1932

Abstract

Levothyroxine (LT4) is effective for most patients with hypothyroidism. However, a minority of the patients remain symptomatic despite the normalization of serum thyrotropin levels. Randomized clinical trials including all types of patients with hypothyroidism revealed that combination levothyroxine and liothyronine (LT4+LT3) therapy is safe and is the preferred choice of patients versus LT4 alone. Many patients who do not fully benefit from LT4 experience improved quality of life and cognition after switching to LT4+LT3. For these patients, new slow-release LT3 formulations that provide stable serum T3 levels are being tested. In addition, progress in regenerative technology has led to the development of human thyroid organoids that restore euthyroidism after being transplanted into hypothyroid mice. Finally, there is a new understanding that, under certain conditions, T3 signaling may be compromised in a tissue-specific fashion while systemic thyroid function is preserved. This is seen, for example, in patients with metabolic (dysfunction)-associated fatty liver disease, for whom liver-selective T3-like molecules have been utilized successfully in clinical trials.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-060622-101007
2024-01-29
2024-04-16
Loading full text...

Full text loading...

/deliver/fulltext/med/75/1/annurev-med-060622-101007.html?itemId=/content/journals/10.1146/annurev-med-060622-101007&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Chaker L, Bianco AC, Jonklaas J, Peeters RP. 2017. Hypothyroidism. Lancet 390:155062
    [Google Scholar]
  2. 2.
    Huang SA, Bianco AC. 2008. Reawakened interest in type III iodothyronine deiodinase in critical illness and injury. Nat. Clin. Pract. Endocrinol. Metab. 4:14855
    [Google Scholar]
  3. 3.
    Jonklaas J, Bianco AC, Bauer AJ et al. 2014. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid 24:1670751
    [Google Scholar]
  4. 4.
    Bianco AC. 2022. Rethinking Hypothyroidism Chicago: Univ. Chicago Press311 pp.
  5. 5.
    Saravanan P, Chau WF, Roberts N et al. 2002. Psychological well-being in patients on ‘adequate’ doses of L-thyroxine: results of a large, controlled community-based questionnaire study. Clin. Endocrinol. 57:57785
    [Google Scholar]
  6. 6.
    Wekking EM, Appelhof BC, Fliers E et al. 2005. Cognitive functioning and well-being in euthyroid patients on thyroxine replacement therapy for primary hypothyroidism. Eur. J. Endocrinol. 153:74753
    [Google Scholar]
  7. 7.
    Samuels MH, Schuff KG, Carlson NE et al. 2007. Health status, psychological symptoms, mood, and cognition in L-thyroxine-treated hypothyroid subjects. Thyroid 17:24958
    [Google Scholar]
  8. 8.
    Peterson SJ, Cappola AR, Castro MR et al. 2018. An online survey of hypothyroid patients demonstrates prominent dissatisfaction. Thyroid 28:70721
    [Google Scholar]
  9. 9.
    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. 103:453342
    [Google Scholar]
  10. 10.
    Peterson SJ, McAninch EA, Bianco AC. 2016. Is a normal TSH synonymous with “euthyroidism” in levothyroxine monotherapy?. J. Clin. Endocrinol. Metab. 101:496473
    [Google Scholar]
  11. 11.
    Idrees T, Prieto WH, Casula S et al. 2021. Use of statins among patients taking levothyroxine: an observational drug utilization study across sites. J. Endocr. Soc. 5:bvab038
    [Google Scholar]
  12. 12.
    Taylor S, Kapur M, Adie R. 1970. Combined thyroxine and triiodothyronine for thyroid replacement therapy. BMJ 2:27071
    [Google Scholar]
  13. 13.
    Taylor S. 1961. A new thyroid preparation. Lancet 277:341
    [Google Scholar]
  14. 14.
    Wool MS, Selenkow HA. 1965. Physiologic combinations of synthetic thyroid hormones in myxedema. Clin. Pharmacol. Ther. 6:71015
    [Google Scholar]
  15. 15.
