open access

Ahead of print
Review paper
Submitted: 2021-08-03
Accepted: 2021-09-20
Published online: 2021-10-22
Get Citation

Liothyronine use in primary hypothyroidism. Current concepts

Marcio José Concepción-Zavaleta1, Sofía Pilar Ildefonso-Najarro2, José Luis Paz-Ibarra3, Freddy Roynall Valdivia Fernández-Dávila2, Diana Carolina Deutz Gómez-Condori2, Katia Eugenia Rivera-Fabián2, Ramiro Grimaldo Herrera-Cabezas4, Luis Alberto Concepción-Urteaga5
DOI: 10.5603/EP.a2021.0093
Affiliations
  1. Division of Endocrinology. Clínica Stella Maris, Paso de los Andes 923 Avenue, 15084 Lima, Peru
  2. Division of Endocrinology. Hospital Nacional Guillermo Almenara Irigoyen, Lima, Peru
  3. Division of Endocrinology. Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru
  4. Division of Internal Medicine. Hospital Nacional Guillermo Almenara Irigoyen, Lima, Peru
  5. School of Medicine. Universidad Nacional de Trujillo, Trujillo, Peru

open access

Ahead of print
Review Article
Submitted: 2021-08-03
Accepted: 2021-09-20
Published online: 2021-10-22

Abstract

Hypothyroidism is an endocrine disorder whose management raises many challenges in clinical practice. Its standard treatment is levothyroxine (LT4). The goal of the treatment is to normalize signs and symptoms, as well as to achieve thyroid-stimulating hormone (TSH) concentrations within the reference range, on an individual basis. It is known that 5–10 % of hypothyroid patients remain to be symptomatic, despite achieving the target TSH levels, which, in turn, affects their quality of life. After ruling out other causes of non-thyroid origin for this persistence, it is suggested that these patients could benefit from the use of liothyronine (LT3), added to LT4, especially if polymorphism of the deiodinase 2 (D2) genes is documented. There exist a variety of LT3 preparations, whose concentrations vary from 5 to 50 ug, with the recommended LT4/LT3 ratio of 13:1–20:1. The goals of combination therapy should be to achieve a physiological ratio of free triiodothyronine/free thyroxine (FT3/FT4) and non-suppression of TSH. Since there is currently no guide that makes evidence-based recommendations on the use of LT3 in primary hypothyroidism, more clinical studies are needed to be able to identify hypothyroid patients who may benefit from the use of LT3, by identifying new biomarkers.

Abstract

Hypothyroidism is an endocrine disorder whose management raises many challenges in clinical practice. Its standard treatment is levothyroxine (LT4). The goal of the treatment is to normalize signs and symptoms, as well as to achieve thyroid-stimulating hormone (TSH) concentrations within the reference range, on an individual basis. It is known that 5–10 % of hypothyroid patients remain to be symptomatic, despite achieving the target TSH levels, which, in turn, affects their quality of life. After ruling out other causes of non-thyroid origin for this persistence, it is suggested that these patients could benefit from the use of liothyronine (LT3), added to LT4, especially if polymorphism of the deiodinase 2 (D2) genes is documented. There exist a variety of LT3 preparations, whose concentrations vary from 5 to 50 ug, with the recommended LT4/LT3 ratio of 13:1–20:1. The goals of combination therapy should be to achieve a physiological ratio of free triiodothyronine/free thyroxine (FT3/FT4) and non-suppression of TSH. Since there is currently no guide that makes evidence-based recommendations on the use of LT3 in primary hypothyroidism, more clinical studies are needed to be able to identify hypothyroid patients who may benefit from the use of LT3, by identifying new biomarkers.

Get Citation

Keywords

liothyronine, levothyroxine, hypothyroidism, deiodinase

About this article
Title

Liothyronine use in primary hypothyroidism. Current concepts

Journal

Endokrynologia Polska

Issue

Ahead of print

Article type

Review paper

Published online

2021-10-22

DOI

10.5603/EP.a2021.0093

Keywords

liothyronine
levothyroxine
hypothyroidism
deiodinase

Authors

Marcio José Concepción-Zavaleta
Sofía Pilar Ildefonso-Najarro
José Luis Paz-Ibarra
Freddy Roynall Valdivia Fernández-Dávila
Diana Carolina Deutz Gómez-Condori
Katia Eugenia Rivera-Fabián
Ramiro Grimaldo Herrera-Cabezas
Luis Alberto Concepción-Urteaga

