Introduction
Thyroid Eye Disease(TED) is also known as thyroid-associated ophthalmopathy or Graves’ orbitopathy, is an autoimmune condition that primarily affects the eyes. It is commonly associated with hyperthyroidism, particularly Grave’s disease. However, TED can show up in people with normal (euthyroid) or low (hypothyroid) thyroid levels too. This makes figuring out and treating the issue more challenging.1
Pathophysiology of TED
TED is characterised by immune-mediated inflammation, leading to changes in orbital and periocular tissues. The primary target is the fibroblasts within the orbital tissue, which express thyroid-stimulating hormone receptors (TSHR). The key mechanisms in TED include:
Autoimmune Activation: Autoantibodies, particularly thyroid-stimulating immunoglobulins(TSIs), attack TSHR-expressing orbital fibroblasts, triggering an inflammatory cascade.
Orbital Tissue Expansion: Inflammatory cell infiltration leads to fibroblast proliferation and differentiation into adipocytes or myofibroblasts, resulting in tissue expansion and fibrosis
Glycosaminoglycan Accumulation: The accumulation of glycosaminoglycans increases tissue osmotic pressure, causing water retention and oedema in the orbital structure.
Muscle involvement: Extraocular muscles become enlarged due to inflammation and fibrosis, restricting eye movement and leading to diplopia.2
TED in euthyroid patients
TED in euthyroid patients is an uncommon but well-documented phenomenon. In these cases, patients exhibit orbital symptoms without overt thyroid dysfunction.
Isolated Orbital Autoimmune Activity: The immune attack may be confined to orbital fibroblasts without significant involvement of the thyroid gland
Subclinical or Fluctuating Thyroid Dysfunction: Euthyroid patients may have subtle thyroid abnormalities that do not yet manifest in routine lab tests.
Genetic and Environmental Factors: A genetic predisposition to autoimmune disorder,along with environmental triggers such as smoking, stress, or infections, may contribute to TED in euthyroid individuals.3
Diagnostic challenges
TED in euthyroid patients can be difficult to diagnose due to the absence of typical thyroid abnormalities. Diagnosis relies on:
Clinical Features: Proptosis, eyelid retraction, conjunctival redness, and orbital pain
Imaging: Orbital CT or MRI can help confirm extraocular muscle enlargement and orbital inflammation
Antibody Testing: Measurement of thyroid-related antibodies (TSI, TPO antibodies) may indicate an underlying immune dysfunction despite normal thyroid hormone levels.4
TED in hypothyroid patients
Hypothyroidism, particularly due to Hashimoto’s thyroiditis, has also been linked to TED. Unlike Graves’ disease, where excess thyroid hormone is present, hypothyroid TED patients experience orbital changes without hyperthyroidism.1
Pathogenic mechanisms
Shared Autoimmune Process: Hashimoto’s thyroiditis and TED share common autoimmune pathways, leading to concurrent orbital involvement.
TSHR and TPO Antibodies: Even in hypothyroid patients, autoantibodies against TSHR or thyroid peroxidase (TPO) may still stimulate orbital fibroblasts.
Delayed Diagnosis: Many hypothyroid patients may develop TED later, often after thyroid dysfunction has been managed, making it an overlooked complication.2
Clinical features
TED in hypothyroid patients generally presents with less severe inflammatory signs but can still result in:
Proptosis and Eyelid Retraction: Due to fibroblast proliferation and tissue expansion.
Dry Eye Symptoms: Increased corneal exposure and reduced tear production.
Diplopia and Strabismus: Due to fibrosis affecting the extraocular muscles.3
Diagnostic approaches
A structured approach is required to diagnose TED in euthyroid and hypothyroid patients, as conventional thyroid tests may not be conclusive.
Clinical assessment
History: Symptoms such as eye discomfort, redness, swelling, and double vision.
Physical Examination: Assessment of proptosis, eyelid changes, and eye movement restriction.4
Imaging studies
CT Scan: Helps assess extraocular muscle thickening and orbital fat expansion.
MRI: More sensitive in detecting early inflammatory changes in orbital tissues.4
Laboratory testing
Thyroid Function Tests (TSH, T3, T4): Essential to rule out hyperthyroidism or hypothyroidism.
