Natural history of covert hepatic encephalopathy: An observational study of 366 cirrhotic patients

Table 1 Comparison of baseline characteristics between cirrhotic patients with and without covert hepatic encephalopathy (unimpaired)

	Unimpaired, n =235	CHE, n = 131	P value
Sex, female/male	67/168	32/99	0.40
Age in yr	46.3 ± 8.9	48.8 ± 7.8	0.009
Cause
HBV-associated	180 (76.7)	94 (71.8)	0.31
HCV-associated	8 (3.4)	4 (3.1)	0.86
Alcohol-associated	25 (10.6)	19 (14.5)	0.28
Others	22 (9.4)	14 (10.7)	0.68
Level of education
Primary school	34 (14.5)	45 (34.4)	< 0.001
Junior high school	99 (42.1)	52 (39.7)	0.65
Senior high school	70 (29.8)	33 (25.2)	0.35
College degree or above	32 (13.6)	1 (0.8)	< 0.001
Creatinine	69.0 ± 16.3	71.3 ± 28.0	0.32
Venous ammonia	44.3 ± 4.2	57.9 ± 8.9	< 0.001
Albumin	33.5 ± 7.7	26.2 ± 6.1	< 0.001
High total bilirubin	17.3 ± 12.3	17.0 ± 9.1	0.76
Platelets, 109/L	102.6 ± 99.7	98.5 ± 96.7	0.70
International normalization ratio	1.14 ± 0.12	1.14 ± 0.15	0.99
Ascites, none/mild/severe	138/65/32	19/30/82	< 0.001
History of OHE	12 (5.1)	54 (41.2)	< 0.001
CPC, N, A/B/C	118/111/6	40/74/17	< 0.001
MELD score	14.6 ± 2.9	16.9 ± 6.0	0.02

Data are presented as n, n (%) or mean ± SD. CHE: Covert hepatic encephalopathy; CPC: Child-Pugh classification; HBV: Hepatitis B virus; HCV: Hepatitis C virus; MELD: Model for end-stage liver disease; OHE: Overt hepatic encephalopathy.

Table 2 Comparison of clinical characteristics between 131 covert hepatic encephalopathy patients with and without overt hepatic encephalopathy development, between those with and without development of the first cirrhosis-related complications requiring hospitalization, between those with and without resolution of covert hepatic encephalopathy, and between survivors and non-survivors during follow-up

	Development of OHE			Complication(s)			Death			Resolution of CHE
	Yes, n = 23	No, n = 108	P value	Yes, n = 37	No, n = 94	P value	Yes, n = 15	No, n = 116	P value	Yes, n = 26	No, n = 105	P value
Male sex	19 (82.6)	80 (74.1)	0.39	33 (89.2)	66 (70.2)	0.02	14 (93.3)	85 (73.3)	0.09	14 (53.8)	85 (81)	0.004
Age in yr	46.4 ± 7.9	47.3 ± 8.7	0.56	47.3 ± 8.3	47.2 ± 8.7	0.90	44.7 ± 7.8	47.4 ± 8.6	0.13	47.8 ± 8.2	49.0 ± 7.8	0.48
HBV-associated	17 (73.9)	77 (71.3)	0.80	27 (73.0)	67 (71.3)	0.85	9 (60)	85 (73.3)	0.28	17 (65.4)	77 (73.3)	0.42
Creatinine	80.5 ± 42.7	68.6 ± 16.8	0.001	76.5 ± 33.2	68.0 ± 16.1	0.001	95.3 ± 46.4	67.9 ± 16.6	< 0.001	72.6 ± 23.7	71.0 ± 29.1	0.80
Albumin in g/L	27.2 ± 8.1	31.3 ± 7.8	0.003	29.9 ± 7.9	31.1 ± 8.0	0.23	29.0 ± 8.4	31.0 ± 7.9	0.21	27.8 ± 5.3	25.8 ± 6.2	0.13
Total bilirubin in μmol/L	23.3 ± 16.7	16.5 ± 10.2	< 0.001	22.5 ± 16.3	15.7 ± 8.9	< 0.001	29.5 ± 24.0	16.3 ± 9.0	< 0.001	15.8 ± 10.5	17.2 ± 8.8	0.47
Platelets, 109/L	62.0 ± 37.2	105.7 ± 102.4	0.009	81.8 ± 105.8	106.6 ± 95.9	0.046	81.3 ± 59.2	102.7 ± 100.8	0.29	131.1 ± 109.2	90.35 ± 92.1	0.05
INR	1.2 ± 0.2	1.1 ± 0.1	< 0.001	1.2 ± 0.1	1.1 ± 0.1	< 0.001	1.3 ± 0.2	1.1 ± 0.1	< 0.001	1.1 ± 0.1	1.1 ± 0.2	0.49
Ascites, none/mild/severe	2/14/2007	12/28/68	0.03	8/21/2008	11/22/61	0.35	1/14/2000	19/29/68	0.03	9/13/2004	15/21/69	0.25
History of OHE	13 (56.5)	41 (38.0)	0.10	17 (45.9)	37 (39.4)	0.49	12 (80)	42 (36.2)	0.001	3 (11.5)	51 (48.6)	0.001
CPC, A/B/C	3/18/2	37/56/15	0.06	6/23/8	34/51/9	0.04	7/8/2000	40/67/9	< 0.001	3/2/2021	19/71/15	< 0.001
MELD score	19.6 ± 4.7	14.9 ± 4.1	< 0.001	19.2 ± 4.2	14.3 ± 3.8	< 0.001	23.3 ± 5.0	14.8 ± 3.7	< 0.001	13.7 ± 4.0	17.7 ± 6.2	0.002
Complications	23 (100)	14 (13.0)	< 0.001	37 (100)	0	< 0.001	10 (66.7)	27 (23.3)	< 0.001	0	37 (35.2)	< 0.001
OHE	23 (100)	0	< 0.001	23 (62.2)	0	< 0.001	7 (46.7)	16 (13.8)	0.002	0	23 (21.9)	< 0.001
Mortality	7 (30.4)	8 (7.4)	0.002	10 (27.0)	5 (5.3)	< 0.001	15 (100)	0	< 0.001	0	15 (14.3)	< 0.001

Data are presented as n, n (%) or mean ± SD. CHE: Covert hepatic encephalopathy; CPC: Child-Pugh classification; HBV: Hepatitis B virus; INR: International normalization ratio; MELD: Model for end-stage liver disease; OHE: Overt hepatic encephalopathy.

Table 3 Cox analysis of predictors for developing overt hepatic encephalopathy, the first cirrhosis-related complications requiring hospitalization, and mortality in 131 covert hepatic encephalopathy patients

	Predictor(s)	β	HR	95%CI	P value
For developing OHE	Albumin < 30 g/L	1.65	5.22	1.22-22.32	0.03
For developing the first cirrhosis-related complications	Cr > 133 μmol/L	1.24	3.46	1.46-8.20	0.005
	MELD score > 20	2.31	10.12	4.14-24.74	< 0.001
	PLT < 80 × 109/L	2.52	2.44	1.69-6.60	0.013
For mortality	Cr > 133 μmol/L	1.51	4.75	1.10-20.44	0.036

Cr: Creatinine; MELD: Model for end-stage liver disease; OHE: Overt hepatic encephalopathy; PLT: Platelet.