Increased international normalized ratio level in hepatocellular carcinoma patients with diabetes mellitus

Table 1 Baseline characteristics of the study population and univariate analysis of comparison of hepatocellular carcinoma patients with and without diabetes n (%)

Variable	Total patients (n = 375)	HCC patients with diabete (n = 63)	HCC patients without diabetes (n = 312)	P value
Male sex	312 (83.2)	51 (81.0)	261 (83.7)	0.601
Mean age, yr (mean ± SD)	56.4 ± 11.0	59.5 ± 10.3	55.8 ± 11.1	0.015
Body weight1, kg (mean ± SD)	68.1 ± 10.9	69.3 ± 13.0	67.8 ± 10.5	0.346
Body height2, cm (mean ± SD)	168.8 ± 7.0	168.6 ± 8.0	168.9 ± 6.8	0.810
BMI3, kg/m2 (mean ± SD)	23.77 ± 3.39	23.69 ± 3.51	23.68 ± 3.71	0.991
Overweight or obesity3	159 (56.6)	27 (57.4)	132 (56.4)	0.896
History of hypertension	88 (23.5)	17 (27.0)	71 (22.8)	0.470
SBP, mmHg (mean ± SD)	130 ± 17	133 ± 17	129 ± 16	0.048
DBP, mmHg (mean ± SD)	79 ± 10	78 ± 10	79 ± 10	0.455
Smoking	154 (41.4)	20 (31.7)	134 (42.9)	0.099
Alcohol intake	104 (27.7)	14 (22.2)	90 (28.8)	0.284
HBV infection	328 (87.5)	50 (79.4)	278 (89.1)	0.033
HCV infection	22 (5.9)	3 (4.8)	19 (6.1)	0.908
Liver cirrhosis	199 (53.1)	38 (60.3)	161 (51.6)	0.206
Fatty liver	11 (2.9)	2 (3.2)	9 (2.9)	1.000
Child-Turcotte-Pugh classification4
Child A	243 (65.5)	35 (56.5)	208 (67.3)	0.101
Child B	92 (24.8)	17 (27.4)	75 (24.3)	0.600
Child C	36 (9.7)	10 (16.1)	26 (8.4)	0.061
AFP > 400 ng/mL5	167 (45.8)	27 (43.5)	140 (46.2)	0.702
Neutrophil, × 109/L (mean ± SD)	4.13 ± 2.49	3.88 ± 2.52	4.18 ± 2.49	0.389
Hemoglobin, g/L (mean ± SD)	132.5 ± 23.8	124.4 ± 23.9	134.2 ± 23.4	0.003
Platelet count, × 109/L	130 (85-189)	113 (64-157)	139 (89-192)	0.020
ALT, U/L	45 (29-81)	44 (27-91)	45 (30-79)	0.943
AST, U/L	62 (38-117)	52 (34-97)	66 (39-119)	0.124
ALP, U/L	111 (82-176)	111 (84-171)	111 (81-177)	0.907
GGT, U/L	106 (55-233)	96 (51-190)	109 (57-239)	0.406
INR6 (mean ± SD)	1.20 ± 0.27	1.31 ± 0.44	1.18 ± 0.21	0.001
Total bilirubin, mg/L	16 (10-27)	17 (10-31)	16 (10-25)	0.561
Albumin, g/L (mean ± SD)	37.4 ± 6.0	36.4 ± 5.9	37.6 ± 6.0	0.148
Total cholesterol, mmol/L (mean ± SD)	4.26 ± 1.34	4.18 ± 1.12	4.28 ± 1.39	0.662
BUN, mmol/L	5.14 (4.00-6.36)	5.12 (3.92-6.46)	5.18 (4.04-6.34)	0.738
Creatinine, μmol/L	80 (71-88)	80 (70-97)	80 (71-88)	0.860

Data were available in

¹366 (60 + 306),

²286 (49 + 237),

³281 (47 + 234),

⁴371 (62 + 309),

⁵365 (62 + 303) and

⁶367 (62 + 305) patients. The numbers before the brackets indicate the total available cases in the two groups. BMI: Body mass index; BUN: Blood urea nitrogen; DBP: Diastolic blood pressure; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; INR: International normalized ratio; SBP: Systolic blood pressure; ALT: Aminoleucine transferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: Galactosylhydroxylysyl glucosyltransferase.

