Defending plasma T3 is a biological priority
Abstract
Triiodothyronine (T3), the active form of thyroid hormone is produced predominantly outside the thyroid parenchyma secondary to peripheral tissue deiodination of thyroxine (T4), with <20% being secreted directly from the thyroid. In healthy individuals, plasma T3 is regulated by the negative feedback loop of the hypothalamus-pituitary-thyroid axis and by homoeostatic changes in deiodinase expression. Therefore, with the exception of a minimal circadian rhythmicity, serum T3 levels are stable over long periods of time. Studies in rodents indicate that different levels of genetic disruption of the feedback mechanism and deiodinase system are met with increase in serum T4 and thyroid-stimulating hormone (TSH) levels, while serum T3 levels remain stable. These findings have focused attention on serum T3 levels in patients with thyroid disease, with important clinical implications affecting therapeutic goals and choice of therapy for patients with hypothyroidism. Although monotherapy with levothyroxine is the standard of care for hypothyroidism, not all patients normalize serum T3 levels with many advocating for combination therapy with levothyroxine and liothyronine. The latter could be relevant for a significant number of patients that remain symptomatic on monotherapy with levothyroxine, despite normalization of serum TSH levels.
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A fraction of 5-15% of hypothyroid patients on L-T4 replacement continue to complain about impaired quality of life despite documented biochemical euthyroidism as defined by reference intervals.
“a fraction of 5–15% of hypothyroid patients on l-T4 replacement continue to complain about impaired QoL, despite documented biochemical euthyroidism as defined by reference intervals (7, 8).”
From Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research (2016) · cites this paper as [8]
Approximately 80% of T3 production in humans comes from deiodination of T4.
“approximately 80% of the T3 production in humans comes from the deiodination of T4 (63).”
From The progression of secondary diabetes: A review of modeling studies (2022) · cites this paper as [63]
The hypothalamus-pituitary-thyroid axis seems to be hardwired to preserve plasma T3 levels within a narrow range.
“The hypothalamus-pituitary-thyroid axis seems to be hardwired to preserve plasma T3 levels within a narrow range (37).”
From Liothyronine and Desiccated Thyroid Extract in the Treatment of Hypothyroidism (2020) · cites this paper as [37]
Deiodinases in central and peripheral tissues are regulated differently, enhancing T3 conversion and providing a differentiated mechanism for oversensitively responding to changes in FT4 in the feedback loop.
“Similarly, deiodinases in central and peripheral tissues are also regulated differently, enhancing T3 conversion and providing a differentiated mechanism for oversensitively responding to changes in FT4 in the feedback loop (55–63).”
From Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment (2015) · cites this paper as [63]
T3 supply is locally controlled by mechanisms including active thyroid hormone uptake, tissue-specific expression and activity of two distinct types of deiodinases converting T3 from T4, and thyroid hormone inactivation by deiodination or degradation.
“T3 supply is locally controlled by several mechanisms, such as active thyroid hormone uptake, tissue-specific expression and activity of two distinct types of deiodinases converting T3 from T4, and thyroid hormone inactivation by deiodination or degradation by sulfatation, deamination, or glucoronidation (57–66).”
From Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment (2015) · cites this paper as [63]
Type 2 deiodinase is upregulated in hypothyroidism.
“The regulation varies by tissue as the brain predominantly expresses type 2 deiodinase, whereas type 1 deiodinase is abundant in other tissues of the body, and by thyroid state, as T3 excess upregulates type 1 deiodinase but downregulates type 2 deiodinase, which is upregulated in hypothyroidism (57–64).”
From Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment (2015) · cites this paper as [63]
T3 excess upregulates type 1 deiodinase but downregulates type 2 deiodinase.
“The regulation varies by tissue as the brain predominantly expresses type 2 deiodinase, whereas type 1 deiodinase is abundant in other tissues of the body, and by thyroid state, as T3 excess upregulates type 1 deiodinase but downregulates type 2 deiodinase, which is upregulated in hypothyroidism (57–64).”
From Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment (2015) · cites this paper as [63]
The brain predominantly expresses type 2 deiodinase, whereas type 1 deiodinase is abundant in other tissues of the body.
“The regulation varies by tissue as the brain predominantly expresses type 2 deiodinase, whereas type 1 deiodinase is abundant in other tissues of the body, and by thyroid state, as T3 excess upregulates type 1 deiodinase but downregulates type 2 deiodinase, which is upregulated in hypothyroidism (57–64).”
From Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment (2015) · cites this paper as [63]
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The Type II Deiodinase Is Retrotranslocated to the Cytoplasm and Proteasomes via p97/Atx3 Complex
Drigo, R. A. E., Egri, P., Jo, S., Gereben, B., & Bianco, A. C. (2013) · Molecular Endocrinology · doi:10.1210/me.2013-1281 · Cited by 24 · see citing works
Visser, T. J. (2007) · Hormone Research in Paediatrics · doi:10.1159/000110469 · Cited by 22 · see citing works
Measurements of serum-free thyroid hormone concentrations by ultrafiltration
Konno, N., Hagiwara, K., Taguchi, H., Murakami, S., & Taguchi, S. (1987) · Annals of Nuclear Medicine · doi:10.1007/bf03164545 · Cited by 4 · see citing works
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Chaker, L., Bianco, A. C., Jonklaas, J., & Peeters, R. P. (2017) · The Lancet · doi:10.1016/s0140-6736(17)30703-1 · Cited by 1,159 · see citing works
Hypothyroidism in Context: Where We’ve Been and Where We’re Going
Chiovato, L., Magri, F., & Carlé, A. (2019) · Advances in Therapy · doi:10.1007/s12325-019-01080-8 · Cited by 491 · see citing works
Thyroid hormone biosynthesis and release
Carvalho, D. P., & Dupuy, C. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.01.038 · Cited by 346 · 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
The classic pathways of thyroid hormone metabolism
van der Spek, A. H., Fliers, E., & Boelen, A. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.01.025 · Cited by 194 · see citing works
Is a Normal TSH Synonymous With “Euthyroidism” in Levothyroxine Monotherapy?
Peterson, S. J., McAninch, E. A., & Bianco, A. C. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2016-2660 · Cited by 182 · see citing works
“However, the present results revealed that few of the clinical parameters were significantly associated with serum free T3, serum free T4 and/or serum free T3:free T4 ratio by univariate analysis, and the strength of the relationship was not always impressive.”
MethodInfluentialSelf-citationDietrich, J. W., Landgrafe-Mende, G., Wiora, E., Chatzitomaris, A., Klein, H. H., Midgley, J. E. M., & Hoermann, R. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00057 · Cited by 164 · see citing works
“Rather, they display symptoms that are compatible with either hypothyroidism and hyperthyroidism, and a fraction of 5–15% of hypothyroid patients on -T4 replacement continue to complain about impaired QoL, despite documented biochemical euthyroidism as defined by reference intervals (7, 8).”
BackgroundHomeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment
Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00177 · Cited by 143 · see citing works
Thyroid Function in Human Obesity: Underlying Mechanisms
Fontenelle, L. F., Feitosa, M. F., Severo, J. S., Freitas, T., Morais, J. B. S., Torres‐Leal, F. L., Henriques, G. S., & Marreiro, D. D. N. (2016) · Hormone and Metabolic Research · doi:10.1055/s-0042-121421 · Cited by 138 · see citing works
Scope and limitations of iodothyronine deiodinases in hypothyroidism
Gereben, B., McAninch, E. A., Ribeiro, M. O., & Bianco, A. C. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.155 · Cited by 146 · see citing works
“Similarly, treatment of cancer patients with the tyrosine kinase inhibitors imatinib and sunitinib is associated with the development of hypothyroidism, which seems to be the result of marked overexpression of DIO3 within the tumour cells.(86)”
BackgroundThyroid Hormone Plays an Important Role in Cardiac Function: From Bench to Bedside
Yamakawa, H., Kato, T., Noh, J. Y., Yuasa, S., Kawamura, A., Fukuda, K., & Aizawa, Y. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.606931 · Cited by 137 · see citing works
“Measurement of T3 does not correlate with therapeutic efficacy (Abdalla and Bianco, 2014).”
BackgroundDIAGNOSIS OF ENDOCRINE DISEASE: How reliable are free thyroid and total T3 hormone assays?
Welsh, K. J., & Soldin, S. J. (2016) · European Journal of Endocrinology · doi:10.1530/eje-16-0193 · Cited by 124 · see citing works
The history and future of treatment of hypothyroidism
McAninch, E. A., & Bianco, A. C. (2016) · Annals of Internal Medicine · doi:10.7326/m15-1799 · Cited by 118 · see citing works
“The development of a novel drug delivery system for L-triiodothyronine would facilitate these studies (5).”
InfluentialDeiodinases and the Metabolic Code for Thyroid Hormone Action
Russo, S. C., Salas-Lucia, F., & Bianco, A. C. (2021) · Endocrinology · doi:10.1210/endocr/bqab059 · Cited by 122 · see citing works
Joseph‐Bravo, P., Jaimes-Hoy, L., Uribe, R.-M., & Charli, J. (2015) · Journal of Endocrinology · doi:10.1530/joe-15-0124 · Cited by 107 · see citing works
Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain
Jo, S., Fonseca, T. L., Bocco, B. M. L. C., Fernandes, G. W., McAninch, E. A., Bolin, A. P., Da Conceição, R. R., Werneck-de-Castro, J. P., Ignacio, D. L., Egri, P., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci123176 · Cited by 107 · see citing works
Self-citationAmiodarone and thyroid physiology, pathophysiology, diagnosis and management
Trohman, R. G., Sharma, P. S., McAninch, E. A., & Bianco, A. C. (2018) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2018.09.005 · Cited by 107 · see citing works
“Given the fundamental role played by D2 in determining the plasma levels of TSH [53] and TSH releasing hormone (TRH) [54] secretion, as well as plasma T3 [55], it is expected that amiodarone/DEA-mediated D2 inhibition explains a substantial component of these drugs’ effect on thyroid economy.”
