Identification of Resistance to Exogenous Thyroxine in Humans
Por:
Lacámara N, Lecumberri B, Barquiel B, Escribano A, González-Casado I, Álvarez-Escolá C, Aleixandre-Blanquer F, Morales F, Alfayate R, Bernal-Soriano MC, Miralles R, Yildirim Simsir I, Özgen AG, Bernal J, Berbel P and Moreno JC
Publicada:
1 dic 2020
Ahead of Print:
1 jul 2020
Resumen:
Background:Thyroxine (T4) to triiodothyronine (T3) deiodination in the hypothalamus/pituitary is mediated by deiodinase type-2 (D2) activity.Dio2((-/-))mice show central resistance to exogenous T4. Patients with resistance to exogenous thyroxine (RETH) have not been described. The aim of this study was to identify hypothyroid patients with thyrotropin (TSH) unresponsiveness to levothyroxine (LT4) and to characterize the clinical, hormonal, and genetic features of human RETH. Methods:We investigated hypothyroid patients with elevated TSH under LT4 treatment at doses leading to clinical and/or biochemical hyperthyroidism. TSH and free T4 (fT4) were determined by chemiluminescence, and total T4, T3, and reverse T3 (rT3) by radioimmunoassay. TSH/fT4 ratio at inclusion and T3/T4, rT3/T4, and T3/rT3 ratios at follow-up were compared with those from patients with resistance to thyroid hormone (RTH) due to thyroid hormone receptor-beta (THRB) mutations.DIO2,including the Ala92-D2 polymorphism, selenocysteine binding protein 2 (SECISBP2), andTHRBwere fully sequenced. Results:Eighteen hypothyroid patients (nine of each sex, 3-59 years) treated with LT4 showed elevated TSH (15.5 +/- 4.7 mU/L; reference range [RR]: 0.4-4.5), fT4 (20.8 +/- 2.4 pM; RR: 9-20.6), and TSH/fT4 ratio (0.74 +/- 0.25; RR: 0.03-0.13). Despite increasing LT4 doses from 1.7 +/- 1.0 to 2.4 +/- 1.7 mu g/kg/day, TSH remained elevated (6.9 +/- 2.7 mU/L). Due to hyperthyroid symptoms, LT4 doses were reduced, and TSH increased again to 7.9 +/- 3.2 mU/L. In the euthyroid/hyperthyrotropinemic state, T3/T4 and T3/rT3 ratios were decreased (9.2 +/- 2.4, RR: 11.3-15.3 and 2.5 +/- 1.4, RR: 7.5-8.5, respectively) whereas rT3/T4 was increased (0.6 +/- 0.2; RR: 0.43-0.49), suggesting reduced T4 to T3 and increased T4 to rT3 conversion. These ratios were serum T4-independent and were not observed in RTH patients. Genetic testing was normal. The Ala92-D2 polymorphism was present in 7 of 18 patients, but the allele dose did not correlate with RETH. Conclusions:Human RETH is characterized by iatrogenic thyrotoxicosis and elevated TSH/fT4 ratio. In the euthyroid/hyperthyrotropinemic state, it is confirmed by decreased T3/T4 and T3/rT3 ratios, and elevated rT3/T4 ratio. This phenotype may guide clinicians to consider combined T4+T3 therapy in a targeted fashion. The absence of germlineDIO2mutations suggests that aberrant post-translational D2 modifications in pituitary/hypothalamus or defects in other genes regulating the T4 to T3 conversion pathway could be involved in RETH.
Filiaciones:
Lacámara N:
Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain
The Rare Diseases Networking Biomedical Research Centre (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
Lecumberri B:
Department of Endocrinology, La Paz University Hospital, Madrid, Spain
Barquiel B:
Department of Endocrinology, La Paz University Hospital, Madrid, Spain
Escribano A:
Department of Pediatric Endocrinology, Virgen de la Arrixaca University Hospital, Murcia, Spain
González-Casado I:
Department of Pediatric Endocrinology, La Paz University Hospital, Madrid, Spain
Álvarez-Escolá C:
Department of Endocrinology, La Paz University Hospital, Madrid, Spain
:
Department of Pediatric Endocrinology, Elda University Hospital, Alicante, Spain
Morales F:
Department of Endocrinology, Virgen Del Rocío University Hospital, Sevilla, Spain
Alfayate R:
Clinical Chemistry Department, Alicante University Hospital, Alicante, Spain
Bernal-Soriano MC:
Clinical Chemistry Department, Alicante University Hospital, Alicante, Spain
Miralles R:
Department of Endocrinology, Alicante University Hospital, Alicante, Spain
Yildirim Simsir I:
Department of Endocrinology and Metabolism Disorders, Ege University Medical Faculty, Izmir, Turkey
Özgen AG:
Department of Endocrinology and Metabolism Disorders, Ege University Medical Faculty, Izmir, Turkey
Bernal J:
Department of Endocrine and Nervous System, Instituto de Investigaciones Biomédicas, CSIC, and CIBERER Instituto de Salud Carlos III, Madrid, Spain
Berbel P:
Department of Histology and Anatomy, Faculty of Medicine, Universidad Miguel Hernández de Elche, Alicante, Spain
Moreno JC:
Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain
The Rare Diseases Networking Biomedical Research Centre (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
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