Skip to main content

Advertisement

SpringerLink
Log in

Recommendations for treatment of hypothyroidism with levothyroxine and levotriiodothyronine: a 2016 position statement of the Italian Society of Endocrinology and the Italian Thyroid Association

  • Consensus Statement
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Levothyroxine (L-T4) is recommended as lifelong replacement therapy for hypothyroidism. Recent clinical and experimental data support the addition of levotriiodothyronine (L-T3) treatment in some selected hypothyroid patients when their symptoms persist and their quality of life remains impaired despite adequate L-T4 monotherapy. An increase in L-T3 prescriptions has been recently observed in Italy due to availability of different L-T3 formulations, making it possible to clinicians to prescribe L-T3 alone or in combination with L-T4. The aim of the present position statement was to define the correct clinical indications, schedule, duration of treatment and contraindications of combined treatment with L-T4 and L-T3 in hypothyroid patients in an attempt to guide clinicians and to avoid potential adverse effects of overtreatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Roberts CG, Ladenson PW (2004) Hypothyroidism. Lancet 363:793–803

    Article  CAS  PubMed  Google Scholar 

  2. Biondi B, Wartofsky L (2014) Treatment with thyroid hormone. Endocr Rev 35:433–512

    Article  CAS  PubMed  Google Scholar 

  3. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC (2000) The Colorado thyroid disease prevalence study. Arch Intern Med 160:526–534

    Article  CAS  PubMed  Google Scholar 

  4. Biondi B, Klein I (2004) Hypothyroidism as a risk factor for cardiovascular disease. Endocrine 24:1–13

    Article  CAS  PubMed  Google Scholar 

  5. Biondi B, Cooper DS (2008) The clinical significance of subclinical thyroid dysfunction. Endocr Rev 29:76–131

    Article  CAS  PubMed  Google Scholar 

  6. Rodondi N, den Elzen WP, Bauer DC et al (2010) Thyroid studies collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA 304:1365–1374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gencer B, Collet TH, Virgini V et al (2012) Thyroid studies collaboration. Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts. Circulation 126:1040–1049

    Article  CAS  PubMed  Google Scholar 

  8. Garber JR, Cobin RH, Gharib H et al (2012) American Association of Clinical Endocrinologists and American Thyroid Association taskforce on hypothyroidism in adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid 22:1200–1235

    Article  CAS  PubMed  Google Scholar 

  9. Jonklaas J, Bianco AC, Bauer AJ et al (2014) 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 24:1670–1751

    Article  PubMed  PubMed Central  Google Scholar 

  10. Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MP (2012) ETA guidelines: the use of L-T4 + L-T3 in the treatment of hypothyroidism. Eur Thyroid J 1:55–71

    Article  PubMed  PubMed Central  Google Scholar 

  11. Biondi B, Wartofsky L (2012) Combination treatment with T4 and T3: toward personalized replacement therapy in hypothyroidism? J Clin Endocrinol Metab 97:2256–2271

    Article  CAS  PubMed  Google Scholar 

  12. Mitchell AL, Hickey B, Hickey JL, Pearce SH (2009) Trends in thyroid hormone prescribing and consumption in the UK. BMC Public Health 9:132–211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hannemann A, Friedrich N, Haring R et al (2010) Thyroid function tests in patients taking thyroid medication in Germany: results from the population-based Study of Health in Pomerania (SHIP). BMC Res Notes 3:227–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Biondi B, Celi F, Duntas L et al (2015) Terapia sostitutiva combinata con L-T4 e L-T3 nell’ipotiroidismo. L’Endocrinologo 16:264–268

    Google Scholar 

  15. Biondi B, Bartalena L, Cooper DS et al (2015) The 2015 European Thyroid Association guidelines on diagnosis and treatment of endogenous subclinical hyperthyroidism. Eur Thyroid J 4(3):149–163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR (2002) Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 23:38–89

    Article  CAS  PubMed  Google Scholar 

  17. Gereben B, McAninch EA, Ribeiro MO, Bianco AC (2015) Scope and limitations of iodothyronine deiodinases in hypothyroidism. Nat Rev Endocrinol 11:642–652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Vita R, Saraceno G, Trimarchi F, Benvenga S (2014) Switching levothyroxine from the tablet to the oral solution formulation corrects the impaired absorption of levothyroxine induced by proton-pump inhibitors. J Clin Endocrinol Metab 99(12):4481–4486

