Serum Metabolites as Diagnostic Biomarkers for Cholangiocarcinoma, Hepatocellular Carcinoma, and Primary Sclerosing Cholangitis

Abstract

Early and differential diagnosis of intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) by noninvasive methods represents a current clinical challenge. The analysis of low‐molecular‐weight metabolites by new high‐throughput techniques is a 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. Because primary sclerosing cholangitis (PSC) is a risk factor for CCA, serum metabolic 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, and PSC and healthy individuals (n = 20/group) showed differential profiles. Several metabolites presented high diagnostic value for iCCA versus control, HCC versus control, and PSC versus control, with areas under the receiver operating characteristic curve (AUC) greater than those found in serum for the nonspecific tumor markers carbohydrate antigen 19‐9 (CA 19‐9) 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 patients with nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. 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.

Pathogenesis, diagnosis and treatment of premalignant and malignant stages of cholangiocarcinoma in primary sclerosing cholangitis

“…Studies on concentration and protein content in extracellular vesicles in bile and serum have also demonstrated the ability to accurately separate patients with malignant vs non‐malignant bile duct stenoses in PSC, and also to discriminate patients with PSC and CCA from healthy individuals . Specific changes in serum concentration of certain metabolites or gene expression patterns in mRNA isolated from biliary brushings may also provide potential sources for development of new biomarkers for the diagnosis of CCA in PSC Mutational profiling of brush cytology specimens has also shown the potential of improving CCA detection compared to cytology assessments alone …”

Blood exosomal micro ribonucleic acid profiling reveals the complexity of hepatocellular carcinoma and identifies potential biomarkers for differential diagnosis

“…At present, the serum αfetoprotein (AFP) test is a common and important early diagnostic test for liver cancer, but this biomarker has a low specificity[ 11 ]. In addition, carbohydrate antigen (CA) 19-9 (CA19-9) and carcinoembryonic antigen have been widely used as serum tumor markers for the clinical diagnosis of HCC[ 12 ]. However, the efficacy of these tumor markers in the clinical diagnosis of HCC remains unsatisfactory.…”

The Rise in the Prevalence of Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma

“…Assessment of changes in the levels of metabolites of samples stratified by race was made using gas chromatography-mass spectrometry in selected ion monitoring mode to identify ethnically diverse biomarkers in HCC between EA and AAs [177]. Race-specific metabolites including alpha tocopherol for AA and EA combined, glycine for EA, and valine for AA exhibited better sensitivity and specificity than the standard serological marker for HCC, alpha-fetoprotein (AFP) that is widely used for the diagnosis of HCC [177][178][179][180]. It is hypothesized that there is a variation in HCC-associated epigenetic modifications between AAs and EAs.…”