Abnormal liver chemistries as a predictor of COVID-19 severity and clinical outcomes in hospitalized patients

Table 1 Baseline and clinical characteristics of patients with a positive test for severe acute respiratory syndrome coronavirus-2

Variables	All patients (n = 3830)	Non-severe1 (n = 2476)	Severe1 (n = 1354)	P value
Age in yr, median (IQR)	64.2 (49.6- 77.3)	62.1 (45.2-76)	67.4 (55.6-79.1)	< 0.001
Sex, n (%), Male	1959 (51.1)	1179 (47.6)	780 (57.6)	< 0.001
Ethnicity, n (%), Hispanic	817 (21.5)	565 (23)	252 (18.8)	0.003
Race, n (%)				0.12
White	1389 (36.6)	877 (35.7)	512 (38.2)
Black	1323 (34.8)	848 (34.5)	475 (35.4)
Asian	203 (5.3)	133 (5.4)	70 (5.2)
Other	883 (23.2)	600 (24.4)	283 (21.1)
BMI (kg/m2), n (%)				0.11
≤ 18.5	794 (23.2)	519 (23.4)	275 (22.8)
18.5-24.9	98 (2.9)	56 (2.5)	42 (3.5)
25-29.9	1036 (30.3)	693 (31.3)	343 (28.4)
≥ 30.0	1494 (43.7)	946 (42.7)	548 (45.4)
Comorbidities, n (%)
Chronic liver disease	465 (12.1)	295 (11.9)	170 (12.6)	0.56
Cardiovascular disease
Congestive heart failure	869 (22.7)	395 (16)	474 (35)	< 0.001
HT without complications	2575 (67.2)	1766 (71.3)	717 (53)	< 0.001
HT with complications	1347 (35.2)	710 (28.7)	637 (47)	< 0.001
Diabetes
Diabetes without complications	1459 (38.1)	856 (34.6)	603 (44.5)	0.017
Diabetes with complications	1270 (33.2)	679 (27.4)	591 (43.6)	< 0.001
Chronic respiratory disease	1065 (27.8)	618 (25)	447 (33)	< 0.001
Chronic neurological disease	1033 (27.0)	569 (23)	464 (34.3)	< 0.001
CKD of any stage	973 (25.4)	491 (19.8)	482 (35.6)	< 0.001
Anemia	1655 (43.2)	906 (36.6)	749 (55.3)	< 0.001
Hypothyroidism	557 (14.5)	330 (13.3)	227 (16.8)	0.004
Malignancies
Primary cancer	458 (12)	276 (11.1)	182 (13.4)	0.036
Metastatic cancer	277 (7.2)	167 (6.7)	110 (8.1)	0.12
Laboratory findings, median (IQR)
Liver biochemistries:
ALT, median (IQR)	28 (18-47)	27 (18-45)	30 (19-49)	0.003
Normal, n (%)	1132 (29.6)	852 (34.4)	280 (20.7)
Abnormal, n (%)	2698 (70.4)	1624 (65.6)	1074 (79.3)	< 0.001
1-2 ULN, n (%)	1225 (32)	829 (33.5)	396 (29.2)
> 2-5 ULN, n (%)	1009 (26.3)	583 (23.5)	426 (31.5)
> 5 ULN, n (%)	464 (12.1)	212 (8.6)	252 (18.6)
AST, median (IQR)	36 (25-55)	34 (24-51.5)	42 (29-64)	< 0.001
Normal, n (%)	2046 (55.6)	1443 (60.5)	603 (46.4)
Abnormal, n (%)	1637 (44.4)	941 (39.5)	696 (53.6)	< 0.001
1-2 ULN, n (%)	1187 (32.2)	704 (29.5)	483 (37.2)
> 2-5 ULN, n (%)	361 (9.8)	194 (8.1)	167 (12.9)
> 5 ULN, n (%)	89 (2.4)	43 (1.8)	46 (3.5)
