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Functional and Symptomatic Individuality in the Response to Levothyroxine Treatment

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Hoermann, Rudolf, Midgley, John E. M., Larisch, Rolf, Dietrich, Johannes W.·2019·Frontiers in Endocrinology
DOI 10.3389/fendo.2019.00664PMC PMC6775211
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Abstract

Background: For significant numbers of patients dissatisfied on standard levothyroxine (LT4) treatment for hypothyroidism, patient-specific responses to T4 could play a significant role. Aim: To assess response heterogeneity to LT4 treatment, identifying confounders and hidden clusters within a patient panel, we performed a secondary analysis using data from a prospective cross-sectional and retrospective longitudinal study. Methods: Multivariate and multivariable linear models adjusted for covariates (gender, age and BMI) were stratified by disease-specific treatment indication. During follow-up, pooled observations were compared from the same patient presenting either with or without self-reported symptoms. Statistical analysis was extended to multilevel models to derive intra-class correlation coefficients and reliability measures during follow-up. Results: Equilibria between TSH, FT4 and FT3 serum concentrations in 342 patients were examined by treatment indication (benign goitre, autoimmune thyroiditis, thyroid carcinoma), consequently displaying complex interactive response patterns. 77 patients treated with LT4 and monitored for thyroid carcinoma presented, in association with changes in LT4 dose, either with hypothyroid symptoms or symptom-free. Significant biochemical differences appeared between the different presentations. Levelled trajectories by subject to relief from hypothyroid symptoms differed significantly, indicating distinct responses, and denying a single shared outcome. These were formally defined by a high coefficient of the intraclass correlation (ICC1, exceeding 0.60 in all thyroid parameters) during follow-up on multiple visits at the same LT4 dose, when lacking symptoms. The intra-personal clusters were clearly differentiated from random variability by random group resampling. Symptomatic change in these patients was strongly associated with serum FT3, but not with FT4 or TSH concentrations. In 25 patients transitioning from asymptomatic to symptomatically hyperthyroid, FT3 concentrations remained within the reference limits, whilst at the same time marked biochemical differences were apparent between the presentations. Conclusions: Considerable intra-individual clustering occurred in the biochemical and symptomatic responses to LT4 treatment, implying statistically multileveled response groups. Unmasking individual differences in the averaged treatment response hereby highlights clinically distinguishable subgroups within an indiscriminate patient panel. This, through well designed larger clinical trials will better target the different therapeutic needs of individual patients.

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Research works printed but not linked: 59

  1. [1]Biondi B Wartofsky L. Treatment with thyroid hormone. Endocr Rev. (2014) 35: 433– 512. 10.1210/er.2013-1083 24433025 · DOI · Paper page
  2. [3]McAninch EA Bianco AC. The history and future of treatment of hypothyroidism. Ann Intern Med. (2016) 164: 50– 6. 10.7326/M15-1799 26747302 PMC4980994 · DOI · Paper page
  3. [5]Hoermann R Midgley JEM Larisch R Dietrich JW. Individualised requirements for optimum treatment of hypothyroidism: complex needs, limited options. Drugs Cont. (2019) 8: 1– 18. 10.7573/dic.212597 31516533 PMC6726361 · DOI
  4. [6]Slater S. The discovery of thyroid replacement therapy. Part 1: in the beginning. J R Soc Med. (2011) 104: 15– 8. 10.1258/jrsm.2010.10k050 21205773 PMC3014555 · DOI
