Serum metabolites as diagnostic biomarkers for cholangiocarcinoma, hepatocellular carcinoma and primary sclerosing cholangitis
Banales JM (1,2,3), Iñarrairaegui M (2,4), Arbelaiz A (1), Milkiewicz P (5), Muntane J (2,6), Muñoz-Bellvis L (7), La Casta A (1), Gonzalez LM (7), Arretxe E (8), Alonso C (8), Martínez-Arranz I (8), Lapitz A (1), Santos-Laso A (1), Avila MA (2,9), Martínez-Chantar ML (2,8), Bujanda L (1,2), Marin JJG (2,10), Sangro B (2,4), Macias RIR (2,10).
(1 Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
(2 National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), Madrid, Spain.
(3 IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
(4 Liver Unit, Clínica Universidad de Navarra-IDISNA, Pamplona, Spain.
(5 Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
(6 Department of General Surgery "Virgen del Rocío" University Hospital/IBiS/CSIC/ University of Seville, Spain.
(7 Service of General and Gastrointestinal Surgery, University Hospital of Salamanca, Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain.
(8 Bizkaia Technology Park, Derio, Spain.
(9 Division of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra-IDISNA, Pamplona, Spain.
(10 Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain.
Early and differential diagnosis of intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) by non-invasive methods represents a current clinical challenge.
The analysis of low-molecular weight metabolites by new high-throughput techniques is a novel strategy for identifying biomarkers. Here, we have investigated whether serum metabolome can provide useful biomarkers in the diagnosis of iCCA and HCC and could discriminate iCCA from HCC. Since primary sclerosing cholangitis (PSC) is a risk factor for CCA, serum metabolomic profiles of PSC and CCA have also been compared.
The analysis of the levels of lipids and amino acids in the serum of patients with iCCA, HCC, PSC and healthy individuals (n=20/group) showed differential profiles. Several metabolites presented high diagnostic value for iCCA vs control, HCC vs control, and PSC vs control, with areas under the receiver operating characteristic curve (AUC) greater than those found in serum for the non-specific tumor markers carbohydrate antigen 19-9 (CA19-9) and alpha-fetoprotein (AFP), commonly used to help in the diagnosis of iCCA and HCC, respectively. The development of an algorithm combining glycine, aspartic acid, SM(42:3) and SM(43:2) permitted to accurately differentiate in the diagnosis of both types of tumors (biopsy-proven).
The proposed model yielded 0.890 AUC, 75% sensitivity and 90% specificity. Another algorithm by combination of PC(34:3) and histidine accurately permitted to differentiate PSC from iCCA, with an AUC of 0.990, 100% sensitivity and 70% specificity. These results were validated in independent cohorts of 14-15 patients per group and compared with profiles found in NAFLD/NASH patients.
CONCLUSION: Specific changes in serum concentrations of certain metabolites are useful to differentiate iCCA from HCC or PSC, and could help in the early diagnosis of these diseases.
CITATION Hepatology. 2018 Oct 16. doi: 10.1002/hep.30319