Scientific letter
Coexistence of thyroid hormone resistance syndrome, pituitary adenoma and Graves’ disease
Coexistencia de síndrome de resistencia a hormonas tiroideas, adenoma hipofisario y enfermedad de Graves
Ana María Ramos-Levía,
, José Carlos Morenob, Cristina Álvarez-Escolác, Nerea Lacámarab, Maria Carmen Montañezd
Corresponding author
a Department of Endocrinology, Hospital Universitario de la Princesa, Instituto de Investigación Princesa, Universidad Autónoma de Madrid, Madrid, Spain
b Institute for Medical and Molecular Genetics (INGEMM), Thyroid Molecular Laboratory, Hospital Universitario La Paz, Madrid, Spain
c Department of Endocrinology, Hospital Universitario La Paz, Instituto de Investigación La Paz, Universidad Autónoma de Madrid, Madrid, Spain
d Department of Endocrinology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos, Madrid, Spain
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true "cabecera" => "<span class="elsevierStyleTextfn">Scientific letter</span>" "titulo" => "Coexistence of thyroid hormone resistance syndrome, pituitary adenoma and Graves’ disease" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "139" "paginaFinal" => "141" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Ana María Ramos-Leví, José Carlos Moreno, Cristina Álvarez-Escolá, Nerea Lacámara, Maria Carmen Montañez" "autores" => array:5 [ 0 => array:4 [ "nombre" => "Ana María" "apellidos" => "Ramos-Leví" "email" => array:1 [ 0 => "ana_ramoslevi@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "José Carlos" "apellidos" => "Moreno" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Cristina" "apellidos" => "Álvarez-Escolá" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "Nerea" "apellidos" => "Lacámara" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 4 => array:3 [ "nombre" => "Maria Carmen" "apellidos" => "Montañez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Department of Endocrinology, Hospital Universitario de la Princesa, Instituto de Investigación Princesa, Universidad Autónoma de Madrid, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Institute for Medical and Molecular Genetics (INGEMM), Thyroid Molecular Laboratory, Hospital Universitario La Paz, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Endocrinology, Hospital Universitario La Paz, Instituto de Investigación La Paz, Universidad Autónoma de Madrid, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Department of Endocrinology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos, Madrid, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Coexistencia de síndrome de resistencia a hormonas tiroideas, adenoma hipofisario y enfermedad de Graves" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2090 "Ancho" => 2783 "Tamanyo" => 230130 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Timeline summarizing the main events the patient underwent. 1. Initial evaluation. 2. Genetic test results confirm syndrome of thyroid hormone resistance. 3. Onset of symptoms of hyperthyroidism. 4. Development of atrial fibrillation. 5. Cardioversion is performed. I-131: ablative treatment with I131 is performed. Values are shown as TSH μU/mL, FT4 ng/dL, FT3 pg/mL. Shaded blue box represents normal reference values.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Thyroid hormone resistance (THR) is a rare genetic syndrome in which tissue sensitivity to thyroid hormones is decreased, determining high levels of serum thyroid hormones and normal or elevated thyroid stimulating hormone (TSH).<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> In most cases THR is due to mutations in the thyroid hormone receptor beta (<span class="elsevierStyleItalic">THRB</span>) gene.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Suspicion of THR arises in the setting of inappropriate TSH secretion, where a TSH-secreting pituitary adenoma should also be ruled out. THR and TSH-omas have been classically considered two distinct entities, but differential diagnosis may be sometimes blurred.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Thyroid autoimmunity may exist in THR,<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> but reports have generally depicted a mild clinical picture. Case records describing the development of overt Graves’ disease with severe cardiac alterations are extremely rare.