Bezafibrate induces hypothyroidism in a patient with resistance to thyroid hormone β due to a G347R variant

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.

Thyroid hormone economy in mice overexpressing iodothyronine deiodinases

“…25,26 The same rT3 kit was used in our previous study involving D3. 27 Compared to Empty mice, no significant changes were observed in D1 and D2 mice, while drastic changes were observed in D3 mice: serum fT3 and fT4 levels decreased (Figure 4A,B), and serum fT3/fT4 ratio and rT3 levels increased (Figure 4C,D). Although serum TSH levels S1.…”

Transcriptomic Landscape of Hyperthyroidism in Mice Overexpressing Thyroid Stimulating Hormone

“…Reverse transcription (RT)-PCR was performed using the Emerald Amp MAX PCR master mix (Takara Bio, Shiga, Japan). Quantitative RT-PCR was performed using THUNDERBIRD SYBR qPCR MIX (TOYOBO Life Science) with the StepOnePlus Real-time PCR System (Thermo Fisher Scientific), as in our previous studies (26, 27, 66, 67). Results were normalized using Ppia and Hprt as reference genes; relative mRNA expression of target genes was evaluated using the comparative threshold cycle method.…”

“…TSH forms a heterodimer consisting of a specific β subunit encoded by TSHB (23) and an α subunit coded by CGA that is common to luteinizing hormone, follicle-stimulating hormone, and chorionic gonadotropin (24). Therefore, we cloned human TSHB and CGA genes into pLIVE vectors and hydrodynamically injected 25 μg of these vectors into C57BL/6J mice according to our previous studies (25)(26)(27). At 1 week after hydrodynamic gene delivery, human TSH was not detected in the serum when each vector was separately injected, but TSH was strongly detected when both vectors were co-injected (Supplementary Figure 1A).…”

TRIAC disrupts cerebral thyroid hormone action via negative feedback and heterogenous distribution among organs

“…We administered TRIAC to mice and analyzed the animals using our methods to evaluate various elements that regulate TH action. 19 , 20 , 21 To determine TRIAC’s effects, we administered 3,3′,5-triiodo-L-thyronine (LT3) to other mice for comparison. We thereby determined that exogenous TRIAC appears to attenuate TH actions exclusively in the cerebrum.…”