Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Impaired sensitivity to thyroid hormone

Samuel Refetoff, MD
Alexandra M Dumitrescu, MD, PhD
Roy E Weiss, MD, PhD
Section Editors
David S Cooper, MD
Douglas S Ross, MD
Deputy Editor
Alison G Hoppin, MD


Impaired sensitivity to thyroid hormone (previously known as reduced sensitivity to thyroid hormone) describes any process that interferes with the effectiveness of thyroid hormone and includes defects in thyroid hormone action, transport, or metabolism [1-4].

The most common category is resistance to thyroid hormone (RTH), a syndrome characterized by reduced intracellular action of T3, the active thyroid hormone. RTH was first identified in 1967 as a syndrome of reduced end-organ responsiveness to thyroid hormone [5] and was subsequently associated with mutations in the gene encoding the beta form of the thyroid hormone receptor (TR-beta) [1,6,7].

Impaired sensitivity to thyroid hormone can be grouped according to the underlying mechanism, as follows (table 1) [8-10]:

Thyroid hormone cell membrane transport defect (THCMTD)

Thyroid hormone metabolism defect (THMD)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Apr 2017. | This topic last updated: May 24, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev 1993; 14:348.
  2. Dumitrescu AM, Liao XH, Best TB, et al. A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet 2004; 74:168.
  3. Friesema EC, Grueters A, Biebermann H, et al. Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet 2004; 364:1435.
  4. Dumitrescu AM, Liao XH, Abdullah MS, et al. Mutations in SECISBP2 result in abnormal thyroid hormone metabolism. Nat Genet 2005; 37:1247.
  5. Refetoff S, DeWind LT, DeGroot LJ. Familial syndrome combining deaf-mutism, stuppled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone. J Clin Endocrinol Metab 1967; 27:279.
  6. Sakurai A, Takeda K, Ain K, et al. Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor beta. Proc Natl Acad Sci U S A 1989; 86:8977.
  7. Usala SJ, Tennyson GE, Bale AE, et al. A base mutation of the C-erbA beta thyroid hormone receptor in a kindred with generalized thyroid hormone resistance. Molecular heterogeneity in two other kindreds. J Clin Invest 1990; 85:93.
  8. Refetoff S, Bassett JH, Beck-Peccoz P, et al. Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism. Thyroid 2014; 24:407.
  9. Refetoff S, Bassett JH, Beck-Peccoz P, et al. Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism. J Clin Endocrinol Metab 2014; 99:768.
  10. Refetoff S, Bassett JH, Beck-Peccoz P, et al. Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism. Eur Thyroid J 2014; 3:7.
  11. Friesema EC, Jansen J, Milici C, Visser TJ. Thyroid hormone transporters. Vitam Horm 2005; 70:137.
  12. Bianco AC, Salvatore D, Gereben B, et al. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 2002; 23:38.
  13. Bassett JH, Harvey CB, Williams GR. Mechanisms of thyroid hormone receptor-specific nuclear and extra nuclear actions. Mol Cell Endocrinol 2003; 213:1.
  14. Zhang J, Lazar MA. The mechanism of action of thyroid hormones. Annu Rev Physiol 2000; 62:439.
  15. Yen PM, Ando S, Feng X, et al. Thyroid hormone action at the cellular, genomic and target gene levels. Mol Cell Endocrinol 2006; 246:121.
  16. Koenig RJ. Thyroid hormone receptor coactivators and corepressors. Thyroid 1998; 8:703.
  17. Di Cosmo C, Liao XH, Dumitrescu AM, et al. Mice deficient in MCT8 reveal a mechanism regulating thyroid hormone secretion. J Clin Invest 2010; 120:3377.
  18. Heuer H, Visser TJ. Minireview: Pathophysiological importance of thyroid hormone transporters. Endocrinology 2009; 150:1078.
  19. Ceballos A, Belinchon MM, Sanchez-Mendoza E, et al. Importance of monocarboxylate transporter 8 for the blood-brain barrier-dependent availability of 3,5,3'-triiodo-L-thyronine. Endocrinology 2009; 150:2491.
  20. Hennemann G, Docter R, Friesema EC, et al. Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocr Rev 2001; 22:451.
  21. Allan W, Herndon CN, Dudley FC. Some examples of the inheritance of mental deficiency: apparently sex-linked idiocy and microcephaly. Am J Ment Defic 1944; 48:325.
