Symptomatic Relief is Related to Serum Free Triiodothyronine Concentrations during Follow-up in Levothyroxine-Treated Patients with Differentiated Thyroid Cancer

Rolf Larisch; John E M Midgley; Johannes W Dietrich; Rudolf Hoermann

doi:10.1055/s-0043-125064

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2018; 126(09): 546-552
DOI: 10.1055/s-0043-125064

Article

Symptomatic Relief is Related to Serum Free Triiodothyronine Concentrations during Follow-up in Levothyroxine-Treated Patients with Differentiated Thyroid Cancer

Rolf Larisch

¹Department of Nuclear Medicine, Klinikum Lüdenscheid, Paulmannshöherstr. 14, 58515 Lüdenscheid, Germany

,

John E M Midgley

²North Lakes Clinical, 20 Wheatley Avenue, Ilkley LS29 8PT, UK

,

Johannes W Dietrich

³Medical Department I, Endocrinology and Diabetology, Bergmannsheil University Hospitals, Ruhr University of Bochum, Buerkle-de-la-Camp-Platz 1, 44789 Bochum, Germany

⁴Ruhr Center for Rare Diseases (CeSER), Ruhr University of Bochum and Witten/Herdecke University, Alexandrinenstr. 5, 44791 Bochum, Germany

,

Rudolf Hoermann

¹Department of Nuclear Medicine, Klinikum Lüdenscheid, Paulmannshöherstr. 14, 58515 Lüdenscheid, Germany

› Author Affiliations

Abstract

Aim Patients on levothyroxine-treatment frequently have complaints although TSH is within the reference range. Moreover, FT3 is often low in these patients. The clinical significance of this disequilibrium is studied here.

Patients, methods We conducted a retrospective longitudinal study including 319 patients with differentiated thyroid carcinoma on LT4-medication (1.8 [1.6,2.1] µg/kg body weight). Patients were followed at 2309 visits for at median 63 [46,81] months. Association of reported complaints during follow-up with changes in thyroid parameters were analysed using a generalised linear mixed model accounting for within-variability and intra-subject correlations.

Results 26% of patients expressed hypothyroid and 9.7% hyperthyroid complaints at any one visit, rates per visit being 6.5% and 2%, respectively. During follow-up, median changes in spans were as follows, LT4-dose 0.49 [IQR 0.29,0.72] µg/kg, FT3 1.77 [1.25,2.32] pmol/l, FT4 9.80 [6.70,12.8] pmol/l and TSH 1.25 [0.42,2.36] mIU/l. While rates of both hypothyroid or hyperthyroid symptoms were significantly related to all three thyroid parameters, the relationship of hypothyroid symptoms with FT3 extended to a below reference TSH range. Hypothyroid symptom relief was associated with both a T4 dose giving TSH-suppression below the lower reference limit and FT3 elevated further into the upper half of its reference range. In multivariable analysis, relationships between complaints and FT3 concentrations remained significant after adjusting for gender, age and BMI.

Conclusion Residual hypothyroid complaints in LT4-treated patients are specifically related to low FT3 concentrations. This supports an important role of FT3 for clinical decision making on dose adequacy, particularly in symptomatic athyreotic patients.

Key words

Levothyroxine treatment - triiodothyronine - differentiated thyroid cancer - quality of life

