Progressive liver injury and increased mortality risk in COVID-19 patients: A retrospective cohort study in China

Table 1 Demographics, clinical characteristics, laboratory parameters, and computed tomography imaging features of 440 patients with coronavirus disease 2019, stratified by severity of cumulative liver abnormality or injury

	All patients (n = 440)	Normal cumulative LB (n = 186)	Cumulative LBA (n = 185)	Cumulative ALI (n = 69)	Cumulative LBAI (n = 254)	OR (95%CI)1	P value2
Characteristics
Age, yr, median (IQR)	63 (25)	61 (18)	63 (23)	65 (17)	64 (18)	2.536	0.012
< 50	65 (14.8)	33 (50.8)	23 (35.4)	9 (13.8)	32 (49.2)	Ref	Ref
50-64	203 (46.1)	91 (44.8)	85 (41.9)	27 (13.3)	112 (55.2)	1.27 (0.73 to 2.22)	0.404
≥ 65	172 (39.1)	62 (36.0)	77 (44.8)	33 (19.2)	110 (64.0)	1.83 (1.03 to 3.26)	0.040
Sex, female	233 (53.0)	79 (33.9)	109 (46.8)	45 (19.3)	154 (66.1)	2.09 (1.42 to 3.06)	< 0.0001
BMI, ≥ 24 kg/m2	124 (49.8)	63 (50.8)	45 (36.3)	16 (12.9)	61 (49.2)	0.95 (0.58 to 1.57)	0.849
Epidemiological exposure3	268 (60.9)	123 (45.9)	104 (38.8)	41 (15.3)	145 (54.1)	0.68 (0.46 to 1.01)	0.055
Smoking history	62 (20.9)	21 (33.9)	31 (50.0)	10 (16.1)	41 (61.1)	1.48 (0.84 to 2.61)	0.176
Comorbidities4	285 (64.8)	109 (38.2)	123 (43.2)	53 (18.6)	176 (61.8)	1.59 (1.07 to 2.37)	0.021
Hypertension	181 (41.1)	69 (38.1)	83 (45.9)	29 (16.0)	112 (61.9)	1.34 (0.91 to 1.97)	0.141
Diabetes	136 (30.9)	48 (35.3)	53 (39.0)	35 (25.7)	88 (64.7)	1.52 (1.00 to 2.31)	0.048
Cardiovascular disease	56 (12.7)	22 (39.3)	19 (33.9)	15 (26.8)	34 (60.7)	1.15 (0.65 to 2.04)	0.628
Cerebrovascular disease	16 (3.6)	4 (25.0)	8 (50.0)	4 (25.0)	12 (75.0)	2.26 (0.72 to 7.11)	0.165
Chronic renal disease	21 (4.8)	11 (52.4)	9 (42.9)	1 (4.8)	10 (47.6)	0.65 (0.27 to 1.57)	0.340
Chronic liver disease	12 (2.7)	4 (33.3)	7 (58.3)	1 (8.3)	8 (66.7)	1.48 (0.44 to 4.99)	0.527
Chronic hepatitis B	8 (1.8)	2 (25.0)	5 (62.5)	1 (12.5)	6 (75.0)	2.23 (0.44 to 11.15)	0.331
Other chronic liver disease5	4 (0.9)	2 (50.0)	2 (50.0)	0	2 (50.0)	0.73 (0.10 to 5.23)	0.754
Chronic respiratory disease	31 (7.0)	16 (51.6)	9 (29.0)	6 (19.4)	15 (48.4)	0.67 (0.32 to 1.39)	0.278
Signs and symptoms at disease onset
Fever (temperature ≥ 37.3 °C)	369 (85.8)	149 (40.4)	159 (43.1)	61 (16.5)	220 (59.6)	1.63 (0.95 to 2.81)	0.079
Sputum	236 (53.6)	93 (39.4)	104 (44.1)	39 (16.5)	143 (60.6)	1.29 (0.88 to 1.88)	0.191
Dyspnoea	243 (55.2)	82 (33.7)	116 (47.7)	45 (18.5)	161 (66.3)	2.2 (1.49 to 3.23)	< 0.0001
Haemoptysis	63 (14.3)	25 (39.7)	26 (41.3)	12 (19.0)	38 (60.3)	1.13 (0.66 to 1.95)	0.653
