Hyperthyroidism

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Hyperthyroidism and thyrotoxicosis result from an excess of thyroid hormone (TH); the former refers to hormone overproduction by the thyroid gland, whereas the latter may arise from either thyroidal or nonthyroidal sources (1).

Description

  • Hyperthyroidism is most commonly caused by Graves disease (GD), toxic multinodular goiter (TMNG), and toxic adenoma (TA) (1),(2).
  • Patients can develop thyrotoxicosis from other causes, such as subacute thyroiditis and drug-induced thyroiditis.
  • Subclinical hyperthyroidism: suppressed thyroid-stimulating hormone (TSH) with normal thyroxine (T4) and triiodothyronine (T3)
  • Thyroid storm: extreme manifestation of hyperthyroidism with acute, severe symptoms affecting multiple organ systems; up to 50% mortality (2)

Epidemiology

Incidence

  • Approximately 0.5 to 1.5 cases per 1,000 person-years globally
  • GD: most common cause in iodine-sufficient areas; peak incidence: 2nd and 3rd decades of life
  • TMNG: more frequent in iodine-deficient areas; most common cause in patients aged >65 years (1)

Prevalence

The global prevalence is 0.2–1.3% (1).

Etiology and Pathophysiology

  • GD: autoimmune disease; characterized by autoantibodies that activate the TSH receptor (TSHr)
  • TMNG: autonomous production and release of T3 and T4 due to constitutive activation of TSHr or somatic mutations in Gsα (1)
  • TA: thyroid nodule with a somatic activating mutation in the TSHr gene, leading to autonomous overproduction of THs
  • TSH-producing pituitary adenoma: rare benign pituitary tumor that secretes excess TSH, causing elevated TH (should be distinguished from TH resistance, which can show similar labs) (1)
  • Gestational transient thyrotoxicosis: results from the thyroid-stimulating activity of human chorionic gonadotropin (hCG); serum hCG peaks at 9 to 12 weeks of gestation, with higher risk in twin pregnancy and in hyperemesis gravidarum.
  • Iodine-induced hyperthyroidism: occurs after exposure to high iodine doses, most often from iodinated contrast media but also from seaweed or potassium iodide tablets; typically develops 3 to 10 weeks after exposure (1)
  • Subacute/de Quervain thyroiditis: granulomatous giant cell thyroiditis, often preceded by an upper respiratory tract infection; viruses such as coxsackievirus, adenovirus, echovirus, and influenza have been implicated; typically benign and self-limited course
  • Postpartum thyroiditis: occurs in 8–11% of pregnancies; the thyrotoxic phase is usually asymptomatic and is associated with a high risk of permanent hypothyroidism.
  • Drug-induced thyroiditis: amiodarone, interferon-α, interleukin-2, lithium, immune check point inhibitors (anti-CTLA-4, anti-PD-1 antibodies), tyrosine-kinase inhibitors (sorafenib, vandetanib) (1),(2)

Genetics

  • GD: concordance rate of GD among monozygotic twins is 30%
  • Polymorphisms involved in immune checkpoints and immune response (FOXP3, PTPN22, CTLA4, CD40, FCRL3) (1)

Risk Factors

  • Female sex, iodine excess, irradiation, infections, postpartum period, drugs
  • Positive family history, especially in maternal relatives
  • Other autoimmune disorders
  • Perturbation of gut microbiota
  • Use of alemtuzumab (30% of patients develop GD)

General Prevention

  • Hyperthyroidism cannot usually be fully prevented, especially autoimmune forms
  • Risk can be reduced by maintaining adequate iodine intake.

Commonly Associated Conditions

  • Autoimmune diseases occur in 9.7% of patients with GD (rheumatoid arthritis, pernicious anemia, systemic lupus, celiac disease, Addison disease, vitiligo) (1)
  • Down syndrome

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