    Lan H, Wen J, Mao Y et al. 2022. Combined T4+T3 therapy versus T4 monotherapy effect on psychological health in hypothyroidism: a systematic review and meta-analysis. Clin. Endocrinol. 97:1325
    [Google Scholar]
  16. 16.
    Millan-Alanis JM, Gonzalez-Gonzalez JG, Flores-Rodríguez A et al. 2021. Benefits and harms of levothyroxine/L-triiothyronine versus levothyroxine monotherapy for adult patients with hypothyroidism: systematic review and meta-analysis. Thyroid 31:161325
    [Google Scholar]
  17. 17.
    Gereben B, McAninch EA, Ribeiro MO, Bianco AC. 2015. Scope and limitations of iodothyronine deiodinases in hypothyroidism. Nat. Rev. Endocrinol. 11:64252
    [Google Scholar]
  18. 18.
    Christoffolete MA, Arrojo e Drigo R, Gazoni F et al. 2007. Mice with impaired extrathyroidal thyroxine to 3,5,3′-triiodothyronine conversion maintain normal serum 3,5,3′-triiodothyronine concentrations. Endocrinology 148:95460
    [Google Scholar]
  19. 19.
    Galton VA, Schneider M, Clark AS, Germain DL. 2009. Life without T4 to T3 conversion: studies in mice devoid of the 5′-deiodinases. Endocrinology 150:295763
    [Google Scholar]
  20. 20.
    Chopra IJ, Hershman JM, Hornabrook RW. 1975. Serum thyroid hormone and thyrotropin levels in subjects from endemic goiter regions of New Guinea. J. Clin. Endocrinol. Metab. 40:32633
    [Google Scholar]
  21. 21.
    Stock JM, Surks MI, Oppenheimer JH. 1974. Replacement dosage of L-thyroxine in hypothyroidism. A re-evaluation. N. Engl. J. Med. 290:52933
    [Google Scholar]
  22. 22.
    Gullo D, Latina A, Frasca F et al. 2011. Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLOS ONE 6:e22552
    [Google Scholar]
  23. 23.
    Garber JR, Cobin RH, Gharib H et al. 2012. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid 22:120035
    [Google Scholar]
  24. 24.
    Jonklaas J, Davidson B, Bhagat S, Soldin SJ. 2008. Triiodothyronine levels in athyreotic individuals during levothyroxine therapy. JAMA 299:76977
    [Google Scholar]
  25. 25.
    Werneck de Castro JP, Fonseca TL, Ueta CB et al. 2015. Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine. J. Clin. Investig. 125:76981
    [Google Scholar]
  26. 26.
    Ettleson MD, Prieto WH, Russo PST et al. 2022. Serum thyrotropin and triiodothyronine levels in levothyroxine-treated patients. J. Clin. Endocrinol. Metab. 108:e25866
    [Google Scholar]
  27. 27.
    Panicker V, Saravanan P, Vaidya B et al. 2009. Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients. J. Clin. Endocrinol. Metab. 94:162329
    [Google Scholar]
  28. 28.
    Jo S, Fonseca TL, Bocco B et al. 2019. Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain. J. Clin. Investig. 129:23045
    [Google Scholar]
  29. 29.
    Castagna MG, Dentice M, Cantara S et al. 2017. DIO2 Thr92Ala reduces deiodinase-2 activity and serum-T3 levels in thyroid-deficient patients. J. Clin. Endocrinol. Metab. 102:162330
    [Google Scholar]
  30. 30.
    Bianco AC, Kim BS. 2018. Pathophysiological relevance of deiodinase polymorphism. Curr. Opin. Endocrinol. Diabetes Obes. 25:34146
    [Google Scholar]
  31. 31.
    Ettleson MD, Bianco AC. 2020. Individualized therapy for hypothyroidism: Is T4 enough for everyone?. J. Clin. Endocrinol. Metab. 105:e3090104
    [Google Scholar]
  32. 32.
    Jonklaas J, Bianco AC, Cappola AR et al. 2021. Evidence-based use of levothyroxine/liothyronine combinations in treating hypothyroidism: a consensus document. Thyroid 31:15682
    [Google Scholar]
  33. 33.
