REPLY.

We appreciate Philips and colleagues’ interest in our report on the associations between liver injury markers and coronavirus disease 2019 (COVID‐19) mortality.( ) They raised the question regarding the application of liver injury markers. However, several of their interpretations of our results are misleading or incorrect.

We understand that the use of aspartate aminotransferase (AST) in isolation cannot comprehensively characterize liver injury. To fully explore the associations of liver injury with COVID‐19, we investigated the dynamic patterns of four respective and extensively applied markers of liver injury: alanine aminotransferase (ALT), AST, alkaline phosphatase, and total bilirubin. Their associations with COVID‐19 mortality were clearly demonstrated. Importantly, we found that the increased levels of all four indicators are consistently associated with higher risk of COVID‐19 death, with AST having the largest hazard ratio. Therefore, in our study, liver injury was characterized by four markers, rather than only AST as mentioned by Philips et al.

Until recently, the definition of acute liver injury (ALI) has been inconsistent in the literature.( ) In our study, ALI was defined by ALT, which has been extensively applied in more than 1,000 studies. However, the international normalized ratio (INR), proposed by Philips et al., is a marker of coagulopathy, which can occur in many pathological conditions.( , ) Although prolonged prothrombin time/INR can occur in chronic liver disease, this condition is more likely to happen at the advanced stage of liver injury because of diminished clotting factor production.( ) Remarkably, COVID‐19 per se is often associated with a major blood hypercoagulability.( ) Thus, INR, as a measure of unspecific and synthetic coagulation, was not appropriate for specifically predicting liver injury in the setting of COVID‐19 and would lead to confounding conclusions.

Based on our rational study design and rigorous statistical analyses, we insist that liver injury exists in the setting of COVID‐19. These findings are further clinically meaningful that indicators of liver injury need to be timely monitored because of their strong association with COVID‐19 mortality.