Detection of novel biomarkers of liver cirrhosis by proteomic analysis.
Hepatic cirrhosis is a life-threatening disease arising from different chronic liver disorders. One major cause for hepatic cirrhosis is chronic hepatitis C. Chronic hepatitis C is characterized by a highly variable clinical course, with at least 20% developing liver cirrhosis within 40 years. Only liver biopsy allows a reliable evaluation of the course of hepatitis C by grading inflammation and staging fibrosis, and thus serum biomarkers for hepatic fibrosis with high sensitivity and specificity are needed. To identify new candidate biomarkers for hepatic fibrosis, we performed a proteomic approach of microdissected cirrhotic septa and liver parenchyma cells. In cirrhotic septa, we detected an increasing expression of cell structure associated proteins, including actin, prolyl 4-hydroxylase, tropomyosin, calponin, transgelin, and human microfibril-associated protein 4 (MFAP-4). Tropomyosin, calponin, and transgelin reflect a contribution of activated stellate cells/myofibroblasts to chronic liver injury. The expression of tropomyosin, transgelin, and MFAP-4, an extracellular matrix associated protein, were further evaluated by immunohistochemistry. Tropomyosin and MFAP-4 demonstrated high serum levels in patients with hepatic cirrhosis of different causes.


CONCLUSIONS
A quantitative analysis of MFAP-4 serum levels in a large number of patients showed MFAP-4 as novel candidate biomarker with high diagnostic accuracy for prediction of nondiseased liver versus cirrhosis [area under receiver operating characteristic curve (AUC) = 0.97, P < 0.0001] as well as stage 0 versus stage 4 fibrosis (AUC = 0.84, P < 0.0001), and stages 0 to 3 versus stage 4 fibrosis (AUC = 0.76, P < 0.0001).
Mölleken
Christian
C
Department of Internal Medicine, Bergmannsheil, Ruhr-Universität Bochum, Germany.
Sitek
Barbara
B
Henkel
Corinna
C
Poschmann
Gereon
G
Sipos
Bence
B
Wiese
Sebastian
S
Warscheid
Bettina
B
Broelsch
Christoph
C
Reiser
Markus
M
Friedman
Scott L
SL
Tornøe
Ida
I
Schlosser
Anders
A
Klöppel
Günter
G
Schmiegel
Wolff
W
Meyer
Helmut E
HE
Holmskov
Uffe
U
Stühler
Kai
K
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D016326:Extracellular Matrix Proteins / Q000097:blood*; D005260:Female; D006023:Glycoproteins / Q000097:blood*; D006526:Hepatitis C / Q000150:complications; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000821:virology; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D040901:Proteomics; D012372:ROC Curve; D014335:Tropomyosin / Q000097:blood
D015415:Biomarkers; D002352:Carrier Proteins; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C400752:MFAP4 protein, human; D014335:Tropomyosin