Diagnosis and management of RTHα – a disorder characterised by tissue-specific hypothyroidism associated with near-normal thyroid function tests.

Dr Carla Moran, Consultant Endocrinologist
Wolfson Diabetes & Endocrine Centre, Addenbrooke's Hospital, Cambridge

Resistance to Thyroid Hormone alpha (RTHα), a newly-identified disorder which we first described, is due to a genetic (inherited) defect in one thyroid hormone receptor subtype (TRα), in which responsiveness to thyroid hormone (TH) in some tissues (such as bone, muscle, the heart and brain) is so reduced that these organs are hypothyroid; other organs, such as the liver, kidney and pituitary gland, which contain a different thyroid receptor subtype (TRβ), respond normally to thyroid hormone.

Although a relatively small number (~14) of cases have been identified so far, the disorder has devastating consequences including stunted growth and development (childhood), abnormal coordination, intellectual impairment, slowed metabolism and constipation. Some of these abnormalities respond to thyroxine treatment. We have identified many subjects with TRα defects in an anonymised database of human genomes, indicating that this disorder is more common but not recognised, probably because conventional thyroid function tests can be almost normal in this context.

This project aims to measure a greater number of other substances in the blood (such as thyroid hormone metabolites, other small molecules and proteins) in RTHα patients before and during thyroxine therapy for two reasons: first, we plan to identify a combination of abnormal metabolites and proteins which can form a specific test to diagnose the disorder; accurate diagnosis, enabling earlier commencement of thyroxine treatment (e.g. in childhood), may correct abnormalities in RTHα more effectively. Second, we wish to discover markers that can guide thyroxine therapy of the disorder; specifically, we hope to identify markers which indicate that TH resistance in TRα-expressing tissues has been corrected and that TRβ-containing organs are not overexposed to thyroid hormone.

These markers will not only be of direct benefit to patients with this rare form of hypothyroidism affecting specific tissues, but also applicable to assessing thyroxine replacement in commoner conventional hypothyroidism. Thus, markers which correlate with how individual tissues respond to thyroid hormone will be useful in patients experiencing symptoms suggestive of persistent tissue hypothyroidism, despite restoration of normal circulating thyroid hormone and TSH levels.