Review Potential novel biomarkers for monitoring the fibrogenic process in liver Axel M. Gressner a, * , Mohamed Rizk a , Chunfang Gao b , Olav A. Gressner a a Institute of Clinical Chemistry and Pathobiochemistry – Central Laboratory, RWTH-University Hospital Aachen, Pauwelsstr. 30, 52074 Aachen, Germany b Department of Laboratory Medicine, Eastern Hepatobiliary Hospital (EHBH), Second Military Medical University, 225 Shanghai Road, Shanghai 200438, China article info abstract The clinical course of chronic liver diseases is significantly dependent on the progression rate of fibrosis, that is, the unstructured replacement of injured parenchyma by extracellular matrix. Fibrogenesis (i.e., the development of fibrosis) can be regarded as an unlimited wound-healing process, which is based on matrix synthesis in activated hepatic stellate cells, fibroblasts and, potentially, by hepatocytes and bil- iary epithelial cells converted to (myo-)fibroblasts. Blood biomarkers of fibrogenesis and fibrosis can be divided into class I and class II. Class I biomarkers are single tests, which are based on the pathophysiol- ogy of fibrosis, whereas class II biomarkers are mostly multiparametric algorithms, which have been sta- tistically evaluated with regard to the detection and follow-up of fibrosis. None of the presently available approach fulfils the criteria of an ideal test, but increased understanding of the pathogenesis of fibrosis offers additional ways for pathophysiologically well-based biomarkers. These include transforming growth factor (TGF)-b-driven marker proteins, bone-marrow-derived cells (fibrocytes) and cytokines, which govern pro- and anti-fibrotic activities. Proteomic and glycomic approaches of serum are under investigation to set up specific protein profiles in patients with liver fibrosis. These and other novel parameters will supplement liver biopsy/histology, high-resolution imaging analysis and elastography for the detection and monitoring of patients with liver fibrosis. Ó 2009 Arab Journal of Gastroenterology. Published by Elsevier B.V. Introduction Fibrosis is characterised by the excess deposition of extracellu- lar matrix (ECM) involving molecular and histological re-arrange- ment of various types of collagens, proteoglycans, structural glycoproteins and hyaluronan. It is a hallmark of liver cirrhosis and contributes significantly to the deleterious outcome of chronic liver diseases. The deposition of ECM in the space of Disse (i.e., perisinusoidal fibrosis), the generation of (incomplete) subendo- thelial basement membranes and the strangulation of hepatocytes by the surrounding matrix impair not only the blood flow through the organ, but also the biosynthetic function of hepatocytes and the clearance capability of these and other cell types. The widely used diagnostic ‘gold standard’ of liver biopsy has many draw- backs, in addition to invasiveness, such as sampling error (about 1/50,000th of liver mass is obtained), irreproducible sample quality depending on the length and size of the tissue specimen (coeffi- cient of variation 45–35%) and a histological evaluation strictly dependent on the experience of the pathologist (observer error). Therefore, the development of non-invasive, objective and quanti- tative serum- or plasma-based biomarkers of fibrogenesis is an important goal, which can be reached by two, principally different, approaches: class I and class II serum fibrosis markers. Classification of biomarkers of fibrosis Class I fibrosis biomarkers are pathophysiologically derived from ECM turnover and/or from changes in the fibrogenic cell types, in particular, hepatic stellate cells (HSCs) and (myo-)fibroblasts [1]. They should reflect the activity of the fibrogenic and/or fibrolytic process and, thus, remodelling of ECM. These biomarkers do not indicate the extent of connective tissue deposition, that is, the stage of fibrotic transition of the organ. Frequently, they are costly laboratory tests and are the result of translation of fibrogenic mechanisms into clinical application. Thus, their selection is driven by hypothesis. Class II fibrosis biomarkers mostly estimate the degree of fibrosis (extent of ECM deposition). In general, they comprise common clinical–chemical tests (e.g., enzymes, proteins and coagulation factors), which do not necessarily reflect ECM metabolism or fibr- ogenic cell changes. Their pathobiochemical relation with fibro- genesis is indirect, if at all. Thus, their selection is not driven by hypothesis, but empiric. The markers are standard laboratory tests and are integrated into multiparametric panels. In general, both types of serum biomarkers follow different pathophysiological concepts. Class I markers inform about ‘what 1687-1979/$ - see front matter Ó 2009 Arab Journal of Gastroenterology. Published by Elsevier B.V. doi:10.1016/j.ajg.2009.12.009 * Corresponding author. E-mail addresses: agressner@ukaachen.de, gressner@t-online.de (A.M. Gressner), gaocf1115@yahoo.com (C. Gao). Arab Journal of Gastroenterology 10 (2010) S12–S16 Contents lists available at ScienceDirect Arab Journal of Gastroenterology journal homepage: www.elsevier.com/locate/ajg