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Relationship between TSH and free thyroxine in outpatient cancer patient population

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Abstract

Background

The inverse log-linear relationship between Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) is well established and reliably used for evaluation of hypothalamus-pituitary-thyroid (HPT) axis function. However, there are limited data regarding oncologic states in the TSH-FT4 relationship. The purpose of this study was to evaluate thyroid pituitary hypothalamic feedback regulation by the inverse log TSH and FT4 relationship in the cancer patient population at the Ohio State University Comprehensive Cancer Center (OSUCCC-James).

Methods

This retrospective study analyzed the correlation between TSH and FT4 results from 18846 outpatient subjects collected in August 2019-November 2021 at the Department of Family Medicine (OSU Wexner Medical Center), Department of Oncology (OSUCCC-James). Patients with diagnoses related to cancers were included in the oncology group. Patients with diagnoses not related to cancers were included in the non-oncology group. Patients of the Department of Endocrinology, Department of Cardiology, Department of Obstetrics & Gynecology and Department of Hematology were excluded from this study. Time of collection for TSH and FT4 was from 7am to 7 pm. Data were analyzed by morning (7am–12pm) and afternoon (12pm–7pm). Spearman correlation and non-linear fit were used for data analysis. Sex differences were analyzed as well in each group.

Results

Overall, an inverse correlation was observed between TSH and FT4 in both groups (non-oncology and oncology) regardless of sample collection time and sex differences. Further analysis by linear model in log TSH and FT4 showed a significant inverse fit in males compared with females in the group of oncology, both in the afternoon (p < 0.05). Data were further analyzed by ranges of FT4, as lower or higher (pathophysiology) or within (physiology) the reference interval of FT4. There was no statistical significance between the non-oncology and oncology groups, but relatively good correlation in non-oncology group in either physiologic or pathophysiologic FT4 levels and sample collection time. Interestingly, the best correlation between TSH and FT4 was found in the non-oncology group at pathophysiologic FT4 concentrations (abnormally high). In addition, at pathophysiologic FT4 concentrations (abnormally low), the oncology group demonstrated a significant TSH response in the morning than in the afternoon (p < 0.05).

Conclusions

Though overall the TSH-FT4 curves showed an inverse relationship, there are variations of TSH-FT4 relationship for collection times when considering FT4 in physiologic or pathophysiologic states. The results advance understanding of TSH response, which is beneficial for the interpretation of thyroid disease. We recommend re-evaluation for interpretation of pituitary hypothalamic axis by TSH results when FT4 is abnormally high in oncology patients or low in non-oncology patients, due to poor predictability and the potential for misdiagnosis. A better understanding of the complex nature of the TSH-FT4 relationship may need further study with better defining subclinical states of cancer patients.

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References

  1. R. Mullur, Y.-Y. Liu, G.A. Brent, Thyroid hormone regulation of metabolism. Physiol. Rev. 94(Apr), 355–382 (2014). https://doi.org/10.1152/physrev.00030.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. S. Razvi, S. Bhana, S. Mrabeti, Challenges in interpreting thyroid stimulating hormone results in the diagnosis of thyroid dysfunction. J. Thyroid Res. 2019(Sep), 4106816 (2019). https://doi.org/10.1155/2019/4106816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Z. Baloch, P. Carayon, B. Conte-Devolx et al. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 13(Jan), 3–126 (2003). https://doi.org/10.1089/105072503321086962

    Article  PubMed  Google Scholar 

  4. N. Benhadi, E. Fliers, T.J. Visser, J.B. Reitsma, W.M. Wiersinga, Pilot study on the assessment of the setpoint of the hypothalamus-pituitary-thyroid axis in healthy volunteers. Eur. J. Endocrinol. 162(Feb), 323–329 (2010). https://doi.org/10.1530/EJE-09-0655

    Article  CAS  PubMed  Google Scholar 

  5. C.A. Meier, M.N. Maisey, A. Lowry, J. Müller, M.A. Smith, Interindividual differences in the pituitary-thyroid axis influence the interpretation of thyroid function tests. Clin. Endocrinol. (Oxf) 39(Jul), 101–107 (1993). https://doi.org/10.1111/j.1365-2265.1993.tb01758.x

    Article  CAS  PubMed  Google Scholar 

  6. K.M. Rothacker, S.J. Brown, N.C. Hadlow, R. Wardrop, J.P. Walsh, Reconciling the log-linear and non-log-linear nature of the TSH-Free T4 relationship: intra-individual analysis of a large population. J. Clin. Endocrinol. Metab. 101(Mar), 1151–1158 (2016). https://doi.org/10.1210/jc.2015-4011

