Non-invasive biomarkers for monitoring the fibrogenic process in liver: A short survey

Table 1 Class I biomarkers of liver fibrogenesis

	Specimen			Method
	Serum	Urine	Liver biopsy
Extracellular matrix-related enzymes
Enzyme
Prolyl hydroxylase	+	-	+	Radioenzymatic, RIA
Monoamine-oxidase	+	-	(+)	Enzymatic
Lysyl oxidase	+	-	+	RIA
Lysyl hydroxylase	+	-	-	RIA
Galactosylhydroxylysyl-glucosyltransferase	+	-	+	RIA
Collagen peptidase	+	-	+	Enzymatic
N-Acetyl-β-D-glucosaminidase	+	+	+	Enzymatic
Collagen fragments and split products
Type of collagen
Type I-procollagen
N-terminal propeptide (PINP)	+	-	+	ELISA
C-terminal propeptide (PICP)	+	-	+	RIA
Type III-Procollagen
Intact Procollagen	+	-	-	RIA
N-terminal propeptide (PIIINP)
Complete propeptide (Col 1-3)	+	-	-	RIA
Globular domain of Propeptide (Col-1)	+	-	-	RIA
Type IV-Collagen
NC1-fragment (C-terminal) crosslinking domain (PIVP)	+	+	-	ELISA, RIA
7S domain ("7S Collagen")	+	+	-	RIA
Type VI-Collagen	+	+	+	RIA
Glycoproteins and matrix-metalloproteinase (inhibitors)
Marker
Laminin, P1-fragment	+	-	-	RIA, EIA
Undulin	+	-	-	EIA
Vitronectin	+	-	-	EIA
Tenascin	+	-	-	ELISA
YKL-40	+	-	+	RIA/ELISA
(pro)matrix metalloproteinase (MMP-2)	+	-	-	ELISA
Tissue inhibitor of metalloproteinases (TIMP-1, TIMP-2)	+	-	-	ELISA
sICAM-1 (soluble intercellular adhesion molecule, sCD54)
sVCAM-1 (soluble vascular cell adhesion molecule, sCD106)	+	-	-	ELISA
Glycosaminoglycans
Marker
Hyaluronic acid (Hyaluronan)	+	-	-	Radioligand assay ELISA
Molecular mediators
Marker
Transforming growth factor β (TGF-β)	+	-	+	ELISA
Connective tissue growth factor (CTGF/CCN2)	+	?	+	ELISA

Table 2 Class II biomarkers of liver fibrogenesis

Index	Parameters	Chronic liver disease	Sensitivity (%)	Specificity (%)
PGAA-Index	Prothrombin time, γGT, apolipoprotein A1, α2-macroglobulin	Alcohol	79	89
Bonacini-Index	ALT/AST-ratio, INR, platelet count	HCV	46	98
Sheth-Index	AST/ALT (De Ritis)	HCV	53	100
Park-Index		HCV	47	96
PGA-Index	Prothrombin time, γGT, apolipoprotein A1	Mixed	91	81
Fortunato-Score	Fibronectin, prothrombin time, PCHE, ALT, Mn-SOD, β-NAG	HCV		94
Fibrotest (Fibro-Score)	Haptoglobin, α2-macroglobulin, apolipoprotein A1, γGT, bilirubin	HCV	75	85
		HBV
Pohl-Score	AST/ALT-ratio, platelet count	HCV	41	99
Actitest	Fibrotest + ALT	HCV
Forns-Index	Age, platelet count, γGT, cholesterol	HCV	94	51
Wai-Index (APRI)	AST, platelet count	HCV	89	75
Rosenberg-Score (ELF-Score)	PIIINP, hyaluronan, TIMP-1	Mixed	90	41
Patel-Index (FibroSpect)	Hyaluronan, TIMP-1, α2-macroglobulin	HCV	77	73
Sud-Index (fibrosis probability-index, FPI)	Age, AST, cholesterol, insulin resistance (HOMA), past alcohol intake	HCV	96	44
Leroy-Score	PIIINP, MMP-1	HCV	60	92
Fibrometer test	Platelet count, prothrombin index, AST, α2-macro-globulin, hyaluronan, urea, age	Mixed	81	84
Hepascore	Bilirubin, γGT, hyaluronan, α2-macroglobulin, age, gender	HCV	63	89
Testa-Index	Platelet count/spleen diameter-ratio	HCV	78	79
FIB-4	Platelet count, AST, ALT, age	HCV/HIV	70	74
FibroIndex	Platelet count, AST, γ-globulin	HCV	38	97

GGT: γ-glutamyltransferase; PIIINP: N-terminal propeptide of type III procollagen; TIMP: Tissue inhibitors of metalloproteinases; MMP: Matrix metalloproteinases; β-NAG: N-acetyl-β-glucosaminidase; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; INR: International normalized ratio.

Table 3 Future candidate biomarkers of non-invasive diagnosis and follow-up of liver fibrogenesis

Biomarker	Specimen	Assay technology	Pathobiochemical basis
CTGF	Serum	Immunoassay	TGF-β induced expression in and secretion by hepatocytes and hepatic stellate cells
Fibrocytes	Blood, buffy coat	Flow cytometry of CD34+, CD45+, Coll I+ cells qPCR	Supplementation of local fibroblasts at site of liver injury by bone-marrow derived fibrocytes
BMP-7	Serum	Immunoassay	Antagonist of TGF-β, inhibitor of EMT
G-CSF	Blood	Immunoassays	Mobilization of bone-marrow derived fibrocytes
GM-CSF
M-CSF
Proteomics	Serum	Mass spectrometry (MS)	Fibrosis-specific serum protein profiles
Glycomics	Serum	Adaptation of DNA-sequencer/fragment analyzer technology to profiling of desialylated N-linked oligo-saccharides	Fibrosis-specific profiles of desialylated serum protein linked oligosaccharides (N-glycans)
Xylosyl-transferase (EC 2.4.2.26)	Serum	LC-MS/MS	Key enzyme in the biosynthesis of glycosaminoglycan chains in proteoglycans, e.g. in hepatic stellate cells and hepatocytes