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• W4295958408 abstract "Clinical ThyroidologyVol. 34, No. 9 HypothyroidismFree AccessObjective Markers of Thyroid Hormone Homeostasis in Levothyroxine Versus Liothyronine MonotherapiesElizabeth A. McAninchElizabeth A. McAninchDivision of Endocrinology, Gerontology and Metabolism, Department of Medicine, Stanford University Medical Center, Stanford, California, U.S.A.Search for more papers by this authorPublished Online:15 Sep 2022https://doi.org/10.1089/ct.2022;34.389-391AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Review of: Bjerkreim BA, Hammerstad SS, Gulseth HL, Berg TJ, Lee-Ødegård S, Eriksen EF 2022 Thyroid signaling biomarkers in female symptomatic hypothyroid patients on liothyronine versus levothyroxine monotherapy: A randomized crossover trial. J Thyroid Res 2022:6423023. PMID: 35572853.SUMMARYBackgroundLevothyroxine (LT4) therapy is the standard of care for patients with hypothyroidism (1). However, the ability of levothyroxine to “normalize” all sequelae of hypothyroidism has come into question, as a minority of patients can experience residual symptoms despite its use to normalize serum thyrotropin (TSH) (2,3). This finding is supported by some clinical data that show that objective markers of hypothyroidism may not be completely normalized by levothyroxine at doses that normalize the serum TSH (4,5). In animal models of hypothyroidism, levothyroxine monotherapy does not normalize all markers of hypothyroidism, but so-called combination therapy with levothyroxine plus liothyronine restores euthyroidism systemically (6–8). In this prospective, crossover clinical trial, markers of thyroid hormone homeostasis were compared in patients with hypothyroidism during levothyroxine monotherapy with those during liothyronine monotherapy (9).MethodsWomen ages 18 to 65 with hypothyroidism with residual symptoms on treatment with thyroid hormone replacement and with cardiac, pulmonary or endocrine comorbidities were enrolled. Presence of residual symptoms was defined as at least three “yes” answers in a 10-question survey. In the first study arm (the first 12 weeks of the study period), participants received either LT4 monotherapy or LT3 (administered thrice daily) monotherapy. At 12 weeks, objective markers of thyroid hormone status were assessed. Participants then switched therapy arms for the second 12 weeks of the study period. At the end of those 12 weeks, objective markers of thyroid hormone status were reassessed. Both participants and investigators were not blinded to the therapies.ResultsThere were 59 participants who were randomly assigned to the two study arms, and their baseline characteristics were similar. The mean (±SD) age was 42.9±9.7 years and the mean duration of prior hypothyroidism treatment was 10.6±7.0 years. The most common residual symptoms were fatigue, cold intolerance, and cognitive and emotional disturbances.For all participants, the median serum TSH at inclusion was 0.64 mU/L. After 12 weeks on LT4, the serum TSH was 0.61 mU/L (n = 48), and after 12 weeks on LT3 (n = 48), the serum TSH was 1.33 mU/L (P = 0.018). The serum free T4 (FT4) and free T3 (FT3) levels also differed significantly. After LT4, the median FT4 was 16.8 pmol/L, versus 3.1 pmol/L after LT3 (P<0.001), and the median FT3 was 4.2 pmol/L after LT4, versus 4.6 pmol/L after LT3 (P = 0.008).These differences in thyroid hormone distribution were associated with differences in other markers of thyroid hormone economy. The total cholesterol after LT4 was 5.1 mmol/L, versus 4.6 mmol/L after LT3 (P<0.001). The LDL cholesterol was 3.1 mmol/L after LT4, versus 2.8 mmol/L after LT3 (P<0.001). The sex-hormone–binding globulin (SHBG) was 56.0 nmol/L after LT4, versus 75.0 nmol/L after LT3 (P = 0.001).Of note, in a separately published article, these authors described the symptomatic characteristics after LT4 and LT3 monotherapies (10), and they found that, as compared with LT4 monotherapy, LT3 monotherapy was associated with improved physical, mental, and social quality-of-life outcomes (10).There were similar subjective reports of mild adverse events between the LT4 and LT3 groups, but whereas only one participant dropped out because of subjective side effects during LT4 treatment, five participants dropped out during LT3 treatment.ConclusionsIn this randomized crossover trial of hypothyroid women with residual symptoms despite the