For Some, l-Thyroxine Replacement Might Not Be Enough: A Genetic Rationale
Abstract
Although the thyroid gland secretes a very small amount of active thyroid hormone (triiodothyronine or T3), the major circulating form is thyroxine (T4), and it is widely accepted that thyroid hormone replacement in patients with hypothyroidism can be fully accomplished with l-T4 monotherapy [see 1995 American Thyroid Association guidelines (Ref. 1)]. The mechanistic basis for this belief stems from the actions of the iodothyronine deiodinases, enzymes that activate thyroid hormone by conversion of T4 to T3 (or inactivate both forms via further deiodination) (2). Thanks to the actions of the type 2 deiodinase (D2) and to some extent the type 1 deiodinase (D1), both endogenous T4 and l-t4 are converted to T3 at a rate sufficient to maintain normal serum T3 concentration. However, despite the extensive literature demonstrating that patients do well clinically on l-t4 monotherapy, most clinicians have at least anecdotally seen benefits from combined T3/T4 therapy for some patients, prompting a search for the biological mechanism of the T3 requirement. In the current issue of JCEM, Panicker et al. (3) examine this question from a novel perspective, asking whether a polymorphism in the Dio2 gene could explain a differential psychological response to the type of thyroid hormone replacement seen in a subpopulation of the Weston Area T4/T3 Study (WATTS) from the United Kingdom (3, 4). D2 was initially characterized in the pituitary gland and hypothalamus, where it plays an important…
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D2 catalyses the conversion of T4 into T3, and is especially important in the local control of thyroid hormone signalling.
“D2 cata lyses the conversion of T4 into T3, and is especially important in the local control of thyroid hormone signal-ling [63] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [63]
Cites
Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation
Watanabe, M., Houten, S. M., Mataki, C., Christoffolete, M. A., Kim, B. W., Sato, H., Messaddeq, N., Harney, J. W., Ezaki, O., Kodama, T., et al. (2006) · Nature · doi:10.1038/nature04330 · Cited by 2,220 · see citing works
Self-citationBianco, A. C., Salvatore, D., Gereben, B., Berry, M. J., & Larsen, P. R. (2002) · Endocrine Reviews · doi:10.1210/edrv.23.1.0455 · Cited by 1,853 · see citing works
Self-citationCellular and Molecular Basis of Deiodinase-Regulated Thyroid Hormone Signaling1
Gereben, B., Zavacki, A. M., Ribich, S., Kim, B. W., Huang, S. A., Simonides, W. S., Zeöld, A., & Bianco, A. C. (2008) · Endocrine Reviews · doi:10.1210/er.2008-0019 · Cited by 891 · see citing works
Self-citationFriesema, E. C., Grueters, A., Biebermann, H., Krude, H., von Moers, A., Reeser, M., Barrett, T. G., Mancilla, E. E., Svensson, J., Kester, M. H., et al. (2004) · The Lancet · doi:10.1016/s0140-6736(04)17226-7 · Cited by 709 · see citing works
Treatment Guidelines for Patients With Hyperthyroidism and Hypothyroidism
Singer, P. A. (1995) · JAMA: The Journal of the American Medical Association · doi:10.1001/jama.1995.03520340064038 · Cited by 427 · see citing works
Mutations in SECISBP2 result in abnormal thyroid hormone metabolism
Dumitrescu, A. M., Liao, X.-H., Abdullah, M. S. Y., Lado-Abeal, J., Majed, F. A., Moeller, L. C., Boran, G., Schomburg, L., Weiss, R. E., & Refetoff, S. (2005) · Nature Genetics · doi:10.1038/ng1654 · Cited by 412 · see citing works
