Description

• Clinical and metabolic state resulting from decreased levels of free thyroid hormone or from resistance to hormone action
• Primary (intrinsic thyroid disease) or central (secondary or tertiary resulting from hypothalamic-pituitary disease)
• Subclinical: serum TSH above the upper reference limit with a normal free thyroxine (T₄) and normal hypothalamic-pituitary-thyroid axis (1)
• Overt: elevated TSH, typically 4 to 5 mIU/L with a subnormal free T₄

Epidemiology

• Women: 3.5/1,000 person-year
• Men: 0.6/1,000 person-year

• The National Health and Nutrition Examination Survey III (NHANES III), subclinical hypothyroidism 4.3%, overt 0.3% in an unselected U.S. population age >12 years, with upper limit TSH 4.5
• Framingham study, 5.9% of women and 2.3% of men age >60 years had a serum TSH >10 mIU/L

Etiology and Pathophysiology

• Primary: abnormality at the thyroid gland (>95% of cases)
• Most common cause worldwide: environmental iodine deficiency (1)[A]
• Most common cause in the United States: Hashimoto thyroiditis (chronic autoimmune thyroiditis)
  • Hashimoto is characterized by loss of thyroid function secondary to autoimmune-mediated destruction from thyroid antibodies.
  • The typical course of the disease is gradual loss of thyroid function.
• Postablative/posttherapeutic: follows radioactive iodine therapy or total subtotal thyroidectomy for hyperthyroidism; radiotherapy or surgery for thyroid cancer, benign nodular thyroid disease, or neck malignancies
• Transient hypothyroidism: de Quervain syndrome (viral), postpartum, silent thyroiditis (2)
• Drug use: propylthiouracil, methimazole, lithium, amiodarone, antiepileptic drugs, and newer chemotherapeutic agents such as tyrosine kinase inhibitors (sunitinib), interleukin-2, or interferon-α
• Central: hypothyroidism due to insufficient stimulation by TSH of an otherwise normal thyroid gland; can be secondary (level of the pituitary) or tertiary (level of the hypothalamus)
• Consumptive: triiodothyronine (T₃) and T₄ excessively degraded by ectopically produced type 3 iodothyronine deiodinase (rare)
• Other etiologies include genetic defects, tumors, vascular, empty sella syndrome, inflammatory, infiltrative, iatrogenic, posttrauma, or drug related.

Risk Factors

• Personal or family history of autoimmune diseases
• Pregnant women or those with previous postpartum thyroiditis
• External head or neck irradiation
• Past history of thyroid dysfunction, radioiodine therapy or thyroid surgery
• Abnormal thyroid examination, presence of goiter, and/or TPOAb positivity
• Treatment with amiodarone, lithium, interferon-α, sunitinib, or sorafenib
• Down syndrome or Turner syndrome

Commonly Associated Conditions

• Diabetes mellitus type 1 and 2
• Pernicious anemia
• Celiac disease
• Primary adrenal failure (Addison disease)
• Myasthenia gravis
• Rheumatoid arthritis
• Systemic lupus erythematosus
• Depression
• Genetic syndromes that have multiple autoimmune endocrinopathies