Impact of COVID-19 pandemic on liver, liver diseases, and liver transplantation programs in intensive care units

Table 4 Reported effects of selected coronavirus disease 2019 therapies on liver

Medication (class)	Pattern of liver injury	Evidence
Corticosteroids (Anti-inflammatory agent)	Acute liver injury[77]	Multicenter cohort study (n = 774); COVID-19 with ARDS: Incidence of ALI versus control (18.3% vs 9.9%; P = 0.001)[77]
		Meta-analysis; critically ill COVID-19 patients: No association with serious adverse effects[78]
		RECOVERY trial: No reported serious ADRs or DILI[79]
Favipiravir (RdRp inhibitor)	Abnormal LFTs[80]	RCT (n = 150); mild-to-moderate COVID-19: Abnormal LFTs versus control 6.8% vs 2.7%)[80]
	Elevation of transaminases levels[81]	RCT; moderate COVID-19: Elevated ALT and AST were reported[81]
Hydroxychloroquine (Antimalarial agent)	Liver toxicity is not common[82]. Elevation of transaminases levels[74,75,82-84]	Retrospective study (n = 153): Elevation in AST (11%) and ALT (9%)[82]
		RCT (n = 504); mild-to-moderate COVID-19: Elevation in ALT or AST elevation 10.6% in HCQ plus azithromycin, 9% in HCQ, and 3.5% in control arm (P = 0.008)[83]
		Systematic review: Elevations of LFTs was transient[84]
		Recovery trial: No reported DILI[85]
Interferon	-	Data on safety in COVID-19 patients is scarce
Lopinavir/ritonavir (Protease inhibitor)	Rise in liver function parameters[5,27,34,74,86]	RCT (n = 199): Elevated AST versus control (2.1% vs 5.1%), elevated ALT (1.1% vs 1 %), elevated TB (3.2% vs 3 %)[86]
	Hyperbilirubinemia[5,34]	Meta-analysis: DILI in 37.2% of patients (as hyperbilirubinemia followed by elevation of transaminases)[5]
Remdesivir (RdRp inhibitor)	Not well established. Elevation of transaminases levels[5,75,87-89]. Elevation of TB levels[88]. Hypoalbuminemia[88]	Case series: Elevated aminotransferases in 23 % discontinuation in 4% of patients[87]
		RCT (n = 237) in severe COVID-19: Elevated TB versus placebo (10% vs 9%) and AST (5% vs 12%), hypoalbuminemia (13% vs 15%). Discontinuation in 1% of patients[88]
		Open-label, phase 3 trial: Elevated ALT (5%-6%) and AST (7%-8%)[89]
		Meta-analysis: Pooled incidence of DILI of 15.2%[5]
		Meta-analysis: No difference as compared to placebo in liver enzymes elevation[90]
Tocilizumab (Humanized recombinant monoclonal antibody)	Elevation of transaminases levels[27,75,91-94]. Liver injury as early as 24 h with a 40-fold increase in transaminases that normalized in 10 d[91]	Case series; 7 severe COVID-19 patients: Up to 4.5 folds elevated baseline ALT and AST. Transaminases normalized in 3 wk[92]
		Retrospective study (n = 1827): AST > 5 × ULN in 69.1%, and ALT > 5 × ULN in 72.1% of patients[75]
		Observational study (n = 104): Minor increase of AST, ALT (P < 0.001) and GGT (P = 0.003; no safety concerns on follow up[93]
		RCT (n = 243): ALT elevation versus placebo (5% vs 4.9%), AST elevation in 3.7%[94]
		RCT (n = 130); moderate or severe COVID-19: No increase in hepatitis risk[95]

COVID-19: Coronavirus disease 2019; ADRs: Adverse drug reactions; ALI: Acute liver injury; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase, ALI: Acute liver injury; ARDS: Acute respiratory distress syndrome; AST: Aspartate aminotransferase; DILI: Drug-induced liver injury; GGT: Gamma-glutamyl transpeptidase; HCQ: Hydroxychloroquine; LFTs: Liver functions tests; RCT: Randomized controlled trial; RdRp: RNA-dependent RNA polymerase; TB: Total bilirubin; ULN: Upper limit of normal.