Energy Metabolism in Thyroidectomized Patients

尽管有足够的替代治疗，但甲状腺功能减退症状仍很常见，体重增加是最常见的症状之一。 经常报告，对生活质量产生负面影响。碘甲状腺原氨酸/左旋甲状腺素联合治疗试图模拟甲状腺激素的内源性产生，产生了混合的结果，主要是因为动力不足和设计不佳的研究。在本研究中，我们的目的是详细研究接受甲状腺全切除术的患者，以及手术后6个月内仅使用左旋甲状腺素或使用碘甲状腺原氨酸/左旋甲状腺素替代治疗的患者。我们假设，与单独使用左旋甲状腺素相比，碘甲状腺原氨酸/左旋甲状腺素联合使用将使甲状腺切除术后体重增加最小化，并预防心血管和脂质代谢功能障碍。 与甲状腺功能减退症有关手术后甲状腺功能减退症是一种独特的实验模型，用于评估甲状腺功能减退症的代谢影响并比较不同的治疗方案，因为：1）患者可以在甲状腺功能正常的状态下在手术前进行研究，2）甲状腺功能减退症的发作是明确的，因此其影响可以明确定义，3）与自身免疫性甲状腺功能减退症相比，没有残留的内源性甲状腺激素产生。 疾病这些因素消除了大量的混杂因素，增加了拟议研究的内部效度。在这里，我们建议进行一项概念验证、对照、双盲、平行设计研究，其中具有甲状腺全切除术临床适应症的患者将在术前基线时在甲状腺功能正常状态下进行表型表征。手术后，患者将被随机分配至单用左旋甲状腺素（标准治疗）或碘甲状腺原氨酸/左旋甲状腺素替代治疗，持续6个月。患者将在术后3个月和6个月接受表型表征。我们将评估身体成分，24小时能量消耗，整个房间间接热量测定，心血管功能和脂质代谢。此外，我们还将收集生活质量变化和2型脱碘酶基因常见多态性调节效应的探索性数据，该基因多态性与甲状腺激素替代治疗的差异反应相关。总的来说，从这项概念验证研究中获得的数据将提供术后甲状腺功能减退症的代谢影响和对碘甲状腺原氨酸/左甲状腺素替代治疗的差异（或缺乏）反应的可靠点估计。这反过来将提供是否在大型干预试验中追求研究假设的理论基础，以及充分支持其评估联合治疗治疗甲状腺功能减退症的有效性和预防其对能量平衡，心血管系统，脂质代谢和生活质量的影响的工具。

Hypothyroid symptoms despite adequate replacement therapy are common, and weight gain is one of the most frequently reported, negatively affecting quality of life. Combination therapy liothyronine/levothyroxine attempts to mimic the endogenous production of thyroid hormone have generated mixed results, mostly because of underpowered and not optimally designed studies. In this proposal we aim to study in detail patients undergoing total thyroidectomy before, and for a six-month period following the procedure while on levothyroxine only or on liothyronine/levothyroxine replacement therapy. We hypothesize that combination liothyronine/levothyroxine when compared to levothyroxine alone will minimize post- thyroidectomy weight gain and prevent the cardiovascular and lipid metabolism dysfunction associated with hypothyroidism. Post-surgical hypothyroidism is a unique experimental model to assess the metabolic effects of hypothyroidism and to compare different therapeutic schemes because: 1) patients can be studied before the procedure in a state of euthyroidism, 2) the onset of hypothyroidism is well defined hence its effects can be clearly defined, and 3) there is no residual endogenous production of thyroid hormone, as compared to autoimmune thyroid disease. These factors eliminate a significant amount of confounders, increasing the internal validity of the proposed study. Here we propose to conduct a proof-of-concept, controlled, double blind, parallel design study whereby patients with clinical indications to total thyroidectomy will undergo phenotype characterization at baseline before surgery while in a euthyroid state. Following surgery, patients will be randomized to levothyroxine alone (standard of care) or liothyronine/levothyroxine replacement therapy for a six-month period. Patients will undergo phenotype characterization at three and six months following surgery. We will assess body composition, 24-hour energy expenditure by whole room indirect calorimetry, cardiovascular function, and lipid metabolism. Additionally we will gather exploratory data on changes in quality of life and on the modulatory effects of a common polymorphism of the type 2 deiodinase gene which has been associated with differential response to thyroid hormone replacement therapy. Collectively, the data obtained from this proof-of-concept study will provide solid point estimates of the metabolic effects of post-surgical hypothyroidism and of differential (or lack thereof) response to liothyronine/levothyroxine replacement therapy. This in turn will provide the rationale whether pursuing the study hypotheses in a large intervention trial, and the tools to adequately power it to evaluate the effectiveness of combination therapy in the treatment of hypothyroidism and for the prevention of its effects on energy balance, cardiovascular system, lipid metabolism, and quality of life.