For US healthcare professionals

Helpful Links

MOD Video TED Patient Burden TED ID Tool

ATTENTION

You are now leaving this educational content and going to a page with information about an FDA-approved treatment for TED.

DISCOVER THE PATHOPHYSIOLOGY OF THYROID EYE DISEASE (TED)

TED is a lifelong, progressive, debilitating autoimmune disease distinct from Graves’ disease

IGF-1R activation on orbital fibroblasts is a cause of the progression1

IGF-1R ACTIVATION ON ORBITAL FIBROBLASTS
CAUSES INFLAMMATION AND EXPANSION OF MUSCLE AND FAT TISSUE BEHIND THE EYE

that can result in a wide range of visible and nonvisible signs and symptoms and significantly impact a patient’s daily activities and quality of life1-4

igf-1r-icon

THE UNDERSTANDING OF TED HAS EVOLVED1,5

  • It was once thought that TED could only be treated non-surgically when the disease was considered "active" or "acute"—the only time it impacts patients’ quality of life

  • We now know that, as an autoimmune disease, TED has a negative impact on patients’ lives throughout the course of the disease and thus can be treated non-surgically at any point

autoimmune-thyroid-eye-disease-icon

AS WITH OTHER AUTOIMMUNE CONDITIONS, TED PATIENTS CAN EXPERIENCE FLARES, LEADING TO PERIODS OF INCREASED INFLAMMATION AND OTHER DISEASE MANIFESTATIONS6-8

thyroid-eye-disease-flare-up-icon

Watch the pathophysiology of Thyroid Eye Disease

Read transcript

Thyroid eye disease, or TED, is a serious, progressive, and debilitating autoimmune disease.

Emerging research demonstrates that the orbital fibroblast, a specialized cell responsible for tissue repair, is central to the pathophysiology of TED.

Pathogenic orbital fibroblasts are believed to recruit fibrocytes and lymphocytes that infiltrate the orbit.

Fibrocytes differentiate into orbital fibroblasts, which enhance T-cell proliferation and activation.

T-cells and B-cells activate orbital fibroblasts and secrete cytokines, thyroid-stimulating hormone receptor, or TSHR, autoantibodies, and insulin-like growth factor-1 receptor, or IGF-1R, autoantibodies, which contribute to the inflammatory cascade.

Two co-localized receptors reside on the surface of orbital fibroblasts:
TSHR and IGF-1R, a gatekeeper of orbital fibroblast activation.
Autoantibodies activate TSHR and IGF-1R, and cross talk mediated by beta-arrestin creates a receptor-signaling complex that stimulates orbital fibroblasts.

INFLAMMATORY CASCADE AND POTENTIAL CONSEQUENCES OF TED

Once activated, orbital fibroblasts proliferate and produce inflammatory cytokines and hydrophilic hyaluronan, which enlarges orbital tissue volume.

Activated orbital fibroblasts differentiate into adipocytes and myofibroblasts, which contribute, respectively, to adipogenesis and fibrosis of the orbital tissues.

The ensuing tissue expansion and remodeling leads to crowding in the fixed bony orbit, and this may have long-term sequelae.

Damage and Consequences can include: Proptosis, Diplopia, Strabismus, Eyelid retraction, Erythema, Excessive tearing, Chemosis and in rare, extreme cases Corneal ulceration, optic nerve compression, and optic neuropathy, or blindness.

Cross talk between TSHR and IGF-1R, as well as IGF-1R-mediated immune function, may play a critical role in the pathophysiology of TED.

Understanding the cross talk may be vital to addressing this debilitating disease.

TARGETING IGF-1R ACTIVATION MAY HELP
REDUCE INFLAMMATION AND PREVENT MUSCLE AND FAT TISSUE REMODELING, AS WELL AS EXPANSION BEHIND THE EYE.1

MRI imaging reveals damage from TED can often start long before visible signs appear9-11

  • While MRI imaging is not required to diagnose TED, it can provide objective confirmation of the substantial inflammatory changes in and around the orbit and show the involvement of individual muscles9

  • Some TED patients may initially experience nonvisible symptoms like eye pain and blurry vision4,12

71%

IN A STUDY OF PATIENTS DIAGNOSED WITH BOTH TED AND GRAVES’ DISEASE 71% (N=17) OF UNTREATED GRAVES' DISEASE PATIENTS WITH NO VISIBLE SIGNS OF TED SHOWED EXTRAOCULAR MUSCULAR SWELLING IN ORBITAL MRI10

Normal MRI13

patient-without-thyroid-eye-disease-mri patient-without-thyroid-eye-disease-mri

Case courtesy of Mohd Radhwan Bin Abidin,
Radiopaedia.org,  rID: 155793

Coronal T2 fat saturation MRI showing the superior (1), lateral (2), inferior (3), and medial (4) recti muscles and orbital fat (6) are normal in size. The optic nerve (5) appears normal.*

MRI with findings suggestive of moderate TED14

severe-thyroid-eye-disease-mri severe-thyroid-eye-disease-mri

Case courtesy of Qutaiba Jaf'ar Mahmoud,
 Radiopaedia.org,  rID: 167879

Coronal T2 fat saturation MRI showing moderate enlargement and inflammation/edema of the superior (1), lateral (2), inferior (3), and medial (4) recti muscles and orbital fat (6) bilaterally. The optic nerve (5) appears normal.*

MRI with findings suggestive of severe TED15

thyroid-ophthalmopathy-radiology thyroid-ophthalmopathy-radiology

Case courtesy of Roberto Schubert,
Radiopaedia.org,  rID: 13874

Coronal T2 fat saturation MRI showing severe enlargement and inflammation/edema of the superior (1), lateral (2), inferior (3), and medial (4) recti muscles and orbital fat (6) bilaterally. There is also minimal crowding of the left optic nerve (5).*

*The numbers correspond with the numbers in the images above.

