PO.PS01.01 · 人群科学
不良肝脏状况进展为肝癌过程中的血浆代谢组学特征
Plasma metabolomics profiles in the progression of adverse liver conditions to liver cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景:循环代谢物可能标志着从代谢功能障碍相关脂肪性肝病(MASLD)和肝硬化进展至肝癌的过程。我们对代谢组学模式进行了表征,并评估了其与分期特异性转变的前瞻性关联。
方法:我们使用了Mass General Brigham Biobank中47,972名参与者的数据,这些参与者具有Nightingale代谢组学数据以及评估前后的纵向病历记录。代谢组学检测时的分期根据是否已按国际疾病分类(ICD)编码发生MASLD、肝硬化或肝癌来定义。对于无不良肝脏状况的参与者,我们排除了Charlson合并症指数>5或在评估后1年内死亡者,以限制其他疾病的影响。使用包括人口统计学、合并症和生活方式在内的协变量估计校正均值和线性趋势。校正后的Cox模型检验了癌前代谢物与新发肝癌的关联。检验了代谢物与肝脏脂肪相关多基因风险评分(PRS)之间的交互作用。
结果:在代谢组学评估时,17,869名参与者无不良肝脏状况,2041名患有MASLD,1774名患有肝硬化,206名患有肝癌。在249个代谢组学变量中,181个显示出按分期的显著线性趋势(FDR<0.05),例如,小型HDL胆固醇以及超大型HDL胆固醇/总脂质比值随进展而降低,而大型HDL游离胆固醇/总脂质比值和酪氨酸随进展而升高。这些代谢物在无肝病或肝硬化的参与者中也显示出与肝癌发病率的显著关联(FDR<0.05)。我们未观察到代谢物×PRS的交互作用(FDR>0.05)。
结论:代谢组学特征捕捉到了MASLD-肝硬化-肝癌连续过程中的信号。这些标志物可能改善风险分层、监测时机,并为肝脏状况谱系中的生物学机制提供信息。
不良肝脏状况进展为肝癌过程中的主要代谢物。校正均值水平 与新发肝癌的关联 无肝病 MASLD 肝硬化 代谢物 无肝病 MASLD 肝硬化 肝癌 FDR-线性 HR(95% CI) FDR HR(95% CI) FDR HR(95% CI) FDR 小型HDL胆固醇 -0.21 -0.11 -0.60 -0.83 <0.001 0.72(0.62, 0.82) <0.001 0.65(0.32, 1.29) 0.67 0.66(0.54, 0.81) 0.004 小型HDL胆固醇酯 -0.20 -0.11 -0.62 -0.88 <0.001 0.72(0.63, 0.82) <0.001 0.62(0.31, 1.23) 0.65 0.66(0.55, 0.80) 0.003 小型HDL颗粒浓度 -0.20 -0.10 -0.59 -0.79 <0.001 0.72(0.62, 0.83) <0.001 0.67(0.32, 1.40) 0.69 0.65(0.52, 0.80) 0.005 超大型HDL胆固醇/总脂质比值 0.01 0.08 -0.24 -0.45 <0.001 0.74(0.63, 0.87) 0.006 0.63(0.35, 1.14) 0.62 0.53(0.38, 0.75) 0.04 大型HDL游离胆固醇/总脂质比值 0.03 -0.09 0.19 0.47 <0.001 1.39(1.16, 1.66) 0.008 1.71(1.21, 2.42) 0.85 1.71(1.21, 2.42) 0.03 酪氨酸 0.03 0.05 0.06 0.20 0.03 1.19(1.03, 1.37) 0.11 1.30(0.68, 2.50) 0.76 1.57(1.28, 1.93) 0.003
查看英文原文 English abstract
Background: Circulating metabolites may mark the progression from metabolic dysfunction-associated steatotic liver disease (MASLD) and liver cirrhosis to liver cancer. We characterized metabolomic patterns and evaluated prospective associations with stage-specific transitions.
Methods: We used data from 47,972 participants in Mass General Brigham Biobank with Nightingale metabolomics and longitudinal medical records before and after assessment. Stage at metabolomics was defined based on if MASLD, liver cirrhosis, or liver cancer had occurred by International Classification of Diseases codes. For participants with no adverse liver condition, we excluded those with Charlson comorbidity index >5 or death in 1 year of assessment to limit the impact of other diseases. Adjusted means and linear trends were estimated with covariates including demographics, comorbidities, and lifestyles. Adjusted Cox models examined the associations of pre-cancer metabolite and incident liver cancer. Interactions between metabolite and the hepatic fat-associated polygenic risk score (PRS) were tested.
Results: At metabolomics assessment, 17,869 participants had no adverse liver condition, 2041 had MASLD, 1774 had liver cirrhosis, and 206 had liver cancer. In the 249 metabolomic variables, 181 displayed significant linear trends by stage (FDR <0.05), e.g., small HDL cholesterol and very large HDL cholesterol / total lipids ratio decreased while large HDL free cholesterol / total lipids ratio and tyrosine increased with progression. These metabolites also show significant associations (FDR <0.05) with liver cancer incidence in participants with no liver disease or cirrhosis. We did not observe metabolite × PRS interactions (FDR >0.05).
Conclusions: Metabolomic profiles capture signals along the MASLD - cirrhosis - liver cancer continuum. These markers may improve risk stratification, timing of surveillance, and inform the biological mechanisms along the liver conditions spectrum.
Top metabolites in the progression of adverse liver conditions to liver cancer. Adjusted mean level Association with incident liver cancer No liver disease MASLD Liver cirrhosis Metabolite No liver disease MASLD Liver cirrhosis Liver cancer FDR-linear HR (95% CI) FDR HR (95% CI) FDR HR (95% CI) FDR Small HDL cholesterol -0.21 -0.11 -0.60 -0.83 <0.001 0.72 (0.62, 0.82) <0.001 0.65 (0.32, 1.29) 0.67 0.66 (0.54, 0.81) 0.004 Small HDL cholesteryl esters -0.20 -0.11 -0.62 -0.88 <0.001 0.72 (0.63, 0.82) <0.001 0.62 (0.31, 1.23) 0.65 0.66 (0.55, 0.80) 0.003 Small HDL particle concentration -0.20 -0.10 -0.59 -0.79 <0.001 0.72 (0.62, 0.83) <0.001 0.67 (0.32, 1.40) 0.69 0.65 (0.52, 0.80) 0.005 Very large HDL cholesterol / total lipids ratio 0.01 0.08 -0.24 -0.45 <0.001 0.74 (0.63, 0.87) 0.006 0.63 (0.35, 1.14) 0.62 0.53 (0.38, 0.75) 0.04 Large HDL free cholesterol / total lipids ratio 0.03 -0.09 0.19 0.47 <0.001 1.39 (1.16, 1.66) 0.008 1.71 (1.21, 2.42) 0.85 1.71 (1.21, 2.42) 0.03 Tyrosine 0.03 0.05 0.06 0.20 0.03 1.19 (1.03, 1.37) 0.11 1.30 (0.68, 2.50) 0.76 1.57 (1.28, 1.93) 0.003
利益披露 Disclosure
X. Zhang, None..
L. Cai, None.