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Association of Thyroid Hormone Therapy With Quality of Life and Thyroid-Related Symptoms in Patients With Subclinical Hypothyroidism: A Systematic Review and Meta-analysis
Open accessAbstract
Importance: The benefit of thyroid hormone therapy for subclinical hypothyroidism is uncertain. New evidence from recent large randomized clinical trials warrants an update of previous meta-analyses. Objective: To conduct a meta-analysis of the association of thyroid hormone therapy with quality of life and thyroid-related symptoms in adults with subclinical hypothyroidism. Data Sources: PubMed, EMBASE, ClinicalTrials.gov, Web of Science, Cochrane Library, CENTRAL, Emcare, and Academic Search Premier from inception until July 4, 2018. Study Selection: Randomized clinical trials that compared thyroid hormone therapy with placebo or no therapy in nonpregnant adults with subclinical hypothyroidism were eligible. Two reviewers independently evaluated eligibility based on titles and abstracts of all retrieved studies. Studies not excluded in this first step were independently assessed for inclusion after full-text evaluation by 2 reviewers. Data Extraction and Synthesis: Two independent reviewers extracted data, assessed risk of bias (Cochrane risk-of-bias tool), and evaluated the quality of evidence (GRADE tool). For synthesis, differences in clinical scores were transformed (eg, quality of life) into standardized mean differences (SMDs; positive values indicate benefit of thyroid hormone therapy; 0.2, 0.5, and 0.8 correspond to small, moderate, and large effects, respectively). Random-effects models for meta-analyses were applied. Main Outcomes and Measures: General quality of life and thyroid-related symptoms after a minimum follow-up of 3 months. Results: Overall, 21 of 3088 initially identified publications met the inclusion criteria, with 2192 adults randomized. After treatment (range, 3-18 months), thyroid hormone therapy was associated with lowering the mean thyrotropin value into the normal reference range compared with placebo (range, 0.5-3.7 mIU/L vs 4.6 to 14.7 mIU/L) but was not associated with benefit regarding general quality of life (n = 796; SMD, -0.11; 95% CI, -0.25 to 0.03; I2=66.7%) or thyroid-related symptoms (n = 858; SMD, 0.01; 95% CI, -0.12 to 0.14; I2=0.0%). Overall, risk of bias was low and the quality of evidence assessed with the GRADE tool was judged moderate to high. Conclusions and Relevance: Among nonpregnant adults with subclinical hypothyroidism, the use of thyroid hormone therapy was not associated with improvements in general quality of life or thyroid-related symptoms. These findings do not support the routine use of thyroid hormone therapy in adults with subclinical hypothyroidism.
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“large RCTs have shown no improvement in hypothyroid symptoms or quality of life (QoL) in older patients with subclinical hypothyroidism during treatment with levothyroxine. 15 -17”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [17]
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“This advice will prevent dissatisfaction with the outcome of LT4 treatment, as a recent meta-analysis showed that treatment of subclinical hypothyroidism does not improve clinical symptoms such as overweight [52].”
From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [52]
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“A meta-analysis among nonpregnant adults with subclinical hypothyroidism showed the use of thyroid hormone therapy was not associated with improvements in general QoL or thyroid-related symptoms [52].”
From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [52]
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“I would exclude patients who initially were treated because of subclinical hypothyroidism, as treatment is unlikely to improve their symptoms [52].”
From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [52]
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“More recently, it has become clear from placebo-controlled RCTs that the use of thyroid hormone in subclinical hypothyroidism is not associated with improvements in QoL or thyroid-related symptoms [52].”
From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [52]
In the citing paper
“A meta-analysis of randomised controlled trials (RCTs) showed no symptomatic benefits of Levothyroxine in adults with subclinical hypothyroidism [56].”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [56]
In the citing paper
“A recent (2018), high quality meta-analysis of 21 randomised, placebocontrolled trials of LT4 (N = 2192 subclinically hypothyroid adults) focussed on QoL and thyroid-related symptoms and confirmed a lack of improvement with LT4 in these subjective endpoints”
From Pharmacodynamic and Therapeutic Actions of Levothyroxine (2021) · cites this paper as [129]
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“17 Therefore, improvement in symptoms with levothyroxine treatment may be an unrealistic expectation for most patients with subclinical hypothyroidism.”
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Metadata
- Authors
- Feller, M., Snel, M., Moutzouri, E., Bauer, D. C., de Montmollin, M., Aujesky, D., Ford, I., Gussekloo, J., Kearney, P. M., Mooijaart, S., Quinn, T., Stott, D., Westendorp, R., Rodondi, N., & Dekkers, O. M.
- Affiliations
- University of Bern (CH)
- Leiden University (NL)
- University of California, San Francisco (US)
- Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- University of Glasgow (GB)
- University College Cork (IE)
- University of Copenhagen (DK)
- Corresponding author
- Feller, Martin
- ORCID
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2018-10-02
- Volume
- 320
- Issue
- 13
- Pages
- 1349
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC6233842
- OpenAlex
- W2894730508
- Cited by
- 266
- References
- 67
- Citations by year
- 2026: 22 · 2025: 28 · 2024: 23 · 2023: 42 · 2022: 32 · 2021: 42 · 2020: 42 · 2019: 31 · 2018: 4
- FWCI
- 4.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (172676)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Keywords
- subclinical hypothyroidism, thyroid hormone replacement, levothyroxine, quality of life, thyroid-stimulating hormone, TSH normalization, adults, risk of bias, quality of evidence, GRADE, standardized mean difference, risk of bias assessment
- MeSH terms
- Adult, Blood Pressure, Humans, Hypothyroidism, Quality of Life, Thyrotropin, Thyroxine, Practice Guidelines as Topic
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