Key Facts

Graves disease is the commonest autoimmune cause of hyperthyroidism. TRAb is both diagnostic and pathogenic. Management involves ATDs, radioiodine, or surgery depending on clinical context. Graves orbitopathy requires specialist management.

Epidemiology

Prevalence ~0.5-1%. F:M 5-10:1. Peak age 30-50 years. Lifetime risk ~3% in women. More common in smokers (especially orbitopathy).

Aetiology

Autoimmune: genetic (HLA-DR3, CTLA-4 polymorphisms) + environmental triggers (stress, smoking, pregnancy, infection, iodine excess). TRAb stimulate TSH receptors on thyroid follicular cells → unregulated thyroid hormone production and gland enlargement.

Pathophysiology

TRAb (IgG) binds TSH receptor → Gs protein activation → cAMP → thyroid hormone synthesis and secretion independent of TSH. Also promotes thyrocyte growth (goitre). Orbitopathy: TRAb cross-reacts with TSH receptors on orbital fibroblasts → inflammation, GAG deposition, adipogenesis → orbital tissue expansion → proptosis, EOM restriction.

Thyrotoxicosis Features

• As per hyperthyroidism: weight loss, tremor, palpitations, heat intolerance, diarrhoea
• Diffuse, smooth, non-tender goitre (may have bruit due to increased vascularity)

Graves-Specific Features

• Orbitopathy (~25-50%): proptosis, periorbital oedema, conjunctival injection/chemosis, EOM restriction (inferior rectus most commonly → diplopia on upgaze), lid retraction, lagophthalmos, optic neuropathy (rare but sight-threatening)
• Pretibial myxoedema (~1-5%): raised waxy plaques/nodules on anterior shins; peau d'orange appearance
• Thyroid acropachy (<1%): digital clubbing, periosteal reaction
• Thyroid dermopathy: localised or generalised

Red Flags

• Visual loss/colour desaturation → optic neuropathy → emergency
• Severe proptosis with corneal exposure → ophthalmology
• Thyroid storm features → emergency

TFTs

• Suppressed TSH, raised free T4 ± free T3

TRAb

• Positive in >95% — diagnostic; also useful for: relapse prediction (high TRAb at ATD cessation → higher relapse risk), neonatal Graves risk (check in 3rd trimester), distinguishing Graves from thyroiditis

Uptake Scan

• Diffuse increased uptake (confirms Graves vs thyroiditis/toxic nodule)

Orbital Assessment

• CT/MRI orbits: if moderate-severe orbitopathy; shows enlarged EOM (especially inferior and medial rectus), orbital fat expansion
• CAS (Clinical Activity Score): grades activity of orbitopathy

Bloods

• FBC, LFTs: baseline before ATDs

Antithyroid Drugs

• Carbimazole: first-line; 20-40mg/day initially; titration or block-and-replace; 12-18 months
• PTU: first trimester pregnancy only
• Warn: agranulocytosis risk

Radioiodine

• For relapse or as first-line definitive therapy; single dose; most become hypothyroid
• Avoid in active moderate-severe orbitopathy (may worsen — give steroid cover: prednisolone 0.3-0.5mg/kg for 3 months)

Surgery

• Total thyroidectomy: large goitre, compression, moderate-severe active orbitopathy, patient preference

Orbitopathy (EUGOGO Guidelines)

• Mild: lubricants, selenium 100μg BD × 6 months
• Moderate-severe active: IV methylprednisolone pulses (500mg weekly × 6, then 250mg weekly × 6)
• Sight-threatening: emergency IV steroids; surgical decompression
• Teprotumumab (anti-IGF-1R): clinical trials show proptosis reduction
• All patients: stop smoking (strongest modifiable risk factor)

Pregnancy

• ATDs cross placenta; carbimazole teratogenic in first trimester → use PTU first trimester, then switch to carbimazole
• TRAb crosses placenta → monitor in 3rd trimester; if elevated → neonatal thyroid monitoring

Referral Criteria

• Endocrinology: all Graves disease
• Ophthalmology: orbitopathy (even mild)
• Surgery: if thyroidectomy indicated

~50% remission after 12-18 months ATDs (lower if: large goitre, high TRAb at cessation, T3-predominant, young age, male, smoker). Radioiodine: >90% cure; hypothyroidism in ~80% at 1 year. Surgery: >95% cure; hypothyroidism expected. Orbitopathy: ~90% mild/self-limiting; ~5% sight-threatening. Neonatal Graves (transient): resolves as maternal TRAb clears (weeks-months).

Graves Disease — Unique Features vs Other Thyrotoxicosis

Clinical Activity Score (CAS) for Graves Orbitopathy