Skip to main content

Persistent Hypothyroid Symptoms Despite Adequate Thyroid Hormone Replacement

  • Chapter
  • First Online:
Management of Patients with Pseudo-Endocrine Disorders

Abstract

The majority of patients with hypothyroidism who are treated with thyroid hormone replacement to maintain serum TSH levels within the population reference range experience complete resolution of their hypothyroid symptoms. However, a significant minority have persistent symptoms and express dissatisfaction with their treatment. These patients usually benefit from seeing attentive and compassionate providers who listen carefully to their concerns and work with them to explore solutions. They should be evaluated for other coexistent autoimmune and systemic disorders and be encouraged to engage in healthy lifestyle practices. It is often productive to carefully explain that nonspecific symptoms are common in the population and are often not related to thyroid disease. A polymorphism (Thr92Ala) of the deiodinase 2 enzyme, which converts thyroxine (T4) to triiodothyronine (T3) in the brain, is present in approximately 16% of the population. These patients have been reported in one study to respond better to combination therapy with levothyroxine (LT4) and liothyronine (LT3); however genetic testing for this polymorphism is expensive and not recommended. Current clinical practice guidelines stress that replacement with LT4 is the treatment of choice for patients with hypothyroidism; however, a trial of combination LT4 and LT3 or of desiccated thyroid extract with maintenance of serum TSH levels within the reference range is considered reasonable to determine if these patients may experience better symptom relief than they have had with LT4 monotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Chaker L, Bianco AC, Jonklass J, Peeters RP. Hypothyroidism. Lancet. 2017;390(10101):1550–62.

    Article  CAS  Google Scholar 

  2. McDermott MT. Hypothyroidism. In: Cooper DS, Sipos J, editors. Medical management of thyroid disease. 3rd ed. New York, NY: Informa Healthcare; 2019. (in press).

    Google Scholar 

  3. McDermott MT. Overview of the clinical manifestations of hypothyroidism. In: Braverman LE, Cooper DS, editors. Werner & Ingbar’s the thyroid: a fundamental and clinical text. 11th ed. Philadelphia: Lippincott Williams & Wilkins; 2019. (in press).

    Google Scholar 

  4. Zulewski HK, Muller B, Exer P, Miserez AR, Staub JJ. Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab. 1997;82:771–6.

    CAS  PubMed  Google Scholar 

  5. Carle A, Pedersen IB, Knudsen N, et al. Hypothyroid symptoms and the likelihood of overt thyroid failure: a population-based case-control study. Eur J Endocrinol. 2014;171:593–602.

    Article  CAS  Google Scholar 

  6. Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, Pessah-Pollack R, For the American Association of Clinical Endocrinologists and American Thyroid Association Task Force on Hypothyroidism in Adults Study Groups, et al. Clinical practice guidelines for hypothyroidism in adults; cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012;18(6):988–1028.

    Article  Google Scholar 

  7. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, For the American Thyroid Association Task Force on Thyroid Hormone Replacement, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on thyroid hormone replacement. Thyroid. 2014;24(12):1670–751.

    Article  Google Scholar 

  8. Guglielmi R, Frasoldati A, Zini M, Grimaldi F, Gharib H, Garber JR, Papini E. Italian association of clinical endocrinologists statement-replacement therapy for primary hypothyroidism: a brief guide for clinical practice. Endocr Pract. 2016;22(11):1319–26.

    Article  Google Scholar 

  9. Santoro N, Braunstein GD, Butts CL, Martin KA, McDermott M, Pinkerton JV. Compounded bioidentical hormones in endocrinology practice: an Endocrine Society scientific statement. J Clin Endocrinol Metab. 2016;101(4):1318–43.

    Article  CAS  Google Scholar 

  10. Negro R, Valcavi R, Agrimi D, Toulis KA. Levothyroxine liquid solution versus tablet for replacement in hypothyroid patients. Endocr Pract. 2014;20(9):901–6.

    Article  Google Scholar 

  11. Bruncato D, Scorsone A, Saura G, Ferrara L, Di Noto A, Aiello V, Fleres M, Provenzano V. Comparison of TSH levels with liquid formulation versus tablet formulations of levothyroxine in the treatment of adult hypothyroidism. Endocr Pract. 2014;20(7):657–62.

    Article  Google Scholar 

  12. Vita R, Saraceno G, Trimarchi F, Benvenga S. Switching levothyroxine from the tablet to the oral solution formulation corrects the impaired absorption of levothyroxine induced by proton-pump inhibitors. J Clin Endocrinol Metab. 2014;99(12):4481–6.

    Article  CAS  Google Scholar 

  13. Biondi B, Wartofsky L. Treatment with thyroid hormone. Endocr Rev. 2014;35(3):433–512.

    Article  CAS  Google Scholar 

  14. McAninch EA, Bianco AC. The history and future treatment of hypothyroidism. Ann Intern Med. 2016;164(1):50–6.

    Article  Google Scholar 

  15. Winther KH, Cramon P, Watt T, Bjorner JB, Ekholm O, Feldt-Rasmussen U, Groenvold M, 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(6):e0156925.

    Article  Google Scholar 

  16. Lee SY, Braverman LE, Pearce EN. Changes in body weight after treatment of primary hypothyroidism with levothyroxine. Endocr Pract. 2014;20(11):1122–8.

    Article  Google Scholar 

  17. Thvilum M, Brandt F, Almind D, Christensen K, Brix TH, Hegedüs L. Increased psychiatric morbidity before and after the diagnosis of hypothyroidism: a nationwide register study. Thyroid. 2014;24(5):802–8.

