Laboratory hematologic features of COVID-19 associated liver injury: A systematic review

Table 1 Studies with a coronavirus disease 2019 (+) cohort with liver injury provided as a distinct group

Ref.	Country	Number of patients	% of total patients	Age, mean	% male	Setting	Study group inclusion criteria	Control group	Evaluated parameters	NOS
Abe et al[46]	Japan	15	68	47	59	Hospitalized patients	ALT OR GGT over ULN	COVID+	WBC, ALC, HGB	8
An et al[47]	China	51	21	52	45.1	Hospitalized patients	AST OR ALT over ULN	COVID+	WBC, ALC, ANC, DDIM	8
Anastasiou et al[48]	Germany	82	56.2	64.5	74	Hospitalized patients	ALT OR BILI over ULN	COVID+	WBC, INR	6
		11	6.8	51	100		EASL ALF criteria (see ref[10])
Cardoso et al[49]	Portugal	20	100	67	90	ICU	GGT OR/AST OR/ALT over ULN	None	SOFA, APACHE II	NA
Chen et al[50]	China	227	38	56	63	Hospitalized patients	ALT OR AST OR GGT over ULN	COVID+	ALC, DDIM	9
Chen et al[51]	China	301	59	62	82	Hospitalized patients	AST OR ALT OVER ULN/ OR elevated ALP/GGT over ULN	COVID+	WBC, ALC, ANC, PLTs, PT, PTT, INR	7
Chu et al[52]	China	429	51	61	65	Hospitalized patients	ALT/ALP ratio over ULN	COVID+	WBC, ALC, ANC, PLTs, HGB, DDIM, PT, INR	7
Da et al[53]	U.S.	109	62	61	78	Hospitalized patients	AST or ALT ≥ 3 times ULN	COVID+	DDIM, PT, INR	8
Fiel et al[54]	United States	2	100	NA	50	Hospitalized patients	Biopsy proven disease without pneumonia	None	DDIM	NA
Huang et al[55]	China	253	37.5	58	59	Hospitalized patients	AST, ALT, TBIL over ULN	COVID+	WBC, ALC, PLTs, HGB	5
		52	7.7	51.5	81		ALT ≥ 3 times ULN
Lagana et al[56]	United States	11	100	70	70	NS	PCR testing of liver	None	DDIM	NA
Li et al[57]	China	7	NS	61	43	Hospitalized patients	AST or ALT over ULN	None	WBC, ALC, ANC, DDIM, HGB	NA
Meszaros et al[58]	France	156	66.7	66.5	73	Hospitalized patients	AST OR ALT OR GGT over ULN	COVID+	ALC, PLTs, DDIM	7
Mishra et al[59]	United States	184	52.9	62.7	58	Hospitalized patients	AST OR ALT over ULN	COVID+	WBC, ALC, ANC, HGB	7
Phipps et al[60]	United States	1784		66	73	Hospitalized patients	ALT > 1-2× ULN	COVID+	WBC, ALC, ANC, PLTs, DDIM, HGB	8
		344		61			ALT 2-5× ULN
		145		63			ALT > 5× ULN
Piano et al[61]	Italy	329	58	66	63	Hospitalized patients	AST OR ALT OR GGT OR ALP OR BILI > ULN	COVID+	WBC, ALC, ANC, PLTs, DDIM, INR	7
Qi et al[62]	China	32	46	41	72	Hospitalized patients	AST OR ALT OR BILI over ULN	COVID+	WBC, ALC, ANC	6
Sadeghi et al[64]	Iran	65	64	55	64	Non-ICU hospitalized	AST OR ALT OR BILI over ULN	COVID+	WBC, ALC, ANC	9
Safari et al[63]	Iran	41	17	52	31	Hospitalized patients	ALT above ULN	COVID+	WBC, PLTs, HGB	8
Tsutsumi et al[65]	Japan	31	52	46	84	Hospitalized patients	ALT ≥ 40 U/L	COVID+	WBC, ALC, PLTs, DDIM, PT	8
Wang et al[66]	China	303	46.1	62	63.4	Hospitalized patients	ALT OR GGT OR BILI over ULN	COVID+	WBC, ALC, ANC, PLTs, HGB, PT	8
Xie et al[26]	China	29	26.9	62	72.4	Non-ICU hospitalized	AST OR ALT OR BILI over ULN	COVID+	WBC, ALC, ANC, DDIM	8

ALC: Absolute lymphocyte count; ALP: Alkaline phosphatase; ALT: Alanine transaminase; ANC: Absolute neutrophil count; APACHE II: Acute Physiology and Chronic Health Evaluation II scoring system; AST: Aspartate transaminase; BILI: Bilirubin; COVID-19: Coronavirus disease 2019; DDIM: D-dimer; EASL ALF criteria: European Association for the Study of the Liver Acute Liver Failure Guidelines; GGT: Gamma-glutamyltransferase; HGB: Hemoglobin; INR: International normalized ratio; NA: Not applicable; NOS: Newcastle-Ottawa Scale; NS: Not stated; PLT: Platelet count; PT: Prothrombin time; PTT: Partial thromboplastin time; SOFA: Sequential Organ Failure Assessment scoring system; ULN: Upper limit of normal; WBC: White blood cell count.

