• Cristiane J. Gomes-Lima
  • Kenneth D. BurmanEmail author


Overt primary hypothyroidism is characterized by a state of decreased circulating thyroid hormones associated with low FT4/TT4 (free and total thyroxine) and elevated thyroid-stimulating hormone (TSH) (thyrotropin). In this chapter, we discuss the epidemiology, pathophysiology, and etiology of overt hypothyroidism. The clinical spectrum is presented according to the manifestations of hypothyroxinemia at each body system. The basis for laboratory diagnosis is discussed, as well as some pitfalls on the interpretation of TSH assays. Finally, we discuss peculiarities of the diagnosis of overt hypothyroidism in special situations, such as pregnancy, depression, and in the elderly. Treatment of overt hypothyroidism is discussed in a separate chapter.


Overt hypothyroidism TSH FT4 Hypothyroxinemia Thyroid hormones 


  1. 1.
    Chiamolera MI, Wondisford FE. Minireview: thyrotropin-releasing hormone and the thyroid hormone feedback mechanism. Endocrinology. 2009;150(3):1091–6.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Costa-e-Sousa RH, Hollenberg AN. Minireview: the neural regulation of the hypothalamic-pituitary-thyroid axis. Endocrinology. 2012;153(9):4128–35.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol. 1977;7(6):481–93.Google Scholar
  4. 4.
    Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham survey. Clin Endocrinol. 1995;43(1):55–68.Google Scholar
  5. 5.
    Walsh JP, Bremner AP, Feddema P, Leedman PJ, Brown SJ, O'Leary P. Thyrotropin and thyroid antibodies as predictors of hypothyroidism: a 13-year, longitudinal study of a community-based cohort using current immunoassay techniques. J Clin Endocrinol Metab. 2010;95(3):1095–104.PubMedGoogle Scholar
  6. 6.
    Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87(2):489–99.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Persani L. Clinical review: central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges. J Clin Endocrinol Metab. 2012;97(9):3068–78.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Akamizu T, Amino N, DeGroot LJ. Hashimoto’s thyroiditis. In: De Groot LJ, Beck-Peccoz P, Chrousos G, Dungan K, Grossman A, Hershman JM, et al., editors. Endotext. South Dartmouth; 2000.Google Scholar
  9. 9.
    Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc Institute of Medicine FaNB, editor. Washington; 2001.Google Scholar
  10. 10.
    de Benoist B, McLean E, Andersson M, Rogers L. Iodine deficiency in 2007: global progress since 2003. Food Nutr Bull. 2008;29(3):195–202.PubMedGoogle Scholar
  11. 11.
    Barbesino G. Drugs affecting thyroid function. Thyroid. 2010;20(7):763–70.PubMedGoogle Scholar
  12. 12.
    Eskes SA, Wiersinga WM. Amiodarone and thyroid. Best Pract Res Clin Endocrinol Metab. 2009;23(6):735–51.PubMedGoogle Scholar
  13. 13.
    Lazarus JH. Lithium and thyroid. Best Pract Res Clin Endocrinol Metab. 2009;23(6):723–33.PubMedGoogle Scholar
  14. 14.
    Makita N, Iiri T. Tyrosine kinase inhibitor-induced thyroid disorders: a review and hypothesis. Thyroid. 2013;23(2):151–9.PubMedGoogle Scholar
  15. 15.
    Desai J, Yassa L, Marqusee E, George S, Frates MC, Chen MH, et al. Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med. 2006;145(9):660–4.PubMedGoogle Scholar
  16. 16.
    Tomer Y, Menconi F. Interferon induced thyroiditis. Best Pract Res Clin Endocrinol Metab. 2009;23(6):703–12.PubMedPubMedCentralGoogle Scholar
  17. 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(2):279–94.PubMedGoogle Scholar
  18. 18.