Backgroundvan den Berg, E. H., van Tienhoven‐Wind, L. J. N., Amini, M., Schreuder, T. C. M. A., Faber, K. N., Blokzijl, H., & Dullaart, R. P. F. (2016) · Metabolism · doi:10.1016/j.metabol.2016.11.002 · Cited by 99 · see citing works
“Triiodothyronine is commonly believed to be more biologically active as a regulator of metabolic processes than is prohormone, thyroxine [29,30].”
BackgroundThe Deiodinase Trio and Thyroid Hormone Signaling
Bianco, A. C., & da Conceição, R. R. (2018) · Methods in Molecular Biology · doi:10.1007/978-1-4939-7902-8_8 · Cited by 96 · see citing works
“Indeed, in rodents D1 is responsible for approximately half of the daily extrathyroidal production of T3, but in humans D1 plays a lesser role in maintaining circulating T3 [25, 26].”
BackgroundOptimal thyroid hormone replacement
Jonklaas, J. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnab031 · Cited by 89 · see citing works
The Role of Thyroid Hormones in Heart Failure
Vale, C., Neves, J. S., von Hafe, M., Borges‐Canha, M., & Leite-Moreira, A. F. (2019) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-019-06870-4 · Cited by 78 · see citing works
Hypothyroidism and Depression: A Narrative Review
Nuguru, S. P., Rachakonda, S., Sripathi, S., Khan, M. I., Patel, N., & Meda, R. T. (2022) · Cureus · doi:10.7759/cureus.28201 · Cited by 103 · see citing works
“Routine triiodothyronine measurements should not be used to evaluate therapy success [42].”
BackgroundJoseph‐Bravo, P., Jaimes-Hoy, L., Uribe, R.-M., & Charli, J. (2015) · Journal of Endocrinology · doi:10.1530/joe-15-0124e · Cited by 81 · see citing works
Individualized Therapy for Hypothyroidism: Is T4 Enough for Everyone?
Ettleson, M. D., & Bianco, A. C. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa430 · Cited by 75 · see citing works
Self-citationSaxena, P., Hamri, G. C., Folcher, M., Zulewski, H., & Fussenegger, M. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1514383113 · Cited by 74 · see citing works
“Early forms of hyperthyroidism are characterized by an increase of T4 levels, because the thyroid gland releases more T4 (80%) than T3 (20%) (2, 3).”
BackgroundTănase, D. M., Gosav, E. M., Neculae, E., Costea, C. F., Ciocoiu, M., Hurjui, L. L., Tărniceriu, C. C., & Floria, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165927 · Cited by 66 · see citing works
Levothyroxine: conventional and novel drug delivery formulations.
Liu, H., Li, W., Zhang, W., Sun, S., & Chen, C. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnac030 · Cited by 63 · see citing works
Liothyronine and Desiccated Thyroid Extract in the Treatment of Hypothyroidism
Idrees, T., Palmer, S., Maciel, R. M. B., & Bianco, A. C. (2020) · Thyroid® · doi:10.1089/thy.2020.0153 · Cited by 58 · see citing works
“The hypothalamus-pituitary-thyroid axis seems to be hardwired to preserve plasma T3 levels within a narrow range (37).”
BackgroundSelf-citationHoermann, R., Midgley, J., Larisch, R., & Dietrich, J. (2015) · Hormone and Metabolic Research · doi:10.1055/s-0034-1398616 · Cited by 50 · see citing works
Kuś, A., Marouli, E., Fabiola Del Greco, M., Chaker, L., Bednarczuk, T., Peeters, R. P., Teumer, A., Medici, M., & Deloukas, P. (2020) · Thyroid · doi:10.1089/thy.2020.0393 · Cited by 52 · see citing works
Relational Stability in the Expression of Normality, Variation, and Control of Thyroid Function
Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00142 · Cited by 48 · see citing works
Thyroid hormone, gene expression, and Central Nervous System: Where we are
Giannocco, G., Kizys, M. M. L., Maciel, R. M. B., & de Souza, J. S. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2020.09.007 · Cited by 50 · see citing works
Epidemiology, Types, Causes, Clinical Presentation, Diagnosis, and Treatment of Hypothyroidism
Zamwar, U. M., & Muneshwar, K. N. (2023) · Cureus · doi:10.7759/cureus.46241 · Cited by 65 · see citing works
Thyrotropin Levels Are Associated with Cardiometabolic Risk Factors in Euthyroid Adolescents
Le, T. N., Celi, F. S., & Wickham, E. P. (2016) · Thyroid® · doi:10.1089/thy.2016.0055 · Cited by 53 · see citing works
“As a consequence, there has been increasing interest in determining if additional serum parameters of thyroid function may better inform assessments of thyroid hormone activity at the tissue level (16).”