normalization of serum TSH levels following thyroid hormone replacement, FT4, total cholesterol and LDL cholesterol were significantly higher and TSH, FT3 and SHBG levels were significantly lower after 12 weeks of LT4 monotherapy than with LT3 monotherapy.COMMENTARYIn endogenous euthyroidism, serum T3 levels are relatively stable throughout the day. This is similar to the stable serum T3 levels achieved in LT4 monotherapy for hypothyroidism (1). Serum T3 levels are lower in LT4-treated hypothyroid patients than in patients with endogenous euthyroidism (1,3–5), lending credence to the hypothesis that LT4-treated patients with normal serum TSH may not exhibit full restoration of thyroid hormone economy.In contrast, after LT3 dosing, a supratherapeutic serum T3 peak is observed and the return to baseline T3 levels is relatively fast (less than 24 hours); this profile is improved with twice- or thrice-daily dosing schedules (1,3). For this reason, LT4 dosing once daily is certainly more convenient. I doubt many physicians are advocating for long-term LT3 monotherapy at this time, owing to its less physiologic pharmacodynamic profile and the lack of safety data, but perhaps this could become a more enticing strategy if and when a long-acting LT3 formulation becomes available (3).In my practice, aside from thyroid hormone withdrawal in preparation for radioactive iodine treatment for thyroid cancer, I do not prescribe LT3 monotherapy. In my opinion, these data support that LT4 monotherapy may not be able to absolutely optimize all markers of hypothyroidism for every patient. It is also interesting that even after 12 weeks on LT3 monotherapy, no patients had any serious adverse effects, so this may provide further reassurance about the safety of combination therapy, in which much lower doses of LT3 are used.Disclosures: Elizabeth McAninch is a consultant for Abbvie, is cofounder of Equilibrate Therapeutics, LLC, and has a patent pending (US20210361921A1).References1. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, et al.; American Thyroid Association Task Force on Thyroid Hormone Replacement 2014 Guidelines for the treatment of hypothyroidism: Prepared by the American Thyroid Association task force on thyroid hormone replacement. Thyroid 24:1670–1751. Link, Google Scholar2. Saravanan P, Chau WF, Roberts N, Vedhara K, Greenwood R, Dayan CM 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. Crossref, Medline, Google Scholar3. Jonklaas J, Bianco AC, Cappola AR, Celi FS, Fliers E, Heuer H, et al. 2021 Evidence-based use of levothyroxine/liothyronine combinations in treating hypothyroidism: A consensus document. Thyroid 31:156–182. Link, Google Scholar3. Peterson SJ, McAninch EA, Bianco AC 2016 Is a normal TSH synonymous with euthyroidism in levothyroxine monotherapy? J Clin Endocrinol Metab 101:4964–4973. Crossref, Medline, Google Scholar5. 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 103:4533–4542. Crossref, Google Scholar6. Werneck de Castro JP, Fonseca TL, Ueta CB, McAninch EA, Abdalla S, Wittmann G, Lechan RM, Gereben B, Bianco AC 2015 Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine. J Clin Invest 125:769–781. Crossref, Medline, Google Scholar7. 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. Crossref, Medline, Google Scholar8. 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. Crossref, Medline, Google Scholar9. Bjerkreim BA, Hammerstad SS, Gulseth HL, Berg TJ, Lee-Odegard S, Eriksen EF 2022 Thyroid signaling biomarkers in female symptomatic hypothyroid patients on liothyronine versus levothyroxine monotherapy: A randomized crossover trial. J Thyr Res 2022:6423023. Medline, Google Scholar10. Bjerkreim BA, Hammerstad SS, Gulseth HL, Berg TJ, Omdal LJ, Lee-Odegard S, Eriksen EF 2022 Effect of liothyronine treatment on quality of life in female hypothyroid patients with residual symptoms on levothyroxine therapy: A randomized crossover study. Front Endocrinol (Lausanne) 13:816566. Medline, Google ScholarFiguresReferencesRelatedDetails Volume 34Issue 9Sep 2022 Information© Copyright 2022, Mary Ann Liebert, Inc.To cite this article:Elizabeth A. McAninch.Objective Markers of Thyroid Hormone Homeostasis in Levothyroxine Versus Liothyronine Monotherapies.Clinical Thyroidology.Sep 2022.389-391.http://doi.org/10.1089/ct.2022;34.389-391Published in Volume: 34 Issue 9: September 15, 2022PDF download" @default.
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