Skip to content

BASICS

Description

  • Autoimmune activation of TSH receptor by thyroid-stimulating immunoglobulins.
  • Most common cause of hyperthyroidism.
  • Classic signs: thyrotoxicosis, diffuse goiter, ophthalmopathy, pretibial myxedema.

Epidemiology

  • Annual incidence: 20-50 per 100,000.
  • Peaks at 30–50 years.
  • 0.2% of pregnancies affected; 95% due to Graves disease.
  • Accounts for 60-80% of hyperthyroidism cases worldwide.
  • Prevalence: 1–1.5% globally.

Etiology and Pathophysiology

  • Excess TSH receptor antibodies produced by B cells due to T cell dysregulation.
  • Antibodies stimulate thyroid hormone synthesis and gland growth.
  • Similar antigen in retro-orbital tissue leads to ophthalmopathy.
  • Genetic predisposition: family history of autoimmune disease; 20% twin concordance.

Risk Factors

  • Female sex (5–10 times more common).
  • Postpartum period.
  • Family history (15% have affected relative).
  • Medications: iodine, selenium, amiodarone, lithium, HAART, interferon.
  • Smoking (increases ophthalmopathy risk).
  • Low vitamin D, infections.

Prevention

  • Screening TSH not recommended in asymptomatic patients.

Common Associations

  • Mitral valve prolapse.
  • Type 1 diabetes mellitus.
  • Addison disease, hypokalemic periodic paralysis.
  • Vitiligo, alopecia areata.
  • Other autoimmune diseases.

DIAGNOSIS

History

  • Symptoms: tachycardia, palpitations, tremor, anxiety, insomnia, heat intolerance, weight loss, fatigue.
  • Ocular: diplopia, retro-orbital pain, proptosis, vision changes.
  • Menstrual irregularities, sexual dysfunction.
  • Worsening of preexisting conditions.

Physical Exam

  • Eye signs: lid lag, proptosis, ophthalmoplegia, optic neuropathy.
  • Thyroid: diffuse, nontender goiter, possible bruit.
  • Skin: warm, moist, fine hair, palmar erythema, onycholysis, pretibial myxedema.
  • Cardiac: tachycardia, atrial fibrillation.
  • Extremities: tremor, hyperreflexia, proximal myopathy.

Differential Diagnosis

  • Toxic multinodular goiter.
  • Toxic adenoma.
  • Hashimoto thyroiditis.
  • Iatrogenic hyperthyroidism.
  • hCG-producing tumors.
  • Thyroid cancer.

Diagnostic Tests

  • Initial: suppressed TSH (<0.1 mIU/L), elevated free T4 (and possibly T3).
  • TRAb and TPO antibodies distinguish Graves from other causes.
  • Pregnancy: TRAb positive in 95% cases.
  • Imaging: RAIU shows diffuse increased uptake.
  • Ultrasound to assess nodularity.

TREATMENT

General Measures

  • Aim to restore euthyroid state with minimal side effects and hypothyroidism risk.

Medications

  • First line: Methimazole preferred except in 1st trimester (PTU preferred in pregnancy 1st trimester).
  • Methimazole: longer half-life, once daily dosing, fewer side effects.
  • PTU: inhibits peripheral conversion of T4 to T3.
  • Minor side effects: rash, fever, arthralgia.
  • Major side effects: agranulocytosis, cholestasis.
  • Duration: 12–18 months.
  • Relapse common (up to 50%), higher if smoker or large goiter.

Radioactive Iodine (RAI)

  • Definitive treatment except with severe orbitopathy or pregnancy.
  • Risks: hypothyroidism (80%), radiation thyroiditis, worsened ophthalmopathy.
  • Pretreat with antithyroid drugs in severe cases.
  • Repeat dose may be needed.

Surgery

  • Indications: relapse, large goiter, orbitopathy, pregnancy (2nd trimester), suspected cancer.

Adjunct Therapies

  • Ξ²-blockers for symptom control.
  • Iodides for rapid control (short term).
  • IV corticosteroids for severe thyrotoxicosis.
  • Bile acid sequestrants to reduce thyroid hormone levels.

Ophthalmopathy Treatment

  • Lubricants, smoking cessation.
  • IV glucocorticoids for moderate/severe disease.
  • Teprotumumab (IGF-1R inhibitor) FDA approved.
  • Emergency: IV steroids, orbital irradiation, surgery.

Dermopathy Treatment

  • Topical corticosteroids with occlusion.

ONGOING CARE

Monitoring

  • TSH and T4 every 1–2 months initially, then less frequently.
  • CBC and liver tests annually.
  • TRAb antibodies after 12 months for remission prediction.
  • Pregnancy: prefer PTU in 1st trimester; monitor postpartum.

Prognosis

  • Good with treatment.
  • Risks: ocular, cardiac, psychiatric complications.
  • Increased morbidity due to osteoporosis, atherosclerosis, insulin resistance.

COMPLICATIONS

  • Hypothyroidism post-treatment.
  • Ophthalmopathy progression.
  • Thyroid storm.

Clinical Pearls

  • Graves disease causes most hyperthyroidism.
  • Smoking worsens eye disease.
  • Methimazole preferred except early pregnancy.
  • RAI contraindicated in pregnancy.

References

  1. Ren Z, Qin L, Wang JQ, et al. Comparative efficacy of four treatments in patients with Graves' disease: a network meta-analysis. Exp Clin Endocrinol Diabetes. 2015;123(5):317-322.
  2. Bahn Chair RS, Burch HB, Cooper DS, et al; American Thyroid Association. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines. Thyroid. 2011;21(6):593-646.
  3. Kotwal A, Stan M. Current and future treatments for Graves' disease and Graves' ophthalmopathy. Horm Metab Res. 2018;50(12):871-886.
  4. Dosiou C, Kossler AL. Thyroid eye disease: navigating the new treatment landscape. J Endocr Soc. 2021;5(5):bvab034.