BackgroundBatistuzzo, A., & Ribeiro, M. O. (2020) · Archives of Endocrinology and Metabolism · doi:10.20945/2359-3997000000201 · Cited by 44 · see citing works
“T3 is a biologically active hormone and is fundamental for growth, differentiation, activity regulation and organ and tissue metabolism, even in adult life (1).”
BackgroundKaminski, J., Miasaki, F. Y., Paz-Filho, G., Graf, H., & Carvalho, G. A. D. (2016) · Archives of Endocrinology and Metabolism · doi:10.1590/2359-3997000000192 · Cited by 42 · see citing works
“The remaining 80% of the circulating T3 derives from peripheral 5’-deiodination of the secreted T4 (17).”
BackgroundIndividualised requirements for optimum treatment of hypothyroidism: complex needs, limited options
Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2019) · Drugs in Context · doi:10.7573/dic.212597 · Cited by 40 · see citing works
Lignell, S., Aune, M., Darnerud, P. O., Stridsberg, M., Hanberg, A., Larsson, S. C., & Glynn, A. W. (2016) · Environmental Health · doi:10.1186/s12940-016-0139-7 · Cited by 40 · see citing works
“4 nmol/L, and total T3 normally is relatively stable over time [41].”
BackgroundThyroid Hormone and Skeletal Development
Gouveia, C. H. D. A., Miranda-Rodrigues, M., Martins, G. M., & Neofiti-Papi, B. (2018) · Vitamins and hormones · doi:10.1016/bs.vh.2017.06.002 · Cited by 39 · see citing works
Persistent hypothyroid symptoms in a patient with a normal thyroid stimulating hormone level
Jonklaas, J. (2017) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000355 · Cited by 38 · see citing works
Das, D., Banerjee, A., Jena, A. B., Duttaroy, A. K., & Pathak, S. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.112613 · Cited by 38 · see citing works
T3-induced enhancement of mitochondrial Ca2+ uptake as a boost for mitochondrial metabolism.
Tawfik, I., Gottschalk, B., Jarc, A., Bresilla, D., Rost, R., Obermayer-Pietsch, B., Graier, W. F., & Madreiter‐Sokolowski, C. (2022) · Free Radical Biology & Medicine · doi:10.1016/j.freeradbiomed.2022.01.024 · Cited by 31 · see citing works
Relation Between Zinc and Thyroid Hormones in Humans: a Systematic Review
Beserra, J. B., Morais, J. B. S., Severo, J. S., Cruz, K. J. C., de Oliveira, A. R. S., Henriques, G. S., & Marreiro, D. D. N. (2021) · Biological Trace Element Research · doi:10.1007/s12011-020-02562-5 · Cited by 35 · see citing works
Andrade, M. N., Santos-Silva, A. P., Rodrigues-Pereira, P., Paiva-Melo, F. D., Lima-Junior, N. C., Teixeira, M. P., Soares, P., Dias, G. R. M., Graceli, J. B., de Carvalho, D. P., et al. (2018) · Environmental Pollution · doi:10.1016/j.envpol.2018.06.006 · Cited by 34 · see citing works
Pharmacokinetics of L-Triiodothyronine in Patients Undergoing Thyroid Hormone Therapy Withdrawal
Van Tassell, B., Wohlford, G. F., Linderman, J. D., Smith, S., Yavuz, S., Pucino, F., & Celi, F. S. (2019) · Thyroid® · doi:10.1089/thy.2019.0101 · Cited by 31 · see citing works
“Because of the renewed interest in LT3/ LT4 combination therapy (23,24), the precise knowledge of the pharmacokinetics (PK) of LT3 at low doses is of paramount importance to design therapeutic regimens and formulations that are able to provide predictable amounts of thyroid hormone while avoiding excursions in the T3…”
BackgroundThermoregulation in hibernating mammals: The role of the “thyroid hormones system”
Frare, C., Williams, C. T., & Drew, K. L. (2020) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2020.111054 · Cited by 33 · see citing works
“Although T3 is considered the biologically active form of TH, a much larger proportion of T4 is secreted into the plasma compared to T3 (Abdalla and Bianco, 2014).”
