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

Table 1 Reported definitions for liver injury in coronavirus disease 2019

Term	Definition(s)
Liver disorder	Serum ALT or AST > 2 × ULN, TB > 2 × ULN, ALP ≥ 2 ULN[75]
Liver injury or acute liver injury	ALT and/or AST above 3 × ULN, ALP, GGT, and/or TB above 2 × ULN[9,34]
	ALT and/or AST ≥ 2 × ULN, with TB ≥ 2 × ULN and/or INR ≥ 1.7[70]
	ALT levels above 3 × the ULN[28]
Mild liver injury	ALT above the ULN and below 2 × the ULN[25]
Moderate liver injury	ALT between 2-5 × the ULN[25]
Severe liver injury	ALT above 5 × the ULN[25]
	Any elevation of enzymes above 3 × the ULN and bilirubin above 2 × the ULN[5]
Liver test abnormalities	Elevation of the following serum liver enzymes: ALT > 40 U/L, AST > 40 U/L, GGT > 49 U/L, ALP > 135 U/L, and TB > 17.1 μmol/L[34]
De novo LFTs abnormality	The occurrence of abnormal LFTs in patients with normal LFTs at admission[27]
LFTs elevation	Increase in serum liver enzyme levels above the ULN[27,28]
Mild LFTs elevations	Elevation 1-2 times above the ULN[25,34]
Hepatocellular or hepatocyte type	The pattern of abnormal LFTs with predominantly elevated ALT and AST[27]
	Patients with raised ALT and/or AST more than 3 × the ULN[34]
	AST/ALT activity is higher than the ALP/GGT activity, with liver enzyme activities calculated by multiples of their ULN[34]
Cholestatic or cholangiocyte type	Pattern of abnormal LFTs with predominantly elevated ALP and GGT[27]
	Patients with raised ALP or GGT 2 × the ULN[34]
	ALP/GGT activity was higher than the AST/ALT activity, with the liver enzyme activities calculated by multiples of their ULN[34]
Mixed type	Mixed pattern when the extents of AST/ALT and ALP/GGT are similar[27]
	A combination of both ALT/AST elevated more than 3 × the ULN and ALP/GGT twice the ULN[34]
Drug-induced liver injury	Any elevation in liver enzymes or TB after the initiation of the drug in the absence of identified common causes of liver disease[5]

ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transpeptidase; INR: International normalized ratio; LFTs: Liver function tests; TB: Total bilirubin; ULN: Upper limit of normal.

Table 2 Reported data on survivors versus non-survivors in coronavirus disease 2019

Ref.	N (all) n (non-survivors)	Age (year)	Male	Pre-existing CLD	Type of liver disease	Elevated LFTs on admission (%)	LFTs levels on admission. ALT/AST/ALP/GGT (U/L)/TB (μmoL)	Selected complications or clinical outcomes
Cao et al[51]. China	N = 102 (n = 17)	53 vs 72	47.1% vs 76.5%	2.4% vs 5.9%	-	ALT: NR vs 41.1%	ALT: NR vs 40	ALI: 24.7% vs 76.5%; ARDS: 5.9% vs 88.2%; Shock: 3.5% vs 41.1%; MV: 2.4% vs 70.6%
Chen et al[52]. China	N = 274 (n = 113)	51 vs 68	55% vs 73%	-	HBV surface antigen positivity	ALT: 19% vs 27%; AST: 16% vs 52%	ALT: 20 vs 28; AST: 25 vs 45; ALP: 64 vs 76; GGT: 28 vs 42; TB: 8.4 vs 12.6	ALI: 2% vs 9%; ARDS: 52% vs 100%; Shock: 0% vs 41%; MV: 82% vs 16%
Chen et al[53]. China	N = 55 (n = 19)1	72 vs 77	50% vs 84.2%	2.8% vs 5.3%	-	ALT: 19.4% vs 31.6%; AST: 50% vs 73.7%	ALT: 40 vs 44;AST: 55 vs 78	MV: 30.6% vs 68.4%
Du et al[54]. China	N = 852	65.8	72.9%	5.9%	-	ALT: 16.5%; AST: 32.9%; TB: 35.3%	ALT: 72.9; AST: 94.4; TB: 18.4	ALI: 35.3%; ARDS: 74.1%; Shock: 81.2%; MV: 93%3
Wu et al[42]. China	N = 84 (n = 44)4	50 vs 68.5	77.5% vs 65.9%	3.5%5	-	-	ALT: 35 vs 39; AST: 38.5 vs 37; TB: 11.6 vs 14.5	MV: 57.5% vs 97.8%3; Others reported as association
Yang et al[55]. China	N = 922	69.8	53.3%	3.3%	-	-	ALT: 27; AST: 31; TB: 13.6	ALI: 16.5%; ARDS: 80.2%; MODS: 15.4%
Yang et al[39]. China	N = 52 (n = 32)	51.9 vs 64.6	70% vs 66%	-	-	-	TB: 13.1 vs 19.5	ALI: 30% vs 28%; ARDS: 45% vs 81%; MV: 35% vs 94%
Zhang et al[44]. China	N = 822	72.5	65.9%	2.4%	-	ALT: 30.6%; AST: 61.1%; TB: 30.6%	ALT: 26; AST: 72; TB: 13.6	Hepatic damage: 78%; Liver-associated death: 1.2%; MV: 40.2%
Zhou et al[43]. China	N = 191 (n = 54)	52 vs 69	59% vs 70%	-	-	ALT: 24% vs 48%	ALT: 27 vs 40	ARDS: 7% vs 93%; Shock: 0% vs 70%; MV: 2% vs 100%3

