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.