Distinct urinary metabolic profiles associated with serum TSH and FT4 concentrations
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Thyroid hormones (THs) affect virtually all tissues and are essential for maintaining energy metabolism, cellular growth and development. Their release depends on a complex feedback regulation including thyrotropin (TSH), offering a unique individual set point compared with a broad interindividual variance. Keeping in mind that crucial role for intermediary metabolism, the aims of the present study were two-pronged. Firstly to screen the urine metabolome for associations with serum TSH and free thyroxine (FT4) concentrations and secondly, in an attempt to join their metabolic associations and taking into account a tight individual set point, to analyze the relations with the ratio log(TSH)/FT4. Therefore, the urine metabolome of 3327 participants of the population-based Study of Health in Pomerania was characterized by 1H-NMR spectroscopy. Multivariate linear and multinomial logistic regression models were used to detect associations between metabolites and THs. We observed different association patterns for serum TSH or FT4 concentrations. Urine metabolites associated with FT4 included various amino acids as well as citrate, formate and ethanolamine, whereas members of tyrosine metabolism were associated with TSH. Despite not significant, overlap existed towards glycine and ethanolamine. The log(TSH)/FT4 ratio mirrored many of the detected associations and further revealed new associated metabolites/ratios including glycine and succinate. Our findings confirmed metabolic consequences of TH actions, thereby emphasizing the need for distinct interpretation of associations related to serum TSH (hypothalamic-pituitary feedback) or FT4 (tissue specific action) concentrations. In particular, the log(TSH)/FT4 ratio joined their metabolic impact, probably offering a new prospect for thyroid function characterization.
KeywordsThyrotropin Free thyroxine Urine metabolome NMR spectroscopy
The contribution to data collection made by field workers, technicians, interviewers and computer assistants is gratefully acknowledged. This work is part of the research projects Greifswald Approach to Individualized Medicine (GANI_MED) and the Community Medicine Research net (CMR) of the University of Greifswald, Germany, which are funded by the Federal Ministry of Education and Research (GANI_MED: Grant 03IS2061A), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Both encompass several research projects which share data from the population-based Study of Health in Pomerania (SHIP; https://ship.community-medicine.de). Analyses were further supported by grants from the German Research Foundation as part of the priority program “Thyroid Trans Act” (DFG WA 1328/5-1) as well as VO 955/10-2.
Conflict of interest
The authors declare that they have no conflict of interest.
Compliance with ethical requirements
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- Andersen, S., Pedersen, K. M., Bruun, N. H., & Laurberg, P. (2002). Narrow individual variations in serum T(4) and T(3) in normal subjects: A clue to the understanding of subclinical thyroid disease. The Journal of Clinical Endocrinology and Metabolism, 87(3), 1068–1072. doi: 10.1210/jcem.87.3.8165.CrossRefPubMedGoogle Scholar
- Benhadi, N., Fliers, E., Visser, T. J., Reitsma, J. B., & Wiersinga, W. M. (2010). Pilot study on the assessment of the setpoint of the hypothalamus–pituitary–thyroid axis in healthy volunteers. European Journal of Endocrinology, 162(2), 323–329. doi: 10.1530/eje-09-0655.CrossRefPubMedGoogle Scholar
- Bictash, M., Ebbels, T. M., Chan, Q., Loo, R. L., Yap, I. K. S., Brown, I. J., et al. (2010). Opening up the “Black Box”: Metabolic phenotyping and metabolome-wide association studies in epidemiology. Journal of Clinical Epidemiology, 63(9), 970–979. doi: 10.1016/j.jclinepi.2009.10.001.
- Gharbi-Chihi, J., Facchinetti, T., Berge-Lefranc, J. L., Bonne, J., & Torresani, J. (1991). Triiodothyronine control of ATP-citrate lyase and malic enzyme during differentiation of a murine preadipocyte cell line. Hormone and Metabolic Research, 23(9), 423–427. doi: 10.1055/s-2007-1003717.CrossRefPubMedGoogle Scholar
- Levey, A. S., Bosch, J. P., Lewis, J. B., Greene, T., Rogers, N., & Roth, D. (1999). A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Annals of Internal Medicine, 130(6), 461–470. doi: 10.7326/0003-4819-130-6-199903160-00002.
- Lindon, J. C., Nicholson, J. K., Holmes, E., & Everett, J. R. (2000). Metabonomics: Metabolic processes studied by NMR spectroscopy of biofluids. Concepts in Magnetic Resonance, 12(5), 289–320. doi: 10.1002/1099-0534(2000)12:5<289:AID-CMR3>3.0.CO;2-W.CrossRefGoogle Scholar
- Montoya, G. A., Strauss, V., Fabian, E., Kamp, H., Mellert, W., Walk, T., et al. (2013). Mechanistic analysis of metabolomics patterns in rat plasma during administration of direct thyroid hormone synthesis inhibitors or compounds increasing thyroid hormone clearance. Toxicology Letters,. doi: 10.1016/j.toxlet.2013.12.010.PubMedCentralGoogle Scholar
- Stockigt, J. R., Lim, C. F., Barlow, J. W., Wynne, K. N., Mohr, V. S., Topliss, D. J., et al. (1985). Interaction of furosemide with serum thyroxine-binding sites: in vivo and in vitro studies and comparison with other inhibitors. Journal of Clincal Endocrinology Metabolism, 60(5), 1025–1031. doi: 10.1210/jcem-60-5-1025.CrossRefGoogle Scholar
- Wu, S., Gao, Y., Dong, X., Tan, G., Li, W., Lou, Z., et al. (2013a). Serum metabonomics coupled with Ingenuity Pathway Analysis characterizes metabolic perturbations in response to hypothyroidism induced by propylthiouracil in rats. Journal of Pharmaceutical and Biomedical Analysis, 72, 109–114. doi: 10.1016/j.jpba.2012.09.030.CrossRefPubMedGoogle Scholar
- Zelinskaia, N. B. (1989). The significance of studying phospholipids in the diagnosis of hypothyroidism. Vrach Delo(5), 79–81.Google Scholar