Clinical Course and Risk Factors for Liver Injury of Severe and Critical Patients with COVID-19

Figures & data

Table 1 Demographic, Clinical, and Laboratory Findings of Patients with COVID‑19 on Admission

	Severe (n=36)	Critical (n=27)	Total (n=63)	P-value
Demographics and clinical characteristics
Male, n (%)	26 (72.22)	15 (55.56)	41 (65.08)	0.134
Age (years), mean (SD)	48.39 (16.03)	67.89 (12.02)	56.75 (17.33)	<0.001
Comorbidities, n (%)
Diabetes	4 (11.11)	5 (18.52)	9 (14.29)	0.317
Hypertension	6 (16.67)	13 (48.15)	19 (30.16)	0.008
Cardiovascular disease	2 (5.56)	2 (7.41)	4 (6.35)	0.577
Chronic pulmonary disease	1 (2.78)	4 (14.82)	5 (7.94)	0.101
Tumor	1 (2.78)	2 (7.41)	3 (4.76)	0.392
Hyperlipemia	2 (5.56)	1 (3.70)	3 (4.76)	0.608
Cerebrovascular disease	0	2 (7.41)	2 (3.17)	0.180
Fever (temperature ≥37.3°C), n (%)	34 (94.44)	24 (88.89)	58 (92.06)	0.364
Heart rate (rate/min), mean (SD)	92.69 (14.84)	94.89 (13.91)	93.63 (14.37)	0.553
Respiratory rate (rate/min), median (IQR)	20 (20, 21)	20 (20, 29)	20 (20, 22)	0.150
Mean blood pressure (mmHg), mean (SD)	94.71 (10.96)	95.10 (10.82)	94.88 (10.81)	0.890
Oxygen therapy, n (%)
High flow oxygen/Non-invasive ventilator	4 (11.11)	6 (22.22)	10 (15.87)	0.198
Invasive ventilator	0	16 (59.26)	16 (25.40)	<0.001
ECMO	0	5 (18.52)	5 (7.94)	0.011
Drug use, n (%)
Antibiotics	21 (58.33)	23 (85.19)	44 (69.84)	0.020
Hormone	3 (8.33)	8 (29.63)	11 (17.46)	0.031
Antiviral drug	35 (97.22)	12 (44.44)	47 (74.60)	<0.001
Vasoactive drugs	0	12 (44.44)	12 (19.05)	<0.001
Oxygenation index, mean (SD)	319.98 (107.84)	220.81 (107.87)		0.001
ARDS, n (%)	15 (41.67)	22 (81.48)	37 (58.73)	<0.01
CURB-65 score, median (IQR)	0 (0, 0)	1 (1, 2)	0 (0, 1)	<0.001
CURB-65 score, n (%)				<0.001
CURB-65<2	35 (97.22)	16 (59.26)	51 (80.95)
CURB-65≥2	1 (2.78)	11 (40.74)	12 (19.05)
SOFA score, median (IQR)	2 (0, 3)	3 (2, 4)	3 (1, 3)	<0.001
SOFA score, n (%)				0.004
SOFA<2	16 (44.44)	3 (11.11)	19 (30.16)
SOFA≥2	20 (55.56)	24 (88.89)	44 (69.84)
Laboratory findings
White-cell count (×10^9/L), median (IQR)	4.67 (3.81, 6.25)	6.78 (4.23, 10.47)	5.01 (3.92, 7.50)	0.012
Neutrophil %, mean (SD)	69.02 (10.93)	79.63 (10.19)	73.57 (11.79)	<0.001
Neutrophil count (×10^9/L), median (IQR)	3.16 (2.34, 5.46)	5.30 (3.02, 9.43)	3.85 (2.65, 6.22)	0.011
Lymphocyte %, mean (SD)	24.17 (9.39)	15.84 (9.10)	20.60 (10.09)	0.001
Lymphocyte count (×10^9/L), median (IQR)	1.07 (0.91, 1.31)	0.90 (0.73, 1.16)	0.98 (0.81, 1.24)	0.042
NLR (%), median (IQR)	3.14 (2.03, 5.02)	5.51 (3.31, 12.02)	3.87 (2.35, 6.49)	0.002
Monocyte %, mean (SD)	6.54 (3.86)	4.01 (1.95)	5.45 (3.41)	0.003
Monocyte count (×10^9/L), mean (SD)	0.30 (0.14)	0.28 (0.18)	0.30 (0.16)	0.654
Haemoglobin (g/L), mean (SD)	139.50 (11.83)	131.04 (16.84)	135.87 (14.69)	0.022
Hematocrit (%), mean (SD)	41.43 (3.80)	38.39 (4.49)	40.12 (4.35)	0.005
Platelet count (×10^9/L), median (IQR)	153.50 (133.25, 228.50)	157.00 (113.00, 213.00)	154.00 (132.00, 218.00)	0.527
CRP (mg/L), median (IQR)	31.90 (12.30, 58.50)	71.75 (39.80, 110.58)	42.60 (17.70, 96.50)	0.002
D-dimer (mg/L), median (IQR)	0.60 (0.37, 0.88)	0.91 (0.31, 1.67)	0.68 (0.36, 1.31)	0.115
BUN (mmol/L), median (IQR)	3.80 (2.96, 4.28)	5.56 (4.72, 7.33)	4.27 (3.61, 5.39)	<0.001
Serum creatinine (μmol/L), median (IQR)	73.00 (58.90, 82.20)	70.60 (55.10, 95.30)	72.35 (55.75, 84.98)	0.739
INR (mmol/L), mean (SD)	1.15 (0.12)	1.16 (0.13)	1.15 (0.12)	0.749
LDH (U/L), median (IQR)	273.30 (213.25, 341.45)	387.50 (291.65, 524.85)	316.00 (235.53, 397.15)	0.004
Creatine kinase (U/L), median (IQR)	80.95 (45.25, 177.83)	100.40 (54.70, 144.75)	89.40 (48.40, 152.80)	0.713
Ct value on admission
N-gene (cycle), median (IQR)	33.26 (27.67, 36.95)	33.37 (29.77, 36.36)	33.32 (28.40, 36.67)	0.908
ORF1ab-gene (cycle), median (IQR)	29.38 (26.57, 36.29)	33.36 (28.55, 35.64)	30.23 (26.77, 35.99)	0.414
Ct ˂40 on day 7, n (%)	29 (80.56)	20 (74.07)	49 (77.78)	0.377
Ct ˂40 on day 14, n (%)	19 (52.78)	13 (48.15)	32 (50.79)	0.457
Days from RNA positive to negative (days)	13.00 (8.25, 28.50)	19 (10.00, 27.00)	16.00 (9.00, 27.00)	0.527