</p><p id="par0020" class="elsevierStylePara elsevierViewall">A 46 year-old woman, with a previous history of simple hysterectomy due to uterine fibroids, was referred for evaluation of the following thyroid hormone profile: TSH 2.86<span class="elsevierStyleHsp" style=""></span>μU/mL (normal 0.3–5.6), FT4 2.87<span class="elsevierStyleHsp" style=""></span>ng/dL (0.8–1.7). She only recalled occasional increased heart rate and headache. Physical examination was unremarkable, except for a subtle goiter (grade Ia).</p><p id="par0025" class="elsevierStylePara elsevierViewall">Repeated laboratory evaluation one month later revealed TSH 10.5, FT4 2.2, FT3 7.32<span class="elsevierStyleHsp" style=""></span>pg/mL (2.5–3.9), anti-thyroperoxidase antibodies (TPOAb) 6170<span class="elsevierStyleHsp" style=""></span>U/mL (<40), anti-thyroglobulin antibodies (TGAb) 126<span class="elsevierStyleHsp" style=""></span>U/mL (<80) and anti-TSH-receptor antibodies (TSI) 11<span class="elsevierStyleHsp" style=""></span>U/mL (<13). Pituitary laboratory evaluation showed IGF-1 142<span class="elsevierStyleHsp" style=""></span>ng/mL (normal for age and sex), prolactin (PRL) 2541<span class="elsevierStyleHsp" style=""></span>μU/mL (100–410), LH 1.2<span class="elsevierStyleHsp" style=""></span>U/L, FSH 3<span class="elsevierStyleHsp" style=""></span>U/L, estradiol 81<span class="elsevierStyleHsp" style=""></span>pg/mL, ACTH 22<span class="elsevierStyleHsp" style=""></span>pg/mL (9–54), cortisol 234<span class="elsevierStyleHsp" style=""></span>ng/mL (65–230). Radioactive iodine uptake (RAIU) was not elevated. Pituitary magnetic resonance imaging (MRI) showed mild pituitary enlargement, with a hypoenhancing 13<span class="elsevierStyleHsp" style=""></span>mm lesion on the left side. Levels of TRH-stimulated TSH, measured in a standard 90<span class="elsevierStyleHsp" style=""></span>min test, increased more than 200% and levels of alpha-subunit were normal (0.31<span class="elsevierStyleHsp" style=""></span>mU/mL, normal <1.6, ratio αTSH/TSH<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.05, normal<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>1). An octreotide suppression test showed no changes in thyroid hormones or PRL. Cabergoline 1<span class="elsevierStyleHsp" style=""></span>mg/week was started, and titrated up to 2<span class="elsevierStyleHsp" style=""></span>mg/week. Hyperprolactinemia was adequately controlled six months later, while biochemical hyperthyroidism persisted (TSH 5, FT4 2.5, PRL 401), and pituitary MRI showed reduction of the adenoma to 7<span class="elsevierStyleHsp" style=""></span>mm.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Genetic testing identified a point mutation in the <span class="elsevierStyleItalic">THRB</span> gene (c.1642C>G) leading to a missense change of Proline 453 to Arginine (p.P453R). During the following months, the patient maintained clinical stability with TSH levels in the upper limit of normal and mildly elevated FT4 and FT3. PRL levels remained normal under cabergoline. The pituitary adenoma remained unchanged.</p><p id="par0035" class="elsevierStylePara elsevierViewall">One year later, the patient developed sleeping difficulties, tremor, and anxiety. Physical examination of her thyroid had not change, but laboratory work up at this time revealed TSH 0.45, FT4 2.91, FT3 8.16, Anti-TPO 2572, Anti-TG 443, Anti-R-TSH 5, and RAIU showed a slightly increased uptake, suggesting the onset of primary hyperthyroidism. She started carbimazole 10<span class="elsevierStyleHsp" style=""></span>mg/day, but, despite correct adherence to treatment and dose increase, euthyroidism was not achieved (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>), and she developed atrial fibrillation. I-131 therapy (16<span class="elsevierStyleHsp" style=""></span>mCi) was performed. Laboratory follow-up showed progressive increase of TSH (up to 40<span class="elsevierStyleHsp" style=""></span>μU/mL), with FT4 and FT3 in the normal-high range. She started low-dose L-T4 (25<span class="elsevierStyleHsp" style=""></span>μg/day), which was then cautiously increased. At the last follow-up, her thyroid hormone levels were still elevated (TSH 20.0, FT4 3.3, FT3 4.0), but she remained asymptomatic, and with an adequate heart rate.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">Most cases of THR occur due to mutations in the <span class="elsevierStyleItalic">THRB</span> gene, but its associated phenotype may vary,<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> and the gene defect may remain unknown in 15% of subjects.