Clinical Outcomes After Discontinuation of Thyroid Hormone Replacement: A Systematic Review and Meta-Analysis
Open accessAbstract
Background: Levothyroxine (LT4) is one of the most commonly prescribed medications. Although considered a life-long replacement therapy, LT4 therapy can be discontinued for some patients. This study aims at: (i) reviewing the evidence on clinical outcomes of patients undergoing thyroid hormone replacement discontinuation, (ii) identifying the predictors of successful discontinuation, and (iii) systematically appraising frameworks used for deprescribing thyroid hormone. Methods: We searched multiple bibliographic databases, including Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus, from inception to February 2020 for studies in which thyroid hormone replacement was discontinued. Clinical outcomes assessed included: proportion of patients that remained euthyroid or needed to restart thyroid hormone replacement after discontinuation and frequency of clinical symptoms of hypothyroidism and adverse effects. We also evaluated predictors for discontinuation and deprescribing frameworks. Reviewers (F.J.K.T., N.B., N.M.S.O., S.M.) evaluated studies for inclusion, extracted data, and assessed methodological quality independently and in duplicate. Results: Seventeen observational studies at moderate to high risk of bias met inclusion criteria, including a total of 1103 patients (86% women) with an age range of 2–81 years. Approximately a third of patients undergoing thyroid hormone discontinuation remained euthyroid at follow-up (37.2%, 95% confidence interval [CI 24.2–50.1%], I 2 97.5%). Subgroup analysis showed that patients with a previous diagnosis of overt hypothyroidism (OH) were less likely to remain euthyroid (11.8% [CI 0.4–23.2%], I 2 90.3%) than patients with a prior diagnosis of subclinical hypothyroidism (SCH) (35.6% [CI 8.2–62.9%], I 2 94.0%). No study followed a framework for systematically deprescribing LT4. Conclusions: Low-quality evidence suggests that up to a third of patients remained euthyroid after thyroid hormone discontinuation, with a higher proportion of patients with an initial diagnosis of SCH remaining euthyroid than patients with an initial diagnosis of OH. A deprescribing framework focusing on adequate selection of patients for deprescribing LT4 and a systematic process is warranted to guide clinicians in re-evaluating the need for LT4 in their patients.
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If levothyroxine therapy is stopped, 30%-50% of patients will remain euthyroid.
“conversely if levothyroxine therapy is stopped, 30% -50% will remain euthyroid. 27”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [27]
The Results report that 37.2% of patients remained euthyroid after thyroid hormone discontinuation, broadly consistent with the claimed 30%–50%. But this was an uncertain pooled estimate from studies at moderate to high risk of bias, not a rate that applies to all patients: the estimate was 11.8% for those previously diagnosed with overt hypothyroidism. (LLM, conf=0.84)
Experimental — accuracy not yet measuredLevothyroxine and liothyronine are overprescribed to people with a transient elevation in TSH.
“Both levothyroxine and liothyronine are currently overprescribed, 20,21,27 including to people with a transient elevation in TSH”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [27]
The Discussion says patients may be overtreated with levothyroxine when treatment begins without a well-documented hypothyroidism diagnosis or depends on the threshold used for subclinical hypothyroidism. The Results include some liothyronine users, but the paper does not establish that liothyronine is overprescribed or specifically identify transient TSH elevation as a reason for prescribing either drug. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBoth levothyroxine and liothyronine are currently overprescribed.
“Both levothyroxine and liothyronine are currently overprescribed, 20,21,27 including to people with a transient elevation in TSH”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [27]
The Introduction (page unavailable) describes extensive levothyroxine prescribing, and the Discussion (page unavailable) says patients may be overtreated with levothyroxine under certain circumstances. The paper includes liothyronine in its discontinuation review but does not establish that liothyronine is overprescribed; it also does not specifically establish prescribing after a transient TSH elevation. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLevothyroxine and liothyronine are overprescribed to those with persistent subclinical hypothyroidism.
“or to those with persistent subclinical hypothyroidism, where trials do not show a benefit from thyroid hormone replacement. 12,15,16,44 -46”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [27]
The Introduction (page unavailable) says no quality-of-life or thyroid-symptom benefit has been demonstrated for levothyroxine in subclinical hypothyroidism, and that randomized trials found no reduction in death. It also suggests some patients taking levothyroxine may receive no significant benefit. It does not establish overprescribing specifically in persistent subclinical hypothyroidism or a lack of benefit from liothyronine. (LLM, conf=0.84)
Experimental — accuracy not yet measured36% of patients with treated subclinical hypothyroidism remain euthyroid after thyroid hormone discontinuation.
“Furthermore, 36% of patients with treated subclinical hypothyroidism remain euthyroid after thyroid hormone discontinuation [56].”
From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [56]
A systematic review highlighted that up to a third of patients remained euthyroid after levothyroxine discontinuation.
“A systematic review highlighted that up to a third of patients remained euthyroid after levothyroxine discontinuation.194”
From Hypothyroidism (2024) · cites this paper as [194]
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- Authors
- Burgos, N., Toloza, F. J. K., Singh Ospina, N. M., Brito, J. P., Salloum, R. G., Hassett, L. C., & Maraka, S.
- Affiliations
- University of Puerto Rico, Medical Sciences Campus (PR)
- Mayo Clinic (US)
- Knowledge and Evaluation Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
- University of Florida Health (US)
- Corresponding author
- Maraka, Spyridoula
- Venue
- Thyroid®
- Publisher
- SAGE Publications
- Published
- 2021-05
- Volume
- 31
- Issue
- 5
- Pages
- 740-751
- ISSN
- 1050-7256 (ISSN-L)
- 1557-9077
- PMC
- PMC8110016
- OpenAlex
- W3100547195
- Cited by
- 53
- References
- 58
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 6 · 2023: 12 · 2022: 7 · 2021: 5
- FWCI
- 0.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Thyroid (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (K08CA248972)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
- Keywords
- levothyroxine, deprescribing, overt hypothyroidism, subclinical hypothyroidism, euthyroid status, quality of life
- MeSH terms
- Deprescriptions, Humans, Hypothyroidism, Thyroxine, Hormone Replacement Therapy, Asymptomatic Diseases
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