Sorafenib-Induced Hypothyroidism Is Associated with Increased Type 3 Deiodination
Abstract
BACKGROUND: Therapy with tyrosine kinase inhibitors is associated with thyroid dysfunction. Decreased serum thyroid hormone levels during tyrosine kinase inhibitors are also observed in athyreotic patients with thyroid carcinoma. We therefore hypothesized that tyrosine kinase inhibitors may influence thyroid hormone metabolism. AIM: The aim was to study the effects of sorafenib therapy on serum thyroid hormone concentrations and iodothyronine deiodination in athyreotic patients. DESIGN: The design included a prospective open, single-center, single-arm 26-wk study. METHODS: We measured serum thyroxine (T4), free T4, 3,5,3-triiodothyronine (T3), free T3, reverse T3 (rT3), and TSH concentrations at baseline and after 26 wk in 21 patients with progressive nonmedullary thyroid carcinoma treated with sorafenib. Ratios of T3/T4 and T3/rT3, which are independent of substrate availability and reflect iodothyronine deiodination, were calculated. RESULTS: Serum free T4 and T3 levels, adjusted for levothyroxine dose per kilogram body weight, decreased by 11 and 18%, respectively, whereas TSH levels increased. The serum T3/T4 and T3/rT3 ratios decreased by 18 and 22%, respectively, which is compatible with increased type 3 deiodination. CONCLUSIONS: Sorafenib enhances T4 and T3 metabolism, which is probably caused by increased type 3 deiodination.
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A substantially increased LT4 dose has been reported in athyreotic patients prescribed tyrosine kinase inhibitors such as imatinib, motesanib, sorafenib, sunitinib, and vandetanib.
“The need for a substantially increased dose of LT4 has been reported in athyreotic patients prescribed tyrosine kinase inhibitors such as imatinib (188), motesanib (189), sorafenib (190), sunitinib, and vandetanib (191).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [190]
Accelerated conversion of T3 to rT3 due to D3 activation has been suggested as one mechanism by which tyrosine kinase inhibitors increase LT4 requirement in hypothyroid patients.
“Accelerated conversion of T3 to rT3 because of activation of D3 has been suggested to be one of the mechanisms by which tyrosine kinase inhibitors increase the LT4 requirement in hypothyroid patients (190,191).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [190]
26 weeks of sorafenib treatment in 21 LT4-treated patients with progressive non-medullary thyroid carcinoma was associated with falls in serum FT4 and FT3 levels and the T3/T4 and T3/rT3 ratios.
“Abdulrahman et al. found that 26 weeks of sorafenib treatment in 21 LT4-treated patients with progressive non-medullary thyroid carcinoma was associate with falls in serum FT4 and FT3 levels and the T3/T4 and T3/rT3 ratios [ 113 ].”
From Factors influencing the levothyroxine dose in the hormone replacement therapy of primary hypothyroidism in adults (2022) · cites this paper as [113]
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- Authors
- Abdulrahman, R. M., Verloop, H., Hoftijzer, H., Verburg, E., Hovens, G. C., Corssmit, E. P., Reiners, C., Gelderblom, H., Pereira, A. M., Kapiteijn, E., Romijn, J. A., Visser, T. J., & Smit, J. W.
- Affiliations
- Leiden University Medical Center (NL)
- University of Würzburg (DE)
- Erasmus MC (NL)
- Corresponding author
- Smit, Johannes W.
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2010-08-01
- Volume
- 95
- Issue
- 8
- Pages
- 3758-3762
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2141352129
- Cited by
- 112
- References
- 21
- Citations by year
- 2025: 4 · 2024: 4 · 2023: 6 · 2022: 11 · 2021: 5 · 2020: 5 · 2019: 5 · 2018: 3 · 2017: 7 · 2016: 5 · 2015: 11 · 2014: 9 · 2013: 11 · 2012: 10
- FWCI
- 8.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Keywords
- sorafenib, hypothyroidism, thyroid hormone metabolism, tyrosine kinase inhibitors, thyroid cancer, serum thyroxine, free triiodothyronine, reverse T3, thyroid-stimulating hormone, drug-induced thyroid dysfunction
- MeSH terms
- Sorafenib, Aged, Aged, 80 and over, Benzenesulfonates, Carcinoma, Female, Humans, Hypothyroidism, Male, Middle Aged, Niacinamide, Phenylurea Compounds, Prospective Studies, Pyridines, Thyroid Neoplasms, Thyrotropin, Thyroxine, Triiodothyronine, Treatment Outcome, Protein Kinase Inhibitors
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