Pebriana Ratna Budhi, Chen Ting, Derks Rico J E, Blomberg Niek, Grefhorst Aldo, Mohammed Yassene, Nieuwdorp Max, Verheij Joanne, Doukas Michail, Rensen Patrick C N, Holleboom Adriaan G, Tushuizen Maarten E, Giera Martin
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia.
Division of Experimental Vascular Medicine, Department of Internal Medicine, Amsterdam UMC, Amsterdam, The Netherlands.
J Lipid Res. 2025 Jun 20;66(8):100845. doi: 10.1016/j.jlr.2025.100845.
The accumulation of cholesterol and other lipids leading to hepatic lipotoxicity drives the progression of metabolic dysfunction-associated steatotic liver (MASL) to metabolic dysfunction-associated steatohepatitis (MASH), the advanced progressive stage of metabolic dysfunction-associated steatotic liver disease (MASLD). For MASH diagnosis, liver biopsy remains the reference standard, despite its invasiveness and limitations. Thus, this study aimed to find blood-derived lipid markers for MASH. We investigated serum samples from 86 patients with histologically characterized MASLD, spanning the disease spectrum (i.e. 62 patients with MASL (Fibrosis grade 0-4) and 24 patients with MASH (Fibrosis grade 2-4) with a balanced distribution of hepatocellular carcinoma) and analyzed sterol composition and lipidome. To identify the presence of MASH, logistic regression was performed on each candidate either in a single or combination with various clinical parameters. Serum levels of desmosterol and phosphatidylcholine are increased in patients with MASH compared to those with MASL. After exclusion of patients using lipid lowering drugs, an increase was also found in serum levels of cholesterol, cholesterol ester, lysophosphatidylcholine, lysophosphatidylethanolamine, phosphatidylethanolamine, and several individual lipid species. The ROC curve of each lipid candidate show the potential use of desmosterol, phosphatidylcholine, and a panel of lipid species in combination with alanine aminotransferase as potential diagnostic markers, characterized by a respective AUROC of 0.79 (95% CI 0.66-0.92), 0.80 (95% CI 0.64-0.97), and 0.91 (95% CI 0.82-1.00). Serum sterol and lipidome markers are characterized by strong AUROC results to distinguish with high accuracy MASH from MASL, potentially paving the way for future MASH biomarker development.
胆固醇和其他脂质的积累导致肝脏脂毒性，推动代谢功能障碍相关脂肪性肝病（MASL）进展为代谢功能障碍相关脂肪性肝炎（MASH），即代谢功能障碍相关脂肪性肝病（MASLD）的晚期进展阶段。对于MASH的诊断，肝脏活检仍然是参考标准，尽管其具有侵入性和局限性。因此，本研究旨在寻找MASH的血液源性脂质标志物。我们调查了86例具有组织学特征的MASLD患者的血清样本，涵盖了疾病谱（即62例MASL患者（纤维化0 - 4级）和24例MASH患者（纤维化2 - 4级），肝细胞癌分布均衡），并分析了甾醇组成和脂质组。为了确定MASH的存在，对每个候选指标单独或与各种临床参数联合进行逻辑回归分析。与MASL患者相比，MASH患者的血清麦角固醇和磷脂酰胆碱水平升高。在排除使用降脂药物的患者后，还发现血清胆固醇、胆固醇酯、溶血磷脂酰胆碱、溶血磷脂酰乙醇胺、磷脂酰乙醇胺和几种单个脂质种类的水平有所升高。每个脂质候选指标的ROC曲线显示，麦角固醇、磷脂酰胆碱以及一组脂质种类与丙氨酸转氨酶联合使用具有作为潜在诊断标志物的潜力，其各自的曲线下面积（AUROC）分别为0.79（95%置信区间0.66 - 0.92）、0.80（95%置信区间0.64 - 0.97）和0.91（95%置信区间0.82 - 1.00）。血清甾醇和脂质组标志物的AUROC结果强劲，能够高精度地区分MASH和MASL，这可能为未来MASH生物标志物的开发铺平道路。