    Article  CAS  PubMed  Google Scholar 

  19. Hennessey JV, Malabanan AO, Haugen BR, Levy EG (2010) Adverse event reporting in patients treated with levothyroxine: results of the Pharmacovigilance Task Force survey of the American Thyroid Association, American Association of Clinical Endocrinologists, and The Endocrine Society. Endocr Pract 16:357–370

    Article  PubMed  Google Scholar 

  20. Wartofsky L (2002) Levothyroxine: therapeutic use and regulatory issues related to bioequivalence. Expert Opin Pharmacother 3:727–732

    Article  CAS  PubMed  Google Scholar 

  21. Hoang TD, Olsen CH, Mai VQ, Clyde PW, Shakir MK (2013) Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomized, double-blind, crossover study. J Clin Endocrinol Metab 98:1982–1990

    Article  CAS  PubMed  Google Scholar 

  22. Yavuz S, Linderman JD, Smith S, Zhao X, Pucino F, Celi FS (2013) The dynamic pituitary response to escalating-dose TRH stimulation test in hypothyroid patients treated with liothyronine or levothyroxine replacement therapy. J Clin Endocrinol Metab 98:E862–E866

    Article  PubMed  PubMed Central  Google Scholar 

  23. Celi FS, Zemskova M, Linderman JD et al (2011) Metabolic effects of liothyronine therapy in hypothyroidism: a randomized, double-blind, crossover trial of liothyronine versus levothyroxine. J Clin Endocrinol Metab 96:3466–3474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jonklaas J, Burman KD. 2016 Daily Administration of Short-Acting Liothyronine Is Associated with Significant Triiodothyronine Excursions and Fails to Alter Thyroid-Responsive Parameters. Thyroid

  25. Smith RN, Taylor SA, Massey JC (1970) Controlled clinical trial of combined triiodothyronine and thyroxine in the treatment of hypothyroidism. Br Med J 4:145–148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Peters A, Ehlers M, Blank B et al (2000) Excess triiodothyronine as a risk factor of coronary events. Arch Intern Med 160:1993–1999

    Article  CAS  PubMed  Google Scholar 

  27. Leese GP, Soto-Pedre E, Donnelly LA (2016) Liothyronine use in a 17 year observational population-based study—the tears study. Clin Endocrinol. doi:10.1111/cen.13052

  28. Escobar-Morreale HF, Obregon MJ, Escobar del Rey F, Morreale de Escobar G (1995) Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. J Clin Invest 96:2828–2838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Escobar-Morreale HF, Rey F, Obregon MJ, Escobar GM (1996) Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology 137:2490–2502

    CAS  PubMed  Google Scholar 

  30. 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 Invest 125:769–781

    Article  PubMed  PubMed Central  Google Scholar 

  31. 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 57:577–585

    Article  CAS  Google Scholar 

  32. Panicker V, Evans J, Bjøro T et al (2009) A paradoxical difference in relationship between anxiety, depression and thyroid function in subjects on and not on T4: findings from the HUNT study. Clin Endocrinol 71:574–580

    Article  Google Scholar 

  33. 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 153:747–753

    Article  CAS  PubMed  Google Scholar 

  34. Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L (2006) Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 91:2592–2599

    Article  CAS  PubMed  Google Scholar 

  35. Ma C, Xie J, Huang X, Wang G et al (2009) Thyroxine alone or thyroxine plus triiodothyronine replacement therapy for hypothyroidism. Nucl Med Commun 30:586–593

    Article  CAS  PubMed  Google Scholar 

  36. Joffe RT, Brimacombe M, Levitt AJ, Stagnaro-Green A (2007) Treatment of clinical hypothyroidism with thyroxine and triiodothyronine: a literature review and metaanalysis. Psychosomatics 48:379–384

    Article  CAS  PubMed  Google Scholar 

  37. Nygaard B, Jensen EW, Kvetny J, Jarløv A, Faber J (2009) Effect of combination therapy with thyroxine (T4) and 3,5,3′-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study. Eur J Endocrinol 161:895–902