  5. [8]Peterson SJ Cappola AR Castro MR Dayan CM Farwell AP Hennessey JV. An online survey of hypothyroid patients demonstrates prominent dissatisfaction. Thyroid. (2018) 28: 707– 21. 10.1089/thy.2017.0681 29620972 PMC6916129 · DOI · Paper page
  6. [10]Hennessey JV Espaillat R. Current evidence for the treatment of hypothyroidism with levothyroxine/levotriiodothyronine combination therapy versus levothyroxine monotherapy. Int J Clin Pract. (2018) 72: e13062– 14. 10.1111/ijcp.13062 29381251 PMC5873391 · DOI · Paper page
  7. [11]Hoermann R Midgley JEM Larisch R Dietrich JW. Lessons from randomised clinical trials for triiodothyronine treatment of hypothyroidism: have they achieved their objectives. J Thyroid Res. (2018) 2018: 3239197. 10.1155/2018/3239197 30174821 PMC6098896 · DOI
  8. [13]Hoermann R Midgley JEM Larisch R Dietrich JW. Recent advances in thyroid hormone regulation: toward a new paradigm for optimal diagnosis and treatment. Front Endocrinol. (2017) 8: 364. 10.3389/fendo.2017.00364 29375474 PMC5763098 · DOI · Paper page
  9. [14]Ito M Miyauchi A Morita S Kudo T Nishihara E Kihara M. TSH-suppressive doses of levothyroxine are required to achieve preoperative native serum triiodothyronine levels in patients who have undergone total thyroidectomy. Eur J Endocrinol. (2012) 167: 373– 8. 10.1530/EJE-11-1029 22711760 · DOI · Paper page
  10. [16]Midgley JEM Larisch R Dietrich JW Hoermann R. Variation in the biochemical response to L-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency. Endocr Connect. (2015) 4: 196– 205. 10.1530/EC-15-0056 26335522 PMC4557078 · DOI · Paper page
  11. [17]Chaker L Van Den Berg ME Niemeijer MN Franco OH Dehghan A Hofman A. Thyroid function and sudden cardiac death: a prospective population-based cohort study. Circulation. (2016) 134: 713– 22. 10.1161/CIRCULATIONAHA.115.020789 27601558 · DOI · Paper page
  12. [18]Baumgartner C Da Costa BR Collet TH Feller M Floriani C Bauer DC. Thyroid function within the normal range, subclinical hypothyroidism, and the risk of atrial fibrillation. Circulation. (2017) 136: 2100– 16. 10.1161/CIRCULATIONAHA.117.028753 29061566 PMC5705446 · DOI
  13. [20]Hoermann R Midgley JEM Dietrich JW Larisch R. Dual control of pituitary thyroid stimulating hormone secretion by thyroxine and triiodothyronine in athyreotic patients. Ther Adv Endocrinol Metab. (2017) 8: 83– 95. 10.1177/2042018817716401 28794850 PMC5524252 · DOI
  14. [21]Larisch R Midgley JEM Dietrich JW Hoermann R. Symptomatic relief is related to serum free triiodothyronine concentrations during follow-up in levothyroxine-treated patients with differentiated thyroid cancer. Exp Clin Endocrinol Diabetes. (2018) 126: 546– 52. 10.1055/s-0043-125064 29396968 · DOI
  15. [22]Larisch R Giacobino A Eckl WA Wahl HG Midgley JEM Hoermann R. Reference range for thyrotropin. Post hoc assessment. Nuklearmedizin. (2015) 54: 112– 7. 10.3413/Nukmed-0671-14-06 25567792 · DOI · Paper page
  16. [23]Bates D Mächler M Bolker B Walker S Fitting linear mixed-effects models using lme4. J Stat Softw. (2015) 67: 1– 48. 10.18637/jss.v067.i01 · DOI · Paper page
  17. [27]Fox J Weisberg S An R Companion to Applied Regression. 3rd ed Thousand Oaks, CA: SAGE Publications (2019). Available online at: http://tinyurl.com/carbook (accessed January 14, 2019).
  18. [31]Feller W An Introduction to Probability Theory and Its Applications. 2nd ed Vol. 2 New Delhi: Wiley India Pvt. Limited (2008). p. 1– 800.
  19. [32]Molenaar PCM Campbell CG The new person-specific paradigm in psychology. Curr Dir Psychol Sci. (2009) 18: 112– 7. 10.1111/j.1467-8721.2009.01619.x · DOI · Paper page
  20. [33]Boker SM Molenaar PC Nesselroade JR. Issues in intraindividual variability: individual differences in equilibria and dynamics over multiple time scales. Psychol Aging. (2009) 24: 858– 62. 10.1037/a0017912 20025401 PMC2845906 · DOI
  21. [34]Hamaker EL Why researchers should think “within-person”: a paradigmatic rationale. In: Mehl MR Conner TS editors. Handbook of Research Methods for Studying Daily Life. New York: Guilford Press (2012). p. 43– 61.
