Apparent resistance to thyroid hormones: From biological interference to genetics

Area of Science:

• Endocrinology
• Molecular Biology
• Clinical Diagnostics

Background:

• Resistance to thyroid hormones (RTH) presents as elevated thyroid hormones (T4, T3) with normal/high TSH.
• This condition is often caused by pathogenic variants in the thyroid hormone receptor beta (THRB) gene.
• Discrepancies in thyroid hormone and TSH levels can also stem from analytical interferences, particularly with transport proteins.

Purpose of the Study:

• To identify the etiology of discrepant thyroid hormone and TSH results in patient samples.
• To evaluate the roles of genetic variants and biological interferences in these discrepancies.
• To establish a diagnostic strategy to minimize errors in RTH diagnosis.

Main Methods:

• Sequencing of genes involved in thyroid hormone regulation, action, and transport (THRB, THRA, SECISBP2, SLC16A, ALB, TTR, SERPINA7).
• Assay of free T4 and free T3 using a second immunoassay (Siemens ADVIA Centaur) for confirmation.
• Clinical correlation of findings with patient presentation.

Main Results:

• A genetic cause (THRB mutation) was identified in 26% of cases.
• Biological interference due to altered TH serum transport proteins was found in 24% of cases.
• No etiology was found in 24% of cases, with biological interference suspected in another 26% without genetic variants.

Conclusions:

• A significant proportion of discrepant thyroid function tests are due to genetic variants in THRB or biological interferences.
• Recommended diagnostic approach includes a second thyroid function test with a different assay and genetic screening of THRB and TH transport proteins.
• This strategy aims to improve diagnostic accuracy for resistance to thyroid hormones and related conditions.