Clinical relevance of thyroid-stimulating immunoglobulins in graves' ophthalmopathy

Ophthalmology. 2011 Nov;118(11):2279-85. doi: 10.1016/j.ophtha.2011.03.030.


Purpose: Thyroid-stimulating immunoglobulins (TSIs) likely mediate Graves' ophthalmopathy (GO). The clinical relevance of these functional autoantibodies was assessed in GO.

Design: Cross-sectional trial.

Participants: A total of 108 untreated patients with GO.

Methods: Thyroid-stimulating immunoglobulins, assessed with a novel bioassay, bind to the thyrotropin receptor (TSHR) and transmit signals for cyclic adenosine monophosphate (cAMP)-dependent activation of luciferase gene expression. The cAMP/cAMP response element-binding protein/cAMP-regulatory element complex induces luciferase that is quantified after cell lysis. The TSI levels were correlated with activity and severity of GO and compared with a TSHR binding inhibitory immunoglobulin (TBII) assay.

Main outcome measures: Thyroid-stimulating immunoglobulins, activity and severity of GO, diplopia, and TBII.

Results: Thyroid-stimulating immunoglobulins were detected in 106 of 108 patients (98%) with GO. All 53 hyperthyroid patients were TSI positive versus 47 patients (89%) who were TBII positive. All 69 patients with active GO were TSI positive, whereas only 58 of 69 patients (84%) were TBII positive. Thyroid-stimulating immunoglobulins correlated with the activity (r=0.83, P < 0.001) and severity (r=0.81, P < 0.001) of GO. All 59 patients with GO with diplopia were TSI positive, and 50 of 59 patients (85%) were TBII positive. Among patients with moderate-to-severe and mild GO, 75 of 75 (100%) and 31 of 33 (94%) were TSI positive compared with TBII positivity in 63 of 75 (84%) and 24 of 33 (73%), respectively. The TSI levels were higher in moderate-to-severe versus mild GO (489%±137% vs. 251%±100%, P < 0.001). Chemosis and GO activity predicted TSI levels alone (P < 0.001, multivariable analysis). The TSI levels were higher in patients with chemosis (527%±131%) than in patients without chemosis (313%±127%, P < 0.001).

Conclusions: Thyroid-stimulating immunoglobulins show more significant association with clinical features of GO than TBII and may be regarded as functional biomarkers for GO.

Financial disclosure(s): Proprietary or commercial disclosure may be found after the references.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Biological Assay
  • Biomarkers / blood
  • Cross-Sectional Studies
  • Diplopia / blood
  • Diplopia / physiopathology
  • Female
  • Graves Ophthalmopathy / immunology*
  • Graves Ophthalmopathy / physiopathology
  • Humans
  • Immunoglobulins, Thyroid-Stimulating / blood*
  • Male
  • Middle Aged
  • Prevalence
  • Sensitivity and Specificity
  • Severity of Illness Index
  • Young Adult


  • Biomarkers
  • Immunoglobulins, Thyroid-Stimulating
  • thyrotropin-binding inhibitory immunoglobulin