BACKGROUND & AIMS Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. Therefore, we aimed to analyze blood metabolome in patients with cirrhosis, with and without ACLF. METHODS We performed untargeted metabolomics using liquid chromatography coupled to high-resolution mass spectrometry in serum from 650 patients with AD (acute decompensation of cirrhosis, without ACLF), 181 with ACLF, 43 with compensated cirrhosis, and 29 healthy subjects. RESULTS Of the 137 annotated metabolites identified, 100 were increased in patients with ACLF of any grade, relative to those with AD, and 38 composed a distinctive blood metabolite fingerprint for ACLF. Among patients with ACLF, the intensity of the fingerprint increased across ACLF grades, and was similar in patients with kidney failure and in those without, indicating that the fingerprint reflected not only decreased kidney excretion but also altered cell metabolism. The higher the ACLF-associated fingerprint intensity, the higher plasma levels of inflammatory markers, tumor necrosis factor α, soluble CD206, and soluble CD163. ACLF was characterized by intense proteolysis and lipolysis; amino acid catabolism; extra-mitochondrial glucose metabolism through glycolysis, pentose phosphate, and D-glucuronate pathways; depressed mitochondrial ATP-producing fatty acid β-oxidation; and extra-mitochondrial amino acid metabolism giving rise to metabolites which are metabotoxins. CONCLUSIONS In ACLF, intense systemic inflammation is associated with blood metabolite accumulation witnessing profound alterations in major metabolic pathways, in particular inhibition in mitochondrial energy production, which may contribute to the existence of organ failures.

中文翻译：

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血液代谢组学揭示炎症相关的线粒体功能障碍是 ACLF 的潜在机制

背景与目的 慢性加急性肝功能衰竭 (ACLF) 发生于肝硬化患者，其特征是严重的全身炎症和器官衰竭。由于全身性炎症在能量上非常昂贵，因此其代谢成本可能会导致器官功能障碍/衰竭。因此，我们旨在分析肝硬化患者的血液代谢组，无论有无 ACLF。方法 我们使用液相色谱结合高分辨率质谱对 650 名 AD 患者（肝硬化急性失代偿，无 ACLF）、181 名 ACLF、43 名代偿期肝硬化和 29 名健康受试者的血清进行了非靶向代谢组学。结果 在鉴定的 137 种带注释的代谢物中，与 AD 患者相比，任何级别的 ACLF 患者中有 100 种增加，和 38 人组成了一个独特的 ACLF 血液代谢物指纹。在 ACLF 患者中，指纹的强度随着 ACLF 等级的增加而增加，并且在肾衰竭患者和没有肾衰竭的患者中相似，这表明指纹不仅反映了肾脏排泄减少，而且还反映了细胞代谢的改变。ACLF 相关指纹强度越高，炎症标志物、肿瘤坏死因子 α、可溶性 CD206 和可溶性 CD163 的血浆水平越高。ACLF 的特点是强烈的蛋白水解和脂解作用；氨基酸分解代谢；通过糖酵解、磷酸戊糖和 D-葡萄糖醛酸途径进行的线粒体外葡萄糖代谢；抑制线粒体产生 ATP 的脂肪酸 β-氧化；线粒体外氨基酸代谢产生代谢物，即代谢毒素。