References (46)
  1. Unnikrishnan AG, Kalra S, Sahay RK, et al. Prevalence of hypothyroidism in adults: An epidemiological study in eight cities of India. Indian J Endocrinol Metab. 2013; 17(4): 647–652.
  2. Santago C. Prevalence of thyroid dysfunction in the elderly population of an outpatient clinic. Acta Méd Colomb. 2018; 43(1): 24–30.
  3. Taylor PN, Eligar V, Muller I, et al. Combination Thyroid Hormone Replacement; Knowns and Unknowns. Front Endocrinol (Lausanne). 2019; 10: 706.
  4. Heald A, Livingston M, Hughes D. Management of Patients Symptomatically Unresponsive to Levothyroxine: Natural Desiccated Thyroid Extract or the Combination of Levothyroxine and Liothyronine? A Research Priority. Exp Clin Endocrinol Diabetes. 2020; 128(9): 596–598.
  5. Mitchell AL, Hegedüs L, Žarković M, et al. Patient satisfaction and quality of life in hypothyroidism: An online survey by the british thyroid foundation. Clin Endocrinol (Oxf). 2021; 94(3): 513–520.
  6. Peterson SJ, Cappola AR, Castro MR, et al. An Online Survey of Hypothyroid Patients Demonstrates Prominent Dissatisfaction. Thyroid. 2018; 28(6): 707–721.
  7. Wartofsky L. Combination L-T3 and L-T4 therapy for hypothyroidism. Curr Opin Endocrinol Diabetes Obes. 2013; 20(5): 460–466.
  8. Celi FS, Zemskova M, Linderman JD, et al. Metabolic effects of liothyronine therapy in hypothyroidism: a randomized, double-blind, crossover trial of liothyronine versus levothyroxine. J Clin Endocrinol Metab. 2011; 96(11): 3466–3474.
  9. Jonklaas J, Bianco AC, Cappola AR, et al. Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document. Thyroid. 2021; 31(2): 156–182.
  10. Taylor PN, Razvi S, Muller I, et al. Liothyronine cost and prescriptions in England. Lancet Diabetes Endocrinol. 2019; 7(1): 11–12.
  11. Fliers E, Kalsbeek A, Boelen A. Beyond the fixed setpoint of the hypothalamus-pituitary-thyroid axis. Eur J Endocrinol. 2014; 171(5): R197–R208.
  12. Feldt-Rasmussen U, Effraimidis G, Klose M. The hypothalamus-pituitary-thyroid (HPT)-axis and its role in physiology and pathophysiology of other hypothalamus-pituitary functions. Mol Cell Endocrinol. 2021; 525: 111173.
  13. Ortiga-Carvalho TM, Chiamolera MI, Pazos-Moura CC, et al. Hypothalamus-Pituitary-Thyroid Axis. Compr Physiol. 2016; 6(3): 1387–1428.
  14. Larsen PR, Zavacki AM. The role of the iodothyronine deiodinases in the physiology and pathophysiology of thyroid hormone action. Eur Thyroid J. 2012; 1(4): 232–242.
  15. Jonklaas J, Bianco AC, Bauer AJ, et al. American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 2014; 24(12): 1670–1751.
  16. Peeters RP, van Toor H, Klootwijk W, et al. Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects. J Clin Endocrinol Metab. 2003; 88(6): 2880–2888.
  17. Luongo C, Dentice M, Salvatore D. Deiodinases and their intricate role in thyroid hormone homeostasis. Nat Rev Endocrinol. 2019; 15(8): 479–488.
  18. Bianco AC, Kim BS. Pathophysiological relevance of deiodinase polymorphism. Curr Opin Endocrinol Diabetes Obes. 2018; 25(5): 341–346.
  19. Wiersinga WM, Duntas L, Fadeyev V, et al. 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism. Eur Thyroid J. 2012; 1(2): 55–71.
  20. Goldman JM, Line BR, Aamodt RL, et al. Influence of triiodothyronine withdrawal time on 131I uptake postthyroidectomy for thyroid cancer. J Clin Endocrinol Metab. 1980; 50(4): 734–739.
  21. Escobar-Morreale HF, del Rey FE, Obregón MJ, et al. Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology. 1996; 137(6): 2490–2502.
  22. Peterson SJ, McAninch EA, Bianco AC. Is a Normal TSH Synonymous With "Euthyroidism" in Levothyroxine Monotherapy? J Clin Endocrinol Metab. 2016; 101(12): 4964–4973.
  23. Jonklaas J, Davidson B, Bhagat S, et al. Triiodothyronine levels in athyreotic individuals during levothyroxine therapy. JAMA. 2008; 299(7): 769–777.
  24. Gereben B, McAninch EA, Ribeiro MO, et al. Scope and limitations of iodothyronine deiodinases in hypothyroidism. Nat Rev Endocrinol. 2015; 11(11): 642–652.
  25. Werneck de Castro JP, Fonseca TL, Ueta CB, et al. Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine. J Clin Invest. 2015; 125(2): 769–781.
