Better performance of PIVKA-II for detecting hepatocellular carcinoma in patients with chronic liver disease with normal total bilirubin

Table 1 Clinical characteristics of patients with non-hepatocellular carcinoma and hepatocellular carcinoma

Variable	Non-HCC			HCC
	Viral liver disease (n = 595)	Nonviral liver disease (n = 189)	P value	Early stage HCC (n = 127)	Late stage HCC (n = 140)	P value
Age (yr)	46.2 ± 13.4	49.6 ± 13.5	0.003	56.5 ± 10.8	55.5 ± 12.1	0.488
Male, n (%)	418 (70.3)	117 (61.9)	0.032	113 (89.0)	125 (89.3)	0.935
Etiology			-			0.333
HBV	561 (94.3)	-		115 (90.6)	130 (92.9)
HCV	34 (5.7)	-		2 (1.6)	2 (1.4)
NAFLD	-	56 (29.6)		2 (1.6)	-
ALD	-	82 (43.4)		6 (4.7)	8 (5.7)
AILD	-	51 (27.0)		2 (1.6)	-
Cirrhosis, n (%)	274 (46.1)	75 (39.7)	0.125	112 (88.2)	120 (85.7)	0.550
ALT (U/L)	48 (25, 171)	40 (24, 74)	< 0.001	31 (22, 42)	40 (25, 67)	0.003
AST (U/L)	44 (27, 101)	38 (25, 60)	0.007	32 (24, 47)	60 (35, 95)	< 0.001
ALP (U/L)	92 (75, 122)	97 (72, 141)	0.153	90 (70, 120)	112 (88, 177)	< 0.001
GGT (U/L)	50 (28, 113)	94 (39, 241)	< 0.001	44 (25, 78)	113 (57, 208)	< 0.001
TBIL (μmol/L)	19.8 (13.2, 31.6)	16.1 (10.5, 35.0)	0.006	18.4 (11.6, 29.4)	19.3 (13.6, 30.2)	0.277
ALB (g/L)	38.8 ± 6.3	38.7 ± 7.7	0.834	38.3 ± 7.0	36.6 ± 6.0	0.036
PLT (109/L)	161 (104, 199)	206 (124, 273)	< 0.001	145 (87, 178)	188 (132, 242)	< 0.001
Tumor size (cm)	-	-	-	2.2 (1.5, 2.9)	9.3 (5.8, 13.2)	< 0.001
Number of tumors (1/2-3/> 3)	-	-	-	115/12/0	62/33/45	< 0.001
Vascular invasion	-	-	-	-	53 (37.9)	-
Extrahepatic metastases	-	-	-	-	13 (9.3)	-
PIVKA II > 40 mAU/mL, n (%)	83 (13.9)	39 (20.6)	0.027	77 (60.6)	131 (93.6)	< 0.001
PIVKA II (mAU/mL)	23.0 (18.0, 31.0)	27.0 (20.0, 38.0)	< 0.001	58.0 (25.0, 228.0)	5124 (691.0, 36245.0)	< 0.001

HCC: Hepatocellular carcinoma; HBV: Hepatitis B virus; HCV: Hepatitis C virus; NAFLD: Nonalcoholic fatty liver disease; ALD: Alcohol-related liver disease; AILD: Autoimmune liver disease; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyltranspeptidase; TBIL: Total bilirubin; ALB: Albumin; PLT: Platelet; PIVKA-II: Protein induced by vitamin K absence or antagonist-II.

Table 2 Factors associated with abnormally elevated protein induced by vitamin K absence or antagonist-II by univariate and multivariate logistic analysis in non-hepatocellular carcinoma patients

Non-HCC	Univariate		Multivariate
	OR (95%CI)	P value	OR (95%CI)	P value
Age (yr)	1.009 (0.995, 1.024)	0.195
Gender (M)	2.102 (1.308, 3.379)	0.002
Etiology		< 0.001		< 0.001
NAFLD	-		-
HBV	4.556 (1.089, 19.055)		3.214 (0.762, 13.548)
HCV	1.687 (0.227, 12.571)		1.528 (0.204, 11.442)
ALD	15.577 (3.542, 68.507)		9.883 (2.216, 44.086)
AILD	4.295 (0.849, 21.729)		1.993 (0.368, 10.792)
Cirrhosis (+)	1.848 (1.250, 2.731)	0.002
ALT/ULN	1.026 (0.991, 1.063)	0.150
AST/ULN	1.076 (1.029, 1.126)	0.001
ALP/ULN	2.630 (1.823, 3.795)	< 0.001	2.146 (1.429, 3.221)	< 0.001
GGT/ULN	1.105 (1.050, 1.163)	< 0.001
TBIL/ULN	1.228 (1.142, 1.321)	< 0.001	1.162 (1.080, 1.250)	< 0.001
ALB/LLN	0.063 (0.024, 0.166)	< 0.001
PLT/LLN	0.618 (0.445, 0.857)	0.004

HCC: Hepatocellular carcinoma; OR: Odds ratio; CI: Confidence interval; M: male; HBV: Hepatitis B virus; HCV: Hepatitis C virus; NAFLD: Nonalcoholic fatty liver disease; ALD: Alcohol-related liver disease; AILD: Autoimmune liver disease; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyltranspeptidase; TBIL: Total bilirubin; ALB: Albumin; PLT: Platelet; ULN: Upper limit of normal; LLN: Lower limit of normal.

