Circulating predictive and diagnostic biomarkers for hepatitis B virus-associated hepatocellular carcinoma

Table 1 Diagnostic serum biomarkers for hepatitis B virus-associated hepatocellular carcinoma

Marker	Cut-off1	Sensitivity	Specificity	Detection method (most reliable)	Ref.
AFP	7.7-112.0 ng/mL	25%-90%	87%-97%	ELISA	[36,73]
AFP-l3	3%-20%	36%-96%	89%-94%	Liquid-Phase Binding Assay	[46,47,52]
DCP	40-150 mAU/mL	44%-91%	68%-99%	Electrochemiluminescence immunoassay	[36,53]
Osteopontin	9.3-642.5 ng/mL	73%-97%	55%-100%	ELISA	[65]
GP73	78-150 ng/mL	68%-95%	9%-97%	Immunoblotting, Western Blotting or ELISA2	[36,71,72]
GPC-3	2-300 ng/mL	36%-100%	40%-100%	ELISA	[36,78]
SCCA	0.12-3.80 ng/mL	42%-80%	50%-88%	ELISA	[36,81]
DKK1	1.01-2.15 ng/mL	69%-91%	62%-91%	ELISA	[86-88]
miRNA-21	NA	84%-90%	71%-92%	qRT-PCR	[83]
miRNA-122	NA	70%-82%	69%-84%	qRT-PCR	[83]

¹Range of cut-off values used in different studies included in the discussed meta-analyses and systematic reviews;

²Equally reliable. Relative levels were used with different internal standards to measure miRNA-concentrations. The choice of the most reliable detection method was based on recent studies involving at least 100 patients. Only biomarkers of which at least 4 different studies discussing their diagnostic potential exist, were included. AFP: Alpha-fetoprotein; DCP: Des-gamma carboxy prothrombin; GP73: Golgi-protein 73; GPC-3: Glypican-3; SCCA: Squamous cell carcinoma antigen; DKK1: Dickkopf-1; miRNA: MicroRNA; ELISA: Enzyme-linked immunosorbent assay; qRT-PCR: Quantitative reverse transcriptase polymerase chain reaction; NA: Not applicable.

Table 2 Predictive serum biomarkers for hepatitis B virus-associated hepatocellular carcinoma

	Marker	Cut-off	Increased risk for HCC	Control group1	Follow-up time	Ref.
Viral	HBeAg	Positive	4-fold	HBeAg negative HBV patients	8 yr	[114]
	HBV DNA	> 1 million copies/mL	11-fold	HBV patients with HBV DNA < 300 copies/mL	11 yr	[115]
	HBsAg	> 1000 IU/mL	3-fold	HBV patients with HBsAg 5-9 IU/mL	14.7 yr	[117]
Host	Gamma-GT Iso-enzyme II	Positive	86-fold	GGT Iso-enzyme II negative HBV patients	10 yr	[128]
	Gamma-GT	> 41 U/L	8-fold	HBV patients with Gamma-GT ≥ 41 U/L	5.9 yr	[129]
	AFP	> 5 ng/mL	8-fold	HBV patients with AFP ≤ 5 ng/mL	5.9 yr	[129]
	COMP	Positive	3-fold	COMP negative HBV and HCV patients	8 yr	[134]
	IL-6	> 7 pg/mL	3-fold	HBV patients with IL-6 < 7 pg/mL	7.25 yr	[135]
	sPD-1	> 637.6 pg/mL	2-fold	HBV patients with sPD-1 < 117.3 pg/mL	20 yr	[138]

¹Control group: group included in the study, to which the increased HCC risk was calculated. HBeAg: Hepatitis B e antigen; HBV: Hepatitis B virus; HBsAg: Hepatitis B surface antigen; Gamma-GT: Gamma glutamyltransferase; AFP: Alpha-fetoprotein; COMP: Cartilage oligomeric matrix protein; IL-6: Interleukin 6; sPD-1: Soluble programmed death 1.