T.Bil, median (IQR)	0.5 (0.3-6.1)	0.4 (0.3-6.0)	0.5 (0.4-7.0)	< 0.001
Normal, n (%)	3496 (94.1)	2286 (95.3)	1210 (91.7)
Abnormal, n (%)	221 (5.9)	112 (4.7)	109 (8.3)	< 0.001
1-2 ULN, n (%)	177 (4.8)	89 (3.7)	88 (6.7)
> 2-5 ULN, n (%)	34 (0.9)	17 (0.7)	17 (1.3)
> 5 ULN, n (%)	10 (0.3)	6 (0.3)	4 (0.3)
ALP, median (IQR)	78 (61-103)	77 (61-100)	79 (61-108)	0.014
Normal, n (%)	3183 (83.9)	2101 (85.6)	1082 (80.7)
Abnormal, n (%)	611 (16.1)	353 (14.4)	258 (19.3)	< 0.001
1-2 ULN, n (%)	525 (13.8)	311 (12.7)	214 (16)
> 2-5 ULN, n (%)	78 (2.1)	38 (1.5)	40 (3)
> 5 ULN, n (%)	8 (0.2)	4 (0.2)	4 (0.3)
GGT, median (IQR)	119 (63-199)	116 (80-161)	144.5 (59-245)	0.54
Serum Albumin, g/dL median (IQR)	3.8 (3.4- 4.1)	3.9 (3.5-4.2)	3.6 (3.1-3.9)	< 0.001
Total protein (g/L), median (IQR)	6.5 (5.9- 7.1)	6.7 (6.1-7.2)	6.3 (5.7-6.9)	< 0.001
Coagulation test: median (IQR)
PT (s)	11 (10.5-11.9)	10.9 (10.4-11.6)	11.4 (10.8-12.4)	< 0.001
INR	1.07 (1-1.14)	1.05 (1.0-1.1)	1.1 (1.02-1.20)	< 0.001
APTT (s)	26.2 (1.2-32.2)	25.9 (1.1-31)	25.7 (1.3-33.6)	< 0.001
D-Dimer	1.0 (0.57, 2.06)	0.83 (0.5-1.62)	0.4 (0.8-3.0)	< 0.001
Routine blood tests: median (IQR)
Hemoglobin (g/dL)	11.9 (10.1, 13.3)	12.2 (10.7-13.6)	10.9 (9-12.7)	< 0.001
White blood cell (/mcL)	7.4 (5.1-10.5)	6.8 (4.7-9.3)	9 (6.4-13)	< 0.001
Red blood cells (/mcL)	4.06 (3.34-4.63)	4.19 (3.59-4.70)	3.81 (3.02-4.46)	< 0.001
Platelets (/mcL)	229 (168-309)	223 (166-298)	238 (172-327)	< 0.001
Neutrophils(/mcL)	36 (5.23-73)	36 (4.6-70.7)	38.9 (6.75-77.9)	< 0.001
Lymphocytes (/mcL)	15.4 (9.2-23.6)	17.8 (11.3-26.1)	11.5 (6.3-18.4)	< 0.001
Renal function tests: median (IQR)
Creatinine (mg/dL)	0.9 (0.7-1.3)	0.85 (0.7-1.1)	1.03 (0.7-1.8)	< 0.001
Blood urea nitrogen, (mmol/L)	17 (11-28)	15 (10-22)	25 (16-42)	< 0.001
Sodium (mEq/L)	138 (136-141)	138 (136-140)	139 (136-143)	< 0.001
Potassium (mEq/L)	4.1 (3.8-4.5)	4.1 (3.8-4.4)	4.2 (3.8-4.6)	< 0.001
Inflammatory markers: median (IQR)
Interleukin-6 (pg/mL)	37 (14.5-90.8)	24.7 (10.6-52.2)	81.83 (31.2-181)	< 0.001
Ferritin (ng/mL)	587 (265-1090)	482 (207-900)	810 (413.5-1462.5)	< 0.001
C reactive protein (mg/L)	8.4 (3.4-21.4)	6.4 (2.5-15.5)	13.6 (6.6-33.2)	< 0.001
Fibrinogen (mg/dL)	495 (387-622)	475 (374-579)	524 (393-653)	< 0.001
Lactate(mmol/L)	1.4 (1.1-2.0)	1.3 (1.0-1.7)	1.6 (1.2-2.3)	< 0.001
Cardiac markers: median (IQR)
Cardiac troponin I (ng/L)	0.07 (0.04-0.18)	0.05 (0.03-0.1)	0.09 (0.05-0.27)	< 0.001
Lactate dehydrogenase (U/L)	327 (245-460)	303 (229-411)	385 (290-533)	< 0.001

