Antibody testing for autoimmune endocrine disease - thyroid disease
The three antibodies
Three antibodies in routine use. Each answers a different question.
| Antibody | Target | Best for |
|---|---|---|
| TRAb (TSHR-Ab) | TSH receptor | Diagnosing Graves'; predicting relapse; fetal risk in pregnancy |
| TPO-Ab | Thyroid peroxidase | Most sensitive marker of Hashimoto's; risk of progression in subclinical hypothyroidism |
| Tg-Ab | Thyroglobulin | Assay interference flag in thyroid cancer surveillance |
TRAb subtypes - same assay, opposite effects
- Stimulating (TSI) -> Graves' hyperthyroidism
- Blocking (TBII) -> hypothyroidism
- Neutral
- A single patient can switch phenotype as the dominant species changes - explains spontaneous conversion between Graves' and hypothyroidism
- Third-generation binding assays measure all three; bioassays distinguish stimulating from blocking
Prevalence
| Disease | General population | |
|---|---|---|
| TRAb | Graves' 70-100% | 1-2% |
| TPO-Ab | Hashimoto's 80-99% | 10-15% (F, rises with age) |
| Tg-Ab | Hashimoto's ~50-70% | ~10% |
- TPO-Ab positivity is common in well people - a positive result in a euthyroid patient is a risk marker, not a diagnosis
- TPO-Ab in ~10% of pregnant women
- F>M for all
Mechanisms
- TRAb - directly pathogenic
- IgG binds TSH receptor -> constitutive cAMP signalling -> hormone synthesis + gland growth, TSH-independent
- Also binds orbital fibroblast TSHR/IGF-1R -> thyroid eye disease (explains why TED tracks TRAb, not thyroid hormone levels)
- Crosses placenta -> fetal/neonatal Graves'
- TPO-Ab - largely a marker, complement-fixing, contributes to lymphocytic infiltration and follicular destruction
- Hashimoto's: Th1-predominant, CD8 cytotoxic destruction + apoptosis -> fibrosis, atrophy
- Tg-Ab - no established role in immunopathology
- Its clinical value is entirely as an assay interferent
Which test, when
- Hyperthyroid, cause unclear -> TRAb
- Sensitivity ~95%+, specificity ~99% for Graves'
- Avoids scintigraphy - preferred in pregnancy and breastfeeding
- Negative TRAb + hyperthyroidism -> toxic nodule, thyroiditis, factitious, amiodarone -> scintigraphy
- Hypothyroid or subclinical hypothyroid -> TPO-Ab
- Confirms autoimmune aetiology; predicts progression to overt disease
- Diffuse goitre / suspected Hashimoto's -> TPO-Ab
- Thyroid cancer follow-up -> Tg-Ab with every thyroglobulin
Traps
- Tg-Ab present -> Tg result uninterpretable (usually falsely low by immunometric assay) -> use the Tg-Ab titre itself as a surrogate tumour marker; a rising Tg-Ab post-thyroidectomy suggests recurrence
- TPO-Ab positive does NOT mean treat - only treat on TSH/fT4
- TRAb titre does not track disease severity closely, but a high titre predicts relapse and orbitopathy
- Biotin supplements interfere with immunoassays -> spurious results; withhold 48 hr
- Heparin/LMWH -> in vitro lipolysis raises measured free T4/T3 with normal TSH - mimics TSH-oma before you chase a pituitary lesion
Other autoimmune endocrine antibodies
Other autoimmune endocrine antibodies (for contrast)
- 21-hydroxylase Ab - autoimmune Addison's
- GAD65, IA-2, ZnT8, insulin - T1DM (GAD65 also LADA)
- Anti-pituitary Ab - hypophysitis (poor performance, not routine)
Acting on the result
- TRAb positive + thyrotoxic -> Graves'
- Antithyroid drug (carbimazole first-line in Australia; propylthiouracil first trimester), RAI or surgery
- RAI transiently raises TRAb and can worsen thyroid eye disease -> avoid or cover with prednisolone if TED active and a smoker
- TRAb to guide antithyroid drug withdrawal
- Persistently high at 12-18 months -> high relapse risk -> extend therapy or move to definitive treatment
- TRAb in pregnancy
- Measure in any woman with current or past Graves' (including post-RAI/surgery - antibodies persist)
- Check at booking; if raised, repeat ~18-22 and 30-34 weeks
- >3x upper limit -> fetal thyrotoxicosis risk -> serial fetal growth/heart rate ultrasound + neonatal monitoring
- TPO-Ab positive, euthyroid -> no treatment; annual TSH
- In pregnancy or subfertility: TPO-Ab+ raises miscarriage and postpartum thyroiditis risk -> monitor TSH each trimester
- Levothyroxine for TPO-Ab+ euthyroid women to prevent miscarriage/preterm birth is NOT supported by trials (TABLET, T4LIFE)
- Tg-Ab positive post-thyroidectomy -> trend the antibody, not the thyroglobulin
- Do not repeat TPO-Ab - titres add nothing once positive
Associations
- Graves' disease, Hashimoto's thyroiditis, atrophic thyroiditis
- Postpartum thyroiditis (TPO-Ab is the strongest predictor)
- Autoimmune polyglandular syndromes: APS-2 (thyroid + T1DM + Addison's), APS-1
- T1DM, coeliac disease, pernicious anaemia, vitiligo, Addison's, alopecia areata
- Turner and Down syndromes
- Amiodarone, lithium, interferon-alpha, checkpoint inhibitors (thyroiditis common), alemtuzumab (late Graves')
- Thyroid eye disease, pretibial myxoedema, thyroid acropachy
- Primary thyroid lymphoma (on a background of Hashimoto's)
Natural history
- TPO-Ab positive + subclinical hypothyroidism -> ~4-5%/yr progression to overt hypothyroidism (vs ~2%/yr if antibody negative)
- TPO-Ab positive + normal TSH -> lower but real lifetime risk
- Graves': ~50% relapse within 1-2 yr of stopping antithyroid drugs; relapse risk tracks TRAb, large goitre, young age, smoking, high fT4 at diagnosis
- TRAb generally falls with antithyroid drug therapy, rises after RAI for 6-12 months
- Blocking-to-stimulating antibody conversion -> apparent switch from hypo- to hyperthyroidism (and vice versa)
- Neonatal Graves': transient, resolves as maternal IgG clears over 3-12 weeks
- Hashimoto's is progressive and permanent; Graves' may remit
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