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Hepatocyte expression of the senescence marker p21 is linked to fibrosis and an adverse liver-related outcome in alcohol-related liver disease

Hepatocyte expression of the senescence marker p21 is linked to fibrosis and an adverse liver-related outcome in alcohol-related liver disease
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 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.

fatty liver, liver diseases, hepatocytes, fibrosis, bipopsy, alcohols
1932-6203
e72904
Aravinthan, A.
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Pietrosi, G.
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Hoare, M.
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Jupp, J.
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Marshall, A.
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Verrill, C.
ef91689a-c1de-4eb1-9cae-2f43369647c3
Davies, S.
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Bateman, A.
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Sheron, N.
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Allison, M.
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Alexander, G.J.
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Aravinthan, A.
4edcb2d4-54ad-48e8-9288-15ba0c00149c
Pietrosi, G.
58abd054-27f2-49a4-b376-49ab810ba934
Hoare, M.
0cf33fd1-0919-44c4-a8ea-c22f89179b98
Jupp, J.
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Marshall, A.
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Verrill, C.
ef91689a-c1de-4eb1-9cae-2f43369647c3
Davies, S.
5b030b81-3805-489a-bb2a-96d9dff61b07
Bateman, A.
d36b7dee-8cba-482f-b0d8-90eae9de8f73
Sheron, N.
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Allison, M.
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Alexander, G.J.
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Aravinthan, A., Pietrosi, G., Hoare, M., Jupp, J., Marshall, A., Verrill, C., Davies, S., Bateman, A., Sheron, N., Allison, M. and Alexander, G.J. (2013) Hepatocyte expression of the senescence marker p21 is linked to fibrosis and an adverse liver-related outcome in alcohol-related liver disease. PLoS ONE, 8 (9), e72904.

Record type: Article

Abstract

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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Published date: 23 September 2013
Keywords: fatty liver, liver diseases, hepatocytes, fibrosis, bipopsy, alcohols
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 359910
URI: https://eprints.soton.ac.uk/id/eprint/359910
ISSN: 1932-6203
PURE UUID: 812031cc-17ba-4cfb-8185-05e824b6acd9
ORCID for N. Sheron: ORCID iD orcid.org/0000-0001-5232-8292

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Date deposited: 18 Nov 2013 09:47
Last modified: 06 Jun 2018 13:07

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Contributors

Author: A. Aravinthan
Author: G. Pietrosi
Author: M. Hoare
Author: J. Jupp
Author: A. Marshall
Author: C. Verrill
Author: S. Davies
Author: A. Bateman
Author: N. Sheron ORCID iD
Author: M. Allison
Author: G.J. Alexander

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