    Article  Google Scholar 

  18. Quinque EM, Villinger A, Kratzsch J, Karger S. Patient-reported outcomes in adequately treated hypothyroidism – insights from the German versions of ThyQoL, ThySRQ and ThyTSQ. Health Qual Life Outcomes. 2013;11:68.

    Article  Google Scholar 

  19. Samuels MH, Kolobova I, Smeraglio A, Peters D, Janowsky JS, Schuff KG. The effects of levothyroxine replacement or suppressive therapy on health status, mood, and cognition. J Clin Endocrinol Metab. 2014;99(3):843–51.

    Article  CAS  Google Scholar 

  20. Samuels MH, Kolobova I, Smeraglio A, Niederhausen M, Janowsky JS, Schuff KG. Effect of thyroid function variations within the laboratory reference range on health status, mood, and cognition in levothyroxine-treated subjects. Thyroid. 2016;26(9):1173–84.

    Article  CAS  Google Scholar 

  21. Peterson SJ, Cappola AR, Castro MR, et al. Degrees of satisfaction and coexistent diseases in those responding to a survey exploring perceptions about treatment of hypothyroidism. Thyroid. 2018 Jun;28(6):707–21.

    Article  CAS  Google Scholar 

  22. Samuels MH, Kolobova I, Smeraglio A, Peters D, Purnell JQ, Schuff KG. Effects of levothyroxine replacement or suppressive therapy on energy expenditure and body composition. Thyroid. 2016;26(3):347–55.

    Article  CAS  Google Scholar 

  23. 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(7):2533–42.

    Article  Google Scholar 

  24. Ito M, Miyauchi A, Kang S, Hisakado M, Yoshioka W, Ide A, Kudo T, et al. Effect of the presence of remnant thyroid tissue on the serum thyroid hormone balance in thyroidectomized patients. Eur J Endocrinol. 2015;173(3):333–40.

    Article  CAS  Google Scholar 

  25. Peterson SJ, McAninch EA, Bianco AC. Is a normal TSH synonymous with “Euthyroidism” in levothyroxine monotherapy? J Clin Endocrinol Metab. 2016;101(12):4964–73.

    Article  CAS  Google Scholar 

  26. Ott J, Promberger R, Kober F, Neuhold N, Tea M, Huber JC, Hermann M. 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(2):161–7.

    Article  Google Scholar 

  27. Boelaert K, Newby PR, Simmonds MJ, Holder RL, Carr-Smith JD, Heward JM, Manji N, et al. Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease. Am J Med. 2010;123(2):183.e1–9.

    Article  Google Scholar 

  28. Roy A, Laszkowska M, Sundstrom J, Lebwohl B, Green PH, Kä mpe O, Ludvigsson JF. Prevalence of celiac disease in patients with autoimmune thyroid disease: a meta-analysis. Thyroid. 2016;26(7):880–90.

    Article  Google Scholar 

  29. Bollerslev J, Rejnmark L, Marcocci C, Shoback DM, Sitges-Serra A, van Biesen W, Dekkers OM, European Society of Endocrinology. European Society of Endocrinology Clinical Guideline: treatment of chronic hypoparathyroidism in adults. Eur J Endocrinol. 2015;173(2):G1–20.

    Article  CAS  Google Scholar 

  30. Panicker V, Saravanan P, Vaidya B, Evans J, Hattersley AT, Frayling TM, Dayan CM. Common variation of in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients. J Clin Endocrinol Metab. 2009;94(5):1623–9.

    Article  CAS  Google Scholar 

  31. Appelhof BC, Peeters RP, Wiersinga WM, Visser TJ, Wekking EM, Huyser J, Schene AH, et al. Polymorphisms in type 2 deiodinase are not associated with well-being, neurocognitive functioning, and preference for combined thyroxine/3,5,3′-triiodothyronine therapy. J Clin Endocrinol Metab. 2005;90(11):6296–9.

    Article  CAS  Google Scholar 

  32. Castagna MG, Dentice M, Cantara S, Ambrosio R, Maino F, Porcelli T, Marzocchi C, et al. DIO2 Thr92Ala reduced deiodinase-2 activity and serum T3 levels in thyroid deficient patients. J Clin Endocrinol Metab. 2017;102(5):1623–30.

    Article  Google Scholar 

  33. Hoang TD, Olsen CH, Mai VQ, Clyde PW, Shakir MK. Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomized, double-blind, crossover study. J Clin Endocrinol Metab. 2013;98(5):1982–90.

    Article  CAS  Google Scholar 

  34. Shresta RT, Malabanan A, Haugen BR, Levy EG, Hennessey JV. Adverse event reporting in patients treated with thyroid hormone extract. Endocr Pract. 2017;23(5):566–75.

    Article  Google Scholar 

  35. Jonklaas J, Burman KD. Daily administration of short-acting liothyronine is associated with significant triiodothyronine excursions and fails to alter thyroid-responsive parameters. Thyroid. 2016;26(6):770–8.

    Article  CAS  Google Scholar 

  36. Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MPJ. 2012 European Thyroid Association (ETA) guidelines: the use of L-T4 + L-T3 in the treatment of hypothyroidism. Eur Thyroid J. 2012;1(2):55–71.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael T. McDermott .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

McDermott, M.T. (2019). Persistent Hypothyroid Symptoms Despite Adequate Thyroid Hormone Replacement. In: McDermott, M. (eds) Management of Patients with Pseudo-Endocrine Disorders. Springer, Cham. https://doi.org/10.1007/978-3-030-22720-3_23

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-22720-3_23

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-22719-7

  • Online ISBN: 978-3-030-22720-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics