Myo-inositol and Selenium in Indeterminate Thyroid Nodules (TIR3a)

Cytological classification of thyroid nodules (TIR 1-5) provides a useful tool in clinical practice. Each TIR class is statistically associated with a certain risk for malignancy, defining the recommended clinical action to undertake. The undetermined diagnosis (TIR 3) should represent less than 20% of patients, with an approximate risk of malignancy of 5-30%. Because of the variable risk of malignancy in the entire TIR 3 category, this is further divided into two groups: TIR 3A (low-risk follicular lesion): a heterogeneous group, with a low expected risk of malignancy (below 10%) and TIR 3B (follicular proliferation or suspected follicular neoplasia) with a higher expected risk of malignancy (15-30%). TIR3A nodules required close clinical and ultrasound follow-up and repetition of fine needle aspiration biopsy is recommended.

Selenium (Se) has the highest concentration in thyroid gland and selenium proteins are involved in thyroid hormone synthesis. Myo-inositol (MI) acts as second messengers both in thyroid differentiation and hormone synthesis and in inhibiting thyroid cells growth by inhibiting PI3K/AKT/mTOR pathway. Inositol is able to reduce NF-KB, a mediator of PI3K/AKT pathway, involved in cellular proliferation. In addition, in vitro studies demonstrated that inositol can reduce apoptosis and angiogenesis, but also inhibit the process of tumor metastasis and invasion by acting on the cytoskeleton. For this reason, this association could have a role in blocking thyroid nodule growth. Evidence from the literature highlights an important role of MI and Se in thyroid physiology and the maintenance of a euthyroid status. Particularly these micronutrients seem fundamental to counteract the onset and the worsening of thyroid alteration that could evolve into different pathological conditions if untreated. In this scenario, MI supplementation seemed to be involved also in the management of thyroidal benign nodules, with a possible effect on the size reduction. Interestingly, the administration of MI plus Se for 6 months of treatment period, was able to induce a morphological change by reducing the size and the stiffness of the nodules classified as class I or II (according to AACE/ACE/AME guidelines) in patients affected by subclinical hypothyroid.

Previous studies demonstrated a beneficial effect on subclinical hypothyroidism, restoring a euthyroid state and reducing both thyroid antibodies and TSH levels, mainly in patients affected by Hashimoto's thyroiditis. Based on these studies, nowadays, in clinical practice, oral supplementation with myoinositol and selenium is widespread and indicated in patients affected by subclinical hypotiroidism with values of TSH in the range 5-10 mcu/I with or without positivity to antibodies TPO-Ab/TG-Ab or in patients affected by Hashimoto's thyroiditis with TSH at the upper limit of the reference range.

The proposed study aims to evaluate the effect of selenium and myoinositol on possible risk factors for malignancy, as proliferation index, elastosonography characteristics (elasticity score) and TSH levels comparing a group of patients with selenium and myoinositol supplementation with a group without supplementation.

Inclusion criteria

• Adult (>18 years old),
• both sexes,
• patients presenting thyroid nodules classified as TIR 3A, based on cytological evaluation on sample from the first fine needle aspiration (FNA),
• written Informed consent,
• Patients with appropriate material for subsequent immunocytochemical analysis of Ki-67 and PCNA

Exclusion criteria

• Patients with diagnosed thyroid malignancies of cytological diagnosis other than TIR3A
• pathological levels of the thyroid stimulating hormone (TSH) which required L-Thyroxine treatment starting
• pregnancy and/or breastfeeding