    Ahluwalia R, Baldeweg SE, Boelaert K et al. 2023. Use of liothyronine (T3) in hypothyroidism: joint British Thyroid Association/Society for Endocrinology consensus statement. Clin. Endocrinol. 99:20616
    [Google Scholar]
  34. 34.
    Casula S, Ettelson M, Bianco AC. 2023. Are we restoring thyroid hormone signaling in LT4-treated patients with residual symptoms of hypothyroidism?. Endocr. Pract. 29:58188
    [Google Scholar]
  35. 35.
    Wiersinga WM, Duntas L, Fadeyev V et al. 2012. 2012 ETA guidelines: the use of L-T4 + L-T3 in the treatment of hypothyroidism. Eur. Thyroid J. 1:5571
    [Google Scholar]
  36. 36.
    Ettelson M, Ibarra S, Wan W et al. 2023. Demographic, healthcare access, and dietary factors associated with different types of thyroid hormone treatment in the US. J. Clin. Endocrinol. Metab. In press
    [Google Scholar]
  37. 37.
    Perros P, Van Der Feltz-Cornelis C, Papini E et al. 2023. The enigma of persistent symptoms in hypothyroid patients treated with levothyroxine: a narrative review. Clin. Endocrinol. 98:46168
    [Google Scholar]
  38. 38.
    Jansen HI, Boelen A, Heijboer AC et al. 2023. Hypothyroidism: the difficulty in attributing symptoms to their underlying cause. Front. Endocrinol. 14:1130661
    [Google Scholar]
  39. 39.
    Kahaly GJ, Gottwald-Hostalek U. 2022. Use of levothyroxine in the management of hypothyroidism: a historical perspective. Front. Endocrinol. 13:1054983
    [Google Scholar]
  40. 40.
    Jonklaas J. 2022. Role of levothyroxine/liothyronine combinations in treating hypothyroidism. Endocrinol. Metab. Clin. North Am. 51:24363
    [Google Scholar]
  41. 41.
    Jonklaas J. 2022. Optimal thyroid hormone replacement. Endocr. Rev. 43:366404
    [Google Scholar]
  42. 42.
    Dayan C, Panicker V. 2018. Management of hypothyroidism with combination thyroxine (T4) and triiodothyronine (T3) hormone replacement in clinical practice: a review of suggested guidance. Thyroid Res 11:1
    [Google Scholar]
  43. 43.
    Shakir MKM, Brooks DI, McAninch EA et al. 2021. Comparative effectiveness of levothyroxine, desiccated thyroid extract, and levothyroxine+liothyronine in hypothyroidism. J. Clin. Endocrinol. Metab. 106:e440013
    [Google Scholar]
  44. 44.
    Hoang TD, Olsen CH, Mai VQ et al. 2013. Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomized, double-blind, crossover study. J. Clin. Endocrinol. Metab. 98:198290
    [Google Scholar]
  45. 45.
    O'Sullivan A, Brazg R, Horowitz B et al. 2022. Dose-conversion from LT4 to armour thyroid. Thyroid 32:A17 Abstr. )
    [Google Scholar]
  46. 46.
    Brazg R, O'Sullivan A, Horowitz B et al. 2022. Primary results from a phase 2 study of armour thyroid in patients with hypothyroidism: the Arch study. Thyroid 32:A54 Abstr .)
    [Google Scholar]
  47. 47.
    Kuye R, Riggs C, King J et al. 2020. Thyroid stimulating hormone stability in patients prescribed synthetic or desiccated thyroid products: a retrospective study. Ann. Fam. Med. 18:45254
    [Google Scholar]
  48. 48.
    Idrees T, Palmer S, Maciel RMB, Bianco AC. 2020. Liothyronine and desiccated thyroid extract in the treatment of hypothyroidism. Thyroid 30:1399413
    [Google Scholar]
  49. 49.
    Heald AH, Premawardhana L, Taylor P et al. 2021. Is there a role for natural desiccated thyroid in the treatment of levothyroxine unresponsive hypothyroidism? Results from a consecutive case series. Int. J. Clin. Pract. 75:e14967
    [Google Scholar]
  50. 50.
