Dataset Information

Individualized Therapy for Hypothyroidism: Is T4 Enough for Everyone?

ABSTRACT:

Context

It is well recognized that some hypothyroid patients on levothyroxine (LT4) remain symptomatic, but why patients are susceptible to this condition, why symptoms persist, and what is the role of combination therapy with LT4 and liothyronine (LT3), are questions that remain unclear. Here we explore evidence of abnormal thyroid hormone (TH) metabolism in LT4-treated patients, and offer a rationale for why some patients perceive LT4 therapy as a failure.

Evidence acquisition

This review is based on a collection of primary and review literature gathered from a PubMed search of "hypothyroidism," "levothyroxine," "liothyronine," and "desiccated thyroid extract," among other keywords. PubMed searches were supplemented by Google Scholar and the authors' prior knowledge of the subject.

Evidence synthesis

In most LT4-treated patients, normalization of serum thyrotropin levels results in decreased serum T3/T4 ratio, with relatively lower serum T3 levels; in at least 15% of the cases, serum T3 levels are below normal. These changes can lead to a reduction in TH action, which would explain the slower rate of metabolism and elevated serum cholesterol levels. A small percentage of patients might also experience persistent symptoms of hypothyroidism, with impaired cognition and tiredness. We propose that such patients carry a key clinical factor, for example, specific genetic and/or immunologic makeup, that is well compensated while the thyroid function is normal but might become apparent when compounded with relatively lower serum T3 levels.

Conclusions

After excluding other explanations, physicians should openly discuss and consider therapy with LT4 and LT3 with those hypothyroid patients who have persistent symptoms or metabolic abnormalities despite normalization of serum thyrotropin level. New clinical trials focused on symptomatic patients, genetic makeup, and comorbidities, with the statistical power to identify differences between monotherapy and combination therapy, are needed.

SUBMITTER: Ettleson MD

PROVIDER: S-EPMC7382053 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundData suggest symptoms of hypothyroidism persist in 5-10% of levothyroxine (L-T4)-treated hypothyroid patients with normal serum thyrotrophin (TSH). The use of L-T4 + liothyronine (L-T3) combination therapy in such patients is controversial. The ETA nominated a task force to review the topic and formulate guidelines in this area.MethodsTask force members developed a list of relevant topics. Recommendations on each topic are based on a systematic literature search, discussions within the task force, and comments from the European Thyroid Association (ETA) membership at large.ResultsSUGGESTED EXPLANATIONS FOR PERSISTING SYMPTOMS INCLUDE: awareness of a chronic disease, presence of associated autoimmune diseases, thyroid autoimmunity per se, and inadequacy of L-T4 treatment to restore physiological thyroxine (T4) and triiodothyronine (T3) concentrations in serum and tissues. There is insufficient evidence that L-T4 + L-T3 combination therapy is better than L-T4 monotherapy, and it is recommended that L-T4 monotherapy remains the standard treatment of hypothyroidism. L-T4 + L-T3 combination therapy might be considered as an experimental approach in compliant L-T4-treated hypothyroid patients who have persistent complaints despite serum TSH values within the reference range, provided they have previously received support to deal with the chronic nature of their disease, and associated autoimmune diseases have been excluded. Treatment should only be instituted by accredited internists/endocrinologists, and discontinued if no improvement is experienced after 3 months. It is suggested to start combination therapy in an L-T4/L-T3 dose ratio between 13:1 and 20:1 by weight (L-T4 once daily, and the daily L-T3 dose in two doses). Currently available combined preparations all have an L-T4/L-T3 dose ratio of less than 13:1, and are not recommended. Close monitoring is indicated, aiming not only to normalize serum TSH and free T4 but also normal serum free T4/free T3 ratios. Suggestions are made for further research.ConclusionL-T4 + L-T3 combination therapy should be considered solely as an experimental treatment modality. The present guidelines are offered to enhance its safety and to counter its indiscriminate use.

Project description:BackgroundPhysician characteristics and perceptions and their effect on choice of therapies for patients with thyroid cancer have been well studied. Some data also exist about physician characteristics and prescribing treatment for subclinical hypothyroidism. The effect of physician characteristics on prescribing thyroid preparations for treating overt hypothyroidism is less studied.MethodsMembers of the American Thyroid Association were surveyed in 2017. Physicians were presented with 13 different theoretical patients with hypothyroidism and asked to choose among six therapeutic options, including levothyroxine, synthetic combination therapy, thyroid extract, and liothyronine monotherapy. The 13 patient scenarios incorporated parameters that potentially provide reasons for considering combination therapy (presence of symptoms, low serum triiodothyronine concentration, and documentation of deiodinase polymorphisms). Repeated-measures logistic regression analysis was performed to examine the prescribing of the various therapies. Data regarding the responding physicians were also collected. These data included number of years in practice, country of practice, and specialty. Multivariate repeated-measures logistic regression analysis of prescribing patterns was also conducted controlling for all patient and physician characteristics.ResultsOf the 389 survey respondents, 93% prescribed therapy for hypothyroidism. Fifty-three percent of respondents had been in practice for >20 years, and 23% had been in practice for 11-20 years. Sixty-four percent practiced in North America, and 18% practiced in Europe. Eight-six percent were endocrinologists, and 5% were surgeons. In multivariate analysis, physicians from North America were both more likely to prescribe any triiodothyronine-containing therapies (odds ratio [OR] = 1.8 [confidence interval (CI) 1.3-2.4]) and more likely to add liothyronine to levothyroxine therapy (OR = 1.9 [CI 1.2-2.9]). In addition, they were more likely to prescribe desiccated thyroid extract or liothyronine monotherapy (OR = 1.7 [CI 1.0-2.9]).ConclusionsA previous analysis of this survey showed that patient characteristics profoundly affect physician prescribing patterns. The current multivariate analysis shows that physician characteristics affect prescribing patterns. Whether this is due to impact upon physicians of patient-related experiences, media exposure, influence from pharmaceutical companies, educational activities, or other concerns cannot be determined. However, these results have potential importance for understanding physician-patient interactions at a time when the benefits and risks of triiodothyronine-containing therapies have not been fully documented.

