睡眠障碍导致原发性TSH升高的临床及分子机理研究

The increased serum TSH with a normal T4 level had been referred to subclinical hypothyroidism (SCH) and the prevalent rate was between 3.1%-20%. However, recent researches indicated that isolated TSH elevation (ITE) caused by disfunction of the hypothalamus-pituitary axis had usually been misdiagnosed as SCH. The adverse impact of inappropriate intervention on ITE was varies. Our previous studies suggestted that increased TSH level with normal T4 is common in patients suffering from sleep disorders which indicated that sleep disorders may be the unknown cause of ITE. The objective of this study is to confirm the relationship between sleep disorders and ITE. By animal model of sleep deprivation, we aim to explore the impact on activity of type 2 deiodinase (D2) in pituitary and the molecular mechanism which may be critical in ITE. Besides, we attempt to validate our hypothesis that decreased D2 activity will reduce T3 concentrations and lead to restrain feed inhibition of TSH gene expression, finally resulted in increased TSH secretion. We proposed that sleep disorders especially sleep deprivation are associated with an increased risk of ITE. Our study will provide theoretical basis for diagnose and treatment of ITE while reduce the incidence of thyroid cancer and risks of cardiovascular events. Therefore, this innovative study will provide important advantages on medical economic values and clinical practice.

血TSH水平升高而T4正常传统上被归类为亚临床甲状腺功能减退（SCH），其患病率高达3.1%-20%。新近研究提示因下丘脑-垂体轴功能紊乱所致原发性TSH升高（ITE）在临床上常被误诊为SCH而予以不适当的干预，对患者身心健康影响较大。我们既往研究发现血TSH水平升高而T4正常的现象在睡眠障碍患者中比较常见，提示睡眠障碍可能是尚未被认识的ITE病因之一。本课题将通过临床试验证实睡眠障碍与ITE发生的因果关系，采用睡眠剥夺动物模型探索睡眠障碍对垂体TSH细胞中2型脱碘酶（D2）活性的影响及其分子机制，证实TSH细胞D2活性降低可能是ITE发生的关键环节，验证TSH细胞内D2活性降低->细胞内T3减少->对TSH分泌反馈抑制减弱->TSH分泌增多这一科学假说，提出睡眠障碍相关的下丘脑-垂体神经内分泌功能紊乱导致ITE这一崭新理论，为临床上降低患者甲状腺结节发病率及心脑血管事件风险，具有重要价值

血TSH水平升高而T4正常传统上被归类为亚临床甲状腺功能减退（SCH），但因下丘脑-垂体轴功能紊乱所致原发性TSH升高（ITE）在临床上常被误诊为SCH。我们既往研究发现血TSH水平升高而T4正常的现象在睡眠障碍患者中比较常见，提示睡眠障碍可能是尚未被认识的ITE病因之一。.本课题将通过临床试验证实睡眠障碍与ITE发生的因果关系并采用睡眠剥夺动物模型探索睡眠障碍对垂体TSH细胞中2型脱碘酶（D2）活性的影响及其分子机制，证实TSH细胞D2活性降低可能是ITE发生的关键环节。.重要结果及科学意义.一、.睡眠障碍患者其TSH水平较正常人群明显增高，超过一半的患者其血清TSH水平高于2.5 mU/L，而血清FT3和FT4水平仍在正常范围之内并且较之于正常人群没有明显变化。睡眠时间<3 h的受试者较之于睡眠时间>6 h的受试者，TSH升高幅度更为明显。.二、.对TPOAb阴性的夜间轮班护士的临床观察发现：(1)夜间轮班工作护士在18：00～02：00和02：00～08：00工作后清晨检测血清单纯性TSH升高的比例均明显高于其未上夜班时；(2)与未上夜班时清晨血清甲状腺激素水平比较时，夜间轮班工作护士在18：00～02：00工作后清晨血清TSH水平明显升高，02：00～08：00工作后清晨血清TSH、FT3和FT4水平均明显升高(未发表资料)。提示睡眠障碍相关的TSH升高并非通过改变甲状腺本身的功能而是直接作用于中枢神经系统进而影响了该部分人群的甲状腺激素水平。.三、.在建造水平台睡眠剥夺模型过程中，发现落水应激因素对甲状腺轴的影响不能排除，该模型不能良好的模拟人睡眠障碍的自然状态，或许该模型下的动物实验结果不能反映真实的睡眠障碍状态。.因此，本项目认为睡眠障碍是影响TSH水平升高的因素之一，临床上因血清TSH水平升高而被诊断为"SCH"的非老年且体重正常者中，部分有可能是因为睡眠时间短或睡眠质量差而导致血TSH升高，通过改善睡眠模式有可能使这部分患者的TSH水平恢复正常。