Background
Hypothyroidism is a common endocrine disorder resulting from deficiency of thyroid hormone. It usually is a primary process in which the thyroid gland produces insufficient amounts of thyroid hormone. It can also be secondary—that is, lack of thyroid hormone secretion due to inadequate secretion of either thyrotropin (ie, thyroid-stimulating hormone [TSH]) from the pituitary gland or thyrotropin-releasing hormone (TRH) from the hypothalamus (secondary or tertiary hypothyroidism). The patient's presentation may vary from asymptomatic to, rarely, coma with multisystem organ failure (myxedema coma). The most common cause in the Unites States is autoimmune thyroid disease (Hashimoto thyroiditis).
Cretinism refers to congenital hypothyroidism, which affects 1 per 4000 newborns.
Subclinical hypothyroidism, also referred to as mild hypothyroidism, is defined as normal serum free T4 levels with slightly high serum TSH concentration.
Recent studies
In a 12-year longitudinal study, Stuckey et al investigated the long-term risk of hypothyroidism in women who previously had had postpartum thyroid dysfunction (PPTD). The study involved 409 women, 71 of whom had previously been diagnosed with PPTD. At 12-year follow-up, 27 women in the PPTD group and 14 women in the non-PPTD group (38% and 4%, respectively) were found to have hypothyroidism. Based on an analysis of odds ratios (ORs), the authors concluded that within the PPTD group, women who had been diagnosed with postpartum hypothyroidism were among those at particularly high long-term risk for hypothyroidism (OR = 9.7).[1]
Pathophysiology
Localized disease of the thyroid gland that results in decreased thyroid hormone production is the most common cause of hypothyroidism. Under normal circumstances, the thyroid releases 100-125 nmol of thyroxine (T4) daily and only small amounts of triiodothyronine (T3). The half-life of T4 is approximately 7-10 days. T4, a prohormone, is converted to T3, the active form of thyroid hormone, in the peripheral tissues by 5’-deiodination. Early in the disease process, compensatory mechanisms maintain T3 levels. Decreased production of T4 causes an increase in the secretion of TSH by the pituitary gland. TSH stimulates hypertrophy and hyperplasia of the thyroid gland and thyroid T4-5'-deiodinase activity. This, in turn, causes the thyroid to release more T3.
Because all metabolically active cells require thyroid hormone, deficiency of the hormone has a wide range of effects. Systemic effects are due to either derangements in metabolic processes or direct effects by myxedematous infiltration (ie, accumulation of glucosaminoglycans in the tissues).
The myxedematous changes in the heart result in decreased contractility, cardiac enlargement, pericardial effusion, decreased pulse, and decreased cardiac output. In the GI tract, achlorhydria and decreased intestinal transit with gastric stasis can occur. Delayed puberty, anovulation, menstrual irregularities, and infertility are common. Decreased thyroid hormone effect can cause increased levels of total cholesterol and low-density lipoprotein (LDL) cholesterol and a possible change in high-density lipoprotein (HDL) cholesterol due to a change in metabolic clearance. In addition, hypothyroidism may result in an increase in insulin resistance.
Epidemiology
Frequency
United States
The National Health and Nutrition Examination Survey (NHANES 1999-2002) of 4,392 individuals reflecting the US population reported hypothyroidism (defined as TSH levels >4.5 mIU/L) in 3.7% of the population.[2] Hypothyroidism is more common in women with small body size at birth and low body mass index during childhood.[3]
International
Iodine deficiency as a cause of hypothyroidism is more common internationally. The prevalence is reported as 2-5% depending on the study, increasing to 15% by age 75 years.
Mortality/Morbidity
In developed countries, death caused by hypothyroidism is uncommon.
Race
NHANES 1999-2002 reported that the prevalence of hypothyroidism (including subclinical) was higher in whites (5.1%) and Mexican Americans than in African Americans (1.7%). African Americans tend to have lower TSH values.[2]
Sex
Community studies use slightly different criteria for determining hypothyroidism; therefore, female-to-male ratios vary. Generally, thyroid disease is much more common in females than in males, with reports of prevalence 2-8 times higher in females.
