Gastroenterology

Gastroenterology

Volume 133, Issue 1, July 2007, Pages 80-90
Gastroenterology

Clinical–liver, pancreas, and biliary tract
Progressive Fibrosis in Nonalcoholic Steatohepatitis: Association With Altered Regeneration and a Ductular Reaction

https://doi.org/10.1053/j.gastro.2007.05.012Get rights and content

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.

Section snippets

Patients and Clinical Data

Participants for this study were recruited through 5 different centers located in Brisbane, Sydney, and Melbourne, Australia; St. Louis, MO; and Innsbruck, Austria. The study protocol was approved by the relevant ethics committees at each of the institutions. Some patients subsequently were treated and only pre-intervention biopsy specimens were used for this study. Some of the patients from Melbourne, St. Louis, and Innsbruck were included in earlier intervention studies describing the effects

Clinical and Histologic Data

The clinical and histologic data are summarized in Table 1. Of a total of 107 subjects, 51 were male and the mean age was 44 years. The body mass index, fasting serum insulin level, fasting serum glucose level, HOMA-IR score, and alanine aminotransferase level were available for 93, 82, 89, 79, and 75 patients, respectively. The mean body mass index was in the obese range at 38.2 kg/m2, and the mean HOMA-IR score was 6.9. Sixty-nine subjects (65%) had NASH, 22 had simple steatosis (21%), and 16

Discussion

There is significant interest in the natural history and prognosis of NAFLD. Progressive disease largely is limited to the subgroup of patients with NASH. Initially characterized by subsinusoidal fibrosis in zone 3, with increasing severity the fibrosis develops in portal/periportal areas, progressing to fibrous linkage and cirrhosis in advanced cases. The presence of portal fibrosis is an important feature in the published NASH staging systems.1, 2

An association between the expansion of HPCs

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  • Cited by (0)

    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.

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