Changing the Pathogenetic Roadmap of Liver Fibrosis? Where Did It Start; Where Will It Go?

Olav A. Gressner; Mohamed S. Rizk; Evgeniya Kovalenko; Ralf Weiskirchen; Axel M. Gressner

Disclosures

J Gastroenterol Hepatol. 2008;23(7):1024-1035. 

In This Article

Where Did It Start?

More than 2000 years ago Erasistratos, the protagonist of the Alexandrian School of Medicine, recognized granular induration of the liver as cause of dropsy (ascites). Since then medical interest in the pathophysiology of hardening of the liver has continued, culminating in R.T.H. Laënnec's 1819 description of this condition as an independent disease, which he designated as 'cirrhosis', in R. Carswell's 1838 statement of fibrosis as a hallmark of cirrhosis, in J. Müller's 1843 observation that chronic inflammation leads to hypertrophy of interlobular connective tissue, and in R. Virchow's 1858 finding that the increase of connective tissue has a cellular source. In 1872 W. Legg recognized liver cell necrosis as the primary event for neoformation of the extracellular matrix (ECM) as being an essential part of a repair process. Indeed, in 1954 W.S. Hartroft suggested passive mechanisms for the development of liver fibrosis based on reticular collapse of necrotic parenchyma, followed by condensation of pre-existing fibrous stroma to septa.[1] However, in 1978 a working group of pathologists recommended definitions and nomenclature for cirrhosis and fibrosis, respectively.[2] Fibrosis was defined 'as the presence of excess collagen due to new fiber formation'. Fibrosis was emphasized as an essential criterion of cirrhosis supplemented by 'conversion of normal liver architecture into structurally abnormal nodules'.[2] Although this definition of fibrosis was still imperfect, because it neglected all important non-collageneous components of the ECM, it recognized active biosynthesis of ECM as the main pathogenetic pathway instead of collapse of the pre-existing reticulin framework. This stimulated further work into the pathogenesis of fibrosis and the identification of cell types engaged in ECM-production. The studies of McGee and Patrick[3] and Kent et al.[4,5,6] were among the first that linked vitamin A-storing perisinusoidal lipocytes with collagen synthesis. The first observation of this cell type in 1869 by F. Boll[7] was followed by a detailed description in 1876 by C.W. von Kupffer using the gold-chloride staining procedure.[8] In 1952 T. Ito discovered a cell type he designated as 'fat storing cell',[9] which in 1971 K. Wake[10] showed to be identical with the stellate cell discovered previously by von Kupffer (for a review of the history of perisinusoidal cells in the liver see K. Atermann[11]) ( Table 1 ). In the past a plethora of names was given to the pericytes located in the subendothelial space of Disse and surrounding the sinusoidal endothelial cell layer, e.g. fat storing cells, vitamin A-storing cells, lipocytes, parasinusoidal cells, Ito-cells, arachnocytes, and others, until in 1996 the term 'hepatic stellate cells' (HSC) was suggested by 98 investigators in this field and consequently accepted in the scientific community.[14] The study on structure, function, and pathophysiology of HSC[15,16] was made possible by the pioneering work of the group of D. Knook in the Netherlands who in 1982 reported methods for isolation and culture of this cell type from rat livers.[17,18] They combined the sequential pronase-collagenase perfusion technique of the liver with density-gradient centrifugation of the initial cell suspension to enrich HSC in the top layer of the metrizamide gradient.[17] The method was successfully adapted to the isolation of HSC from wedge sections of normal human liver.[19] Since then, numerous studies have followed which all point to the pivotal role of HSC in the pathogenesis of liver fibrosis and synthesis of collagen,[20] sulfated glycosaminoglycans,[21,22] hyaluronan,[23] fibronectin,[24] and tenascin.[25] The discovery of morphologically similar cells at extrahepatic sites, e.g. the pancreas, kidney, and colon, led to the concept of a diffuse stellate cell system in mammals.[26]

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