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What Causes TED (Pathogenesis)?

What Causes TED (Pathogenesis)?

The pathologic hallmark of TED is a lymphocytic infiltration of orbital muscle and fat with expansion of these tissues from edema and deposition of hyaluronic acid and other glycosaminoglycans. 

TED often occurs in conjunction with autoimmune thyroid diseases such as Graves’ disease (90%) or Hashimoto thyroiditis (3%); 90% of orbitopathy patients have current or previous abnormal systemic thyroid hormone levels, whereas others may develop abnormal levels in the future. It is important for patients to understand that orbitopathy is associated with, but not caused by, abnormal thyroid hormone levels; it is a common misconception that the orbital disease should resolve once normal thyroid levels are reached.In Graves’ disease, an aberrant population of lymphocytes produce thyrotropin-receptor antibodies (TRAB), also known as thyroid-stimulating hormone receptor (TSH-R) antibodies. Differing subtypes may cause more, less, or unchanged levels of serum thyroxine.Similar receptor sites on skin and orbital fat and muscle fibrocytes also may be targeted by these autoantibodies in Graves’ disease, resulting in orbitopathy in 50% and dermopathy (pretibial myxedema or acropachy) in 5%–10%.

Orbital fibrocytes showing binding of TSH-R Ab to surface receptors

The target cell in TED is the CD 34+ pluripotential orbital fibrocyte, present in orbital fat, striated muscle and lacrimal gland. These cells have increased Thyrotropin receptors (TSH-R) and insulin-like growth factor receptors (IGFR-1) in close apposition on their surface.  Click on figure RIGHT to enlarge. Binding of circulating TRAB to these fibrocyte receptors may cause cross-talk which induces adipogenesis and hyaluronic acid production, resulting in expansion and remodeling of orbital tissues. The process is enhanced by activation of T-helper cells with the release of cytokines (including IL-16) that potentiates the inflammatory cascade.

TED Severity and Activity