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Open AccessArticle

Comprehensive Metabolomic Search for Biomarkers to Differentiate Early Stage Hepatocellular Carcinoma from Cirrhosis

Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Korea
Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea
Department of Statistics, Seoul National University, Seoul 08826, Korea
Authors to whom correspondence should be addressed.
Cancers 2019, 11(10), 1497;
Received: 20 August 2019 / Revised: 2 October 2019 / Accepted: 2 October 2019 / Published: 6 October 2019
(This article belongs to the Special Issue Human Hepatocellular Carcinoma (HCC))
The established biomarker for hepatocellular carcinoma (HCC), serum α-fetoprotein (AFP), has suboptimal performance in early disease stages. This study aimed to develop a metabolite panel to differentiate early-stage HCC from cirrhosis. Cross-sectional metabolomic analyses of serum samples were performed for 53 and 47 patients with early HCC and cirrhosis, respectively, and 50 matched healthy controls. Results were validated in 82 and 80 patients with early HCC and cirrhosis, respectively. To retain a broad spectrum of metabolites, technically distinct analyses (global metabolomic profiling using gas chromatography time-of-flight mass spectrometry and targeted analyses using liquid chromatography with tandem mass spectrometry) were employed. Multivariate analyses classified distinct metabolites; logistic regression was employed to construct a prediction model for HCC diagnosis. Five metabolites (methionine, proline, ornithine, pimelylcarnitine, and octanoylcarnitine) were selected in a panel. The panel distinguished HCC from cirrhosis and normal controls, with an area under the receiver operating curve (AUC) of 0.82; this was significantly better than that of AFP (AUC: 0.75). During validation, the panel demonstrated significantly better predictability (AUC: 0.94) than did AFP (AUC: 0.78). Defects in ammonia recycling, the urea cycle, and amino acid metabolism, demonstrated on enrichment pathway analysis, may reliably distinguish HCC from cirrhosis. Compared with AFP alone, the metabolite panel substantially improved early-stage HCC detection.
Keywords: hepatocellular carcinoma; cirrhosis; metabolomics; biomarker hepatocellular carcinoma; cirrhosis; metabolomics; biomarker
MDPI and ACS Style

Kim, D.J.; Cho, E.J.; Yu, K.-S.; Jang, I.-J.; Yoon, J.-H.; Park, T.; Cho, J.-Y. Comprehensive Metabolomic Search for Biomarkers to Differentiate Early Stage Hepatocellular Carcinoma from Cirrhosis. Cancers 2019, 11, 1497.

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