Table 2 Tumor-node-metastasis stage and clinical type of the study population n (%)

Variable	Total patients (n = 375)	HCC patients with diabetes (n = 63)	HCC patients without diabetes (n = 312)	P value
T stage
T1	82 (21.9)	15 (23.8)	67 (21.5)	0.683
T2	90 (24.0)	19 (30.2)	71 (22.8)	0.210
T3a	157 (41.9)	22 (34.9)	135 (43.3)	0.221
T3b	37 (9.9)	6 (9.5)	31 (9.9)	0.920
T4	9 (2.4)	1 (1.6)	8 (2.6)	0.991
N stage
N0	334 (89.1)	57 (90.5)	277 (88.8)	0.694
N1	41 (10.9)	6 (9.5)	35 (11.2)	-
M stage
M0	269 (71.7)	49 (77.8)	220 (70.5)	0.243
M1	106 (28.3)	14 (22.2)	92 (29.5)	-
Clinical classification
Massive	213 (56.8)	29 (46.0)	184 (59.0)	0.059
Nodular	117 (31.2)	22 (34.9)	95 (30.4)	0.485
Small-cancer	28 (7.5)	8 (12.7)	20 (6.4)	0.142
Diffuse	17 (4.5)	4 (6.3)	13 (4.2)	0.503

HCC: Hepatocellular carcinoma; T: Tumor; N: Node; M: Metastasis.

Table 3 Multivariable analysis: Increased international normalized ratio level in hepatocellular carcinoma patients with diabetes mellitus

Variable	AOR	95%CI	P value
Model 1
INR	3.650	1.372-9.714	0.010
SBP	1.019	1.002-1.036	0.029
Hemoglobin	0.987	0.975-0.999	0.038
Model 2
INR	4.487	1.713-11.754	0.002
Age	1.032	1.005-1.059	0.020

Model 1: Based on the results of univariate analysis, unconditional multivariable logistic regression analysis was performed. Six variables were included, including age, systolic blood pressure (SBP), hepatitis B virus (HBV) infection, hemoglobin, platelet count and international normalized ratio (INR). Statistical differences were shown for 3 variables (shown in Table), and other four variables were omitted because no significant differences were found; Model 2: According to the published literatures and our current knowledge, more potential confounding factors were controlled, including age, sex, HBV infection, hepatitis C virus infection, alcohol drinking, liver cirrhosis, Child-Turcotte-Pugh classification and INR. AOR: Adjusted odds ratio.

Table 4 Results of multivariable analysis for sub-group analysis

Variable1	AOR2	95%CI	P value
HCC patients with liver cirrhosis
INR	5.161	1.618-16.455	0.006
HCC patients without liver cirrhosis
INR	2.082	0.130-33.333	0.604
Age	1.060	1.015-1.107	0.008
HCC patients with HBV infection
INR	2.508	0.860-7.315	0.092
Hemoglobin	0.984	0.970-0.998	0.024

¹International normalized ratio (INR) and variables with significant difference were shown;

²Adjusted odds ratio (AOR) for the confounding effect of age, systolic blood pressure, hemoglobin, platelet count, and hepatitis B virus (HBV) infection using unconditional multivariable logistic regression analyses, based on the results of univariate analysis shown in Table 1. HCC: Hepatocellular carcinoma.

Table 5 Association between diabetes duration/treatment and International normalized ratio level n (%)

Variable	INR < 1.20 (n = 36)	INR≥1.20 (n = 27)	P value	INR < 1.50 (n = 52)	INR≥1.50 (n = 11)	P value
Duration of diabetes, yr
< 5	15 (41.70)	13 (48.10)	0.608	23 (44.20)	5 (45.50)	1.000
≥ 5	21 (58.30)	14 (51.90)	-	29 (55.80)	6 (54.50)	-
Age at diabetes diagnosis, yr
< 50	11 (30.60)	12 (44.40)	0.257	15 (28.80)	8 (72.70)	0.016
≥ 50	25 (69.40)	15 (55.60)	-	37 (71.20)	3 (27.30)	-
Diabetes treatment
Oral treatment
Non-users	21 (58.30)	19 (70.40)	0.326	31 (59.60)	9 (81.80)	0.296
Users	15 (41.70)	8 (29.60)	-	21 (40.40)	2 (18.20)	-
Insulin treatment
Non-users	27 (75.00)	25 (92.60)	0.138	43 (82.70)	9 (81.80)	1.000
Users	9 (25.00)	2 (7.40)	-	9 (17.30)	2 (18.20)	-
Diet only
Non-users	16 (44.40)	17 (63.00)	0.145	26 (50.00)	7 (63.60)	0.411
Users	20 (55.60)	10 (37.00)	-	26 (50.00)	4 (36.40)	-
Type of oral treatment
Biguanide
Non-users	32 (88.90)	22 (81.50)	0.640	43 (82.70)	11 (100)	0.310
Users	4 (11.10)	5 (18.50)	-	9 (17.30)	0 (0)	-
Sulfonylureas
Non-users	29 (80.60)	23 (85.20)	0.886	42 (80.80)	10 (90.9)	0.713
Users	7(19.40)	4 (14.80)	-	10 (19.20)	1 (9.1)	-
α-glucosidase inhibitor
Non-users	29 (80.60)	25 (92.60)	0.323	44 (84.60)	10 (90.9)	0.946
Users	7 (19.40)	2 (7.40)	-	8 (15.40)	1 (9.1)	-

INR: International normalized ratio.