Graves disease

Graves disease is the most common cause of hyperthyroidism and often affects women. It is an autoimmune condition that is associated with circulating TSH receptor autoantibodies leading to overstimulation of the thyroid gland with excess thyroid hormone production. The classic clinical triad of Graves disease involves a diffuse vascular goiter, ophthalmopathy, and pretibial myxedema, although not all features may be present in a patient. The clinical diagnosis of Graves disease is confirmed via assessment of TSH and T₃/T₄ levels as well as through detection of thyroid antibodies (TRAb, TPOAb, TgAb). In addition, a diffuse uptake of ¹²³I may be seen on thyroid scintigraphy. Treatment includes beta blockers to quickly alleviate symptoms, antithyroid drugs to achieve euthyroid status, and radioiodine ablation or, less commonly, near-total thyroidectomy for definitive control of the disease.

• Most common cause of hyperthyroidism in the United States
• Incidence: ∼ 30 cases per 100,000 people per year
• Sex: ♀ > ♂ (8:1)
• Typical age range: 20–40 years

References:^[1]

Epidemiological data refers to the US, unless otherwise specified.

• Genetic predisposition
  • 50% of patients with Graves disease have a family history of autoimmune disorders (e.g., type 1 diabetes mellitus, Hashimoto disease, pernicious anemia, myasthenia gravis)
  • Associated with HLA-DR3 and HLA-B8 alleles
• Autoimmunity: B and T lymphocyte-mediated disorder
• Triggers
  • Infectious agents: Yersinia enterocolitica and Borrelia burgdorferi have been shown to trigger antigen mimicry for homologies between their protein constituents and thyroid autoantigens.
  • Stress
    • Physical: surgery, trauma
    • Psychological
  • Pregnancy ^[2]
  • Environmental factors: smoke, irradiations, drugs, endocrine disruptors

References:^[1][3]

• General mechanism: B and T cell-mediated autoimmunity → production of stimulating immunoglobulin G (IgG) against TSH-receptor (TRAb; type II hypersensitivity reaction) → ↑ thyroid function and growth → hyperthyroidism and diffuse goiter
• Thyroid-associated ophthalmopathy: activated B and T cells infiltrate retro-orbital space targeting orbital fibroblasts → cytokine release (e.g. TNF-α, IFN-γ) → local inflammatory response → fibroblast proliferation and differentiation to adipocytes → production of hyaluronic acid and GAGs and increased amount of adipocytes → increase in the volume of intraorbital fat and muscle tissues → exophthalmos, lid retraction, disturbances in ocular motility (causing diplopia)
• Pretibial myxedema: dermal fibroblast stimulation and deposition of glycosaminoglycans in connective tissue

References:^[4]

• Symptoms of hyperthyroidism
• Triad of Graves disease
  • Diffuse goiter
    • Smooth, uniformly enlarged goiter
    • Bruit may be heard at the superior poles of the lobes
  • Ophthalmopathy (see Graves ophthalmopathy)
    • Exophthalmos
    • Ocular motility disturbances
    • Lid retraction and conjunctival conditions
  • Dermopathy (pretibial myxedema): non-pitting edema and firm plaques on the anterior/lateral aspects of both legs

References:^[5][6][7]

The diagnosis of Graves disease is often apparent on clinical examination and is confirmed through detection of specific thyroid antibodies.

• Best initial test: ↓/undetectable TSH and ↑ T₃/T₄ (see “Diagnostics” in hyperthyroidism)
• Measure thyroid antibodies
  • ↑ TRAbs (specific)
  • ↑ Anti-TPO antibodies and anti-Tg antibodies (nonspecific)
• Thyroid scintigraphy
  • Indicated if TRAbs are low to establish a diagnosis
  • Shows a diffuse uptake of radioactive iodine (¹²³I)
  • Contraindicated in pregnancy
• Thyroid ultrasound (with color Doppler)
  • Indicated in pregnant women if TRAbs are low
  • Shows an enlarged, hypervascular thyroid

References:^[5][8]