Age
The frequency of hypothyroidism, goiters, and thyroid nodules increases with age. Hypothyroidism is most prevalent in elderly populations, with 2% to as much as 20% of older age groups having some form of hypothyroidism. The Framingham study found hypothyroidism (TSH >10 mIU/L) in 5.9% of women and 2.4% of men older than 60 years.[4] In NHANES 1999-2002, the odds of having hypothyroidism were 5 times greater in persons aged 80 years and older than in individuals aged 12-49 years.[2]
Stuckey B, Kent G, Ward L, et al. Postpartum thyroid dysfunction and the long-term risk of hypothyroidism: results from a 12 year follow-up study of women with and without postpartum thyroid dysfunction. Clin Endocrinol (Oxf). Feb 23 2010;[Medline].
Aoki Y, Belin RM, Clickner R, Jeffries R, Phillips L, Mahaffey KR. Serum TSH and total T4 in the United States population and their association with participant characteristics: National Health and Nutrition Examination Survey (NHANES 1999-2002). Thyroid. Dec 2007;17(12):1211-23. [Medline].
Kajantie E, Phillips DI, Osmond C, Barker DJ, Forsen T, Eriksson JG. Spontaneous hypothyroidism in adult women is predicted by small body size at birth and during childhood. J Clin Endocrinol Metab. Dec 2006;91(12:4953-4956. [Medline].
Sawin CT, Castelli WP, Hershman JM, McNamara P, Bacharach P. The aging thyroid. Thyroid deficiency in the Framingham Study. Arch Intern Med. Aug 1985;145(8):1386-8. [Medline].
Kreisman SH, Hennessey JV. Consistent reversible elevations of serum creatinine levels in severe hypothyroidism. Arch Intern Med. 159(1);Jan 11 1999:79-82. [Medline].
Eskes SA, Endert E, Fliers E, et al. Prevalence of Growth Hormone Deficiency in Hashimoto's Thyroiditis. J Clin Endocrinol Metab. Mar 12 2010;[Medline].
Woeber KA. Iodine and thyroid disease. Med Clin North Am. Jan 1991;75(1):169-178. [Medline].
Yamada M, Mori M. Mechanisms related to the pathophysiology and management of central hypothyroidism. Nat Clin Pract Endocrinol Metab. Dec 2008;4(12):683-94. [Medline].
Nebesio TD, McKenna MP, Nabhan ZM, et al. Newborn Screening Results in Children with Central Hypothyroidism. J Pediatr. Mar 10 2010;[Medline].
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. Feb 2002;87(2):489-99. [Medline]. [Full Text].
Liu Y. Clinical significance of thyroid uptake on F18-fluorodeoxyglucose positron emission tomography. Ann Nucl Med. Jan 2009;23(1):17-23. [Medline].
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. Jul 2006;91(7):2592-9. [Medline].
LeBeau SO, Mandel SJ. Thyroid disorders during pregnancy. Endocrinol Metab Clin North Am. Mar 2006;35(1):117-136, vii. [Medline].
Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab. Jul 2006;91(7):2587-2591. [Medline].
US Preventive Services Task Force. Screening for thyroid disease: recommendation statement. Ann Intern Med. Jan 20 2004;140(2):125-7. [Medline]. [Full Text].
Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. Jan 14 2004;291(2):228-38. [Medline]. [Full Text].
The Endocrine Society. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. National Guideline Clearinghouse. Available at http://guideline.gov/summary/summary.aspx?doc_id=11283. Accessed April 24, 2009.
Gyamfi C, Wapner RJ, D'Alton ME. Thyroid dysfunction in pregnancy: the basic science and clinical evidence surrounding the controversy in management. Obstet Gynecol. Mar 2009;113(3):702-7. [Medline].
