Neither Baseline nor Changes in Serum Triiodothyronine during Levothyroxine/Liothyronine Combination Therapy Predict a Positive Response to This Treatment Modality in Hypothyroid Patients with Persistent Symptoms

Medici, Bjarke Borregaard; Cour, Jeppe Lerche la; Michaelsson, Luba Freja; Faber, Jens; Nygaard, Birte

doi:10.1159/000454878

Cited by 20 publications

(11 citation statements)

References 17 publications

(30 reference statements)

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“…Nevertheless, despite almost normal FT3/FT4 ratios in these five trials, the outcome of combination therapy was not superior over T4 monotherapy. A recent Danish study also raised doubts whether serum T3 levels are related to persistent symptoms (16). T4 + T3 combination therapy was given to 37 patients; after 12 months 65% were classified as responders and 35% as non-responders.…”

Section: Introductionmentioning

confidence: 99%

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: 99%

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

Wiersinga

2017

European Journal of Endocrinology

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“…Twelve additional patient scenarios then introduced factors that have been suggested in the literature to potentially provide reasons for considering combination therapy. Examples of these factors included presence of symptoms, low serum T3 concentration, a patient request for T3, documentation of deiodinase polymorphism status (28–30) etc (see Table 1), table also included in prior reports (26, 27). Survey respondents were asked to select from the following treatment options for each of the 13 patient scenarios presented: (a) Continue current levothyroxine, (b) Increase levothyroxine dose, (c) Add 2.5 mcg liothyronine (Cytomel) twice daily and reduce levothyroxine, (d) Add 2.5 mcg liothyronine (Cytomel) twice daily to current levothyroxine, (e) Replace levothyroxine with thyroid extract (e.g., armor thyroid), (f) Replace levothyroxine with liothyronine (Cytomel) as single therapy (see left hand columns of Tables 2A,B).…”

Section: Methodsmentioning

confidence: 99%

Short-Term Time Trends in Prescribing Therapy for Hypothyroidism: Results of a Survey of American Thyroid Association Members

2019

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Objective: Hypothyroid patients frequently request specific therapies from their physicians. Combination therapy is vigorously discussed at professional meetings. We wished to determine if physician prescribing patterns for hypothyroidism changed during 2017 after specific educational events.Methods: A survey addressing treatment of hypothyroidism was emailed to American Thyroid Association (ATA) members on three occasions in 2017. The Spring emails were sent prior to a satellite symposium addressing hypothyroidism, and prior to the annual Endocrine Society and ATA meetings; the December emails were sent after these events. Physicians were presented with thirteen theoretical patients and chose from 6 therapeutic options, including levothyroxine, synthetic combination therapy, thyroid extract, and liothyronine monotherapy. The patient scenarios successively incorporated factors potentially providing reasons for considering combination therapy. Multivariate repeated measures logistic regression analyses first examined effects of physician characteristics on prescribing the various therapies. Then, analyses also incorporated timing, by comparing prescribing patterns in February, March, and December.Results: In analyses of prescribing levothyroxine monotherapy vs. any T3 therapy, there was a trend of borderline significance (p = 0.053) for T3 therapy to be prescribed more in December compared with February-March combined. When multivariate analyses were performed controlling for time and physician characteristics, choice of therapy was only significantly affected by country of practice (OR 1.7, CI 1.3–2.2). Physician choice of therapies was also examined for the options of continuing (1) levothyroxine, vs. (2) increasing levothyroxine, (3) adding liothyronine either with or without levothyroxine reduction, or (4) replacing levothyroxine with desiccated thyroid extract or liothyronine. When multivariate analyses incorporating time and physician characteristics were performed, respondents in December (OR 1.5, CI 1.0–2.3) and those practicing in North America (OR 1.8, CI 1.2–2.6) were more likely to prescribe liothyronine.Conclusions: This survey shows that although current North American guidelines do not recommend combination therapy, such therapy is being prescribed more over time and is also more commonly prescribed in North America. It is possible our guidelines are failing to incorporate evidence that physicians are considering when prescribing combination therapy. Such evidence could include data about patient preferences, and this needs to be a focus of future studies.

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“…In RCTs the serum FT3/FT4 ratio is 0.30 (IQR 0.25–0.45) during L-T4 + L-T3 combination therapy, higher than the value of 0.24 (IQR 0.18–0.25) during L-T4 monotherapy but still somewhat lower than in controls [1]. A retrospective observational study in Denmark reports on patients with persistent symptoms despite L-T4 therapy and normal serum TSH [45]. Treatment was changed into L-T4 + L-T3 combination therapy in a 17:1 ratio (weight/weight).…”

Section: What Is the Appropriate Dosage Of L-t4 + L-t3 Combination Thmentioning

confidence: 99%

T4 + T3 combination therapy: any progress?

Wiersinga

2019

Endocrine

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Guidelines on T4 + T3 combination therapy were published in 2012. This review investigates whether the issue is better understood 7 years later. Dissatisfaction with the outcome of T4 monotherapy remains high. Persistent symptoms consist mostly of fatigue, weight gain, problems with memory and thinking and mood disturbances. T4 monotherapy is associated with low serum T3 levels, which often require TSH-suppressive doses of L-T4 for normalization. Peripheral tissue thyroid function tests during T4 treatment indicate mild hyperthyroidism at TSH < 0.03 mU/L and mild hypothyroidism at TSH 0.3–5.0 mU/L; tissues are closest to euthyroidism at TSH 0.03–0.3 mU/L. This is explained by the finding that whereas T4 is usually ubiquinated and targeted for proteasomal degradation, hypothalamic T4 is rather stable and less sensitive to ubiquination. A normal serum TSH consequently does not necessarily indicate a euthyroid state. Persistent symptoms in L-T4 treated patients despite a normal serum TSH remain incompletely understood. One hypothesis is that a SNP (Thr92Ala) in DIO2 (required for local production of T3 out of T4) interferes with its kinetics and/or action, resulting in a local hypothyroid state in the brain. Effective treatment of persistent symptoms has not yet realized. One may try T4 + T3 combination treatment in selected patients as an experimental n = 1 study. The 2012 ETA guidelines are still valid for this purpose. More well-designed randomized clinical trials in selected patients are key in order to make progress. In the meantime the whole issue has become rather complicated by commercial and political overtones, as evident from skyrocketing prices of T3 tablets, aggressive pressure groups and motions in the House of Lords.

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Neither Baseline nor Changes in Serum Triiodothyronine during Levothyroxine/Liothyronine Combination Therapy Predict a Positive Response to This Treatment Modality in Hypothyroid Patients with Persistent Symptoms

Cited by 20 publications

References 17 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?

Short-Term Time Trends in Prescribing Therapy for Hypothyroidism: Results of a Survey of American Thyroid Association Members

T4 + T3 combination therapy: any progress?

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