Evolving concepts of liver fibrogenesis provide new diagnostic and therapeutic options

Experimental and clinical studies of the past twenty years or so provide a detailed knowledge of structure and composition of extracellular matrix (ECM) in normal and fibrotic liver tissue [1,2], of the cellular origin of the various matrix components [3], of the cytokine- and growth factor-regulated stimulation of ECM synthesis (fibrogenesis) and regulation of matrix degradation (fibrolysis) [4-6], of several genetic conditions predisposing for fibrogenesis [7,8], and of multiple, experimentally successful therapeutic approaches [9]. However, up to now the clinical benefit derived from basic research in the context of translational medicine is scarce with regard to an effective, harmless and site-directed antifibrotic therapy and approved non-invasive diagnostic measures of the activity of fibrogenesis ("grading") and/or of the extent of the fibrotic organ transition ("staging") using serum parameters [10]. The failure of clinical success boosts current research on fibrosis and fibrogenesis not only of the liver, but also of the lung, kidney, pancreas, heart, skin, bone marrow, and other organs with the result that during the last four to five years very important new insights into the pathogenesis of fibrosis and of related diagnostic and therapeutic options have been made [11]. Evolving pathogenetic concepts supplement the so called "canonical principle" of liver fibrogenesis, which has been worked out in detail during the last twenty years and which is based, in principle, on the activation of hepatic stellate cells (HSC).Fibrosis is characterized by a severalfold increase of the extracellular matrix that comprises collagens, structural glycoproteins, sulphated proteoglycans and hyaluronan, by a histological redistribution with preferred initial matrix deposition in the subendothelial space of Disse leading to the formation of an incomplete subendothelial basement membrane creating additional diffusion barriers between hepatocytes and the liver sinusoid ("capill