Throughout this thesis, metabolic profiling using a global mass spectrometry-based approach
was utilised to explore cholangiocarcinoma (CCA) metabolic signature in urine and
serum. CCA is an aggressive disease with a poor prognosis. The geographical distribution
of CCA cases is markedly uneven and it closely mirrors the prevalence of its predisposing
risk factors. CCA is most commonly seen in Southeast Asia where liver fluke infection is
endemic, whereas in Western countries it is a rare malignancy with an unknown aetiology in
most cases. To date, a multi-disciplinary approach with multi-modal tools are often applied
for the diagnosis of this complex disease.
The primary aim of this thesis was to provide insights into the perturbed biological pathways
underlying cholangiocarcinogenesis as a mean to identify metabolite biomarkers to
improve CCA screening and diagnosis. The first four results chapters describes the urinary
metabolome associated with liver fluke induced-CCA and sporadic CCA in patients from
Thailand and the UK, respectively. Overall, CCA induces a metabolic profile change that can
distinguish patients from healthy and control groups with various hepatobiliary pathologies.
Dysregulation in acylcarnitine, bile acid, steroid and purine metabolism was characteristic
of the CCA urinary metabolic signature in both populations. A panel of 10 metabolites (primarily
acylcarnitine and steroid species) achieved a diagnostic accuracy of 93.4% and AUC
value of 98.8% (CI= 96.3%-100%) in distinguishing CCA cases from healthy participants.
Phenotypic disparities between the two distinct populations were primarily related to differences
in dietary practices and body composition. Furthermore, regardless of the underlying
aetiology, biological perturbations associated with the CCA urine metabolome signature appeared
to be influenced by gut microbial community metabolism. Sporadic bile duct disease exhibited altered nucleotide metabolism, possibly indicating differences in mitochondrial energy
production pathways related to differences in CCA underlying aetiology.
Similarly, the serum metabolic patterns were differential in bile duct cancer, compared to
healthy participants and individuals with benign and malignant hepatobiliary diseases. Impaired
phospholipid homoeostases was particularly observed in CCA serum profiles, possibly
suggesting influence of genetic variants that impair biliary phospholipid secretion on
circulating lipids. A common metabotype, primarily indicative of inflammatory signature, was
found to be associated with liver pathologies, both benign and malignant.
Overall, it is possible to conclude that metabonomic profiling can identify disease-related
metabotypes and may possibly contribute to uncovering novel candidate diagnostic biomarkers
in CCA.