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

Table 1 Drug induced hepatoxicity outcome and other relevant information in the included studies

Sr. No.	Ref.	Type of study	Location	Number of study participants	Medication	Outcome
1	Grein et al[20], 2020	Cross sectional/follow-up study	United States, Canada, Europe, Japan	53	Remdesivir	Elevation of liver enzymes in 12/53 patients
2	Goldman et al[76], 2020	Randomized, open-label, phase 3 trial	United States, Italy, Spain, Germany, Hong Kong, Singapore, South Korea, Taiwan	397	Remdesivir	Elevated ALT in 26; elevated AST in 23; elevated bilirubin in 5
3	Wang et al[1], 2020	Randomized, double-blind, placebo-controlled, multicenter trial	China	158	Remdesivir	Elevated ALT in 2; elevated AST in 7, elevated bilirubin in 16, decreased albumin in 20
4	Antinori et al[77], 2020	Prospective (compassionate), open-label study	Italy	35	Remdesivir	Elevated transaminase in 15; elevated bilirubin in 7
5	Leegwater et al[23], 2021	Case study	Netherlands	1	Remdesivir	Elevated ALT, AST, ALP and GGT
6	Lee et al[24], 2020	Case series	South Korea	10	Remdesivir	Elevated ALT in 5; elevated AST in 5
7	Zampino et al[25], 2020	Case series	Italy	5	Remdesivir	Elevated ALT in 4; elevated AST in 4
8	Carothers et al[26], 2020	Case series	United States	2	Remdesivir	Elevated ALT, AST, bilirubin, INR, ammonia in both patients; elevated ALP in 1
9	Sun et al[27], 2020	Active monitoring study by hospital pharmacovigilance system	China	217	LPV/ritonavir, umifenovir	Elevated ALT in 30
10	Fan et al[28], 2020	Retrospective, single-center study	China	148	LPV/ritonavir	Elevated ALT in 27; elevated AST in 32; elevated GGT in 26; elevated ALP in 6; elevated bilirubin in 18
11	Cai et al[9], 2020	Cross-sectional study	China	417	LPV/ ritonavir, oseltamivir, interferon, NSAIDs, ribavirin	Elevated ALT in 167; elevated AST in 137; elevated GGT in 143; elevated ALP in 71; elevated bilirubin in 196
12	Jiang et al[29], 2020	Multicenter, retrospective, observational study	China	131	LPV/ritonavir	Elevated ALT in 45; elevated AST in 4; elevated bilirubin in 43
13	Serviddio et al[30], 2020	Case series	Italy	7	LPV/ritonavir, HCQ, azithromycin	Elevated ALT, AST, GGT in all patients
14	Guaraldi et al[32], 2020	Retrospective cohort study	Italy	179	Tocilizumab	No elevation of ALT or bilirubin was noted
15	Muhović et al[33], 2020	Case report	Montenegro	1	Tocilizumab	Elevated ALT and AST
16	Hundt et al[34], 2020	Retrospective observational cohort study	United States	1827	LPV/ritonavir, HCQ, remdesivir, tocilizumab	Elevated ALT in 1080 out of 1753; elevated AST in 1465 out of 1756; elevated ALP in 399 out of 1754; elevated total bilirubin in 284 out of 1747
17	Kelly et al[35], 2021	Retrospective analysis of hospitalized patients	Ireland	82	HCQ, azithromycin	Elevation of LFTs of more than ULN after 5 d therapy in 51/85 patients
18	Falcão et al[36], 2020	Case report	Brazil	1	HCQ	Elevated ALT and AST with normal bilirubin and GGT
19	Yamazaki et al[38], 2021	Case report	Japan	1	Favipiravir	Elevated ALT, AST, ALP, total bilirubin and LDH
20	Aiswarya et al[49], 2021	Observational prospective study	India	48	Remdesivir	No significant change in serum transaminases and LDH
22	Kaur et al[78], 2022	Case study	India	1	Remdesivir	Elevated ALT, AST and total bilirubin
23	Gao et al[79], 2022	Retrospective study	China	4010	Oseltamivir, arbidol, interferon, ribavirin, LPV/ritonavir, HCQ/CQ, antibiotics, antifungals, corticosteroids	395 out of 4010 developed DILI. 293 out of 395 received antibiotics, 25 out of 395 received antifungal, 42 out of 395 received oseltamivir, 52 out of 395 received ribavirin, 51 out of 395 received LPV/ritonavir, 47 out of 395 received interferon, 200 out of 395 received corticosteroid, 226 out of 395 received arbidol, 18 out of 395 received HCQ/CQ
24	Naseralallah et al[80], 2022	Retrospective study	Qatar	72	Azithromycin, HCQ, LPV	Elevated ALT and AST was implicated in 24 patients due to azithromycin, in 11 patients due to HCQ and in 11 patients due to LPV
25	Chew et al[21], 2021	Retrospective study	United States	834	Tocilizumab, remdesivir	105 out of 834 (12.6%) had elevated AST
26	Delgado et al[22], 2021	Retrospective observational study	Spain	8719	Remdesivir, hydroxychloroquine, azithromycin, tocilizumab and ceftriaxone	4.9% of 8719 patients developed DILI. Out of which remdesivir had the highest incidence of DILI per 10000 defined daily doses
27	Durante-Mangoni et al[81], 2020	Case report	Italy	4	Remdesivir	3 out of 4 patients had elevated AST and ALT
28	Wong et al[82], 2022	Self-controlled case series study	China	860	Remdesivir	334 (38.8%) out of 860 had acute liver injury
29	Montastruc et al[83], 2020	Multicenter study	France	387	Remdesivir	130 (34%) out of 387 developed liver injury

ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; AST: Aspartate aminotransferase; DILI: Drug induced liver injury; HCQ: Hydroxychloroquine; LPV: Lopinavir; LDH: Lactate dehydrogenase; GGT: Gamma-glutamyl transferase; ULN: Upper limit of normal; INR: International normalized ratio; LFT: Liver function test; NSAID: Nonsteroidal anti-inflammatory drug.

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.

Table 3 Mechanism of hepatic damage in severe acute respiratory syndrome coronavirus 2 infection

Proposed main mechanism	Explanation
Direct cytotoxicity	Active SARS-CoV-2 replication in hepatic cells, which further binds to hepatic and biliary epithelial cells by angiotensin-converting enzyme 2 and damage them by direct infection[57]
Immunological damage	Severe inflammatory response generated by SARS-CoV-2 further damages hepatic cells by immune mediated pathogenesis[58]
Drug-induced	Antiviral drugs such as remdesivir, chloroquine and ritonavir are possibly hepatotoxic[59]
Reactivation of pre-existing liver illness	Increased risk to develop hepatotoxicity in the presence of pre-existing liver diseases. In addition, baricitinib also causes reactivation of hepatitis B virus infection[60]
Anoxia	Anoxia or hypoxia leads to respiratory failure in SARS-CoV-2, which further leads to hypoxic hepatitis[61]

SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.