What are the diagnostic markers for Graves' disease?

Diagnostic Markers for Graves' Disease

The primary diagnostic markers for Graves' disease include elevated thyroid function tests (TSH, Free T4, Free T3), positive TSH receptor antibodies (TRAb), and characteristic clinical findings such as diffuse goiter, ophthalmopathy, and pretibial myxedema.

Laboratory Markers

Essential Thyroid Function Tests

• TSH: Typically suppressed (<0.1 mIU/L) 1
• Free T4: Elevated in overt hyperthyroidism
• Free T3: Elevated, often disproportionately higher than T4 2, 3

Antibody Testing

• TSH Receptor Antibodies (TRAb): The most specific marker for Graves' disease
  • Available in two forms:
    • Thyroid-Stimulating Immunoglobulin (TSI): Bioassay that measures stimulating activity
    • Thyrotropin-Binding Inhibitory Immunoglobulin (TBII): Competitive binding assay 4
  • Sensitivity and specificity >95% for diagnosis of Graves' disease 5
  • TRAb >12 IU/L at diagnosis is associated with 60% risk of relapse at 2 years 5

Other Laboratory Tests

• FT3/FT4 ratio: Higher in Graves' disease (>4.4 × 10^-2 pg/ng) compared to other causes of thyrotoxicosis 2, 3
• T3/T4 ratio: Elevated in Graves' disease compared to destructive thyroiditis 3

Imaging Studies

• Thyroid Ultrasound with Color Doppler:

  • Increased vascularity (thyroid inferno pattern)
  • Mean peak systolic velocity in inferior thyroid artery (mean PSV-ITA) has 85.2% sensitivity and 90.9% specificity 3

• Radioactive Iodine Uptake (RAIU) Scan:

  • Diffusely increased uptake in Graves' disease
  • Helps differentiate from thyroiditis (which shows decreased uptake) 3

• Orbital CT or MRI (when ophthalmopathy is present):

  • Tendon-sparing enlargement of extraocular muscles
  • Proptosis (often bilateral but frequently asymmetric) 6

Clinical Markers

• Diffuse goiter: Symmetrically enlarged thyroid gland
• Graves' ophthalmopathy: Lid retraction, proptosis, periorbital edema, extraocular muscle dysfunction
  • Measure exophthalmos using exophthalmometer 6
• Pretibial myxedema: Localized thickening of the skin

Diagnostic Pitfalls and Considerations

1. False-positive TRAb results:

   • Can occur in transient thyrotoxicosis 7
   • Mildly elevated TRAb (<2× upper limit) requires cautious interpretation 7

2. False-negative TRAb results may occur in:

   • Subclinical hyperthyroidism
   • Normal radionuclide uptake
   • Longer duration of thyrotoxicosis
   • Absence of goiter or ophthalmopathy 4

3. Differential diagnosis considerations:

   • Subacute thyroiditis (lower FT3/FT4 ratio, decreased RAIU)
   • Toxic adenoma/multinodular goiter (focal uptake on scan)
   • Factitious thyrotoxicosis (suppressed thyroglobulin)

Monitoring and Follow-up

• TRAb levels decline with antithyroid drug therapy and after thyroidectomy 5
• TRAb levels increase for a year following radioactive iodine therapy, then gradually fall 5
• TSH and Free T4 should be checked every 4-6 weeks initially, then every 6-12 months if stable 1

Management Implications of Diagnostic Findings

• TRAb >7.5 IU/L at 12 months or >3.85 IU/L at cessation of antithyroid drug therapy predicts >90% risk of relapse 5
• In pregnant women, TRAb ≥5 IU/L indicates increased risk of fetal and neonatal thyrotoxicosis 5
• Elevated TRAb with ophthalmopathy may warrant steroid prophylaxis before radioactive iodine therapy 5

The combination of clinical features, thyroid function tests, TRAb testing, and imaging studies provides the most accurate diagnosis of Graves' disease and helps guide appropriate treatment decisions.