Abbreviations: ARDS, Acute Respiratory Distress Syndrome; A/G, albumin/globulin; BUN, blood urea nitrogen; CRP, C-reactive protein; Ct, cycle threshold; ECMO, extracorporeal membrane oxygenation; INR, international normalized ratio; LDH, lactate dehydrogenase; NLR, neutrophil to lymphocyte ratio; SOFA, Sequential Organ Failure Assessment.

Table 2 Peak Values of Serum Liver Enzyme Parameters in Severe and Critical Patients with COVID‑19

	Severe (n=36)	Critical (n=27)	P-value
AST (U/L)	37.80 (29.60, 56.50)	93.50 (46.30, 119.30)	<0.001
AST, n (%)			0.009
Normal	19 (54.29)	5 (18.52)
1–3 ULN	14 (40.00)	16 (59.26)
>3 ULN	2 (5.71)	6 (22.22)
ALT (U/L)	63.25 (31.93, 107.03)	88.90 (51.30, 134.90)	0.187
ALT, n (%)			0.309
Normal	13 (36.11)	5 (18.52)
1–3 ULN	16 (44.44)	15 (55.56)
>3 ULN	7 (19.44)	7 (25.93)
TBIL (umol/L)	13.50 (9.80, 18.40)	24.60 (15.90, 68.10)	<0.001
TBIL, n (%)			0.001
Normal	27 (77.14)	10 (37.04)
1–3 ULN	8 (22.86)	10 (37.04)
>3 ULN	0	7 (25.93)
Albumin (g/L), mean (SD)	35.49 (3.68)	29.38 (3.85)	<0.001
A/G ratio, median (IQR)	1.10 (1.00, 1.30)	0.90 (0.80, 1.10)	<0.001
INR (mmol/L), median (IQR)	1.22 (1.14, 1.27)	1.39 (1.20, 1.61)	<0.001

Abbreviations: AST, aspartate aminotransferase; ALT, alanine transaminase; A/G, albumin/globulin; INR, international normalized ratio.