Autoantibody Testing (TSI, TPO, TRAb): Important in identifying autoimmune thyroid disease in euthyroid cases.5
Management and treatment
TED treatment in euthyroid and hypothyroid patients follows similar principles to conventional TED management but requires individualised approaches.
Conservative treatment
Lubricating Eye Drops: To alleviate dry eyes and irritation.
Smoking Cessation: Smoking significantly worsens TED severity and should be stopped.5
Selenium Supplementation: May help mild TED cases by reducing oxidative stress in orbital tissues.
Medical therapy
Corticosteroids: Used for active, moderate-to-severe TED to reduce inflammation.
Immunosuppressants (Methotrexate, Mycophenolate Mofetil): Beneficial in refractory cases.
Teprotumumab: A newer targeted therapy that inhibits insulin-like growth factor 1 receptor (IGF-1R) in orbital fibroblasts.6
Surgical management
Orbital Decompression Surgery: Performed in severe cases with optic nerve compression or significant proptosis.
Strabismus Surgery: Corrects double vision caused by extraocular muscle fibrosis.
Eyelid Surgery: Addresses eyelid retraction and exposure keratopathy.5
FAQs
What are the symptoms of TED?
Symptoms include eyelid retraction, bulging eyes (exophthalmos), double vision, eye pain, and sensitivity to light.
How is TED diagnosed?
Diagnosis is based on clinical examination, laboratory tests (e.g., thyroid hormone levels, autoantibodies), and imaging studies (e.g., CT, MRI).
What are the treatment options for TED?
Treatment depends on the severity of the disease and may include medications (e.g., corticosteroids, teprotumumab), orbital radiation, and surgery (e.g., orbital decompression, strabismus surgery).
Summary
Thyroid Eye Disease (TED) is a rare autoimmune disorder that affects the orbital tissues, including the eyelids, eye socket, and lacrimal gland. While it's commonly associated with hyperthyroidism, TED can also occur in euthyroid and hypothyroid patients, making these cases atypical.
Atypical Cases:
Euthyroid TED: Patients with normal thyroid hormone levels can still develop TED, making diagnosis and treatment more challenging.
Hypothyroid TED: TED can occur in patients with hypothyroidism, which may require different treatment approaches.
Key points:
TED is a rare autoimmune disorder that affects the orbital tissues.
Atypical cases include euthyroid and hypothyroid patients.
Diagnosis is based on clinical examination, laboratory tests, and imaging studies.
Treatment options depend on the severity of the disease and may include medications, orbital radiation, and surgery.
References
- Davies TF, Andersen S, Latif R, Nagayama Y, Barbesino G, Brito M, et al. Graves’ disease. Nat Rev Dis Primers [Internet]. 2020 [cited 2025 Mar 28]; 6(1):52. Available from: https://www.nature.com/articles/s41572-020-0184-y.
- Stan MN, Bahn RS. Risk Factors for Development or Deterioration of Graves’ Ophthalmopathy. Thyroid [Internet]. 2010 [cited 2025 Mar 28]; 20(7):777–83. Available from: https://www.liebertpub.com/doi/10.1089/thy.2010.1634.
- Smith TJ, Kahaly GJ, Ezra DG, Fleming JC, Dailey RA, Tang RA, et al. Teprotumumab for Thyroid-Associated Ophthalmopathy. N Engl J Med [Internet]. 2017 [cited 2025 Mar 28]; 376(18):1748–61. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1614949.
- Taylor PN, Zhang L, Lee RWJ, Muller I, Ezra DG, Dayan CM, et al. New insights into the pathogenesis and nonsurgical management of Graves orbitopathy. Nat Rev Endocrinol [Internet]. 2020 [cited 2025 Mar 28]; 16(2):104–16. Available from: https://www.nature.com/articles/s41574-019-0305-4.
- Bahn RS. Graves’ Ophthalmopathy. N Engl J Med [Internet]. 2010 [cited 2025 Mar 28]; 362(8):726–38. Available from: http://www.nejm.org/doi/abs/10.1056/NEJMra0905750.
- Esser J. W.M. Wiersinga, G.J. Kahaly (eds): Graves’ Orbitopathy: A Multidisciplinary Approach. Graefes Arch Clin Exp Ophthalmol [Internet]. 2009 [cited 2025 Mar 28]; 247(12):1725–1725. Available from: https://doi.org/10.1007/s00417-009-1047-0