  22. Kakinuma H, Itoh M, Takahashi H. A novel mutation in the monocarboxylate transporter 8 gene in a boy with putamen lesions and low free T4 levels in cerebrospinal fluid. J Pediatr 2005; 147:552.
  23. Visser WE, Friesema EC, Jansen J, Visser TJ. Thyroid hormone transport in and out of cells. Trends Endocrinol Metab 2008; 19:50.
  24. Papadimitriou A, Dumitrescu AM, Papavasiliou A, et al. A novel monocarboxylate transporter 8 gene mutation as a cause of severe neonatal hypotonia and developmental delay. Pediatrics 2008; 121:e199.
  25. Frints SG, Lenzner S, Bauters M, et al. MCT8 mutation analysis and identification of the first female with Allan-Herndon-Dudley syndrome due to loss of MCT8 expression. Eur J Hum Genet 2008; 16:1029.
  26. Friesema EC, Ganguly S, Abdalla A, et al. Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter. J Biol Chem 2003; 278:40128.
  27. Jansen J, Friesema EC, Kester MH, et al. Genotype-phenotype relationship in patients with mutations in thyroid hormone transporter MCT8. Endocrinology 2008; 149:2184.
  28. Dumitrescu AM, Liao XH, Weiss RE, et al. Tissue-specific thyroid hormone deprivation and excess in monocarboxylate transporter (mct) 8-deficient mice. Endocrinology 2006; 147:4036.
  29. Trajkovic M, Visser TJ, Mittag J, et al. Abnormal thyroid hormone metabolism in mice lacking the monocarboxylate transporter 8. J Clin Invest 2007; 117:627.
  30. Bernal J. Role of monocarboxylate anion transporter 8 (MCT8) in thyroid hormone transport: Answers from mice. Endocrinology 2006; 147:4034.
  31. Brockmann K, Dumitrescu AM, Best TT, et al. X-linked paroxysmal dyskinesia and severe global retardation caused by defective MCT8 gene. J Neurol 2005; 252:663.
  32. Herzovich V, Vaiani E, Marino R, et al. Unexpected peripheral markers of thyroid function in a patient with a novel mutation of the MCT8 thyroid hormone transporter gene. Horm Res 2007; 67:1.
  33. Gika AD, Siddiqui A, Hulse AJ, et al. White matter abnormalities and dystonic motor disorder associated with mutations in the SLC16A2 gene. Dev Med Child Neurol 2010; 52:475.
  34. Holden KR, Zuñiga OF, May MM, et al. X-linked MCT8 gene mutations: characterization of the pediatric neurologic phenotype. J Child Neurol 2005; 20:852.
  35. Namba N, Etani Y, Kitaoka T, et al. Clinical phenotype and endocrinological investigations in a patient with a mutation in the MCT8 thyroid hormone transporter. Eur J Pediatr 2008; 167:785.
  36. Vaurs-Barrière C, Deville M, Sarret C, et al. Pelizaeus-Merzbacher-Like disease presentation of MCT8 mutated male subjects. Ann Neurol 2009; 65:114.
  37. Wémeau JL, Pigeyre M, Proust-Lemoine E, et al. Beneficial effects of propylthiouracil plus L-thyroxine treatment in a patient with a mutation in MCT8. J Clin Endocrinol Metab 2008; 93:2084.
  38. Di Cosmo C, Liao XH, Dumitrescu AM, et al. A thyroid hormone analog with reduced dependence on the monocarboxylate transporter 8 for tissue transport. Endocrinology 2009; 150:4450.
  39. Verge CF, Konrad D, Cohen M, et al. Diiodothyropropionic acid (DITPA) in the treatment of MCT8 deficiency. J Clin Endocrinol Metab 2012; 97:4515.
  40. Koenig RJ. Regulation of type 1 iodothyronine deiodinase in health and disease. Thyroid 2005; 15:835.
  41. Copeland PR. Regulation of gene expression by stop codon recoding: selenocysteine. Gene 2003; 312:17.
  42. Lescure A, Allmang C, Yamada K, et al. cDNA cloning, expression pattern and RNA binding analysis of human selenocysteine insertion sequence (SECIS) binding protein 2. Gene 2002; 291:279.