TED is often linked to thyroid conditions like Graves’ disease, but has a distinct pathophysiology16,17

  • Up to 90% of TED patients have a thyroid condition18

  • TED has been referred to as Graves’ orbitopathy (GO), Graves’ ophthalmopathy, thyroid-associated orbitopathy (TAO), Graves’ Eye Disease, or thyroid ophthalmopathy3

  • In Graves’ disease, TSHR autoantibodies drive inflammation of the thyroid epithelial cell membranes11; in TED, IGF-1R autoantibodies activate and cause inflammation of the orbital fibroblasts, which can lead to a range of clinical symptoms1-3

  • The connection between TED and other thyroid conditions highlights the importance of screening all patients with a thyroid condition who are experiencing ocular signs and symptoms of TED19

thyroid-eye-disease-pathogenesis-orbital-fibroblast

TREATING ONLY THE THYROID GLAND WON’T TREAT TED1-3,11

Next Page    >    Learn about the signs and symptoms of TED

IGF-1R, insulin-like growth factor-1 receptor; MRI, magnetic resonance imaging; TSHR, thyroid-stimulating hormone receptor; T2, transverse relaxation time.

REFERENCES
  1. Wang Y, Patel A, Douglas RS. Thyroid Eye Disease: how a novel therapy may change the treatment paradigm. Ther Clin Risk Manag. 2019;15:1305-1318.
  2. Patel A, Yang H, Douglas RS. A new era in the treatment of thyroid eye disease. Am J Ophthalmol. 2019;208:281-288.
  3. Bahn RS. Graves’ ophthalmopathy. N Engl J Med. 2010;362(8):726-738.
  4. Cockerham KP, Padnick-Silver L, Stuertz N, Francis-Sedlak L, Holt RJ. Quality of life in patients with chronic Thyroid Eye Disease in the United States. Ophthalmol Ther. 2021;10:975-987.
  5. Ugradar S, et al. Whole genome transcriptome comparison of acute and chronic thyroid eye disease: emergence of a molecular signature. Presented at: American Academy of Ophthalmology; September 30-October 3, 2022; Chicago, IL.
  6. Patel P, Khandji J, Kazim M. Recurrent Thyroid Eye Disease. Ophthalmic Plast Reconstr Surg. 2015 Nov-Dec;31(6):445-8.
  7. Liaboe CA, Clark TJ, Simmons BA, Carter K, Shriver EM. Thyroid Eye Disease: an introductory tutorial and overview of disease. April 23, 2020. Accessed January 24, 2023.
  8. Hahn E, Laperriere N, Millar BA, et al. Orbital radiation therapy for Graves’ ophthalmopathy: measuring clinical efficacy and impact. Pract Radiat Oncol. 2014;4(4):233-239.
  9. Kilicarslan R, Alkan A, Ilhan MM, Yetis H, Aralasmak A, Tasan E. Graves’ ophthalmopathy: the role of diffusion-weighted imaging in detecting involvement of extraocular muscles in early period of disease. Br J Radiol. 2015;88(1047):20140677.
  10. Villadolid MC, Yokoyama N, Isumi M, et al. Untreated Graves’ disease patients without clinical ophthalmopathy demonstrate a high frequency of extraocular muscle (EOM) enlargement by magnetic resonance. J Clin Endocrinol Metab. 1995;80(9):2830-2833.
  11. Smith TJ, Hegedüs L. Graves’ disease. N Engl J Med. 2016;375(16):1552-1665.
  12. Barrio-Barrio J, Sabater AL, Bonet-Farriol E, Velázquez-Villoria Á, Galofré JC. Graves’ ophthalmopathy: VISA versus EUGOGO classification, assessment, and management. J Ophthalmol. 2015;2015:249125.
  13. Abidin MRB. Normal MRI orbits: Radiology case. Radiopaedia. 2022. Accessed July 23, 2024. https://radiopaedia.org/cases/normal-mri-orbits-2
  14. Mahmoud QJ. Thyroid-associated orbitopathy: Radiology case. Radiopaedia. 2023. Accessed July 23, 2024. https://radiopaedia.org/cases/thyroid-associated-orbitopathy-23 Mahmoud Q. Thyroid-associated orbitopathy. Radiopaedia.org. Accessed July 22, 2024. https://doi.org/10.53347/rID-167879
  15. Schubert R. Thyroid associated orbitopathy: Radiology case. Radiopaedia. November 23, 2011. Accessed July 23, 2024. https://radiopaedia.org/cases/thyroid-associated-orbitopathy-6
  16. Krieger CC, Boutin A, Jang D, et al. Arrestin-β-1 Physically Scaffolds TSH and IGF1 Receptors to Enable Crosstalk. Endocrinology. 2019;160(6):1468-1479.
  17. Dik WA, Virakul S, van Steensel L. Current perspectives on the role of orbital fibroblasts in the pathogenesis of Graves' ophthalmopathy. Exp Eye Res. 2016;142:83-91.
  18. Bartley GB. The epidemiologic characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted County, Minnesota. Trans Am Ophthalmol Soc. 1994;92:477-588.
  19. Burch HB, Perros P, Bednarczuk T, et al. Management of Thyroid Eye Disease: a consensus statement by the American Thyroid Association and the European Thyroid Association. Thyroid. 2022;32(12):1-32.

Sign Up

Receive the latest news and updates about Thyroid Eye Disease (TED).