The type 2 iodothyronine deiodinase is expressed primarily in glial cells in the neonatal rat brain
Guadaño-Ferraz, A., Obregón, M. J., Germain, D. L. S., & Bernal, J. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.19.10391 · Cited by 372 · see citing works
Bianco, A. C., & Silva, J. E. (1987) · Journal of Clinical Investigation · doi:10.1172/jci112798 · Cited by 347 · see citing works
Self-citationKester, M. H. A., de Mena, R. M., Obregón, M.-J., Marinkovic, D., Howatson, A. G., Visser, T. J., Hume, R., & de Escobar, G. M. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-031832 · Cited by 330 · see citing works
Panicker, V., Saravanan, P., Vaidya, B., Evans, J., Hattersley, A. T., Frayling, T. M., & Dayan, C. M. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-1301 · Cited by 327 · see citing works
Tu, H. M., Kim, S.-W., Salvatore, D., Bartha, T., Legradi, G., Larsen, P. R., & Lechan, R. M. (1997) · Endocrinology · doi:10.1210/endo.138.8.5318 · Cited by 302 · see citing works
Perspectives in the Study of Thyroid Hormone Action on Brain Development and Function
Bernal, J., Guadaño‐Ferraz, A., & Morte, B. (2003) · Thyroid · doi:10.1089/105072503770867174 · Cited by 287 · see citing works
Escobar-Morreale, H. F., Obregón, M. J., Escobar del Rey, F., & Morreale de Escobar, G. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118353 · Cited by 287 · see citing works
Peeters, R. P., van Toor, H., Klootwijk, W., de Rijke, Y. B., Kuiper, G. G. J. M., Uitterlinden, A. G., & Visser, T. J. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-021592 · Cited by 242 · see citing works
The Thyroid Axis and Depression
JACKSON, I. M. D. (1998) · Thyroid · doi:10.1089/thy.1998.8.951 · Cited by 230 · see citing works
Dentice, M., Bandyopadhyay, A., Gereben, B., Callebaut, I., Christoffolete, M. A., Kim, B. W., Nissim, S., Mornon, J.-P., Zavacki, A. M., Zeöld, A., et al. (2005) · Nature Cell Biology · doi:10.1038/ncb1272 · Cited by 227 · see citing works
Self-citationMentuccia, D., Proietti-Pannunzi, L., Tanner, K., Bacci, V., Pollin, T. I., Poehlman, E. T., Shuldiner, A. R., & Celi, F. S. (2002) · Diabetes · doi:10.2337/diabetes.51.3.880 · Cited by 205 · see citing works
Canani, L. H. S., Capp, C., Dora, J. M., Meyer, E. L. D. S., Wagner, M. S., Harney, J. W., Larsen, P. R., Gross, J. L., Bianco, A. C., & Maia, A. L. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1977 · Cited by 204 · see citing works
Self-citationIdentification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis
Meulenbelt, I., Min, J. L., Bos, S. D., Riyazi, N., Houwing‐Duistermaat, J. J., van der Wijk, H.-J., Kroon, H. M. J. A., Nakajima, M., Ikegawa, S., Uitterlinden, A. G., et al. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn082 · Cited by 202 · see citing works
Geffner, D. L., Azukizawa, M., & Hershman, J. M. (1975) · Journal of Clinical Investigation · doi:10.1172/jci107925 · Cited by 192 · see citing works
Galton, V. A., Wood, E. T., Germain, E. A. S., Withrow, C.-A., Aldrich, G., Germain, G. M. S., Clark, A. S., & Germain, D. L. S. (2007) · Endocrinology · doi:10.1210/en.2006-1727 · Cited by 174 · see citing works
Gereben, B., Goncalves, C., Harney, J. W., Larsen, P. R., & Bianco, A. C. (2000) · Molecular Endocrinology · doi:10.1210/mend.14.11.0558 · Cited by 161 · see citing works
Self-citationReduction in extrathyroidal triiodothyronine production by propylthiouracil in man.