    Dumitrescu AM, Refetoff S. Impaired sensitivity to thyroid hormone: defects of transport, metabolism and action. In: De Groot LJ, Beck-Peccoz P, Chrousos G, Dungan K, Grossman A, Hershman JM, et al, editors. Endotext. South Dartmouth; 2000.Google Scholar
  19. 19.
    Sakurai A, Takeda K, Ain K, Ceccarelli P, Nakai A, Seino S, et al. Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor beta. Proc Natl Acad Sci U S A. 1989;86(22):8977–81.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S. A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet. 2004;74(1):168–75.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Bochukova E, Schoenmakers N, Agostini M, Schoenmakers E, Rajanayagam O, Keogh JM, et al. A mutation in the thyroid hormone receptor alpha gene. N Engl J Med. 2012;366(3):243–9.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Refetoff S, Bassett JH, Beck-Peccoz P, Bernal J, Brent G, Chatterjee K, et al. Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism. J Clin Endocrinol Metab. 2014;99(3):768–70.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Brent GA, Weetman AP. Hypothyroidism and thyroiditis. In: Melmed S, Polonsky K, Larsen PR, Kronenberg H, editors. Williams textbook of endocrinology. 13th ed. Elsevier; 2016.Google Scholar
  24. 24.
    Burmeister LA, Ganguli M, Dodge HH, Toczek T, DeKosky ST, Nebes RD. Hypothyroidism and cognition: preliminary evidence for a specific defect in memory. Thyroid. 2001;11(12):1177–85.PubMedGoogle Scholar
  25. 25.
    Bauer M, Goetz T, Glenn T, Whybrow PC. The thyroid-brain interaction in thyroid disorders and mood disorders. J Neuroendocrinol. 2008;20(10):1101–14.PubMedGoogle Scholar
  26. 26.
    Khemka D, Ali JA, Koch CA. Primary hypothyroidism associated with acute mania: case series and literature review. Exp Clin Endocrinol Diabetes. 2011;119(8):513–7.PubMedGoogle Scholar
  27. 27.
    Wiersinga WM. Adult hypothyroidism. In: De Groot LJ, Beck-Peccoz P, Chrousos G, Dungan K, Grossman A, Hershman JM, et al., editors. Endotext. South Dartmouth: 2000.Google Scholar
  28. 28.
    Lambert EH, Underdahl LO, Beckett S, Mederos LO. A study of the ankle jerk in myxedema. J Clin Endocrinol Metab. 1951;11(10):1186–205.PubMedGoogle Scholar
  29. 29.
    Duntas LH, Brenta G. The effect of thyroid disorders on lipid levels and metabolism. Med Clin North Am. 2012;96(2):269–81.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Becker C. Hypothyroidism and atherosclerotic heart disease: pathogenesis, medical management, and the role of coronary artery bypass surgery. Endocr Rev. 1985;6(3):432–40.PubMedGoogle Scholar
  31. 31.
    Attal P, Chanson P. Endocrine aspects of obstructive sleep apnea. J Clin Endocrinol Metab. 2010;95(2):483–95.PubMedGoogle Scholar
  32. 32.
    Kyriacou A, McLaughlin J, Syed AA. Thyroid disorders and gastrointestinal and liver dysfunction: a state of the art review. Eur J Intern Med. 2015;26(8):563–71.PubMedGoogle Scholar
  33. 33.
    Iglesias P, Diez JJ. Thyroid dysfunction and kidney disease. Eur J Endocrinol. 2009;160(4):503–15.PubMedGoogle Scholar
  34. 34.
    Krassas GE, Papadopoulou F, Tziomalos K, Zeginiadou T, Pontikides N. Hypothyroidism has an adverse effect on human spermatogenesis: a prospective, controlled study. Thyroid. 2008;18(12):1255–9.PubMedGoogle Scholar
  35. 35.
    Krassas GE, Tziomalos K, Papadopoulou F, Pontikides N, Perros P. Erectile dysfunction in patients with hyper- and hypothyroidism: how common and should we treat? J Clin Endocrinol Metab. 2008;93(5):1815–9.PubMedGoogle Scholar
  36. 36.
