SARS-CoV-2 induced liver injury: Incidence, risk factors, impact on COVID-19 severity and prognosis in different population groups

Table 1 Liver function tests and factors associated significantly with clinical outcomes in COVID-19

Author/yr	Type of study (n of patients)	Factor	Outcome - statistical significance (severity/mechanical ventilation/ICU/mortality)
Krishnan et al[321], 2022, United States	Retrospective (n = 3830)	TBIL1
		2–5 × ULN	Mortality risk significantly increased 6-fold (P < 0.001)
		> 5 × ULN	Mortality risk increased 7.86-fold (P = 0.005)
		AST1
		2–5 × ULN	All-cause mortality HR, 1.49; P < 0.001
		> 5 × ULN	All-cause mortality HR, 2.19; P = 0.005
		ALP1
		1–2 × ULN	All-cause mortality risk increased 1.42-fold (P = 0.009)
		> 2–5 × ULN	All-cause mortality risk increased 1.81-fold (P = 0.032)
		Inflammatory markers
		CRP	aHR, 1.04 associated with mortality (P = 0.001)
		Ferritin	aHR, 1.0 associated with mortality (P = 0.001)
		IL-6	aHR, 1.0 associated with mortality (P = 0.001)
		neutrophil count	aHR, 1.0 associated with mortality (P = 0.008)
		D-Dimer	aHR, 1.03 associated with mortality (P = 0.004)
		LDH	aHR, 1.0 associated with mortality (P < 0.001)
		AST, ALT, TBIL	Significantly increased for those who received MV (P < 0.0001)
Kodavoor et al[180], 2022, India	Retrospective (n = 708)	AST1	aOR 1.007, per 1 IU/L increase for SD
		AST1	aHR 1.002 per 1 IU/L increase for mortality
		Sensitivity/specificity	90.6%/67% to predict mortality
		PPV/NPV	17.5%/95.73% to predict mortality
		Albumin1	aOR 0.217 per 1 g/dL increase for SD
			aHR 0.396 per 1 g/dL increase for mortality
Lombardi et al[230], 2022, Italy	Retrospective (n = 382)	Transaminases1
		> 2 × ULN	OR 2.6, 95%CI: 1.3–6.7 for SD
		FIB-4 score < 1.451	(OR 0.4; P = 0.04) protective factor for mortality
Hartl et al[326], 2022, Austria	Retrospective (n = 900)	AST1	aHR: 1.47; P = 0.043 for mortality
		TBIL1	aHR: 2.20; P = 0.009 for mortality
Siddiqui et al[229], 2022, United States	Retrospective (n = 1935)	Abnormal LFTs
		Liver injury defined as: (AST/ALT > 3 × ULN or ALP/TBIL > 2 × ULN)	RR, 4.26; P < 0.0001 risk for mortality
		Mild elevated enzymes	RR, 5.52; P < 0.0001 for ICU admission
		(Levels lower than LI)	RR, 11.01; P < 0.0001 for MV
			RR, 2.16; P < 0.0001 for mortality
			RR, 2.48; P < 0.0001 ICU admission
		Cirrhotics	RR, 3.76; P < 0.0001 for MV
			RR, 2.19; P = 0.0022 for mortality
Cai et al[20], 2020, China	Retrospective (n = 417)	Hepatocellular LI	OR, 2.73; P = 0.02 for severe disease
		Mixed LI	OR, 4.44; P < 0.001 for severe disease
		LI1	aOR, 9.04; P < 0.001 for severe disease
Huang et al[191], 2020, China	Retrospective (n = 675)	AST1 3-fold ULN	aOR, 19.27; P < 0.0001 for mortality
			aOR, 116.72; P < 0.0001 for MV
Lei et al[192], 2020, China	Retrospective (n = 5771)	AST1 40-120 U/L	aOR, 4.81; P < 0.001 for all-cause mortality
		AST1 > 120 U/L	aOR, 14.87; P < 0.001 for all-cause mortality
Ding et al[22], 2020, China	Retrospective (n = 2073)	Abnormal AST1	aHR, 1.39; P = 0.027 for mortality
		Abnormal DBIL1	aHR, 1.66; P = 0.001 for mortality
		LI during hospitalization1	aHR, 4.63; P < 0.001 for in-hospital mortality
		LI at admission1	aHR 1.87; P = 0.003 for in-hospital mortality
		Mixed LI1	aHR, 4.77; P < 0.001 for in-hospital mortality
		Cholestatic LI1	aHR, 3.99; P = 0.008 for in-hospital mortality
Phipps et al[23], 2020, United States	Retrospective (n = 3381)	Ferritin1	OR, 2.40; P < 0.001 for SLI
		IL-61	OR, 1.45; P = 0.009 for SLI
		Peak ALT1	OR, 1.14; P = 0.044 for mortality
		Older age1	OR, 1.07; P < 0.001 for mortality
		DM1	OR, 1.30; P = 0.045 for mortality
Medetalibeyoglu et al[221], 2020, Turkey	Retrospective (n = 554)	AST/ALT > 1	AUC = 0.713, P = 0.001 marker of mortality risk
			AUC = 0.636, P = 0.001 for ICU admission
Chen et al[199], 2020, China	Retrospective (n = 502)	Grade of Liver damage1	aHR, 1.377; P = 0.049 risk factor for mortality
