Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and is the major cause of death in patients with chronic liver disease [1,2]
As a combination of multiple analytical methods may enable the capture of a broad spectrum of metabolites, we identified HCC-specific metabolite alterations using a combination of gas chromatography (GC)- and liquid chromatography (LC)-mass spectrometry (MS)-based analyses and determined their potential as diagnostic biomarkers for HCC
Serum are scarce. Even α-fetoprotein (AFP) levels were significantly higher in the HCC group than in the cirrhosis and control groups
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and is the major cause of death in patients with chronic liver disease [1,2]. To ensure an early diagnosis and reduction of disease-related mortality, HCC surveillance is essential for at-risk populations [3]. Tumor biomarkers for the early detection of HCC are scarce. Even α-fetoprotein (AFP), the most commonly used tumor marker, has suboptimal performance, providing only a 6–8% higher rate of detection for HCCs not identified on ultrasound [4]. The development of new biomarkers for early diagnosis of HCC is necessary for improving the efficacy of surveillance.
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