Randomized double-blind placebo-controlled trial on levothyroxine and liothyronine combination therapy in totally thyroidectomized subjects: the LEVOLIO study.

OBJECTIVE: Despite having normal thyroid-stimulating hormone levels, many hypothyroid patients are dissatisfied with the treatment. The primary aim of this study was to evaluate the effect of twice-daily, combination therapy with levothyroxine (LT4) and liothyronine (LT3), at doses adapted according to TSH-level, on peripheral tissues as reflected by sex hormone binding globulin (SHBG) levels in totally thyroidectomized patients. Changes in other tissue markers and quality of life considering DIO2-rs225014 and MCT10-rs17606253 genetic variants were also assessed. DESIGN: Double-blind, randomized, placebo-controlled. METHODS: One hundred and forty-one subjects were randomized to LT4 + LT3 group (LT4 + LT3 in the morning and LT3 in the evening; n = 70) or placebo group (LT4 in the morning and placebo in the evening; n = 71). Pituitary-thyroid axis compensation was assessed after 6, 12, and 24 weeks. Clinical parameters, quality of life, and tissue markers (sex hormone binding globulin, serum lipids, bone markers) were evaluated at 12 and 24 weeks. DIO2 and MCT10 single nucleotide polymorphisms were genotyped. RESULTS: The LT4 + LT3 group was treated with mean daily LT3 doses of 5.00 µg, with a mean daily LT4 reduction of 15 µg. After 6 months of treatment, neither SHBG and other tissue markers nor quality of life differed significantly between groups. Combination treatment required greater dose adjustments than placebo (25% vs 54%, P < .001), due to thyroid-stimulating hormone reduction, without hyperthyroidism signs or symptoms. At the end of treatment, the LT4 + placebo group had significantly lower fT3/fT4 compared to the LT4 + LT3 group (0.26 ± 0.05 vs 0.32 ± 0.08, P < .001). No preference for combination therapy was found. Genetic variants did not influence any outcomes. CONCLUSIONS: Six months of combination therapy with twice-daily LT3 dose adapted according to TSH-level do not significantly change peripheral tissue response or quality of life, despite an increase in the fT3/fT4 ratio.

Real-life use of BRAF-V600E mutation analysis in thyroid nodule fine needle aspiration: consequences on clinical decision-making.

PURPOSE: This study aimed to evaluate the real-life use of BRAF-V600E mutation analysis in washout liquid from thyroid nodule fine needle aspiration (FNA), and the consequences of genetic result on clinical decision-making. METHODS: We retrospectively considered subjects tested for BRAF-V600E among those attending the Endocrinology Unit of Modena for FNA between 2014 and 2018. Washing fluid was collected together with cytological sample and stored at -20 °C. If the clinician deemed it necessary, the sample was thawed, DNA extracted, and genetic test performed by high-resolution melting technique. We collected data on cytology according to the Italian Consensus for the cytological classification of thyroid nodules, type of surgery (when performed), histology, and adverse events. RESULTS: Out of 7112 subjects submitted to FNA, BRAF analysis was requested for 683 (9.6%). Overall, 896 nodules were analyzed: 74% were indeterminate at cytology, mainly TIR3A (low risk). Twenty-two nodules were mutant (BRAF+). Only 2% of indeterminate, mainly TIR3B, were BRAF+. Based on final histological diagnosis, BRAF test had high specificity (100%) but poor sensitivity (21%), also in indeterminate nodules. Mutant subjects underwent more extensive surgery compared to wild type (p = 0.000), with frequent prophylactic central lymph node dissection. One third had local metastases. Higher prevalence of hypoparathyroidism was found in BRAF+ compared to wild type (p = 0.018). CONCLUSIONS: The analysis of BRAF-V600E outside of gene panels has low sensitivity, especially in indeterminate nodules, and a positive result could lead to more extensive surgery with greater risk of hypoparathyroidism and questionable clinical utility.