A Pilot Study of Losartan in the Treatment of Pediatric NAFLD

描述(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，除非开发有效的治疗方法来改变这一轨迹。虽然改变生活方式可以改善组织学和心血管疾病风险，但许多患者在持续减肥方面并不成功。因此，迫切需要药物来治疗非酒精性脂肪性肝病的心血管风险和肝脏炎症、脂肪变性和纤维化。我们一直在研究患有NAFLD的青少年，并有初步数据将NAFLD的炎症机制与心血管疾病风险增加联系起来。血管紧张素受体阻滞剂(ARB)已被提出作为治疗NAFLD的新方法，部分原因是它们可以治疗增加心血管风险的因素，并有可能改善脂肪变性、纤维化和肝脏炎症。氯沙坦是一种公认的ARB，已在动物模型中显示出巨大的潜力，在成人NAFLD中进行的有限的初步研究一直很有希望。然而，目前还没有关于氯沙坦对NAFLD儿童的影响的数据。我们建议对患有NAFLD的青少年进行一项为期26周的先导性研究，以测试氯沙坦是否会改善心血管风险以及肝脏脂肪变性、炎症和纤维化的非侵入性标记物。这一建议具有很高的创新性，因为ARB以前从未在患有NAFLD的青少年中进行过测试，而且除了典型的标记外，还将测试新的心血管疾病风险标记。这项研究意义重大，因为NAFLD是当今儿童中最常见的肝病，随着这些青少年进入成年期，患心血管疾病的风险和死亡率都会显著增加。

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.