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Signals for Hepatic Figrogenesis in Pediatric Cholestatic Liver Disease: Review and Hypothesis
© Ramm et al; licensee BioMed Central Ltd 2004
Published: 14 January 2004
Neonatal Cholestatic Liver Diseases
Cholestatic liver disease in children occurs as a result of either an alteration in hepatocyte bile formation or disruption of bile flow out of the hepatocyte through intrahepatic bile ductules or extrahepatic bile ducts . Liver disease usually appears within the first few weeks following birth. A large number of disorders exhibit cholestatic jaundice in neonatal life including (a) numerous cholangiopathies, such as extrahepatic biliary atresia, cystic fibrosis (CF), choledochal cyst, alpha1-Antitrypsin deficiency and Alagille's syndrome, (b) several abnormalities of the gall bladder, such as cholelithiasis and cholecystitis, and (c) bile acid transport disorders. The most commonly occurring form of neonatal cholestasis is biliary atresia, representing a relative frequency of approximately 30% . In order to administer effective therapeutic intervention early diagnosis is critical. This can prove difficult as a number of phenotypic manifestations of the many different forms of neonatal cholestasis are similar and may even overlap.
Role of Hepatic Stellate Cells
If left untreated cholestatic liver injury results in the development of hepatic fibrosis and ultimately may progress to cirrhosis. The precise pathophysiological mechanisms responsible for hepatic fibrogenesis in pediatric cholestatic liver disease are unknown. Hepatic stellate cells have been shown to be responsible for increased production of fibrillar collagens in a number of adult liver diseases and in experimental models of liver injury. Recent studies by our group have identified stellate cells as the principal source of type I collagen in neonatal cholestatic liver diseases such as biliary atresia  and in the focal biliary cirrhosis associated with CF . In these studies, large numbers of myofibroblast-like cells were demonstrated in the extracellular matrix surrounding expanded bile ducts and within fibrosis septa bridging between portal tracts (2). Activated hepatic stellate cells, demonstrated by the expression of –-smooth muscle actin and their stellate morphology, were particularly evident at the interface between scar and normal tissue [2, 3]. This growing margin of scar tissue formation appeared to be the site of maximal stellate cell activation and type I collagen mRNA expression, although some evidence of collagen gene expression was also seen in myofibroblast-like cells within established fibrous septa. This clearly suggests a role for hepatic stellate cells in the deposition of fibrillar collagens as the scar expands with continued cholestatic liver injury. Whether the myofibroblast-like cells which surround expanded bile ducts within the fibrotic septa are derived from activated hepatic stellate cells or portal fibroblasts remains unclear.
Mediators of Fibrogenesis
Transforming Growth Factor-beta1 and Matrix Production
Role of Mitogens and Chemokines
Another key regulator of fibrogenesis is the mitogenic cytokine, platelet-derived growth factor-BB (PDGF-BB). The observation of abundant myofibroblast-like cells within the peri-biliary and scar interface regions of the acinus in both biliary atresia and CF liver disease suggests either local activation and proliferation of portal fibroblasts or recruitment of stellate cells. Therefore, we hypothesize that bile duct epithelial cells and hepatocytes at the scar interface produce mitogens and chemokines in response to biliary obstruction (Figures 1 and 2). There is recent evidence to support a role for PDGF-BB in cholestatic liver injury. In a study using bile duct-ligated rats, Kinnman and colleagues demonstrated that bile duct cells express PDGF-BB . Using an in vitro culture system they showed that hepatic stellate cells are recruited to bile duct segments by PDGF-BB . While this is an important observation, the role of PDGF-BB in human neonatal cholestasis has not been evaluated. Hepatic stellate cells also respond to numerous other chemokines in vitro, such as monocyte chemotaxis protein-1 (MCP-1), interleukin-8, RANTES, endothelin-1  (Figure 1). It is possible that these chemokines may also play a role in stellate cell recruitment in cholestatic liver disease (Figure 2). Marra and colleagues have reported that MCP-1 causes stellate cell recruitment in vitro  and MCP-1 expression is increased in cirrhotic adult liver . We propose that MCP-1 may play a major role in the development of pediatric cholestatic liver injury. In preliminary studies, we have reported marked hepatic expression of MCP-1 in biliary atresia and CF liver disease, although the role of MCP-1 in stellate cell recruitment in vivo remains to be determined .
While the precise pathways involved in the initiation of hepatic fibrogenesis in neonatal cholestasis remain elusive, a number of cytokines and growth factors have been identified which contribute to the progression of injury through matrix production and recruitment of inflammatory cells. With this knowledge it may be possible to develop novel approaches for therapeutic intervention which could assist in the suppression of fibrogenesis and may potentially lead to the reduced requirement for liver transplantation.
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