Saberi, M., Sterling, F. H., & Utiger, R. D. (1975) · Journal of Clinical Investigation · doi:10.1172/jci107924 · Cited by 138 · see citing works
Saravanan, P., Simmons, D. J., Greenwood, R., Peters, T. J., & Dayan, C. M. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1672 · Cited by 136 · see citing works
Role of Thyroid Hormone Deiodination in the Hypothalamus
Lechan, R. M., & Fekete, C. (2005) · Thyroid · doi:10.1089/thy.2005.15.883 · Cited by 104 · see citing works
Mebis, L., Langouche, L., Visser, T. J., & Van den Berghe, G. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-0510 · Cited by 101 · see citing works
Campos‐Barros, Á., Hoell, T., Musa, A., Sampaolo, S., Stoltenburg, G., Pinna, G., Eravci, M., MEINHOLD, H., & Baumgartner, A. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.6.8964848 · Cited by 93 · see citing works
Torlontano, M., Durante, C., Torrente, I., Crocetti, U., Augello, G., Ronga, G., Montesano, T., Travascio, L., Verrienti, A., Bruno, R., et al. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-1067 · Cited by 92 · see citing works
Guo, T.-W., Zhang, F.-C., Yang, M.-S., Gao, X.-C., Bian, L., Duan, S.-W., Zheng, Z.-J., Gao, J.-J., Wang, H., Li, R.-L., et al. (2004) · Journal of Medical Genetics · doi:10.1136/jmg.2004.019190 · Cited by 91 · see citing works
Ala92 Type 2 Deiodinase Allele Increases Risk for the Development of Hypertension
Gumieniak, O., Perlstein, T. S., Williams, J. S., Hopkins, P. N., Brown, N. J., Raby, B. A., & Williams, G. H. (2007) · Hypertension · doi:10.1161/01.hyp.0000256295.72185.fd · Cited by 84 · see citing works
Grarup, N., Andersen, M. K., Andreasen, C. H., Albrechtsen, A., Borch-Johnsen, K., Jørgensen, T., Auwerx, J. H., Schmitz, O., Hansen, T. F., & Pedersen, O. B. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-1958 · Cited by 66 · see citing works
Mentuccia, D., Thomas, M., Coppotelli, G., Reinhart, L. J., Mitchell, B. D., Shuldiner, A. R., & Celi, F. S. (2005) · Thyroid · doi:10.1089/thy.2005.15.1223 · Cited by 53 · see citing works
Zeöld, A., Pormüller, L., Dentice, M., Harney, J. W., Curcio‐Morelli, C., Tente, S. M., Bianco, A. C., & Gereben, B. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m604728200 · Cited by 44 · see citing works
Self-citationvan der Deure, W. M., Peeters, R. P., Uitterlinden, A. G., Albert Hofman, D., Breteler, M. M. B., Witteman, J. C. M., & Visser, T. J. (2008) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2008.03447.x · Cited by 22 · see citing works
Brouwer, J. P., Appelhof, B. C., Peeters, R. P., Hoogendijk, W. J. G., Huyser, J., Schene, A. H., Tijssen, J. G. P., van Dyck, R., Visser, T. J., Wiersinga, W. M., et al. (2006) · European Journal of Endocrinology · doi:10.1530/eje.1.02155 · Cited by 21 · see citing works
Maia, A. L., Hwang, S., Levy, D. A., Larson, M. G., Larsen, P. R., & Fox, C. S. (2008) · Hypertension · doi:10.1161/hypertensionaha.107.109454 · Cited by 18 · see citing works
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2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism
Wiersinga, W. M., Duntas, L., Fadeyev, V., Nygaard, B., & Vanderpump, M. P. J. (2012) · European Thyroid Journal · doi:10.1159/000339444 · Cited by 427 · see citing works
Paradigms of dynamic control of thyroid hormone signaling
Bianco, A. C., Dumitrescu, A., Gereben, B., Ribeiro, M. O., Fonseca, T. L., Fernandes, G. W., & Bocco, B. M. L. C. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00275 · Cited by 293 · see citing works
Self-citationHoang, T. D., Olsen, C. H., Mai, V. Q., Clyde, P. W., & Shakir, M. K. M. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-4107 · Cited by 151 · see citing works
Combination Treatment with T4 and T3: Toward Personalized Replacement Therapy in Hypothyroidism?
