Endocrine Abstracts

Introduction: Hypothyroidism treatment is classically based on levothyroxine (LT4). However, 10% of hypothyroid patients treated with LT4 complain of hypothyroidism symptoms, despite normal thyroid stimulating hormone (TSH) serum levels. This ”peripheral hypothyroidism” has been linked to decreased availability of free triiodothyronine (fT3), likely related to single nucleotide polymorphisms (SNP) in deiodinase genes (DIO), reducing enzymatic activity. Since Thr92Ala-DIO2 was associated to altered responsiveness to LT4, combined levothyroxine/liothyronine (LT4/lT3) therapy was suggested to improve quality of life in hypothyroid patients encoding Thr92Ala-DIO2.

Aims: To evaluate the influence of Thr92Ala-DIO2 variant on thyroid therapeutic compensation in thyroidectomized subjects treated with LT4 or LT4/lT3.

Methods: An interim analysis of a prospective, randomized, placebo-controlled, double-blinded clinical trial was performed. Totally thyroidectomized patients treated with LT4 and with TSH levels within reference range in the previous 3 months were enrolled. Subjects were randomized in two groups: personalized-combined-twice-daily therapy with LT4/lT3 at 13-20:1 ratio (study group) and LT4+placebo (control group). Subjects were evaluated three times during the 6-month treatment. Iatrogenic thyrotoxicosis and hypothyroidism rates were assessed at each visit, measuring serum levels of TSH, fT4 and fT3. DNA was extracted from blood samples and the DIO2 genotype was analysed by Sanger’s sequencing. The Thr92Ala-DIO2 rate was calculated in both groups.

Results: A total of 139 patients (age 55.6&plusmn;12.1 years, TSH 1.3&plusmn;1.4 microIU/ml) were enrolled, 70 in the study (age 55.1&plusmn;10.9 years) and 69 in the control group (age 56.0&plusmn;13.4 years). Thr92Ala-DIO2 frequency (11.4%) was similar to general population (12-36%). Drop-out rate did not differ between groups (11.4 vs 14.5%, respectively, P=0.591) and no difference was found in biochemical thyroid function examinations (considering also fT3/fT4 ratio) and LT4 pro-Kg dosage comparing study and control groups at baseline. Combined LT4/lT3 therapy resulted in more frequent iatrogenic thyrotoxicosis than LT4 monotherapy (9.8% vs 2.2%; P<0.05), with a significantly higher incidence in Thr92Ala-DIO2 carriers. More frequent dose adjustments were required in the study group compared to controls (44.5% vs 22.5%; P<0.001) and, among cases, in those with Thr92Ala-DIO2 compared to wild-type (52.0% vs 37.6%; P< 0.05).

Conclusion: Thr92Ala-DIO2 variant seems to have no influence on LT4 monotherapy effectiveness. In our interim analysis, carriers of Thr92Ala-DIO2 are at higher risk of iatrogenic thyrotoxicosis when treated with LT4/lT3: this result surprisingly suggest an increased enzymatic activity in SNP carriers. Accordingly, the management of these patients is more challenging, requiring more frequent dose adjustments in the first six months of therapy.