Hepatocyte Expression of the Senescence Marker p21 Is Linked to Fibrosis and an Adverse Liver-Related Outcome in Alcohol-Related Liver Disease
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BACKGROUND AND AIM: Alcohol-related liver disease (ALD) remains a leading cause of liver-related morbidity and mortality. Age, fibrosis stage, MELD score and continued alcohol consumption predict outcome in everyday clinical practice. In previous studies increased hepatocyte nuclear area and hepatocyte expression of p21, both markers of senescence, were associated with increased fibrosis stage and a poor outcome in non-alcohol-related fatty liver disease, while increased hepatocyte nuclear area was related to liver dysfunction in ALD cirrhosis. This study, therefore, investigated the pattern of hepatocyte cell cycle phase distribution and hepatocyte p21 expression in relation to outcome in ALD. METHODS: Liver sections from two cohorts were studied. The first comprised 42 patients across the full spectrum of ALD. The second cohort comprised 77 patients with ALD cirrhosis. Immunohistochemistry assessed hepatocyte expression of cell cycle phase markers and p21. Regenerating liver (n=12) and "normal" liver sections (n=5) served as positive and negative controls, respectively. RESULTS: In the first cohort there was little cell cycle progression beyond G1/S phase and increased hepatocyte p21 expression (p<0.0001), which correlated independently with fibrosis stage (p=0.005) and an adverse liver-related outcome (p=0.03). In the second cohort, both hepatocyte p21 expression (p<0.001) and MELD score (p=0.006) were associated independently with an adverse liver-related outcome; this association was stronger with hepatocyte p21 expression (AUROC 0.74; p=0.0002) than with MELD score (AUROC 0.59; p=0.13). Further, hepatocyte p21 expression co-localised with increased hepatic stellate cell activation. CONCLUSIONS: The findings are consistent with impaired cell cycle progression beyond the G1/S phase in ALD. The striking independent associations between increased hepatocyte p21 expression and both fibrosis stage and an adverse liver-related outcome in both cohorts suggests hepatocyte senescence plays an important role in ALD. Measuring hepatocyte p21 expression is simple and cheap and in this series was a useful measure of long-term prognosis in ALD.
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In the CDE model, there is minimal hepatocyte senescence, in contrast to advanced human diseases and rat models of HPC activation where high levels of hepatocyte senescence occur.
“We found minimal hepatocyte senescence (Supplementary figure 1b), in contrast to advanced human diseases and rat models of HPC activation where high levels of hepatocyte senescence occur29.”
From Hepatic progenitor cells of biliary origin with liver repopulation capacity (2015) · cites this paper as [29]
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- Authors
- Aravinthan, A., Pietrosi, G., Hoare, M., Jupp, J., Marshall, A., Verrill, C., Davies, S., Bateman, A., Sheron, N., Allison, M., & Alexander, G. J. M.
- Affiliations
- University of Cambridge (GB)
- University Hospital Southampton NHS Foundation Trust (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Corresponding author
- Alexander, Graeme J. M.
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-09-23
- Volume
- 8
- Issue
- 9
- Pages
- e72904
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3781134
- OpenAlex
- W2026914673
- Cited by
- 117
- References
- 20
- Citations by year
- 2026: 16 · 2025: 13 · 2024: 12 · 2023: 8 · 2022: 7 · 2021: 13 · 2020: 4 · 2019: 9 · 2018: 6 · 2017: 11 · 2016: 5 · 2015: 7 · 2014: 6
- FWCI
- 4.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
- Keywords
- alcoholic liver disease, hepatocyte senescence, p21, liver fibrosis, hepatocyte cell cycle, G1/S phase, MELD score, hepatic stellate cell activation, liver cirrhosis, prognosis
- MeSH terms
- Adult, Aged, Biopsy, Female, Humans, Liver Cirrhosis, Liver Diseases, Alcoholic, Male, Middle Aged, Cohort Studies, Biomarkers, Cellular Senescence, Hepatocytes, Cyclin-Dependent Kinase Inhibitor p21
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