Outcome of NASH in Adolescents after Bariatric Surgery vs. Lifestyle Intervention

描述（由申请人提供）：在支持或反对减肥手术（WLS）治疗严重肥胖青少年NASH的建议方面，存在一个关键的证据缺口。由于严重肥胖的青少年在儿童患者中占很大比例，因此迫切需要一项关于WLS与综合生活方式干预（CLI）治疗NASH有效性的前瞻性对照研究来指导建议。评估治疗效果的非侵入性工具也严重缺乏。鉴于儿童肥胖和NASH患病率的上升，以及目前有限的治疗方法，长期目标是确定儿童和青少年NASH的高效治疗和非侵入性诊断生物标志物。本应用的总体目的是评估WLS与CLI治疗严重肥胖青少年NASH的有效性。中心假设是，与CLI相比，WLS会显著改善严重肥胖青少年的NASH。这一假设来源于申请人提供的强有力的初步数据。提出这项研究的主要理由是，在完成后，该研究将为指导严重肥胖青少年NASH的治疗建议提供关键证据。中心假设将通过以下具体目标进行检验：1)评估WLS与CLI在实现严重肥胖青少年NASH显著组织学改善方面的有效性；2)测试新型非侵入性生物标志物在预测NASH治疗后组织学预后方面的敏感性和特异性。在第一个目标下，将在13-19岁、体重指数为35-60 kg/m2的青少年中进行WLS与CLI的前瞻性平行队列研究。1年后测量主要组织学结果，控制可能影响体重减轻和NASH结果的重要协变量。在演出现场，NASH、青少年WLS和多学科CLI中存在着完善的项目，这使得这种方法在申请人手中是可行的。在第二个目标下，血清细胞死亡标志物的测量和创新的肝脂肪和纤维化的磁共振测量，在申请人产生的初步数据的支持下，将结合起来确定与1年组织学NASH结局的相关性。该方法的创新之处在于：1)专注于严重肥胖的NASH青少年，他们在先前的CLI研究中代表性不足；2)选择一种手术入路，即垂直袖胃切除术，这与减肥对NASH发病机制的独立有益作用有关；3)评估新兴的成像方法和血清学生物标志物如何能够集体和纵向地用于衡量NASH治疗干预措施的疗效。作为首个WLS与CLI治疗NASH的对照研究，该研究具有重要意义，因为它将填补证据指导的关键空白

DESCRIPTION (provided by applicant): There is a critical gap in evidence to guide recommendations to support or reject bariatric (weight loss) surgery (WLS) to treat severely obese adolescents with NASH. A prospective well-controlled study of the effectiveness of WLS vs. comprehensive lifestyle intervention (CLI) in treating NASH is urgently needed to guide recommendations, as severely obese adolescents are a large proportion of affected pediatric patients. Non-invasive tools to evaluate efficacy of treatment are also critically lacking. The lon-term goal is to identify highly effective treatment and non-invasive diagnostic biomarkers for NASH in children and adolescents given the rise in prevalence of pediatric obesity and NASH, and limited current therapy. The overall objective of this application is to assess the effectiveness of WLS vs. CLI as a treatment for NASH in severely obese adolescents. The central hypothesis is that WLS will result in significantly greater improvement in NASH in severely obese adolescents compared with CLI. This hypothesis derives from strong preliminary data generated by the applicants. The primary rationale for the proposed research is that, at completion, the study will provide critical evidence to guide treatment recommendations for severely obese adolescents with NASH. The central hypothesis will be tested by pursuing the following specific aims: 1) Evaluate the effectiveness of WLS vs. CLI in achieving significant histological improvement of NASH in severely obese adolescents; and 2) Test the sensitivity and specificity of novel non-invasive biomarkers in predicting histological outcome of NASH after treatment. Under the first aim, a prospective parallel cohort study of WLS vs. CLI will be conducted in adolescents, ages 13-19 with body mass index of 35-60 kg/m2. Primary histological outcomes will be measured after 1 year, controlling for important covariates that may impact weight loss and NASH outcomes. Well-established programs in NASH, adolescent WLS and multidisciplinary CLI exist at the performance site making this approach feasible in the applicants' hands. Under the second aim, measurements of serum cell death markers and innovative magnetic resonance measures of hepatic fat and fibrosis, supported by preliminary data generated by the applicants, will be combined to determine the correlation with histological NASH outcome at 1 year. The approach is innovative in: 1) focusing on severely obese adolescents with NASH, who are underrepresented in prior studies of CLI; 2) selecting a surgical approach, vertical sleeve gastrectomy, that has been linked to weight-loss independent beneficial effects on NASH pathogenesis; and 3) evaluating how emerging imaging methods and serological biomarkers can be used collectively and longitudinally to measure efficacy of treatment interventions on NASH. As the first controlled study of WLS vs. CLI in treatment of NASH, the proposed research is significant because it will fill a critical gap in evidence to guide patient and provider decision-making and may identify more effective treatments for NASH in severely obese adolescents. Cumulatively, this has the potential to yield dramatic improvements in medical and quality of life outcomes for a large proportion of pediatric patients with NASH, and reduce long term health care costs by ultimately decreasing progression to end-stage liver disease.