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

Dr Carla Moran, Consultant Endocrinologist, Addenbrooke's Hospital, Cambridge


Resistance to Thyroid Hormone (RTHα) is a newly-recognised genetic condition with resistance to hormone action in particular tissues (e.g. skeletal muscle, heart, brain, bone), but near-normal circulating thyroid hormones. As such, it represents a disorder that enables the tissue- specific effects of hypothyroidism to be studied. So far, 29 cases have been described in the worldwide published literature and we have identified a further five individuals with the condition.

Final Report

The current challenges in RTHα include: making a diagnosis, since the changes in thyroid biochemistry are very subtle; and assessing whether treatment with thyroxine is overcoming hormone resistance in some tissues without causing toxicity in other tissues that retain hormone sensitivity.

Identification of substances in the blood that could predict patients likely to have RTHα or that could accurately guide therapy would be very helpful in clinical practice. In order to try to address this need, I collaborated with a company called Metabolon to measure approximately 1000 circulating small molecules in blood samples from 15 patients with RTHα and compared the results with healthy individuals.

Results from this analysis identified 14 substances (“metabolites”) that can discriminate RTHα patients from healthy individuals with a very high degree of accuracy (93%). If these findings are validated by further research, it may be possible to identify a circulating metabolite profile that could be used to diagnose RTHα in the future.

My results have also identified numerous physiological pathways that are perturbed in RTHα and delineated how these changes are affected by thyroxine treatment. Some pathways are known to be regulated by thyroid hormone, but others are novel. If thyroxine therapy in RTHα patients reverses the changes in these pathways, restoring levels of specific metabolites comparable to those of healthy individuals, these substances may be useful markers to guide thyroxine therapy.

In summary, my studies may identify a profile of specific metabolites that could be used to diagnose RTHα. Following thyroxine therapy in this disorder, metabolite levels may also indicate reversal of hormone resistance in specific tissues with avoidance of toxicity in other, hormone-sensitive, organs.