Preliminary Results of a Double-Blind Randomized Controlled Trial Evaluating the Cardiometabolic Effects of Levothyroxine and Liothyronine Compared to Levothyroxine with Placebo in Athyreotic Low-Risk Thyroid Cancer Patients.

Background: Evidence is needed on the risks and benefits of combination therapy with levothyroxine (LT4)+liothyronine (LT3) for the treatment of hypothyroidism. Objective and Methods: We performed a randomized, double-blind placebo-controlled study to assess the effects of LT4+LT3 therapy versus LT4+placebo in a homogeneous group of athyreotic patients, without cardiovascular risk factors during long-term replacement monotherapy with LT4. The primary objective of the study was to assess the effects of combination LT4+LT3 therapy on heart rate, cardiac rhythm, and sensitive cardiovascular parameters of cardiac morphology and function by means of electrocardiography and Doppler echocardiography. The secondary objective of the study was to evaluate patient compliance, tolerability, and potential adverse events. Results: Thirty-eight patients with postsurgical hypothyroidism satisfying the inclusion criteria were selected from a group of 300 patients with low-risk thyroid cancer followed for a routine follow-up; they were randomized to receive LT4+LT3 or LT4+placebo. Twenty-four patients were evaluated after 1 year of treatment. All clinical and laboratory parameters were compared with the results obtained from 50 healthy euthyroid volunteers without comorbidities, matched for gender, age, physical activity, and lifestyle. Participants and clinicians remained blinded to the treatment allocation. After 1 year of combination therapy, a significant improvement in the diastolic function, evidenced by a significant reduction in the E/e' ratio (p = 0.046) and its positive trend over time, was observed in the LT4+LT3 group versus the LT4+placebo group. In addition, the univariate analyses showed a significant relationship between free triiodothyronine (fT3) levels (in pg/mL) with Δ of variation of the E/e' ratio in the LT4+LT3 group (standardized ß coefficient = 0.603 [confidence interval: 0.001-1.248], p = 0.050) after combination therapy. No adverse events including tachycardia, arrhythmias, atrial fibrillation, or other important events occurred between the first administration and the end of the study. Conclusions: In this preliminary report, combination treatment with LT4+LT3 induced favorable changes in cardiovascular parameters of diastolic function without any adverse cardiovascular events. Trial Registration: EUDRACT number: 2017-001261-25.

Active Moderate-to-Severe Graves' Orbitopathy in a Patient With Type 2 Diabetes Mellitus and Vascular Complications.

Background: Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease (GD). Diabetes mellitus (DM) has been reported to be a risk factor in patients with GO. Moreover, GO can be more frequent and severe in type 2 diabetes patients. High doses of intravenous glucocorticoids represent the first line treatment of moderate-to-severe and active GO according to the international guidelines. However, this therapy is contraindicated in uncontrolled diabetes and in patients with increased cardiovascular risk. Some anti-diabetic drugs can exacerbate GO. We reported the clinical case of an active and moderate-to-severe GO in a patient with uncontrolled type 2 DM and vascular complications. Case Report: A 61-years-old patient came to our ambulatory for a recurrence of GD and a moderate-to-severe bilateral GO. The patient had uncontrolled type 2 DM during insulin therapy and a history of micro and macrovascular complications. At the physical examination, the clinical activity score was 5 and the severity of GO was moderate-to-severe. A blood sample showed overt hyperthyroidism and the persistence of anti-TSH receptor antibodies (TRAb) during treatment with methimazole. A computed tomography scan showed a moderate-to-severe bilateral exophthalmos. We discuss the benefit/risk of treatment of GO in our patient. Conclusion: The available guidelines do not focus on the treatment of diabetic patients with uncontrolled diabetes and severe vascular complications, therefore our patient represents a difficult therapeutic challenge. The screening of thyroid function and the evaluation of GO could be useful in diabetic patients with autoimmune thyroid disease to perform a correct treatment of these disorders.

Is the Isthmus Location an Additional Risk Factor for Indeterminate Thyroid Nodules? Case Report and Review of the Literature.

