Background: Individuals with resistance to thyroid hormone owing to mutations in the thyroid hormone receptor β gene (RTHβ) exhibit impaired tissue sensitivity to thyroid hormones, but retain sensitivity in cardiac tissue. Long-term health and survival outcomes in this rare disorder have not been evaluated. We investigated all-cause mortality and cardiovascular event risk in a cohort of patients with RTHβ, followed-up in UK endocrine clinics.
Methods: In a retrospective cohort design, we linked genetically confirmed patients with RTHβ and age-matched and sex-matched population controls to outcomes in datasets within the Welsh Secure Anonymised Information Linkage (SAIL) Databank. Kaplan-Meier and Cox regression models analysed associations of RTHβ with all-cause mortality and cardiovascular events.
Findings: We identified 61 patients with a genetic diagnosis of RTHβ between Jan 1, 1997, and Dec 31, 2019, and matched them with 2750 controls. Compared with controls, patients exhibited increased risks for all-cause mortality (hazard ratio [HR] 2·84, 95% CI 1·59-5·08), atrial fibrillation (10·56, 4·72-23·63), heart failure (HR 6·35, 95% CI 2·26-17·86), and major adverse cardiovascular events (MACE), comprising cardiovascular death, acute myocardial infarction, heart failure, or strokes (HR 3·49, 95% CI 2·04-5·99). The median age of first occurrence of any adverse event was 11 years earlier in patients (56 years, 95% CI 44-65) compared with controls (67 years, 65-70). Cubic spline analyses showed positive associations between FT4 concentrations at diagnosis and mortality or MACE, with FT4 concentration of 30 pmol/L or greater conferring increased risk. Compared with no intervention, treatment with antithyroid drugs, surgery or radioiodine gland ablation, or thyroxine did not control thyroid hormone excess.
Interpretation: We have documented reduced survival and increased cardiovascular morbidity in a cohort of patients with RTHβ for the first time. These outcomes might be driven by lifelong cardiac exposure to thyroid hormone excess; and effective therapies, targeting hormone resistant pathways, could potentially curtail this risk.
Funding: Royal College of Physicians, Wellcome Trust Investigator Award, and NIHR Cambridge Biomedical Research Centre.
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