Hepatocyte Expression of the Senescence Marker p21 Is Linked to Fibrosis and an Adverse Liver-Related Outcome in Alcohol-Related Liver Disease

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 p2...

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Published in:PloS one Vol. 8; no. 9; p. e72904
Main Authors: Aravinthan, Aloysious, Pietrosi, Giada, Hoare, Matthew, Jupp, James, Marshall, Aileen, Verrill, Clare, Davies, Susan, Bateman, Adrian, Sheron, Nick, Allison, Michael, Alexander, Graeme J. M.
Format: Journal Article
Language:English
Published: United States Public Library of Science 23.09.2013
Public Library of Science (PLoS)
Subjects:
Adult
Aged
Alcohol use
Alcohols
Automation
Biomarkers - metabolism
Biopsy
Cell activation
Cell cycle
Cellular Senescence
Cirrhosis
Cohort Studies
Cyclin-dependent kinase inhibitor p21
Cyclin-Dependent Kinase Inhibitor p21 - metabolism
Drinking (Alcoholic beverages)
Fatty liver
Female
Fibrosis
Gene expression
Health aspects
Hepatitis
Hepatocytes - metabolism
Hepatology
Histology
Histopathology
Hospitals
Humans
Immunohistochemistry
Liver
Liver cancer
Liver cirrhosis
Liver Cirrhosis - metabolism
Liver Cirrhosis - pathology
Liver diseases
Liver Diseases, Alcoholic - metabolism
Liver Diseases, Alcoholic - pathology
Liver transplants
Male
Markers
Medical prognosis
Medical research
Medicine
Metastasis
Middle Aged
Morbidity
Mortality
Patients
Phase distribution
Prognosis
Rodents
S phase
Senescence
United Kingdom > UK
ISSN:1932-6203, 1932-6203
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Summary: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. 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. 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. 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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Conceived and designed the experiments: AA GA. Performed the experiments: AA GP. Analyzed the data: AA MA. Contributed reagents/materials/analysis tools: AA GP MH AM JJ CV SD AB MA. Wrote the manuscript: AA GA. Acquisition of data: AA JJ CV. Provision of clinical data: NS MA. Drafting of the manuscript: AA. Histological interpretation: SD AB. Critical review of the manuscript: MA GA. Technical assistance and review of manuscript: GP MA AM. Overall supervision of the study: GA.
Competing Interests: The authors have declared that no competing interests exist.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0072904