BackgroundThe Relationship between Population T4/TSH Set Point Data and T4/TSH Physiology
Fitzgerald, S. P., & Bean, N. G. (2016) · Journal of Thyroid Research · doi:10.1155/2016/6351473 · Cited by 31 · see citing works
“Though T3, the active thyroid hormone [19], acting via the TRβ2 receptor, and not T4, is regarded as the regulator of TSH physiology and gene expression [20–22], and though there is also a negative log-linear relationship between T3 and TSH [2], Goede et al.”
Iacovides, S., Maloney, S. K., Bhana, S., Angamia, Z., & Meiring, R. M. (2022) · PLoS ONE · doi:10.1371/journal.pone.0269440 · Cited by 32 · see citing works
Sudden Cardiac Arrest in a Patient With Myxedema Coma and COVID-19
Dixit, N. M., Truong, K. P., Rabadia, S. V., Li, D., Srivastava, P. K., Mosaferi, T., Press, M. C., Donangelo, I., & Kelesidis, T. (2020) · Journal of the Endocrine Society · doi:10.1210/jendso/bvaa130 · Cited by 31 · see citing works
“Given that the conversion of T 4 to metabolically active T3 occurs over the course of hours, we suspect it is unlikely the levothyroxine infusion precipitated SCA in our case [29].”
BackgroundSun, J., Letcher, R. J., Waugh, C. A., Jaspers, V. L. B., Covaci, A., & Fernie, K. J. (2021) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2021.145346 · Cited by 31 · see citing works
Midgley, J. E. M., Larisch, R., Dietrich, J. W., & Hoermann, R. (2015) · Endocrine Connections · doi:10.1530/ec-15-0056 · Cited by 31 · see citing works
Risks and safety of combination therapy for hypothyroidism
Jonklaas, J. (2016) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2016.1182019 · Cited by 27 · see citing works
µ-Crystallin: A thyroid hormone binding protein
Kinney, C. J., & Bloch, R. J. (2021) · Endocrine Regulations · doi:10.2478/enr-2021-0011 · Cited by 26 · see citing works
“T3 has a 10-fold higher affinity for TRs than T4 and therefore, it is a more potent transcription factor (Abdalla and Bianco 2014).”
BackgroundLawton, R. I., Sabatini, B. L., & Hochbaum, D. R. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2308652121 · Cited by 26 · see citing works
“Changes in T3 levels alter the function of tissues throughout the body (17).”
BackgroundPrevalence of amiodarone-induced hypothyroidism; A systematic review and meta-analysis
Mohammadi, K., Shafie, D., Vakhshoori, M., Bondariyan, N., Rezvanian, H., & Heidarpour, M. (2022) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2022.01.001 · Cited by 24 · see citing works
The Swinging Pendulum in Treatment for Hypothyroidism: From (and Toward?) Combination Therapy
McAninch, E. A., & Bianco, A. C. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00446 · Cited by 24 · see citing works
“The study of a number of animal models indicate that maintaining normal serum T3 levels is a biological priority (18).”
BackgroundDa Conceição, R. R., Fernandes, G. W., Fonseca, T. L., Bocco, B. M. L. C., & Bianco, A. C. (2018) · Thyroid · doi:10.1089/thy.2018.0205 · Cited by 23 · see citing works
“Maintaining fairly stable serum T3 levels is a priority for the HPT axis, given that T3 levels are kept quite stable within the normal reference range, even in animals that are genetically modified not to convert T4 to T3 (4–6).”
Self-citationMasika, L. S., Zhao, Z., & Soldin, S. J. (2016) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2016.02.004 · Cited by 23 · see citing works
A review of potential biomarkers for assessing physical and psychological trauma in paediatric burns
Carlton, M., Voisey, J., Parker, T., Punyadeera, C., & Cuttle, L. (2021) · Burns & Trauma · doi:10.1093/burnst/tkaa049 · Cited by 14 · see citing works
“T3 is produced in the periphery by enzymatic cleavage of its precursor [110] and has been reported to remain lower than normal for up to 4 weeks post-burn [103].”
BackgroundUcci, S., Renzini, A., Russi, V., Mangialardo, C., Cammarata, I., Cavioli, G., Santaguida, M. G., Virili, C., Centanni, M., Adamo, S., et al. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20225754 · Cited by 21 · see citing works
“Importantly, in our experimental conditions, administration of T3 significantly affected the expression of numerous wellknown T3-target genes in skeletal muscle, without increasing the Dio2 expression levels in skeletal muscle, which resulted significantly down-regulated by starvation, as previously reported [55], or…”
BackgroundLow serum selenium in pregnancy is associated with reduced T3 and increased risk of GDM
Hofstee, P., James‐McAlpine, J., McKeating, D. R., Vanderlelie, J. J., Cuffe, J. S. M., & Perkins, A. V. (2020) · Journal of Endocrinology · doi:10.1530/joe-20-0319 · Cited by 21 · see citing works
Midgley, J. E. M., Larisch, R., Dietrich, J. W., & Hoermann, R. (2015) · Endocrine Connections · doi:10.1530/ec-150056 · Cited by 31 · see citing works
“Dosing strategies solely based on a TSH definition of euthyroidism neglect the 308 important role of FT3, which has recently emerged as an equally significant parameter in 309 defining thyroid physiology (20,22,29,30,40,41).”