Project description:BackgroundIt is unclear whether the offspring of subclinical hypothyroidism (SCH) pregnant rats still have abnormal cardiac development, and whether early intervention with L-T4 can improve the abnormality of these offspring. Therefore, the aim of this study was to investigate the effect of early L-T4 intervention on the heart development of offspring of SCH pregnant rats and its possible molecular mechanism.MethodsEighty female Wistar rats were randomly divided into Sham group (placebo control), SCH group, LT4-E10 group (L-T4 treatment started on the 10th day of gestation), and LT4-E13 group (L-T4 treatment started on the 13th day of gestation). Each group was further divided into E16 (16th day of gestation), E18 (18th day of gestation), P5 (5th day postnatal day), and P10 (10th day postnatal day) subgroups. The levels of serum TT4 and TSH, the ratio of heart weight to body weight of offspring rats, the expression of metabolic enzymes, and the histopathology of cardiomyocytes were determined. To elucidate the effects of L-T4 on cardiac development of offspring of SCH pregnant rats, the expression levels of GATA4, Nkx2-5 and proteins involved in BMP4/Smad4 signaling pathway were detected by immunohistochemistry, real time quantitative polymerase chain reaction and Western blotting to elucidate the molecular mechanism of L-T4 regulating the heart development of the offspring of SCH pregnant rats.ResultsCompared with Sham group, serum TSH was significantly increased in SCH pregnant rats. Moreover, early L-T4 intervention significantly reduced the levels of serum TSH. Compared with the offspring in the SCH group, early L-T4 intervention significantly increased the heart weight, heart weight to body weight ratio, the activities of succinate dehydrogenase (SDH), Na+/K+-ATPase and Ca2+-ATPase, but reduced myocardial cell shrinkage and nuclear staining, hyperemia/congestion and vacuolar degeneration. In addition, early L-T4 intervention not only significantly increased the mRNA and protein expression of Gata4 and Nkx2-5, but also increased the protein expression involved in BMP4/Smad4 signal pathway in myocardium of the offspring of SCH pregnant rats.ConclusionsEarly L-T4 intervention can regulate the cardiac development of the offspring of SCH pregnant rats by activating BMP4/Smad4 signaling pathway and increasing the expression of Gata4 and Nkx2-5 proteins.

Project description:BackgroundMost endocrinologists encounter patients who are dissatisfied with their current hypothyroidism therapy and request combination therapy with either liothyronine (LT3) or thyroid extract.MethodsA survey of American Thyroid Association members was conducted in 2017. Respondents were presented with 13 scenarios describing patients with hypothyroidism and were asked to choose among six therapeutic options. The index patient was satisfied taking levothyroxine (LT4) therapy. Twelve variations introduced parameters that potentially provide reasons for considering combination therapy (presence of symptoms, low serum triiodothyronine concentration, documentation of deiodinase polymorphisms). Therapeutic options included (i) continuing LT4, (ii) increasing LT4, (iii) adding LT3 to a reduced LT4 dose, (iv) adding LT3 to the current LT4 dose, (v) replacing LT4 with thyroid extract, and (vi) replacing LT4 with LT3. Repeated-measures logistic regression analysis was performed to examine both the prescribing of LT4 (options i and ii) versus all other therapies and the choice of continuing LT4 (option i) versus either increasing LT4 (option ii), adding LT3 (options iii and iv), or replacing LT4 with thyroid extract or LT3 (options v and vi).ResultsOf the 389 survey respondents, 363 physicians prescribed therapy for hypothyroidism. For the index patient, 98% of physicians continued current LT4 therapy. However, as the patient scenario incorporated other patient characteristics, physicians opted to increase LT4 dose or prescribe other therapies. The tendency to prescribe alternative therapies was powerfully increased by patient symptoms (odds ratio = 25.6 [confidence interval 9-73], p < 0.0001). Older age and the presence of a comorbidity reduced the likelihood that an alternative therapy was prescribed (p = 0.0002 and <0.0001, respectively). All other characteristics, except athyreotic status, patient sex, and body mass index, significantly increased the likelihood that alternative therapies would be prescribed in multivariate analyses (p < 0.0001).ConclusionsEven with the acknowledged limitations of survey methodology, this analysis appears to show a marked increase in the willingness of physicians to prescribe combination therapy in specific circumstances. If current prescribing patterns do incorporate the use of therapies other than LT4, there is a critical need for more research into the benefits and risks of these therapies.