Identification of Resistance to Exogenous Thyroxine in Humans

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Thyroid hormone deiodination in the hypothalamus/pituitary is crucial for regulating thyroid-stimulating hormone (TSH).
• Deiodinase type-2 (D2) activity mediates thyroxine (T4) to triiodothyronine (T3) conversion.
• Central resistance to exogenous T4 has been observed in mice, but human cases were undescribed.

Purpose of the Study:

• To identify hypothyroid patients exhibiting TSH unresponsiveness to levothyroxine (LT4) therapy.
• To characterize the clinical, hormonal, and genetic features of human resistance to exogenous thyroxine (RETH).

Main Methods:

• Investigated hypothyroid patients with elevated TSH despite LT4 treatment leading to hyperthyroid symptoms.
• Measured TSH, free T4 (fT4), total T4, T3, and reverse T3 (rT3) using chemiluminescence and radioimmunoassay.
• Sequenced genes including DIO2, SECISBP2, and THRB, and compared hormonal ratios with patients with resistance to thyroid hormone (RTH).

Main Results:

• Eighteen patients showed elevated TSH and fT4 with a high TSH/fT4 ratio, persisting despite dose adjustments.
• Hormonal profiles indicated reduced T4 to T3 conversion and increased T4 to rT3 conversion.
• No germline mutations in DIO2, SECISBP2, or THRB were found, although the Ala92-D2 polymorphism was present in some patients.

Conclusions:

• Human RETH is characterized by iatrogenic thyrotoxicosis and an elevated TSH/fT4 ratio.
• Distinctive peripheral T3/T4 and T3/rT3 ratios suggest impaired central T4 to T3 conversion.
• The findings suggest potential post-translational D2 modifications or other pathway defects, guiding consideration for combined T4+T3 therapy.