¹Based on the World Health Organization disease severity classification.

SARS-CoV-2: Severe acute respiratory syndrome coronavirus-2; IQR: Interquartile range; BMI: Body mass index; Fio2: Fraction of inspired oxygen; HIV/AIDS: Human immunodeficiency virus/acquired immunodeficiency síndrome; HT: Hypertension; CKD: Chronic kidney disease; ALT: Alanine aminotransferases; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: γ-glutamyl transpeptidase; T-Bil: Total bilirubin; PT: Prothrombin time; INR: International normalized ratio; APTT: Activated partial thromboplastin time; ULN: Upper limit of normal.

Table 2 In-hospital management and outcomes of patients with a positive test for severe acute respiratory syndrome coronavirus-2

Characteristics	All patients (n = 3830)	Non-severe1 (n = 2476)	Severe1 (n = 1354)	P value
Respiratory support, n (%)
Non-rebreathing oxygen face mask	3147 (82.2)	1821 (73.5)	1326 (97.9)	< 0.001
High-flow nasal cannula oxygen therapy	843 (22)	18 (0.7)	825 (60.9)	< 0.001
Pharmacological treatment, n (%)
NSAIDs	3303 (86.2)	2107 (85.1)	1196 (88.3)	0.005
Antiviral therapy	192 (5)	106 (4.3)	86 (6.4)	0.005
Antibacterial therapy	2649 (69.2)	1483 (59.9)	1166 (86.1)	< 0.001
Antifungal therapy	234 (6.1)	59 (2.4)	175 (12.9)	< 0.001
Azithromycin	947 (24.7)	530 (21.4)	417 (30.8)	< 0.001
Hydroxychloroquine	423 (11)	239 (9.7)	184 (13.6)	< 0.001
Oseltamivir	10 (0.3)	4 (0.2)	6 (0.4)	0.10
Remdesivir	1303 (34)	741 (29.9)	562 (41.5)	< 0.001
Vitamin D	391 (10.2)	227 (9.2)	164 (12.1)	0.004
Statins	1457 (38)	865 (34.9)	592 (43.7)	< 0.001
ACE inhibitors	378 (9.9)	215 (8.7)	163 (12)	< 0.001
ARB inhibitors	414 (10.8)	246 (9.9)	168 (12.4)	0.018
Immunomodulatory therapy, n (%)
Dexamethasone	1560 (40.7)	881 (35.6)	679 (50.1)	< 0.001
Tocilizumab	95 (2.5)	3 (0.1%)	92 (6.8)	< 0.001
Advanced therapies, n (%)
Vasopressors	587 (15.3)	2 (0.1)	585 (43.2)	< 0.001
Renal replacement therapy/dialysis	188 (4.9 )	6 (0.2)	182 (13.4)	< 0.001
Clinical outcome, n (%)
Discharged alive from hospital	3138 (87.2)	2372 (100)	766 (62.4)	< 0.001
Median length of hospital stay (IQR)	6.3 (3.4-12.1)	4.8 (2.8-7.7)	12.3 (7.1-22.3)	< 0.001

¹Based on the World Health Organization disease severity classification.

SARS-CoV-2: Severe acute respiratory syndrome coronavirus; IQR: Interquartile range; NSAIDs: Nonsteroidal anti-inflammatory drugs; ACE: Angiotensin-converting enzyme; ARB: Angiotensin II receptor blockers.

Table 3 Major outcome as the need for mechanical ventilation and mortality among patients with a positive test for severe acute respiratory syndrome coronavirus-2

