Endocrine Abstracts

The actions of thyroid hormones (TH) are mediated by receptors (TRα1, TRβ1, TRβ2), encoded by separate genes (THRA, THRB), with differing tissue distribution. TRβ2 mediates negative feedback within the hypothalamic-pituitary axis, with TRβ1 being expressed in the liver & kidney; TRα1 predominates in the myocardium and skeletal muscle.

Resistance to Thyroid Hormone, usually due to heterozygous TRβ mutations (RTHβ), is characterised by elevated TH and non-suppressed TSH levels. Cardiac features include tachycardia and atrial arrhythmias; indices of myocardial contractility are in the hyperthyroid range. Marked cardiac hyperthyroidism in rare, homozygous RTHβ can lead to life-threatening cardiac failure. Management of cardiac features in RTHβ includes beta blockade, antiarrhythmics or lowering TH levels with triiodothyroacetic acid (TRIAC) therapy. It is not known whether raised cholesterol and triglyceride levels, hepatic steatosis and insulin resistance in RTHβ confers excess cardiometabolic risk, but TRβ-selective thyromimetics represent a rational approach to treatment of these metabolic abnormalities.

Recognised more recently, features of Resistance to Thyroid Hormone due to defective TRα (RTHα) include growth retardation, neurodevelopmental delay, skeletal dysplasia and constipation, but with near-normal thyroid function tests. The cardiovascular manifestations of this disorder include bradycardia and lower blood pressure; following thyroxine therapy, changes in these parameters and cardiac indices are blunted, reflecting myocardial resistance to hormone action.

The divergent phenotypes of RTHβ and RTHα highlight the relative importance of α and β receptor subtypes in mediating TH action in myocardium and other tissues.