  22. [37]Rücker G Schumacher M. Simpson's paradox visualized: the example of the rosiglitazone meta-analysis. BMC Med Res Methodol. (2008) 8: 34. 10.1186/1471-2288-8-34 18513392 PMC2438436 · DOI
  23. [39]Andersen S Bruun NH Pedersen KM Laurberg P. Biologic variation is important for interpretation of thyroid function tests. Thyroid. (2003) 13: 1069– 78. 10.1089/105072503770867237 14651790 · DOI · Paper page
  24. [41]Hoermann R Midgley JEM Larisch R Dietrich JW. Advances in applied homeostatic modelling of the relationship between thyrotropin and free thyroxine. PLoS ONE. (2017) 12: e0187232. 10.1371/journal.pone.0187232 29155897 PMC5695809 · DOI
  25. [42]Hoermann R Midgley JEM Larisch R Dietrich JW. Relational stability in the expression of normality, variation, and control of thyroid function. Front Endocrinol. (2016) 7: 142. 10.3389/fendo.2016.00142 27872610 PMC5098235 · DOI · Paper page
  26. [43]Seely AJE Macklem PT. Complex systems and the technology of variability analysis. Crit Care. (2004) 8: R367– 84. 10.1186/cc2948 15566580 PMC1065053 · DOI
  27. [44]Jones JC. Honey bee nest thermoregulation: diversity promotes stability. Science. (2004) 305: 402– 4. 10.1126/science.1096340 15218093 · DOI
  28. [45]Kotas ME Medzhitov R. Homeostasis, inflammation, and disease susceptibility. Cell. (2015) 160: 816– 27. 10.1016/j.cell.2015.02.010 25723161 PMC4369762 · DOI · Paper page
  29. [47]Ott J Promberger R Kober F Neuhold N Tea M Huber JC. Hashimoto's thyroiditis affects symptom load and quality of life unrelated to hypothyroidism: a prospective case-control study in women undergoing thyroidectomy for benign goiter. Thyroid. (2011) 21: 161– 7. 10.1089/thy.2010.0191 21186954 · DOI · Paper page
  30. [48]Quinque EM Villringer A Kratzsch J Karger S. Patient-reported outcomes in adequately treated hypothyroidism - insights from the German versions of thydqol, thysrq and thytsq. Health Qual Life Outcomes. (2013) 11: 68. 10.1186/1477-7525-11-68 23618009 PMC3735043 · DOI
  31. [49]Kelderman-Bolk N Visser TJ Tijssen JP Berghout A. Quality of life in patients with primary hypothyroidism related to BMI. Eur J Endocrinol. (2015) 173: 507– 15. 10.1530/EJE-15-0395 26169304 · DOI
  32. [50]Applewhite MK James BC Kaplan SP Angelos P Kaplan EL Grogan RH. Quality of life in thyroid cancer is similar to that of other cancers with worse survival. World J Surg. (2016) 40: 551– 61. 10.1007/s00268-015-3300-5 26546191 · DOI
  33. [51]Massolt ET Van Der Windt M Korevaar TIM Kam BLR Burger JW Franssen GJH. Thyroid hormone and its metabolites in relation to quality of life in patients treated for differentiated thyroid cancer. Clin Endocrinol. (2016) 85: 781– 8. 10.1111/cen.13101 27175823 · DOI · Paper page
  34. [52]Blum MR Wijsman LW Virgini VS Bauer DC Den Elzen WP Jukema JW. Subclinical thyroid dysfunction and depressive symptoms among the elderly: a prospective cohort study. Neuroendocrinology. (2016) 103: 291– 9. 10.1159/000437387 26202797 · DOI
  35. [53]Carlé A Pedersen IB Knudsen N Perrild H Ovesen L Andersen S. Hypothyroid symptoms fail to predict thyroid insufficiency in old people: a population-based case-control study. Am J Med. (2016) 129: 1082– 92. 10.1016/j.amjmed.2016.06.013 27393881 · DOI · Paper page
  36. [55]Jorde R Waterloo K Storhaug H Nyrnes A Sundsfjord J Jenssen TG. Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatment. J Clin Endocrinol Metab. (2006) 91: 145– 53. 10.1210/jc.2005-1775 16263815 · DOI
