scholarly journals T4 + T3 combination therapy: any progress?

Endocrine ◽  
2019 ◽  
Vol 66 (1) ◽  
pp. 70-78 ◽  
Author(s):  
Wilmar M. Wiersinga
Keyword(s):  
Combination Therapy ◽  
Randomized Clinical Trials ◽  
Normal Serum ◽  
Thyroid Function Tests ◽  
Pressure Groups ◽  
Persistent Symptoms ◽  
House Of Lords ◽  
Serum T3 ◽  
With Memory ◽  
Serum Tsh

Abstract 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.

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

2017 ◽  
Vol 177 (6) ◽  
pp. R287-R296 ◽  
Author(s):  
Wilmar M Wiersinga
Keyword(s):  
Combination Therapy ◽  
Thyroid Function ◽  
Healthy Subjects ◽  
Randomized Clinical Trials ◽  
Peripheral Tissue ◽  
Thyroid Function Tests ◽  
Peripheral Tissues ◽  
Persistent Symptoms ◽  
Function Tests ◽  
Number Of Patients

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.

T3 TOXICOSIS IN ADOLESCENCE: PRESENTATION AS RECURRENT HYPERTHYROIDISM

PEDIATRICS ◽  
1973 ◽  
Vol 52 (5) ◽  
pp. 649-652
Author(s):  
T. W. AvRuskin ◽  
S. Tang ◽  
L. Shenkman ◽  
C. S. Hollander
Keyword(s):  
Female Patient ◽  
Intravenous Infusion ◽  
Pediatric Population ◽  
Normal Serum ◽  
Thyrotropin Releasing Hormone ◽  
Graves Disease ◽  
Adolescent Patient ◽  
Serum T3 ◽  
Recurrent Hyperthyroidism ◽  
Serum Tsh

The second adolescent patient with recurrent hyperthyroidism caused by isolated hypersecretion of T3 (T3 toxicosis) has been discovered. In 1969, this 17-year-old female patient initially presented with conventional Graves' disease was treated with propylthiouracil, but discontinued her medication after three months. Two and one-half half years later, she developed clinical and laboratory tory features of recurrent Graves' disease, save for a normal total and free thyroxine (T4). Serum T3 by radioimmunoassay was elevated (210 ng/100 ml) and thyroid binding globulin capacity for T4 was normal. Serum TSH was not detectable and failed to rise after intravenous infusion of 400 mg thyrotropin-releasing hormone. Other parameters of T3 toxicosis, as noted in adults with this syndrome, were confirmed. T3 toxicosis presenting as recurrent hyperthyroidism may be more common than previously recognized in the pediatric population.

scholarly journals Individualized Therapy for Hypothyroidism: Is T4 Enough for Everyone?

2020 ◽  
Vol 105 (9) ◽  
pp. e3090-e3104 ◽  
Author(s):  
Matthew D Ettleson ◽  
Antonio C Bianco
Keyword(s):  
Combination Therapy ◽  
Statistical Power ◽  
Evidence Synthesis ◽  
Elevated Serum ◽  
Review Literature ◽  
Lower Serum ◽  
Clinical Factor ◽  
Persistent Symptoms ◽  
Serum T3 ◽  
Hypothyroid Patients

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.

Benefit of Combined Triiodothyronine (LT3) and Thyroxine (LT4) Treatment in Athyreotic Patients Unresponsive to LT4 Alone

2011 ◽  
Vol 120 (02) ◽  
pp. 121-123 ◽  
Author(s):  
D. Solter ◽  
M. Solter
Keyword(s):  
Thyroid Hormone ◽  
Combination Therapy ◽  
Genetic Basis ◽  
Normal Range ◽  
Serum T3 ◽  
Serum T4 ◽  
Serum Tsh ◽  
Tsh Levels