BackgroundThe Hypothalamic-Pituitary-Thyroid Axis: Physiological Regulation and Clinical Implications
Gavrila, A., & Hollenberg, A. N. (2019) · Springer eBooks · doi:10.1007/978-3-319-72102-6_2 · Cited by 19 · see citing works
Goodchild, C. G., Karouna‐Renier, N. K., Henry, P. F. P., Letcher, R. J., Schultz, S., Maddox, C. M., Bean, T. G., Peters, L. E., Palace, V. P., & Fernie, K. J. (2021) · Environment International · doi:10.1016/j.envint.2021.106826 · Cited by 20 · see citing works
Physiological Role and Use of Thyroid Hormone Metabolites - Potential Utility in COVID-19 Patients
Fröhlich, E., & Wahl, R. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.587518 · Cited by 20 · see citing works
“When LT4was dosed to reachT3 levels of the controls, TSHwas lowered or suppressed (126).”
BackgroundBagga, A. D., Johnson, B. P., & Zhang, Q. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1168663 · Cited by 18 · see citing works
“It has been argued that net efflux of T3 into the circulation could occur in deiodinase 1 (DIO1) and DIO2expressing tissues whose capacity of T3 elimination is poor (68).”
BackgroundThyroid Hormone Homeostasis in Levothyroxine-treated Patients: Findings From ELSA-Brasil
Penna, G. C., Bensenor, I. M., Bianco, A. C., & Ettleson, M. D. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae139 · Cited by 16 · see citing works
Kanegusuku, A. G., Araque, K., Nguyen, H., Wei, B., Hosseini, S., & Soldin, S. J. (2021) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/2042018821989240 · Cited by 15 · see citing works
Fitzgerald, S. P., & Falhammar, H. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.920854 · Cited by 16 · see citing works
“T3 is the active intracellular hormone, and it has been suggested that physiological processes act to maintain stable plasma T3 levels (6).”
BackgroundAssessment of thyroid function tests and harmonization: opinion on thyroid hormone harmonization
Araque, K. A., Klubo-Gwiezdzinska, J., Nieman, L. K., Welsh, K., & Soldin, S. J. (2019) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/2042018819897049 · Cited by 14 · see citing works
Myocardial Inactivation of Thyroid Hormones in Patients with Aortic Stenosis
Paolino, B. S., Pomerantzeff, P. M. A., Dallan, L. A. O., Gaiotto, F. A., Preite, N. Z., Latronico, A. C., Nicolau, J. C., Bianco, A. C., & Giraldez, R. R. (2017) · Thyroid · doi:10.1089/thy.2016.0514 · Cited by 13 · see citing works
“Of these, six were excluded due to subclinical hypothyroidism (4), use of amiodarone during surgery (1) or technical limitations in the collection of central blood samples (1).”
Variants in MCT10 protein do not affect FT3 levels in athyreotic patients
Cantara, S., Ricci, C., Maino, F., Marzocchi, C., Pacini, F., & Castagna, M. G. (2019) · Endocrine · doi:10.1007/s12020-019-02001-z · Cited by 12 · see citing works
Kim, T. H., Joung, J. Y., Kang, M., Choi, S. K., Kim, K., Jang, J. Y., Cho, Y. Y., Min, Y., Chung, J. H., & Kim, S. W. (2015) · PLoS ONE · doi:10.1371/journal.pone.0145292 · Cited by 13 · see citing works
“Plasma levels of active thyroid hormone T3 are remarkably stable in healthy adult individuals [15] as a result of combined homeostatic mechanisms by the hypothalamic-pituitary-thyroid axis and a group of deiodinases found in extrathyroidal tissues, including the skeleton [16, 17].”
BackgroundEffect of thyroid disruption on ovarian development following maternal exposure to Bisphenol S
Chouchene, L., Boughammoura, S., Rhouma, M. B., Mlouka, R., Bannı, M., Messaoudi, I., & Kessabi, K. (2024) · Environmental Science and Pollution Research · doi:10.1007/s11356-024-34666-z · Cited by 11 · see citing works
“Astoundingly, Abdalla et al. (2014) came up with a very interesting finding.”
