Molecular mechanisms underlying the effectiveness of triiodothyroacetic acid (Triac) in patients with resistance to thyroid hormone β (RTHβ): a multicentre, international, retrospective cohort study

BACKGROUND: Disease features in resistance to thyroid hormone beta (RTHβ), caused by THRB mutations, arise from insensitivity to thyroid hormone in tissues expressing thyroid hormone receptor (TR)β and from lifelong thyrotoxic effects in TRα1-expressing tissues, posing substantial cardiovascular morbidity/mortality. The T3-analogue triiodothyroacetic acid (Triac) holds potential as an effective treatment. Systematic data on Triac therapy in RTHβ are lacking, and the mechanisms through which Triac acts are unclear. This study aims to elucidate these knowledge gaps. METHODS: Clinical and biochemical data were obtained through an, international retrospective cohort study in patients with RTHβ. Transcriptional activity of all TRβ mutants, on the background of the pituitary-expressed β2 receptor isoform and positively (DR+4-TRE) or negatively (TSHα-TRE) regulated reporter genes plus T3 or Triac, was studied. Thyroid function and TSH responses to T3 and Triac were tested in zebrafish expressing TRβ mutants. FINDINGS: We collected data from 28 patients with RTHβ (range: 0.4-73.1 years) with 18 unique mutations treated with Triac in 6 centres. Triac reduced TSH (by 43%) and FT4 (by 37%) concentrations in all heterozygous patients, supported by consistent findings in zebrafish. Our functional studies showed that TRβ2 mutants exhibited reduced (all) or absent (G432del) T3-dependent transcriptional activity, with similar EC50 and IC50 values for T3 and Triac, except for R316H, which showed a 5-times lower EC50/IC50 value for Triac compared to T3. INTERPRETATION: In this international, multicentre study we have documented that Triac lowers elevated FT4 concentrations in patients with RTHβ effectively. Integrating our clinical and molecular observations we suggest that Triac can act via different modes of action, with activation of the wild-type receptor being a relevant mechanism. Our study may inform clinical management and could shape future interventional studies in patients with RTHβ. FUNDING: Financial support is acknowledged by WL (Affiliated Hospital of Southwest Medical University) WEV (ZonMw (Dutch Research Council, VIDI 09150172210071)), KC (Wellcome (210755/Z/18/Z), NIHR Cambridge Biomedical Research Centre (NIHR20312) and Medical Research Council United Kingdom (MRC_MU_UU_00014/40)), LP (European Union - Next Generation EU - NRRP M6C2 - Investment 2.1 Enhancement and strengthening of biomedical research in the NHS (code: PNRR-MR1-2022-12375726).