Chest pain/tightness	227 (51.6)	88 (38.8)	100 (44.1)	39 (17.2)	139 (61.2)	1.35 (0.92 to 1.97)	0.125
Pharyngalgia/nasal congestion/running	94 (21.4)	47 (50.0)	33 (35.1)	14 (14.9)	47 (50.0)	0.67 (0.42 to 1.06)	0.088
Headaches/dizziness	135 (30.7)	57 (42.2)	54 (40.0)	24 (17.8)	78 (57.8)	1.00 (0.67 to 1.51)	0.989
Myalgia/fatigue	289 (65.7)	122 (42.2)	120 (41.5)	47 (16.3)	167 (57.8)	1.01 (0.68 to 1.50)	0.973
Nausea/vomiting	133 (30.2)	53 (39.8)	59 (44.4)	21 (15.8)	80 (60.2)	1.15 (0.76 to 1.75)	0.498
Abdominal pain	70 (15.9)	29 (41.4)	26 (37.1)	15 (21.4)	41 (58.6)	1.04 (0.62 to 1.75)	0.876
Diarrhea	185 (42.0)	78 (42.2)	83 (44.9)	24 (13.0)	107 (57.8)	1.01 (0.69 to 1.48)	0.968
On-admission vital signs
Temperature, ≥ 37.3 °C	103 (23.8)	26 (25.2)	50 (48.5)	27 (26.2)	77 (74.8)	2.74 (1.67 to 4.49)	< 0.0001
Respiratory rate, ≥ 30 breaths per min	53 (12.1)	13 (24.5)	21 (39.6)	19 (35.8)	40 (75.5)	2.50 (1.30 to 4.82)	0.006
Pulse oximeter O2 saturation, ≤ 93%	146 (35.0)	25 (17.1)	82 (56.2)	39 (26.7)	121 (82.9)	6.37 (3.89 to 10.43)	< 0.0001
Systolic blood pressure, < 90 mmHg	4 (0.9)	2 (50.0)	2 (50.0)	0	2 (50.0)	0.74 (0.10 to 5.27)	0.760
Heart rate, > 125 beats per min	23 (5.2)	5 (21.7)	10 (43.5)	8 (34.8)	18 (78.3)	2.77 (1.01 to 7.61)	0.048
Severity of illness
In-hospital disease severity status, general	128 (29.1)	88 (68.8)	37 (28.9)	3 (2.3)	40 (31.3)	Ref	Ref
Severe	184 (41.8)	80 (43.5)	84 (45.7)	20 (10.9)	104 (56.5)	2.86 (1.78 to 4.59)	< 0.0001
Critical	128 (29.1)	18 (14.1)	64 (50.0)	46 (35.9)	110 (85.9)	13.44 (7.21 to 25.07)	< 0.0001
qSOFA score, 0	231 (52.7)	114 (49.4)	95 (41.1)	22 (9.5)	117 (50.6)	Ref	Ref
1	179 (40.9)	59 (33.0)	80 (44.7)	40 (22.3)	120 (67.0)	1.98 (1.32 to 2.97)	< 0.0001
2-3	28 (6.4)	13 (46.4)	9 (32.1)	6 (21.4)	15 (53.6)	1.12 (0.51 to 2.47)	0.770
CURB-65 score, 0-1	330 (75.3)	159 (48.2)	132 (40.0)	39 (11.8)	171 (51.8)	Ref
2	71 (16.2)	17 (23.9)	41 (57.7)	13 (18.3)	54 (76.1)	2.95 (1.64 to 5.31)	< 0.0001
3-5	37 (8.4)	10 (27.0)	11 (29.7)	16 (43.2)	27 (73.0)	2.51 (1.18 to 5.35)	0.017
Routine blood results
White blood cell count, < 3.5 × 109/L	44 (10.0)	17 (38.6)	19 (43.2)	8 (18.2)	27 (61.4)	0.68 (0.35 to 1.29)	0.234
3.5-9.5	313 (71.3)	151 (48.2)	126 (40.3)	36 (11.5)	162 (51.8)	Ref	Ref
> 9.5	82 (18.7)	18 (22.0)	40 (48.8)	24 (29.3)	64 (78.0)	2.24 (1.00 to 4.99)	0.049
Lymphocyte count, < 1.1 × 109/L	232 (52.8)	62 (26.7)	115 (49.6)	55 (23.7)	170 (73.3)	4.1 (2.74 to 6.12)	< 0.0001
Neutrophil count, > 6.3 × 109/L	149 (33.9)	44 (29.5)	73 (49.0)	32 (21.5)	105 (70.5)	2.29 (1.50 to 3.49)	< 0.0001
Hemoglobin, < 130 g/L for male; < 115 g/L for female	194 (44.4)	85 (43.8)	76 (39.2)	33 (17.0)	109 (56.2)	0.90 (0.61 to 1.31)	0.576