¹Patients ≥ 65 years subgroup (55 of 203 patients).

²Reported fatal cases only.

³Invasive and non-invasive mechanical ventilation.

⁴Subgroup of patients who developed acute respiratory distress syndrome (ARDS) after admission and those who progressed from ARDS to death (total patients = 201).

⁵Reported for all patients.

ALT: Alanine aminotransferase; ALI: Acute liver injury; ALP: Alkaline phosphatase; ARDS: Acute respiratory distress syndrome; AST: Aspartate aminotransferase; CLD: Chronic liver disease; GGT: Gamma-glutamyl transpeptidase; HBV: Hepatitis B virus; LFTs: Liver function tests; MODS: Multiple organ dysfunction syndrome; MV: Mechanical ventilation; N and n: Number of patients; NR: Not reported; TB: Total bilirubin.

Table 3 Reported data on critically ill, intensive care units, or severe coronavirus disease 2019 patients

Ref.	N (all), n (severe disease). Patient population	Age (year)	Male	Pre-existing CLD	Type of pre-existing CLD	Elevated LFTs on admission (%)	LFTs levels on admission. ALT/AST/ALP/GGT (U/L)/TB (μmoL)	Selected complications or clinical outcomes
Arentz et al[56]. United States	N = 21. Critically ill	70	52%	4.8%	Cirrhosis	-	ALT: 108; AST: 273; ALP: 80; TB: 0.6 mg/dL	ALI: 14.3%; Severe ARDS: 57.1%; MV:71%; Death: 52.4%
Cai et al[34]. China	N = 318 (n = 85)1. Non-severe vs severe	47. All patients	47.5%. All patients	5%. All patients	ALD, NAFLD, HVB	ALT: 6.4% vs 21.1%; AST: 0.68% vs 18.8%; GGT: 5.1% vs 29.4%; TB: 1.2% vs 7%	-	MOF: 0% vs 11.7%
Cai et al[9]. China	N = 298 (n = 58). Non-severe vs severe	41 vs 62.5	44.1% vs 67.2%	8.3% vs 13.7%	NAFLD: 3.3% vs 10.3%; ALD: 3.3% vs 1.7%; HBV: 1.7% vs 1.7%	-	ALT: 20 vs 26.8; AST: 26 vs 36; ALP: 61 vs 58; GGT: 21 vs 35.2; TB: 10.9 vs 11.2	ALI: 9.6% vs 36.2%; Discharge: 93.3% vs 75.9%; Hospital-stay: 19 d vs 27 d; Death: 0% vs 5.2%
Du et al[57]. China	N = 109. Non-ICU vs ICU	72.7 vs 68.4	65.5% vs 70.6%	3.4% vs 0%	-	ALT: 13.8% vs 19.6%; AST: 49% vs 43.1%	ALT: 21.6 vs 27; AST: 32 vs 40	Invasive MV: 0% vs 64.7%; Hospital-stay: 12.5 d vs 15.9 d
Guan et al[40]. China	N = 1099 (n = 173). Non-severe vs severe	45 vs 52	58.2% vs 57.8%	2.4% vs 0.6%	HBV	ALT: 19.8% vs 28.1%; AST: 18.2% vs 39.4%; TB: 9.9% vs 13.3%	-	ARDS: 1.1% vs 15.6%; MV: 0% vs 38.7%; Discharge: 5.4% vs 2.9%; Hospital-stay: 11 d vs 13 d; Death: 0.1% vs 8.1%
Huang et al[2]. China	N = 41 (n = 13). Non-ICU vs ICU	49 vs 49	68% vs 85%	4% vs 0%	-	AST: 25% vs 62%	ALT: 27 vs 49; AST: 34 vs 44; TB: 10.8 vs 14	ARDS: 4% vs 85%; Shock: 0% vs 23%; Invasive MV: 0% vs 15%; Discharge: 75% vs 54%; Death: 4% vs 38%
Lei et al[28]. China	N = 5771 (n = 1186). Non-severe vs severe	55 vs 59	45.1% vs 55.3%	1.2% vs 2.1%	Viral hepatitis Cirrhosis	-	ALT: 23 vs 26; AST: 22 vs 31; ALP: 65 vs 63; TB: 10.3 vs 10.6	Reported as association not absolute values
