Research Research awards BTF Research Award 2010 Investigation of metabolism and insulin sensitivity in the syndrome of Resistance to Thyroid Hormone Dr Carla Moran, Institute of Metabolic Science, University of Cambridge & Addenbrooke's Hospital, Cambridge Final Report Resistance to thyroid hormone (RTH) is a rare condition which results in high levels of thyroid hormone, but variable resistance to its actions in different tissues of the body. It is most commonly due to an abnormal form of the thyroid hormone receptor – a protein that binds to, and brings about, thyroid hormone action. Clinical features range from apparently asymptomatic individuals, to those presenting with growth delay and attention-deficit hyperactivity disorder (ADHD) in childhood, or with goitre (enlarged thyroid gland) and/or symptoms of an overactive thyroid in adult life. Making a diagnosis of RTH is not always straightforward and the disorder can therefore remain unrecognised or not be treated correctly. In addition, little is known regarding the long term adverse effects of this disorder. Our previous studies suggested that individuals with RTH do not handle glucose normally and have unhealthy levels of cholesterol compared with individuals without RTH. It is known that these abnormalities can, in turn, be associated with increased fat within the liver, stiffer arteries and a predisposition to diabetes, heart disease and strokes. It is not known whether patients with RTH may be affected in the same way. Our study was designed to examine these aspects of the condition in detail. To date twenty four patients with RTH have come to our clinical research facility to participate in the study. We have performed comprehensive assessments which have included detailed hormonal and metabolic analyses evaluating the body’s response to a glucose drink, scans to measure the amount of fat and muscle in the whole body and an MRI scan to assess the amount of fat deposited within the liver. We assessed the stiffness of the patients’ arteries by measuring the response of their blood vessels to stimuli which dilate the blood vessels. So far, we have found that individuals with RTH have higher levels of LDL cholesterol and triglycerides ('bad' types of cholesterol) and lower levels of HDL ('good') cholesterol. They also have higher levels of fat deposited within their liver. We are in the process of analysing the results from the blood vessel tests. We plan to enrol more RTH patients into the study. These studies will, for the first time, provide detailed information on how the combination of elevated thyroid hormones and partial tissue resistance affects metabolism in RTH. Eventually, we hope to determine whether RTH patients are at greater risk of cardiovascular problems; if so, it may be possible to target therapies (both with conventional drugs and newer agents) to this patient group. Our observations may also increase understanding of thyroid hormone action in general.