    Article  CAS  PubMed  Google Scholar 

  7. N.C. Hadlow, K.M. Rothacker, R. Wardrop, S.J. Brown, E.M. Lim, J.P. Walsh, The relationship between TSH and free T4 in a large population is complex and nonlinear and differs by age and sex. J. Clin. Endocrinol. Metab. 98(Jul), 2936–2943 (2013). https://doi.org/10.1210/jc.2012-4223

    Article  CAS  PubMed  Google Scholar 

  8. D. Strich, G. Karavani, S. Edri, D. Gillis, TSH enhancement of FT4 to FT3 conversion is age dependent. Eur. J. Endocrinol. 175(Jul), 49–54 (2016). https://doi.org/10.1530/EJE-16-0007

    Article  CAS  PubMed  Google Scholar 

  9. M. Wilmar, Wiersinga. Smoking and thyroid. Clin. Endocrinol. (Oxf) 79(Aug), 145–151 (2013). https://doi.org/10.1111/cen.12222

    Article  CAS  Google Scholar 

  10. Y. Carter, R.S. Sippel, H. Chen, Hypothyroidism after a cancer diagnosis: etiology, diagnosis, complications, and management. Oncologist. 19(Jan), 34–43 (2014). https://doi.org/10.1634/theoncologist.2013-0237

    Article  CAS  PubMed  Google Scholar 

  11. W.G. Kim, S.-yann Cheng, Thyroid hormone receptors and cancer. Biochim. Biophys. Acta 1830(Jul), 3928–3936 (2013). https://doi.org/10.1016/j.bbagen.2012.04.002

    Article  CAS  PubMed  Google Scholar 

  12. G. Barbesino, Drugs affecting thyroid function. Thyroid 20(Jul), 763–770 (2010). https://doi.org/10.1089/thy.2010.1635

    Article  PubMed  Google Scholar 

  13. D. Mannavola, P. Coco, G. Vannucchi, R. Bertuelli, M. Carletto, P.G. Casali, P. Beck-Peccoz, L. Fugazzola, A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. J. Clin. Endocrinol. Metab. 92(Sep), 3531–3534 (2007). https://doi.org/10.1210/jc.2007-0586

    Article  CAS  PubMed  Google Scholar 

  14. H. Miyake, T. Kurahashi, K. Yamanaka, Y. Kondo, M. Muramaki, A. Takenaka, T.-A. Inoue, M. Fujisawa, Abnormalities of thyroid function in Japanese patients with metastatic renal cell carcinoma treated with sorafenib: a prospective evaluation. Urol. Oncol. 28(Sep-Oct), 515–519 (2010). https://doi.org/10.1016/j.urolonc.2009.08.011

    Article  CAS  PubMed  Google Scholar 

  15. C. Giani, P. Fierabracci, R. Bonacci, A. Gigliotti, D. Campani, F. De Negri, D. Cecchetti, E. Martino, A. Pinchera, Relationship between breast cancer and thyroid disease: relevance of autoimmune thyroid disorders in breast malignancy. J. Clin. Endocrinol. Metab. 81(Mar), 990–994 (1996). https://doi.org/10.1210/jcem.81.3.8772562

    Article  CAS  PubMed  Google Scholar 

  16. J.G. Ratcliffe, B.H. Stack, R.W. Burt, W.A. Radcliffe, W.G. Spilg, J. Cuthbert, R.S. Kennedy, Thyroid function in lung cancer. Br. Med. J. 1(Jan), 210–212 (1978). https://doi.org/10.1136/bmj.1.6107.210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. E. Krashin, A. Piekiełko-Witkowska, M. Ellis, O. Ashur-Fabian, Thyroid hormones and cancer: a comprehensive review of preclinical and clinical studies. Front. Endocrinol. (Lausanne) 10(Feb), 59 (2019). https://doi.org/10.3389/fendo.2019.00059

    Article  PubMed  Google Scholar 

  18. J. Gómez-Izquierdo, K.B. Filion, J.-F.ҫois Boivin, L. Azoulay, M. Pollak, O.H.Y. Yu, Subclinical hypothyroidism and the risk of cancer incidence and cancer mortality: a systematic review. BMC Endocr. Disord. 20(Jun), 83 (2020). https://doi.org/10.1186/s12902-020-00566-9

    Article  PubMed  PubMed Central  Google Scholar 

  19. M.V. Deligiorgi, D.T. Trafalis, The clinical relevance of hypothyroidism in patients with solid non-thyroid cancer: a tantalizing conundrum. J. Clin. Med. 11(Jun), 3417 (2022). https://doi.org/10.3390/jcm11123417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. O.-P.R. Hamnvik, P.R. Larsen, E. Marqusee, Thyroid dysfunction from antineoplastic agents. J. Natl Cancer Inst. 103(Nov), 1572–1587 (2011). https://doi.org/10.1093/jnci/djr373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Y. Qiu, Y. Hu, Z. Xing, Q. Fu, J. Zhu, A. Su, Birth control pills and risk of hypothyroidism: a cross-sectional study of the National Health and Nutrition Examination Survey, 2007-2012. BMJ Open 11(Jun), e046607 (2021). https://doi.org/10.1136/bmjopen-2020-046607