AbstractDespite some reports, the usefulness of levothyroxine ( LT4) and levotriiodothyronine (LT3) combination therapy in hypothyroidism remains controversial. The objective of this paper is to study a benefit of additional LT3 in athyreotic patients who failed to normalize TSH on LT4 alone even with hyperthyroid serum T4 values.In a survey of 200 athyreotic patients treated between 2006 and 2009, about 7% failed to normalize serum TSH levels following treatment with LT4, though serum T4 values in the hyperthyroid range were achieved. These patients (characterized by serum T4≥160 nmol/L and TSH≥5.0 mIU/L), were additionally treated with 10 μg b. i. d LT3. LT3 and LT4 combination therapy resulted in decreased serum TSH levels into the normal range (12.8 vs. 1.22 mIU/L; p<0.01) and reduced LT4 dose (153.3 vs. 117.5 μg; p<0.01) required for normalization of serum T4 values (170.6 vs. 123.3 nmol/L; p<0.01). Serum T3 values were higher (1.3 vs. 2.26 nmol/L; p<0.01) than those during monotherapy with LT4.Our results indicate a subpopulation of athyreotic patients that could significantly benefit from combined LT4 + LT3 therapy in restoring normal TSH and thyroid hormone patterns. Further research should be undertaken to provide a genetic basis for these findings.

scholarly journals Guest Editor: Raffaella Origa THYROID DISORDERS IN HOMOZYGOUS β-THALASSEMIA: CURRENT KNOWLEDGE, EMERGING ISSUES AND OPEN PROBLEMS

2019 ◽  
Vol 11 (1) ◽  
pp. e2019029
Author(s):  
Vincenzo De Sanctis
Keyword(s):  
Thyroid Function ◽  
Current Knowledge ◽  
Normal Serum ◽  
Thyroid Disorders ◽  
Thyroid Function Tests ◽  
Hormone Regulation ◽  
Open Problems ◽  
Secondary Hypothyroidism ◽  
Emerging Issues ◽  
Serum Tsh

Abstract. Changes in thyroid function and thyroid function tests occur in patients with β-thalassemia major (TM). The frequency of hypothyroidism in TM patients ranges from 4% to 29 % in different reports. The wide variation has been attributed to several factors such as patients' genotype, age, ethnic variations, treatment protocols of transfusions and chelation, and varying compliance to treatment. Hypothyroidism is the result of primary gland failure or insufficient thy­roid gland stimulation by the hypothalamus or pituitary gland. The main laboratory parameters of thyroid function are the assessments of serum thyroid-stimulating hor­mone (TSH) and serum free thyroxine (FT4). It is of primary importance to interpret these measure­ments within the context of the laboratory-specific normative range for each test. An ele­vated serum TSH level with a normal range of serum FT4 level is consistent with subclinical hypothyroidism. A low serum FT4 level with a low, or inappropriately normal, serum TSH level is consistent with secondary hypothyroidism. Doctors caring for TM patients most commonly encounter subjects with subclinical primary hypothy­roidism in the second decade of life. Several aspects remain to be elucidated as the frequency of thyroid cancer and the possible existence of a relationship between thyroid dysfunction on one hand, cardiovascular diseases, components of metabolic syndrome (insulin resistance) and hypercoagulable state on the other hand. Further studies are needed to explain these emerging issues. Following a brief description of thyroid hormone regulation, production and actions, this article is conceptually divided into two parts; the first reports the spectrum of thyroid disease occurring in patients with TM, and the second part focuses on the emerging issues and the open problems in TM patients with thyroid disorders.

scholarly journals Systematic review with network meta-analysis of antivascular endothelial growth factor use in managing polypoidal choroidal vasculopathy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sheng-Chu Chi ◽  
Yi-No Kang ◽  
Yi-Ming Huang
Keyword(s):  
Combination Therapy ◽  
Polypoidal Choroidal Vasculopathy ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Evaluation Methodology ◽  
Combination Group ◽  
Anti Vegf ◽  
Searching Strategy ◽  
Early Combination Therapy ◽  
Choroidal Vasculopathy

AbstractPolypoidal choroidal vasculopathy (PCV) is a vision-threatening disease common in Asian populations. However, the optimal treatment for PCV remains under debate. We searched the databases with optimal searching strategy. The study included randomized clinical trials and prospective studies that recruited patients with active PCV who had received interventions, including PDT, anti-VEGF, or a combination of PDT and anti-VEGF. The Grading of Recommendations Assessment, Development, and Evaluation methodology was used for rating the quality of evidence. Our study included 11 studies involving 1277 patients. The network meta-analysis of RCTs revealed the anti-VEGF group, early combination group, and late combination group had significant BCVA changes compared with the PDT group. Early combination therapy led to a significant decrease in CRT compared with PDT, anti-VEGF, and late combination therapy. Additionally, the early combination group had a significantly higher complete polyp regression rate than the anti-VEGF group. No significant differences were detected in the analysis of the number of anti-VEGF injections and safety profile. This network meta-analysis revealed that early combination therapy exhibited better efficacy related to anatomical outcomes than other therapies. Nonetheless, no significant differences related to BCVA change could be detected between anti-VEGF and late combination therapy.

