| Summary: | Acute liver failure (ALF) is a devastating condition with a high associated mortality rate. Paracetamol hepatotoxicity remains the leading cause of ALF in the developed world. The studies outlined in this thesis explore the current management of ALF, and systematically review the prognostic tests currently used in paracetamol-induced ALF. Using a database of over 900 acute liver injury patients, the impact of unintentional paracetamol overdose is retrospectively analysed, demonstrating a strong association between this mode of paracetamol overdose and adverse clinical outcomes, including the requirement for emergency orthotopic liver transplantation. Current prognostic tests for severe paracetamol-induced hepatotoxicity have been criticised for their relatively low sensitivity, with the result that not all patients who might benefit from tertiary level care are identified. This thesis demonstrates that the development of the Systemic Inflammatory Response Syndrome (SIRS) or extrahepatic organ failure is strongly associated with death following paracetamol overdose. Due to their very high sensitivity in this condition, both the SIRS and Sequential Organ Failure Assessment scores have potential as future gatekeepers to improve the triage of paracetamol overdose patients, thereby delivering tertiary level care to those most likely to require emergency transplantation. A greater understanding of the pathophysiological links between the initial hepatic injury and development of the SIRS could help to identify novel biomarkers for ALF, and help guide future therapeutic avenues. Using serum samples from a prospectively collected cohort of acute liver injury patients, this thesis identifies two novel biomarkers, serum ferritin and the long pentraxin PTX3, which show a strong association with outcome following paracetamol hepatotoxicity. These biomarkers illustrate the importance that the innate immune system plays in the pathogenesis of paracetamol-induced ALF, and identifies several exciting areas for future cellular and animal-based studies.
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