Novel markers of endothelial dysfunction in hepatitis C virus-related cirrhosis: More than a mere prediction of esophageal varices

Table 1 Baseline laboratory and endoscopic findings of the enrolled patients

Variable	Liver cirrhosis with EVs	Liver cirrhosis without EVs	Control group	P value1
n	90	90	60	-
Sex (M/F)	62/28	60/30	40/20	0.4
Age (yr)	49.6 ± 8.4	47.7 ± 9.7	46 ± 6.7	0.32
BMI (kg/m2)	26.3 ± 2.1	25.8 ± 1.3	26.6 ± 0.9	0.21
ABI	0.94 ± 0.09	1.08 ± 0.13	1.16 ± 0.11	0.001
AST (IU/L)	53.7 ± 10.2	43.7 ± 5.6	31.1 ± 10.8	0.001
ALT (IU/L)	47.2 ± 7.8	36.2 ± 8.5	30.6 ± 7.7	0.001
Platelet count × 103	79.2 ± 21.2	189.3 ± 43.2	197.7 ± 18.7	0.001
Total cholesterol (mg/dL)	177.6 ± 18.8	199.2 ± 27.4	210.4 ± 12.6	0.01
HDL (mg/dL)	39.5 ± 4.3	44.6 ± 7.1	35.4 ± 5.3	0.004
TGs (mg/dL)	135.7 ± 14.4	168.8 ± 12.8	180.8 ± 8.4	0.01
VLDL (mg/dL)	16.6 ± 4.3	26.5 ± 5.3	25 ± 5.7	0.001
LDL (mg/dL)	105.8 ± 14.5	128.9 ± 20.6	138.9 ± 16.5	0.03
FIB-4	4.97 ± 1.8	1.54 ± 0.47	1.51 ± 0.3	0.001
Platelets/SD ratio	449 ± 167	1375 ± 380	1702 ± 238	0.001
LDL/platelet count ratio	1.41 ± 0.4	0.71 ± 0.21	0.75 ± 0.09	0.001
Child-Pugh class (n)	A (26), B (46), C (18)	A (88), B (2)	Non-cirrhotic	-
Endoscopy	-	-	-	-
EVs	-	-	-	-
Grade I-II, n (%)	32 (35.5)	-	-	-
Grade III, n (%)	42 (46.7)	-	-	-
Grade IV, n (%)	16 (17.8)	-	-	-
2Fundal varix, n (%)	12 (13.3)	-	-	-

¹P value less than 0.05 is considered significant.

²Fundal varices were not isolated but associated with G I esophageal varices (EV) (n = 2), G II EV (n = 6), G III-IV EV (n = 4).

BMI: Body mass index; ABI: Ankle-brachial index; LDL: Low-density lipoproteins; HDL: High-density lipoproteins; VLDL: Very low-density lipoproteins; TGs: Triglycerides; EVs: Esophageal varices; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; SD: Splenic diameter; FIB-4: Fibrosis index-4.

Table 2 Ultrasonographic and liver stiffness values of the enrolled patients

Variable	Liver cirrhosis with EVs	Liver cirrhosis without EVs	Control group	P value
Splenic diameter	182.9 ± 21.4	141 ± 12.8	111.2 ± 9.7	0.003
Platelets/SD ratio	449 ± 166	1374.9 ± 380	1701 ± 239	0.001
FibroScan (kPa)	24.4 ± 6.02	14.8 ± 1.9	5.2 ± 0.82	0.001
CIMT (mm)	1.2 ± 0.13	0.69 ± 0.14	0.62 ± 0.11	0.001

CIMT: Carotid-intima media thickness; EVs: Esophageal varices; SD: Splenic diameter.

