admittomedicine

graves' disease

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graves' disease

A systemic autoimmune disorder characterized by the triad of Hyperthyroidism, Orbitopathy, and Dermopathy. Caused by TSH-Receptor Antibodies (TRAb) stimulating the TSH receptor in the thyroid and retroorbital fibroblasts.

pathophysiology

  • Mechanism: Loss of tolerance B-cell production of TRAb (Thyrotropin Receptor Antibodies), specifically TSI (Thyroid Stimulating Immunoglobulin).
  • Thyroid: TSI stimulates TSH-R Unregulated synthesis of T4/T3 + Gland hypertrophy (Goitre).
  • Orbit/Skin: TSH-R is expressed on fibroblasts Antibody binding Adipogenesis + Hyaluronic acid accumulation Oedema/Expansion.

diagnosis

  1. Biochemical: Suppressed TSH + Elevated fT4/fT3 (See Hyperthyroidism).
  2. Serology: TRAb / TSI Positive (>99% specificity).
    • Pearl: If TRAb is positive and clinical features (orbitopathy) are present, RAIU is not strictly necessary.
  3. Imaging:
    • RAI Scan: Diffuse, homogeneous uptake (High, >25-30%).
    • Doppler US: “Thyroid Inferno” (increased vascularity).

clinical features (the triad)

1. hyperthyroidism

  • Goitre (diffuse, firm, bruit may be present).
  • Sympathetic overactivity (tachycardia, tremor, lid lag).
  • Management: See Hyperthyroidism.

2. graves’ orbitopathy (GO)

  • Mechanism: Retroorbital inflammation and expansion.
  • Key Signs: Proptosis (exophthalmos), Diplopia (muscle restriction), Chemosis, Periorbital oedema.
  • Exam Trap: Lid Lag (sympathetic) is seen in any thyrotoxicosis. Proptosis is specific to Graves’.

3. graves’ dermopathy

  • Pretibial Myxoedema: Non-pitting, violaceous, “orange-peel” induration on shins.
  • Acropachy: Clubbing + soft tissue swelling of digits (rare, late finding).

management: hyperthyroidism

Three modalities: Antithyroid drugs (ATD), Radioactive Iodine (RAI), Surgery.

1. medical therapy (thionamides)

Inhibits thyroid peroxidase (TPO). Immunomodulatory effect may induce remission (30–50% after 12–18 months).

  • Methimazole (MMZ):
    • Preferred agent (longer half-life, less hepatotoxic).
    • Dosing: Start 10–30 mg PO daily based on severity. Maintenance 5–10 mg.
  • Propylthiouracil (PTU):
    • Inhibits peripheral T4 T3 conversion.
    • Indications: 1st Trimester Pregnancy, Thyroid Storm, minor reaction to MMZ.
    • Black Box: Severe hepatotoxicity.

adverse effects of thionamides

  • Agranulocytosis (<0.5%): Sudden fever/sore throat. STOP DRUG and check CBC. Do not switch agents (cross-reactivity).
  • Hepatotoxicity: PTU (hepatocellular necrosis), MMZ (cholestasis).
  • Vasculitis: ANCA-positive (usually PTU).

2. radioactive iodine (RAI - I)

  • Mechanism: Ablation of gland via -emission.
  • Outcome: Permanent hypothyroidism (lifelong Levothyroxine).
  • Contraindications: Pregnancy, breastfeeding (stop 6 weeks prior), moderate-to-severe active orbitopathy.
  • Orbitopathy Risk: RAI can worsen eye disease. Prophylax with Prednisone (0.4–0.5 mg/kg) if mild active orbitopathy or smoker.

3. surgery (thyroidectomy)

  • Indications: Large compressive goitre (>80g), suspected malignancy, severe orbitopathy (avoids RAI risk), refractory to ATD/RAI.
  • Prep: Must be euthyroid pre-op (ATD + Beta-blockers). Potassium Iodide (Lugol’s) given 10 days pre-op to reduce vascularity (Wolff-Chaikoff effect).

management: graves’ orbitopathy (GO)

Management is independent of thyroid status. Smoking cessation is the single most important modifiable risk factor.

assessment (EUGOGO)

  • Activity (CAS - Clinical Activity Score): Is it active/inflamed? (Pain, redness, swelling, changing vision).
    • Active (CAS 3/7): Responds to immunosuppression.
    • Inactive (Burned out): Does not respond to steroids; requires surgery.
  • Severity: Mild vs. Moderate-Severe vs. Sight-Threatening.

treatment by severity (active disease)

SeverityFirst-Line Management
Mild• Lubricants / Artificial tears.
• Selenium (200 µg/d x 6 months) – improves QoL/ocular signs in mild disease.
• Control thyroid dysfunction.
Mod-Severe• IV Methylprednisolone (Pulse therapy) Oral Prednisone (better efficacy, less toxicity).
• Mycophenolate: Now recommended as adjunct to steroids (EUGOGO 2021).
Sight-ThreateningOptic Neuropathy or Corneal Breakdown
• Urgent IV Methylprednisolone (500mg-1g x 3 days).
• If no response: Urgent Orbital Decompression surgery.

teprotumumab (tepezza): An IGF-1 Receptor Inhibitor.

  • Role: Dramatic reduction in proptosis and diplopia in active GO.
  • Status: Health Canada approved for moderate-to-severe active GO.
  • Side Effects: Hearing impairment, hyperglycaemia, muscle spasms.

prevention of GO progression

  • RAI Risk: Radioactive iodine can worsen active orbitopathy (15% risk).
  • Prophylaxis: If mild active GO + Smoker Give Prednisone (0.3–0.5 mg/kg taper) alongside RAI to prevent flare.
  • Contraindication: Do not use RAI in moderate-severe active GO.

prognosis & remission

  • Natural History: “Rule of Thirds” for medical therapy (30% remit, 30% relapse, 30% fail).
  • Predicting Remission:
    • TRAb Titres: Measurement at 12–18 months.
    • Negative TRAb: Good chance of remission (stop ATD).
    • Positive TRAb: High risk of relapse (continue ATD or switch to RAI/Surgery).
  • Relapse Risk Factors: Smoking, large goitre, high baseline TRAb, male sex.

dermopathy management

Unlike orbitopathy (systemic steroids), pretibial Myxoedema can be treated with topical high-potency corticosteroids Systemic steroids are rarely needed.

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