{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T17:43:45Z","timestamp":1787247825777,"version":"build-2736575974"},"reference-count":60,"publisher":"SAGE Publications","issue":"12","license":[{"start":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T00:00:00Z","timestamp":1606780800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Thyroxine (T4) to triiodothyronine (T3) deiodination in the hypothalamus\/pituitary is mediated by deiodinase type-2 (D2) activity.\n                      <jats:italic toggle=\"yes\">\n                        Dio2\n                        <jats:sup>(\u2212\/\u2212)<\/jats:sup>\n                      <\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      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-\u03b2 (\n                      <jats:italic toggle=\"yes\">THRB<\/jats:italic>\n                      ) mutations.\n                      <jats:italic toggle=\"yes\">DIO2,<\/jats:italic>\n                      including the Ala92-D2 polymorphism, selenocysteine binding protein 2 (\n                      <jats:italic toggle=\"yes\">SECISBP2<\/jats:italic>\n                      ), and\n                      <jats:italic toggle=\"yes\">THRB<\/jats:italic>\n                      were fully sequenced.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>Eighteen hypothyroid patients (nine of each sex, 3\u201359 years) treated with LT4 showed elevated TSH (15.5\u2009\u00b1\u20094.7\u2009mU\/L; reference range [RR]: 0.4\u20134.5), fT4 (20.8\u2009\u00b1\u20092.4 pM; RR: 9\u201320.6), and TSH\/fT4 ratio (0.74\u2009\u00b1\u20090.25; RR: 0.03\u20130.13). Despite increasing LT4 doses from 1.7\u2009\u00b1\u20091.0 to 2.4\u2009\u00b1\u20091.7\u2009\u03bcg\/kg\/day, TSH remained elevated (6.9\u2009\u00b1\u20092.7\u2009mU\/L). Due to hyperthyroid symptoms, LT4 doses were reduced, and TSH increased again to 7.9\u2009\u00b1\u20093.2\u2009mU\/L. In the euthyroid\/hyperthyrotropinemic state, T3\/T4 and T3\/rT3 ratios were decreased (9.2\u2009\u00b1\u20092.4, RR: 11.3\u201315.3 and 2.5\u2009\u00b1\u20091.4, RR: 7.5\u20138.5, respectively) whereas rT3\/T4 was increased (0.6\u2009\u00b1\u20090.2; RR: 0.43\u20130.49), 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      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 germline\n                      <jats:italic toggle=\"yes\">DIO2<\/jats:italic>\n                      mutations 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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/thy.2019.0825","type":"journal-article","created":{"date-parts":[[2020,6,5]],"date-time":"2020-06-05T03:04:46Z","timestamp":1591326286000},"page":"1732-1744","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":13,"title":["Identification of Resistance to Exogenous Thyroxine in Humans"],"prefix":"10.1177","volume":"30","author":[{"given":"Nerea","family":"Lac\u00e1mara","sequence":"first","affiliation":[{"name":"Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain."},{"name":"The Rare Diseases Networking Biomedical Research Centre (CIBERER), Instituto de Salud Carlos III, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Lecumberri","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, La Paz University Hospital, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Barquiel","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, La Paz University Hospital, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arancha","family":"Escribano","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology, Virgen de la Arrixaca University Hospital, Murcia, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Gonz\u00e1lez-Casado","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology, La Paz University Hospital, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"\u00c1lvarez-Escol\u00e1","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, La Paz University Hospital, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Aleixandre-Blanquer","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology, Elda University Hospital, Alicante, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Morales","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Virgen Del Roc\u00edo University Hospital, Sevilla, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roc\u00edo","family":"Alfayate","sequence":"additional","affiliation":[{"name":"Clinical Chemistry Department, Alicante University Hospital, Alicante, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari Carmen","family":"Bernal-Soriano","sequence":"additional","affiliation":[{"name":"Clinical Chemistry Department, Alicante University Hospital, Alicante, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Miralles","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Alicante University Hospital, Alicante, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilgin","family":"Yildirim Simsir","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism Disorders, Ege University Medical Faculty, Izmir, Turkey."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmet G\u00f6khan","family":"\u00d6zgen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism Disorders, Ege University Medical Faculty, Izmir, Turkey."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Bernal","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Nervous System, Instituto de Investigaciones Biom\u00e9dicas, CSIC, and CIBERER Instituto de Salud Carlos III, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pere","family":"Berbel","sequence":"additional","affiliation":[{"name":"Department of Histology and Anatomy, Faculty of Medicine, Universidad Miguel Hern\u00e1ndez de Elche, Alicante, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Carlos","family":"Moreno","sequence":"additional","affiliation":[{"name":"Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain."},{"name":"The Rare Diseases Networking Biomedical Research Centre (CIBERER), Instituto de Salud Carlos III, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2020,12,7]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2018-00275"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI29812"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2005.15.787"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2012.08.019"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2011.05.016"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1210\/mend.15.12.0740"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI61231"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.138.9.5412"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.1994.4.225"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1210\/mend.11.1.9867"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.137.6.8641203"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2018.04.572"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2017-00618"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1654"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI43653"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2005-0739"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI26240"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2016-2587"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI123176"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yhbeh.2013.11.008"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2006-0448"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2014.0028"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1159\/000339444"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-2111"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1530\/EC-12-0064"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-17-0645"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1159\/000469709"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-0365"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0022552"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13044-015-0023-5"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-16-0007"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0030-1267997"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI108030"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2539642"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI6397"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1186\/1479-5876-9-144"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.50.33374"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-2281"},{"key":"e_1_3_5_40_2","first-page":"351864","article-title":"TSH and thyrotropic agonists: key actors in thyroid homeostasis","volume":"12","author":"Dietrich JW","year":"2012","unstructured":"Dietrich JW, , Landgrafe G, , Fotiadou EH. 2012. TSH and thyrotropic agonists: key actors in thyroid homeostasis. J Thyroid Res, 12:351864.","journal-title":"J Thyroid Res"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI110854"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-66-4-740"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2014.07.001"},{"key":"e_1_3_5_44_2","first-page":"4533","article-title":"Systemic thyroid hormone status during levothyroxine therapy In hypothyroidism: a systematic review and meta-analysis","volume":"103","author":"McAninch EA","year":"2018","unstructured":"McAninch EA, , Rajan KB, , Miller CH, , Bianco AC. 2018. Systemic thyroid hormone status during levothyroxine therapy In hypothyroidism: a systematic review and meta-analysis. J Clin Endocrinol Metab, 103:4533\u20134542.","journal-title":"J Clin Endocrinol Metab"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1159\/000452489"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2013.3393.nomen"},{"key":"e_1_3_5_47_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2012-1504"},{"key":"e_1_3_5_48_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2010-0462"},{"key":"e_1_3_5_49_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2008-1301"},{"key":"e_1_3_5_50_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2016-1043"},{"key":"e_1_3_5_51_2","doi-asserted-by":"publisher","DOI":"10.1159\/000358590"},{"key":"e_1_3_5_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12941"},{"key":"e_1_3_5_53_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.6b01116"},{"key":"e_1_3_5_54_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-018-2595-6"},{"key":"e_1_3_5_55_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI77588"},{"key":"e_1_3_5_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1272"},{"key":"e_1_3_5_57_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01498-08"},{"key":"e_1_3_5_58_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI18348"},{"key":"e_1_3_5_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06356-1"},{"key":"e_1_3_5_60_2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2019.0080"},{"key":"e_1_3_5_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-018-0281-4"}],"container-title":["Thyroid\u00ae"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1089\/thy.2019.0825","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/thy.2019.0825","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/thy.2019.0825","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T22:07:01Z","timestamp":1777586821000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1089\/thy.2019.0825"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12]]},"references-count":60,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["10.1089\/thy.2019.0825"],"URL":"https:\/\/doi.org\/10.1089\/thy.2019.0825","relation":{},"ISSN":["1050-7256","1557-9077"],"issn-type":[{"value":"1050-7256","type":"print"},{"value":"1557-9077","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12]]}}}