    Unuane D, Tournaye H, Velkeniers B, Poppe K. Endocrine disorders & female infertility. Best Pract Res Clin Endocrinol Metab. 2011;25(6):861–73.PubMedGoogle Scholar
  37. 37.
    Kamilaris TC, DeBold CR, Pavlou SN, Island DP, Hoursanidis A, Orth DN. Effect of altered thyroid hormone levels on hypothalamic-pituitary-adrenal function. J Clin Endocrinol Metab. 1987;65(5):994–9.PubMedGoogle Scholar
  38. 38.
    Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, et al. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid. 2003;13(1):3–126.PubMedGoogle Scholar
  39. 39.
    Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 2012;22(12):1200–35.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Karmisholt J, Andersen S, Laurberg P. Variation in thyroid function tests in patients with stable untreated subclinical hypothyroidism. Thyroid. 2008;18(3):303–8.PubMedGoogle Scholar
  41. 41.
    Wong ET, Bradley SG, Schultz AL. Elevations of thyroid-stimulating hormone during acute nonthyroidal illness. Arch Intern Med. 1981;141(7):873–5.PubMedGoogle Scholar
  42. 42.
    Halsall DJ, English E, Chatterjee VK. Interference from heterophilic antibodies in TSH assays. Ann Clin Biochem. 2009;46(Pt 4):345–6.PubMedGoogle Scholar
  43. 43.
    Lum SM, Nicoloff JT, Spencer CA, Kaptein EM. Peripheral tissue mechanism for maintenance of serum triiodothyronine values in a thyroxine-deficient state in man. J Clin Invest. 1984;73(2):570–5.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Mannisto T, Mendola P, Grewal J, Xie Y, Chen Z, Laughon SK. Thyroid diseases and adverse pregnancy outcomes in a contemporary US cohort. J Clin Endocrinol Metab. 2013;98(7):2725–33.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Su PY, Huang K, Hao JH, Xu YQ, Yan SQ, Li T, et al. Maternal thyroid function in the first twenty weeks of pregnancy and subsequent fetal and infant development: a prospective population-based cohort study in China. J Clin Endocrinol Metab. 2011;96(10):3234–41.PubMedGoogle Scholar
  46. 46.
    Ghassabian A, Bongers-Schokking JJ, Henrichs J, Jaddoe VW, Visser TJ, Visser W, et al. Maternal thyroid function during pregnancy and behavioral problems in the offspring: the generation R study. Pediatr Res. 2011;69(5 Pt 1):454–9.PubMedGoogle Scholar
  47. 47.
    Dayan CM, Panicker V. Hypothyroidism and depression. Eur Thyroid J. 2013;2(3):168–79.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Panicker V, Saravanan P, Vaidya B, Evans J, Hattersley AT, Frayling TM, et al. Common variation 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.PubMedGoogle Scholar
  49. 49.
    Kim M. Hypothyroidism in the Elderly. In: De Groot LJ, Beck-Peccoz P, Chrousos G, Dungan K, Grossman A, Hershman JM, et al., editors. Endotext. South Dartmouth; 2000.Google Scholar
  50. 50.
    Boucai L, Hollowell JG, Surks MI. An approach for development of age-, gender-, and ethnicity-specific thyrotropin reference limits. Thyroid. 2011;21(1):5–11.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, 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.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Dan L. Longo, Michael A. Postow, Robert Sidlow, Matthew D. Hellmann, (2018) Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. New England Journal of Medicine 378 (2):158-168PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  1. 1.MedStar Washington Hospital CenterMedStar Health Research InstituteHyattsvilleUSA
  2. 2.Division of Endocrinology, Diabetes and Metabolism, Department of Internal MedicineMedStar Washington Hospital CenterHyattsvilleUSA

Personalised recommendations