Platelet count, < 125 × 109/L	59 (13.5)	17 (28.8)	31 (52.5)	11 (18.6)	42 (71.2)	1.98 (1.09 to 3.6)	0.026
Biochemical results-basic values
Albumin, < 35 g/L	232 (52.7)	58 (25.0)	118 (50.9)	56 (24.1)	174 (75.0)	4.80 (3.19 to 7.22)	< 0.0001
ALT, > 41 U/L for male; > 33 U/L for female	113 (25.7)	0	77 (68.1)	36 (31.9)	113 (100.0%)	-	-
AST, > 40 U/L for males; > 32 U/L for females	144 (32.7)	0	91 (63.2)	53 (36.8)	144 (100.0)	-	-
Total bilirubin, > 26 mmol/L for males; > 21 mmol/L for females	25 (5.7)	0	12 (48.0)	13 (52.0)	25 (100.0)	-	-
Direct bilirubin, > 8.0 mmol/L	61 (13.9)	4 (6.6)	29 (47.5)	28 (45.9)	57 (93.4)	13.16 (4.68 to 37.01)	< 0.0001
Lactate dehydrogenase, > 225 U/L for males; > 214 U/L for females	332 (75.5)	105 (31.6)	162 (48.8)	65 (19.6)	227 (68.4)	6.49 (3.96 to 10.62)	< 0.0001
γ-Glutamyl transferase, > 71 U/L for males; > 42 U/L for females	115 (26.4)	20 (17.4)	62 (53.9)	33 (28.7)	95 (82.6)	5.12 (3.01 to 8.7)	< 0.0001
Creatinine, > 104 μmol/L for males; > 84 μmol/L for females	70 (16.0)	22 (31.4)	31 (44.3)	17 (24.3)	48 (68.6)	1.73 (1.01 to 2.99)	0.048
C-reactive protein, ≥ 1 mg/L	369 (87.6)	145 (39.3)	161 (43.6)	63 (17.1)	224 (60.7)	2.92 (1.59 to 5.36)	0.0010
Coagulation and inflammation index results
Prothrombin time, ≤ 14.5 s	289 (66.3)	144 (49.8)	116 (40.1)	29 (10.0)	145 (50.2)	0.35 (0.23 to 0.54)	< 0.0001
Prothrombin activity, < 75%	82 (18.8)	14 (17.1)	43 (52.4)	25 (30.5)	68 (82.9)	4.39 (2.38 to 8.09)	< 0.0001
Activated partial thromboplastin time, > 42.0 s	166 (38.2)	46 (27.7)	89 (53.6)	31 (18.7)	120 (72.3)	2.69 (1.77 to 4.07)	< 0.0001
D-dimer, > 0.5 μg/mL	295 (68.4)	87 (29.5)	145 (49.2)	63 (21.4)	208 (70.5)	5.17 (3.33 to 8.03)	< 0.0001
Serum ferritin, > 400 μg/L for males; > 150 μg/L for females	319 (81.0)	111 (34.8)	153 (48.0)	55 (17.2)	208 (65.2)	6.91 (3.80 to 12.57)	< 0.0001
Interleukin-6, ≥ 7 pg/mL	255 (62.3)	73 (28.6)	123 (48.2)	59 (23.1)	182 (71.4)	4.62 (3.01 to 7.08)	< 0.0001
Interleukin-10, ≥ 5 pg/mL	177 (44.1)	41 (23.2)	90 (50.8)	46 (26.0)	136 (76.8)	4.67 (3.01 to 7.25)	< 0.0001
Procalcitonin, ≥ 0.5 ng/mL	57 (13.6)	10 (17.5)	29 (50.9)	18 (31.6)	47 (82.5)	3.76 (1.84 to 7.68)	< 0.0001
Imaging features
Bilateral	381 (93.2)	155 (40.7)	162 (42.5)	64 (16.8)	226 (59.3)	2.62 (1.18 to 5.84)	0.018
Ground-glass opacity	306 (74.8)	119 (38.9)	131 (42.8)	56 (18.3)	187 (61.1)	1.73 (1.10 to 2.72)	0.017
Consolidation	89 (21.8)	29 (32.6)	36 (40.4)	24 (27.0)	60 (67.4)	1.69 (1.03 to 2.78)	0.037
Pleural effusion	47 (11.5)	6 (12.8)	25 (53.2)	16 (34.0)	41 (87.2)	5.85 (2.42 to 14.13)	< 0.0001

