Thyroid Hormone Resistance Syndrome

Resistance to thyroid hormone (RTH) is a rare syndrome characterized by elevated serum free iodothyronines levels and non-suppressed thyroid stimulating hormones (TSH). The most common cause of RTH is heterozygous pathogenic mutations in thyroid hormone receptor β gene (THRB). Because of the similarities in biochemical profiles, differential diagnosis between RTHβ and TSH-secreting pituitary adenoma (TSHoma) is important, and accurate RTHβ diagnosis is essential to prevent inappropriate treatment. A 13-year-old boy was referred to our hospital for a microadenoma and uncontrolled hyperthyroidism despite use of methimazole for more than one year. He suffered from thyrotoxic clinical features and elevated serum T3 and fT4, and normal ranges for TSH and other pituitary hormones were noted. TSH receptor antibody was undetectable, and pituitary MRI revealed a 3mm-sized microadenoma. A TRH stimulation test showed normal TSH response, and the TSH-α-subunit level was not elevated, which is consistent with RTH. The patient was diagnosed with RTHβ and coexistent non-functioning pituitary microadenoma based on identification of a heterozygous mutation, c.1021C>G (p.Leu341Val), in THRB. Methimazole treatment was stopped, and a β-adrenergic blocking agent was started, subsequently thyrotoxic symptoms were relieved. Currently, only one pediatric case diagnosed with RTH and TSHoma has been reported so far, and this case is the first to report a pediatric case of coexistence of RTH and non-functioning pituitary microadenoma. Also, this case shows that inappropriate secretion of thyroid hormones requires careful clinical diagnosis to avoid unnecessary and potentially harmful management.

Thyroid hormone resistance (THR) is a rare inherited disorder that affects approximately one in every 40,000 live births. This condition arises from a mutation in the thyroid hormone receptor β, leading to reduced responsiveness of target tissues. It can result in a combination of hypothyroidism and hyperthyroidism symptoms in different tissues. The thyroid hormone is crucial for controlling blood pressure, and even small changes in its levels can have an effect on vascular resistance, cardiac performance, and heart rhythm. Both hypo- and hyperthyroidism have been associated with elevated blood pressure, underscoring the significant link between thyroid hormone sensitivity and vascular function. Considering thyroid hormone sensitivity is essential in clinical practice, particularly when managing patients with hypertension, to ensure personalized and effective treatment approaches. Monitoring thyroid function is essential during the diagnosis of hypertension, as thyroid dysfunction can often be corrected to normalize blood pressure. It's crucial to distinguish between essential hypertension and hypertension associated with a thyroid abnormality in THR. The mechanisms behind the development of hypertension in THR include reduced nitric oxide production, dysregulation of the renin-angiotensin-aldosterone system, impaired endothelial function, and mutations in the deiodinases. Physicians should understand the underlying mechanisms of THR and identify new therapeutic targets for hypertension in THR.

Yellow fever virus (YFV) infection is a major public concern that threatens a large population in South America and Africa. No specific antiviral drugs are available for treating yellow fever. Here, we report that tiratricol (triiodothyroacetic acid, TRIAC), a clinically approved drug used to treat thyroid hormone resistance syndrome (THRS), is a potent YFV inhibitor both in host cells andin animal models.Anin vitro study demonstrates that TRIAC remarkably suppresses viral RNA synthesis and protein expression in a dose-dependent manner in human hepatoma cell lines (Huh-7) with anEC50 value of 2.07 μM and a CC50 value of 385.77 μM respectively. The surface plasmon resonance assay and molecular docking analysis indicate that TRIAC hinders viral replication by binding to the RNA-dependent RNA polymerase (RdRp) domain of viral nonstructural protein NS5, probably through interacting with the active sites of RdRp.The inhibitory effect of TRIAC in vivo is also confirmed in 3-week old C57BL/6 mice challenged with YFV infection, from which the survival of the mice as well as lesions and infection in their tissues and serum issignificantly promoted following oral administration of TRIAC (0.2 mg/kg/day). Additionally, TRIAC shows a broad-spectrum antiviral activity against multiple flaviviruses such as TBEV, WNV,ZIKV, andJEV in vitro. Our data demonstrate that the TH analogue TRIAC is an effective anti-YFV compound and may act as a potential therapeutic candidate for the treatment of YFV infection if its clinical importance is determined in patients in future.