Thyroid dysfunction in the era of precision medicine
Galofré, J. C., Díez, J. J., & Cooper, D. S. (2016) · Endocrinología y Nutrición · doi:10.1016/j.endonu.2016.04.009 · Cited by 11 · see citing works
Sun, Q., Avallone, L., Stolze, B. R., Araque, K., Özarda, Y., Jonklaas, J., Parikh, T. P., Welsh, K. J., Masika, L., & Soldin, S. J. (2020) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/2042018820922688 · Cited by 11 · see citing works
Wang, X., Zhang, W., & Zhou, S. (2024) · Phytotherapy Research · doi:10.1002/ptr.8208 · Cited by 12 · see citing works
Zhang, H., Tong, W., Zeng, W., Luo, H., Zhang, L., Feng, J., Xiao, Y., & Wang, G. A. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1627787 · Cited by 12 · see citing works
“However, a consensus regarding the clinical signi fi cance of reduced T3 and whether this should be corrected is unknown (5, 41).”
Post, A., Garcia, E., Gruppen, E. G., Kremer, D., Connelly, M. A., Bakker, S. J. L., & Dullaart, R. P. F. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac044 · Cited by 10 · see citing works
Local hyperthyroidism promotes pancreatic acinar cell proliferation during acute pancreatitis
Malagola, E., Chen, R., Bombardo, M., Saponara, E., Dentice, M., Salvatore, D., Reding, T., Myers, S., Hills, A. P., Graf, R., et al. (2019) · The Journal of Pathology · doi:10.1002/path.5247 · Cited by 10 · see citing works
“Increased F-T3 levels in pancreatic tissue may derive from increased uptake from the circulation of T3 and/or of T4, with subsequent conversion into T3 by the action of deiodinase (DIO) enzymes, which regulate the intracellular hormone concentration in a time- and tissue-specific fashion, independently of the levels p…”
BackgroundTemporal Pole Responds to Subtle Changes in Local Thyroid Hormone Signaling
Marcelino, C. P., McAninch, E. A., Fernandes, G. W., Bocco, B. M. L. C., Ribeiro, M. O., & Bianco, A. C. (2020) · Journal of the Endocrine Society · doi:10.1210/jendso/bvaa136 · Cited by 9 · see citing works
“For example, could the relatively lower serum T3 levels observed in LT4-treated patients [28] affect TH signaling in the brain? Or explain symptoms of impaired mood and cognition seen in some of these patients [29]? Here we used data from a previous study of the cerebral temporal pole transcriptome of 19 deceased dono…”
MethodVargas‐Uricoechea, H., & Wartofsky, L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25179218 · Cited by 11 · see citing works
“Therefore, a “physiological” replacement therapy aimed at providing the T3 that is not produced (for example, in athyrotic patients) would require minimal doses of LT3 [76,85,86].”
BackgroundPATEL, V. G., Joharapurkar, A. A., Kshirsagar, S. G., Patel, M. S., Patel, H., Savsani, H. H., & Jain, M. R. (2021) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2021.115825 · Cited by 9 · see citing works
Yuan, J., Chen, Z., Zhang, J., Chen, X., Chen, S., Wang, X., zhang, J., Su, X., Zhu, W., Sheng, J., et al. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae601 · Cited by 8 · see citing works
Structural insights into thyroid hormone transporter MCT8
Tan, J., Xiao, Y., Kong, F., Qian, J., Zhu, A., & Yan, C. (2025) · Nature Communications · doi:10.1038/s41467-025-58131-8 · Cited by 7 · see citing works
“Thyroid follicular cells primarily secrete T4, but T3 is recognized as the biologically active TH responsible for most of its actions by binding to nuclear receptors 2,17,18 .”
Liu, Y., Osinga, J. A. J., Feldt‐Rasmussen, U., Vrijkotte, T. G. M., Taylor, P. N., Aminorroaya, A., Ashoor, G., Bliddal, S., Chen, L., Vaidya, B., et al. (2025) · Journal of Autoimmunity · doi:10.1016/j.jaut.2025.103491 · Cited by 7 · see citing works
“…(approximately 20 % and 80 %, respectively) [50,51], although TAI can decrease the thyroid functional capacity, the T3 that is produced by peripheral deiodination presumably is able to maintain T3 concentrations within the normal range even if the circulating FT4 is mildly reduced [52,53].”
Role of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism
Jonklaas, J. (2022) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2021.12.003 · Cited by 7 · see citing works
Ma, S., Li, L., Chen, X., Chen, S., Dong, Y., Gao, Q., Zhou, Y., & Dong, S. (2023) · Frontiers in Marine Science · doi:10.3389/fmars.2023.1116719 · Cited by 7 · see citing works
“They mainly exist in the form of FT3 and FT4 in blood (Johnson and Lema, 2011; Peter, 2011; Mullur et al., 2014; Abdalla and Bianco, 2014).”
