Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism

Wiersinga, Wilmar M.

doi:10.1038/nrendo.2013.258

Cited by 99 publications

(96 citation statements)

References 91 publications

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“…T4 + T3 combination therapy may result in serum FT3, FT4 and FT3/FT4 ratios which more closely resemble values in healthy subjects. This was indeed observed in five randomized clinical trials, which had measured FT3 and FT4 (Table 2) (14,15). Nevertheless, despite almost normal FT3/FT4 ratios in these five trials, the outcome of combination therapy was not superior over T4 monotherapy.…”

Section: Introductionmentioning

confidence: 69%

THERAPY OF ENDOCRINE DISEASE: T4 + T3 combination therapy: is there a true effect?

Wiersinga

2017

European Journal of Endocrinology

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About 5%-10% of hypothyroid patients on T4 replacement therapy have persistent symptoms, despite normal TSH levels. It was hoped that T4 + T3 combination therapy might provide better outcomes, but that was not observed according to a meta-analysis of 11 randomized clinical trials comparing T4 monotherapy with T4 + T3 combination therapy. However, the issue is still subject of much research because normal thyroid function tests in serum may not necessarily indicate an euthyroid state in all peripheral tissues. This review evaluates recent developments in the field of T4 + T3 combination therapy. T4 monotherapy is associated with higher serum FT4 levels than in healthy subjects, and subnormal serum FT3 and FT3/FT4 ratios are observed in about 15% and 30% respectively. T4 + T3 combination therapy may mimic more closely thyroid function tests of healthy subjects, but it has not been demonstrated that relatively low serum FT3 or FT3/FT4 ratios are linked to persistent symptoms. One study reports polymorphism Thr92Ala in DIO2 is related to lower serum FT3 levels after thyroidectomy, and that the D2-Ala mutant reduces T4 to T3 conversion in cell cultures. Peripheral tissue function tests such as serum cholesterol reflect thyroid hormone action in target tissues. Using such biochemical markers, patients who had a normal serum TSH during postoperative T4 monotherapy, were mildly hypothyroid, whereas those with a TSH 0.03-≤0.3 mU/L were closest to euthyroidism. Peripheral tissue function tests suggest euthyroidism more often in patients randomized to T4 + T3 rather than that to T4. Preference for T4 + T3 combination over T4 monotherapy was dose-dependently related to the presence of two polymorphisms in MCT10 and DIO2 in one small study. It is not known if persistent symptoms during T4 monotherapy disappear by switching to T4 + T3 combination therapy. The number of patients on T4 + T3 therapy has multiplied in the last decade, likely induced by indiscriminate statements on the internet. Patients are sometimes not just asking but rather demanding this treatment modality. It creates tensions between patients and physicians. Only continued research will answer the question whether or not T4 + T3 combination therapy has true benefits in some patients.

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Section: Introductionmentioning

confidence: 69%

THERAPY OF ENDOCRINE DISEASE: T4 + T3 combination therapy: is there a true effect?

Wiersinga

2017

European Journal of Endocrinology

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“…The main goal of T 4 treatment is to promptly achieve the therapeutic target, avoiding overor under-treatments (5), but some patients require several dose adjustments prior to attaining an adequate pharmacological T 4 homeostasis (6,7). Despite some reports on the inability of T 4 alone to warrant euthyroidism in all tissues (8), L-T 4 monotherapy is as yet the preferred treatment (9). Oral T 4 is asymmetrically deiodinated to triiodothyronine (T 3 ) in peripheral tissues and mimics a nearly physiological T 4 /T 3 ratio (9,10).…”

Section: Introductionmentioning

confidence: 99%

“…Despite some reports on the inability of T 4 alone to warrant euthyroidism in all tissues (8), L-T 4 monotherapy is as yet the preferred treatment (9). Oral T 4 is asymmetrically deiodinated to triiodothyronine (T 3 ) in peripheral tissues and mimics a nearly physiological T 4 /T 3 ratio (9,10). In keeping with the American Thyroid Association (ATA) and European Thyroid Association (ETA) guidelines, patients with DTC, after total thyroidectomy, should be treated with T 4 according to risk stratification (2,11).…”

Section: Introductionmentioning

confidence: 99%

“…In patients with a low risk of recurrences of DTC, T 4 treatment in semisuppressive mode is required in the first year after surgery, according to ATA guidelines (2,5). Several studies dealing with T 4 requirement have been carried out on patients with primary hypothyroidism, with or without thyroid in situ (see (6,9) for a review). Some of these studies focused on factors affecting the therapeutic dose, such as body weight (6,12), BMI (13), amount of residual thyroid tissue, patients' age and drugs (14,15,16), and only a fraction of them examined T 4 requirement after total thyroidectomy (7,8,9,10,11).…”

