Liver fibrosis: perspectives in pathobiochemical research and clinical outlook.
Disturbances of the equilibrium between parenchyma and extracellular matrix, leading to a disproportionate increase in and an irregular deposition of newly formed connective tissue components (fibrosis), is a common sequel of chronic active liver diseases with serious clinical consequences. Significant progress has been made in recent years in the analysis of the structural composition of extracellular matrix in normal and fibrotic liver and in the dissection of the molecular and cellular mechanisms of exaggerated extracellular matrix deposition in necroinflammatory areas. Under the influence of inflammatory stimuli, perisinusoidal, retinoid-storing cells (Ito cells, parasinusoidal lipocytes), which are qualitatively and quantitatively the most important connective tissue-producing cell type in human and animal liver, transform to myofibroblast-like cells. Activation and transformation of perisinusoidal cells are mediated by paracrine and autocrine loops involving transforming growth factor beta as the main fibrogenic mediator, which is secreted by activated liver macrophages, possibly also by endothelial cells, and liberated by disintegrated thrombocytes. The molecular and cellular interactions during liver fibrogenesis have become a model for a number of other organ fibrotic processes, wound repair and even atherogenesis. Therapeutic interference with the early steps of fibrogenesis seems feasible but a breakthrough has not yet been achieved. For clinical-chemical, non-invasive diagnosis and monitoring of ongoing fibrogenesis, a rather limited repertoire of more or less organ- and disease-unspecific parameters is available. Split products of the extracellular maturation pathway of the procollagen types, laminin and hyaluronan, can be assayed but the clinical interpretation of the results has to be made with caution. Strategies and major topics of future pathobiochemical and clinically oriented research are highlightened.
Gressner
A M
AM
Department of Clinical Chemistry, Philipps University, Marburg, Lahn, Germany.
D003238:Connective Tissue / Q000503:physiopathology; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000453:epidemiology / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology; D011509:Proteoglycans / Q000378:metabolism
D011509:Proteoglycans