Mishra et al[200], 2021, United States	Retrospective (n = 348)	AST1 (1 unit increase) IU/L Peak AST1 (1 unit increase)	OR, 1.011; P = 0.006 for mortality
		Peak ALT1 (1 unit increase)	OR, 1.007; P < 0.001 for mortality
		TBIL1 (1 unit increase) mg/dL	OR, 1.005; P = 0.003 for mortality
		Alb1 (1 unit increase) g/dL	OR, 1.997; P = 0.04
		Male1	OR, 0.5; P = 0.01
		BMI > 40 kg/m2	OR, 1.94; P = 0.001
		LI1	OR, 2.17; P = 0.003
			OR, 1.79; P = 0.008
Chew et al[190], 2021, United States	Retrospective (n = 834)	Ischemic disease state1	OR, 2.4; P = 0.001 for mortality
		Hypecoagulable1	OR, 1.7; P = 0.02 for mortality
		Hyperinflammatory1	OR, 1.9; P = 0.02 for mortality
Ponziani et al[327], 2021, Italy	Retrospective (n = 515)	ALP1 peak value	aOR, 1.007; P = 0.005 for mortality
		CRP1	aOR, 1.007; P = 0.008 for mortality
Piano et al[246], 2020, Italy	Retrospective (n = 565)	Abnormal LFTs1	OR, 3.53; P < 0.001 for ICU admission/death
Yip et al[287], 2021, China	Retrospective (n = 1040)	ALT/AST1 ≥ 2 × ULN	aOR, 7.92; P < 0.001 for ICU/MV/death
Marjot et al[237], 2021, multinational	Retrospective (n = 785)	Age1	OR, 1.02; P = 0.011 for mortality
		Cirrhotics CTP-A1	OR, 1.90; P = 0.040 for mortality
		Cirrhotics CTP-B1	OR, 4.14; P < 0.001 for mortality
		Cirrhotics CTP-C1	OR, 9.32; P < 0.001 for mortality
		ArLD1	OR, 1.79; P = 0.040 for mortality
Lee et al[328], 2020, South Korea	Retrospective (n = 1005)	Age1	aHR = 4.96; P < 0.001 for mortality
		Liver cirrhosis1	aHR = 2.86; P = 0.042 fro mortality
		DM1	aHR = 2.29; P < 0.001 for mortality
		COPD1	aHR = 4.52; P = 0.001 for mortality
Singh et al[236], 2020, United States	Retrospective (n = 2780)	CLD1	RR, 2.8; P < 0.001 risk of mortality
		propensity matching	RR, 3.0; P = 0.001 risk of mortality
		Cirrhotics1	RR, 4.6; P < 0.001 risk of mortality
Hashemi et al[232], 2020, United States	Retrospective (n = 363)	CLD1	aOR 1.77; P = 0.04 for ICU admission
			aOR, 2.08; P = 0.0092 for IMV
		Cirrhotics1	aOR, 12.5; P = 0.009 mortality risk
Sarin et al[235], 2020, Asian	Retrospective (n = 228 CLD)	Cirrhotics1
		AST/ALT > 1.4	HR = 1.4; P = 0.02 for mortality
		Obesity	OR = 8.1; P = 0.002 for LI
		Decompensated	OR = 2.5; P = 0.05 for mortality
		CTP score > 8	HR = 19.2; P < 0.001 for mortality
		DM in CLD non-cirrhotics	OR = 2.1; P = 0.01 for LI
Wang et al[51], 2020, China	Retrospective (n = 657)	Male gender1	OR, 2.038; P < 0.001 for LI
		hsCRP ≥ 10 mg/L	OR, 1.733; p = 0.014 for LI
		NLR ≥ 5	OR, 2.154; P < 0.001 for LI
Zhang et al[183], 2020, China	Retrospective (n = 218)	Male1	OR, 6.203; P < 0.001 risk for LI
		Neutrophil percentage1	OR, 1.004; P = 0.003 risk for LI
		CRP1	P < 0.001 in LI patients
		D-dimer1	OR, 1.486; P < 0.001 risk for LI
Shauly-Aharonov et al[329], 2021, Israel	Retrospective (n = 37121)	Age	OR = 1.1 for every year increase; P < 0.001) risk for severity
		Male gender	OR = 1.34; P = 0.012 risk for severity
		BMI	OR = 1.02 for 1 kg/m2 increase; P = 0.025 risk for severity
Kovalic et al[208], 2020, United States	Meta-analysis (n = 24299)	CLD1	Pooled OR, 1.48; P = 0.001 for severity
			Pooled OR, 1.78; P = 0.02 for mortality
Kulkarni et al[6], 2020, India	Meta-analysis Multinational (n = 20874)	Increased LFTs	OR, 3.46; P < 0.001 for mortality
			OR, 2.87; P < 0.001 for severe disease
Sharma et al[207], 2021, United States	Meta-analysis (n = 12882)	AST1	Pooled OR, 2.98; P < 0.00001 for poor outcomes
		ALT1	Pooled OR, 1.73; P < 0.0001 for poor outcomes
Del Zompo et al[323], 2020, Italy	Meta-analysis (n = 20724)	ALT1	OR 1.54, 95%CI: 1.17-2.03 for severity
		ALT1	OR 1.48, 95%CI: 1.12-1.96 for mortality
		AST1	OR 3.17, 95%CI: 2.10-4.77 for severity
		AST1	OR 4.39, 95%CI: 2.68-7.18 for mortality
		TBIL1	OR 2.32, 95%CI: 1.18-4.58 for severity
		TBIL1	OR 7.75, 95%CI: 2.28-26.40 for mortality