  37. [57]Samuels MH Kolobova I Niederhausen M Janowsky JS Schuff KG. Effects of altering levothyroxine (L-T4) doses on quality of life, mood, and cognition in L-T4 treated subjects. J Clin Endocrinol Metab. (2018) 103: 1997– 2008. 10.1210/jc.2017-02668 29509918 PMC6457033 · DOI · Paper page
  38. [59]Hedman C Djärv T Strang P Lundgren CI Fear of recurrence and view of life affect health-related quality of life in patients with differentiated thyroid carcinoma: a prospective Swedish population-based study. Thyroid. (2018) 28: 1609– 17. 10.1089/thy.2018.0388 30244657 · DOI
  39. [61]Parmentier T Sienaert P. The use of triiodothyronine (T3) in the treatment of bipolar depression: a review of the literature. J Affect Disord. (2018) 229: 410– 4. 10.1016/j.jad.2017.12.071 29331701 · DOI
  40. [62]Samuels MH Kolobova I Antosik M Niederhausen M Purnell JQ Schuff KG. Thyroid function variation in the normal range, energy expenditure, and body composition in L-T4-treated subjects. J Clin Endocrinol Metab. (2017) 102: 2533– 42. 10.1210/jc.2017-00224 28460140 PMC5505196 · DOI
  41. [63]Ylli D Wartofsky L. Can we link thyroid status, energy expenditure, and body composition to management of subclinical thyroid dysfunction. J Clin Endocrinol Metab. (2019) 104: 209– 12. 10.1210/jc.2018-01997 30247562 · DOI
  42. [65]George BJ Li P Lieberman HR Pavela G Brown AW Fontaine KR. Randomization to randomization probability: estimating treatment effects under actual conditions of use. Psychol Methods. (2018) 23: 337– 50. 10.1037/met0000138 28406674 PMC5640450 · DOI
  43. [66]Hedman C Djärv T Strang P Lundgren CI. Effect of thyroid-related symptoms on long-term quality of life in patients with differentiated thyroid carcinoma: a population-based study in Sweden. Thyroid. (2017) 27: 1034– 42. 10.1089/thy.2016.0604 28474541 · DOI
  44. [67]Boesen VB Feldt-Rasmussen U Bjorner JB Cramon P Groenvold M Nygaard B. How should thyroid-related quality of life be assessed? Recalled patient-reported outcomes compared to here-and-now measures. Thyroid. (2018) 28: 1561– 70. 10.1089/thy.2018.0210 30369298 · DOI
  45. [69]Cheng S-Y Leonard JL Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev. (2010) 31: 139– 70. 10.1210/er.2009-0007 20051527 PMC2852208 · DOI · Paper page
  46. [71]Schweizer U Johannes J Bayer D Braun D. Structure and function of thyroid hormone plasma membrane transporters. Eur Thyroid J. (2014) 3: 143– 53. 10.1159/000367858 25538896 PMC4224232 · DOI
  47. [72]Gereben B Zavacki AM Ribich S Kim BW Huang SA Simonides WS. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev. (2008) 29: 898– 938. 10.1210/er.2008-0019 18815314 PMC2647704 · DOI · Paper page
  48. [73]Citterio CE Veluswamy B Morgan SJ Galton VA Banga JP Atkins S. De novo triiodothyronine formation from thyrocytes activated by thyroid-stimulating hormone. J Biol Chem. (2017) 292: 15434– 44. 10.1074/jbc.M117.784447 28743746 PMC5602401 · DOI · Paper page
  49. [74]Ishii H Inada M Tanaka K Mashio Y Naito K Nishikawa M. Induction of outer and inner ring monodeiodinases in human thyroid gland by thyrotropin. J Clin Endocrinol Metab. (1983) 57: 500– 5. 10.1210/jcem-57-3-500 6308028 · DOI