• Macroscopic
  • Diffuse, uniform gland enlargement
  • Cut surfaces show beefy red appearance
• Microscopic: histological features of an overactive gland
  • Diffuse hyperplasia of thyroid follicles
  • Tall, hyperplastic and hypertrophic follicular cells
  • Colloid reabsorption with peripheral scalloping
  • Irregular stromal lymphocytic infiltration

References:^[9]

• β-blockers: rapid control of hyperthyroidism symptoms
• Antithyroid drugs: thionamides (e.g., methimazole, propylthiouracil)
  • Goal: achieve euthyroid state
  • Patients with a small goiter and mild hyperthyroidism may undergo remission on antithyroid drugs alone (in ∼ 50% of cases).
  • Once remission is achieved, slowly taper and stop.
• Radioactive iodine ablation
  • First-line therapy in nonpregnant patients with small goiters
  • Second-line therapy in patients who relapse after long-term therapy with antithyroid drugs
• Surgery: near-total thyroidectomy is rarely done in Graves disease
• Complications of therapy
  • Permanent hypothyroidism after radioactive iodine ablation or surgery → need for lifelong thyroid replacement therapy
  • New-onset/exacerbation of Graves ophthalmopathy after radioactive iodine ablation
• See “Therapy” in hyperthyroidism for more information.
• Also see orbital disorders for the treatment of Graves ophthalmopathy.

References:^[1][10]

Graves disease in children

• Epidemiology: most common cause of hyperthyroidism in children
• Clinical features
  • Features of hyperthyroidism: See “Clinical features” in “Hyperthyroidism.”
  • Most children develop a goiter, which can be large and cause compressive symptoms (See “Symptoms/clinical findings” in goiter)
  • Younger children often show a growth spurt
  • Graves ophthalmopathy, if present, is often mild. However, lid lag causing apparent proptosis is often seen.
  • Graves dermopathy rarely occurs in children.
• Treatment
  • Antithyroid drugs
    • Best initial treatment
    • Methimazole is the drug of choice
    • Most children go into remission within 2 years of treatment.
  • Symptom control with β blockers: atenolol, propranolol
  • Radioactive iodine (RAI) ablation
    • In children > 10 years/adolescents without large goiters: potential first-line treatment option
    • In children who relapse after long-term therapy with antithyroid drugs: as a second-line treatment
    • In children > 5 years: lower dose is recommended
    • Contraindicated in children < 5 years
    • Nearly half the children treated with radioiodine ablation become hypothyroid (thyroid hormone replacement is necessary)
    • Risk of thyroid cancer is not elevated with therapeutic/diagnostic doses of radioactive iodine.
  • Surgery (near-total thyroidectomy) is indicated in:
    • Children < 5 years who relapse/do not improve with antithyroid drugs
    • In children/adolescents with large goiters
  • Lifelong monitoring of thyroid function
    • To detect recurrence of hyperthyroidism
    • To detect hypothyroidism after treatment

Graves disease in the elderly

• Epidemiology: the second most common cause of hyperthyroidism in elderly individuals, after toxic multinodular goiter
• Clinical features
  • Classic signs of thyrotoxicosis are often absent/minimal in elderly individuals
  • Treatment of other co-existing diseases may mask the symptoms of hyperthyroidism (e.g., β blockers for hypertension/angina may mask tachycardia and tremors).
  • Monosymptomatic hyperthyroidism: Elderly patients may present with only one symptom of hyperthyroidism, myopathy being the most common.
  • Apathetic hyperthyroidism: A common presentation of Graves in the elderly
    • Absence of ophthalmopathy
    • No/small goiter
    • No tremor
    • Neuropsychiatric symptoms: apathy, depression, lethargy
    • Thyroid myopathy: proximal muscle weakness is the predominant symptom and sign
    • Excessive weight loss and cardiac arrhythmias are often present
• Diagnostics: The diagnosis of thyrotoxicosis in the elderly is often made during laboratory workup for unexplained weight loss or worsening cardiovascular disease (see “Diagnostics” above).
• Management
  • RAI ablation is the treatment of choice.
  • Antithyroid drugs: to achieve a euthyroid state before RAI ablation.
  • Surgery: rarely indicated