  43. Bianco AC, Kim BW. Deiodinases: implications of the local control of thyroid hormone action. J Clin Invest 2006; 116:2571.
  44. Di Cosmo C, McLellan N, Liao XH, et al. Clinical and molecular characterization of a novel selenocysteine insertion sequence-binding protein 2 (SBP2) gene mutation (R128X). J Clin Endocrinol Metab 2009; 94:4003.
  45. Schoenmakers E, Agostini M, Mitchell C, et al. Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans. J Clin Invest 2010; 120:4220.
  46. Azevedo MF, Barra GB, Naves LA, et al. Selenoprotein-related disease in a young girl caused by nonsense mutations in the SBP2 gene. J Clin Endocrinol Metab 2010; 95:4066.
  47. Köhrle J. Selenium and the control of thyroid hormone metabolism. Thyroid 2005; 15:841.
  48. Saito Y, Shichiri M, Hamajima T, et al. Enhancement of lipid peroxidation and its amelioration by vitamin E in a subject with mutations in the SBP2 gene. J Lipid Res 2015; 56:2172.
  49. Schomburg L, Dumitrescu AM, Liao XH, et al. Selenium supplementation fails to correct the selenoprotein synthesis defect in subjects with SBP2 gene mutations. Thyroid 2009; 19:277.
  50. Hamajima T, Mushimoto Y, Kobayashi H, et al. Novel compound heterozygous mutations in the SBP2 gene: characteristic clinical manifestations and the implications of GH and triiodothyronine in longitudinal bone growth and maturation. Eur J Endocrinol 2012; 166:757.
  51. Beck-Peccoz P, Chatterjee VK. The variable clinical phenotype in thyroid hormone resistance syndrome. Thyroid 1994; 4:225.
  52. Lafranchi SH, Snyder DB, Sesser DE, et al. Follow-up of newborns with elevated screening T4 concentrations. J Pediatr 2003; 143:296.
  53. Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metab 2007; 21:277.
  54. Flamant F, Samarut J. Thyroid hormone receptors: lessons from knockout and knock-in mutant mice. Trends Endocrinol Metab 2003; 14:85.
  55. Wikström L, Johansson C, Saltó C, et al. Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1. EMBO J 1998; 17:455.
  56. Weiss RE, Murata Y, Cua K, et al. Thyroid hormone action on liver, heart, and energy expenditure in thyroid hormone receptor beta-deficient mice. Endocrinology 1998; 139:4945.
  57. Takeda K, Sakurai A, DeGroot LJ, Refetoff S. Recessive inheritance of thyroid hormone resistance caused by complete deletion of the protein-coding region of the thyroid hormone receptor-beta gene. J Clin Endocrinol Metab 1992; 74:49.
  58. Ando S, Sarlis NJ, Oldfield EH, Yen PM. Somatic mutation of TRbeta can cause a defect in negative regulation of TSH in a TSH-secreting pituitary tumor. J Clin Endocrinol Metab 2001; 86:5572.
  59. Weiss RE, Marcocci C, Bruno-Bossio G, Refetoff S. Multiple genetic factors in the heterogeneity of thyroid hormone resistance. J Clin Endocrinol Metab 1993; 76:257.
  60. Weiss RE, Hayashi Y, Nagaya T, et al. Dominant inheritance of resistance to thyroid hormone not linked to defects in the thyroid hormone receptor alpha or beta genes may be due to a defective cofactor. J Clin Endocrinol Metab 1996; 81:4196.
  61. Reutrakul S, Sadow PM, Pannain S, et al. Search for abnormalities of nuclear corepressors, coactivators, and a coregulator in families with resistance to thyroid hormone without mutations in thyroid hormone receptor beta or alpha genes. J Clin Endocrinol Metab 2000; 85:3609.
  62. Persani L, Borgato S, Romoli R, et al. Changes in the degree of sialylation of carbohydrate chains modify the biological properties of circulating thyrotropin isoforms in various physiological and pathological states. J Clin Endocrinol Metab 1998; 83:2486.
  63. Hayashi Y, Weiss RE, Sarne DH, et al. Do clinical manifestations of resistance to thyroid hormone correlate with the functional alteration of the corresponding mutant thyroid hormone-beta receptors? J Clin Endocrinol Metab 1995; 80:3246.
