This pilot, genotype-stratified clinical trial aims to evaluate the safety and preliminary efficacy of combined selenomethionine and myo-inositol supplementation in patients with autoimmune thyroiditis (AIT), including Hashimoto's thyroiditis, who carry the Thr92Ala (rs225014) variant in the DIO2 gene. The study will compare changes in thyroid function tests, autoantibody titers, and clinical symptoms between two cohorts: (1) carriers (homozygous or heterozygous) of the Thr92Ala variant and (2) individuals without this variant ("wild-type"). The hypothesis is that patients with the "unfavorable" DIO2 genotype will experience greater improvements in TSH levels, the free T3/ free T4 ratio, and autoimmunity markers when receiving selenomethionine plus myo-inositol, potentially due to enhanced support of thyroid hormone conversion and reduced autoimmune activity.

Rationale

• The DIO2 gene encodes the type II iodothyronine deiodinase, which converts T4 (thyroxine) to the more active T3 (triiodothyronine) in peripheral tissues.

• The Thr92Ala (rs225014) polymorphism may reduce enzyme activity, potentially leading to lower tissue T3 levels, even in patients with normal or slightly elevated T4 and TSH.

• Selenium (as selenomethionine) supports the function of various selenoproteins, including deiodinases, and has been reported to reduce anti-thyroid antibody levels (particularly anti-TPO).

• Myo-inositol has shown promise in modulating autoimmune and metabolic processes in thyroid disorders, possibly improving tissue sensitivity to thyroid hormones and reducing autoimmune inflammation.

• A genotype-focused approach may reveal whether individuals carrying the DIO2 Thr92Ala variant derive a more substantial benefit from combined supplementation than those without the variant. 2. Study Goals

• Primary Goal: To assess changes in TSH levels and the fT3/fT4 ratio over 12 weeks of combined selenomethionine and myo-inositol supplementation.

• Secondary Goals:

  • To evaluate changes in thyroid autoantibody titers (anti-TPO, anti-Tg).
  • To assess thyroid ultrasound findings (vascularization, gland volume).
  • To measure improvements in patient-reported symptoms and quality of life using standardized questionnaires.
  • To determine the safety and tolerability of the combined intervention.

Inclusion Criteria:

• Adults aged 18-65 years with a clinical diagnosis of autoimmune thyroiditis (elevated anti- TPO and/or anti-Tg).
• TSH range consistent with subclinical hypothyroidism (e.g., TSH 4.5-10 mIU/L) or euthyroid status with AIT; patients on stable levothyroxine therapy are eligible if dose was unchanged for at least 6 weeks.
• Willingness to undergo genotyping for the DIO2 Thr92Ala variant. Confirmation of the Thr92Ala variant (homozygous or heterozygous) for Cohort A; absence of this variant for Cohort B.
• Ability to provide informed consent and comply with study procedures.

Exclusion Criteria:

• Overt hypothyroidism with TSH >10 mIU/L requiring immediate treatment adjustment.
• Significant comorbidities (e.g., uncompensated heart failure, severe renal or hepatic dysfunction, uncontrolled diabetes).
• Pregnancy or lactation (given potential changes in thyroid requirements and supplement safety considerations).
• Known hypersensitivity to selenium or inositol supplements.
• Severe psychiatric disorder interfering with protocol adherence.
• Concurrent use of high-dose selenium (>50 µg/day) or other thyroid-influencing nutraceuticals that cannot be discontinued prior to study entry.