Neurocognitive and Metabolic Effects of Mild Hypothyroidism

描述（由申请人提供）：甲状腺功能减退症是常见的，影响3%的美国人口，高达20%的老年妇女。治疗是直接的，当使用L-甲状腺素（L-T4）使促甲状腺激素（TSH）水平正常化时，预期靶器官功能会得到优化。尽管如此，数以百万计的患者有轻度升高的TSH水平，最近的数据也表明，如果患者的TSH水平高-正常，则可能治疗不足。生活质量、情绪、认知功能和燃料代谢的下降见于甲状腺功能减退症，但对轻度甲状腺功能减退症或TSH水平正常高的L-T4治疗受试者的这些结果知之甚少。初步数据：研究人员的工作利用了一个独特的实验模型，在长期L-T4治疗的甲状腺功能减退受试者中实验诱导的轻度甲状腺疾病。这项由NIDDK R21资助的工作产生了有趣的初步数据，这些数据构成了当前R 01应用的基础。实验设计：目前的建议是将该模型扩展到最轻微的甲状腺功能减退症，与正常高或轻度升高的TSH水平相关。将L-T4治疗的甲状腺功能减退受试者随机分配至目标三个TSH范围的L-T4剂量：0.28 - 2.49 mU/L（正常范围下限，理论最佳范围）、2.5 - 5.0 mU/L（正常范围上限）或5.1 - 12 mU/L（轻度甲状腺功能减退范围）。将在持续6个月的双盲、平行研究中给予精确滴定的L-T4剂量，以达到这些TSH水平。结果集中在临床上最相关和研究最少的系统：大脑（情绪和认知）和中间代谢（能量消耗和身体成分），研究人员已经在以前的工作中发现了影响。将在基线和6个月时使用经验证的技术测量这些结局变量，并进行中期访视，以精确滴定L-T4剂量。相关性：这是第一个研究，重点是神经认知和代谢的影响，轻度甲状腺功能减退症采用严格的研究设计和验证，相关的结果措施。对于是否治疗TSH水平在本研究建议范围内的患者没有共识，并且这些TSH范围是甲状腺领域内激烈辩论的主题。因此，这项研究对数百万接受甲状腺激素替代疗法的美国人以及另外数百万血清TSH水平正常的人具有重大的公共卫生意义。公共卫生相关性：在美国，数百万人患有轻度甲状腺功能减退症或甲状腺功能处于低正常范围。最近的初步研究，包括研究者实验室的研究，表明在这个范围内，甲状腺功能有临床相关的终末器官效应，但缺乏结论性数据，特别是在脑功能和燃料代谢的关键领域。这项研究将利用严格的干预设计和经过验证的结果指标首次对此进行研究，其结果有可能为数百万人的治疗决策提供信息。

DESCRIPTION (provided by applicant): Hypothyroidism is common, affecting 3% of the U.S. population, and up to 20% of older women. Therapy is straightforward, with optimization of target organ function expected when thyroid stimulating hormone (TSH) levels are normalized using L-thyroxine (L-T4). Despite this, millions of patients have mildly elevated TSH levels, and recent data also imply that patients may be undertreated if their TSH levels are high- normal. Decrements in quality of life, mood, cognitive function, and fuel metabolism are seen in hypothyroidism, but much less is known regarding these outcomes in mild hypothyroidism, or in L-T4 treated subjects with high-normal TSH levels. Preliminary data: The investigator's work utilizes a unique experimental model of experimentally-induced mild thyroid disease in hypothyroid subjects on chronic L-T4 therapy. This NIDDK R21-funded work has resulted in intriguing preliminary data that form the basis for the current R01 application. Experimental design: The current proposal is to extend this model to the mildest forms of hypothyroidism, associated with high-normal or mildly elevated TSH levels. L-T4 treated hypothyroid subjects will be randomized to doses of L-T4 that target three TSH ranges: 0.28 2.49 mU/L (the lower normal range, the theoretical optimal range), 2.5 5.0 mU/L (the upper normal range), or 5.1 12 mU/L (the mild hypothyroid range). Precisely titrated L-T4 doses will be given in a double-blinded, parallel study lasting 6 months, in order to achieve these TSH levels. Outcomes focus on the most clinically relevant and least studied systems: the brain (mood and cognition) and intermediary metabolism (energy expenditure and body composition), for which the investigator has already found effects in previous work. These outcome variables will be measured using validated techniques at baseline and at 6 months, with interim visits to allow precise titration of L-T4 doses. Relevance: This is the first investigation that focuses on neurocognitive and metabolic effects of mild hypothyroidism utilizing a rigorous study design and validated, relevant outcome measures. There is no consensus over whether to treat patients with TSH levels in the ranges proposed in this study, and these TSH ranges are the subject of intense debate within the thyroid field. Therefore, this study has major public health implications for the millions of Americans who receive thyroid hormone replacement therapy, as well as for the additional millions with high-normal serum TSH levels. PUBLIC HEALTH RELEVANCE: Millions of people in the U.S. have mild hypothyroidism or thyroid function in the low-normal range. Recent preliminary studies, including those from the investigator's laboratory, suggest that there are clinically relevant end-organ effects of thyroid function in this range, but there is a dearth of conclusive data, especially in the critical areas of brain function and fuel metabolism. This study will utilize a rigorous interventional design and validated outcome measures to study this for the first time, with results that have the potential to inform treatment decisions for millions of people.