Li et al[58]. China	N = 548 (n = 269). Non-severe vs severe	56 vs 65	45.2% vs 56.9%	1.1% vs 0.7%	HBV	ALT: 22.3% vs 24.1%; AST: 23.3% vs 43.4%; TB: 2.3% vs 6.4%	-	ALI: 15.8% vs 23%; ARDS: 9.7% vs 68%; MV: 4% vs 34.2%2; Discharge: 72.9% vs 31.7%; Death: 1.1% vs 32.5%
Mo et al[59]. China	N = 155 (n = 85)3. General vs refractory	47 vs 61	44.3% vs 64.7%	2.9% vs 5.9%	-	-	ALT: 20 vs 28; AST: 32 vs 37	Critical case: 4.3% vs 40%; MV: 0% vs 41.2%; Others reported as association
Wan et al[60]. China	N = 135 (n =40). Mild vs severe	44 vs 56	54.7% vs 52.5%	1% vs 2.5%	-	AST: 16% vs 37.5%	ALT: 21.7 vs 26.6; AST: 22.4 vs 33.6; TB: 8.6 vs 9.8	ARDS: 1.1% vs 50%; Shock: 0% vs 2.5%; Discharge: 10.5% vs 12.5%; Death: 0% vs 2.5%
Wang et al[1]. China	N = 138 (n = 36). Non-ICU vs ICU	51 vs 66	52% vs 61.1%	3.9% vs 0%	-	-	ALT: 23 vs 35; AST: 29 vs 52; TB: 9.3 vs 11.5	ARDS: 4.9% vs 61.1%; Shock: 1% vs 30.6%; Invasive MV: 0% vs 47.2%
Wu et al[42]. China	N = 201 (n = 84)4. Non-ARDS vs ARDS	48 vs 58.5	58.1% vs 71.4%	3.5%5	-	-	ALT: 27 vs 35; AST: 30 vs 38; TB: 10.5 vs 12.9	MV: 0% vs 78.6%2; Others reported as association
Zhang et al[61]. China	N = 221 (n = 55). Non-severe vs severe	51 vs 62	44% vs 63.6%	1.8% vs 7.3%	-	-	ALT: 22 vs 32; AST: 27 vs 51; TB: 9.6 vs 11.4	ARDS: 0% vs 87.3%; Shock: 0% vs 27.3%; MV: 1.2% vs 74.6%2; Discharge: 21.1% vs 12.7%; Death: 0% vs 21.8%
Zhang et al[62]. China	N = 140 (n = 58). Non-severe vs severe	51.1 vs 64	46.3% vs 56.9%	5% vs 6.9%	Fatty liver and abnormal liver function	-	-	-
Zheng et al[63]. China	N = 161 (n = 30). Non-severe vs severe	40 vs 57	50.4% vs 46.7%	3.1% vs 0%	-	ALT: 6.1% vs 16.7%; AST: 7.6% vs 40%; TB: 4.6% vs 10%	ALT: 19.3 vs 23.9; AST: 23.4 vs 31.6; TB: 10.7 vs 12.7	-

¹Total number of patients is 417 and 318 is the number for patients with liver injury (for which the comparison between severe and non-severe disease was done).

²Invasive and non-invasive mechanical ventilation.

³Reported patients with refractory and critical illness and ≥ 10 d of treatment in hospital.

⁴Subgroup of patients who developed acute respiratory distress syndrome (ARDS) after admission and those who progressed from ARDS to death.

⁵Reported for all patients.

ICU: Intensive care units; ALD: Alcoholic liver disease; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; ALI: Acute liver injury; ARDS: Acute respiratory distress syndrome; AST: Aspartate aminotransferase; CLD: Chronic liver disease; GGT: Gamma-glutamyl transpeptidase; HBV: Hepatitis B virus; LFTs: Liver function tests; MOF: Multiorgan failure; MV: Mechanical ventilation; N and n: Number of patients; NAFLD: Non-alcoholic fatty liver disease; TB: Total bilirubin.

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.