Metabolic phenotyping applied to pre-clinical drug induced liver injury and acute liver failure

Abstract

Liver disease is a prevalent clinical challenge caused by a variety of factors including viral infections and xenobiotic overdose. Improving our mechanistic understanding of disease development will lead to an improved stratification of patients and ultimately a better prognosis. This thesis addresses the role of metabonomics in providing insight into a variety of preclinical models and a clinical study. The metabolic phenotype of preclinical models of paracetamol (APAP) and methotrexate (MTX) toxicity were characterised, together with the study of clinical samples from decompensated cirrhosis, acute on chronic liver failure (ACLF) and acute liver failure (ALF) patients. A comparative metabonomic approach was applied to study the metabolic consequences following administration of APAP and its non-hepatotoxic isomer; N-acetyl-m-aminophenol (AMAP), in mice. The analysis revealed an APAP-induced hepatotoxicity through mitochondrial dysfunction which was characterized by an upregulation of glycolysis as well as the inhibition of beta-oxidation and the Krebs cycle. The metabolic and toxic effects of MTX were investigated in healthy rats and in a model of non-alcoholic steatohepatitis (NASH; as modelled by the methionine choline deficient diet). MTX was shown to have an enhanced toxicity in the context of NASH, which was associated with unique metabolic changes. The clinical work revealed that the serum metabolic phenotypes of clinical decompensated cirrhosis, ACLF and ALF patients were also each characterized by unique metabolic perturbations. The ALF phenotype was associated with the most metabolic changes and consisted of markers of oxidative and energetic stress, as well as markers of amino acid metabolism dysfunction. Subsequently, the novel serum metabolic profiling of the hepatic vein, hepatic portal vein and peripheral artery of patients during liver transplantation aimed to characterize the hepatic disease microenvironment, which was discovered to mainly consist of a perturbed amino acid metabolism.