Graves' Ophthalmopathy in the Absence of Elevated Free Thyroxine and Triiodothyronine Levels: Prevalence, Natural History, and Thyrotropin Receptor Antibody Levels

Abstract

The aims of this study were to (a) determine the prevalence of patients without elevated thyroid hormone levels in Graves' ophthalmopathy (GO) using current generation free thyroid hormone assays, (b) measure the prevalence of thyrotropin receptor antibodies (TRAb) in these cases, and (c) identify possible predictors of hyperthyroidism. Over a 30-month period, 1020 cases of thyroid eye disease were evaluated, of which only 19 (1.9%) met the diagnostic criteria. Ten (1%) had subclinical thyrotoxicosis, 7 (0.7%) were euthyroid, and 2 (0.2%) were hypothyroid as determined by a third-generation thyrotropin (TSH) assay. TRAb levels were measured in 16 of these 19 patients. The prevalence of TRAb varied according to the assay used. Polyethylene glycol-extracted thyroid-stimulating immunoglobulin (PEG-TSI), unfractionated thyroid-stimulating immunoglobulin (uTSI), first-generation porcine TSH-binding inhibitory immunoglobulin (pTBII), and second-generation human TSH-binding inhibitory immunoglobulin (hTBII) assays were positive in 93.8%, 50%, 18.8%, and 81.3% of patients, respectively. TRAb was detected by at least one method in all patients. Patients were followed up for 15 to 45 months. Hyperthyroidism developed in 4 patients (25%). Suppressed TSH levels and elevated TBII were predictors of hyperthyroidism. When sensitive assays are used, the prevalence of GO patients without elevated thyroid hormone levels is extremely low. The sensitivities of assays for TRAb detection differ substantially in these cases. PEG extraction improves the detection rate of TSI (p = 0.02), and hTBII assays improve the detection of TBII in these patients (p = 0.002). The high prevalence of TRAb in such cases supports a role for these antibodies in the pathogenesis of thyroid-associated eye disease.

Clinical features of thyroid-associated ophthalmopathy in clinically euthyroid Korean patients

“…As TAO occurs in a close temporal relationship with hyperthyroidism, 5 it is reasonable that TAO is rare in patients with normal or hypothyroid function. Khoo et al,6 in studies conducted in Singapore using 1020 Asian patients with GO, reported that the prevalence of euthyroid TAO was 0.7% and hypothyroid TAO was 0.2%. Thus, euthyroid TAO is rarely encountered in a clinical situation, making it difficult to diagnose.…”

“…[7][8][9] Because most cases involving euthyroid TAO showed no thyroid abnormalities except testing positive for thyroidstimulating hormone receptor antibodies (TRAbs), 7,9 the clinical significance of TRAb as a criterion in the diagnosis of euthyroid TAO has been suggested. 3,6 Recently, Eckstein et al 10 reported that the TRAb titer was low in euthryoid and hypothyroid patients, suggesting that a more sensitive assay technique was necessary to utilize the TRAb assay for diagnosis of euthyroid/hypothyroid TAO. The TRAb assay used in this report was the thyrotropin-binding inhibitor immunoglobulin (TBII) assay, which cannot discriminate between thyroid-blocking immunoglobulin and thyroidstimulating immunoglobulin (TSI).…”

Oftalmopatía distiroidea asociada a hipotiroidismo

“…En un estudio realizado en Singapur sobre más de 1000 pacientes con este tipo de oftalmopatía se comprobó que sólo un 1,9% no eran hipertiroideos, y de ellos sólo un 0,2% eran hipotiroideos (2). Se han publicado casos aislados de esta variante de la EG, en ocasiones con formas de oftalmopatía severa, con hipotiroidismos muy marcados y con títulos muy altos de Ac anti-TSHr (5).…”

“…Las formas clínica-mente evidentes, que cursarían con exoftalmos, quemosis, edemas palpebrales u oftalmoplejia, se presentan en un 10-20% de los pacientes con EG, aunque las formas sutiles, demostrables en una tomografía axial computarizada por ejemplo, son mucho más prevalentes (1). De modo infrecuente esta oftalmopatía puede aparecer en ausencia de hipertiroidismo, bien asociada a normofunción tiroidea o -excepcionalmente-a hipofunción (2). Presentamos un caso de EG con hipotiroidismo y exoftalmos.…”

Orbitopatía de Graves en pediatría

“…Se asocia a hipertiroidismo autoinmune en 80-90% de los casos, 3-4% de los casos se presenta en pacientes con tiroiditis de Hashimoto y 5-10% en pacientes eutiroideos 4 . El 80% de los casos de OG se presenta dentro de los primeros 18 meses desde que se diagnostica la enfermedad tiroidea, sin embargo, se puede desarrollar antes o después de la aparición del hipertiroidismo 5 .…”