Susceptibility factors in paracetamol-induced acute liver failure

• Main Author: Possamai, Lucia
• Other Authors: Thursz, Mark
• Published: Imperial College London 2015
• Subjects: 610
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.749063

Paracetamol is a popular antipyretic and analgesic medication. It is a known hepatotoxin in overdose and is the commonest cause of acute liver failure in the UK. There is significant variability in inter-individual susceptibility to the hepatotoxic effects of paracetamol, which is incompletely understood. This thesis describes work done in murine models of paracetamol-induced acute liver failure with the aim of identifying causes of variable susceptibility and understanding the immune response to liver injury. A quantitative trait locus (QTL) mapping approach was taken using a murine strain susceptible to paracetamol hepatotoxicity (C3H/HeH) crossed with a relatively resistant strain (C57BL/6). Novel QTLs on murine chromosome 17 and 18 were identified that associated with response to paracetamol. Within the loci a number of candidate genes were identified. A survey of 10 inbred mouse strains for their response to paracetamol was conducted and highlighted the large variability within each strain. It was hypothesised that this variability might be due to differences in intestinal microbiota. A study of the role of intestinal microbiota in paracetamol-induced liver failure was conducted, by comparing response in germ free (GF) mice and conventional (CV) controls. This demonstrated that the presence of intestinal microbiota influenced the sulphonation:glucuronidation ratio during paracetamol metabolism. Although the extent of liver injury as assessed by necrosis and liver enzyme elevation was the same in GF and CV mice, there was evidence of a protective effect of a sterile intestine. Finally a reverse genetics approach was taken to study the influence of the gene Slpi in the secondary immune response to liver injury. It was shown that absence of SLPI protected mice against peak liver injury. The work presented in this thesis highlights some potential sources of variability in response to paracetamol and a number of targets that with further research could have therapeutic potential.