Hyopthyroidism Treatment in Aging and Thyroid Cancer

描述(由申请人提供)：甲状腺疾病在美国是一个重大的医疗和公共卫生挑战，影响着1900多万美国人。甲状腺功能减退症(HT)在4.6%的美国人口中发现，在老年人中越来越常见，超过20%的女性和11%的男性受到影响。甲状腺功能减退的定义是血清促甲状腺激素(TSH)浓度升高，而血清甲状腺激素(T4)和三碘甲腺原氨酸(T3)浓度较低。人群研究表明，TSH浓度与年龄相关，但目前，对于应该开始替代治疗的TSH浓度还没有达成共识。知识上的另一个重大差距是缺乏左旋甲状腺素的药代动力学数据，特别是在衰老过程中。内源性甲状腺激素的存在使得使用常规实验室测试无法区分内源性和外源性甲状腺激素。在AIMS 1中，我们将进行13C-LT4在老年人体内的药代动力学研究。我们使用最先进的技术设计并验证了这种方法，它允许测量外源性LT4并进行单剂量口服LT4替代的药代动力学研究。第二个目标(目标2)将检查促甲状腺激素的生物活性，假设与年龄相关的促甲状腺激素浓度的升高由相对较不活跃的促甲状腺激素组成。AIM 3将检测外周组织中与年龄相关的甲状腺激素活性，以反映药物疗效。我们在乔治敦大学医学中心(GUMC)使用最先进的LC/MS/MS(LC/MS/MS)进行患者招募和PK研究方面的经验，以及我们的初步数据，确保了这项建议的成功。如果这项研究的目标得以实现，它将推进该领域的知识，并对老龄化人口产生重大影响；随着美国婴儿潮一代的老龄化，需要充分了解甲状腺疾病的进展，改进诊断和治疗对我们的国家和我们的医疗体系至关重要。我们相信，这些独特和创新的研究将提供丰富的信息，这些信息将转化为改善治疗干预的诊断、评估和管理。 公共卫生相关性：甲状腺疾病在美国是一个重大的医疗和公共卫生挑战，影响着1900多万美国人。为了正确诊断、治疗和管理甲状腺功能减退症，我们需要阐明和描述甲状腺激素代谢的年龄差异，尤其是在女性。这将有助于制定治疗目标，并帮助数百万人诊断、治疗和管理老龄化中的甲状腺疾病。

DESCRIPTION (provided by applicant): Thyroid disease represents a significant medical and public health challenge in the United States affecting over 19 million Americans. Hypothyroidism (HT) found in 4.6% of the US population, is increasingly common in the elderly affecting more than 20% of women and 11% of men. Hypothyroidism is defined by an elevated serum thyroid stimulating hormone (TSH) concentration with low serum thyroxine (T4) and tri- iodothyronine (T3) concentrations. Population studies demonstrate an age-related elevation in TSH concentrations, but at present, there is no consensus regarding the TSH concentration at which replacement therapy should be initiated. Another significant gap in knowledge is a lack of pharmacokinetic data of levothyroxine specifically in aging. The presence of endogenous thyroxine makes it impossible to differentiate between internally and externally-derived thyroxine using conventional laboratory tests. In Aims 1 we will conduct pharmacokinetic studies of 13C-LT4 in the elderly. We have designed and validated this method, using state-of- the-art technology, which permit the measurement of exogenous LT4 and conduct pharmacokinetic studies of single dose oral LT4 replacement. A secondary aim (Aim 2) will examine the bioactivity of TSH, assuming the age-related elevation in TSH concentrations consists of relatively more inactive TSH. Aim 3 will examine age-related thyroid hormone activity in peripheral tissues reflecting drug effectiveness. Our experience in patient recruitment and conducting PK studies using state-of-the- art liquid chromatography tandem mass spectrometry (LC/MS/MS) at Georgetown University Medical Center (GUMC), as well as our preliminary data, assure the success of this proposal. If the goals of this research are achieved it will advance the knowledge in the field and have a major impact on the aging population; with the aging of America's baby boomers the need to fully understand the progression thyroid disease, to improve diagnosis and treatment is vitally important to our nation and to our healthcare systems. We believe that these unique and innovative studies will provide a wealth of information that will translate to improved diagnosis, evaluation and management of therapeutic interventions. PUBLIC HEALTH RELEVANCE: Thyroid disease represents a significant medical and public health challenge in the United States affecting over 19 million Americans. In order to diagnose, treat and manage hypothyroid disease appropriately we need elucidate and characterize the age- associated differences in thyroid hormone metabolism, especially in women. This will help in setting therapeutic goals and help millions in diagnosis, treatment and management of thyroid disease in aging.