¹Age, gender, ethnicity, race, BMI, and all the pre-existing comorbidities were adjusted as confounders.

Results come from multivariate analysis and logistic regression (studies with more than 200 individuals are included). aHR: Adjusted hazard ratio; ALB: Albumin; ALI: Acute liver injury; ALT: Alanine transaminase; ALP: Alkaline phosphatase; aOR: Adjusted odds ratio; ArLD: Alcohol related liver disease; AST: Aspartate transaminase; BMI: Body mass index; COPD: Chronic obstructive pulmonary disease; CRP: C-reactive protein; CTP: Child-Turcotte-Pugh; CLD: Chronic liver disease; DM: Diabetes mellitus; FIB-4: Risk of fibrosis score; GGT: Gamma-glutamyl transferase; HR: Hazard ratio; ICU: Intensive care unit; IMV: Invasive mechanical ventilation; LDH: Lactate dehydrogenase; LI: Liver injury; LFTs: Liver function tests; NLR: Neutrophil-to-lymphocyte ratio; NPV: Negative predictive value OR: Odds ratio; RR: Relative risk; PPV: Positive predictive value; SLI: Severe liver injury; MOF: Multiple organ failure; TBIL: Total bilirubin; ULN: Upper limit of normal.

Table 2 Incidence of abnormal liver function tests (liver injury)

Author/citation LFTs performed	Type of study (n = participants)	Incidence (%)	Country/year of publication
Cai et al[20]	Study (n = 417)		China/2020
Abnormal LFTs
SLI (AST/ALT > 3 × ULN		76.3
or ALP/γGT > 2 × ULN)		21.8
ALT (> 3 × ULN)		37
GGT (> 3 × ULN)		41
AST (> 3 × ULN)		20
TBIL (> 3 × ULN)		10
MOF		23.3
Phipps et al[23]	Study (n = 2273)		United States/2020
Mild (peak ALT < 2 × ULN)		45
Moderate (peak ALT 2-5 × ULN)		21
SLI (peak ALT > 5 × ULN)		6.4
Huang et al[191]	Study (n = 675)		China/2020
Abnormal LFTs		37.5
SLI		7.7
Guan et al[284]	Study (n = 1099)		China/2020
AST/ALT
mild disease		18.2–19.8
severe disease		28.1–39.4
Hundt et al[185]	Study (n = 1827)		United States/2020
LFTs (on admission)
AST		66.9
ALT		41.6
TBIL		4.3
ALP		13.5
Wang et al[65]	Study (n = 657)		China/2020
Liver injury		46.1
ALT		42.2
GGT		24.4
TBIL		4.9
Chu et al[320]	Study (n = 838)		China/2020
Liver Injury		51.2
Yip et al[287]	Study (n = 1040)		China/2021
Aminotransferases		22.5
ALP		58.5
TBIL		52.1
Ding et al[22]	Study (n = 2073)		China/2021
Survivors		90.3
Any abnormal LFT		61.8
Mild abnormal LFT		47.5
SLI		14.3
LI type
Hepatocellular		25.8
Cholestatic		6.7
Mixed		25.7
Specific liver indices
ALT		43.3
AST		38.9
GGT		31.8
Shao et al[38]	Study (n = 1520)		China/2021
SLI		17.9
Mishra et al[200]	Study (n = 348)		United States/2021
New-onset LI		52.8
Sikkema et al[204]	Study (n = 382)		Netherlands/2021
LI		41.6
