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

 Icon representing IGF-1R

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
 Icon representing Thyroid Eye Disease as an autoimmune disease

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

 Icon representing Thyroid Eye Disease flare up

Watch the pathophysiology of Thyroid Eye Disease

Chapter 1: Pathophysiology of Thyroid Eye Disease (TED)

Thyroid Eye Disease, or TED, is a serious, progressive, and vision-threatening autoimmune disease. Emerging research demonstrates that the orbital fibroblast, a specialized cell responsible for tissue repair, is central to the pathophysiology of TED.1-4

Pathogenic orbital fibroblasts are believed to recruit fibrocytes and lymphocytes that infiltrate the orbit.4,5

Fibrocytes differentiate into orbital fibroblasts, which enhance T-cell proliferation and activation.2,4,6

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.4,7

Two co-localized receptors reside on the surface of orbital fibroblasts: TSHR and IGF-1R, a gatekeeper of orbital fibroblast activation.2,4,8-10

Autoantibodies activate TSHR and IGF-1R, and cross talk mediated by beta-arrestin creates a receptor-signaling complex that stimulates orbital fibroblasts.4,11

Chapter 2: Inflammatory Cascade and Potential Consequences of TED

Once activated, orbital fibroblasts proliferate and produce inflammatory cytokines and hydrophilic hyaluronan, which enlarges orbital tissue volume.1,4

Activated orbital fibroblasts differentiate into adipocytes and myofibroblasts, which contribute, respectively, to adipogenesis and fibrosis of the orbital tissues.4,12

The ensuing tissue expansion and remodeling leads to crowding in the fixed bony orbit, and this may have long-term sequelae.4

Damage can include:

  • Proptosis
  • Strabismus
  • Corneal ulceration
  • Optic nerve compression
  • And vision impairment, such as diplopia, optic neuropathy, or even blindness.13-15

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.4,10,16

REFERENCES:

  1. Bahn RS. Graves’ ophthalmopathy. N Engl J Med. 2010;362(8):726-738.
  2. Shan SJ, Douglas RS. The pathophysiology of thyroid eye disease. J Neuroophthalmol. 2014;34(2):177-185.
  3. Weiler DL. Thyroid eye disease: a review. Clin Exp Optom. 2017;100(1):20-25.
  4. 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.
  5. Tsui S, Naik V, Hoa N, et al. Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves’ disease. J Immunol. 2008;181(6):4397-4405.
  6. Chesney J, Bacher M, Bender A, Bucala R. The peripheral blood fibrocyte is a potent antigen-presenting cell capable of priming naive T cells in situ. Proc Natl Acad Sci U S A. 1997;94(12):6307-6312.
  7. Virakul S, van Steensel L, Dalm VA, Paridaens D, van Hagen PM, Dik WA. Platelet-derived growth factor: a key factor in the pathogenesis of Graves’ ophthalmopathy and potential target for treatment. Eur Thyroid J. 2014;3(4):217-226.
  8. Smith TJ. Rationale for therapeutic targeting insulin-like growth factor-1 receptor and bone marrow-derived fibrocytes in thyroid-associated ophthalmopathy. Expert Rev Ophthalmol. 2016;11(2):77-79.
  9. Gupta S, Douglas R. The pathophysiology of thyroid eye disease (TED): implications for immunotherapy. Curr Opin Ophthalmol. 2011;22(5):385-390.
  10. Mohyi M, Smith TJ. IGF1 receptor and thyroid-associated ophthalmopathy. J Mol Endocrinol. 2018;61(1):T29-T43.
  11. 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.
  12. Li H, Yuan Y, Zhang Y, Zhang X, Gao L, Xu R. Icariin inhibits AMPK-dependent autophagy and adipogenesis in adipocytes in vitro and in a model of Graves’ orbitopathy in vivo. Front Physiol. 2017;8.
  13. Bruscolini A, Sacchetti M, La Cava M, et al. Quality of life and neuropsychiatric disorders in patients with Graves’ orbitopathy: current concepts. Autoimmun Rev. 2018;17(7):639-643.
  14. Mamoojee Y, Pearce SHS. Natural history. In: Wiersinga WM, Kahaly GJ, eds. Graves’ Orbitopathy: A Multidisciplinary Approach—Questions and Answers. 3rd ed. Basel, Switzerland: Karger; 2017:93-104.
  15. McAlinden C. An overview of thyroid disease. Eye Vis (Lond). 2014;1:9.
  16. Strianese D, Rossi F. Interruption of autoimmunity for thyroid eye disease: B-cell and T-cell strategy. Eye (Lond). 2019;33(2):191-199.
Icon representing IGF-1R targeting

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 MUSCLE SWELLING IN ORBITAL MRI10

Normal MRI13

MRI scan of patient without Thyroid Eye Disease

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

Moderate 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

Severe Thyroid Eye Disease MRI

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
Icon representing the role of orbital fibroblasts in Thyroid Eye Disease pathogenesis

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

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

  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 on July 24, 2023. https://eyerounds.org/tutorials/thyroid-eye-disease/index.htm
  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
  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.

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