Table 3 Discriminating ability of the novel markers in the studied groups

Variable	VLDL			CIMT			LDL/platelet ratio			ABI
Cutoff value	Below 16.5	Above 16.5	P value	Below 1.1	Above 1.1	P value	Below 1	Above 1	P value	Below 0.94	Above 0.94	P value
n	76	164	-	96	144	-	98	142	-	70	170	-
Sex (M/F)	56/20	106/58	0.2	64/32	98/46	0.86	66/32	96/46	0.83	47/23	115/55	0.45
Age (yr)	50.3 ± 10	48.5 ± 8.3	0.3	49.6 ± 8.6	48.7 ± 9	0.56	49.8 ± 8.8	48 ± 9	0.78	51.5 ± 8.9	48.2 ± 7.4	0.2
AST (IU/L)	46 ± 11.6	38.4 ± 12.1	0.01	47.5 ± 11.8	34.9 ± 8.4	0.01	52 ± 11	35 ± 9	0.001	49 ± 12	38 ± 11	0.03
ALT (IU/L)	45 ± 8.4	37.5 ± 8.5	0.03	46 ± 8	35.4 ± 7	0.03	45 ± 7.8	34 ± 5.6	0.02	43 ± 8	32 ± 8	0.047
Platelet count × 103	83.6 ± 47	165.5 ± 62.2	0.001	82.5 ± 41.4	182 ± 40	0.001	81 ± 26	188 ± 41	0.001	87 ± 23	160 ± 61	0.001
Total cholesterol	166 ± 21	198 ± 24	0.02	170 ± 18	200.5 ± 26	0.034	168 ± 26	197 ± 28	0.04	173 ± 27	196 ± 25	0.023
Triglycerides (mg/dL)	135.7 ± 15	164 ± 19	0.03	137 ± 15	168 ± 15	0.032	140 ± 19	168 ± 16	0.045	143 ± 18	162 ± 24	0.01
VLDL (mg/dL)	14.6 ± 1.5	26.2 ± 5.6	0.001	17 ± 4.9	28 ± 7	0.001	15 ± 4	32 ± 6	0.001	17 ± 5	25 ± 12	0.03
LDL (mg/dL)	106 ± 15	126 ± 21	0.001	102 ± 13	130 ± 20	0.023	110 ± 17	122 ± 20	0.06	109 ± 19	129 ± 22	0.021
HDL (mg/dL)	40 ± 4	43 ± 8	0.89	39 ± 5	42 ± 8.2	0.45	40 ± 5	42 ± 8	0.82	39 ± 4	42 ± 8	0.34
FIB-4	5.03 ± 1.8	2.2 ± 1.6	0.001	5 ± 2	1.7 ± 0.6	0.001	4.9 ± 1.9	1.6 ± 0.5	0.001	4.2 ± 2	2.4 ± 1.9	0.01
LDL/platelet count ratio	1.5 ± 0.48	0.84 ± 0.3	0.001	1.4 ± 0.4	0.75 ± 0.21	0.001	1.5 ± 0.3	0.7 ± 0.15	0.001	1.24 ± 0.21	0.91 ± 0.34	0.001S
Splenic diameter (mm)	186.3 ± 25.4	141.5 ± 24	0.001	185.4 ± 20	133 ± 17	0.001	181 ± 24	122 ± 11	0.001	171 ± 29	136 ± 13	0.001
Platelets/SD	492.6 ± 76.2	1237.7 ± 502	0.001	463.3 ± 43	1400 ± 410	0.001	471 ± 213	1440 ± 402	0.001	678 ± 298	1173 ± 554	0.001

ABI: Ankle-brachial index; LDL: Low-density lipoproteins; HDL: High-density lipoproteins; VLDL: Very low-density lipoproteins; CIMT: Carotid-intima media thickness; SD: Splenic diameter; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; FIB-4: Fibrosis index-4.

Table 4 Performance of the novel markers when compared to the traditional tools

Cutoff value	PLT/SD ratio above 872	FIB-4 above 3.25	ABI below 0.94	LDL/PLT ratio above 1	CIMT above 1.1	VLDL below 16.5	P value
n	90	90	70	98	96	76
LS (kPa)	24.4 ± 6.2	26. 5 ± 5.2	22 ± 8.2	23 ± 7	24.6 ± 6.7	25.3 ± 6.3	F = 1.87, P = 0.117
ABI	1.08 ± 0.09	1.09 ± 0.1	0.887 ± 0.04	0.93 ± 0.1	0.88 ± 0.1	0.96 ± 0.08	F = 30, P = 0.001
Endoscopy	-	-	-	-	-	-	-
EVs, n (%)	82/90 (91.1)	56/90 (62.2)	65/70 (92.9)	92/98 (94)	90/96 (93.8)	68/76 (89.5)	P = 0.001
Grade I-II, n (%)	26/32 (81.3)	14/32 (35)	20/32 (62.5)	24/32 (75)	24/32 (75)	10/32 (31.3)	χ2 = 13.3, P = 0.009
Grade III, n (%)	32/42 (76.2)	30/42 (71.4)	30/42 (71.4)	42/42 (100)	40/42 (95)	34/42 (81)	χ2= 7.67, P = 0.104
Grade IV, n (%)	14/16 (87.5)	6/16 (37.5)	9/16 (56.3)	16/16 (100)	16/16 (100)	12/16 (75)	χ2= 9.55, P = 0.048
Fundal varix, n (%)	10/12 (83.3)	6/12 (50)	6/12 (50)	10/12 (83)	10/12 (83)	12/12 (100)	χ2= 3.47,P = 0.48

LS: Liver stiffness; ABI: Ankle-brachial index; LDL: Low-density lipoproteins; VLDL: Very low-density lipoproteins; EVs: Esophageal varices; CIMT: Carotid-intima media thickness; PLT: Platelets; SD: Splenic diameter; FIB-4: Fibrosis index-4.