Liu Chang-Hai, Zheng Shanshan, Wang Shisheng, Wu Dongbo, Jiang Wei, Zeng Qingmin, Wei Yi, Zhang Yong, Tang Hong
Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, China.
Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu 610041, China.
Diagnostics (Basel). 2022 Jun 7;12(6):1412. doi: 10.3390/diagnostics12061412.
Background: In patients with metabolic-associated fatty liver disease (MAFLD), hepatic steatosis is the first step of diagnosis, and it is a risk predictor that independently predicts insulin resistance, cardiovascular risk, and mortality. Urine biomarkers have the advantage of being less complex, with a lower dynamic range and fewer technical challenges, in comparison to blood biomarkers. Methods: Hepatic steatosis was measured by magnetic resonance imaging (MRI), which measured the proton density fat fraction (MRI-PDFF). Mild hepatic steatosis was defined as MRI-PDFF 5−10% and severe hepatic steatosis was defined as MRI-PDFF > 10%. Results: MAFLD patients with any kidney diseases were excluded. There were 53 proteins identified by mass spectrometry with significantly different expressions among the healthy control, mild steatosis, and severe steatosis patients. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of these significantly changed urinary molecular features correlated with the liver, resulting in the dysregulation of carbohydrate derivative/catabolic/glycosaminoglycan/metabolic processes, insulin-like growth factor receptor levels, inflammatory responses, the PI3K−Akt signaling pathway, and cholesterol metabolism. Urine alpha-1-acid glycoprotein 1 (ORM1) and ceruloplasmin showed the most significant correlation with the clinical parameters of MAFLD status, including liver fat content, fibrosis, ALT, triglycerides, glucose, HOMA-IR, and C-reactive protein. According to ELISA and western blot (30 urine samples, normalized to urine creatinine), ceruloplasmin (ROC 0.78, p = 0.034) and ORM1 (ROC 0.87, p = 0.005) showed moderate diagnostic accuracy in distinguishing mild steatosis from healthy controls. Ceruloplasmin (ROC 0.79, p = 0.028) and ORM1 (ROC 0.81, p = 0.019) also showed moderate diagnostic accuracy in distinguishing severe steatosis from mild steatosis. Conclusions: Ceruloplasmin and ORM1 are potential biomarkers in distinguishing mild and severe steatosis in MAFLD patients.
在代谢相关脂肪性肝病（MAFLD）患者中，肝脂肪变性是诊断的第一步，并且是独立预测胰岛素抵抗、心血管风险和死亡率的风险指标。与血液生物标志物相比，尿液生物标志物具有复杂性较低、动态范围较小和技术挑战较少的优势。方法：通过磁共振成像（MRI）测量肝脂肪变性，MRI测量质子密度脂肪分数（MRI-PDFF）。轻度肝脂肪变性定义为MRI-PDFF为5%-10%，重度肝脂肪变性定义为MRI-PDFF>10%。结果：排除患有任何肾脏疾病的MAFLD患者。通过质谱鉴定出53种蛋白质，其在健康对照、轻度脂肪变性和重度脂肪变性患者之间具有显著不同的表达。对这些与肝脏相关的显著变化的尿液分子特征进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析，导致碳水化合物衍生物/分解代谢/糖胺聚糖/代谢过程、胰岛素样生长因子受体水平、炎症反应、PI3K-Akt信号通路和胆固醇代谢失调。尿α-1-酸性糖蛋白1（ORM1）和铜蓝蛋白与MAFLD状态的临床参数（包括肝脂肪含量、纤维化、谷丙转氨酶、甘油三酯、葡萄糖、胰岛素抵抗指数（HOMA-IR）和C反应蛋白）显示出最显著的相关性。根据酶联免疫吸附测定（ELISA）和蛋白质印迹法（30份尿液样本，以尿肌酐标准化），铜蓝蛋白（受试者工作特征曲线下面积（ROC）为0.78，p=0.034）和ORM1（ROC为0.87，p=0.005）在区分轻度脂肪变性与健康对照方面显示出中等诊断准确性。铜蓝蛋白（ROC为0.79，p=0.028）和ORM1（ROC为0.81，p=0.019）在区分重度脂肪变性与轻度脂肪变性方面也显示出中等诊断准确性。结论：铜蓝蛋白和ORM1是区分MAFLD患者轻度和重度脂肪变性的潜在生物标志物。