  50. [75]Hoermann R Midgley JEM Larisch R Dietrich JW. Relational stability of thyroid hormones in euthyroid subjects and patients with autoimmune thyroid disease. Eur Thyroid J. (2016) 5: 171– 9. 10.1159/000447967 27843807 PMC5091265 · DOI
  51. [79]Ito M Miyauchi A Hisakado M Yoshioka W Ide A Kudo T. Biochemical markers reflecting thyroid function in athyreotic patients on levothyroxine monotherapy. Thyroid. (2017) 27: 484– 90. 10.1089/thy.2016.0426 28056660 PMC5385443 · DOI · Paper page
  52. [81]Nieto H Boelaert K. Women in cancer thematic review: thyroid-stimulating hormone in thyroid cancer: does it matter? Endocr Relat Cancer. (2016) 23: T109– 21. 10.1530/ERC-16-0328 27633516 · DOI
  53. [82]Carhill AA Litofsky DR Ross DS Jonklaas J Cooper DS Brierley JD. Long-term outcomes following therapy in differentiated thyroid carcinoma: NTCTCS registry analysis 1987-2012. J Clin Endocrinol Metab. (2015) 100: 3270– 9. 10.1210/JC.2015-1346 26171797 PMC5393522 · DOI · Paper page
  54. [83]Haugen BR Alexander EK Bible KC Doherty GM Mandel SJ Nikiforov YE. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid. (2016) 26: 1– 133. 10.1089/thy.2015.0020 26462967 PMC4739132 · DOI · Paper page
  55. [84]Thvilum M Brandt F Almind D Christensen K Hegedüs L Brix TH. Excess mortality in patients diagnosed with hypothyroidism: a nationwide cohort study of singletons and twins. J Clin Endocrinol Metab. (2013) 98: 1069– 75. 10.1210/jc.2012-3375 23365121 PMC3590474 · DOI
  56. [85]Porcu E Medici M Pistis G Volpato CB Wilson SG Cappola AR. A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. PLoS Genet. (2013) 9: e1003266. 10.1371/journal.pgen.1003266.s011 23408906 PMC3567175 · DOI
  57. [86]McAninch EA Jo S Preite NZ Farkas E Mohácsik P Fekete C. Prevalent polymorphism in thyroid hormone-activating enzyme leaves a genetic fingerprint that underlies associated clinical syndromes. J Clin Endocrinol Metab. (2015) 100: 920– 33. 10.1210/jc.2014-4092 25569702 PMC4333048 · DOI
  58. [87]Chng CL Lim AY Tan HC Kovalik JP Tham KW Bee YM. Physiological and metabolic changes during the transition from hyperthyroidism to euthyroidism in Graves' disease. Thyroid. (2016) 26: 1422– 30. 10.1089/thy.2015.0602 27465032 · DOI
  59. [88]Massolt ET Chaker L Visser TJ Gillis AJM Dorssers LCJ Beukhof CM. Serum microRNA profiles in athyroid patients on and off levothyroxine therapy. PLoS ONE. (2018) 13: e0194259. 10.1371/journal.pone.0194259 29649216 PMC5896904 · DOI

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Sorted by citations

Authors
Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W.
Affiliations
  • Klinikum Lüdenscheid (DE)
  • Witten/Herdecke University (DE)
Corresponding author
Hoermann, Rudolf
ORCID
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2019-09-26
Volume
10
Pages
664-664
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2019.00664
PMC
PMC6775211
OpenAlex
W2975340760
Cited by
22
References
26
Citations by year
2025: 5 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 3 · 2020: 4 · 2019: 2 · 2018: 1
FWCI
2.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
Keywords
levothyroxine, hypothyroidism, treatment response heterogeneity, interindividual variability, free thyroxine, free triiodothyronine, thyroid-stimulating hormone, thyroid cancer, autoimmune thyroiditis, hyperthyroidism, intraclass correlation coefficient, patient subgroups, dose adjustment

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