scholarly journals Inhibition of pituitary type 2 deiodinase by reverse triiodothyronine does not alter thyroxine-induced inhibition of thyrotropin secretion in hypothyroid rats

2005 ◽  
Vol 153 (3) ◽  
pp. 429-434 ◽  
Author(s):  
P Cettour-Rose ◽  
T J Visser ◽  
A G Burger ◽  
F Rohner-Jeanrenaud
Keyword(s):  
Specific Inhibitor ◽  
Adult Rats ◽  
Reverse T3 ◽  
Brown Adipose ◽  
Tsh Secretion ◽  
Serum T3 ◽  
Serum T4 ◽  
Serum Tsh ◽  
Tsh Levels

Objectives: Intrapituitary triiodothyronine (T3) production plays a pivotal role in the control of TSH secretion. Its production is increased in the presence of decreased serum thyroxine (T4) concentrations and the enzyme responsible, deiodinase type 2 (D2), is highest in hypothyroidism. In order to document the role of this enzyme in adult rats we developed an experimental model that inhibited this enzyme using the specific inhibitor, reverse T3 (rT3). Methods: Hypothyroidism was induced with propylthiouracil (PTU; 0.025 g/l in drinking water) which in addition blocked deiodinase type 1 (D1) activity, responsible for the rapid clearance of rT3 in vivo. During the last 7 days of the experiment, the hypothyroid rats were injected (s.c.) for 4 days with 0.4 or 0.8 nmol T4 per 100 g body weight (bw) per day. For the last 3 days, the same amount of T4 was infused via s.c. minipumps. In additional groups, 25 nmol rT3/100 g bw per day were added to the 3-day infusion of T4. Results: Infusion of 0.4 nmol T4/100 g bw per day did not affect the high serum TSH levels, 0.8 nmol T4/100 g bw per day decreased them to 57% of the hypothyroid values. The infusions of rT3 inhibited D2 activity in all organs where it was measured: the pituitary, brain cortex and brown adipose tissue (BAT). In the pituitary, the activity was 27%, to less than 15% of the activity in hypothyroidism. Despite that, serum TSH levels did not increase, serum T4 concentrations did not change and the changes in serum T3 were minimal. Conclusions: We conclude that in partly hypothyroid rats, a 3-day inhibition of D2 activity, without concomitant change in serum T4 and minimal changes in serum T3 levels, is not able to upregulate TSH secretion and we postulate that this may be a reflection of absent or only minimal changes in circulating T3 concentrations.

scholarly journals Determinants of Extraocular Muscle Volume in Patients with Graves' Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Samer El-Kaissi ◽  
Jack R. Wall
Keyword(s):  
Extraocular Muscle ◽  
Tsh Receptor ◽  
Graves Disease ◽  
Thyroid Function Tests ◽  
Thyroid Scintigraphy ◽  
Free T4 ◽  
Receptor Antibody ◽  
Tsh Receptor Antibody ◽  
Antibody Positivity ◽  
Serum Tsh

Background. To examine factors contributing to extraocular muscle (EOM) volume enlargement in patients with Graves’ hyperthyroidism.Methods. EOM volumes were measured with orbital magnetic resonance imaging (MRI) in 39 patients with recently diagnosed Graves’ disease, and compared to EOM volumes of 13 normal volunteers. Thyroid function tests, uptake on thyroid scintigraphy, anti-TSH-receptor antibody positivity and other parameters were then evaluated in patients with EOM enlargement.Results. 31/39 patients had one or more enlarged EOM, of whom only 2 patients had clinical EOM dysfunction. Compared to Graves’ disease patients with normal EOM volumes, those with EOM enlargement had significantly higher mean serum TSH (0.020±0.005versus0.007±0.002mIU/L;Pvalue 0.012), free-T4 (52.9±3.3versus41.2±1.7 pmol/L;Pvalue 0.003) and technetium uptake on thyroid scintigraphy (13.51±1.7%versus8.55±1.6%;Pvalue 0.045). There were no differences between the 2 groups in anti-TSH-receptor antibody positivity, the proportion of males, tobacco smokers, or those with active ophthalmopathy.Conclusions. Patients with recently diagnosed Graves’ disease and EOM volume enlargement have higher serum TSH and more severe hyperthyroidism than patients with normal EOM volumes, with no difference in anti-TSH-receptor antibody positivity between the two groups.