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> Suspicion of THR arises in the setting of inappropriate TSH production, but its diagnosis may be hindered if pituitary enlargement coexists,<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> or by pitfalls in laboratory findings.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> In our patient, although the lack of family history could favor the existence of a TSH-secreting tumor, the null response to the octreotide test, the elevated levels of PRL, and the mild clinical picture despite high thyroid hormone levels, supported the hypothesis of THR and prolactinoma coexistence. THR was confirmed with a positive genetic testing, whilst the significant response to cabergoline suggested the existence of a prolactinoma.</p><p id="par0045" class="elsevierStylePara elsevierViewall">THR and TSH-secreting pituitary tumors have been classically considered two different entities.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> Although long-standing absence of negative feedback has been suggested to determine enlargement of thyrotroph cells, the etiology of TSH-omas is not fully understood.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> Furthermore, given that T3 down-regulates transcription of the human PRL gene in pituitary cells through T3-responsive elements in its promoter, TRβ mutations may lead to hyperprolactinemia, determining pituitary hyperplasia and adenoma development. However, to our knowledge, hyperprolactinemia and prolactinomas have not been specifically addressed in the setting of THR. We could hypothesize that mutations in certain TRβ isoforms could lead to the development of pituitary tumors, so THR and pituitary adenomas would coexist as a result of the same physiopathogenic mechanism, and would not be two independent alterations.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Another distinctive feature of our patient is that she developed a marked autoimmune primary hyperthyroidism one year later. Autoimmune thyroid disease has been documented in cases of THR,<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> but in the majority of publications, either THR coexisted with Hashimoto's disease, or suspicion of THR arose after an initial diagnosis of Graves’ disease.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">6,7</span></a> However, to our knowledge, only two reports have described the development of Graves’ disease in patients with a known and stable THR.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">8,9</span></a> The natural history explaining this outcome is not clear.</p><p id="par0055" class="elsevierStylePara elsevierViewall">THR and autoimmunity may merely coexist, given the high prevalence of thyroid autoimmunity in general, but other reports suggest that autoimmunity develops following persistent stimulation of thyroid lymphocytes, and assert that these entities are truly associated, and not merely coincidental.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> It has been proposed that the immune system may be activated by another mechanism in THR, for instance via either the TRβ or the TRα,<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> in a similar way as in the development of tachycardia.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Favoring the latter hypothesis, our patient already presented thyroid autoimmunity at the first evaluation. However, she subsequently developed hyperthyroidism and cardiac alterations, which, although relatively frequent in Graves’ disease, are less common in THR.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> The reason for such a clinical course of hyperthyroidism in our patient is not fully elucidated. Maybe THR delayed an overt hyperthyroid spectrum, but once hyperthyroidism developed, it outweighed peripheral resistance. Future research deems necessary to investigate the autoimmune environment in individuals with THR.</p><p id="par0065" class="elsevierStylePara elsevierViewall">In conclusion, we remark the difficulties encountered in distinguishing the cause of inappropriate TSH secretion when a pituitary adenoma coexists. These two entities may comprise the phenotypic expression of a unique genetic alteration. Thyroid autoimmunity may coexist with THR, or subsequently develop due to chronic TSH stimulation. The extent to which this may influence progression to severe Graves’ disease, like in our patient, remains to be clarified. Ablative treatment may be necessary in cases of persistent hyperthyroidism that outweighs peripheral resistance.