Increased cardiovascular morbidity and reduced life expectancy in a large Italian cohort of patients with resistance to thyroid hormone β (RTHβ)

Objective: Decreased survival and higher cardiovascular morbidity have been recently reported in a UK cohort of 61 RTHβ patients, but there is no evidence from other countries. Design: Retrospective cohort study from an historical group of 284 Italian RTHβ patients, diagnosed between 1984 and 2023. Methods: We collected data on diagnosis of 284 cases and longitudinal data of 249 RTHβ who carried heterozygous pathogenic variants in the THRB gene. We studied how thyroid function and recognized risk factors for cardiovascular disease, such as hypertension and diabetes, affected overall mortality and major cardiovascular events. Results: The cumulative prevalence of sinus/supraventricular tachycardia and atrial fibrillation was 40% and 18%, respectively. FT4 values 57% higher than the upper limit of normal were associated with premature cardiovascular manifestations. Major cardiovascular events (MACEs) occurred in RTHβ patients at a median age (IQR) of 59.4 years (50.4-66.4) and early mortality resulted in a mean of 11 years of life lost. While at univariable analysis hypertension, dyslipidemia, high fasting glucose/diabetes were also associated with MACEs, at multivariable analysis only age at diagnosis, increased fT4 levels, and male gender remained significantly associated with MACEs and age at diagnosis and higher fT4 levels with mortality. Previous thyroidectomy or radioiodine therapy had no statistically significant effect in the prevention of major cardiovascular events or all-cause mortality. Conclusions: These data should raise the general awareness on the cardiovascular risk and prompt a proactive cardiovascular monitoring in RTHβ, especially in men and those with fT4 levels above 30 pmol/L.