Moderate LI (ALT > 100 or ALP > 200)		6.5
Cholestatic LI		9.2
Chew et al[190]	Study (n = 834)		United States/2021
AST		62.5
ALT		33.7
ALP		11.9
TBIL		3.1
Richardson et al[25]	Study (n = 5700)		United States/2020
AST		58.4
ALT		39
Bernal-Monterde et al[187]	Study (n = 540)		Spain/2020
Abnormal LFTs		64.3
ALT		28.6
AST		40.9
GGT		47.3
Krishnan et al[321]	Study (n = 3830)		United States/2022
ALT		70.4
AST		44.4
ALP		16.1
TBIL		5.9
Kodavoor et al[180]	Study (n = 708)		India/2022
AST		69.91
< 1–2 times ULN		42.51
2–3 times ULN		14.26
3–5 times ULN		8.19
> 5		4.94
ALT		80.22
< 1–2 times ULN		42.93
2–3 times ULN		17.93
3–5 times ULN		12.14
> 5		7.2
Russo et al[234]	Study (n = 1641)		Italy/2022
AST		27.7
ALT		23
TBIL		12.6
Marjot et al[44]	Review		United Kingdom/2021
AST		29–39
ALT		38–63
Cai et al[82]	Review		China/2021
ALT		11–56.3
AST		15–86.8
TBIL		2.7–30.6
CLD		2–11
Ekpanyapong et al[322]	Review		Multinational/2022
Aminotransferases		10–58
ALP		1–10
TBIL		3–23
GGT		13–54
Esteban et al[209]	Review		United States/2022
Aminoransferases (admission)		20–67
Aminoransferases (hospitalization)		61–83
ALP		23–30
TBIL		4–16
Garrido et al[59]	Review		Portugal/2020
ALT		2.5–50
AST		2.5–61.1
TBIL		0–35.3
Kullar et al[2]	Meta-analysis (n = 3046)		United States/2020
ALT		21
AST		24
TBIL		9
Wijarnpreecha et al[198]	Meta-analysis (n = 64 studies) (n = 11245 pts)		United States/2021
AST		23.2
ALT		21.2
TBil		9.7
GGT		15
ALP		4
AST
Severe cases		45.5
Non-severe		15
Wu et al[253]	Meta-analysis (n = 45 studies)		Multinational/2018
Admission
Any abnormal LFT		27.2
ALT		20.4
AST		21.8
ALP		4.7
GGT		35.8
TBIL		8.8
Hospitalization
Any abnormal LFT		36
ALT		38.4
AST		28.1
TBIL		23.2
Del Zompo et al[323]	Meta-analysis (n = 36 studies) (n = 20724 patients)		Italy/2020
At admission (pooled prevalence)
Abnormal LFT		46.9
ALT		22.8
AST		26.5
GGT		22.5
ALP		5.7
TBIL		8
Zhu et al[262]	Meta-analysis (n = 38 studies) (n = 3063 pts)		China/2020
Abnormal LFTs		29
Mao et al[18]	Meta-analysis (n = 1267)		China/2020
Abnormal LFTs		19
Alqahtani et al[324]	Meta-analysis (n = 30 studies)		Multinational/2020
Abnormal LFTs		61.1
Sultan et al[325]	Meta-Analysis (n = 47 studies) (n = 10,890 pts)		United States/2020
Pooled prevalence
ALT		15
AST		15
TBIL		16.7
Kumar et al[210]	Meta-analysis (n = 128 studies)		India/2020
Pooled prevalence
TBIL		13.71
ALT		31.1
AST		33.95
ALP		6.99
GGT		30.62
ALB		61.57
Severe vs non-severe pts
TBIL		18.80 vs 9.24
ALT		39.58 vs 24.15
AST		49.68 vs 19.40
ALP		11.33 vs 4.0
GGT		46.90 vs 18.66
ALB		75.91 vs 31.04