scholarly journals Distinct Roles of Deiodinases on the Phenotype of Mct8 Defect: A Comparison of Eight Different Mouse Genotypes

Endocrinology ◽  
2011 ◽  
Vol 152 (3) ◽  
pp. 1180-1191 ◽  
Author(s):  
Xiao-Hui Liao ◽  
Caterina Di Cosmo ◽  
Alexandra M. Dumitrescu ◽  
Arturo Hernandez ◽  
Jacqueline Van Sande ◽  
...  
Keyword(s):  
Growth Response ◽  
Pituitary Thyroid Axis ◽  
Severe Impairment ◽  
Serum T3 ◽  
Serum T4 ◽  
Thyroid Axis ◽  
Mct8 Deficiency ◽  
The Brain ◽  
Insight Into ◽  
Serum Tsh

Mice deficient in the thyroid hormone (TH) transporter Mct8 (Mct8KO) have increased 5′-deiodination and impaired TH secretion and excretion. These and other unknown mechanisms result in the low-serum T4, high T3, and low rT3 levels characteristic of Mct8 defects. We investigated to what extent each of the 5′-deiodinases (D1, D2) contributes to the serum TH abnormalities of the Mct8KO by generating mice with all combinations of Mct8 and D1 and/or D2 deficiencies and comparing the resulting eight genotypes. Adding D1 deficiency to that of Mct8 corrected the serum TH abnormalities of Mct8KO mice, normalized brain T3 content, and reduced the impaired expression of TH-responsive genes. In contrast, Mct8D2KO mice maintained the serum TH abnormalities of Mct8KO mice. However, the serum TSH level increased 27-fold, suggesting a severely impaired hypothalamo-pituitary-thyroid axis. The brain of Mct8D2KO manifested a pattern of more severe impairment of TH action than Mct8KO alone. In triple Mct8D1D2KO mice, the markedly increased serum TH levels produced milder brain defect than that of Mct8D2KO at the expense of more severe liver thyrotoxicosis. Additionally, we observed that mice deficient in D2 had an unexplained marked reduction in the thyroid growth response to TSH. Our studies on these eight genotypes provide a unique insight into the complex interplay of the deiodinases in the Mct8 defect and suggest that D1 contributes to the increased serum T3 in Mct8 deficiency, whereas D2 mainly functions locally, converting T4 to T3 to compensate for distinct cellular TH depletion in Mct8KO mice.

Hypothyrosis syndrome: role of triodthyronine in diagnostics and combination therapy (review of literature)

2021 ◽  
Vol 66 (5) ◽  
pp. 261-265
Author(s):  
I. A. Tsanava ◽  
S. V. Bulgakova ◽  
A. V. Melikova
Keyword(s):  
Combination Therapy ◽  
Endocrine System ◽  
Review Of Literature ◽  
Free T4 ◽  
Combined Use ◽  
Number Of Patients ◽  
Serum T3 ◽  
Euthyroid Status ◽  
System Assessment

Hypothyroidism syndrome is one of the most common pathologies of the endocrine system. Assessment of euthyroid status can not always be carried out according to the TSH indicator. In a number of patients with normal TSH levels and a clinical picture of hypothyroidism, the serum T3 concentration is determined at the lower limit of the norm or below it with a high content of free T4 in the blood. In world practice, positive experience has been accumulated in the combined use of preparations of sodium levothyroxine and liothyronine, a synthetic form of exogenous triiodothyronine. A number of studies have noted the advantages of using combination therapy for hypothyroidism over levothyroxine monotherapy in certain groups of patients. Possible reasons for the ineffectiveness of standard treatment for hypothyroidism are described.

Sign in / Sign up

Export Citation Format

Share Document