Data are presented as medians (interquartile range) or n (%) according to the corresponding conditions.

¹ORs were calculated using univariate unconditional logistic regression.

²All P values were calculated using univariate unconditional logistic regression for the characteristics between the patients with normal cumulative liver biochemistry and those with cumulative liver biochemical abnormality or injury, but two independent samples (unpaired) Student's t-test was used to compare the median ages.

³Referring to exposure to confirmed coronavirus disease 2019 patients.

⁴Comorbidities were defined as history of at least one disease out of the following: Hypertension, diabetes, cardiovascular disease, cerebrovascular disease, chronic renal disease, chronic respiratory disease, and chronic liver disease.

⁵Four patients reported history of either fatty liver or cirrhosis. “-“: It is not applicable due to the no individuals with abnormal alanine aminotransferase or aspartate aminotransferase or total bilirubin in normal cumulative liver biochemistry group. COVID-19: Coronavirus disease 2019; LB: Liver biochemistry; LBA: Liver biochemical abnormality; ALI: Acute liver injury; LBAI: Liver biochemical abnormality or injury; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CURB-65: Confusion, uremia, respiratory rate, blood pressure, and age ≥ 65; IQR: Interquartile range; OR: Odds ratio; CI: Confidence interval; qSOFA: Quick Sequential Organ Failure Assessment; BMI: Body mass index.

Table 2 Outcomes for 440 patients of coronavirus disease 2019, stratified by severity of cumulative liver abnormality or injury

	All patients (n = 440)	Normal cumulative LB (n = 186)	Cumulative LBA (n = 185)	Cumulative ALI (n = 69)	Cumulative LBAI (n = 254)	P value1
Outcomes
Discharge	304 (69.1)	166 (54.6)	117 (38.5)	21 (6.9)	138 (45.4)	< 0.00012
Death	98 (22.3)	11 (11.2)	45 (45.9)	42 (42.9)	87 (88.8)
Still in hospital	38 (8.6)	9 (23.7)	23 (60.5)	6 (15.8)	29 (76.3)
ICU admission	91 (20.7)	11 (12.1)	45 (49.5)	35 (38.5)	80 (88.0)	< 0.0001
Time from illness onset to hospital admission (median, IQR), d	438	19 (11 to 35)	13 (9 to 19)	11 (8 to 16)	12 (9 to 18)	< 0.0001
Hospital stay time (median, IQR), d	402	12 (6 to 22)	19 (11 to 29)	17 (8 to 28)	19 (10 to 29)	< 0.0001
Time from illness onset to death (median, IQR), d	93	19 (9 to 26)	23 (16 to 33)	28 (18 to 33)	25 (17 to 33)	0.037
Time from illness onset to discharge (median, IQR), d	303	40 (32 to 49)	40 (34 to 51)	42 (31 to 51)	40 (34 to 50)	0.088
Time from illness onset to last day of follow-up (median, IQR), d	37	61 (52 to 66)	59 (49 to 64)	58 (52 to 67)	59 (51 to 65)	0.689
Time from illness onset to ICU admission (median, IQR), d	90	15 (13 to 25)	18 (11 to 30)	19 (14 to 26)	18 (12 to 26)	0.478
Duration of viral shedding after illness onset (median, IQR), d	298	33 (24 to 42)	30 (25 to 38)	26 (21 to 36)	30 (24 to 38)	0.172

Data are presented as n (%).

¹Comparison of the characteristics between normal cumulative liver biochemistry and cumulative liver biochemical abnormality or injury was calculated by Pearson's chi-square test for outcomes and a nonparametric Mann-Whitney U test was used for time.

²Comparison of the distribution of disease outcomes (discharge, death, and still in hospital) between normal cumulative liver biochemistry and cumulative liver biochemical abnormality or injury. COVID-19: Coronavirus disease 2019; LB: Liver biochemistry; LBA: Liver biochemical abnormality; LBAI: Liver biochemical abnormality or injury; ALI: Acute liver injury; ICU: Intensive care unit; IQR: Interquartile.