Table 2 Summary of statistical data from studies comparing liver injury vs non-liver injury

LFT criteria	Parameter	Significance
		NS	< 0.05	< 0.01	< 0.001
LFT > ULN	WBC	4	2	0	6
	ANC	4	1	0	4
	ALC	4	2	1	5
	HGB	4	2	0	5
	PLT	4	2	0	2
	DDIM	4	2	1	0
	PT	4	2	1	0
	PTT	4	2	0	0
	INR	4	2	1	0
LFT > 2 × ULN	WBC	4	2	0	3
	ANC	4	2	0	1
	ALC	4	2	1	1
	HGB	4	2	0	2
	PLT	4	2	0	1
	DDIM	4	2	0	1
	PT	4	2	0	0
	INR	4	2	0	0
Studies with > 100 patients in high LFT cohort	WBC	0	0	0	5
	ANC	1	0	0	5
	ALC	4	0	1	5
	HGB	0	0	0	5
	PLT	5	0	0	2
	DDIM	3	0	0	3
	PT	2	1	1	0
	PTT	1	0	0	0

Numbers indicate number of studies. ALC: Absolute lymphocyte count; ANC: Absolute neutrophil count; DDIM: D-dimer; HGB: Hemoglobin; INR: International normalized ratio; LFT: Liver function test; NS: Not significant; PLT: Platelet count; PT: Prothrombin time; PTT: Partial thromboplastin time; ULN: Upper limit of normal; WBC: White blood cell count.

Table 3 Studies comparing coronavirus disease 2019 patients with severe vs non-severe disease

Ref.	Country	Patients with severe disease (% of total)	Setting	Definition of SEVERE disease	Definition of liver Injury	Evaluated parameters	Summary of main findings	NOS
Cai et al[67]	China	58 (19.5)	Hospitalized patients	Radiography supporting severe disease	ALT OR AST > 3 times ULN or GGT or TBIL > 2 times ULN	WBC, ANC, ALC, DDIM	LFT significantly elevated in severe cohort at admission	8
Jiang et al[68]	China	27 (20.6)	Hospitalized patients	Chinese National Health Committee criteria (see ref[82])	AST OR ALT OR ALP OR TBIL > 5 times ULN	WBC, ANC, ALC, PLTS, HGB	Liver injury in 81% of severe cohort over course of hospitalization; slow recovery from liver injury compared to other cohorts	7
Lei et al[69]	China	48 Severe cohort	Hospitalized patients	National Health Commission of the People’s Republic of China and National Administration of Traditional Chinese Medicine of the People’s Republic of China criteria (see ref[83])	CT showing liver hypodensity and pericholecystic fat stranding	WBC, ALC, PLTS	Severity of COVID-19 disease correlated with liver function	7
	China	48 Critical cohort	Hospitalized patients	Health Commission of the People’s Republic of China and National Administration of Traditional Chinese Medicine of the People’s Republic of China criteria (see ref[83])	CT showing liver hypodensity and pericholecystic fat stranding	WBC, ALC, PLTS	Severity of COVID-19 disease correlated with liver function
Liao et al[70]	China	29 (15.1)	Hospitalized patients	National Guidelines for 2019 novel coronavirus-associated pneumonia (the fifth revised version)	AST OR ALT OR TBIL over ULN	WBC, ANC, ALC, HGB, DDIM	Liver injury in high percentages of patients from both groups; correlated with inflammatory cytokine levels	7
Yang et al[71]	China	215 (72.9)	Hospitalized patients	WHO criteria (see ref[8] from[68])	AST > 1.5 times ULN	WBC, ANC, ALC, PLT, DDIM, PT	AST and GGT levels correlated with disease severity	7

ALC: Absolute lymphocyte count; ALT: Alanine transaminase; ANC: Absolute neutrophil count; AST: Aspartate transaminase; COVID-19: Coronavirus disease 2019; CT: Computerized tomography; DDIM: D-dimer; GGT: Gamma-glutamyltransferase; HGB: Hemoglobin; NOS: Newcastle-Ottawa Score; PLT: Platelet count; PT: Prothrombin time; TBIL: Total bilirubin; WBC: White blood cell count; WHO: World Health Organization; ULN: Upper limit of normal.

Table 4 Other retrospective cohort studies

Ref.	Country	Setting	Evaluated parameters	Comparison	Summary of main findings	NOS
Cao et al[72]	China	Hospitalized patients	WBC, ANC, ALC, DDIM	Elevated ferritin vs disease controls	Elevated ferritin corelated with disease severity and degree of liver injury	7
Chen et al[73]	China	Hospitalized patients	ANC, ALC, PLT, DDIM	Recurrent cases vs disease controls	Elevated AST and ALT are predictive of COVID-19 recurrence	7
Ding et al[74]	China	Hospitalized patients	ALC, PLT, DDIM	Deceased vs discharged	Abnormal AST and D-Bil were independent predictors of mortality	7
Lei et al[75]	China	Hospitalized patients	ANC, ALC, PLT, DDIM	Comparison of parameters for peak levels of each LFT	Associated ANC, ALC, PLT, and DDIM with peak levels of AST, ALC, ALP, and TBIL	6
Luan et al[76]	China	ICU hospitalized	WBC, HGB, ANC, ALC, PLTS, DDIM, PT, PTT, INR	CAC vs non-CAC	CAC correlates with liver injury	8

ALC: Absolute lymphocyte count; ALP: Alkaline phosphatase; ANC: Absolute neutrophil count; CAC: COVID-associated coagulopathy; COVID-19: Coronavirus disease 2019; D-Bil: Direct bilirubin; DDIM: D-dimer; HGB: Hemoglobin; ICU: Intensive care unit; INR: International normalized ratio; LFT: Liver function test; NOS: Newcastle-Ottawa Scale; PLT: Platelet count; PT: Prothrombin time; PTT: Partial thromboplastin time; WBC: White blood cell count.