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

描述（由申请方提供）：在指导支持或拒绝减肥（减肥）手术（WLS）治疗重度肥胖青少年NASH的建议方面，存在关键的证据差距。迫切需要一项关于WLS与综合生活方式干预（CLI）治疗NASH的有效性的前瞻性良好对照研究，以指导建议，因为严重肥胖的青少年在受影响的儿科患者中占很大比例。评估治疗效果的非侵入性工具也严重缺乏。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，因为儿童肥胖和NASH的患病率上升，目前治疗有限。本申请的总体目的是评估WLS与CLI作为重度肥胖青少年NASH治疗的有效性。中心假设是，与CLI相比，WLS将导致严重肥胖青少年NASH的显著更大改善。该假设来自申请人生成的强有力的初步数据。拟议研究的主要理由是，在完成时，该研究将提供关键证据，以指导严重肥胖青少年NASH的治疗建议。将通过追求以下特定目标来检验中心假设：1）评价WLS与CLI在实现严重肥胖青少年NASH的显著组织学改善方面的有效性;和2）检验新型非侵入性生物标志物在预测治疗后NASH的组织学结局方面的灵敏度和特异性。根据第一个目标，将在体重指数为35-60 kg/m2的13-19岁青少年中进行WLS与CLI的前瞻性平行队列研究。将在1年后测量主要组织学结局，控制可能影响体重减轻和NASH结局的重要协变量。在NASH，青少年WLS和多学科CLI的完善方案存在于性能现场，使这种方法在申请人手中可行。在第二个目标下，将结合血清细胞死亡标志物的测量和肝脂肪和纤维化的创新磁共振测量（由申请人生成的初步数据支持），以确定与1年时组织学NASH结局的相关性。该方法在以下方面具有创新性：1）关注患有NASH的严重肥胖青少年，他们在CLI的先前研究中代表性不足; 2）选择与对NASH发病机制的体重减轻独立有益作用相关的手术方法，垂直袖状胃切除术; 3）评估新兴的成像方法和血清学生物标志物如何共同和纵向用于测量NASH治疗干预的疗效。作为WLS与CLI治疗NASH的第一个对照研究，拟议的研究具有重要意义，因为它将填补证据的关键空白，以指导 患者和提供者的决策，并可能确定更有效的治疗严重肥胖的青少年NASH。累积起来，这有可能使大部分NASH儿科患者的医疗和生活质量结局得到显著改善，并通过最终减少进展为终末期肝病来降低长期医疗保健成本。

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.