Elevated serum tetrac in Graves’ disease: potential pathogenic role in thyroid-associated ophthalmopathy

Context: The sources and biological impact of 3,3’,5,5’ tetraiodothyroacetic acid (TA4) are uncertain. CD34+ fibrocytes express several proteins involved in the production of thyroid hormones. They infiltrate the orbit in Graves’ disease (GD), an autoimmune process known as thyroid-associated ophthalmopathy. It appears that the thyrotropin receptor (TSHR) plays an important role in the pathogenesis of TAO. Objective: To quantify levels of TA4 in healthy subjects and those with Graves’ disease. To determine whether fibrocytes generate this TH analogue. To determine whether TA4 influences the actions of TSH and thyroid-stimulating immunoglobulins in orbital fibroblasts. Design/Setting/Participants: Patients with GD and healthy donors in an academic medical center clinical practice were recruited. Main outcome measures: liquid chromatography-tandem mass spectrometry, autoradiography, real-time PCR, hyaluronan immunoassay Results: Serum levels of TA4 are elevated in GD. TA4 levels are positively correlated with those of thyroxine and negatively correlated with serum levels of triiodothyronine. Several cell types in culture generate TA4 from ambient thyroxine, including fibrocytes, HELA cells, human Muller stem cells, and retinal pigmented epithelial cells. Propylthiouracil inhibited TA4 generation. TA4 enhances the induction by thyrotropin and thyroid-stimulating immunoglobulins of several participants in the pathogenesis of TAO, including IL-6, hyaluronan synthase-1, prostaglandin endoperoxide H synthase-2, and haluronan production. Conclusion: TA4 may be ubiquitously generated in many tissues and enhances the biological impact of thyrotropin and thyroid-stimulating immunoglobulins in orbital connective tissue. These findings may identify a physiologically important determinant of extra-thyroidal TSH action.