Rosario PW, Bessa B, Valadao MM, et al. Natural history of mild subclinical hypothyroidism: prognostic value of ultrasound. Thyroid. Jan 2009;19(1):9-12. [Medline].
Ito M, Arishima T, Kudo T, Nishihara E, Ohye H, Kubota S, et al. Effect of levo-thyroxine replacement on non-high-density lipoprotein cholesterol in hypothyroid patients. J Clin Endocrinol Metab. Feb 2007;92(2):608-611. [Medline]. [Full Text].
Peleg RK, Efrati S, Benbassat C, Fygenzo M, Golik A. The effect of levothyroxine on arterial stiffness and lipid profile in patients with subclinical hypothyroidism. Thyroid. Aug 2008;18(8):825-30. [Medline].
Cinemre H, Bilir C, Gokosmanoglu F, Bahcebasi T. Hematologic effects of levothyroxine in iron-deficient subclinical hypothyroid patients: a randomized, double-blind, controlled study. J Clin Endocrinol Metab. Jan 2009;94(1):151-6. [Medline].
American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. Nov-Dec 2002;8(6):457-469. [Medline].
Wartofsky L. Myxedema coma. Endocrinol Metab Clin North Am. Dec 2006;35(4):687-698, vii-viii. [Medline].
Zamfirescu I, Carlson HE. Absorption of levothyroxine when coadministered with various calcium formulations. Thyroid. May 2011;21(5):483-6. [Medline]. [Full Text].
Ladenson PW, Singer PA, Ain KB, Bagchi N, Bigos ST, Levy EG, et al. American Thyroid Association Guidelines For Detection Of Thyroid Dysfunction. Arch Internal Med. 2000;160:1573-75. [Medline].
American College of Physicians. Clinical guideline, part 1. Screening for thyroid disease. Ann Intern Med. 1998;129(2):141-3. [Medline].
Helfand M, Redfern CC. Clinical guideline, part 2. Screening for thyroid disease: an update. American College of Physicians. Ann Intern Med. Jul 15 1998;129(2):144-58. [Medline].
Turner MR, Camacho X, Fischer HD, et al. Levothyroxine dose and risk of fractures in older adults: nested case-control study. BMJ. 2011;342:d2238. [Medline].
Alexander EK, Marqusee E, Lawrence J, et al. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med. Jul 15 2004;351(3):241-9. [Medline].
Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med. Feb 11 1999;340(6):424-9. [Medline].
Clyde PW, Harari AE, Getka EJ, Shakir KM. Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. JAMA. Dec 10 2003;290(22):2952-8. [Medline].
Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. Feb 2006;16(2):109-142. [Medline].
Glinoer D. Management of hypo- and hyperthyroidism during pregnancy. Growth Horm IGF Res. Aug 2003;13 Suppl A:S45-54. [Medline].
Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. Aug 19 1999;341(8):549-55. [Medline].
Helfand M. Screening for subclinical thyroid dysfunction in nonpregnant adults: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. Jan 20 2004;140(2):128-41. [Medline].
Kita M, Goulis DG, Avramides A. Post-partum thyroiditis in a Mediterranean population: a prospective study of a large cohort of thyroid antibody positive women at the time of delivery. J Endocrinol Invest. Jun 2002;25(6):513-9. [Medline].
Ladenson PW. Recognition and management of cardiovascular disease related to thyroid dysfunction. Am J Med. Jun 1990;88(6):638-41. [Medline].
Ladenson PW. Diagnosis of hypothyroidism. In: Werner and Ingbar's The Thyroid. 7th ed. New York: Lippincott-Raven; 1996:880.
Morris MS. The association between serum thyroid-stimulating hormone in its reference range and bone status in postmenopausal American women. Bone. Apr 2007;40(4):1128-1134. [Medline].
Prummel MF, Wiersinga WM. Thyroid autoimmunity and miscarriage. Eur J Endocrinol. Jun 2004;150(6):751-5. [Medline].
Roberts CG, Ladenson PW. Hypothyroidism. Lancet. Mar 6 2004;363(9411):793-803. [Medline].