Table 3 Clinical Characteristics of COVID-19 Patients in Different Liver Test Groups at Admission

Characteristics	Normal Liver Test (n=11)	Abnormal Liver Test (n=32)	Liver Injury (n=20)	P-value
Male, n (%)	5 (45.45,)	21 (65.63)	15 (75.00)	0.255
Age (years), mean (SD)	53.73 (20.95)	56.41 (16.42)	58.95 (17.28)	0.722
Oxygen therapy, n (%)
High flow oxygen/Non-invasive ventilator	1 (9.09)	5 (15.63)	4 (20.00)	0.728
Invasive ventilator	0	6 (18.75)	10 (50.00)	0.004
ECMO	0	0	5 (25.00)	0.003
Drug use, n (%)
Antibiotics	5 (45.45)	22 (68.75)	17 (85.00)	0.070
Hormone	0	7 (21.88)	4 (20)	0.241
Antiviral drug	10 (90.91)	24 (75.00)	13 (65.00)	0.284
Vasoactive drug	0	4 (12.50)	8 (40.00)	0.010
White-cell count (×10^9/L), median (IQR)	4.34 (3.95, 4.84)	5.33 (3.61, 7.44)	6.09 (4.11, 7.99)	0.238
Neutrophil %, mean (SD)	64.09 (10.18)	74.82 (14.71)	76.77 (10.48)	0.009
Neutrophil count (×10^9/L), median (IQR)	2.75 (2.33, 3.29)	4.15 (2.66, 6.73)	4.73 (2.81, 6.45)	0.086
Lymphocyte %, mean (SD)	27.63 (9.85)	19.52 (9.74)	18.47 (9.54)	0.034
Lymphocyte count (×10^9/L), median (IQR)	1.29 (0.92, 1.71)	0.94 (0.73, 1.15)	1.04 (0.85, 1.17)	0.109
NLR (%), median (IQR)	2.24 (1.48, 3.62)	5.08 (2.41, 8.47)	4.37 (3.12, 6.40)	0.032
Monocyte %, mean (SD)	7.93 (4.77)	5.35 (3.25)	4.26 (1.92)	0.013
Monocyte count (×10^9/L), mean (SD)	0.36 (0.17)	0.27 (0.14)	0.30 (0.17)	0.283
Haemoglobin (g/L), mean (SD)	135.91 (16.20)	135.38 (14.53)	136.65 (14.86)	0.956
Hematocrit (%), mean (SD)	40.72 (5.07)	39.88 (4.37)	40.20 (4.08)	0.858
Platelet count (×10^9/L), median (IQR)	207.00 (153.00, 238.00)	149.50 (129.00, 181.75)	155.50 (113.00, 224.25)	0.177
CRP (mg/L), median (IQR)	27.10 (5.40, 41.70)	43.10 (18.80, 77.85)	66.65 (25.23, 122.70)	0.044
D-dimer (mg/L), median (IQR)	0.85 (0.67, 1.43)	0.59 (0.31, 1.08)	0.67 (0.32, 1.67)	0.356
BUN (mmol/L), median (IQR)	4.09 (2.40, 4.27)	4.35 (3.64, 5.22)	5.07 (3.85, 7.33)	0.044
Serum creatinine (μmol/lL), median (IQR)	66.20 (57.90, 82.30)	70.80 (51.00, 88.10)	76.70 (62.30, 91.70)	0.350
Albumin (g/L), median (IQR)	35.90 (33.30, 39.60)	36.55 (32.78, 40.93)	35.75 (30.40, 38.70)	0.675
A/G ratio, mean (SD)	1.06 (0.40)	1.15 (0.36)	1.06 (0.33)	0.573
INR (mmol/L), mean (SD)	1.12 (0.08)	1.17 (0.13)	1.14 (0.13)	0.471
LDH (U/L), median (IQR)	236.30 (190.90, 315.80)	306.90 (234.35, 382.83)	387.50 (322.65, 595.90)	0.002
Creatine kinase (U/L), median (IQR)	53.80 (42.50, 142.80)	87.80 (44.95, 202.18)	117.30 (62.15, 154.05)	0.374
Ct value on admission
N-gene (cycle), median (IQR)	35.71 (28.54, 37.19)	34.30 (28.14, 37.03)	31.23 (27.64, 34.76)	0.390
ORF1ab-gene (cycle), median (IQR)	28.92 (26.77, 32.63)	33.66 (26.88, 38.90)	29.62 (26.54, 34.69)	0.197
Ct ˂40 on day 7, n (%)	10 (90.91)	25 (78.13)	14 (70.00)	0.407
Ct ˂40 on day 14, n (%)	7 (63.64)	17 (53.13)	8 (40.00)	0.422
Virus duration (day), median (IQR)	16 (11, 30)	13.50 (10.25, 29.50)	16 (4.75, 25.25)	0.711
CURB-65 score, median (IQR)	0 (0, 1)	0 (0, 1)	1 (0, 2)	0.146
CURB-65 score, n (%)				0.086
CURB-65<2, n (%)	10 (90.91)	28 (87.50)	13 (65.00)
CURB-65≥2, n (%)	1 (9.09)	4 (12.50)	7 (35.00)
Oxygenation index	368.59 (133.43)	282.39 (105.70)	225.47 (111.67)	0.015
ARDS, n (%)	3 (27.27)	17 (53.13)	17 (85.00)	0.005
SOFA score, median (IQR)	0 (0, 1.00)	3.00 (1.25, 3.00)	3 (2, 4)	0.001
SOFA score, n (%)				<0.001
SOFA<2	9 (81.82)	8 (25.00)	2 (10.00)
SOFA≥2	2 (18.18)	24 (75.00)	18 (90.00)

