Volume 133, Issue 1, Pages 80-90 (July 2007) Progressive Fibrosis in Nonalcoholic Steatohepatitis: Association With Altered Regeneration and a Ductular Reaction  Michelle M. Richardson, Julie R. Jonsson, Elizabeth E. Powell, Elizabeth M. Brunt, Brent A. Neuschwander–Tetri, Prithi S. Bhathal, John B. Dixon, Martin D. Weltman, Herbert Tilg, Alexander R. Moschen, David M. Purdie, Anthony J. Demetris, Andrew D. Clouston  Gastroenterology  Volume 133, Issue 1, Pages 80-90 (July 2007) DOI: 10.1053/j.gastro.2007.05.012 Copyright © 2007 AGA Institute Terms and Conditions

Figure 1 Ductular reaction in NASH. (A) Periportal ductular reaction in NASH, stage 3, with bridging fibrosis. (B) CK7 staining of single putative progenitor cells, canals of Hering, and ductular structures. The ductules are seen at the bottom of the picture. (C) Normal liver. (D) Simple steatosis with no significant ductular reaction. (E) NASH cirrhosis. Biopsy specimens with advanced-stage fibrosis showed the most extensive DR. CK7 immunoperoxidase original magnifications: (A) 100×; (B) 400×; (C and D) 200×; and (E) 100×. Gastroenterology 2007 133, 80-90DOI: (10.1053/j.gastro.2007.05.012) Copyright © 2007 AGA Institute Terms and Conditions

Figure 2 There is a highly significant correlation between the expansion of HPCs and the extent of DR (r = 0.582, P < .0001). pt, portal tract. Gastroenterology 2007 133, 80-90DOI: (10.1053/j.gastro.2007.05.012) Copyright © 2007 AGA Institute Terms and Conditions

Figure 3 (A–F) The relationship between the expansion of HPCs and the extent of ductular reaction according to type and stage of NAFLD. Expansion of HPCs can be seen in (B–E) all types of NAFLD compared with (A) nondiseased liver, but an extensive DR is seen mainly in NASH patients with (D and F) portal and linking fibrosis. **P < .01, ***P < .001. As a visual aid, dotted lines enclose the extent of DR and HPCs for nondiseased liver. Gastroenterology 2007 133, 80-90DOI: (10.1053/j.gastro.2007.05.012) Copyright © 2007 AGA Institute Terms and Conditions

Figure 4 The extent of DR increases with stage of fibrosis. *P < .05, **P < .01, ***P < .001. Gastroenterology 2007 133, 80-90DOI: (10.1053/j.gastro.2007.05.012) Copyright © 2007 AGA Institute Terms and Conditions

Figure 5 Increased replicative arrest of hepatocytes (p21 index) is associated with a more extensive periportal DR. *P < .05, **P < .01. Gastroenterology 2007 133, 80-90DOI: (10.1053/j.gastro.2007.05.012) Copyright © 2007 AGA Institute Terms and Conditions

Figure 6 Increased replicative arrest of hepatocytes (p21 index) is associated with increased insulin resistance as assessed by HOMA-IR. **P < .01 compared with no replicative arrest. Gastroenterology 2007 133, 80-90DOI: (10.1053/j.gastro.2007.05.012) Copyright © 2007 AGA Institute Terms and Conditions

Figure 7 Increased replicative arrest of hepatocytes (p21 index) is seen in patients with NASH compared with steatosis alone. **P < .01, ***P < .001 compared with steatosis only. Gastroenterology 2007 133, 80-90DOI: (10.1053/j.gastro.2007.05.012) Copyright © 2007 AGA Institute Terms and Conditions