The Pathophysiology of Thyroid Eye Disease

Abstract

The pathophysiology of thyroid eye disease (TED) is complex and incompletely understood. Orbital fibroblasts (OFs) seem to be the key effector cells that are responsible for the characteristic soft tissue enlargement seen in TED. They express potentially pathogenic autoantigens, such as thyrotropin receptor and insulin-like growth factor-1 receptor. An intricate interplay between these autoantigens and the autoantibodies found in Graves disease may lead to the activation of OFs, which then leads to increased hyaluronan production, proinflammatory cytokine synthesis, and enhanced differentiation into either myofibroblasts or adipocytes. Some of the OFs in TED patients seem to be derived from infiltrating fibrocytes. These cells originate from the bone marrow and exhibit both fibroblast and myeloid phenotype. In the TED orbit, they may mediate the orbital expansion and inflammatory infiltration. Last, lymphocytes and cytokines are intimately involved in the initiation, amplification, and maintenance of the autoimmune process in TED.

TSH-Mediated TNFα Production in Human Fibrocytes Is Inhibited by Teprotumumab, an IGF-1R Antagonist

“…A limited understanding of the pathogenesis of GO has hindered the development of disease-modifying therapeutic agents [22, 23]. Uncovering the cellular and molecular mechanisms underlying the pathogenesis of GO would facilitate the development of more efficacious treatment options.…”

“…A subset of patients with GD also develop extrathyroidal manifestations, such as the enlargement of orbital soft tissues as observed in GO. The pathogenesis of GO is incompletely understood [22, 23]. The principal effector cell responsible for the anatomical changes in GO is the orbital fibroblast (OF), which are CD34 positive and analogous to fibrocytes [22, 24, 25].…”

“…The pathogenesis of GO is incompletely understood [22, 23]. The principal effector cell responsible for the anatomical changes in GO is the orbital fibroblast (OF), which are CD34 positive and analogous to fibrocytes [22, 24, 25]. Two autoantigens seem to be critical for the aberrant activation of OFs in GO: TSHR, and the insulin-like growth factor-1 receptor (IGF-1R) [22, 23].…”

“…Once in the orbit, fibrocytes can differentiate into myofibroblasts and adipocytes, synthesize extracellular matrix proteins, and produce cytokines [12]. A proinflammatory cytokine milieu plays a crucial rule in the activation of OFs [22, 33, 34]. …”

Isolated primary amyloidosis of the inferior rectus muscle mimicking Graves’ orbitopathy

“…Its pathophysiology is closely related to that of Graves’ disease. (1) Typical findings in GO include proptosis, eyelid retraction, periorbital edema, chemosis and restrictive ophthalmoplegia that may precede, coincide with, or follow systemic signs of thyroid disease. Upgaze is typically limited initially, since the inferior rectus muscle is the most frequently involved extraocular muscle in GO.…”