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Serum thyrotropin and triiodothyronine levels in levothyroxine-treated patients

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Ettleson, Matthew D, Prieto, Wesley H, Russo, Pedro S T, de Sa, Jose, Wan, Wen, Laiteerapong, Neda, Maciel, Rui M B, Bianco, Antonio C·2023·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/clinem/dgac725PMC PMC10413428
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Abstract

CONTEXT: Small adjustments in levothyroxine (LT4) dose do not appear to provide clinical benefit despite changes in thyrotropin (TSH) levels within the reference range. We hypothesize that the accompanying changes in serum total triiodothyronine (T3) levels do not reflect the magnitude of the changes in serum TSH. OBJECTIVE: This work aims to characterize the relationships of serum free thyroxine (FT4) vs T3, FT4 vs TSH, and FT4 vs the T3/FT4 ratio. METHODS: This cross-sectional, observational study comprised 9850 participants aged 18 years and older treated with LT4 from a large clinical database from January 1, 2009, to December 31, 2019. Patients had been treated with LT4, subdivided by serum FT4 level. Main outcome measures included model fitting of the relationships between serum FT4 vs TSH, FT4 vs T3, and FT4 vs T3/FT4. Mean and median values of TSH, T3, and T3/FT4 were calculated. RESULTS: The relationships T3 vs FT4 and TSH vs FT4 were both complex and best represented by distinct, segmented regression models. Increasing FT4 levels were linearly associated with T3 levels until an inflection point at an FT4 level of 0.7 ng/dL, after which a flattening of the slope was observed following a convex quadratic curve. In contrast, increasing FT4 levels were associated with steep declines in TSH following 2 negative sigmoid curves. The FT4 vs T3/FT4 relationship was fit to an asymptotic regression curve supporting less T4 to T3 activation at higher FT4 levels. CONCLUSION: In LT4-treated patients, the relationships between serum FT4 vs TSH and FT4 vs T3 across a range of FT4 levels are disproportionate. As a result, dose changes in LT4 that robustly modify serum FT4 and TSH values may only minimally affect serum T3 levels and result in no significant clinical benefit.

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Crossref · 10.1210/clinem/dgac725

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  • Under certain conditions, T3 signaling may be compromised in a tissue-specific fashion while systemic thyroid function is preserved.

    “Finally, there is a new understanding that, under certain conditions, T3 signaling may be compromised in a tissue-specific fashion while systemic thyroid function is preserved.”

    From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [26]

    The Discussion describes a possible difference between central and peripheral T4-to-T3 conversion in LT4-treated patients, consistent with tissue-specific differences despite a TSH response. But it says that T3 action in other tissues was not evaluated, so it does not establish compromised tissue T3 signaling while systemic thyroid function is preserved. (LLM, conf=0.82)

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  • Small changes in LT4 dose can lead to substantial variation in serum TSH levels.

    “This is because small changes in LT4 dose can lead to substantial variation in serum TSH levels (71).”

    From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [71]

  • Due to tissue-specific mechanisms that regulate local conversion of T4 to T3, including ubiquitination of type 2 deiodinase, T4 is very effective in triggering pituitary feedback and normalizing serum TSH levels but is not nearly as good at normalizing serum T3 levels, hence T3 deficiency in the setting of normal serum TSH levels.

    “Due to tissue-specific mechanisms that regulate the local conversion of T4 to T3 (ubiquitination of the type 2 deiodinase, D2), T4 is very effective in triggering the pituitary feedback mechanism and normalizing serum TSH levels. In contrast, T4 is not nearly as good at normalizing serum T3 levels (D2 is inactivated by T4), hence the T3 deficiency in the setting of normal serum TSH levels (25, 26”

    From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [26]

  • LT4 is a drug with a narrow therapeutic index.

    “The World Health Organization (WHO) has classed levothyroxine (LT4) as a narrow therapeutic index drug.”

    From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [71]

    The Conclusion discusses how LT4 dose changes affect thyroid hormone and TSH levels, but does not describe LT4 as a narrow therapeutic index drug. Searches of our copy for “narrow therapeutic index” and the WHO classification found no passage addressing either point. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 2

  1. [41]41. Welsh K, Soldin S. How reliable are free thyroid and total T-3 hormone assays? Eur J Endocrinol. 2016;175(6):R255‐R263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. [43]43. Documentation for package ‘stats’ version 4.3.0. Vol. 20222022. https://stat.ethz.ch/R-manual/R-devel/library/stats/html/00Index.html

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Authors
Ettleson, M. D., Prieto, W. H., Russo, P. S. T., de Sa, J., Wan, W., Laiteerapong, N., Maciel, R. M. B., & Bianco, A. C.
Affiliations
  • University of Chicago (US)
  • Fleury S.A. (Brazil) (BR)
  • Fleury Group , Sao Paulo, SP 04344 , Brazil
Corresponding author
Ettleson, Matthew D
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2022-12-14
Volume
108
Issue
6
Pages
e258-e266
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/clinem/dgac725
PMC
PMC10413428
OpenAlex
W4311469647
Cited by
25
References
50
Citations by year
2026: 4 · 2025: 11 · 2024: 5 · 2023: 5
FWCI
3.89
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
NIH
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
levothyroxine, free thyroxine, triiodothyronine, thyroid-stimulating hormone, hyperthyroidism, thyroid hormone metabolism, segmented regression
MeSH terms
Cross-Sectional Studies, Humans, Thyroid Function Tests, Thyrotropin, Thyroxine, Triiodothyronine

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