  64. Ercan-Fang S, Schwartz HL, Mariash CN, Oppenheimer JH. Quantitative assessment of pituitary resistance to thyroid hormone from plots of the logarithm of thyrotropin versus serum free thyroxine index. J Clin Endocrinol Metab 2000; 85:2299.
  65. Brucker-Davis F, Skarulis MC, Grace MB, et al. Genetic and clinical features of 42 kindreds with resistance to thyroid hormone. The National Institutes of Health Prospective Study. Ann Intern Med 1995; 123:572.
  66. Mitchell CS, Savage DB, Dufour S, et al. Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia. J Clin Invest 2010; 120:1345.
  67. Yagi H, Pohlenz J, Hayashi Y, et al. Resistance to thyroid hormone caused by two mutant thyroid hormone receptors beta, R243Q and R243W, with marked impairment of function that cannot be explained by altered in vitro 3,5,3'-triiodothyroinine binding affinity. J Clin Endocrinol Metab 1997; 82:1608.
  68. Yoh SM, Chatterjee VK, Privalsky ML. Thyroid hormone resistance syndrome manifests as an aberrant interaction between mutant T3 receptors and transcriptional corepressors. Mol Endocrinol 1997; 11:470.
  69. Tagami T, Gu WX, Peairs PT, et al. A novel natural mutation in the thyroid hormone receptor defines a dual functional domain that exchanges nuclear receptor corepressors and coactivators. Mol Endocrinol 1998; 12:1888.
  70. Hauser P, Zametkin AJ, Martinez P, et al. Attention deficit-hyperactivity disorder in people with generalized resistance to thyroid hormone. N Engl J Med 1993; 328:997.
  71. Abel ED, Boers ME, Pazos-Moura C, et al. Divergent roles for thyroid hormone receptor beta isoforms in the endocrine axis and auditory system. J Clin Invest 1999; 104:291.
  72. Campi I, Cammarata G, Bianchi Marzoli S, et al. Retinal photoreceptor functions are compromised in patients with resistance to thyroid hormone syndrome (RTHβ). J Clin Endocrinol Metab 2017.
  73. Barkoff MS, Kocherginsky M, Anselmo J, et al. Autoimmunity in patients with resistance to thyroid hormone. J Clin Endocrinol Metab 2010; 95:3189.
  74. Beck-Peccoz P, Brucker-Davis F, Persani L, et al. Thyrotropin-secreting pituitary tumors. Endocr Rev 1996; 17:610.
  75. Anselmo J, Refetoff S. Regression of a large goiter in a patient with resistance to thyroid hormone by every other day treatment with triiodothyronine. Thyroid 2004; 14:71.
  76. Anselmo J, Cao D, Karrison T, et al. Fetal loss associated with excess thyroid hormone exposure. JAMA 2004; 292:691.
  77. Vaidya B, Campbell V, Tripp JH, et al. Premature birth and low birth weight associated with nonautoimmune hyperthyroidism due to an activating thyrotropin receptor gene mutation. Clin Endocrinol (Oxf) 2004; 60:711.
  78. Weiss RE, Dumitrescu A, Refetoff S. Approach to the patient with resistance to thyroid hormone and pregnancy. J Clin Endocrinol Metab 2010; 95:3094.
  79. Bochukova E, Schoenmakers N, Agostini M, et al. A mutation in the thyroid hormone receptor alpha gene. N Engl J Med 2012; 366:243.
  80. Moran C, Chatterjee K. Resistance to thyroid hormone due to defective thyroid receptor alpha. Best Pract Res Clin Endocrinol Metab 2015; 29:647.
  81. Demir K, van Gucht AL, Büyükinan M, et al. Diverse Genotypes and Phenotypes of Three Novel Thyroid Hormone Receptor-α Mutations. J Clin Endocrinol Metab 2016; 101:2945.
  82. Espiard S, Savagner F, Flamant F, et al. A Novel Mutation in THRA Gene Associated With an Atypical Phenotype of Resistance to Thyroid Hormone. J Clin Endocrinol Metab 2015; 100:2841.
  83. van Gucht AL, Meima ME, Zwaveling-Soonawala N, et al. Resistance to Thyroid Hormone Alpha in an 18-Month-Old Girl: Clinical, Therapeutic, and Molecular Characteristics. Thyroid 2016; 26:338.