Unraveling the Molecular Basis for Successful Thyroid Hormone Replacement Therapy: The Need for New Thyroid Tissue- and Pathway-Specific Biomarkers
Thyroid function is conventionally assessed by measurement of thyroid-stimulating hormone (TSH) and free circulating thyroid hormones, which is in most cases sufficient for correct diagnosis and monitoring of treatment efficiency. However, several conditions exist, in which these parameters may be insufficient or even misleading. For instance, both, a TSH-secreting pituitary adenoma and a mutation of thyroid hormone receptor β present with high levels of TSH and circulating hormones, but the optimal treatment is substantially different. Likewise, changes in thyroid hormone receptor α signaling are not captured by routine assessment of thyroid status, as serum parameters are usually inconspicuous. Therefore, new biomarkers are urgently needed to improve the diagnostic management and monitor treatment efficiency for e. g., replacement therapy in hypothyroidism or thyroid hormone resistance. By comparing animal models to human data, the present minireview summarizes the status of this search for new tissue- and pathway-specific biomarkers of thyroid hormone action.
Keywordsproteome - metabolome - transcriptome - hypothyroidism - hyperthyroidism - selenium - copper
Received: 08 August 2019
Received: 09 September 2019
Accepted: 12 September 2019
07 October 2019 (online)
© Georg Thieme Verlag KG
Stuttgart · New York
- 1 Meisinger C, Ittermann T, Wallaschofski H. et al. Geographic variations in the frequency of thyroid disorders and thyroid peroxidase antibodies in persons without former thyroid disease within Germany. Eur J Endocrinol. / European Federation of Endocrine Societies 2012; 167: 363-371. DOI: 10.1530/EJE-12-0111.
- 2 Jonklaas J, Bianco AC, Bauer AJ. et al. Guidelines for the treatment of hypothyroidism: Prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid 2014; 24: 1670-1751 DOI: 10.1089/thy.2014.0028.
- 3 Pearce SH, Brabant G, Duntas LH. et al. 2013 ETA Guideline: Management of Subclinical Hypothyroidism. Eur Thyroid J 2013; 2: 215-228. DOI: 10.1159/000356507.
- 4 Wiersinga WM, Duntas L, Fadeyev V. et al. 2012 ETA Guidelines: The use of L-T4 + L-T3 in the treatment of hypothyroidism. Eur. Thyroid J 2012; 1: 55-71 DOI: 10.1159/000339444.
- 5 Mendoza A, Hollenberg AN. New insights into thyroid hormone action. Pharmacol Therapeut 2017; 173: 135-145. DOI: 10.1016/j.pharmthera.2017.02.012.
- 6 Yen PM. Physiological and molecular basis of thyroid hormone action. Physiol Rev 2001; 81: 1097-1142
- 7 Fonseca TL, Fernandes GW, McAninch EA. et al. Perinatal deiodinase 2 expression in hepatocytes defines epigenetic susceptibility to liver steatosis and obesity. Proceedings of the National Academy of Sciences of the United States of America 2015; 112: 14018-14023 DOI: 10.1073/pnas.1508943112.
- 8 Krause C, Grohs M, El Gammal A. et al. Reduced expression of thyroid hormone receptor beta in human nonalcoholic steatohepatitis. Endocrine Connections 2018; DOI: 10.1530/EC-18-0499.
- 9 de Vries EM, Fliers E, Boelen A. The molecular basis of the non-thyroidal illness syndrome. J Endocrinol 2015; 225: R67-R81
- 10 Bochukova E, Schoenmakers N, Agostini M. et al. A mutation in the thyroid hormone receptor alpha gene. N Engl J Med 2012; 366: 243-249
- 11 Friesema EC, Grueters A, Biebermann H. et al. Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet 2004; 364: 1435-1437. DOI: 10.1016/S0140-6736(04)17226-7.
- 12 Biondi B, Cooper DS. Subclinical Hyperthyroidism. N Engl J Med 2018; 378: 2411-2419. DOI: 10.1056/NEJMcp1709318.