Background: The management of indeterminate thyroid lesions is controversial. The American Thyroid Association (ATA) guidelines suggest a conservative approach for low risk indeterminate thyroid lesions (TIR3A). Case Report: We report a clinical case of a young girl who had TIR3A in a thyroid nodule located in the isthmus. After considering clinical and ultrasound (US) risk factors, we assessed literature data and guidelines to plan the extension of surgery. We found several studies supporting that the isthmus malignant lesions were associated with a higher rate of multifocality, capsular invasion, extrathyroidal extension, and central lymph node (LN) metastases. These data could predict a more aggressive behavior and a poor prognosis of the isthmus thyroid cancer compared to differentiated thyroid cancer, originating in the thyroid lobes. On the basis of these literature data and considering the familial risk for thyroid cancer of our patient, we decided to perform a total thyroidectomy. The histological examination revealed a follicular variant of papillary carcinoma located in the isthmus with capsular invasion. Conclusion: The isthmus location could be an additional risk factor to consider for a correct surgical approach in indeterminate thyroid lesions and thyroid cancer at fine-needle aspiration (FNA). We suggest that a careful ultrasonography should be carried out in patients with isthmus nodules. Total thyroidectomy should be performed in aggressive nodular disease. Prospective studies are needed to establish the best treatment for these lesions.

Importance of recombinant human thyrotropin as an adjuvant in the radioiodine treatment of thyroid cancer.

INTRODUCTION: Radioiodine (RAI) therapy for treatment of differentiated thyroid cancer (DTC) requires high serum thyroid-stimulating hormone (TSH) levels to induce a sufficient iodine uptake within thyroid cells. Recombinant Human TSH (rhTSH) induces an exogenous TSH level increase without LT4 withdrawal. It is a valid alternative to LT4-withdrawal (LT4-W) to achieve the TSH levels required for RAI therapy. According to the recent American Thyroid Association (ATA) guidelines, candidates for RAI therapy should be selected based on their DTC risk of recurrence. Areas covered: In this review, we report the studies assessing the effects of rhTSH on RAI ablation compared to thyroid hormone withdrawal in patients with thyroid cancer at different ATA risk of recurrence. We focus our attention on high risk patients and metastatic disease in which RAI treatment is routinely recommended although there are few controversial data about the best possible way of preparing for it. Expert commentary: rhTSH-aided therapy is associated to a better quality of life and to a lower body radiation exposure. Several studies have reported an equivalent efficacy of RAI ablation after TSH stimulation with rhTSH or LT4-W in patients with DTC at low and intermediate risk of recurrence. Although more studies are required, the results are promising even in patients with high risk DTC and metastatic disease.

Recombinant Human Thyrotropin Improves Endothelial Coronary Flow Reserve in Thyroidectomized Patients with Differentiated Thyroid Cancer.

BACKGROUND: The role of thyrotropin (TSH) on the cardiovascular system has been poorly investigated. It is unknown whether the changes in the vasculature associated with thyroid diseases result from altered thyroid hormone action or whether they are a consequence of a direct effect of TSH on endothelial cells. The present study was designed to evaluate the endothelial response of coronary flow to TSH in patients with differentiated thyroid cancer (DTC) without cardiovascular risk factors. METHODS: The study population consisted of three men and seven women (Mage = 32.6 ± 8 years) who underwent total thyroidectomy for DTC. All were receiving therapy with L-thyroxine to maintain TSH within the reference range. No patient was obese, or had hypertension, diabetes, or dyslipidemia. Patients underwent standard echo-Doppler examination with evaluation of the coronary flow reserve (CFR) of the distal left anterior descending artery obtained by cold pressure test (CPT) before and 24 h after the second recombinant human TSH (rhTSH) injection. RESULTS: Left ventricular morphology and systolic and diastolic function were normal in all patients. Levels of thyroid hormones and thyroglobulin and antithyroglobulin antibodies did not differ significantly pre- versus post-rhTSH treatment, whereas TSH levels were higher after rhTSH administration. Blood pressure and heart rate were not affected by rhTSH. Coronary flow peak velocity at rest (22.3 ± 6 vs 23.2 ± 8.7; p = 0.66) did not differ between baseline and 24 h after rhTSH, while post-CPT velocity (29.3 ± 6.8 vs 34.4 ± 10.9; p < 0.05) and the CFR were higher after rhTSH administration (1.32 ± 0.2 vs. 1.53 ± 0.2; p < 0.01). CONCLUSIONS: rhTSH administration may improve the CFR after the non-pharmacological stressor CPT in DTC patients. The increase of coronary blood flow after rhTSH suggests that TSH may exert a protective effect on the coronary endothelium.