    Article  CAS  PubMed  Google Scholar 

  38. Schmidt U, Nygaard B, Jensen EW et al (2013) Peripheral markers of thyroid function: the effect of T4 monotherapy vs T4/T3 combination therapy in hypothyroid subjects in a randomized crossover study. Endocr Connect 2:55–60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fadeyev VV, Morgunova TB, Melnichenko GA, Dedov I (2010) Combined therapy with l-thyroxine and l-triiodothyronine compared to l-thyroxine alone in the treatment of primary hypothyroidism. Hormones 9:245–252

    Article  PubMed  Google Scholar 

  40. WalshJ P, Shiels L, Lim EM et al (2003) Combined thyroxine/liothyronine treatment does not improve well-being, quality of life or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab 88:4543–4550

    Article  CAS  Google Scholar 

  41. Bunevicius R, Kazanavicius G, Zalinkevicius R, Jr Prange A J (1999) Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 340:424–429

    Article  CAS  PubMed  Google Scholar 

  42. Escobar-Morreale HF, Botella-Carretero JI et al (2005) Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine alone. Ann Intern Med 142:412–424

    Article  CAS  PubMed  Google Scholar 

  43. Bunevicius R, Jakubonien N, Jurkevicius R et al (2002) Thyroxine vs thyroxine plus triiodothyronine in treatment of hypothyroidism after thyroidectomy for Graves’ disease. Endocrine 18:129–133

    Article  CAS  PubMed  Google Scholar 

  44. Wiersinga WM (2014) Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism. Nat Rev Endocrinol 10:164–174

    Article  CAS  PubMed  Google Scholar 

  45. Appelhof BC, Fliers E, Wekking EM et al (2005) Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial. J Clin Endocrinol Metab 90:2666–2674

    Article  CAS  PubMed  Google Scholar 

  46. Jonklaas J, Davidson B, Bhagat S, Soldin SJ (2008) Triiodothyronine levels in athyreotic individuals during Levothyroxine therapy. JAMA 299:769–777

    Article  CAS  PubMed  Google Scholar 

  47. Gullo D, Latina A, Frasca F et al (2011) Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS ONE 6:e2255

    Article  CAS  Google Scholar 

  48. Ito M, Miyauchi A, Morita S et al (2012) TSH-suppressive doses of levothyroxine are required to achieve preoperative native serum triiodothyronine levels in patients who have undergone total thyroidectomy. Eur J Endocrinol 167:373–378

    Article  CAS  PubMed  Google Scholar 

  49. Ito M, Miyauchi A, Kang S et al (2015) Effect of the presence of remnant thyroid tissue on the serum thyroid hormone balance in thyroidectomized patients. Eur J Endocrinol 173:333–340

    Article  CAS  PubMed  Google Scholar 

  50. Carr D, McLeod DT, Parry G, Thornes HM (1988) Fine adjustment of thyroxine replacement dosage: comparison of the thyrotrophin releasing hormone test using a sensitive thyrotrophin assay with measurement of free thyroid hormones and clinical assessment. Clin Endocrinol 28:325–333

    Article  CAS  Google Scholar 

  51. Al-Adsani H, Hoffer LJ, Silva JE (1997) Resting energy expenditure is sensitive to small dose changes in patients on chronic thyroid hormone replacement. J Clin Endocrinol Metab 82:1118–1125

    CAS  PubMed  Google Scholar 

  52. Walsh JP, Ward LC, Burke V et al (2006) Small changes in thyroxine dosage do not produce measurable changes in hypothyroid symptoms, well-being, or quality of life: results of a double-blind, randomized clinical trial. J Clin Endocrinol Metab 91:2624–2630

    Article  CAS  PubMed  Google Scholar 

  53. Carr D, McLeod DT, Parry G, Thornes HM (1988) Fine adjustment of thyroxine replacement dosage: comparison of the thyrotrophin releasing hormone test using a sensitive thyrotrophin assay with measurement of free thyroid hormones and clinical assessment. Clin Endocrinol 28:325–333

    Article  CAS  Google Scholar 

  54. Biondi B, Cooper DS (2010) Benefits of thyrotropin suppression versus the risks of adverse effects in differentiated thyroid cancer. Thyroid 20:135–146

    Article  CAS  PubMed  Google Scholar 

  55. Haugen BR, Alexander EK, Bible KC et al (2016) 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 26:1–133

    Article  PubMed  Google Scholar 

  56. 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 94:1623–1629

    Article  CAS  PubMed  Google Scholar 

  57. Mentuccia D, Proietti-Pannunzi L, Tanner K et al (2002) Association between a novel variant of the human type 2 deiodinase gene Thr92Ala and insulin resistance: evidence of interaction with the Trp64Arg variant of the β3adrenergic receptor. Diabetes 51:880–883

