Cutaneous biomarkers of pediatric non-alcoholic fatty liver disease

儿童非酒精性脂肪肝的皮肤生物标志物

• 批准号: 10649514
• 负责人: Marialena Mouzaki
• 金额: $ 66.1万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-17 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649514
• 关键词: 21 year old; Acceleration; Adult; Affect; Age; Alanine Transaminase; Animal Model; Attenuated; Biological Markers; Biopsy; Ceramides; Characteristics; Child; Childhood; Cirrhosis; Clinical; Collection; Cutaneous; Dermal; Diabetes Mellitus; Diagnostic; Diet; Disease; Endocrine; Fatty Liver; Fatty acid glycerol esters; Feces; Fibrosis; Foundations; Health; Hepatic; High Pressure Liquid Chromatography; Histologic; Histology; Human; Immune; Incidence; Insulin Resistance; Lipids; Liver; Liver Fibrosis; Liver diseases; Magnetic Resonance Imaging; Masks; Methodology; Modality; Monitor; Multicenter Studies; Obesity; Painless; Participant; Pathogenesis; Pathologist; Patients; Pediatrics; Performance; Pharmacotherapy; Plasma; Prevalence; Procedures; Protons; Race; Research; Role; Sampling; Seasons; Sebaceous Glands; Serum; Severities; Severity of illness; Skin; Stratum corneum; Surface; Testing; Therapeutic; Transplantation; United States Food and Drug Administration; Validation; Venipunctures; Youth; advanced disease; arm; biomarker development; clinical practice; cohort; density; disorder control; drug development; lipidome; lipidomics; liver biopsy; metabolomics; microbiome; non-alcoholic fatty liver; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; noninvasive diagnosis; novel; obesity in children; patient subsets; pediatric non-alcoholic fatty liver disease; pharmacologic; progression marker; recruit; screening; sex; stool sample; therapeutic development; time of flight mass spectrometry; treatment response; urinary; weight loss intervention; young adult

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.

项目摘要/摘要 这项多中心研究的目的是开发和验证一种新颖的，无创的生物标志物的小儿标志物 nafld。具体的目的是招募NAFLD和80个控件的80名年轻人（6-21岁） 使用肥胖和研究其皮肤表面脂质的脂质状态脂质组分析的状态：1。 皮肤脂质将NAFLD与对照组区分开来； 2。研究检测到的皮肤脂肪组 在患有NAFLD的患者中存在晚期疾病（非酒精性脂肪性肝炎[NASH]，纤维化）； 3。进一步支持使用皮肤表面脂质作为NAFLD的生物标志物在儿童中的生物标志物 可重复性和可变性。参与者将使用质子密度脂肪分数进行磁共振成像 （MRI-PDFF）在基线时确定NAFLD的存在/不存在。该方法已被证明 确定肝脂肪变性的存在时要准确。然后，他们将拥有皮肤脂肪组 使用胶带剥离进行采样。后者是一种快速（<5分钟），无痛的过程，样品 皮肤的最浅层层（来自角质层和皮脂腺分泌的脂质）。 所有NAFLD患者都将对其疾病进行过组织学证实，并将重新审查，并 由一位病理学家评分，在儿科NAFLD方面具有专业知识，他们将被掩盖到患者临床和 人口特征。将使用收集的皮肤样品进行未靶向的脂质组分析 超高效果液相色谱 - 四极杆的飞行质谱时间，以确定皮肤 单独或组合组合的表面脂质预测NAFLD的存在。皮肤的表现 在预测肥胖年轻人中NAFLD的存在时，将与当前的脂肪组进行比较 使用的筛选测试，即血清丙氨酸氨基转移酶水平。在有NAFLD的人中 将评估皮肤表面脂质在预测NASH和纤维化的存在方面的评估。最后，一部分患者 使用NAFLD会重复采样：从对面的同一天，测试可重复性 皮肤脂肪组和b。 1个月后，以测试脂质组作为生物标志物的变异性。变量 可能会影响皮肤表面脂质，例如性别，年龄/青春期状态，饮食变化，肥胖严重性和胰岛素 在这些分析中将评估和控制电阻状态。小儿无创的生物标志物 由于这种疾病的普遍性以及目前的事实，迫切需要NAFLD 可用的侵入性诊断方式（肝活检）是不切实际的，并且阻碍了治疗发现和 进展。