Thyroid eye disease

What it is

Thyroid eye disease (TED) is an autoimmune inflammatory condition affecting 25–50% of people with Graves' disease, with severe disease occurring in roughly 3–5% of cases. Also called Graves' ophthalmopathy or thyroid-associated ophthalmopathy, TED involves inflammation and tissue expansion within the bony eye socket (orbit), pushing the eyeball forward and restricting eye movement. It is more common in women but tends to run a more severe course in men and in people who smoke. Critically for Canadian patients, TED can appear before, during, or after thyroid treatment — and sometimes in people whose thyroid hormone levels are entirely normal — meaning a Graves' diagnosis alone warrants a baseline eye assessment regardless of symptoms.

Causes and mechanism

TED is driven by autoantibodies against the TSH receptor (TRAb/TSI) — the same antibodies responsible for Graves' hyperthyroidism. These antibodies bind to TSH receptors expressed on orbital fibroblasts, triggering two downstream effects:

1. Fibroblasts produce hyaluronic acid and glycosaminoglycans, which accumulate in the orbital fat and extraocular muscles, causing them to swell.
2. Activated fibroblasts differentiate into adipocytes (fat cells), expanding orbital fat volume, or into myofibroblasts that cause fibrosis and restricted eye movement in the chronic phase.

A co-receptor pathway involving insulin-like growth factor 1 receptor (IGF-1R) amplifies this signalling, and is the target of newer biologic therapies.

Key risk factors for developing or worsening TED:

Risk factor	Effect
Smoking	7–8× increased risk of clinically significant TED; reduces treatment response
Radioactive iodine (RAI)	May transiently worsen TED in predisposed individuals
High TRAb levels	Correlates with disease activity and severity
Poorly controlled thyroid function	Both hypo- and hyperthyroidism worsen orbital inflammation
Male sex	Associated with more severe disease despite lower overall prevalence

Symptoms and diagnosis

TED follows a biphasic course: an active inflammatory phase lasting 6 months to 2 years, followed by a stable inactive phase. Structural damage that accumulates during the active phase may not resolve spontaneously.

Active phase: eyelid redness and swelling, gritty or irritated eyes, photophobia, excessive tearing or dry eye, periorbital puffiness on waking, and a pressure or aching sensation behind the eyes.

Progressive disease: proptosis (exophthalmos) — forward protrusion giving a wide-eyed appearance — eyelid retraction, double vision (diplopia) from restricted extraocular muscles, and incomplete eyelid closure that risks corneal damage.

Sight-threatening TED: optic nerve compression causing colour vision changes or visual acuity loss. This is a medical emergency.

Diagnosis combines clinical examination (Hertel exophthalmometry for proptosis measurement, eyelid position, eye movement, visual acuity), TRAb serology, thyroid function panel (TSH, free T3, free T4), and CT or MRI of the orbits to assess muscle enlargement and optic nerve compression. The Clinical Activity Score (CAS) is a validated tool used to determine whether TED is in the active inflammatory phase and therefore likely to respond to immunosuppressive treatment. In Canada, orbital imaging and TRAb testing are available through most tertiary centres; LifeLabs and Dynacare both process TRAb panels on referral.

Treatment options

Treatment is matched to disease phase and severity.

For all patients:

• Smoking cessation — the single most impactful modifiable action.
• Maintaining euthyroidism (normal thyroid hormone levels).
• Selenium supplementation (200 mcg/day) for mild active TED: a randomized trial showed it slows progression compared with placebo.
• Lubricating eye drops and eyelid taping at night to protect the cornea.

Moderate to severe active TED:

• Intravenous methylprednisolone (pulsed high-dose steroids) is the standard first-line treatment per the 2021 European Thyroid Association/EUGOGO guidelines.
• Teprotumumab (Tepezza) — a monoclonal antibody targeting IGF-1R — demonstrated reductions in proptosis of 2–3 mm or more in the majority of patients in phase 3 trials and is approved in the United States. As of 2024, it is not approved by Health Canada, meaning Canadian patients face access barriers; some pursue cross-border or compassionate-access pathways.
• Mycophenolate mofetil is used as a steroid-sparing agent.
• Orbital radiotherapy is used adjunctively for moderate to severe disease.

Inactive or rehabilitative phase: Orbital decompression surgery reduces orbital volume to correct proptosis and relieve optic nerve compression. Strabismus surgery corrects persistent diplopia. Eyelid surgery addresses retraction and incomplete closure. These procedures are typically performed in sequence, in that order, once the active phase has resolved.

When to see a clinician in Canada

Any person with a new Graves' disease diagnosis should receive a baseline ophthalmological assessment, even without eye symptoms. See an ophthalmologist promptly if you notice eye protrusion, double vision, eye pain or pressure, significant redness or swelling, or difficulty closing your eyes fully.

Go to an emergency department immediately if you experience sudden vision loss or a change in colour vision — these may signal optic nerve compression requiring urgent decompression.

In Canada, TED is typically co-managed by an endocrinologist and an ophthalmologist with orbital subspecialty training. Referral pathways vary by province; patients in rural areas may face longer wait times and should ask their GP for an urgent ophthalmology referral at the time of Graves' diagnosis rather than waiting for eye symptoms to develop.

Limitations and open questions

Research is still emerging on the optimal sequencing of thyroid treatments (antithyroid drugs vs. RAI vs. thyroidectomy) in patients at high risk for TED. The evidence that RAI worsens TED is real but not universal — risk appears concentrated in patients with high TRAb levels and active smoking, and prophylactic steroids can mitigate it. Health Canada has not yet approved teprotumumab, leaving a meaningful gap between Canadian and U.S. access to the most effective biologic therapy for active TED. The long-term recurrence rate after teprotumumab treatment and the optimal retreatment strategy are not yet well defined. It is also not fully understood why TED sometimes occurs in people with normal thyroid function or with Hashimoto's thyroiditis rather than Graves' disease, though TRAb positivity appears to be the common thread.