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Author contribution statement</span><p id="par0070" class="elsevierStylePara elsevierViewall">ARL followed the patient, analyzed and interpreted data, and wrote, reviewed and edited the manuscript. JM performed molecular studies and revised the manuscript. NL performed molecular studies. CAE followed the patient and contributed to interpretation of the clinical setting. MM followed the patient and revised and edited the manuscript. All authors contributed to the final version of this manuscript.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflict of interest</span><p id="par0075" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Author contribution statement" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflict of interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2090 "Ancho" => 2783 "Tamanyo" => 230130 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Timeline summarizing the main events the patient underwent. 1. Initial evaluation. 2. Genetic test results confirm syndrome of thyroid hormone resistance. 3. Onset of symptoms of hyperthyroidism. 4. Development of atrial fibrillation. 5. Cardioversion is performed. I-131: ablative treatment with I131 is performed. Values are shown as TSH μU/mL, FT4 ng/dL, FT3 pg/mL. Shaded blue box represents normal reference values.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Thyroid hormone resistance syndromes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "J. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 8 | 0 | 8 |
| 2024 October | 21 | 7 | 28 |
| 2024 September | 47 | 14 | 61 |
| 2024 August | 38 | 6 | 44 |
| 2024 July | 35 | 8 | 43 |
| 2024 June | 28 | 4 | 32 |
| 2024 May | 28 | 7 | 35 |
| 2024 April | 27 | 4 | 31 |
| 2024 March | 56 | 11 | 67 |
| 2024 February | 36 | 6 | 42 |
| 2024 January | 40 | 7 | 47 |
| 2023 December | 69 | 14 | 83 |
| 2023 November | 51 | 11 | 62 |
| 2023 October | 83 | 13 | 96 |
| 2023 September | 28 | 3 | 31 |
| 2023 August | 26 | 4 | 30 |
| 2023 July | 25 | 8 | 33 |
| 2023 June | 26 | 7 | 33 |
| 2023 May | 28 | 4 | 32 |
| 2023 April | 22 | 1 | 23 |
| 2023 March | 18 | 5 | 23 |
| 2023 February | 20 | 7 | 27 |
| 2023 January | 16 | 5 | 21 |
| 2022 December | 18 | 5 | 23 |
| 2022 November | 24 | 13 | 37 |
| 2022 October | 16 | 11 | 27 |
| 2022 September | 27 | 30 | 57 |
| 2022 August | 45 | 12 | 57 |
| 2022 July | 21 | 6 | 27 |
| 2022 June | 22 | 6 | 28 |
| 2022 May | 40 | 13 | 53 |
| 2022 April | 54 | 6 | 60 |
| 2022 March | 78 | 8 | 86 |
| 2022 February | 69 | 10 | 79 |
| 2022 January | 52 | 12 | 64 |
| 2021 December | 46 | 14 | 60 |
| 2021 November | 61 | 12 | 73 |
| 2021 October | 40 | 12 | 52 |
| 2021 September | 22 | 14 | 36 |
| 2021 August | 16 | 8 | 24 |
| 2021 July | 13 | 11 | 24 |
| 2021 June | 17 | 9 | 26 |
| 2021 May | 19 | 8 | 27 |
| 2021 April | 17 | 13 | 30 |
| 2021 March | 25 | 12 | 37 |
| 2021 February | 6 | 8 | 14 |
| 2021 January | 13 | 10 | 23 |
| 2020 December | 14 | 16 | 30 |
| 2020 November | 12 | 9 | 21 |
| 2020 October | 8 | 4 | 12 |
| 2020 September | 23 | 26 | 49 |
| 2020 August | 15 | 21 | 36 |
| 2020 July | 26 | 12 | 38 |
| 2020 June | 13 | 6 | 19 |
| 2020 May | 15 | 9 | 24 |
| 2020 April | 8 | 7 | 15 |
| 2020 March | 15 | 3 | 18 |
| 2020 February | 21 | 9 | 30 |
| 2020 January | 16 | 5 | 21 |
| 2019 December | 16 | 16 | 32 |
| 2019 November | 11 | 5 | 16 |
| 2019 October | 7 | 3 | 10 |
| 2019 September | 13 | 6 | 19 |
| 2019 August | 12 | 8 | 20 |
| 2019 July | 11 | 25 | 36 |
| 2019 June | 33 | 12 | 45 |
| 2019 May | 99 | 13 | 112 |
| 2019 April | 21 | 13 | 34 |
| 2019 March | 5 | 7 | 12 |
| 2019 February | 10 | 5 | 15 |
| 2019 January | 4 | 5 | 9 |
| 2018 December | 5 | 5 | 10 |
| 2018 November | 8 | 2 | 10 |
| 2018 October | 7 | 3 | 10 |
| 2018 September | 11 | 7 | 18 |
| 2018 August | 6 | 1 | 7 |
| 2018 July | 3 | 2 | 5 |
| 2018 June | 9 | 1 | 10 |
| 2018 May | 8 | 1 | 9 |
| 2018 April | 7 | 1 | 8 |
| 2018 March | 1 | 1 | 2 |
| 2018 February | 13 | 1 | 14 |
| 2018 January | 12 | 1 | 13 |
| 2017 December | 13 | 1 | 14 |
| 2017 November | 16 | 1 | 17 |
| 2017 October | 15 | 1 | 16 |
| 2017 September | 13 | 0 | 13 |
| 2017 August | 14 | 1 | 15 |
| 2017 July | 16 | 1 | 17 |
| 2017 June | 19 | 4 | 23 |
| 2017 May | 21 | 2 | 23 |
| 2017 April | 16 | 9 | 25 |
| 2017 March | 21 | 14 | 35 |
| 2017 February | 26 | 4 | 30 |
| 2017 January | 11 | 2 | 13 |
| 2016 December | 19 | 2 | 21 |
| 2016 November | 17 | 0 | 17 |
| 2016 October | 18 | 1 | 19 |
| 2016 September | 17 | 1 | 18 |
| 2016 August | 1 | 1 | 2 |
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