Macdonald, Stewart; (2024) The role of hepatic cell death in the acute decompensation of cirrhotic liver disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

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.

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