Comparative Effectiveness of Levothyroxine, Desiccated Thyroid Extract, and Levothyroxine+Liothyronine in Hypothyroidism
Mohamed K M Shakir, Daniel I Brooks, Elizabeth A McAninch, Tatiana L Fonseca, Vinh Q Mai, Antonio C Bianco, Thanh D Hoang, Mohamed K M Shakir, Daniel I Brooks, Elizabeth A McAninch, Tatiana L Fonseca, Vinh Q Mai, Antonio C Bianco, Thanh D Hoang
Abstract
Introduction: Studies comparing levothyroxine (LT4) therapy with LT4 + liothyronine (LT3) or desiccated thyroid extract (DTE) did not detect consistent superiority of either treatment. Here, we investigated these therapies, focusing on the whole group of LT4-treated hypothyroid patients, while also exploring the most symptomatic patients.
Methodology: Prospective, randomized, double-blind, crossover study of 75 hypothyroid patients randomly allocated to 1 of 3 treatment arms, LT4, LT4 + LT3, and DTE, for 22 weeks. The primary outcomes were posttreatment scores on the 36-point thyroid symptom questionnaire (TSQ-36), 12-point quality of life general health questionnaire (GHQ-12), the Wechsler memory scale-version IV (VMS-IV), and the Beck Depression Inventory (BDI). Secondary endpoints included treatment preference, biochemical and metabolic parameters, etiology of hypothyroidism, and Thr92Ala-DIO2 gene polymorphism. Analyses were performed with a linear mixed model using subject as a random factor and group as a fixed effect.
Results: Serum TSH remained within reference range across all treatment arms. There were no differences for primary and secondary outcomes, except for a minor increase in heart rate caused by DTE. Treatment preference was not different and there were no interferences of the etiology of hypothyroidism or Thr92Ala-DIO2 gene polymorphism in the outcomes. Subgroup analyses of the 1/3 most symptomatic patients on LT4 revealed strong preference for treatment containing T3, which improved performance on TSQ-36, GHQ-12, BDI, and visual memory index (VMS-IV component).
Conclusions: As a group, outcomes were similar among hypothyroid patients taking DTE vs LT4 + T3 vs LT4. However, those patients that were most symptomatic on LT4 preferred and responded positively to therapy with LT4 + LT3 or DTE.
Trial registration: ClinicalTrials.gov NCT02317926.
Keywords: desiccated thyroid extract; hypothyroidism; levothyroxine; liothyronine; quality of life.
© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.
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References
- Chaker L, Bianco AC, Jonklaas J, Peeters RP. Hypothyroidism. Lancet. 2017;390(10101):1550-1562.
- Aoki Y, Belin RM, Clickner R, Jeffries R, Phillips L, Mahaffey KR. Serum TSH and total T4 in the United States population and their association with participant characteristics: National Health and Nutrition Examination Survey (NHANES 1999-2002). Thyroid. 2007;17(12):1211-1223.
- Idrees T, Palmer S, Maciel RMB, Bianco AC. Liothyronine and desiccated thyroid extract in the treatment of hypothyroidism. Thyroid. 2020;30(10):1399-1413.
- Taylor S, Kapur M, Adie R. Combined thyroxine and triiodothyronine for thyroid replacement therapy. Br Med J. 1970;2(5704):270-271.
- Roberts ND. Psychological problems in thyroid disease. Br Thyroid Foundation Newsl. 1996;18:3.
- Saravanan P, Chau WF, Roberts N, Vedhara K, Greenwood R, Dayan CM. Psychological well-being in patients on ‘adequate’ doses of l-thyroxine: results of a large, controlled community-based questionnaire study. Clin Endocrinol (Oxf). 2002;57(5):577-585.
- Wekking EM, Appelhof BC, Fliers E, et al. . Cognitive functioning and well-being in euthyroid patients on thyroxine replacement therapy for primary hypothyroidism. Eur J Endocrinol. 2005;153(6):747-753.
- 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.
- 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.
- Appelhof BC, Fliers E, Wekking EM, et al. . 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. 2005;90(5):2666-2674.
