Plasma phenylalanine and glutamine concentrations correlate with subsequent hepatocellular carcinoma occurrence in liver cirrhosis patients: an exploratory study
Kung‐Hao Liang, Mei‐Ling Cheng, Chi-Jen Lo, Yang-Hsiang Lin, Ming‐Wei Lai, Wey‐Ran Lin, Chau‐Ting Yeh
Abstract
Abstract 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): $$\begin{aligned} {\text{R }} & = {\text{ Age }}* \, \left( {0.0694} \right) + {\text{ Phe }}* \, \left( {0.3399} \right) + {\text{ Phe }^{2}}* \, \left( { - 0.00188154} \right) \hfill \\ & \quad + {\text{ Gln }}* \, \left( { - 0.0133} \right) + {\text{ Gln }^{2}}* \, \left( { \, 0.00002244} \right) \hfill \\ \end{aligned}$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mtable> <mml:mtr> <mml:mtd> <mml:mrow> <mml:mtext>R</mml:mtext> <mml:mspace/> </mml:mrow> </mml:mtd> <mml:mtd> <mml:mrow> <mml:mo>=</mml:mo> <mml:mrow> <mml:mspace/> <mml:mtext>Age</mml:mtext> <mml:mspace/> </mml:mrow> <mml:mrow/> <mml:mo>∗</mml:mo> <mml:mspace/> <mml:mfenced> <mml:mrow> <mml:mn>0.0694</mml:mn> </mml:mrow> </mml:mfenced> <mml:mo>+</mml:mo> <mml:mrow> <mml:mspace/> <mml:mtext>Phe</mml:mtext> <mml:mspace/> </mml:mrow> <mml:mrow/> <mml:mo>∗</mml:mo> <mml:mspace/> <mml:mfenced> <mml:mrow> <mml:mn>0.3399</mml:mn> </mml:mrow> </mml:mfenced> <mml:mo>+</mml:mo> <mml:mrow> <mml:mspace/> <mml:mtext>Phe</mml:mtext> <mml:msup> <mml:mspace/> <mml:mn>2</mml:mn> </mml:msup> </mml:mrow> <mml:mrow/> <mml:mo>∗</mml:mo> <mml:mspace/> <mml:mfenced> <mml:mrow> <mml:mo>-</mml:mo> <mml:mn>0.00188154</mml:mn> </mml:mrow> </mml:mfenced> </mml:mrow> </mml:mtd> </mml:mtr> <mml:mtr> <mml:mtd> <mml:mrow/> </mml:mtd> <mml:mtd> <mml:mrow> <mml:mspace/> <mml:mo>+</mml:mo> <mml:mrow> <mml:mspace/> <mml:mtext>Gln</mml:mtext> <mml:mspace/> </mml:mrow> <mml:mrow/> <mml:mo>∗</mml:mo> <mml:mspace/> <mml:mfenced> <mml:mrow> <mml:mo>-</mml:mo> <mml:mn>0.0133</mml:mn> </mml:mrow> </mml:mfenced> <mml:mo>+</mml:mo> <mml:mrow> <mml:mspace/> <mml:mtext>Gln</mml:mtext> <mml:msup> <mml:mspace/> <mml:mn>2</mml:mn> </mml:msup> </mml:mrow> <mml:mrow/> <mml:mo>∗</mml:mo> <mml:mspace/> <mml:mfenced> <mml:mrow> <mml:mspace/> <mml:mn>0.00002244</mml:mn> </mml:mrow> </mml:mfenced> </mml:mrow> </mml:mtd> </mml:mtr> <mml:mtr> <mml:mtd> <mml:mrow/> </mml:mtd> </mml:mtr> </mml:mtable> </mml:mrow> </mml:math> R correlates with the time to HCC significantly (Hazard ratio [HR] = 2.368, 95% confidence interval [CI] 1.760–3.187, P < 0.001). An additional cross-sectional analysis showed that Phe and Gln concentrations both correlates with HCC occurrence in the next 3 years (area under the receiver operating characteristic curve [AUC] = 0.607 and 0.629, P = 0.033 and 0.010 respectively). In conclusion, phenylalanine and glutamine concentrations in the peripheral blood correlate with subsequent HCC.