Table_1_Metabolomics reveals altered metabolites in cirrhotic patients with severe portal hypertension in Tibetan population.DOCX

BackgroundPortal hypertension (PHT) presents a challenging issue of liver cirrhosis. This study aims to identify novel biomarkers for severe PHT (SPHT) and explore the pathophysiological mechanisms underlying PHT progression.MethodsTwenty-three Tibetan cirrhotic patients who underwent hepatic venous pressure gradient (HVPG) measurement were included. Eleven patients had an HVPG between 5 mmHg and 15 mmHg (MPHT), while 12 had an HVPG ≥16 mmHg (SPHT). Peripheral sera were analyzed using liquid chromatograph-mass spectrometer for metabolomic assessment. An additional 14 patients were recruited for validation of metabolites.ResultsSeven hundred forty-five metabolites were detected and significant differences in metabolomics between MPHT and SPHT patients were observed. Employing a threshold of p 1, 153 differential metabolites were identified. A significant number of these metabolites were lipids and lipid-like molecules. Pisumionoside and N-decanoylglycine (N-DG) exhibited the highest area under the curve (AUC) values (0.947 and 0.9091, respectively). Additional differential metabolites with AUC >0.8 included 6-(4-ethyl-2-methoxyphenoxy)-3,4,5-trihydroxyoxane-2-carboxylic acid, sphinganine 1-phosphate, 4-hydroxytriazolam, 4,5-dihydroorotic acid, 6-hydroxy-1H-indole-3-acetamide, 7alpha-(thiomethyl)spironolactone, 6-deoxohomodolichosterone, glutaminylisoleucine, taurocholic acid 3-sulfate, and Phe Ser. Enzyme-linked immunosorbent assay further confirmed elevated levels of sphinganine 1-phosphate, N-DG, and serotonin in SPHT patients. Significant disruptions in linoleic acid, amino acid, sphingolipid metabolisms, and the citrate cycle were observed in SPHT patients.ConclusionPisumionoside and N-DG are identified as promising biomarkers for SPHT. The progression of PHT may be associated with disturbances in lipid, linoleic acid, and amino acid metabolisms, as well as alterations in the citrate cycle.

背景门脉高压症（PHT）是肝硬化所面临的一项具有挑战性的问题。本研究旨在识别严重门脉高压症（SPHT）的新型生物标志物，并探讨PHT进展背后的病理生理学机制。方法纳入了23名接受肝静脉压力梯度（HVPG）测量的藏族肝硬化患者。其中11名患者的HVPG在5至15毫米汞柱之间（MPHT），而12名患者的HVPG≥16毫米汞柱（SPHT）。通过液相色谱-质谱联用技术对周围血清进行分析，以进行代谢组学评估。此外，还招募了14名患者以验证代谢物。结果检测到745种代谢物，在MPHT和SPHT患者之间观察到显著的代谢组学差异。以p值阈值为1的情况下，确定了153种差异代谢物。其中，相当数量的代谢物为脂质和类似脂质分子。豌豆苷和N-癸酰甘氨酸（N-DG）表现出最高的曲线下面积（AUC）值（分别为0.947和0.9091）。AUC>0.8的额外差异代谢物还包括6-(4-乙基-2-甲氧基苯氧基)-3,4,5-三羟基氧烷-2-羧酸、鞘氨醇1-磷酸、4-羟基三唑alam、4,5-二氢尿酸、6-羟基-1H-吲哚-3-乙酰胺、7alpha-(硫甲基)螺内酯、6-脱氧同二醇胆酸、谷氨酰异亮氨酸、牛磺胆酸3-硫酸盐和Phe Ser。酶联免疫吸附测定进一步证实了SPHT患者中鞘氨醇1-磷酸、N-DG和血清素水平的升高。在SPHT患者中观察到亚油酸、氨基酸、鞘脂和柠檬酸循环代谢的显著紊乱。结论豌豆苷和N-DG被认定为SPHT的有希望的生物标志物。PHT的进展可能与脂质、亚油酸和氨基酸代谢的紊乱，以及柠檬酸循环的改变有关。