Progressive Fibrosis in Nonalcoholic Steatohepatitis: Association With Altered Regeneration and a Ductular Reaction
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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 (r(s) = 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 (r(s) = 0.510, P < .0001). The DR increased with the grade of NASH activity (r(s) = 0.478, P < .0001), grade of portal inflammation (r(s) = 0.445, P < .0001), and extent of hepatocyte replicative arrest (r(s) = 0.446, P < .0001). Replicative arrest was in turn associated with insulin resistance (r(s) = 0.450, P < .0001) and NASH activity (r(s) = 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.
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Higher ductular cell densities have been associated with an increased extent of hepatocyte loss and with the number of monocytes accumulating in inflamed portal areas in MASLD/MASH.
“Similarly, despite very distinct disease features, higher ductular cell densities have been associated with an increased extent of hepatocyte loss and with the number of monocytes accumulating in inflamed portal areas in MASLD/MASH [175, 206, 207].”
From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [207]
Ductular cells express an array of fibrogenic mediators that are upregulated in the human fibrotic liver, most notably PDGFBB, TGFβ1, TGFβ2 and sonic hedgehog, all of which promote myofibroblast activation.
“Moreover, ductular cells express an array of fibrogenic mediators that have been shown to be upregulated in the human fibrotic liver.52,53 The most notable of these are platelet-derived growth factor (PDGF)BB, TGFβ1 and TGFβ2, and sonic hedgehog, all of which promote myofibroblast activation.[54], [55], [56]”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [52]
Ductular reaction is frequent in MASH and strongly correlates with fibrosis severity in patients, for reasons that remain unclear.
“Ductular reaction in MASH is frequent and strongly correlates with fibrosis severity in patients for unclear reasons (32, 33).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [32]
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- Authors
- Richardson, M. M., Jonsson, J. R., Powell, E. E., Brunt, E. M., Neuschwander–Tetri, B. A., Bhathal, P. S., Dixon, J. B., Weltman, M. D., Tilg, H., Moschen, A. R., Purdie, D. M., Demetris, A. J., & Clouston, A. D.
- Affiliations
- The University of Queensland (AU)
- University of Pittsburgh (US)
- The University of Melbourne (AU)
- Monash University (AU)
- Nepean Hospital (AU)
- Innsbruck Medical University (AT)
- Genentech (US)
- Corresponding author
- Clouston, Andrew D.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2007-07
- Volume
- 133
- Issue
- 1
- Pages
- 80-90
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2054912517
- Cited by
- 482
- References
- 57
- Citations by year
- 2026: 10 · 2025: 18 · 2024: 15 · 2023: 19 · 2022: 32 · 2021: 33 · 2020: 22 · 2019: 17 · 2018: 38 · 2017: 31 · 2016: 29 · 2015: 22 · 2014: 37 · 2013: 26 · 2012: 28
- FWCI
- 18.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, liver fibrosis, ductular reaction, hepatic progenitor cells, p21, CK7, insulin resistance, hepatocyte ballooning, portal inflammation, fibrogenesis, liver regeneration, portal fibrosis, portal hypertension
- MeSH terms
- Adult, Biliary Tract Diseases, Biopsy, Cell Division, Fatty Liver, Female, Hepatitis, Humans, Insulin Resistance, Liver, Liver Cirrhosis, Liver Regeneration, Male, Middle Aged, Stem Cells, Proto-Oncogene Proteins p21(ras), Disease Progression, Hepatocytes
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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