BackgroundBalkrishna, A., Paliwal, R., Maity, M., Varshney, Y., Sinha, S., & Varshney, A. (2024) · Clinical Phytoscience · doi:10.1186/s40816-024-00371-0 · Cited by 7 · see citing works
“T3 has a greater biological activity as compared to T4; the latter acting as a prohormone, which needs to be converted to T3 [23].”
BackgroundThe progression of secondary diabetes: A review of modeling studies
Yang, B., Li, J., Haller, M. J., Schatz, D. A., & Rong, L. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1070979 · Cited by 6 · see citing works
“Although T3 is the biologically active thyroid hormone in target tissues, approximately 80% of the T3 production in humans comes from the deiodination of T4 (63).”
BackgroundTobi, D., Krashin, E., Davis, P. J., Cody, V., Ellis, M. H., & Ashur‐Fabian, O. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.895240 · Cited by 6 · see citing works
Efficacy of Ayurvedic Interventions in Hypothyroidism
Dixit, A. K., Sarkar, M., Nair, P. G., Puia, L., Bora, M., Gaidhani, S. N., & Hazra, J. (2019) · Journal of Research in Ayurvedic Sciences · doi:10.5005/jras-10064-0090 · Cited by 6 · see citing works
“5 Furthermore, the human recipients of both T3 and L-thyroxine (LT4), simultaneously, had benefited as compared to monotherapy recipients; however, this has not been justified with repetitive clinical trials.”
BackgroundJonklaas, J. (2019) · Springer eBooks · doi:10.1007/978-3-319-72102-6_19 · Cited by 6 · see citing works
Guo, X., Tang, S., Li, Y., Mu, C., Zhang, H., Jiang, Q., Jiang, M., Han, W., Zheng, Y., & Piao, J. (2024) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2024.174535 · Cited by 5 · see citing works
Shared Decisionmaking in the Treatment of Hypothyroidism
Bianco, A. C. (2025) · Clinical Endocrinology · doi:10.1111/cen.15228 · Cited by 5 · see citing works
“The existence of such elaborate mechanisms indicates that the hypothalamus ‐ pituitary ‐ thyroid axis is hard ‐ wired to preserve/defend plasma T3 levels [18].”
Sirsat, T., & Dzialowski, E. (2020) · Journal of Experimental Biology · doi:10.1242/jeb.237701 · Cited by 9 · see citing works
Metabolic Consequences of Thyroidectomy and Patient-Centered Management
Wang, K., & Güleç, S. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13237465 · Cited by 5 · see citing works
Lüdtke, L., Ittermann, T., Großjohann, R., Jürgens, C., Völzke, H., Tost, F., & Stahl, A. (2024) · Medical Science Monitor · doi:10.12659/msm.943140 · Cited by 4 · see citing works
“Thyroid function influences other metabolic processes, such as lipid metabolism. fT3 is more biologically active than the prohor-mone fT4 [49].”
BackgroundElghawy, O., Hafey, A. C., McCartney, C. R., & Steinman, J. R. (2021) · Journal of Clinical and Translational Endocrinology Case Reports · doi:10.1016/j.jecr.2021.100095 · Cited by 4 · see citing works
No association between zinc and thyroid activity in obese women
Beserra, J. B., Morais, J. B. S., Severo, J. S., Cruz, K. J. C., de Oliveira, A. R. S., de Oliveira, F. E., Neto, E. M. D. M., Henriques, G. S., & Marreiro, D. D. N. (2019) · International Journal for Vitamin and Nutrition Research · doi:10.1024/0300-9831/a000600 · Cited by 4 · see citing works
- Authors
- Abdalla, S. M., & Bianco, A. C.
- Affiliations
- Rush University Medical Center (US)
- Corresponding author
- Bianco, Antonio C.
- ORCID
- Bianco, Antonio C.
- Venue
- Clinical Endocrinology
- Publisher
- Wiley
- Published
- 2014-08-07
- Volume
- 81
- Issue
- 5
- Pages
- 633-641
- ISSN
- 0300-0664 (ISSN-L)
- 1365-2265
- OpenAlex
- W2065359672
- Cited by
- 147
- References
- 89
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 18 · 2023: 11 · 2022: 16 · 2021: 14 · 2020: 15 · 2019: 16 · 2018: 7 · 2017: 8 · 2016: 17 · 2015: 11
- FWCI
- 1.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK065055)
- 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
- triiodothyronine, thyroid hormone regulation, deiodinases, hypothalamic-pituitary-thyroid axis, hypothyroidism, levothyroxine, liothyronine, combination thyroid hormone therapy, thyroxine, thyroid-stimulating hormone
- MeSH terms
- Blood Chemical Analysis, Humans, Hypothalamo-Hypophyseal System, Hypothyroidism, Iodide Peroxidase, Thyroid Function Tests, Thyroid Gland, Thyroxine, Triiodothyronine
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