Evidence for Tissue Level Hyperthyroidism and Uncoupled Oxidative/Phosphorylation in RTH

Mitchell CS , Savage DB , Dufour S , Schoenmakers N , Murgatroyd P , Befroy D , Halsall D , Northcott S , Raymond-Barker P , Curran S , Henning E , Keogh J , Owen P , Lazarus J , Rothman DL , Farooqi IS , Shulman GI , Chatterjee K , Petersen KF

Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia.

J Clin Invest. 2010 Apr 1;120(4):1345-54. doi: 10.1172/JCI38793. Epub 2010 Mar 8.

Resistance to thyroid hormone (RTH), a dominantly inherited disorder usually associated with mutations in thyroid hormone receptor beta (THRB), is characterized by elevated levels of circulating thyroid hormones (including thyroxine), failure of feedback suppression of thyrotropin, and variable tissue refractoriness to thyroid hormone action. Raised energy expenditure and hyperphagia are recognized features of hyperthyroidism, but the effects of comparable hyperthyroxinemia in RTH patients are unknown. Here, we show that resting energy expenditure (REE) was substantially increased in adults and children with THRB mutations. Energy intake in RTH subjects was increased by 40%, with marked hyperphagia particularly evident in children. Rates of muscle TCA cycle flux were increased by 75% in adults with RTH, whereas rates of ATP synthesis were unchanged, as determined by 13C/31P magnetic resonance spectroscopy. Mitochondrial coupling index between ATP synthesis and mitochondrial rates of oxidation (as estimated by the ratio of ATP synthesis to TCA cycle flux) was significantly decreased in RTH patients. These data demonstrate that basal mitochondrial substrate oxidation is increased and energy production in the form of ATP synthesis is decreased in the muscle of RTH patients and that resting oxidative phosphorylation is uncoupled in this disorder. Furthermore, these observations suggest that mitochondrial uncoupling in skeletal muscle is a major contributor to increased REE in patients with RTH, due to tissue selective retention of thyroid hormone receptor alpha sensitivity to elevated thyroid hormone levels.

Download PDF

Thank you for using and supporting THYROID MANAGER

One click download of a complete current PDF version of this chapter is available by payment of $5.00 (including sales tax) to ENDOCRINE EDUCATION / MDTEXT.COM,INC.

Please note:

You will be directed to a Paypal site for entering payment information, and then returned immediately to this site for delivery of the PDF download. If you do not wish to secure the PDF version, you are of course free to download the material directly from the chapter on our Website without charge.

We welcome comments on this service, and this charge, to- ldegroot@earthlink.net. May we note that we must secure income from advertisements and chapter downloads in order to continue providing our (otherwise) totally free, comprehensive, authoritative, constantly up-dated, Endocrinology web-book to the thousands of physicians and trainees around the world who visit the website each day of the year. We also welcome contributions.