Plasma phenylalanine and glutamine concentrations correlate with subsequent hepatocellular carcinoma occurrence in liver cirrhosis patients: an exploratory study

Aberrant metabolisms have been hypothesized to precede the occurrence of hepatocellular carcinoma (HCC), therefore, we investigated biomarkers associated with subsequent HCC in peripheral bloods using metabolomic technologies. A cohort of 475 HCC-naïve liver cirrhotic patients were recruited and prospectively followed. A total of 39 patients developed HCC in the follow-up period. Baseline plasma metabolites were explored using untargeted nuclear magnetic resonance. Candidates were then quantified by ultra-performance liquid chromatography. A series of univairiate and multivariate analysis showed that Phenylalanine (Phe) and Glutamine (Gln) levels are associated with time to HCC, independent of viological etiologies and age. A HCC risk score R was then constructed using the polynomial combination of age, Phe and Gln in the units of micromolar (μM):$$\begin{aligned} {\text{R }} & = {\text{ Age }}* \, \left( {0.0694} \right) + {\text{ Phe }}* \, \left( {0.3399} \right) + {\text{ Phe }^{2}}* \, \left( { - 0.00188154} \right) \hfill \\ & \quad + {\text{ Gln }}* \, \left( { - 0.0133} \right) + {\text{ Gln }^{2}}* \, \left( { \, 0.00002244} \right) \hfill \\ \end{aligned}$$ R = Age ∗ 0.0694 + Phe ∗ 0.3399 + Phe 2 ∗ - 0.00188154 + Gln ∗ - 0.0133 + Gln 2 ∗ 0.00002244 R correlates with the time to HCC significantly (Hazard ratio [HR] = 2.368, 95% confidence interval [CI] 1.760–3.187, P