Cholangiocarcinoma (CCA) is a tumor with increasing prevalence around the world. The prevalence of CCA is highest in East Asia and most significantly in the countries through which the Mekong River flows, owing to the presence of liver flukes, which are consumed in raw fish dishes. Outside Asia, the causes of bile duct cancers for the most part are unknown. In this review, we assess the current state of knowledge in both fluke-associated and sporadic CCA, from etiological, diagnostic, and treatment perspectives.

Background: Outside South-East Asia, most cases of cholangiocarcinoma (CCA) have an obscure etiology. There is often diagnostic uncertainty. Metabolomics using ultraperformance liquid chromatography mass spectrometry (UPLC-MS) offers the portent to distinguish disease-specific metabolic signatures. We aimed to define such a urinary metabolic signature in a patient cohort with sporadic CCA and investigate whether there were characteristic differences from those in patients with hepatocellular carcinoma (HCC), metastatic secondary liver cancer, pancreatic cancer and ovarian cancer (OCA). Methods: Spot urine specimens were obtained from 211 subjects in seven participating centers across the UK. Samples were collected from healthy controls and from patients with benign hepatic disease (gallstone, biliary strictures, sphincter of Oddi dysfunction and viral hepatitis) and patients with malignant conditions (HCC, pancreatic cancer, OCA and metastatic cancer in the liver). The spectral metabolite profiles were generated using a UPLC-MS detector and data were analyzed using multivariate and univariate statistical analyses. Results: The greatest class differences were seen between the metabolic profiles of disease-free controls compared to individuals with CCA with altered acylcarnitine, bile acid and purine levels. Individuals with benign strictures showed comparable urine profiles to patients with malignant bile duct lesions. The metabolic signatures of patients with bile duct tumors were distinguishable from patients with hepatocellular and ovarian tumors, but no difference was observed between CCA cases and patients with pancreatic cancer or hepatic secondary metastases. Conclusion: CCA causes subtle but detectable changes in the urine metabolic profiles. The findings point toward potential applications of metabonomics in early tumor detection. However, it is key to utilize both global and targeted metabonomics in a larger cohort for in-depth characterization of the urine metabolome in hepato-pancreato-biliary disease.

Background: Human infection with Opisthorchis viverrini, a carcinogenic liver fluke inhabiting the biliary tree, is endemic in Southeast Asia. Chronic infection is associated with a fatal complication, cholangiocarcinoma (CCA), a late-presenting and aggressive malignancy. Currently, annual mortality rates from CCA mirror trends in incidence, due in part to limited availability of efficient prognostic and early diagnostic biomarkers. With ability to detect thousands of urinary metabolites using metabonomics, the urine metabolome holds great potential in providing an insight into system-level alterations in carcinogenesis and in identifying metabolic markers altered in response to disturbed homoeostasis. Methods: Global molecular profiling using reversed-phase ultraperformance liquid chromatography mass spectrometry was utilised to acquire the urinary spectral profile of 137 Thai subjects (48 at high risk of infection, 41 with O. viverrini infection, 34 periportal fibrosis and 14 CCA) from Khon Kaen, Thailand. Results: Multivariate statistical analysis identified perturbation in several molecular classes related to purine metabolism and lipid metabolism in the CCA urine metabolome. These markers mainly reflect changes in energy metabolism to support proliferation (increased fatty acid oxidation and purine recycling), DNA methylation and hepatic injury. Conclusions: Several metabolites of biological interest were discovered from this proof-of-principle dataset. Augmenting these findings is essential to accelerate the development of urinary metabolic markers in CCA.

Metabolic phenotyping of obese populations can shed light on understanding environmental interactions underpinning obesogenesis. Obesity and its comorbidities are a major health and socioeconomic concern globally and are highly prevalent in the Middle East. We employed nuclear magnetic resonance spectroscopy to characterize the metabolic signature of urine and blood plasma for a cohort of obese (n = 50) compared to non-obese (n = 48) Saudi participants. The urinary metabolic phenotype of obesity was characterized by higher concentrations of N-acetyl glycoprotein fragments, bile acids, lysine, and methylamines and lower concentrations of tricarboxylic acid cycle intermediates, glycine, and gut microbial metabolites. The plasma metabolic phenotype of obesity was dominated by sugars, branched chain amino acids, and lipids, particularly unsaturated lipids, with lower levels of plasma phosphorylcholine and HDL. Serum hepatic enzymes, triglycerides, and cholesterol mapped to specific metabolic phenotypes, potentially indicating the dysregulation of multiple distinct obesity-related pathways. Differences between urine and plasma phenotypes of obesity for this Saudi population and that reported for Caucasian individuals indicate population disparities in pathways relating to ketogenesis (more apparent in the Saudi obese population), dysregulated liver function, and the gut microbiome. Mapping population-specific metabolic perturbations may hold promise in establishing population differences relevant to disease risk and stratification of individuals with respect to discovery of new therapeutic targets.

Background: A distinct serum metabonomic pattern has been previously revealed to be associated with various forms of liver disease. Here, we aimed to apply mass spectrometry to obtain serum metabolomic profiles from individuals with cholangiocarcinoma and benign hepatobiliary diseases to gain an insight into pathogenesis and search for potential early-disease biomarkers. Methods: Serum samples were profiled using a hydrophilic interaction liquid chromatography platform, coupled to a mass spectrometer. A total of 47 serum specimens from 8 cholangiocarcinoma cases, 20 healthy controls, 8 benign disease controls (bile duct strictures) and 11 patients with hepatocellular carcinoma (as malignant disease controls) were included. Data analysis was performed using univariate and multivariate statistics. Results: The serum metabolome disparities between the metabolite profiles from healthy controls and patients with hepatobiliary disease were predominantly related to changes in lipid and lipid-derived compounds (phospholipids, bile acids and steroids) and amino acid metabolites (phenylalanine). A metabolic pattern indicative of inflammatory response due to cirrhosis and cholestasis was associated with the disease groups. The abundance of phospholipid metabolites was altered in individuals with liver disease, particularly cholangiocarcinoma, but no significant difference was seen between profiles from patients with benign biliary strictures and cholangiocarcinoma. Conclusion: The serum metabolome in cholangiocarcinoma exhibited changes in metabolites related to inflammation, altered energy production and phospholipid metabolism. This study serves to highlight future avenues for biomarker research in large-scale studies.