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.

项目概要/摘要 这项多中心研究的目的是开发和验证一种新型的、非侵入性的儿科生物标志物 非酒精性脂肪性肝病。具体目标是招募 80 名患有 NAFLD 的青少年（6-21 岁）和 80 名对照者 肥胖症患者并使用最先进的脂质组学分析研究他们的皮肤表面脂质，以： 1. 确定 皮肤脂质可将患有 NAFLD 的青少年与对照组区分开来； 2. 研究检测的皮肤脂质组 NAFLD 患者是否存在晚期疾病（非酒精性脂肪性肝炎 [NASH]、纤维化）； 3. 通过研究皮肤表面脂质作为儿童 NAFLD 的生物标志物，进一步支持其使用 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) 基线以确定是否存在 NAFLD。该方法已被证明可以 可以准确地确定肝脂肪变性的存在。然后他们将获得皮肤脂质组 使用胶带剥离进行采样。后者是一种快速（<5 分钟）、无痛的程序，可对脂质进行采样。 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 的患者都将事先对其疾病进行组织学确认，并将对其进行重新审查和 由一位具有儿科 NAFLD 专业知识的病理学家进行评分，该病理学家将不了解患者的临床和临床情况 人口特征。将使用以下方法对收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 脂质组学在预测肥胖青年中是否存在 NAFLD 方面将与目前的脂质组学进行比较 采用筛查试验，即血清谷丙转氨酶水平。在 NAFLD 患者中，表现 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 的患者将需要重复进行皮肤采样：同一天从另一只手臂，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。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 由于 NAFLD 的患病率惊人且目前的事实，因此迫切需要 NAFLD 现有的侵入性诊断方式（肝活检）并不实用，并且阻碍了治疗的发现和 进展。