Bezafibrate induces hypothyroidism in a patient with resistance to thyroid hormone β due to a G347R variant. (13th September 2021)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Clinical endocrinology. Volume 96:Number 2(2022)
• Page Start: 236
• Page End: 245
• Publication Date: 2021-09-13
• Subjects: bezafibrate -- hypothyroidism -- iodothyronine deiodinase -- peroxisome proliferator‐activated receptor α -- thyroid hormone resistance; Endocrinology -- Periodicals; 616.4005
• DOI: 10.1111/cen.14591
• Languages: English
• ISSNs: 0300-0664

Abstract

Abstract: Objective: A unique clinical course was observed in a patient with resistance to thyroid hormone β (RTHβ) caused by a variant of the THRB gene 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. Methods: A 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. Results: In non‐RTHβ patients ( n = 7), BZ treatment did not change serum free T3 and TSH but significantly increased fT4 ( p = .008). BZ administration increased DIO3 reporter activity in the context of G347R TRβ, whereas did not change DIO1 and DIO2 reporter activity. In the livers of mice with G347R TRβ, BZ administration increased reverse T3 content, which corresponded to an increase in Dio3 messenger RNA. Conclusions: While 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. Liver DIO3 upregulation might involve this hypothyroidism.