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, which is characterized by a highly variable clinical course, with at least ˜20% developing liver cirrhosis within 40 years. Since so far only liver biopsy allows a reliable evaluation of the course of hepatitis C by grading inflammation and staging fibrosis, serum biomarkers for hepatic fibrosis with high sensitivity and specificity are needed.

In order to identify new candidate biomarkers for hepatic fibrosis, we microdissected cirrhotic septa and liver parenchyma cells from patients with chronic hepatitis C infection for proteomic analysis. In cirrhotic septa we detected an increasing expression of structure associated proteins like e.g. actin alpha/gamma, prolyl 4-hydroxylase, tropomyosin, calponin, transgelin and human microfibril associated glycoprotein 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 microfibril associated glycoprotein 4 demonstrated high serum levels in patients with hepatic cirrhosis of different etiologies. Quantification analysis in an extended number of patients revealed MFAP-4 as novel candidate biomarker with high diagnostic accuracy for the prediction of non-diseased and cirrhosis (area under receiver operating characteristic curve (AUC)=0.97, p<0.0001) as well as stage 0 and stage 4 fibrosis (AUC=0.84, p<0.0001), stage 1 and stage 4 fibrosis (AUC=0.89, p<0.0001).