.

In conclusion, we believe that Ding et al. have meticulously analyzed various liver biochemistry abnormalities during COVID-19. However, the retrospective nature of the cohort, limitations of data, lack of external validation and other confounding factors described merit further investigation and research. It would be premature to attribute deranged liver function to COVID-19 infection alone with the available evidence.