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      LT4 and Slow Release T3 Combination: Optimum Therapy for Hypothyroidism?

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          Abstract

          Context

          Levothyroxine (LT4) is recommended as replacement therapy for thyroid hormone deficiency. However, some hypothyroid patients receiving LT4 therapy do not feel as well as healthy subjects. This article aimed to review current knowledge regarding LT4 monotherapy versus LT4+LT3 combination therapy and propose future directions regarding LT4+slow release T3 combination treatment for hypothyroidism.

          Evidence Acquisition

          We searched PubMed and Scopus using related keywords.

          Results

          The LT4 monotherapy causes higher serum free T4 (fT4), subnormal serum free T3 (fT3), and fT3/fT4 ratio in one-fourth of patients. The LT4+LT3 combination therapy increases serum T3 and fT3 concentrations and may normalize the fT3/fT4 ratio. However, the primary outcomes, including thyroid hormone deficiency, anxiety, depression, and quality of life, may not be better in LT4+LT3 combination therapy than in LT4 monotherapy. Recent surveys show that combination therapy is on the rise, in particular, due to patient demand. The LT4 plus slow-release LT3 preparation has shown promising results in improving serum thyroid hormone concentrations.

          Conclusions

          The beneficial effect of LT4+LT3 combination therapy is not clear, and the safety of long-term therapy is yet under question. More scientific well-designed research projects are required in this field.

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          Most cited references42

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          Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association.

          Jeffrey R. Garber, Rhoda H. Cobin, Hossein Gharib … (2012)
          Hypothyroidism has multiple etiologies and manifestations. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions. This paper describes evidence-based clinical guidelines for the clinical management of hypothyroidism in ambulatory patients. The development of these guidelines was commissioned by the American Association of Clinical Endocrinologists (AACE) in association with American Thyroid Association (ATA). AACE and the ATA assembled a task force of expert clinicians who authored this article. The authors examined relevant literature and took an evidence-based medicine approach that incorporated their knowledge and experience to develop a series of specific recommendations and the rationale for these recommendations. The strength of the recommendations and the quality of evidence supporting each was rated according to the approach outlined in the American Association of Clinical Endocrinologists Protocol for Standardized Production of Clinical Guidelines-2010 update. Topics addressed include the etiology, epidemiology, clinical and laboratory evaluation, management, and consequences of hypothyroidism. Screening, treatment of subclinical hypothyroidism, pregnancy, and areas for future research are also covered. Fifty-two evidence-based recommendations and subrecommendations were developed to aid in the care of patients with hypothyroidism and to share what the authors believe is current, rational, and optimal medical practice for the diagnosis and care of hypothyroidism. A serum thyrotropin is the single best screening test for primary thyroid dysfunction for the vast majority of outpatient clinical situations. The standard treatment is replacement with L-thyroxine. The decision to treat subclinical hypothyroidism when the serum thyrotropin is less than 10 mIU/L should be tailored to the individual patient.
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            2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism

            Wilmar M. Wiersinga, Leonidas Duntas, Valentin Fadeyev … (2012)
            Background Data suggest symptoms of hypothyroidism persist in 5–10% of levothyroxine (L-T4)-treated hypothyroid patients with normal serum thyrotrophin (TSH). The use of L-T4 + liothyronine (L-T3) combination therapy in such patients is controversial. The ETA nominated a task force to review the topic and formulate guidelines in this area. Methods Task force members developed a list of relevant topics. Recommendations on each topic are based on a systematic literature search, discussions within the task force, and comments from the European Thyroid Association (ETA) membership at large. Results Suggested explanations for persisting symptoms include: awareness of a chronic disease, presence of associated autoimmune diseases, thyroid autoimmunity per se, and inadequacy of L-T4 treatment to restore physiological thyroxine (T4) and triiodothyronine (T3) concentrations in serum and tissues. There is insufficient evidence that L-T4 + L-T3 combination therapy is better than L-T4 monotherapy, and it is recommended that L-T4 monotherapy remains the standard treatment of hypothyroidism. L-T4 + L-T3 combination therapy might be considered as an experimental approach in compliant L-T4-treated hypothyroid patients who have persistent complaints despite serum TSH values within the reference range, provided they have previously received support to deal with the chronic nature of their disease, and associated autoimmune diseases have been excluded. Treatment should only be instituted by accredited internists/endocrinologists, and discontinued if no improvement is experienced after 3 months. It is suggested to start combination therapy in an L-T4/L-T3 dose ratio between 13:1 and 20:1 by weight (L-T4 once daily, and the daily L-T3 dose in two doses). Currently available combined preparations all have an L-T4/L-T3 dose ratio of less than 13:1, and are not recommended. Close monitoring is indicated, aiming not only to normalize serum TSH and free T4 but also normal serum free T4/free T3 ratios. Suggestions are made for further research. Conclusion L-T4 + L-T3 combination therapy should be considered solely as an experimental treatment modality. The present guidelines are offered to enhance its safety and to counter its indiscriminate use.
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              Psychological well-being in patients on 'adequate' doses of l-thyroxine: results of a large, controlled community-based questionnaire study.

