Bezafibrate induces hypothyroidism in a patient with resistance to thyroid hormone β due to a G347R variant
Bezafibrate induces hypothyroidism in a patient with resistance to thyroid hormone β due to a G347R variant
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苯扎贝特会导致因 G347R 变异而对甲状腺激素 β 产生抵抗的患者出现甲状腺功能减退症
DOI：
10.1111/cen.14591
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发表时间：
2021
影响因子：
3.2
通讯作者：
Inagaki Nobuya
中科院分区：
文献类型：
--
作者：
Yamauchi Ichiro;Yamashita Takafumi;Sugawa Taku;Tagami Tetsuya;Hanaoka Ikuko;Usui Takeshi;Hirota Keisho;Hakata Takuro;Ueda Yohei;Fujii Toshihito;Sakane Yoriko;Yasoda Akihiro;Inagaki Nobuya
1例甲状腺激素β抵抗（RTHβ resistance，RTHβ resistance，RTHβ resistance）患者的临床表现为THB 347位密码子甘氨酸被精氨酸取代（p.G347R）。患者出现促甲状腺激素（TSH）分泌不当综合征（游离T4 [fT 4]：32.43 pmol/L，TSH：4.67 mIU/L），但缓慢发展为进行性甲状腺功能减退症（fT 4：8.37 pmol/L，TSH：100.90 mIU/L），暂停苯扎贝特（BZ）治疗后消退（fT 4：32.18 pmol/L，TSH：7.14 mIU/L）。这项研究的临床和实验评估这一有趣的phenomenon.MethodsA回顾性队列分析non-RTH β患者在京都大学医院进行。将BZ治疗前的数据与治疗后的首次数据进行比较。利用HEK 293 T细胞中的碘甲腺原氨酸脱碘酶（DIO 1、DIO 2、DIO 3）的报告基因分析方法，对突变型甲状腺激素受体β（G347 R TRβ）进行了功能分析。结果在非RTHβ患者（n= 7）中，BZ治疗没有改变血清游离T3和TSH，但显著增加fT 4（p= 0.008）。在G347 R TRβ的情况下，BZ的施用增加了DIO 3报告基因活性，而DIO 1和DIO 2报告基因活性没有改变。在G347 R TRβ小鼠的肝脏中，BZ给药增加了反向T3含量，这对应于Dio 3信使RNA.ConclusionsWhile甲状腺功能减退症与BZ治疗相关未发生在非RTHβ患者中，但在RTHβ患者中观察到由于p.G347 R变体。肝DIO 3上调可能涉及这种甲状腺功能减退。
ObjectiveA unique clinical course was observed in a patient with resistance to thyroid hormone β (RTHβ) caused by a variant of theTHRBgene leading to the replacement of glycine with arginine in codon 347 (p.G347R). He presented with the syndrome of inappropriate secretion of thyrotropin (TSH) (free T4 [fT4]: 32.43 pmol/L, TSH: 4.67 mIU/L), but slowly developed progressive hypothyroidism (fT4: 8.37 pmol/L, TSH: 100.90 mIU/L) that resolved after suspending bezafibrate (BZ) treatment (fT4: 32.18 pmol/L, TSH: 7.14 mIU/L). This study clinically and experimentally evaluated this interesting phenomenon.MethodsA retrospective cohort analysis of non‐RTHβ patients was performed at Kyoto University Hospital. Data before BZ treatment were compared to the first data after treatment. Using reporter assays of iodothyronine deiodinases (DIO1,DIO2,DIO3) in HEK293T cells, we performed functional analyses of mutant thyroid hormone receptor β with p.G347R (G347R TRβ). Mice with G347R TRβ were generated by hydrodynamic gene delivery.ResultsIn non‐RTHβ patients (n= 7), BZ treatment did not change serum free T3 and TSH but significantly increased fT4 (p= .008). BZ administration increasedDIO3reporter activity in the context of G347R TRβ, whereas did not changeDIO1andDIO2reporter activity. In the livers of mice with G347R TRβ, BZ administration increased reverse T3 content, which corresponded to an increase inDio3messenger RNA.ConclusionsWhile hypothyroidism associated with BZ treatment did not occur in non‐RTHβ patients, it was observed in a patient with RTHβ due to the p.G347R variant. LiverDIO3upregulation might involve this hypothyroidism.