Abstract

The current guideline-based management of hypothyroidism recommends monotherapy with levothyroxine (LT4), titrated to maintain the level of thyrotropin within a euthyroid reference range. This has been successful for most people with hypothyroidism, but a substantial minority still report symptoms of hypothyroidism unexplained by a comorbid medical condition. LT4 is essentially a prodrug for triiodothyronine (T3), the thyroid hormone that acts on target tissues in the brain and the periphery. Thyroid hormone replacement with LT4 alone does not restore physiological tissue levels of thyroid hormones, particularly T3. During the last two decades, much interest has focussed on the potential of combinations of LT4 and T3 to provide a superior outcome to LT4 monotherapy for people with hypothyroidism, especially those with residual symptoms despite thyrotropin-optimized LT4. This review seeks to provide an overview of currently available evidence on combination (LT4 + T3) therapy to be used for personalized medicine in patients with hypothyroidism. A number of randomized, controlled trials (RCTs) have failed to demonstrate superiority for the combination therapy approach, largely due to non-physiological T3 doses. However, patients with hypothyroidism are highly heterogeneous in terms of their residual thyroid function, individual set points for optimal thyroid homeostasis and for the presence or absence of polymorphisms in deiodinase enzymes in tissues that activate and deactivate circulating thyroid hormones. Accordingly, these RCTs may have failed to demonstrate benefits of combination therapy in individual hypothyroid phenotypes. The pharmacokinetics of LT4 and T3 also differ, which is a barrier to their co-administration. Future clinical trials using LT4 + T3 tablets better suited for combination therapy will resolve the outstanding research questions relating to the place of LT4 + T3 combination therapy in the management of hypothyroidism.

摘要

目前基于指南的甲状腺功能减退症管理建议使用左甲状腺素 (LT4) 进行单药治疗，滴定以将促甲状腺素水平维持在甲状腺功能正常的参考范围内。这对大多数甲状腺功能减退症患者来说是成功的，但仍有相当一部分人报告了无法由合并症解释的甲状腺功能减退症症状。LT4 本质上是三碘甲状腺原氨酸 (T3) 的前药，T3 是作用于大脑和外周靶组织的甲状腺激素。仅用 LT4 替代甲状腺激素并不能恢复甲状腺激素的生理组织水平，尤其是 T3。在过去的二十年里，很多兴趣都集中在 LT4 和 T3 联合治疗为甲状腺功能减退症患者提供优于 LT4 单一疗法的潜力上，尤其是那些尽管经过促甲状腺素优化的 LT4 仍有残留症状的人。本综述旨在概述目前可获得的关于联合（LT4 + T3）治疗用于甲状腺功能减退患者个体化治疗的证据。许多随机对照试验 (RCT) 未能证明联合治疗方法的优越性，这主要是由于非生理性 T3 剂量。然而，甲状腺功能减退症患者在其残余甲状腺功能、最佳甲状腺稳态的个体设定点以及激活和停用循环甲状腺激素的组织中脱碘酶多态性的存在或不存在方面具有高度异质性。因此，这些 RCT 可能未能证明联合治疗对个体甲状腺功能减退表型的益处。LT4 和 T3 的药代动力学也不同，这是它们共同给药的障碍。未来使用更适合联合治疗的 LT4 + T3 片剂的临床试验将解决与 LT4 + T3 联合治疗在甲状腺功能减退症管理中的地位相关的突出研究问题。