Lifestyle Interventions to Tackle Cardiovascular Risk in Thyroid Hormone Signaling Disorders

Abstract

Thyroid hormones (THs) play a central role in cardiovascular and metabolic regulation, influencing lipid metabolism, insulin sensitivity and resting energy expenditure. Inherited disorders of impaired sensitivity to THs-including resistance to thyroid hormone alpha (RTHα) and beta (RTHβ), monocarboxylate transporter 8 (MCT8) deficiency and selenoprotein deficiency-lead to complex, multisystemic clinical features. Although these conditions are rare, with RTHβ being the most common and affecting about 1 in 20,000 newborns, they share clinical features with more prevalent thyroid disorders, such as hypothyroidism and hyperthyroidism, as well as neurological manifestations including muscle wasting and spasticity. These conditions present abnormal patterns of thyroid function and are associated with tissue-specific comorbidities such as arrhythmias, heart failure, dyslipidemia, hepatic steatosis, insulin resistance, and metabolic syndrome. To date, no targeted or controlled studies have evaluated the impact of lifestyle modifications in these patient populations. Therefore, this narrative review proposes plausible management strategies based on pathophysiological insights into the effects of thyroid hormones on target organs, combined with clinical reasoning and evidence extrapolated from related disorders. Physical exercise and diet may complement pharmacological treatments (e.g., levothyroxine or TRIAC) to improve cardiovascular and metabolic outcomes. In RTHβ, aerobic exercise enhances cardiovascular health, while a Mediterranean diet supports lipid control and glycemic parameters. In RTHα, physical exercise may aid neuromotor development, and a fluid-rich, fiber-moderated diet can alleviate constipation. In MCT8 deficiency, physiotherapy may improve mobility and relieve contractures, while nutritional support (e.g., feeding tube, gastrostomy) can be necessary to tackle feeding difficulties and reduce pulmonary complications. In selenoprotein deficiency, low-to-moderate physical exercise and an antioxidant-rich diet may protect against oxidative stress at several tissue levels. Although quantitative evidence is limited, this narrative review synthesizes current insights, providing a meaningful basis for future validation and research.

Keywords: cardiovascular risk; diet; lifestyle; monocarboxylate transporter 8 (MCT8) defects; nutrition; physical exercise; resistance to thyroid hormone β (RTHβ) and α (RTHα); selenoprotein deficiency.

Figure 1

The hypothalamus–pituitary–thyroid axis (HPTA) and mechanism involved in disorders of impaired sensitivity to thyroid hormones (THs). THs, thyroxine, T4, and triiodothyronine, T3, bind to nuclear TH receptors (TRs), which are present in two isoforms, TRα and TRβ, encoded by two different genes, THRA and THRB, respectively. Genetic mutations in THRA and THRB cause two different syndromes, called resistance to thyroid hormone alpha (RTHα) and beta (RTHβ). MCT8, encoded by the SLC16A2 gene, is essential for the uptake of T3 into neurons. Loss-of-function mutations in SLC16A2 result in Allan–Herndon–Dudley syndrome. Selenoproteins reduce antioxidative stress and regulate TH metabolism, assisting the activity of deiodinases. Mutations in genes involved in selenoprotein synthesis cause selenoprotein deficiency. Legend: TRH, thyrotropin-releasing hormone; TRHR, thyrotropin-releasing hormone receptor; TSH, thyroid stimulating hormone; TSHR, thyroid stimulating hormone receptor; T4, thyroxine; T3, triiodothyronine; MCT8, Monocarboxylate Transporter 8; TRα, thyroid hormone receptor α; TRβ, thyroid hormone receptor β; DIO, iodothyronine deiodinase.

Figure 2

The influence of physical activity on a 35-year-old male affected by resistance to thyroid hormone β (RTHβ). (A–C) Changes in TSH, fT4 and fT3 after discontinuing intensive physical activity and transitioning to a sedentary lifestyle. After discontinuation of physical activity, TSH and fT4 levels remained stable, while fT3 levels reduced and BMI increased. (D) An inverse correlation between circulating fT3 and BMI, demonstrating the relationship between thyroid function and body weight in RTHβ. (E) Heart rate (HR) changes following cessation of intensive physical activity, highlighting the impact of physical activity on cardiovascular and metabolic outcomes. fT4 is presented relative to the upper limit of the normal (ULN) to mitigate variations across different analytical methods. Legend: PA, physical activity; TSH, thyroid stimulating hormone; fT4, free thyroxine; fT3, free triiodothyronine; ULN upper limit of normal; HR, heart rate; BMI, body mass index.