              Leena Chau, Colin M. Dayan, Tiffany Greenwood … (2002)
              Over 1% of the UK population is receiving thyroid hormone replacement with l-thyroxine (T4). However, many patients complain of persistent lethargy and related symptoms on T4 even with normal TSH levels. To date there has been no large study to determine whether this is related to thyroxine replacement or coincidental psychological morbidity. We have therefore attempted to address this issue using a large, community-based study. Computerized prescribing records of five general practices were used to identify 961 patients who had been on thyroxine for a minimum of 4 months from a population of 63 000 (1.5%), along with age- and sex-matched controls. All 1922 individuals were sent a two-page questionnaire, made up of the short form of the General Health Questionnaire (GHQ-12), designed to detect minor psychiatric disorders in the community, and a 12-question 'thyroid symptom questionnaire' (TSQ) in the same format. A covering letter explained that we were interested in 'how patients felt on medication' and made no direct reference to thyroxine. Scores from the GHQ and TSQ were marked for each individual using the GHQ and Likert scoring methods. Patients' latest TSH measurements were obtained from laboratory records. Comparisons were then made on scores for the total GHQ-12, TSQ and individual questions between patients (P) and control (C) groups. Separate analyses were made comparing the patients with a normal TSH (nP) and the control group. Five hundred and ninety-seven (62%) of the patients (P) and 551 (57%) of the controls (C) responded and fully completed at least one of the two questionnaire. Three hundred and ninety-seven responding patients (nP) had a TSH estimation performed in the previous 12 months with the last result being in the local laboratory normal range for TSH (0.1-5.5 or 0.2-6.0 mU/l, according to the assay method used). The responding P, nP and C populations were well matched for age (59.96, 59.73, 59.35 years) and sex (85%, 83%, 87% female). The number of individuals scoring 3 or more on the GHQ-12 (indicating 'caseness') was 21% higher in P than C [185/572 (32.3%) vs. 137/535 (25.6%), P = 0.014] and 26% higher in nP than C [131/381 (34.4%) vs. 137/535 (25.6%), P < 0.005]. Stronger differences were seen with the TSQ scores [C = 187/535 (35.0%), P = 273/583 (46.8%), P < 0.001, P vs. C; and nP = 189/381 (48.6%), P < 0.001, nP vs. C]. Differences existed in chronic drug use and chronic disease prevalence between the control and patient groups, but the differences in GHQ and TSQ scores between the groups remained significant even after correction for these factors as well as age and sex in multiple regression analysis. This community-based study is the first evidence to indicate that patients on thyroxine replacement even with a normal TSH display significant impairment in psychological well-being compared to controls of similar age and sex. In view of the large numbers of people on thyroxine replacement, we believe that these differences, although not large, could contribute to significant psychological morbidity in a substantial number of individuals.
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                Author and article information

                Contributors
                Fereidoun Azizi
                Atieh Amouzegar
                Ladan Mehran
                Hengameh Abdi
                Journal
                Journal ID (nlm-ta): Int J Endocrinol Metab
                Journal ID (iso-abbrev): Int J Endocrinol Metab
                Journal ID (doi): 10.5812/ijem
                Journal ID (publisher-id): Kowsar
                Title: International Journal of Endocrinology and Metabolism
                Publisher: Kowsar
                ISSN (Print): 1726-913X
                ISSN (Electronic): 1726-9148
                Publication date (Electronic): 07 April 2020
                Publication date Collection: April 2020
                Volume: 18
                Issue: 2
                Electronic Location Identifier: e100870
                Affiliations
                [1 ]Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
                Author notes
                [* ]Corresponding Author: Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Email: amouzegar@ 123456endocrine.ac.ir
                Article
                DOI: 10.5812/ijem.100870
                PMC ID: 7322563
                PubMed ID: 32636887
                SO-VID: dd21962a-4144-4b2e-87b1-c70560d17fb1
                Copyright © Copyright © 2020, International Journal of Endocrinology and Metabolism
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

                History
                Date received : 08 January 2020
                Date revision received : 18 March 2020
                Date accepted : 24 March 2020
                Categories
                Subject: Review Article

                Keywords: hypothyroidism,treatment,t3+t4 combination
                Data availability:
                Keywords: hypothyroidism, treatment, t3+t4 combination

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