Cargando…
Hepatocyte Expression of the Senescence Marker p21 Is Linked to Fibrosis and an Adverse Liver-Related Outcome in Alcohol-Related Liver Disease
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 hepatoc...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781134/ https://www.ncbi.nlm.nih.gov/pubmed/24086266 http://dx.doi.org/10.1371/journal.pone.0072904 |
_version_ | 1782285375181422592 |
---|---|
author | Aravinthan, Aloysious Pietrosi, Giada Hoare, Matthew Jupp, James Marshall, Aileen Verrill, Clare Davies, Susan Bateman, Adrian Sheron, Nick Allison, Michael Alexander, Graeme J. M. |
author_facet | Aravinthan, Aloysious Pietrosi, Giada Hoare, Matthew Jupp, James Marshall, Aileen Verrill, Clare Davies, Susan Bateman, Adrian Sheron, Nick Allison, Michael Alexander, Graeme J. M. |
author_sort | Aravinthan, Aloysious |
collection | PubMed |
description | 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 G(1)/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 G(1)/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. |
format | Online Article Text |
id | pubmed-3781134 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-37811342013-10-01 Hepatocyte Expression of the Senescence Marker p21 Is Linked to Fibrosis and an Adverse Liver-Related Outcome in Alcohol-Related Liver Disease Aravinthan, Aloysious Pietrosi, Giada Hoare, Matthew Jupp, James Marshall, Aileen Verrill, Clare Davies, Susan Bateman, Adrian Sheron, Nick Allison, Michael Alexander, Graeme J. M. PLoS One Research Article 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 G(1)/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 G(1)/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. Public Library of Science 2013-09-23 /pmc/articles/PMC3781134/ /pubmed/24086266 http://dx.doi.org/10.1371/journal.pone.0072904 Text en © 2013 Aravinthan et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Aravinthan, Aloysious Pietrosi, Giada Hoare, Matthew Jupp, James Marshall, Aileen Verrill, Clare Davies, Susan Bateman, Adrian Sheron, Nick Allison, Michael Alexander, Graeme J. M. Hepatocyte Expression of the Senescence Marker p21 Is Linked to Fibrosis and an Adverse Liver-Related Outcome in Alcohol-Related Liver Disease |
title | Hepatocyte Expression of the Senescence Marker p21 Is Linked to Fibrosis and an Adverse Liver-Related Outcome in Alcohol-Related Liver Disease |
title_full | Hepatocyte Expression of the Senescence Marker p21 Is Linked to Fibrosis and an Adverse Liver-Related Outcome in Alcohol-Related Liver Disease |
title_fullStr | Hepatocyte Expression of the Senescence Marker p21 Is Linked to Fibrosis and an Adverse Liver-Related Outcome in Alcohol-Related Liver Disease |
title_full_unstemmed | Hepatocyte Expression of the Senescence Marker p21 Is Linked to Fibrosis and an Adverse Liver-Related Outcome in Alcohol-Related Liver Disease |
title_short | Hepatocyte Expression of the Senescence Marker p21 Is Linked to Fibrosis and an Adverse Liver-Related Outcome in Alcohol-Related Liver Disease |
title_sort | hepatocyte expression of the senescence marker p21 is linked to fibrosis and an adverse liver-related outcome in alcohol-related liver disease |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781134/ https://www.ncbi.nlm.nih.gov/pubmed/24086266 http://dx.doi.org/10.1371/journal.pone.0072904 |
work_keys_str_mv | AT aravinthanaloysious hepatocyteexpressionofthesenescencemarkerp21islinkedtofibrosisandanadverseliverrelatedoutcomeinalcoholrelatedliverdisease AT pietrosigiada hepatocyteexpressionofthesenescencemarkerp21islinkedtofibrosisandanadverseliverrelatedoutcomeinalcoholrelatedliverdisease AT hoarematthew hepatocyteexpressionofthesenescencemarkerp21islinkedtofibrosisandanadverseliverrelatedoutcomeinalcoholrelatedliverdisease AT juppjames hepatocyteexpressionofthesenescencemarkerp21islinkedtofibrosisandanadverseliverrelatedoutcomeinalcoholrelatedliverdisease AT marshallaileen hepatocyteexpressionofthesenescencemarkerp21islinkedtofibrosisandanadverseliverrelatedoutcomeinalcoholrelatedliverdisease AT verrillclare hepatocyteexpressionofthesenescencemarkerp21islinkedtofibrosisandanadverseliverrelatedoutcomeinalcoholrelatedliverdisease AT daviessusan hepatocyteexpressionofthesenescencemarkerp21islinkedtofibrosisandanadverseliverrelatedoutcomeinalcoholrelatedliverdisease AT batemanadrian hepatocyteexpressionofthesenescencemarkerp21islinkedtofibrosisandanadverseliverrelatedoutcomeinalcoholrelatedliverdisease AT sheronnick hepatocyteexpressionofthesenescencemarkerp21islinkedtofibrosisandanadverseliverrelatedoutcomeinalcoholrelatedliverdisease AT allisonmichael hepatocyteexpressionofthesenescencemarkerp21islinkedtofibrosisandanadverseliverrelatedoutcomeinalcoholrelatedliverdisease AT alexandergraemejm hepatocyteexpressionofthesenescencemarkerp21islinkedtofibrosisandanadverseliverrelatedoutcomeinalcoholrelatedliverdisease |