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Autoimmune thyroid disease is characterized by the presence of autoantibodies against various thyroid components, namely the thyrotropin receptor (TSHR), thyroid peroxidase (TPO), and thyroglobulin (Tg), as well as by an inflammatory cellular infiltrate of variable severity within the gland.
Among the autoantibodies found in autoimmune thyroid disease, TSHR autoantibodies are most closely associated with disease pathogenesis. All forms of autoimmune thyrotoxicosis (Graves disease, Hashitoxicosis, neonatal thyrotoxicosis) are caused by the production of TSHR-stimulating autoantibodies. These autoantibodies, also known as long-acting-thyroid-stimulator (LATS) or thyroid-stimulating immunoglobulins (TSI), bind to the receptor and transactivate it, leading to stimulation of the thyroid gland independent of the normal feedback-regulated thyrotropin (TSH) stimulation.
Some patients with Graves disease also have TSHR-blocking antibodies, which do not transactivate the TSHR. The balance between TSI and TSHR-blocking antibodies, as well as their individual titers, are felt to be determinants of Graves disease severity. Some patients with autoimmune hypothyroidism also have evidence of either TSHR-blocking antibodies or, rarely, TSI.
TSHR autoantibodies may be detected before autoimmune thyrotoxicosis becomes biochemically or clinically manifest. Since none of the treatments for Graves disease are aimed at the underlying disease process, but rather ablate thyroid tissue or block thyroid hormone synthesis, TSI may persist after apparent clinical cure. This is of particular relevance for pregnant women with a history of Graves disease that was treated with thyroid-ablative therapy. Some of these women may continue to produce TSI. Since TSI are IgG antibodies, they can cross the placental barrier causing neonatal thyrotoxicosis.
While the gold standard for thyroid-stimulating immunoglobulins is the bioassay (see TSI / Thyroid-Stimulating Immunoglobulin [TSI], Serum), the thyrotropin receptor antibody test has a shorter turnaround time, less analytical variability, and is less expensive.
Recommended first-line test for detection of thyrotropin receptor (TSHR) antibodies, and used in the following situations:
-Differential diagnosis of etiology of thyrotoxicosis in patients with ambiguous clinical findings and/or contraindicated (eg, pregnant or breast-feeding) or nondiagnostic thyroid radioisotope scans
-Diagnosis of clinically suspected Graves disease (eg, extrathyroidal manifestation of Graves disease include endocrine exophthalmos, pretibial myxedema, thyroid acropachy) in patients with normal thyroid function tests
-Determining the risk of neonatal thyrotoxicosis in a fetus of a pregnant female with active or past active Graves disease
-Differential diagnosis of gestational thyrotoxicosis versus first trimester manifestation or recurrence of Graves disease
-Assessing the risk of Graves disease relapse after antithyroid drug treatment
The sensitivity and specificity of an elevated thyrotropin receptor antibody (TRAb) test for Graves disease diagnosis depends on whether patients have disease treated with antithyroid drugs or clinically active, untreated disease. Based on a study that included specimens from 436 apparently healthy individuals, 210 patients with thyroid diseases without diagnosis of Graves disease, and 102 patients with untreated Graves disease, a decision limit of 1.75 IU/L showed a sensitivity of 97% and a specificity of 99% for detection of Graves disease.(1) In healthy individuals and in patients with thyroid disease without diagnosis of Graves disease, the upper limit of anti-thyrotropin receptor (anti-TSHR) values are 1.22 IU/L and 1.58 IU/L, respectively (97.5th percentiles).(1) A Mayo study of 115 patients, including 42 patients with Graves disease, showed a sensitivity of 95% and a specificity of 97% for detection of Graves disease at a decision limit of 1.75 IU/L.
Assessment of TRAb status is particularly relevant in women who have undergone thyroid ablative therapy or are on active antithyroid treatment and, therefore, no longer display biochemical or clinical evidence of thyrotoxicosis. Significant neonatal thyrotoxicosis is likely if a pregnant woman with a history of Graves disease has TRAb concentrations of >3.25 IU/L during the last trimester, regardless of her clinical remission status. Lesser elevations are only occasionally associated with neonatal thyrotoxicosis. Gestational thyrotoxicosis, which is believed to be due to a combination of human chorionic gonadotropin cross-reactivity on the TSHR and transient changes in thyroid hormone protein binding, is only very rarely associated with an elevated TRAb test. Finding an elevated TRAb test in this setting suggests usually underlying Graves disease.
An elevated TRAb test at the conclusion of a course of antithyroid drug treatment is highly predictive of relapse of Graves disease. However, the converse, a normal TRAb test, is not predictive of prolonged remission.
In patients receiving therapy with high biotin doses (ie, >5 mg/day), no specimen should be drawn until at least 8 hours after the last biotin administration.
Do not use specimens from patients receiving heparin treatment.
In rare cases, interference due to extremely high titers of antibodies to streptavidin and ruthenium can occur.
< or =1.75 IU/L
1. Schott M, Hermsen D, Broecker-Preuss M, et al: Clinical value of the first automated TSH receptor autoantibody assay for the diagnosis of Graves disease: an international multicentre trial. Clin Endocrinol (Oxf) 2009 Oct;71(4):566-573
2. Hermsen D, Broecker-Preuss M, Casati M, et al: Technical evaluation of the first fully automated assay for the detection of TSH receptor autoantibodies. Clin Chim Acta 2009 Mar;401(1-2):84-89
3. Grebe SKG: Thyroid disease. In The Genetic Basis of Common Diseases. Second edition. Edited by RA King, JI Rotter, AG Motulsky. New York, Oxford University Press, 2002, pp 397-430