  26. Leese GP. Nice guideline on thyroid disease: where does it take us with liothyronine? Thyroid Res. 2020; 13: 7.
  27. Okosieme O, Gilbert J, Abraham P, et al. Management of primary hypothyroidism: statement by the British Thyroid Association Executive Committee. Clin Endocrinol (Oxf). 2016; 84(6): 799–808.
  28. Escobar-Morreale HF, Obregón MJ, Escobar del Rey F, et al. Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. J Clin Invest. 1995; 96(6): 2828–2838.
  29. Jonklaas J, Davidson B, Bhagat S, et al. Triiodothyronine levels in athyreotic individuals during levothyroxine therapy. JAMA. 2008; 299(7): 769–777.
  30. Gullo D, Latina A, Frasca F, et al. Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS One. 2011; 6(8): e22552.
  31. Ito M, Miyauchi A, Morita S, et al. TSH-suppressive doses of levothyroxine are required to achieve preoperative native serum triiodothyronine levels in patients who have undergone total thyroidectomy. Eur J Endocrinol. 2012; 167(3): 373–378.
  32. McAninch EA, Rajan KB, Miller CH, et al. Systemic Thyroid Hormone Status During Levothyroxine Therapy In Hypothyroidism: A Systematic Review and Meta-Analysis. J Clin Endocrinol Metab. 2018 [Epub ahead of print].
  33. Lee YKi, Lee H, Han S, et al. Association between Thyroid-Stimulating Hormone Level after Total Thyroidectomy and Hypercholesterolemia in Female Patients with Differentiated Thyroid Cancer: A Retrospective Study. J Clin Med. 2019; 8(8).
  34. Ito M, Miyauchi A, Hisakado M, et al. Biochemical Markers Reflecting Thyroid Function in Athyreotic Patients on Levothyroxine Monotherapy. Thyroid. 2017; 27(4): 484–490.
  35. Wiersinga WM. T4 + T3 combination therapy: any progress? Endocrine. 2019; 66(1): 70–78.
  36. Foeller ME, Silver RM. Combination Levothyroxine + Liothyronine Treatment in Pregnancy. Obstet Gynecol Surv. 2015; 70(9): 584–586.
  37. Planck T, Hedberg F, Calissendorff J, et al. Liothyronine Use in Hypothyroidism and its Effects on Cancer and Mortality. Thyroid. 2021; 31(5): 732–739.
  38. Biondi B, Bartalena L, Chiovato L, et al. Recommendations for treatment of hypothyroidism with levothyroxine and levotriiodothyronine: a 2016 position statement of the Italian Society of Endocrinology and the Italian Thyroid Association. J Endocrinol Invest. 2016; 39(12): 1465–1474.
  39. Zavaleta MJ, Arroyo JC, Gutiérrez FE, et al. T3 therapy in hypothyroidism. Still more questions than answers. Arch Endocrinol Metab. 2021; 65(3): 392–393.
  40. Vasileiou M, Gilbert J, Fishburn S, et al. Guideline Committee. Thyroid disease assessment and management: summary of NICE guidance. BMJ. 2020; 368: m41.
  41. Taylor PN, Peeters R, Dayan CM. Genetic abnormalities in thyroid hormone deiodinases. Curr Opin Endocrinol Diabetes Obes. 2015; 22(5): 402–406.
  42. Panicker V, Saravanan P, Vaidya B, et al. 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. 2009; 94(5): 1623–1629.
  43. Carlé A, Faber J, Steffensen R, et al. Hypothyroid Patients Encoding Combined MCT10 and DIO2 Gene Polymorphisms May Prefer L-T3 + L-T4 Combination Treatment - Data Using a Blind, Randomized, Clinical Study. Eur Thyroid J. 2017; 6(3): 143–151.
  44. Appelhof BC, Peeters RP, Wiersinga WM, et al. Polymorphisms in type 2 deiodinase are not associated with well-being, neurocognitive functioning, and preference for combined thyroxine/3,5,3'-triiodothyronine therapy. J Clin Endocrinol Metab. 2005; 90(11): 6296–6299.
  45. Madan R, Celi FS. Combination Therapy for Hypothyroidism: Rationale, Therapeutic Goals, and Design. Front Endocrinol (Lausanne). 2020; 11: 371.
  46. Saravanan P, Simmons DJ, Greenwood R, et al. Partial substitution of thyroxine (T4) with tri-iodothyronine in patients on T4 replacement therapy: results of a large community-based randomized controlled trial. J Clin Endocrinol Metab. 2005; 90(2): 805–812.

Regulations

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

Via MedicaWydawcą serwisu jest  "Via Medica sp. z o.o." sp.k., ul. Świętokrzyska 73, 80–180 Gdańsk

tel.:+48 58 320 94 94, faks:+48 58 320 94 60, e-mail:  viamedica@viamedica.pl