Hypothyroidism occurs when there is inadequate thyroid hormone production by the thyroid gland or insufficient stimulation by the hypothalamus or pituitary gland. Causes may include primary gland failure or can be iatrogenic, transient, or central (Table 1).^1–4 Central causes, such as low levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT₄), are rare.

Clinical hypothyroidism occurs in 0.3% of the U.S. general population, with a higher prevalence in people older than 65 years.^5–7 It is seven times more common in females than in males (40 out of 10,000 vs. six out of 10,000).⁸ Other risk factors include autoimmune disease (e.g., type 1 diabetes mellitus, celiac disease, autoimmune gastric atrophy, multiple autoimmune endocrinopathies), Down syndrome, and Turner syndrome.² Cigarette smoking and moderate alcohol intake decrease the risk of thyroid cancer and hypothyroidism.^2,9 Untreated hypothyroidism can contribute to numerous physiologic and metabolic derangements.

Signs and symptoms are nonspecific and can vary in individual presentations (Table 2 and Table 3^1,3,10). Diagnosis is based on blood levels of decreased FT₄, with a corresponding elevated thyrotropin (i.e., TSH) level in primary causes (thyroid source); the TSH level may be normal to low in secondary (pituitary source) or tertiary (hypothalamic source) causes.⁵ Subclinical hypothyroidism describes the state of normal FT₄ levels when the TSH level is elevated. This article focuses on primary hypothyroidism in adults.

Pathophysiology

A sensitive negative feedback loop regulates the thyroid hormone. The hypothalamus produces thyrotropin-releasing hormone that controls anterior pituitary gland secretion of TSH, regulating the secretion of thyroid hormone (triiodothyronine [T₃] and thyroxine [T₄]) by the thyroid gland.^11,12 Thyroid hormone affects the metabolism and function of many cells and organs. This central role is reflected by the signs and symptoms of thyroid dysregulation. Thyroid hormone also regulates thyroid metabolism by providing negative feedback to the hypothalamus and pituitary gland. The hypothalamus adjusts the release of thyrotropin-releasing hormone based on circulating levels of thyroid hormone. Together, these hormones regulate the secretion of TSH from the anterior lobe of the pituitary gland. This functioning feedback loop keeps the blood level of the thyroid hormone normal.

Screening

The U.S. Preventive Services Task Force concludes that there is insufficient evidence to assess the balance of benefits and harms of screening for thyroid dysfunction in nonpregnant, asymptomatic adults.¹³ Consider targeted screening at initial diagnosis or medication initiation in patients with Down syndrome, Turner syndrome, subtotal thyroidectomy, type 1 diabetes, autoimmune adrenal insufficiency (Addison disease), radioiodine treatment, radiation therapy of the neck, and use of medications such as amiodarone, lithium, interferons, and rifampin.^2,3 Other medications that may prompt screening include tyrosine kinase inhibitors, phenobarbital, interleukin-2, and immune checkpoint inhibitors.^3,14

Diagnosis

TSH elevation indicates hypothyroidism. Low-end normal TSH is 0.4 mIU per L.^2,5–7 The upper-end normal range is from 4.0 to 4.5 mIU per L.^2,5–7 FT₄ level is used to distinguish clinical (low FT₄) from subclinical (normal FT₄) hypothyroidism. Routinely evaluating total T₃, total T₄, or FT₃ levels is not indicated.² Testing for the thyroid peroxidase (TPO) antibody does not help diagnose hypothyroidism; however, a positive test result suggests an autoimmune etiology.² Thyroid ultrasonography is used to evaluate palpable thyroid nodules and is not part of routine evaluation.⁴