COVID-19-related liver injury: Focus on genetic and drug-induced perspectives

Table 2 Hepatoxicity and likelihood score of therapeutic agents of coronavirus disease 2019

Drug	Hepatotoxicity	Likelihood score
Remdesivir	A duration of 7-14 d of administration caused elevation of serum aminotransferases up to > 5 times of ULN. Elevation of > 5 times ULN were reported in 9% of patients but returned to normal after discontinuation. Prolonged and more severe effects were seen in critically ill patients with multiorgan involvement, pre-existing comorbidities and who had received combination therapy with other hepatotoxic agents like amiodarone	D
Lopinavir/ritonavir	A greater degree of rise in serum aminotransferase levels (> 5 times ULN) is mostly seen in association with immunodeficiency states. The pattern varies from hepatocellular to cholestatic or mixed type. Discontinuation leads to the normalization of enzyme levels. However, severe cases of acute liver failure or end stage liver disease are also reported with re-exposure of the drug	D
Tocilizumab	Reported to cause mild elevation of aminotransferases commonly, that is usually transient and asymptomatic, but rare instances of liver injury manifesting as jaundice and reactivation of hepatitis B are seen. ALT elevation (1-3 times ULN) was seen in 10%-50% of patients, which returned to baseline within 8 wk after stopping treatment. No effect on bilirubin or ALP levels were seen	C
Hydroxychloroquine	Clinically apparent liver injury is rare. In clinical trials for COVID-19 prevention and treatment, there were no reports of hepatotoxicity, and serum enzyme elevation was also low	C
Corticosteroids	Long-term use and high doses can result in hepatomegaly and steatosis. Can also trigger or exacerbate pre-existing or co-existing conditions like NASH, viral hepatitis or autoimmune hepatitis. Serum aminotransferase levels can rise up to 10-40 times ULN	A
Enoxaparin	4%-13% of patients showed mild elevation in serum aminotransferase levels. Rapid onset of liver injury symptoms after starting the drug (within 3-5 d) but rapid recovery (1-4 wk) after discontinuation of therapy is seen	E
Favipiravir	Pretreatment with other hepatotoxic drugs like lopinavir/ritonavir and IF-β 1B lead to an increase in liver transaminase and bilirubin levels by manifold suggesting cholestatic injury. Isolated use is not known to cause any severe liver injury	D

A: Well known hepatotoxicity; B: Highly likely hepatotoxicity; C: Probable hepatotoxicity; D: Possible hepatotoxicity; E: Unlikely hepatotoxicity. COVID-19: Coronavirus disease 2019; ULN: Upper limit of normal; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; NASH: Nonalcoholic steatohepatitis.