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Pathogenesis of Thyroid Eye Disease

Katherine Davis, MD; and Alon Kahana, MD, PhD

Reviewed by Edward J. Wladis, MD, FACS on March 24, 2020

Introduction

    • In 1835, Robert Graves described six pregnant women with diffuse goiter and hyperthyroidism. (Graves, 1835)

      • The initial description did not suggest autoimmune disease.
    • In 1956, Adams and Purves reported that sera of Graves’ patients contain a thyroid stimulating factor with duration of action longer than thyroid stimulating hormone (TSH), termed “long-acting thyroid stimulator” (LATS). (Adams, 1956)
    • In 1964, LATS was found to be an IgG (Meek, 1964)
      • IgA and IgE LATS antibodies have also been observed. (Metcalfe, 2002)
    • In 1966, the TSH receptor was found to be the binding site on thyrocytes for LATS and TSH (Pastan, 1966).
    • Autoimmune thyroid disease (AITD) is one of the most common autoimmune diseases.
      • Affects 5% of the general population
      • Strong predilection for women.
      • Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) both arise from autoreactive lymphocytic attacking thyroid tissue
      • Hyperthyroidism and GD, caused by activation of the thyroid stimulating hormone receptor (TSHR) by autologous thyroid receptor antibodies
      • Hypothryoidism and HT, caused by lymphocytic infiltration and destruction of thyroid tissue.
    • Many patients with AITD suffer extrathyroidal manifestations, such as thyroid eye disease (TED)
      • TED is the most common orbital disease worldwide, with an annual incidence of 14/100,000 in females and approximately one-fifth that in males.
      • The pathogenic mechanism of TED is not fully understood
      • Auto-antigens and paracrine signals play important roles in the process.

Genetic Predisposition

  • 33% of siblings of patients with GD or HT develop AITD (Hall, 1967)
  • Twin concordance studies are positive in as many as 80% of AITD cases (BRIX, 2001)

Orbital Inflammation

  • The primary orbital antigen for autoreactive T cells in early TED is the TSHR
    • TSHR is expressed on orbital connective and adipose tissue (Heufelder, 1995).
    • Support for the presence of extrathyroidal TSHR expression derives from animal studies that describe the binding of thyroid-stimulating hormone (TSH) to guinea pig adipose and retro-orbital tissues (Roselli, 1992).
    • TSHR expression in humans is higher in orbital muscle and adipose tissue from GO patients compared to normal orbital tissue (Bahn, 1998).
  • Orbital fibroblasts from TED patients with active disease have a higher cell surface expression of the TSH receptor than patients with quiescent disease (Gerding, 2000)
  • Orbital tissue from patients with active GO has an abundance of proinflammatory cytokines, such as interleukin 1ß (IL-1ß), interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα) (Smith, 2002).
  • Autoreactive T cells are recruited to the orbit by cytokines and adhesion molecules, expressed on the surface of orbital connective tissue (Heufelder, 1997).
  • Diffuse infiltration of mononuclear cells (primarily T cells with occasional B cells) can be seen in the orbital connective tissue and extraocular muscle of patients with GO [35, 36].
  • The T cells initiate an inflammatory cascade, producing additional cytokines, fibrogenic growth factors, and free radicals.
  • Chronic inflammation leads to glycosaminoglycan synthesis, fibroblast proliferation, tissue fibrosis and increased adipogenesis.
  • Fibrosis within muscle sheaths leads to restrictive myopathy and eyelid retraction

Orbital Fibroblasts

  • Orbital fibroblasts appear to play a central role in TED pathogenesis, (Virakul, 2016)
  • Unlike fibroblasts from other tissue types, orbital fibroblasts seem to have the ability to differentiate into mature adipocytes (Sorisky, 1996).
  • Valyasevi (1999) found that late-passage GO preadipocyte fibroblasts, unlike control cultures of the immature fibroblasts, differentiated into mature adipocytes.
  • Mature fibroblasts are also involved in the inflammatory response of TED.
    • CD40 ligation with T cells activates orbital fibroblasts, inducing glycosaminoglycan synthesis and the production of inflammatory cytokines like interleukin 6 (IL-6) and interleukin 8 (IL-8) (Sepmpowski, 1998).
  • It has been proposed that there are two subpopulations of orbital fibroblasts: (1) Thy-1-positive (CD90) fibroblasts are responsible for the production of hyaluronan, a glycosaminoglycan capable of absorbing high amounts of water, while (2) Thy-1-negative fibroblasts are those that differentiate into adipose tissue with proper stimulation (Koumas, 2003).

Circulating Fibroblasts

  • Bone marrow-derived circulating fibrocytes are activated by a combination of autoantibodies against TSHR and IGF1 receptor (IGF1R) to trigger their migration to the orbit (Douglas, 2010).
  • These activated circulating fibroblasts interact with resident orbital fibroblasts to propagate the inflammatory process and fibrosis (Gillespie, 2012).

Mast Cells

  • Mast cells are derived from mononuclear cell precursors in the bone marrow and undergo terminal differentiation at destination tissues (Dawicki, 2007).
    • They have FcεRI receptors on their cell surface that mediate allergic reactions.
    • Surface receptors for IgG and complement play a role in non-allergic inflammation
    • Binding immunoglobulin leads to degranulation and release of preformed mediators notably histamine and serotonin.
  • Degranulated mast cells are more common in TED orbital tissue than controls (Berenbom, 2008).
  • Cockerham (2002) found a predominance of mast cells on histopathology in Mullerectomy specimens of TED associated lid retraction.
  • Lauer (2008) demonstrated diffuse mast cell infiltration with degranulation in a case of acute thyroid orbitopathy.
  • The hallmarks of acute TED are itching and edema, more than pain and erythema, consistent with mast cell mediated more than lymphocyte mediated inflammation.
  • The large secretory granules of mast cells contain proteases, small molecule biogenic amines and cytokines packed within glycosaminoglycan.
  • The accumulation of glycosaminoglycan in the orbit may, therefore, represent the residua of chronic mast cell degranulation, rather than the end produce of lymphocyte and fibroblast mediated inflammation.   

Conclusion

  • The working hypothesis developed in this outline, autoimmunity leading to inflammation, causing tissue expansion and fibrosis helps explain most of the periocular process in TED.
  • Much of the clinical picture is incompletely explained:
    • Predilection for the medial and inferior rectus muscles
    • Expansion of extraocular muscles with sparing of tendon insertion.
    • Lid retraction rather than ptosis, from inflammation and fibrosis in the upper lid.   
    • Unilateral or markedly asymmetric disease.
  • Alternative hypotheses on the pathogenesis of TED, should explain why the immune system, which is primarily tasked with protecting the body from invasion, would stimulate the thyroid or induce the complex manifestations of TED. 
  • Thyroid autoantibodies may be a secondary moderator of thyroid function and metabolic activity
    • Graves disease may represent a pathophysiologic exaggeration of this secondary homeostatic system. 

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