    Van Tassell B, Wohlford GF, Linderman JD et al. 2019. Pharmacokinetics of L-triiodothyronine in patients undergoing thyroid hormone therapy withdrawal. Thyroid 29:137179
    [Google Scholar]
  51. 51.
    Leese GP, Soto-Pedre E, Donnelly LA. 2016. Liothyronine use in a 17 year observational population-based study—the tears study. Clin. Endocrinol. 85:91825
    [Google Scholar]
  52. 52.
    Planck T, Hedberg F, Calissendorff J, Nilsson A. 2021. Liothyronine use in hypothyroidism and its effects on cancer and mortality. Thyroid 31:73239
    [Google Scholar]
  53. 53.
    Yi W, Kim BH, Kim M et al. 2022. Heart failure and stroke risks in users of liothyronine with or without levothyroxine compared with levothyroxine alone: a propensity score-matched analysis. Thyroid 32:76471
    [Google Scholar]
  54. 54.
    Bakhteyar H, Cassone C, Kohan HG, Sani SN. 2017. Kinetic analysis of drug release from compounded slow-release capsules of liothyronine sodium (T3). Int. J. Pharm. Compd. 21:41825
    [Google Scholar]
  55. 55.
    Hennemann G, Docter R, Visser TJ et al. 2004. Thyroxine plus low-dose, slow-release triiodothyronine replacement in hypothyroidism: proof of principle. Thyroid 14:27175
    [Google Scholar]
  56. 56.
    Jonklaas J, Burman KD, Wang H, Latham KR. 2015. Single-dose T3 administration: kinetics and effects on biochemical and physiological parameters. Ther. Drug Monit. 37:11018
    [Google Scholar]
  57. 57.
    Sekura RD, Sato K, Cahnmann HJ et al. 1981. Sulfate transfer to thyroid hormones and their analogs by hepatic aryl sulfotransferases. Endocrinology 108:45456
    [Google Scholar]
  58. 58.
    Santini F, Chopra IJ, Wu SY et al. 1992. Metabolism of 3,5,3′-triiodothyronine sulfate by tissues of the fetal rat: a consideration of the role of desulfation of 3,5,3′-triiodothyronine sulfate as a source of T3. Pediatr. Res. 31:54144
    [Google Scholar]
  59. 59.
    Peeters RP, Visser TJ 2017. Metabolism of thyroid hormone. Endotext KR Feingold, B Anawalt, MR Blackman et al. South Dartmouth, MA: MDText.com, Inc https://www.ncbi.nlm.nih.gov/books/NBK285545/
    [Google Scholar]
  60. 60.
    Santini F, Hurd RE, Lee B, Chopra IJ. 1993. Thyromimetic effects of 3,5,3′-triiodothyronine sulfate in hypothyroid rats. Endocrinology 133:10510
    [Google Scholar]
  61. 61.
    Santini F, Giannetti M, Ricco I et al. 2014. Steady state serum T3 concentrations for 48 hours following the oral administration of a single dose of 3,5,3′-triiodothyronine sulfate (T3S). Endocr. Pract. 20:68089
    [Google Scholar]
  62. 62.
    Santini F, Ceccarini G, Pelosini C et al. 2019. Treatment of hypothyroid patients with L-thyroxine (L-T4) plus triiodothyronine sulfate (T3S). A phase II, open-label, single center, parallel groups study on therapeutic efficacy and tolerability. Front. Endocrinol. 10:826
    [Google Scholar]
  63. 63.
    Da Conceicao RR, Fernandes GW, Fonseca TL et al. 2018. Metal coordinated poly-zinc-liothyronine provides stable circulating triiodothyronine levels in hypothyroid rats. Thyroid 28:142533
    [Google Scholar]
  64. 64.
    Dumitrescu AM, Hanlon EC, Arosemena M et al. 2022. Extended absorption of liothyronine from poly-zinc-liothyronine: results from a phase 1, double-blind, randomized, and controlled study in humans. Thyroid 32:196205
    [Google Scholar]
  65. 65.