- Escobar-Morreale HF, Botella-Carretero JI, Gómez-Bueno M, Galán JM, Barrios V, Sancho J. Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine alone. Ann Intern Med. 2005;142(6):412-424.
- Hoang TD, Olsen CH, Mai VQ, Clyde PW, Shakir MK. Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomized, double-blind, crossover study. J Clin Endocrinol Metab. 2013;98(5):1982-1990.
- 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.
- Mentuccia D, Proietti-Pannunzi L, Tanner K, et al. . 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 beta-3-adrenergic receptor. Diabetes. 2002;51(3):880-883.
- Wechsler DA. The Wechsler Memory Scalle-IV. 4th ed. San Antonio, TX: Psychological Corp; 2009.
- Benson N, Hulac DM, Kranzler JH. Independent examination of the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV): what does the WAIS-IV measure? Psychol Assess. 2010;22(1):121-130.
- Clyde PW, Harari AE, Getka EJ, Shakir KM. Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. Jama. 2003;290(22):2952-2958.
- Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry. 1961;4:561-571.
- McDowell I, Newell C.. The General Health Questionnaire, Measuring Health. A guide to Rating Scales and Questionnaires. 2nd ed. New York, NY: Oxford University Press; 1996.
- Jaeschke R, Guyatt G, Cook D, Harper S, Gerstein HC. Spectrum of quality of life impairment in hypothyroidism. Qual Life Res. 1994;3(5):323-327.
- Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC. L-Thyroxine therapy in subclinical hypothyroidism. A double-blind, placebo-controlled trial. Ann Intern Med. 1984;101(1):18-24.
- Turner HL, van Etten J, Firth D, Kosmids J. Modelling rankings in R: the PlackettLuce package. Comput Stat. 2020;35:1027-1057.
- Peterson SJ, Cappola AR, Castro MR, et al. . An online survey of hypothyroid patients demonstrates prominent dissatisfaction. Thyroid. 2018;28(6):707-721.
- 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.
- Ettleson MD, Bianco AC. Individualized therapy for hypothyroidism: is T4 enough for everyone? J Clin Endocrinol Metab. 2020;105(9):e3090-e3104.
- Valizadeh M, Seyyed-Majidi MR, Hajibeigloo H, Momtazi S, Musavinasab N, Hayatbakhsh MR. Efficacy of combined levothyroxine and liothyronine as compared with levothyroxine monotherapy in primary hypothyroidism: a randomized controlled trial. Endocr Res. 2009;34(3):80-89.
- Walsh JP, Shiels L, Lim EM, et al. . 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. 2003;88(10):4543-4550.
- Rodriguez T, Lavis VR, Meininger JC, Kapadia AS, Stafford LF. Substitution of liothyronine at a 1:5 ratio for a portion of levothyroxine: effect on fatigue, symptoms of depression, and working memory versus treatment with levothyroxine alone. Endocr Pract. 2005;11(4):223-233.
- Sawka AM, Gerstein HC, Marriott MJ, MacQueen GM, Joffe RT. Does a combination regimen of thyroxine (T4) and 3,5,3’-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab. 2003;88(10):4551-4555.
- Bianco AC, Dumitrescu A, Gereben B, et al. . Paradigms of dynamic control of thyroid hormone signaling. Endocr Rev. 2019;40(4):1000-1047.
- López-Espíndola D, García-Aldea Á, Gómez de la Riva I, et al. . Thyroid hormone availability in the human fetal brain: novel entry pathways and role of radial glia. Brain Struct Funct. 2019;224(6):2103-2119.
- Morte B, Bernal J. Thyroid hormone action: astrocyte-neuron communication. Front Endocrinol (Lausanne). 2014;5:82.
- Marcelino CP, McAninch EA, Fernandes GW, Bocco BMLC, Ribeiro MO, Bianco AC. Temporal pole responds to subtle changes in local thyroid hormone signaling. J Endocr Soc. 2020;4(11):bvaa136.
- Freitas BC, Gereben B, Castillo M, et al. . Paracrine signaling by glial cell-derived triiodothyronine activates neuronal gene expression in the rodent brain and human cells. J Clin Invest. 2010;120(6):2206-2217.
Source: PubMed