Cutaneous biomarkers of pediatric non-alcoholic fatty liver disease

项目总结/摘要 这项多中心研究的目的是开发和验证一种新的，非侵入性的生物标志物，用于儿童 NAFLD。具体目标是招募80名NAFLD青年（6-21岁）和80名对照组 并使用现有技术的脂质组学分析来研究他们的皮肤表面脂质，以：1.确定 区分NAFLD青年与对照的皮肤脂质; 2.研究皮肤脂质组， NAFLD患者中存在晚期疾病（非酒精性脂肪性肝炎[NASH]、纤维化）; 和3.通过研究其进一步支持使用皮肤表面脂质作为儿童NAFLD的生物标志物 重复性和可变性。参与者将接受质子密度脂肪分数的磁共振成像 （MRI-PDFF）以确定NAFLD的存在/不存在。该方法已被证明 准确判断是否存在肝脂肪变性。他们的皮肤脂质体 使用胶带剥离取样。后者是一种快速（<5分钟）、无痛的程序， 皮肤的最表层（来自角质层和皮脂腺分泌的脂质）。 所有患有NAFLD的患者都将有其疾病的先前组织学确认，这将被重新审查， 由一名具有儿科NAFLD专业知识的病理学家进行评分，该病理学家将对患者临床和 人口特征。将使用以下方法对采集的皮肤样本进行非靶向脂质组学分析： 超高效液相色谱-四极杆飞行时间质谱法测定皮肤 表面脂质单独或组合预测NAFLD的存在。皮肤的表现 脂质组预测肥胖青年NAFLD的存在将与目前的 采用筛选试验，即血清丙氨酸氨基转移酶水平。在NAFLD患者中， 将评估皮肤表面脂质在预测NASH和纤维化存在中的作用。最后，一部分患者 患有NAFLD的患者将重复皮肤取样：a.在同一天从对侧臂，以测试重复性 皮肤脂质组，和B. 1个月后，测试脂质组作为生物标志物的变异性。的变量 可能影响皮肤表面脂质，例如性别、年龄/青春期状态、饮食变化、肥胖严重程度和胰岛素 耐药状态，将在这些分析中进行评估和控制。儿科非侵入性生物标志物 NAFLD是迫切需要的，由于这种疾病的惊人流行率和目前的事实， 可用的侵入性诊断方式（肝活检）是不实用的，并且阻碍了治疗发现， 进展

PROJECT SUMMARY/ABSTRACT The objective of this multicenter study is to develop and validate a novel, non-invasive biomarker for pediatric NAFLD. The specific aims are to recruit a cohort of 80 youth (6-21 years of age) with NAFLD and 80 controls with obesity and study their skin surface lipids using state of the art lipidomic analyses to: 1. Determine the cutaneous lipids that differentiate youth with NAFLD from controls; 2. Investigate the skin lipidome that detects the presence of advanced disease (non-alcoholic steatohepatitis [NASH], fibrosis) among those with NAFLD; and, 3. Further support the use of skin surface lipids as a biomarker of NAFLD in children by studying its repeatability and variability. Participants will undergo magnetic resonance imaging with proton density fat fraction (MRI-PDFF) at baseline to determine the presence/absence of NAFLD. This methodology has been shown to be accurate in determining the presence of hepatic steatosis. They will then have their cutaneous lipidome sampled using tape stripping. The latter is a rapid (<5 min), painless procedure that samples the lipids of the most superficial layer of the skin (from the stratum corneum and the lipids secreted by the sebaceous glands). All patients with NAFLD will have had prior histologic confirmation of their disease, which will be re-reviewed and scored by a single pathologist, with expertise in pediatric NAFLD, who will be masked to patient clinical and demographic characteristics. Untargeted lipidomic analyses of the collected skin samples will be performed using ultra high-performance liquid chromatography-quadrupole time of flight mass spectrometry to determine the skin surface lipids that alone or in combination predict the presence of NAFLD. The performance of the cutaneous lipidome in predicting the presence of NAFLD in youth with obesity will be compared against that of the currently used screening test, namely serum alanine aminotransferase levels. Among those with NAFLD, the performance of skin surface lipids in predicting the presence of NASH and fibrosis will be assessed. Lastly, a subset of patients with NAFLD will have repeat skin sampling: a. on the same day from the opposite arm, to test the repeatability of cutaneous lipidome, and b. 1 month later, to test the variability of the lipidome as a biomarker. Variables that may affect the skin surface lipids, such as sex, age/pubertal status, change in diet, obesity severity and insulin resistance status, will be assessed and controlled for in these analyses. A non-invasive biomarker for pediatric NAFLD is urgently needed, due to the staggering prevalence of this disease and the fact that the currently available invasive diagnostic modalities (liver biopsy) are not practical and hinder therapeutic discovery and progression.