Table 3 Factors associated with abnormally elevated protein induced by vitamin K absence or antagonist-II by univariate and multivariate logistic analyses in hepatocellular carcinoma patients

HCC	Univariate		Multivariate
	OR (95%CI)	P value	OR (95%CI)	P value
Age (yr)	1.002 (0.977, 1.027)	0.895
Gender (M)	1.692 (0.726, 3.944)	0.223
Etiology (viral)	1.008 (0.319, 3.185)	0.989
Cirrhosis (+)	0.712 (0.280, 1.810)	0.475
ALT/ULN	2.242 (1.235, 4.068)	0.008
AST/ULN	2.745 (1.573, 4.788)	< 0.001	1.759 (1.072, 2.887)	0.025
ALP/ULN	3.542 (1.478, 8.490)	0.005
GGT/ULN	1.436 (1.120, 1.843)	0.004
TBIL/ULN	1.287 (0.947, 1.749)	0.108
ALB/LLN	0.202 (0.042, 0.974)	0.046
PLT/LLN	1.558 (0.985, 2.464)	0.058
Tumor size (cm)	1.394 (1.221, 1.592)	< 0.001	1.349 (1.175, 1.549)	< 0.001
Number of tumors (1/2-3/> 3)	2.242 (1.340, 3.752)	0.002
Vascular invasion (+)	5.907 (1.772, 19.696)	0.004
Extrahepatic metastases (+)	3.551 (0.452, 27.887)	0.228

HCC: Hepatocellular carcinoma; OR: Odds ratio; CI: Confidence interval; M: Male; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyltranspeptidase; TBIL: Total bilirubin; ALB: Albumin; PLT: Platelet; ULN: Upper limit of normal; LLN: Lower limit of normal.

Table 4 Performance characteristics of serum protein induced by vitamin K absence or antagonist-II in diagnosing early-stage hepatocellular carcinoma in different subgroups

Early HCC	AUC (95%CI)	Cutoff value (mAU/mL)	Se (%)	Sp (%)	LR+	LR-	P value
All early	0.765 (0.714, 0.815)	41.0	60.63	85.08	4.06	0.46
Etiology							0.678
Viral	0.783 (0.732, 0.835)	42.8	58.97	87.73	4.81	0.47
Nonviral	0.736 (0.519, 0.952)	177.0	60.00	94.18	10.31	0.42
ALP							0.398
≤ 1 ULN	0.783 (0.725, 0.840)	41.0	58.42	89.95	5.81	0.46
> 1 ULN	0.729 (0.618, 0.841)	42.0	69.23	71.07	2.39	0.43
TBIL							0.015
≤ 1 ULN	0.817 (0.762, 0.872)	41.0	60.67	91.73	7.34	0.43
> 1 ULN	0.669 (0.563, 0.775)	42.0	60.53	73.19	2.26	0.54
AST							0.941
≤ 1 ULN	0.774 (0.712, 0.836)	41.0	57.95	88.08	4.86	0.48
> 1 ULN	0.778 (0.691, 0.864)	41.0	66.67	82.41	3.79	0.40

AUC: Area under the ROC curve; CI: Confidence interval; Se: Sensitivity; Sp: Specificity; LR+: Positive likelihood ratio; LR-: Negative likelihood ratio; ALP: Alkaline phosphatase; TBIL: Total bilirubin; AST: Aspartate aminotransferase; ULN: Upper limit of normal.

Table 5 Sensitivity, specificity, positive/negative likelihood ratio of protein induced by vitamin K absence or antagonist-II in diagnosing early-stage hepatocellular carcinoma at the cutoff value of 40 mAU/mL in patients with viral etiology and hepatitis B virus alone, respectively

	Cutoff value (mAU/mL)	Viral etiology				HBV
		Se (%)	Sp (%)	+LR	-LR	Se (%)	Sp (%)	+LR	-LR
ALP
≤ 1ULN	40	52.88	91.39	6.14	0.52	53.00	90.80	5.76	0.52
1ULN	40	30.61	92.45	4.06	0.75	30.61	92.23	3.94	0.75
TBIL
≤ 1ULN	40	57.47	91.37	6.66	0.47	57.14	90.72	6.16	0.47
1ULN	40	30.30	92.02	3.80	0.76	30.77	91.76	3.73	0.75

HBV: Hepatitis B virus; Se: Sensitivity; Sp: Specificity; LR+: Positive likelihood ratio; LR-: Negative likelihood ratio; ALP: Alkaline phosphatase; TBIL: Total bilirubin; ULN: Upper limit of normal.