    Article  CAS  PubMed  Google Scholar 

  58. Estivalet A, Leiria LB, Dora JM et al (2010) D2 Thr92Ala and PPARγ2 Pro12Ala polymorphisms interact in the modulation of insulin resistance in type 2 diabetic patients. Obesity 19:825–832

    Article  CAS  PubMed  Google Scholar 

  59. Dora JM, Machado WE, Rheinheimer J, Crispim D, Maia AL (2010) Association of the type 2 deiodinase Thr92Ala polymorphism with type 2 diabetes: case-control study and meta-analysis. Eur J Endocrinol 163:427–434

    Article  CAS  PubMed  Google Scholar 

  60. Guo TW, Zhang FC, Yang MS et al (2004) Positive association of the DIO2 (deiodinase type 2) gene with mental retardation in the iodine-deficient areas of China. J Med Genet 41:585–590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. He B, Li J, Wang G, Ju W et al (2009) Association of genetic polymorphisms in the type II deiodinase gene with bipolar disorder in a subset of Chinese population. Prog Neuropsychopharmacol Biol Psychiatry 33:986–990

    Article  CAS  PubMed  Google Scholar 

  62. Taylor P, Okosieme O, Sayers A et al (2014) Effect of low thyroid hormone bioavailability on childhood cognitive development: data from the Avon Longitudinal Study of Parents and Children birth cohort. Lancet 383:S100

    Article  Google Scholar 

  63. de Jong FJ, Peeters RP, den Heijer T et al (2007) The association of polymorphisms in the type 1 and 2 deiodinase genes with circulating thyroid hormone parameters and atrophy of the medial temporal lobe. J Clin Endocrinol Metab 92:636–640

    Article  CAS  PubMed  Google Scholar 

  64. van der Deure WM, Appelhof BC, Peeters RP et al (2008) Polymorphisms in the brain-specific thyroid hormone transporter OATP1C1 are associated with fatigue and depression in hypothyroid patients. Clin Endocrinol 69:804–811

    Article  CAS  Google Scholar 

  65. Roef GL, Rietzschel ER, De Meyer T et al (2013) Associations between single nucleotide polymorphisms in thyroid hormone transporter genes (MCT8, MCT10 and OATP1C1) and circulating thyroid hormones. Clin Chim Acta 425:227–232

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Prof. Leonidas Duntas, University of Athens, and Prof. Francesco Celi for their valuable suggestions in the preparation of the manuscript.

Author information

Authors and Affiliations

  1. Department of Clinical Medicine and Surgery, University of Naples Federico II, Via S. Pansini 5, 80131, Naples, Italy

    B. Biondi

  2. Department of Clinical and Experimental Medicine, ASST dei Sette Laghi, Ospedale di Circolo, University of Insubria, Varese, Italy

    L. Bartalena

  3. Unit of Internal Medicine and Endocrinology, Fondazione Salvatore Maugeri and University of Pavia, Pavia, Italy

    L. Chiovato

  4. Department of Experimental Medicine, Medical Pathophysiology, Food and Science and Endocrinology Section, Sapienza University of Rome, Rome, Italy

    A. Lenzi

  5. Endocrinology Unit, Department of Medical Sciences “M. Aresu”, University of Cagliari, Cagliari, Italy

    S. Mariotti

  6. Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy

    F. Pacini

  7. Unità di Endocrinologia, Università Cattolica del Sacro Cuore, Rome, Italy

    A. Pontecorvi

  8. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    P. Vitti

  9. Accademia Peloritana dei Pericolanti, Università di Messina, Messina, Italy

    F. Trimarchi

Authors
  1. B. Biondi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. Bartalena
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. Chiovato
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Lenzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Mariotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. F. Pacini
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Pontecorvi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P. Vitti
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. F. Trimarchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B. Biondi.

Ethics declarations

Conflict of interest

The panel members worked on this statement without any financial or commercial support.

Ethical approval

This article does not contain any study with human participants or animals performed by any of the authors.

Informed consent

No informed consent.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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 39, 1465–1474 (2016). https://doi.org/10.1007/s40618-016-0511-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-016-0511-z

Keywords

Search

Navigation