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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.

Background Resistance to thyroid hormone manifests as high serum levels of free thyroxine and free triiodothyronine, with nonsuppressed thyroid stimulating hormone (TSH) levels. We report a case series of three patients with this condition, the changes in thyroid function tests during their pregnancies, and their obstetric outcome. Cases Three pregnant women with asymptomatic resistance to thyroid hormone developed goiter, and the levels of TSH in one case suppressed progressively, necessitating treatment. The neonates born to all these reported cases were healthy, with normal growth scans and normal thyroid function tests at 1 week. Conclusion The prenatal diagnosis of resistance to thyroid hormone is important for adequate management of both mother and fetus in pregnancy and avoiding unnecessary intervention. The only clinical manifestation of resistance to thyroid hormone may be the presence of a goiter, and treatment in asymptomatic patients solely to normalize thyroid hormone levels is not required during pregnancy. Careful evaluation of the neonate is indicated after delivery.