Peer-review started: June 30, 2016
First decision: August 18, 2016
Revised: September 20, 2016
Accepted: October 22, 2016
Article in press: October 24, 2016
Published online: January 8, 2017
We elucidate major pathways of hepatocarcinogenesis and accurate diagnostic metabolomic biomarkers of hepatocellular carcinoma (HCC) identified by contemporary HCC metabolomics studies, and delineate a model HCC metabolomics study design. A literature search was carried out on Pubmed for HCC metabolomics articles published in English. All relevant articles were accessed in full text. Major search terms included “HCC”, “metabolomics”, “metabolomics”, “metabonomic” and “biomarkers”. We extracted clinical and demographic data on all patients and consolidated the lead candidate biomarkers, pathways, and diagnostic performance of metabolomic expression patterns reported by all studies in tables. Where reported, we also extracted and summarized the metabolites and pathways most highly associated with the development of cirrhosis in table format. Pathways of lysophospholipid, sphingolipid, bile acid, amino acid, and reactive oxygen species metabolism were most consistently associated with HCC in the cited works. Several studies also elucidate metabolic alterations strongly associated with cirrhosis, with γ-glutamyl peptides, bile acids, and dicarboxylic acids exhibiting the highest capacity for stratifying cirrhosis patients from appropriately matched controls. Collectively, global metabolomic profiles of the referenced works exhibit a promising diagnostic capacity for HCC at a capacity greater than that of conventional diagnostic biomarker alpha-fetoprotein. Metabolomics is a powerful strategy for identifying global metabolic signatures that exhibit potential to be leveraged toward the screening, diagnosis, and management of HCC. A streamlined study design and patient matching methodology may improve concordance among metabolomic datasets in future works.
Core tip: The high-throughput, validated nature of metabolomics makes it an ideal methodology for rapidly identifying the global metabolic alterations associated with hepatocarcinogenesis - alterations that not only enhance our understanding of the metabolic underpinnings of cirrhosis and hepatocellular carcinoma (HCC), but that can be leveraged to improve HCC diagnostic, therapeutic, and disease monitoring efficacy. Indeed, contemporary HCC metabolomics works time and again demonstrate this promise that metabolomics platforms hold in serving as standalone non-invasive HCC diagnostic and disease monitoring modalities.