Section: Introductionmentioning

confidence: 99%

“…Several studies dealing with T 4 requirement have been carried out on patients with primary hypothyroidism, with or without thyroid in situ (see (6,9) for a review). Some of these studies focused on factors affecting the therapeutic dose, such as body weight (6,12), BMI (13), amount of residual thyroid tissue, patients' age and drugs (14,15,16), and only a fraction of them examined T 4 requirement after total thyroidectomy (7,8,9,10,11). However, most of these latter reports were retrospective and/or compared results obtained in different groups of patients (15,16,17), and/or in heterogeneous therapeutic settings (7,16).…”

Section: Introductionmentioning

confidence: 99%

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Individually-tailored thyroxine requirement in the same patients before and after thyroidectomy: a longitudinal study

Duca

Santaguida

Brusca

et al. 2015

European Journal of Endocrinology

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Objective: Thyroxine (T 4 ) requirement after total thyroidectomy for differentiated thyroid carcinoma (DTC) is a debated issue. As most of the studies in the area have been retrospective and/or performed with heterogeneous therapeutic approaches, we designed our study to determine T 4 requirement in the same patients and treatment settings, before and after total thyroidectomy. Design, patients and methods: This was a longitudinal study including 23 goitrous patients treated with T 4 in an individually tailored fashion. All patients exhibited a stable TSH (median TSHZ0.28 mU/l) at a stable T 4 dose for at least 1 year before surgery (median T 4 doseZ1.50 mg/kg per day). The patients underwent total thyroidectomy based on cancer suspicion or compressive symptoms. Eventually diagnosed as having DTC (pT1b-pT2N0) and following surgical and radiometabolic treatment, they were treated with the same pre-surgical doses of T 4 . Results: Three months after surgery,using the same pre-surgical dose, median TSH increased up to 5.38 mU/l (P!0.0001) and so the T 4 dose had to be increased (median T 4 doseZ1.95 mg/kg per day; C30%; P!0.0001). Once divided by patients' age, we observed that, after thyroidectomy and maintaining the same pre-surgical dose, serum TSH significantly increased both in younger and in older patients (median TSHZ4.57 and 6.11 mU/l respectively). Serum TSH was restored to the pre-surgical level by increasing the dose up to 1.95 and 1.77 mg/kg per day (C25 and C21%) respectively. Conclusions: Following the same treatment regimen, a thyroidectomized patient requires one-third higher therapeutic T 4 dose than before surgery. Despite this increase, the dose of T 4 needed in our patients remains significantly lower than that previously described in athyreotic patients.

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Thyroid‐on‐a‐Chip: An Organoid Platform for In Vitro Assessment of Endocrine Disruption

Carvalho

Kip

Romitti

et al. 2023

Adv Healthcare Materials

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Thyroid is a glandular tissue in the human body in which the function can be severely affected by endocrine disrupting chemicals (EDCs). Current in vitro assays to test endocrine disruption by chemical compounds are largely based on 2D thyroid cell cultures, which often fail to precisely evaluate the safety of these compounds. New and more advanced 3D cell culture systems are urgently needed to better recapitulate the thyroid follicular architecture and functions and help to improve the predictive power of such assays. Herein, the development of a thyroid organoid‐on‐a‐chip (OoC) device using polymeric membranous carriers is described. Mouse embryonic stem cell derived thyroid follicles are incorporated in a microfluidic chip for a 4 day experiment at a flow rate of 12 µL min−1. A reversible seal provides a leak‐tight sealing while enabling quick and easy loading/unloading of thyroid follicles. The OoC model shows a high degree of functionality, where organoids retain expression of key thyroid genes and a typical follicular structure. Finally, transcriptional changes following benzo[k]fluoranthene exposure in the OoC device demonstrate activation of the xenobiotic aryl hydrocarbon receptor pathway. Altogether, this OoC system is a physiologically relevant thyroid model, which will represent a valuable tool to test potential EDCs.

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Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism

Cited by 99 publications

References 91 publications

THERAPY OF ENDOCRINE DISEASE: T4 + T3 combination therapy: is there a true effect?

THERAPY OF ENDOCRINE DISEASE: T4 + T3 combination therapy: is there a true effect?

Individually-tailored thyroxine requirement in the same patients before and after thyroidectomy: a longitudinal study

Thyroid‐on‐a‐Chip: An Organoid Platform for In Vitro Assessment of Endocrine Disruption

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