Alteration of amino acid and biogenic amine metabolism in hepatobiliary cancers: Findings from a prospective cohort study

Magdalena Stepien, Talita Duarte-Salles, Veronika Fedirko, Anne Floegel, Dinesh Kumar Barupal, Sabina Rinaldi, David Achaintre, Nada Assi, Anne Tjønneland, Kim Overvad, Nadia Bastide, Marie Christine Boutron-Ruault, Gianluca Severi, Tilman Kühn, Rudolf Kaaks, Krasimira Aleksandrova, Heiner Boeing, Antonia Trichopoulou, Christina Bamia, Pagona LagiouCalogero Saieva, Claudia Agnoli, Salvatore Panico, Rosario Tumino, Alessio Naccarati, H. B. Bueno-De-Mesquita, Petra H. Peeters, Elisabete Weiderpass, J. Ramõn Quirõs, Antonio Agudo, María José Sánchez, Miren Dorronsoro, Diana Gavrila, Aurelio Barricarte, Bodil Ohlsson, Klas Sjöberg, Mårten Werner, Malin Sund, Nick Wareham, Kay Tee Khaw, Ruth C. Travis, Julie A. Schmidt, Marc Gunter, Amanda Cross, Paolo Vineis, Isabelle Romieu, Augustin Scalbert, Mazda Jenab

Research output: Contribution to journalArticlepeer-review


Perturbations in levels of amino acids (AA) and their derivatives are observed in hepatocellular carcinoma (HCC). Yet, it is unclear whether these alterations precede or are a consequence of the disease, nor whether they pertain to anatomically related cancers of the intrahepatic bile duct (IHBC), and gallbladder and extrahepatic biliary tract (GBTC). Circulating standard AA, biogenic amines and hexoses were measured (Biocrates AbsoluteIDQ-p180Kit) in a case-control study nested within a large prospective cohort (147 HCC, 43 IHBC and 134 GBTC cases). Liver function and hepatitis status biomarkers were determined separately. Multivariable conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95%CI) for log-transformed standardised (mean = 0, SD = 1) serum metabolite levels and relevant ratios in relation to HCC, IHBC or GBTC risk. Fourteen metabolites were significantly associated with HCC risk, of which seven metabolites and four ratios were the strongest predictors in continuous models. Leucine, lysine, glutamine and the ratio of branched chain to aromatic AA (Fischer's ratio) were inversely, while phenylalanine, tyrosine and their ratio, glutamate, glutamate/glutamine ratio, kynurenine and its ratio to tryptophan were positively associated with HCC risk. Confounding by hepatitis status and liver enzyme levels was observed. For the other cancers no significant associations were observed. In conclusion, imbalances of specific AA and biogenic amines may be involved in HCC development. What's new? Perturbations in levels of circulating amino acid metabolites are observed in hepatocellular carcinoma (HCC). Yet it is unclear whether these imbalances are apparent from earlier stages of the disease. In this study nested within a prospective cohort, and based on pre-diagnostically collected blood samples, here the authors show strong HCC risk associations for circulating levels of some aromatic, branched-chain and glucogenic amino acids and biogenic amines. This observation of impaired metabolism in early HCC development may be applied towards further research into the aetiology of, and pathways leading to, this disease.

Original languageEnglish
Pages (from-to)348-360
Number of pages13
JournalInternational Journal of Cancer
Issue number2
Publication statusPublished - Jan 15 2016


  • amino acids
  • biliary tract cancers
  • hepatocellular carcinoma
  • prospective cohort
  • targeted metabolomics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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