Liver function test	No mechanical ventilation ( n = 3205)	Mechanical ventilation (n = 625)	P value	Survivor (n = 3369)	Non-survivors (n = 461)	P value
Age in yr, median (IQR)	63.8 (48.4-77.7)	66.3 (54.9-75.2)	0.030	62.3 (47.7-74.7)	78.1 (66.9-87.6)	< 0.001
Comorbidities, n (%)
Chronic liver disease	385 (12)	80 (12.8)	0.58	419 (12.4)	46 (10)	0.13
Cardiovascular disease
Congestive heart failure	662 (20.7)	207 (33.1)	< 0.001	693 (20.6)	176 (38.2)	< 0.001
HT without complications	2112 (65.9)	463 (74.1)	< 0.001	2214 (65.7)	361 (78.3)	< 0.001
HT with complications	1059 (33)	288 (46.1)	< 0.001	1097 (32.6)	250 (54.2)	< 0.001
Diabetes
Diabetes without complications	1161 (36.2)	298 (47.7)	< 0.001	1269 (37.7)	190 (41.2)	0.14
Diabetes with complications	979 (30.5)	291 (46.6)	< 0.001	1076 (31.9)	194 (42.1)	< 0.001
Chronic respiratory disease	865 (27)	200 (32)	0.011	910 (27)	155 (33.6)	0.03
Chronic neurological disease	810 (25.3)	223 (35.7)	< 0.001	835 (24.8)	198 (43)	< 0.001
CKD of any stage	764 (23.8)	209 (33.4)	< 0.001	787 (23.4)	186 (40.3)	< 0.001
Anemia	1281 (40)	374 (59.8)	< 0.001	1379 (40.9)	276 (59.9)	< 0.001
ALT, median (IQR)	27 (18-46)	33 (21-54)	< 0.001	28 (18-47)	27 (17-45)	0.28
Normal, n (%)	1055 (32.9)	77 (12.3)		1011 (30)	121 (26.2)
1-2 ULN, n (%)	1065 (33.2)	160 (25.6)	< 0.001	1090 (32.4)	135 (29.3)	< 0.001
> 2-5 ULN, n (%)	786 (24.5)	223 (35.7)		902 (26.8)	107 (23.2)
> 5 ULN, n (%)	299 (9.3)	165 (26.4)		366 (10.9)	98 (21.3)
AST, median (IQR)	35 (24-54)	44.5 (31-70)	< 0.001	35 (25 -54)	45 (29 -71)	< 0.001
Normal, n (%)	1794 (58.3)	252 (41.7)		1856 (57.2)	190 (43.5)
1-2 ULN, n (%)	946 (30.7)	241 (39.9)	< 0.001	1023 (31.5)	164 (37.5)	< 0.001
> 2-5 ULN, n (%)	283 (9.2)	78 (12.9)		300 (9.2%)	61 (14.0)
> 5 ULN, < 0.001 (%)	56 (1.8)	33 (5.5)		67 (2.1%)	22 (5)
Bilirubin, median (IQR)	0.5 (0.3-0.6)	0.5 (0.4-0.7)	< 0.001	0.5 (0.3-0.6)	0.5 (0.4-0.8)	< 0.001
Normal, n (%)	2943 (94.7)	553 (90.8)		3102 (94.9)	394 (88.1)
1-2 ULN, n (%)	133 (4.3)	44 (7.2)	< 0.001	135 (4.1)	42 (9.4)	< 0.001
> 2-5 ULN, n (%)	23 (0.7)	11 (1.8)		26 (0.8)	8 (1.8)
> 5 ULN, n (%)	9 (0.3)	1 (0.2)		7 (0.2)	3 (0.7)
ALP, median (IQR))	77 (61-101)	80 (62-110)	0.062	77 (61-100)	87 (64-118)	< 0.001
Normal, n (%)	2686 (84.5)	497 (80.7)		2837 (85)	346 (75.7)
1-2 ULN, n (%)	420 (13.2)	105 (17)	0.091	435 (13)	90 (19.7)	< 0.001
> 2-5 ULN, n (%)	65 (2)	13 (2.1)		58 (1.7)	20 (4.4)
> 5 ULN, n (%)	7 (0.2)	1 (0.2)		7 (0.2)	1 (0.2)
GGT, median (IQR)	116 (56-199)	144.5 (106-235.5)	0.483	117 (56-199)	180 (116.5-447.5)	0.28

SARS-CoV-2: Severe acute respiratory syndrome coronavirus-2; IQR: Interquartile range; HT: Hypertension; CKD: Chronic kidney disease; ALT: Alanine aminotransferases; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: γ-glutamyl transpeptidase; T-Bil: Total bilirubin; ULN: Upper limit of normal.

Table 4 Multivariable Cox proportional hazards model for outcomes among hospitalized patients with a positive test for severe acute respiratory syndrome coronavirus-2

