A Pilot Study of Losartan in the Treatment of Pediatric NAFLD

氯沙坦治疗小儿 NAFLD 的初步研究

• 批准号: 8512111
• 负责人: MIRIAM B. VOS
• 金额: $ 8.02万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512111
• 关键词: Acids; Address; Adolescence; Adolescent; Adult; Affect; Age; Alanine Transaminase; Angiotensin Receptor; Animal Model; Antioxidants; Atherosclerosis; Body Weight decreased; Cardiovascular Diseases; Cell Death; Child; Childhood; Cytokeratin 18; Data; Development; Dose; Double-Blind Method; Dyslipidemias; Enzymes; Fasting; Fatty Liver; Fibrosis; Future; Genetic Crossing Over; HDL-triglyceride; Health; Hepatic; Hepatocyte; High Density Lipoproteins; Histology; Hypertriglyceridemia; Inflammation; Inflammatory; Intervention; Kinetics; Lead; Life Style; Link; Liver; Liver Fibrosis; Liver diseases; Losartan; Low-Density Lipoproteins; Magnetic Resonance Spectroscopy; Measures; Metabolic syndrome; Morbidity - disease rate; Natural History; Obesity; Overweight; Patients; Pharmaceutical Preparations; Pilot Projects; Placebo Control; Placebos; Plasminogen Activator Inhibitor 1; Proteinuria; Randomized; Randomized Controlled Trials; Research; Risk; Serum; Severity of illness; Staging; Testing; Therapeutic; Triglycerides; Work; atheroprotective; base; cardiovascular disorder risk; chronic liver disease; conventional therapy; design; effective therapy; improved; inflammatory marker; innovation; liver biopsy; liver inflammation; liver injury; mortality; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; novel marker; oxidized low density lipoprotein; prevent; public health relevance

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) is an obesity associated chronic liver disease that is the most common liver disease in adolescents today. It is closely associated with the metabolic syndrome and dyslipidemia. Research suggests that adolescents with NAFLD will be at substantial risk of increased morbidity in the future from both cardiovascular disease and end stage liver disease unless effective therapies are developed to change this trajectory. While lifestyle changes can improve histology and CVD risk, many patients are unsuccessful at sustained weight loss. Thus, medications to treat CVD risk and liver inflammation, steatosis and fibrosis in NAFLD are critically needed. We have been studying adolescents with NAFLD and have pilot data linking inflammatory mechanisms in NAFLD and increased CVD risk. Angiotensin receptor blockers (ARB) have been proposed as a novel treatment of NAFLD in part because they would treat both the factors increasing CVD risk as well as potentially improve steatosis, fibrosis and hepatic inflammation. Losartan, an established ARB has demonstrated significant potential in animal models and limited pilot studies in adults with NAFLD have been promising. However, no data exists on the effects of losartan in children with NAFLD. We propose a 26 week pilot study in adolescents with NAFLD to test if losartan will improve non-invasive markers of CVD risk and liver steatosis, inflammation and fibrosis. This proposal is highly innovative because an ARB has not previously been tested in adolescents with NAFLD and because novel markers of CVD risk will be tested in addition to the typical markers. This study is highly significant because NAFLD is the most common liver disease among children today and is associated with substantially increased risk of CVD and increased mortality as these adolescents age into adulthood.

描述（由申请人提供）：非酒精性脂肪性肝病（NAFLD）是一种肥胖相关的慢性肝病，是当今青少年中最常见的肝病。它与代谢综合征和血脂异常密切相关。研究表明，患有NAFLD的青少年在未来将面临心血管疾病和终末期肝病发病率增加的巨大风险，除非开发出有效的治疗方法来改变这一轨迹。虽然生活方式的改变可以改善组织学和CVD风险，但许多患者在持续减肥方面并不成功。因此，治疗CVD风险和肝脏炎症、脂肪变性和NAFLD纤维化的药物是迫切需要的。我们一直在研究NAFLD青少年，并有初步数据将NAFLD的炎症机制与CVD风险增加联系起来。血管紧张素受体阻滞剂（ARB）已被提出作为NAFLD的一种新型治疗方法，部分原因是它们可以治疗增加CVD风险的因素，并可能改善脂肪变性，纤维化和肝脏炎症。Losartan是一种成熟的ARB，已在动物模型中显示出巨大的潜力，在NAFLD成人中进行的有限的初步研究也很有希望。然而，没有关于氯沙坦对NAFLD儿童的影响的数据。我们建议在NAFLD青少年中进行一项为期26周的试点研究，以测试氯沙坦是否会改善CVD风险和肝脏脂肪变性，炎症和纤维化的非侵入性标志物。这项建议是高度创新的，因为ARB以前没有在NAFLD青少年中进行过测试，而且除了典型的标志物外，还将测试CVD风险的新标志物。这项研究非常重要，因为NAFLD是当今儿童中最常见的肝脏疾病，并且随着这些青少年进入成年期，与CVD的风险大幅增加和死亡率增加有关。