早期代謝體變化與HBV帶原者發生肝細胞癌的關係:擴展研究

Abstract

背景與目的: B型肝炎病毒感染肝細胞並干擾代謝途徑，在過去的病例對照研究中，肝細胞癌患者與非肝細胞癌患者有明顯的代謝差異，然而，與B型肝炎病毒相關肝細胞癌自然病程及發病機制仍尚未清楚。本研究主旨在前瞻性地調查男性B型肝炎帶原者中肝細胞癌發展相關的代謝變化。 材料與方法: 首先，從已發表的病例世代研究中選擇108名肝細胞癌病例並配對108名對照個案探索重要代謝物，後續由另一個獨立巢式病例對照研究進行驗證(63名肝細胞癌病例和107名對照)，上述所有參與者皆為B型肝炎表面抗原陽性且年齡大於30歲之男性。我們檢測了基線及長期追縱下的血漿代謝組學圖譜，鑑定出的差異代謝物也與12名Child-Pugh B級和24 Child-Pugh C級的臨床肝硬化患者進行比較。代謝體實驗使用一維度氫原子核磁共振質譜儀測定，而多變量分析則以PLS-DA進行，利用廣義線性混合模型和廣義估計方程式探討特定代謝物與肝細胞癌之間的縱向關係。 結果: 從長期趨勢可以發現，tyrosine、glutamine、glutamate於病例組與對照組有顯著差異，具體而言，tyrosine和glutamate在病例組有相對較高的濃度，並與病毒量有顯著正相關，而glutamine則在病例組有相對較低的濃度，與病毒量有顯著負相關。Tyrosine、glutamine在肝硬化族群中也發現相似的關係。 結論: 本研究發現胺基酸代謝小分子的改變與B型肝炎病毒相關肝細胞癌的發展有關，其中glutamine觀察到負相關，tyrosine和glutamate觀察到正相關。

Background and Aims: Hepatitis B virus (HBV) infects hepatocytes that can interfere with some of metabolic pathways. Previous case-control studies have shown distinct metabolic profiles in patients with hepatocellular carcinoma (HCC) vs. those without. However, the natural history and pathogenesis of HBV-related HCC remained largely unknown. This study aimed to prospectively investigate metabolic changes in relation to the development of HCC among male HBV carriers. Materials and Methods: In the discovery phase, 108 HCC cases and 108 matched controls were selected from a published case-cohort study. The results were replicated in an independent nested case-control study of 63 HCC cases and 107 controls. All participants were hepatitis B surface antigen-positive men aged ≥30. We examined metabolomics profiles in plasma collected at baseline and follow-up. Differential metabolites identified were also compared with clinical cirrhotic patients, with 12 Child-Pugh class B and 24 Child-Pugh class C. Metabolic profiles were analyzed by 1H nuclear magnetic resonance spectroscopy follow by multivariate analysis, specifically partial least squares discriminant analysis. The longitudinal relationship between specific metabolites and HCC were explored using generalized linear mixed model (GLMM) and generalized estimating equation (GEE) model. Result: From longitudinal analysis, we found that tyrosine, glutamine, and glutamate were significantly different between cases and controls. Specifically, tyrosine and glutamate had a relatively high abundance in the HCC cases also had a significantly positive correlation with HBV viral load, whereas glutamine had a relatively low abundance in the HCC cases as well as having a significantly negative correlation with viral load. Similar associations with liver cirrhosis were also found for tyrosine and glutamine. Conclusion: The data showed that metabolic alteration in amino acids was associated with the development of HBV-related HCC, with negative association observed for glutamine and positive associations observed for tyrosine and glutamate.