- 13 Peeters RP. Subclinical Hypothyroidism. N Engl J Med 2017; 377: 1404 DOI: 10.1056/NEJMc1709853.
- 14 Koulouri O, Moran C, Halsall D. et al. Pitfalls in the measurement and interpretation of thyroid function tests. Best Pract Res Clin Endocrinol Metab 2013; 27: 745-762
- 15 Baloch Z, Carayon P, Conte-Devolx B. et al. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003; 13: 3-126. DOI: 10.1089/105072503321086962.
- 16 Persani L, Brabant G, Dattani M. et al. 2018 European Thyroid Association (ETA) Guidelines on the diagnosis and management of central hypothyroidism Eur. Thyroid J 2018; 7: 225-237. DOI: 10.1159/000491388.
- 17 Refetoff S, DeWind LT, DeGroot LJ. Familial syndrome combining deaf-mutism, stuppled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone. J Clin Endocrinol Metab 1967; 27: 279-294
- 18 Pappa T, Refetoff S. Human Genetics of Thyroid Hormone Receptor Beta: Resistance to Thyroid Hormone Beta (RTHbeta). Methods in Molecular Biology 2018; 1801: 225-240. DOI: 10.1007/978-1-4939-7902-8_18.
- 19 Gullo D, Latina A, Frasca F. et al. Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PloS One 2011; 6: e22552. DOI: 10.1371/journal.pone.0022552.
- 20 Hoermann R, Midgley JE, Larisch R. et al. Is pituitary TSH an adequate measure of thyroid hormone-controlled homoeostasis during thyroxine treatment? Eur. J Endocrinol / European Federation of Endocrine Societies 2013; 168: 271-280 DOI: 10.1530/EJE-12-0819.
- 21 Williams G. Extrathyroidal expression of TSH receptor. Ann Endocrinol (Paris) 2011; 72: 68-73
- 22 Wiersinga WM. Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism. Nature reviews Endocrinology 2014; 10: 164-174 DOI: 10.1038/nrendo.2013.258.
- 23 Thaler MA, Seifert-Klauss V, Luppa PB. The biomarker sex hormone-binding globulin - from established applications to emerging trends in clinical medicine. Best Pract Res Clin Endocrinol Metab 2015; 29: 749-760 DOI: 10.1016/j.beem.2015.06.005.
- 24 Pietzner M, Kacprowski T, Friedrich N. Empowering thyroid hormone research in human subjects using OMICs technologies. J Endocrinol 2018; 238: R13-R29 DOI: 10.1530/JOE-18-0117.
- 25 Mittag J, Behrends T, Hoefig CS. et al. Thyroid hormones regulate selenoprotein expression and selenium status in mice. PloS One 2010; 5: e12931
- 26 Mittag J, Behrends T, Nordstrom K. et al. Serum copper as a novel biomarker for resistance to thyroid hormone. Biochem J 2012; 443: 103-109
- 27 Pietzner M, Engelmann B, Kacprowski T. et al. Plasma proteome and metabolome characterization of an experimental human thyrotoxicosis model. BMC Medicine 2017; 15: 6 DOI: 10.1186/s12916-016-0770-8.
- 28 Blasig S, Kuhnen P, Schuette A. et al. Positive correlation of thyroid hormones and serum copper in children with congenital hypothyroidism. J Trace Elem Med Biol: Organ of the Society for Minerals and Trace Elements 2016; 37: 90-95. DOI: 10.1016/j.jtemb.2016.05.007.
- 29 Jain RB. Thyroid function and serum copper, selenium, and zinc in general U.S. population. Biological Trace Element Research 2014; 159: 87-98 DOI: 10.1007/s12011-014-9992-9.
- 30 Massolt ET, Meima ME, Swagemakers SMA. et al. Thyroid state regulates gene expression in human whole blood. J Clin Endocrinol Metab 2018; 103: 169-178. DOI: 10.1210/jc.2017-01144.
