Biomarkers in bile-complementing advanced endoscopic imaging in the diagnosis of indeterminate biliary strictures

Table 1 Potential biomarkers in bile

Bile biomarkers	Cut off value	Identification of CCA/pancreatic cancer	Sensitivity	Specificity	Comments
VEGF[57]	0.5 ng/mL	Pancreatic cancer (vs benign)	93.3%	72.7%	VEGF level in bile in CCA was not elevated. Another study[58] demonstrated increased serum VEGF in CCA-possible basolateral secretion of VEGF in bile duct epithelia in CCA?
	0.5 ng/mL	Pancreatic cancer (vs CCA)	93.3%	88.9%
IGF[58]	NA	CCA	NA	NA	ROC (area under the curve = 1); Serum IGF levels were similar among CCA, pancreatic cancer and benign groups
CEAM6[50] CEAM6 + Serum CA 19-9	67.9 ng/mL	Malignant (CCA + pancreatic cancer)	93%	83%	Biliary levels were not critically affected by bile duct obstruction; Serum CEAM6 levels were not significantly different between the malignant and benign groups
			97%	83%
	67.9 ng/mL, 157 kU/L
NGAL[37] NGAL + Serum CA 19-9	459 ng/mL 459 ng/mL, 30.1 U/mL	Malignant (CCA + pancreatic cancer)	77.3% 91%	72.2% 66.7%	In both the studies, serum NGAL levels were not significantly different between benign and malignant groups; biliary levels were independent of serum bilirubin levels. Especially elevated in early well differentiated carcinomas in tissue immunohistochemistry-possible future application in PSC to R/O early malignant lesions/dysplasias
NGAL[38] NGAL + Serum CA 19-9	570 ng/mL 3000 ng /mL, 125 U/L	Malignant (CCA + Pancreatic cancer + GB carcinoma + metastasis)	94% 85%	55% 82%
HSP[67]
HSP 27	2.52 ng/mL	CCA	90%	90%	Serum levels of these markers were not significantly different between CCA and benign strictures
HSP 70	5.67 ng/mL		80%	80%
HSP 27 + HSP 70	10.2 ng/mL		90%	100%
Galectin Ligands
Mac 2-BP[76]	853 ng/mL	All malignant strictures	69%	67%	Serum levels were not elevated in malignancies
Fibronectin[77]	40 ng/μmol	CCA	57%	79%	-
MCM 5[82]	1000 (cells)	CCA + Pancreatic cancer	66%	94%	MCM 5 levels in bile were significantly more sensitive than brush cytology (66% vs 20%; P = 0.004)
Pancreatic Elastase/ Amylase[83]	0.065	CCA	82%	89%	mRNA of PE 3B was also up-regulated in CCA tissues
Lipids[84]
ON-PC	6020.1 nmol/L	CCA	85.7%	80.3%	-
S-PC	12 nmol/L	CCA	83.3%	77.8%
ON-PC + S-PC	6032.2 nmol/L	CCA	100%	83.3%
VOCs
(TMA, acetone, isoprene, dimethyl sulfide, and acetaldehyde)[86]	Logarithmic model	Pancreatic cancer	83.3%	81.9%	-
(Acrylonitrile, methyl hexane and benzene)[87]	Logarithmic model	CCA in the setting of PSC	90.5%	72.7%	Biliary levels of VOCs in CCA (in the setting of PSC) were significantly lower than (benign) PSC

CCA: Cholangiocarcinoma; VEGF: Vascular endothelial growth factor; IGF: Insulin like growth factor; CEAM6: Carcinoembryonic cell adhesion molecule 6; NGAL: Neutrophil gelatinase-associated lipocalin; HSP: Heat shock proteins; PSC: Primary sclerosing cholangitis; MCM: Minichromosome maintenance proteins; VOC: Volatile organic compounds.