ECE2016 Oral Communications Thyroid - Clinical (5 abstracts)
Molecular fingerprint of experimental thyrotoxicosis on human metabolism: combined metabolome and proteome study
Maik Pietzner 1 , Beatrice Engelmann 2 , Tim Kacprowski 2 , Janine Golchert 2 , Anna-Luise Dirk 3 , Georg Homuth 2 , Elke Hammer 2, , Matthias Nauck 1, , Henri Wallaschofski 1 , Thomas Münte 5 , Nele Friedrich 1, , Uwe Völker 2, & Georg Brabant 3
1Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany; 2Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany; 3Medical Clinic I, University of Lübeck, Lübeck, Germany; 4DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany; 5Department of Neurology, University of Lübeck, Lübeck, Germany.
The functional state of the thyroid is usually determined by thyrotropin (TSH), whose serum levels depend on circulating thyroid hormone (TH) levels. This feedback mechanism is tightly controlled in the individual and contrasts broad reference range for TSH in the general population, leading to the concept of subclinical thyroid disease. We studied a model of experimental thyrotoxicosis in humans employing an untargeted metabolome and proteome approach. This allowed us to gain a comprehensive picture of TH action on human metabolism as well as to derive metabolic surrogates for thyroid function.
Levothyroxine was prescribed to sixteen healthy young men at a dose of 250 μg/day for 8 weeks. Plasma was samples were obtained every 4 weeks, starting before the treatment and ending 8 week after stopping the application. Mass spectrometry was used to determine protein and metabolite levels. Serum free thyroxine (FT4) concentrations were associated with metabolite/protein levels by means of mixed-effect linear regression models in a subsampling setting. Predictive character of a bio-molecule signature for thyrotoxicosis was assessed by a random forest via a two-stage cross-validation procedure, separating training and validation.
Strong molecular alterations were observed despite no indication of clinical symptoms. Metabolites and proteins were affected to a similar amount (~60 each). TH action on lipid and amino acid metabolism could be confirmed and extended. Novel findings included a strong, positive association with γ-glutamyl amino acids. Significantly associated proteins were aggregated into pathways and revealed established TH targets, e.g. coagulation cascade and apolipoproteins, but also novel associations related to the complement system. A signature of 15 metabolites/proteins attained promising (AUC=0.86) discrimination between thyrotoxicosis and euthyroidism.
The use of untargeted OMICS approaches allowed us to reveal novel pathways of TH action and possess ability to identify new molecular signatures, beyond TSH and FT4, for diagnosis and treatment of thyroid disorders.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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