- 31 Alfadda AA, Benabdelkamel H, Masood A. et al. Differences in the plasma proteome of patients with hypothyroidism before and after thyroid hormone replacement: A proteomic analysis. Int J Mol Sci 2018; 19 DOI: 10.3390/ijms19010088.
- 32 Feller M, Snel M, Moutzouri E. et al. Association of Thyroid Hormone Therapy With Quality of Life and Thyroid-Related Symptoms in Patients with subclinical hypothyroidism: A systematic review and meta-analysis. Jama 2018; 320: 1349-1359 DOI: 10.1001/jama.2018.13770.
- 33 Engelmann B, Bischof J, Dirk AL. et al. Effect of experimental thyrotoxicosis onto blood coagulation: A proteomics study Eur. Thyroid J 2015; 4: 119-124 DOI: 10.1159/000381769.
- 34 Elbers LP, Moran C, Gerdes VE. et al. The hypercoagulable state in hyperthyroidism is mediated via the thyroid hormone beta receptor pathway. Eur J Endocrinol / European Federation of Endocrine Societies 2016; DOI: 10.1530/EJE-15-1249.
- 35 Hooper JM, Stuijver DJ, Orme SM. et al. Thyroid dysfunction and fibrin network structure: A mechanism for increased thrombotic risk in hyperthyroid individuals. J Clin Endocrinol Metab 2012; 97: 1463-1473 DOI: 10.1210/jc.2011-2894.
- 36 Hoefig CS, Harder L, Oelkrug R. et al. Thermoregulatory and cardiovascular consequences of a transient thyrotoxicosis and recovery in male mice. Endocrinology 2016; 157: 2957-2967 DOI: 10.1210/en.2016-1095.
- 37 Montoya GA, Strauss V, Fabian E. et al. Mechanistic analysis of metabolomics patterns in rat plasma during administration of direct thyroid hormone synthesis inhibitors or compounds increasing thyroid hormone clearance. Toxicology Letters 2014; 225: 240-251 DOI: 10.1016/j.toxlet.2013.12.010.
- 38 Wu S, Gao Y, Dong X. et al. Serum metabonomics coupled with Ingenuity Pathway Analysis characterizes metabolic perturbations in response to hypothyroidism induced by propylthiouracil in rats. J Pharmaceut Biomed 2013; 72: 109-114. DOI: 10.1016/j.jpba.2012.09.030.
- 39 Srisawat S, Sitasuwan T, Ungprasert P. Increased risk of venous thromboembolism among patients with hyperthyroidism: A systematic review and meta-analysis of cohort studies. Eur J Intern Med 2019; DOI: 10.1016/j.ejim.2019.06.012.
- 40 Nock S, Johann K, Harder L. et al. Identification of new thyroid hormone dependent biomarkers for a successful replacement therapy. Endocrine Abstracts 2018; 56: GP253 DOI: 10.1530/endoabs.56.GP253.
- 41 Pietzner M, Budde K, Homuth G. et al. Distinct urinary metabolic profiles associated with serum TSH and FT4 concentrations. Metabolomics 2015; 11: 1316-1326 DOI: https://doi.org/10.1007/s11306-015-0788-5.
- 42 Friedrich N, Pietzner M, Cannet C. et al. Urinary metabolomics reveals glycemic and coffee associated signatures of thyroid function in two population-based cohorts. PloS One 2017; 12: e0173078 DOI: 10.1371/journal.pone.0173078.
- 43 Boumaza H, Markossian S, Busi B. et al. Metabolomic profiling of body fluids in mouse models demonstrates that NMR is a Putative Diagnostic Tool For The Presence Of Thyroid Hormone Receptor alpha1 mutations. Thyroid 2019; DOI: 10.1089/thy.2018.0730.
- 44 Bianco AC, Anderson G, Forrest D. et al. American Thyroid Association Guide to investigating thyroid hormone economy and action in rodent and cell models. Thyroid 2014; 24: 88-168