Low Dose Thyroid Hormone, Mitochondrial Fatty Acid Oxidation, and Treatment of Nonalcoholic Steatohepatitis (NASH)

非酒精性脂肪性肝炎(NASH)是非酒精性脂肪病理谱系中侵袭性的一部分 肝病(NAFLD)已演变为全球流行，是最常见的慢性肝脏 美国的疾病。NASH与肥胖和2型糖尿病密切相关，可能 进展为肝硬变和肝癌。令人不安的是，NASH的患病率似乎在 退伍军人人数与美国总人口相比。因此，纳什的负担对 退伍军人。尽管NASH被认为是一个主要的公共卫生问题，但只有改变生活方式的目的是 在增加体力活动和减少卡路里摄入量方面，目前建议作为 有限的成功。因此，非常需要对NASH进行有效的治疗。这项研究的目标是测试 小剂量甲状腺激素是否用于经活检证实为NASH的退伍军人，滴定剂量为 将甲状腺功能维持在正常范围内，可导致NASH的组织学改善，测量 通过显著降低非酒精性脂肪性肝病评分(NAS)。假设是低剂量的甲状腺 激素通过增加肝脏线粒体粮农组织介导的方式改善NASH的组织学 粮农组织循环中的关键酶--线粒体三功能蛋白(MTP)的增加。初步临床应用 对包括退伍军人在内的人类受试者的研究支持减少粮农组织在NASH的研究。此外，临床前的体内试验 动物研究和体外细胞培养研究支持低剂量的甲状腺激素可以有效地增加 线粒体脂肪酸氧化，挽救NAFLD。在随机、双盲、安慰剂对照的研究中 临床试验，甲状腺水平正常且经活检证实为NASH的退伍军人将被招募并随机分配到 接受52周的积极治疗(小剂量左旋甲状腺素)或安慰剂对照组，以完成 遵循特定的目标。1)确定小剂量甲状腺激素改善NASH的疗效 组织学特征。为了实现这一目标，将在肝活检前和肝活检后的样本中测量NAS。2) 确定小剂量甲状腺激素对线粒体FAO、MTP和线粒体健康的影响 肝脏中的标志物与对照组相比。为了实现这一目标，线粒体粮农组织和基因表达 支持线粒体健康的基因将在肝脏活检前后的样本中进行测量。初级阶段 临床结果是NASH的组织学改善通过NAS和继发性 临床结果是纤维化期的改善。机械性的结果包括改善 线粒体粮农组织、MTP和质量标记。该项目将分两个阶段进行。在阶段1(证明- 概念，2年)，32名患有活检证实的NASH的退伍军人将被招募并随机分配到 积极治疗组或安慰剂组(16个/组)。在第二年年底，中期分析将是 根据标准执行，其中将包括早期疗效的条件功率分析，以确定 完整研究将在主要结果(组织学)中产生统计上有意义的发现的概率 NASH的改善)在临床相关方向。其他里程碑包括第二季度的趋势 结果、不良事件和可行性。概念验证阶段的结果将指导GO或 不通过阶段2的决定，继续研究，招募更多的退伍军人，为期整整6年 临床试验(共招募128名经活检证实的退伍军人NASH：/积极治疗组和 /安慰剂对照组)。该项目将在该领域产生持续和强大的影响，为 治疗NASH的信息和策略将与NASH的健康高度相关和有影响 退伍军人。

Nonalcoholic steatohepatitis (NASH) is an aggressive part of the pathological spectrum of nonalcoholic fatty liver disease (NAFLD) that has evolved into a world-wide epidemic and is the most common chronic liver disease in the United States. NASH is strongly linked to obesity, and type 2 diabetes mellitus and may progress to cirrhosis and liver cancer. Disturbingly, prevalence rates of NASH appear to be greater in the Veteran population compared with the general US population. Thus, the burden of NASH is substantial to Veterans. Despite the recognition of NASH as a major public health problem, only lifestyle modifications aimed at increasing physical activity and reducing caloric intake are currently recommended as treatments with limited success. Thus, there is a great need for effective therapy of NASH. The goal of this study is to test whether low dose thyroid hormone administered to Veterans with biopsy-proven NASH, at a titrated dose that will maintain thyroid function within normal range, can result in histological improvement of NASH, measured by significant reduction in nonalcoholic fatty liver disease score (NAS). The hypothesis is that low dose thyroid hormone causes histological improvement in NASH by increasing mitochondrial FAO in the liver mediated by an increase in mitochondrial trifunctional protein (MTP), the key enzyme in FAO cycle. The preliminary clinical studies in human subjects, including Veterans, support reduced FAO in NASH. In addition, preclinical in vivo animal studies and in vitro cell culture studies support that low dose thyroid hormone can effectively increase mitochondrial fatty acid oxidation and rescue NAFLD. In a randomized double-blinded placebo-controlled clinical trial, Veterans with normal thyroid levels and biopsy-proven NASH will be recruited and randomized to receive 52 weeks of either active treatment (low dose levothyroxine) or placebo control to accomplish the following Specific Aims. 1) To determine the efficacy of low dose thyroid hormone in improving NASH histological features. To accomplish this aim, NAS will be measured in pre- and post-liver biopsy samples. 2) To determine the effect of low dose thyroid hormone on mitochondrial FAO, MTP, and mitochondrial health markers in the liver compared to control. To accomplish this aim, mitochondrial FAO and the expression of genes supporting mitochondrial health will be measured in the pre- and post-liver biopsy samples. The primary clinical outcome is histological improvement in NASH measured by improvement in NAS and the secondary clinical outcome is improvement in fibrosis stage. The mechanistic outcomes include improvements in mitochondrial FAO, MTP, and quality markers. This project will be conducted in two stages. In stage 1 (proof- of-concept, 2 years), 32 Veterans with biopsy-proven NASH will be recruited and randomized to either the active treatment or placebo groups (16/group). At the end of the second year, interim analysis will be performed based on criteria that will include conditional power analysis for early efficacy to determine the probability that the full study will yield a statistically significant finding in the primary outcome (histological improvement in NASH) in the clinically relevant direction. Other milestones include trend in the secondary outcome, adverse events, and feasibility. The outcome from the proof-of-concept stage will guide the Go or No-Go decision to stage 2 for continuation of the study with recruitment of additional Veterans for a full 6-year clinical trial (total recruitment of 128 Veterans with biopsy-proven NASH: 64/active treatment group and 64/placebo control group). This project will exert a sustained and powerful impact in the field by providing new information and strategies for treatment of NASH that will be highly relevant and impactful to the health of the Veteran population.