TY  - UNPB
PB  - UCL (University College London)
UR  - https://discovery.ucl.ac.uk/id/eprint/10192493/
ID  - discovery10192493
N2  - Whilst the acute decompensation of cirrhosis (AD) is a common presentation to
hospital it is associated with significant mortality through the evolution of multi-organ
failure a syndrome termed acute-on chronic liver failure (ACLF) for which there is little
widely available treatment. Whilst the pathobiology of this process is not well
understood it is clear that systemic inflammation plays an important role. Small studies
have also demonstrated that hepatic cell death is associated with AD and ACLF but
this was not well described and its role is unclear. The main aims of this thesis were
to i) describe the pattern of cell death markers in AD and ACLF in comparison to health
and stable cirrhosis ii) explore the contribution of the regulated form of necrosis termed
necroptosis to AD and ACLF and iii) explore the role of histones derived from hepatic
cell death as triggers for the aggravation of portal hypertension seen in AD and ACLF.
Initial experiments confirmed marked elevation of markers of hepatic cell death in
patients with AD and ACLF as opposed to stable cirrhosis or health and that levels
rose in line with clinical severity moving from primarily apoptotic cell death towards
more immunogenic non-apoptotic modes of cell death.
Further experiments demonstrated elevated plasma and histological markers of
necroptosis in human ACLF and these findings were recapitulated in the BDL+LPS
rodent model of ACLF. Additionally, RIPK1 blockade, a key necroptosis kinase, was
found to reduce liver injury and modulate multi-organ injury.
Finally, experiments demonstrated that cell death derived histone is a potent activator
of TLR4 receptors, able to drive human hepatic stellate cell contraction and activation
and that human albumin solution (HAS) is able to mitigate these affects. Furthermore,
HAS administration in a rodent model of AD and ACLF significantly reduced both portal
pressure and circulating histone levels.
In summary hepatic cell death is a key feature of AD and ACLF and severity of cell
death reflects the severity of the clinical presentation. Necroptosis is of pathobiological
relevance in ACLF and histone production from hepatic cell death is able to directly
aggravate portal hypertension by hepatic stellate cell activation and this can be
modulated by albumin administration.
A1  - Macdonald, Stewart
M1  - Doctoral
EP  - 201
Y1  - 2024/06/28/
AV  - public
TI  - The role of hepatic cell death in the acute
decompensation of cirrhotic liver disease
N1  - Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/).  Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms.  Access may initially be restricted at the author?s request.
ER  -