TY - JOUR
T1 - Progressive Fibrosis in Nonalcoholic Steatohepatitis
T2 - Association With Altered Regeneration and a Ductular Reaction
AU - Richardson, Michelle M.
AU - Jonsson, Julie R.
AU - Powell, Elizabeth E.
AU - Brunt, Elizabeth M.
AU - Neuschwander-Tetri, Brent A.
AU - Bhathal, Prithi S.
AU - Dixon, John B.
AU - Weltman, Martin D.
AU - Tilg, Herbert
AU - Moschen, Alexander R.
AU - Purdie, David M.
AU - Demetris, Anthony J.
AU - Clouston, Andrew D.
N1 - Funding Information:
Supported by the National Health and Medical Research Council, the Queensland Government’s Smart State Health and Medical Research Fund, the Princess Alexandra Hospital Research and Development Foundation, the Royal Children’s Hospital Foundation, and the Sasakawa Foundation.
PY - 2007/6
Y1 - 2007/6
N2 - Background & Aims: Portal fibrosis and linkage is a key feature of progressive disease in nonalcoholic steatohepatitis (NASH), but not simple steatosis. It is underappreciated and poorly understood. Fatty liver has impaired regeneration that induces a secondary replicative pathway using bipotential, periportal, hepatic progenitor cells (HPCs). We propose that activation of this pathway, with increased cell injury in NASH, also induces a periportal ductular reaction (DR) that could produce a profibrogenic stimulus. Methods: Biopsy specimens from 107 patients with nonalcoholic fatty liver disease and 11 controls were immunostained with cytokeratin-7 to quantify the DR and HPCs, and with p21 to assess hepatocyte replicative arrest. These results were correlated with clinicopathologic variables. Results: Patients with nonalcoholic fatty liver disease had expansion of HPCs, with a strong association between HPCs and the DR (rs = 0.582, P < .0001). In those with NASH (n = 69) there was an increased DR compared with simple steatosis, which correlated with the stage of fibrosis (rs = 0.510, P < .0001). The DR increased with the grade of NASH activity (rs = 0.478, P < .0001), grade of portal inflammation (rs = 0.445, P < .0001), and extent of hepatocyte replicative arrest (rs = 0.446, P < .0001). Replicative arrest was in turn associated with insulin resistance (rs = 0.450, P < .0001) and NASH activity (rs = 0.452, P < .0001). By multivariate analysis, the extent of DR (odds ratio [OR] = 17.9, P = .016), hepatocyte ballooning (OR = 8.1, P < .0001), and portal inflammation (OR = 3.3, P = .005) were associated independently with fibrosis. Conclusions: These findings suggest that an altered replication pathway in active NASH promotes a periportal DR, which in turn may provoke progressive periportal fibrogenesis.
AB - Background & Aims: Portal fibrosis and linkage is a key feature of progressive disease in nonalcoholic steatohepatitis (NASH), but not simple steatosis. It is underappreciated and poorly understood. Fatty liver has impaired regeneration that induces a secondary replicative pathway using bipotential, periportal, hepatic progenitor cells (HPCs). We propose that activation of this pathway, with increased cell injury in NASH, also induces a periportal ductular reaction (DR) that could produce a profibrogenic stimulus. Methods: Biopsy specimens from 107 patients with nonalcoholic fatty liver disease and 11 controls were immunostained with cytokeratin-7 to quantify the DR and HPCs, and with p21 to assess hepatocyte replicative arrest. These results were correlated with clinicopathologic variables. Results: Patients with nonalcoholic fatty liver disease had expansion of HPCs, with a strong association between HPCs and the DR (rs = 0.582, P < .0001). In those with NASH (n = 69) there was an increased DR compared with simple steatosis, which correlated with the stage of fibrosis (rs = 0.510, P < .0001). The DR increased with the grade of NASH activity (rs = 0.478, P < .0001), grade of portal inflammation (rs = 0.445, P < .0001), and extent of hepatocyte replicative arrest (rs = 0.446, P < .0001). Replicative arrest was in turn associated with insulin resistance (rs = 0.450, P < .0001) and NASH activity (rs = 0.452, P < .0001). By multivariate analysis, the extent of DR (odds ratio [OR] = 17.9, P = .016), hepatocyte ballooning (OR = 8.1, P < .0001), and portal inflammation (OR = 3.3, P = .005) were associated independently with fibrosis. Conclusions: These findings suggest that an altered replication pathway in active NASH promotes a periportal DR, which in turn may provoke progressive periportal fibrogenesis.
UR - http://www.scopus.com/inward/record.url?scp=34447100647&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2007.05.012
DO - 10.1053/j.gastro.2007.05.012
M3 - Article
C2 - 17631134
AN - SCOPUS:34447100647
VL - 133
SP - 80
EP - 90
JO - Gastroenterology
JF - Gastroenterology
SN - 0016-5085
IS - 1
ER -