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References

References
1 Garmendia Madariaga A, Santos Palacios S, Guillén-Grima F. et al. The incidence and prevalence of thyroid dysfunction in Europe: A meta-analysis. J Clin Endocrinol Metab 2014; 99: 923-931
2 Biondi B, Wartofsky L. Treatment with thyroid hormone. Endocr Rev 2014; 35: 433-512
3 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
4 Okosieme O, Gilbert J, Abraham P. et al. Management of primary hypothyroidism: Statement by the British Thyroid Association Executive Committee. Clin Endocrinol (Oxf) 2016; 84: 799-808
5 Haugen BR, Alexander EK, Bible KC. et al. 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
6 Saravanan P, Visser TJ, Dayan CM. Psychological well-being correlates with free thyroxine but not free 3,5,3'-triiodothyronine levels in patients on thyroid hormone replacement. J Clin Endocrinol Metab 2006; 91: 3389-3393
7 Wekking EM, Appelhof BC, Fliers E. et al. Cognitive functioning and well-being in euthyroid patients on thyroxine replacement therapy for primary hypothyroidism. Eur J Endocrinol 2005; 153: 747-753
8 Hedman C, Djärv T, Strang P. et al. 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: 1034-1042
9 Ott J, Promberger R, Kober F. et al. 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: 161-167
10 Kelderman-Bolk N, Visser TJ, Tijssen JP. et al. Quality of life in patients with primary hypothyroidism related to BMI. Eur J Endocrinol 2015; 173: 507-515
11 Applewhite MK, James BC, Kaplan SP. et al. Quality of life in thyroid cancer is similar to that of other cancers with worse survival. World J Surg 2016; 40: 551-561
12 Hamilton TE, Davis S, Onstad L. et al. Thyrotropin levels in a population with no clinical, autoantibody, or ultrasonographic evidence of thyroid disease: implications for the diagnosis of subclinical hypothyroidism. J Clin Endocrinol Metab 2008; 93: 1224-1230
13 Grozinsky-Glasberg S, Fraser A, Nahshoni E. et al. Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: Meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 2006; 91: 2592-2599
14 Hoermann R, Midgley JEM, Larisch R. et al. Is pituitary TSH an adequate measure of thyroid hormone-controlled homoeostasis during thyroxine treatment?. Eur J Endocrinol 2013; 168: 271-280
15 Gullo D, Latina A, Frasca F. et al. Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS One 2011; 6: e22552
16 Ito M, Miyauchi A, Morita S. et al. 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: 373-378
17 Hoermann R, Midgley JEM, Giacobino A. et al. Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment. Clin Endocrinol (Oxf) 2014; 81: 907-915
18 Hoermann R, Midgley JEM, Larisch R. et al. Homeostatic control of the thyroid–pituitary axis: perspectives for diagnosis and treatment. Front Endocrinol 2015; 6: 1-17
19 Hoermann R, Midgley JEM, Dietrich JW. et al. Dual control of pituitary thyroid stimulating hormone secretion by thyroxine and triiodothyronine in athyreotic patients. Ther Adv Endocrinol Metab 2017; 8: 83-95
20 Dietlein M, Grünwald F, Schmidt M. et al. Luster M. [Radioiodine therapy for benign thyroid diseases (version 5). German Guideline]. Nuklearmedizin 2016; 55: 213-220
21 Larisch R, Giacobino A, Eckl WA. et al. Reference range for thyrotropin. Post hoc assessment. Nuklearmedizin 2015; 54: 112-117
22 Bates D, Mächler M, Bolker B. et al. Fitting linear mixed-effects models using lme4. J Stat Soft 2015; 67: 1-48
23 R Core Team. R: A Language and Environment for Statistical Computing.Vienna: R Foundation for Statistical Computing [Internet]; 2016ISBN 3-900051-07-0. Available from http://www.R-project.org/ Accessed: November 2, 2016
24 Hoermann R, Midgley JEM, Larisch R. et al. Relational stability in the expression of normality, variation, and control of thyroid function. Front Endocrinol 2016; 7: 57-58
25 Maia AL, Wajner SM. New insights toward the acute non-thyroidal illness syndrome. Front Endocrinol 2012; 3: 1-7
26 Van den Berghe G. Non-thyroidal illness in the ICU: a syndrome with different faces. Thyroid 2014; 24: 1456-1465
27 Watt T, Cramon P, Hegedüs L. et al. The thyroid-related quality of life measure ThyPRO has good responsiveness and ability to detect relevant treatment effects. J Clin Endocrinol Metab 2014; 99: 3708-3717
28 Nexø MA, Watt T, Cleal B. et al. Exploring the experiences of people with hypo- and hyperthyroidism. Qual Health Res 2015; 25: 945-953
29 Watt T, Groenvold M, Rasmussen ÅK. et al. Quality of life in patients with benign thyroid disorders. A review. Eur J Endocrinol 2006; 154: 501-510
30 Watt T, Hegedüs L, Rasmussen ÅK. et al. Which domains of thyroid-related quality of life are most relevant? Patients and clinicians provide complementary perspectives. Thyroid 2007; 17: 647-654
31 Wekking EM, Appelhof BC, Fliers E. et al. Cognitive functioning and well-being in euthyroid patients on thyroxine replacement therapy for primary hypothyroidism. Eur J Endocrinol 2005; 153: 747-753
32 Winther KH, Cramon P, Watt T. et al. Disease-specific as well as generic quality of life is widely impacted in autoimmune hypothyroidism and improves during the first six months of levothyroxine therapy. PLoS ONE 2016; 11: e0156925
33 Ito M, Miyauchi A, Fujiwara M. et al. Biochemical markers reflecting thyroid function in athyreotic patients on levothyroxine monotherapy. Thyroid 2017; 27: 484-490
34 Midgley JEM, Larisch R, Dietrich JW. et al. Variation in the biochemical response to L-thyroxine therapy and relationship with peripheral thyroid hormone conversion. Endocr Connect 2015; 4: 196-205
35 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
36 Wartofsky L. Combination L-T3 and L-T4 therapy for hypothyroidism. Curr Opin Endocrinol Diabetes Obes 2013; 20: 460-466