Abbreviations: ARDS, Acute Respiratory Distress Syndrome; A/G, albumin/globulin; BUN, blood urea nitrogen; CRP, C-reactive protein; Ct, cycle threshold; ECMO, extracorporeal membrane oxygenation; INR, international normalized ratio; LDH, lactate dehydrogenase; NLR, neutrophil to lymphocyte ratio; SOFA, Sequential Organ Failure Assessment.

Figure 1 The percentage of liver injury in different groups and dynamic changes of liver function indicators between the severe group and the critical group. (A) The percentage of liver injury in CURB-65 score, sequential organ failure assessment (SOFA) score, acute respiratory distress syndrome (ARDS) and ventilator groups. (B) Dynamic changes of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) between the severe group and the critical group. (C) Dynamic changes of total bilirubin (TBIL) and albumin between the severe group and the critical group. (D) Dynamic changes of INR and albumin/globulin (A/G) ratio between the severe group and the critical group.

Figure 2 Dynamic changes of cycle threshold (Ct) values among different groups. (A) Dynamic changes of Ct values between the severe group and the critical group. (B) Dynamic changes of Ct values in the normal, abnormal, and liver injury group.

Table 4 Independent Factors Associated with Severity of Liver Injury

	Crude OR (95% CIs)	P-value	Adjusted OR (95% CIs)	P-value
Invasive ventilator	7.79 (−1.07, 5.18)	0.198	60.99 (0.23, 8.00)	0.038
ECMO		NS		NS
Vasoactive drugs	0.68 (−0.90, 0.12)	0.134	0.59 (−1.24, 0.18)	0.143
Neutrophil %	0.28 (−3.70, 1.16)	0.306	0.03 (−7.03, −0.14)	0.042
Lymphocyte %	0.27 (−3.74, 1.11)	0.289	0.03 (−7.14, −0.18)	0.039
NLR	0.89 (−0.34, 0.11)	0.321	0.83 (−0.47, 0.11)	0.224
Monocyte %	0.25 (−3.95, 1.14)	0.280	0.03 (−7.14,-0.08)	0.045
CRP	1.00 (−0.01, 0.02)	0.448	1.01 (−0.01, 0.04)	0.247
BUN	1.06 (−0.13, 0.26)	0.528	1.15 (−0.11, 0.39)	0.265
LDH	1 (−0.01, 0.01)	0.580	1.00 (−0.01, 0.01)	0.485
Oxygenation index	0.99 (−0.03, 0)	0.149	0.99 (−0.03, 0.01)	0.198
ARDS	0.20 (−4.38, 1.19)	0.263	0.09 (−5.67, 0.93)	0.159
SOFA score	0.31 (−2.49, 0.14)	0.081	0.51 (−2.10, 0.77)	0.365
SOFA score ≥2	165.41 (1.57, 8.64)	0.005	1630.70 (2.52, 12.27)	0.003

Abbreviations: ARDS, Acute Respiratory Distress Syndrome; BUN, blood urea nitrogen; CRP, C-reactive protein; ECMO, extracorporeal membrane oxygenation; LDH, lactate dehydrogenase; NLR, neutrophil to lymphocyte ratio; SOFA, Sequential Organ Failure Assessment.

Figure 3 The correlation between the severity of liver injury and laboratory results. (A) the correlation between the severity of liver injury and the percentage of neutrophils and lymphocytes. (B) the correlation between the severity of liver injury and CURB-65 and sequential organ failure assessment (SOFA) score. (C) the correlation between the severity of liver injury and C-reactive protein (CRP). (D) the correlation between the severity of liver injury and oxygenation index.