    Article  PubMed  PubMed Central  Google Scholar 

  22. P.H. Bisschop, A.W. Toorians, E. Endert, W.M. Wiersinga, L.J. Gooren, Eric Fliers. The effects of sex-steroid administration on the pituitary-thyroid axis in transsexuals. Eur. J. Endocrinol. 155(Jul), 11–16 (2006). https://doi.org/10.1530/eje.1.02192

    Article  CAS  PubMed  Google Scholar 

  23. R. Hoermann, A.S. Cheung, M. Milne, M. Grossmann, Hypothalamic-pituitary-thyroid axis set point alterations are associated with body composition in androgen-deprived men. J. Endocr. Soc. 1(May), 874–885 (2017). https://doi.org/10.1210/js.2017-00057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Y. Kajita, M. Ishida, T. Hachiya, T. Miyazaki, M. Yoshimura, H. Ijichi, Y. Ochi, Clinical study on increased serum thyroxine-binding globulin in cancerous state. Endocrinol. Jpn 28(Dec), 785–791 (1981). https://doi.org/10.1507/endocrj1954.28.785

    Article  CAS  PubMed  Google Scholar 

  25. D.P. Rose, T.E. Davis, Plasma thyronine levels in carcinoma of the breast and colon. Arch. Intern. Med. 141(Aug), 1161–1164 (1981)

    Article  CAS  PubMed  Google Scholar 

  26. K. Ikegami, S. Refetoff, E. Van Cauter, T. Yoshimura, Interconnection between circadian clocks and thyroid function. Nat. Rev. Endocrinol. 15(Oct), 590–600 (2019). https://doi.org/10.1038/s41574-019-0237-z

    Article  PubMed  PubMed Central  Google Scholar 

  27. C. Gallo, V. Fragliasso, B. Donati, F. Torricelli, A. Tameni, S. Piana, A. Ciarrocchi, The bHLH transcription factor DEC1 promotes thyroid cancer aggressiveness by the interplay with NOTCH1. Cell Death Dis. 9(Aug), 871 (2018). https://doi.org/10.1038/s41419-018-0933-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. L.J. DeGroot, Graves’ disease and the manifestations of thyrotoxicosis in Endotext, eds. Feingold K.R. et al. (MDText.com, Inc., 2000), p. 1–77

  29. K. Hartmann, Thyroid disorders in the oncology patient. J. Adv. Pract. Oncol. 6(Mar-Apr), 99–106 (2015). https://doi.org/10.6004/jadpro.2015.6.2.2

    Article  PubMed  PubMed Central  Google Scholar 

  30. T. Nishikawa, S. Yamashita, H. Namba, T. Usa, T. Tominaga, H. Kimura, M. Izumi, S. Nagataki, Interferon-gamma inhibition of human thyrotropin receptor gene expression. J. Clin. Endocrinol. Metab. 77(Oct), 1084–1089 (1993). https://doi.org/10.1210/jcem.77.4.8408457

    Article  CAS  PubMed  Google Scholar 

  31. P.-M. Schumm-Draeger, Sodium/iodide symporter (NIS) and cytokines. Exp. Clin. Endocrinol. Diabetes 109, 32–34 (2001). https://doi.org/10.1055/s-2001-11018

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. College of Medicine, the Ohio State University, Columbus, OH, USA

    Hussam Alkhalaileh

  2. Department of Pathology, Duke University School of Medicine, Durham, NC, USA

    Ruhan Wei

  3. Department of Clinical Laboratory, University Hospital, the Ohio State University, Columbus, OH, USA

    Jason K. Y. Lee

  4. Department of Pathology, the Ohio State University Wexner Medical Center, Columbus, OH, USA

    JoAnna Jones & Jieli Li

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Contributions

H.A.: data analysis, interpretation of data; drafted the work. R.W.: interpretation of data; revised the work. J.K.Y.L.: interpretation of data; revised the work. J.J.: interpretation of data; revised it critically for important intellectual content; approved the version to be published. J.L.: design of the work; data analysis, interpretation of data; revised it critically for important intellectual content; approved the version to be published; agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to JoAnna Jones or Jieli Li.

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Alkhalaileh, H., Wei, R., Lee, J.K.Y. et al. Relationship between TSH and free thyroxine in outpatient cancer patient population. Endocrine 82, 319–325 (2023). https://doi.org/10.1007/s12020-023-03399-3

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