    Zhao J, Ren Y, Ge Z et al. 2023. Thyroid organoids: advances and applications. Endokrynol. Pol. 74:12127
    [Google Scholar]
  66. 66.
    Longmire TA, Ikonomou L, Hawkins F et al. 2012. Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells. Cell Stem Cell 10:398411
    [Google Scholar]
  67. 67.
    Antonica F, Kasprzyk DF, Opitz R et al. 2012. Generation of functional thyroid from embryonic stem cells. Nature 491:6671
    [Google Scholar]
  68. 68.
    Kurmann AA, Serra M, Hawkins F et al. 2015. Regeneration of thyroid function by transplantation of differentiated pluripotent stem cells. Cell Stem Cell 17:52742
    [Google Scholar]
  69. 69.
    Romitti M, Tourneur A, de Faria da Fonseca B et al. 2022. Transplantable human thyroid organoids generated from embryonic stem cells to rescue hypothyroidism. Nat. Commun. 13:7057
    [Google Scholar]
  70. 70.
    Yang Y, Opara EC, Liu Y et al. 2017. Microencapsulation of porcine thyroid cell organoids within a polymer microcapsule construct. Exp. Biol. Med. 242:28696
    [Google Scholar]
  71. 71.
    Zhu HT, Lu L, Liu XY et al. 2015. Treatment of diabetes with encapsulated pig islets: an update on current developments. J. Zhejiang Univ. Sci. B 16:32943
    [Google Scholar]
  72. 72.
    Shimoda M, Matsumoto S. 2017. Microencapsulation in clinical islet xenotransplantation. Methods Mol. Biol. 1479:33545
    [Google Scholar]
  73. 73.
    Crunkhorn S, Dearie F, Mantzoros C et al. 2007. Peroxisome proliferator activator receptor gamma coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation. J. Biol. Chem. 282:1543950
    [Google Scholar]
  74. 74.
    Pihlajamaki J, Boes T, Kim EY et al. 2009. Thyroid hormone-related regulation of gene expression in human fatty liver. J. Clin. Endocrinol. Metab. 94:352129
    [Google Scholar]
  75. 75.
    Castillo M, Freitas BC, Rosene ML et al. 2010. Impaired metabolic effects of a thyroid hormone receptor beta-selective agonist in a mouse model of diet-induced obesity. Thyroid 20:54553
    [Google Scholar]
  76. 76.
    Sinha RA, You SH, Zhou J et al. 2012. Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy. J. Clin. Investig. 122:242838
    [Google Scholar]
  77. 77.
    Bruinstroop E, Dalan R, Cao Y et al. 2018. Low-dose levothyroxine reduces intrahepatic lipid content in patients with type 2 diabetes mellitus and NAFLD. J. Clin. Endocrinol. Metab. 103:2698706
    [Google Scholar]
  78. 78.
    Chaves C, Bruinstroop E, Refetoff S et al. 2021. Increased hepatic fat content in patients with resistance to thyroid hormone beta. Thyroid 31:112734
    [Google Scholar]
  79. 79.
    Trost SU, Swanson E, Gloss B et al. 2000. The thyroid hormone receptor-beta-selective agonist GC-1 differentially affects plasma lipids and cardiac activity. Endocrinology 141:305764
    [Google Scholar]
  80. 80.
    Zhou J, Waskowicz LR, Lim A et al. 2019. A liver-specific thyromimetic, VK2809, decreases hepatosteatosis in glycogen storage disease type Ia. Thyroid 29:115867
    [Google Scholar]
  81. 81.
    Harrison SA, Bashir MR, Guy CD et al. 2019. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 394:201224
    [Google Scholar]
  82. 82.
    Finan B, Clemmensen C, Zhu Z et al. 2016. Chemical hybridization of glucagon and thyroid hormone optimizes therapeutic impact for metabolic disease. Cell 167:84357.e14
    [Google Scholar]
/content/journals/10.1146/annurev-med-060622-101007
Loading
  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error