The table encompasses several studies and meta-analyses which included more than 200 individuals.

ALB: Albumin; ALI: Acute liver injury; ALT: Alanine transaminase; ALP: Alkaline phosphatase; AST: Aspartate transaminase; GGT: Gamma-glutamyl transferase; LI: Liver injury; LFTs: Liver function tests; SLI: Severe liver injury; MOF: Multiple organ failure; TBIL: Total bilirubin; ULN: Upper limit of normal; γGT: Gamma-glutamyltransferase; LFT: Liver function tests; pts: Patients.

Table 3 Serum parameters alone or in combination associated with specific outcomes

Parameters	Associated conditions
ALT	CSS inflammatory markers
Elevated serum IL-2R, IL-6, TNF-α	LI
IL-6, ferritin, CRP, ESR, Procalcitonin, hypoalbuminemia, low PLTs, low CD4+ T-cells and B-lymphocytes	Non-favorable course of LI
Simultaneous increase in IL-6 + ferritin + ALT + hypoalbuminaemia	Significant LI
On admission increased inflammatory markers + AST + GGT + LDH + lymphopenia+eosinopenia	More Severe clinical course
Lymphopenia, Thrombocytopenia	Disease severity
Thrombocytopenia	Consumptive coagulopathy
Low Hb	Controversial data

ALI: Acute liver injury; ALT: Alanine transaminase; AST: Aspartate transaminase; CRP: C-reactive protein; GGT: Gamma-glutamyl transferase; LDH: Lactate dehydrogenase; LI: Liver injury; CSS: Cytokine storm syndrome; IL: Interleukin; ESR: Equivalent series resistance; TNF-α: Tumor necrosis factor-α; PLT: Platelet; Hb: Hemoglobin.

Table 4 Most frequent liver-related histopathological findings in COVID-19 patients

Findings	Frequency (%)
Portal and sinusoidal microthrombosis	29.4–100
Hepatic/macrovesicular steatosis	50–75
Mild portal inflammation	13.2–66
Centrilobular necrosis	50
Mild acute hepatitis	50
Congestion/dilation of hepatic sinuses	34.7
Portal fibrosis	20.5
Kupffer cell hyperplasia	13.5
Lobular inflammation	11.6
Inflamed cells within the sinusoids (neutrophils, plasmatocytes and Kupffer)	N/A
Panacinar hepatitis, zone 3 necrosis	N/A

N/A: Not applicable; COVID-19: Coronavirus disease 2019.