Serum copper as a novel biomarker for resistance to thyroid hormone

Thyroid hormone action is mediated by the thyroid hormone receptors TRα1 and TRβ. Defects in TRβ lead to RTH (resistance to thyroid hormone) β, a syndrome characterized by high levels of thyroid hormone and non-suppressed TSH (thyroid-stimulating hormone). However, a correct diagnosis of RTHβ patients is difficult as the clinical picture varies. A biochemical serum marker indicative of defects in TRβ signalling is needed and could simplify the diagnosis of RTHβ, in particular the differentiation to TSH-secreting pituitary adenomas, which present with clinically similar symptoms. In the present paper we show that serum copper levels are regulated by thyroid hormone, which stimulates the synthesis and the export of the hepatic copper-transport protein ceruloplasmin into the serum. This is accompanied by a concerted reduction in the mRNA levels of other copper-containing proteins such as metallothioneins 1 and 2 or superoxide dismutase 1. The induction of serum copper is abolished in genetically hyperthyroid mice lacking TRβ and human RTHβ patients, demonstrating an important role of TRβ for this process. Together with a previously reported TRα1 specific regulation of serum selenium, we show that the ratio of serum copper and selenium, which is largely independent of thyroid hormone levels, volume changes or sample degradation, can constitute a valuable novel biomarker for RTHβ. Moreover, it could also provide a suitable large-scale screening parameter to identify RTHα patients, which have not been identified to date.