Clinical predictors	Mechanical ventilation1		Mortality1
	Multivariable HR (95%CI)	P Value	Multivariable HR (95%CI)	P Value
Age	1.00 (0.99-1.01)	0.553	1.04 (1.03-1.05)	< 0.001
Male Gender	1.19 (0.99-1.43)	0.067	1.11 (0.90-1.37)	0.338
Overweight	0.93 (0.73-1.19)	0.577	0.75 (0.59-0.97)	0.030
Obesity	0.94 (0.74-1.19)	0.609	0.58 (0.44-0.77)	< 0.001
Liver diseases	0.84 (0.65-1.09)	0.198	0.78 (0.55-1.11)	0.164
Chronic respiratory disease	1.15 (0.95-1.38)	0.156	1.16 (0.94-1.45)	0.167
HT without complications	0.85 (0.68-1.06)	0.152	0.68 (0.53-0.89)	0.005
HT with complications	1.29 (1.01-1.66)	0.045	1.06 (0.78-1.430)	0.727
Congestive heart failure	0.78 (0.64-0.95)	0.014	1.00 (0.80-1.25)	0.987
Chronic neurological disease	0.78 (0.65-0.95)	0.012	1.44 (1.18-1.76)	< 0.001
Chronic kidney disease	0.94 (0.76-1.15)	0.535	1.55 (1.26-1.88)	< 0.001
ALT	1.00 (1.00-1.00)	0.420	1.00(1.00 - 1.00)	0.892
ALP	1.00 (1.00-1.00)	0.916	1.02 (1.02-1.03)	< 0.001
AST	1.00 (1.00-1.00)	0.003	1.00 (1.00-1.01)	< 0.001
T-Bil	1.06 (0.99-1.14)	0.008	1.21 (1.14-1.28)	< 0.001
Albumin	0.87 (0.76-1.01)	0.071	0.84 (0.71-1.01)	0.057
INR	0.91 (0.77-1.09)	0.312	1.12 (0.99-1.26)	0.071
PT	1.00 (0.98-1.02)	0.814	1.03 (1.02-1.05)	< 0.001
Neutrophil	1.00 (1.00-1.00)	0.858	1.00 (1.00-1.01)	0.008
BUN	1.01 (1.00-1.01)	<0.001	1.01 (1.01-1.02)	< 0.001
Creatinine	1.07 (1.02-1.13)	0.007	1.16 (1.11-1.22)	< 0.001
Interleukin-6	1.00 (1.00-1.00)	<0.001	1.00 (1.00-1.00)	< 0.001
CRP	1.02 (1.01-1.03)	0.001	1.04 (1.03-1.05)	< 0.001
Ferritin	1.00 (1.00-1.00)	0.002	1.00 (1.00-1.00)	0.001
D-Dimer	1.00 (0.98-1.02)	0.721	1.03 (1.01-1.05)	0.004
LDH	1.00 (1.00-1.00)	0.063	1.00 (1.00-1.01)	< 0.001

¹Age, gender, ethnicity, race, body mass index, and all the preexisting comorbidities were adjusted as confounders in the Multivariable Cox proportional hazards model.

SARS-CoV-2: Severe acute respiratory syndrome coronavirus-2; HT: Hypertension; ALT: Alanine aminotransferases; ALP: Alkaline phosphatase; GGT: γ-glutamyl transpeptidase; AST: Aspartate aminotransferase; T-Bil: Total bilirubin; INR: International normalized ratio; BUN: Blood urea nitrogen; PT: Prothrombin time; CRP: C-reactive protein; LDH: Lactate Dehydrogenase; HR:Hazard ratio; CI: Confidence interval.

Table 5 Association of abnormal liver chemistries and mortality in patients with a positive test for severe acute respiratory syndrome coronavirus-2

Parameters	Unadjusted, Cox regression		Adjusted1, Cox regression		Log-rank test
	HR (95%CI)	P value	HR (95%CI)	P value	P value
ALT, Abnormality type
Normal,	Reference		Reference
1-2 ULN	0.83 (0.65-1.07)	0.146	0.95 (0.72-1.25)	0.719	< 0.001
> 2-5 ULN	0.52 (0.40-0.68)	< 0.001	0.68 (0.53-0.92)	0.013
> 5 ULN	0.84 (0.64-1.11)	0.219	1.31 (0.98-1.79)	0.092
AST, Abnormality type
Normal	Reference		Reference
1-2 ULN	1.16 (0.94-1.43)	0.169	1.07 (0.84-1.35)	0.584	0.001
> 2-5 ULN	1.48 (1.11-1.98)	0.008	1.49 (1.06-2.10)	0.021
> 5 ULN	2.13 (1.37-3.32)	0.001	2.19 (1.27-3.76)	0.005
Bilirubin, Abnormality type
Normal	Reference		Reference
1-2 ULN	1.74 (1.27-2.40)	0.001	1.58 (1.04-2.22)	0.032	< 0.001
> 2-5 ULN	2.49 (1.24-5.02)	0.011	6.00 (2.90-12.41)	< 0.001
> 5 ULN	2.78 (0.89-8.65)	0.078	7.86 (1.88-32.96)	0.005
ALP, Abnormality type
Normal	Reference		Reference
1-2 ULN	1.52 (1.20-1.92)	< 0.001	1.42 (1.09-1.86)	0.009	0.001
> 2-5 ULN	2.13 (1.36-3.35)	0.001	1.81 (1.05-3.10)	0.032
> 5 ULN	1.05 (0.15-7.45)	0.964	1.84 (0.25-13.38)	0.547

¹Age, gender, ethnicity, race, body mass index, and all the preexisting comorbidities were adjusted as confounders in the Multivariable Cox proportional hazards model.

SARS-CoV-2: Severe acute respiratory syndrome coronavirus-2; ALT: Alanine aminotransferases; AST: Aspartate aminotransferase; T-Bil: Total bilirubin; ALP: Alkaline phosphatase; HR: Hazard ratio; CI: Confidence interval; ULN: Upper limit of normal.