Biondi, B., & Wartofsky, L. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-3399 · Cited by 124 · see citing works
Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism
Wiersinga, W. M. (2014) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.258 · Cited by 114 · see citing works
Diagnosis and management of treatment-refractory hypothyroidism: an expert consensus report
Centanni, M., Benvenga, S., & Sachmechi, I. (2017) · Journal of Endocrinological Investigation · doi:10.1007/s40618-017-0706-y · Cited by 113 · see citing works
“Kim and Bianco [76] postulated that some thyroid patients have a less effective deiodinase D2 enzyme for the conversion of T4 to T3.”
BackgroundPathophysiological relevance of deiodinase polymorphism
Bianco, A. C., & Kim, B. S. (2018) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0000000000000428 · Cited by 59 · see citing works
Self-citationVerloop, H., Dekkers, O. M., Peeters, R. P., Schoones, J. W., & Smit, J. W. A. (2014) · European Journal of Endocrinology · doi:10.1530/eje-14-0302 · Cited by 56 · see citing works
Do we need still more trials on T4 and T3 combination therapy in hypothyroidism?
Wiersinga, W. M. (2009) · European Journal of Endocrinology · doi:10.1530/eje-09-0879 · Cited by 43 · see citing works
Al-Azzam, S. I., Alzoubi, K. H., Khabour, O. F., & AlAzzeh, O. (2014) · HORMONES · doi:10.14310/horm.2002.1488 · Cited by 11 · see citing works
Traini, E., Ianni, F., Vergani, E., Carnassale, G., Daloiso, G., Mancini, A., & Silvestrini, A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26104521 · Cited by 3 · see citing works
Solís, J. C., Orozco, A., García, C., Robles‐Osorio, L., & Valverde, C. (2011) · PubMed · Cited by 2 · see citing works
Wilson’s Syndrome (Low T3 Syndrome)
Tang, C. J., & Garber, J. R. (2019) · Springer eBooks · doi:10.1007/978-3-030-22720-3_21 · Cited by 1 · see citing works
Combined LT3 and LT4 therapy for precision medicine: easier with TTCombo system
Gatta, E., Ippolito, S., & Cappelli, C. (2024) · Endocrine · doi:10.1007/s12020-024-04084-9 · Cited by 1 · see citing works
Merk, D., & Schubert‐Zsilavecz, M. (2012) · Pharmazie in unserer Zeit · doi:10.1002/pauz.201200486
Treatment-resistant hypothyroidism due to storage of levothyroxine at cold temperature
Barros, R. P. D. A., & Warszawski, L. (2022) · GSC Advanced Research and Reviews · doi:10.30574/gscarr.2022.12.1.0186
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Palička, V. (2009) · Klinická biochemie a metabolismus · doi:10.61568/kbm.2009.035
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Hoermann, R., & Dietrich, J. W. (2025) · Springer eBooks · doi:10.1007/978-981-96-3682-2_12
- Authors
- Kim, B. W., & Bianco, A. C.
- Affiliations
- University of Miami (US)
- Corresponding author
- Kim, Brian W.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2009-05-01
- Volume
- 94
- Issue
- 5
- Pages
- 1521-1523
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2015507181
- Cited by
- 18
- References
- 36
- Citations by year
- 2025: 2 · 2024: 1 · 2022: 1 · 2019: 2 · 2018: 1 · 2017: 1 · 2014: 3 · 2013: 1 · 2012: 3
- FWCI
- 0.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- 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
- hypothyroidism, type 2 deiodinase, endoplasmic reticulum, ubiquitination
- MeSH terms
- Iodothyronine Deiodinase Type II, Humans, Hypothyroidism, Iodide Peroxidase, Thyroxine, Triiodothyronine, Hormone Replacement Therapy
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