Resistance to Thyroid Hormone (RTH) and Resistance to TSH (RTSH)

Abstract

Resistance to thyroid hormone (RTH) is a syndrome characterized by variable tissue hyporesponsiveness to thyroid hormone (TH). Mutations in both TH receptors (THRA and THRB) isoforms have been identified and manifest different phenotypes of RTH, RTH-alpha, and RTH-beta. Patients with the RTH-beta phenotype seek medical attention for goiter, abnormal thyroid function tests (TFTs), or through neonatal screening programs. Biochemically, RTH-beta is characterized by elevated TH values in the setting of non-suppressed thyrotropin (TSH) levels. Resistance at the level of the hypothalamus and pituitary leads to elevated TSH, which stimulates the thyroid gland to increase production of TH; however, reduced action elsewhere results in compensated TH hyporesponsiveness to a lesser or greater degree depending on the predominant TH receptor (TR) isoform in the tissue, alpha (α) or beta (β). THRA gene mutations have remained elusive until recently. The first case of RTH-α was identified through whole genome sequencing. Because TRα is not involved in the feedback regulation of the hypothalamic-pituitary-thyroid axis, the TFTs are different from patients with RTH-β, namely, low or normal T4, high normal T3, and normal or slightly elevated TSH. These mild thyroid abnormalities lead patients to present themselves in non-endocrinological clinical departments.