Thyroid-Stimulating Immunoglobulin (TSI), Serum
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Autoimmune thyroid disease is characterized by the presence of autoantibodies against various thyroid components, namely the thyrotropin receptor (thyroid-stimulating hormone receptor: TSHR), thyroid-peroxidase (TPO), and thyroglobulin (Tg), as well as 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. The role of the TPO and Tg autoantibodies in either autoimmune thyrotoxicosis or autoimmune hypothyroidism is less well established; they may merely represent epiphenomena. Detectable concentrations of anti-TPO antibodies are observed in most patients with autoimmune thyroid disease (eg, Hashimoto's thyroiditis, idiopathic myxedema, and Graves disease).
Autoantibodies that bind and transactivate the TSHR lead to stimulation of the thyroid gland independent of the normal feedback-regulated thyroid-stimulating hormone (TSH) stimulation. These TSHR autoantibodies also are known as long-acting-thyroid-stimulator or thyroid-stimulating immunoglobulins (TSI). 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. At least 20% of patients with autoimmune hypothyroidism also have evidence either of TSHR-blocking antibodies or, less commonly, TSI.
TSHR autoantibodies may be found 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 cure.
TSI are IgG antibodies and can therefore cross the placental barrier, causing neonatal thyrotoxicosis.
First-order tests for autoimmune thyroid disease include TPO / Thyroperoxidase (TPO) Antibodies, Serum (most suited for suspected cases of autoimmune hypothyroidism) and THYRO / Thyrotropin Receptor Antibody, Serum. Thyrotropin receptor antibody (TSHR-antibody) is a binding assay that detects both TSI and TSHR-blocking autoantibodies; it can be used instead of this TSI assay for most applications, as long as the results are interpreted in the clinical context. The TSHR-antibody test has a shorter turnaround time than the TSI assay, is less expensive, and if interpreted within the clinical context, has excellent correlation with the TSI assay. Specific detection of TSI is accomplished by this second-order bioassay.
Second-order testing for autoimmune thyroid disease, including:
-Differential diagnosis of etiology of thyrotoxicosis in patients with ambiguous clinical signs and/or contraindicated (eg, pregnant or breast-feeding) or indeterminate thyroid radioisotope scans
-Diagnosis of clinically suspected Graves disease (eg, extrathyroidal manifestations of Graves disease: endocrine exophthalmos, pretibial myxedema, thyroid acropachy) but normal thyroid function tests
-Determining the risk of neonatal thyrotoxicosis in a fetus of a pregnant female with active or past Graves disease
-Differential diagnosis of gestational thyrotoxicosis versus first trimester manifestation or recurrence of Graves disease
-Assessing the risk of Graves disease relapse after anti-thyroid drug treatment
A combination of TSI / Thyroid-Stimulating Immunoglobulin (TSI), Serum and THYRO / Thyrotropin Receptor Antibody, Serum is useful as an adjunct in the diagnosis of unusual cases of hypothyroidism (eg, Hashitoxicosis).
The sensitivity and specificity of an elevated thyroid-stimulating immunoglobulins (TSI) index for Graves disease diagnosis depends on whether patients have clinically active, untreated disease or disease treated with antithyroid drugs. Using a TSI index of 1.3 as the cutoff level in newly diagnosed, untreated patients, the sensitivity and specificity are >90%. For a higher cutoff of 1.8, specificity approaches 100%, but sensitivity decreases somewhat. In patients with inactive or treated Graves disease the specificity is similar, while sensitivity is lower, ranging from 50% to 80%.
Significant neonatal thyrotoxicosis is likely if a pregnant woman with a history of Graves disease has a TSI index of >3.9 during the last trimester, regardless of her remission status. Lesser elevations are only occasionally associated with neonatal thyrotoxicosis. This is particularly relevant for women who have previously undergone thyroid-ablative therapy or are on active antithyroid drug treatment and, therefore, no longer display biochemical or clinical evidence of thyrotoxicosis.
Gestational thyrotoxicosis, which is believed to be due to a combination of human chorionic gonadotropin cross-reactivity on the thyroid-stimulating hormone receptor (TSHR) and transient changes in thyroid hormone protein binding, is not associated with an elevated TSI index. Finding an elevated TSI index in this setting suggests underlying Graves disease.
An elevated TSI index at the conclusion of a course of anti-thyroid drug treatment is highly predictive of relapse of Graves disease. However, the converse, a normal TSI index, is not predictive of prolonged remission.
In patients with thyroid function tests that fluctuate between hypo- and hyperthyroidism or vice versa, a clearly elevated TSHR-antibody level (>25%) and a simultaneous TSI index that is normal or only minimally elevated (1.3-1.8) suggest a diagnosis of possible Hashitoxicosis.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Positive results are strongly indicative of Graves disease, but do not always correlate with the presence and severity of hyperthyroidism.
Patients with Hashimoto's disease may have an elevated thyroid-stimulating immunoglobulins (TSI) index, which can be >1.8. A TSI index of >1.3 and < or =1.8 also is occasionally observed in various other thyroid disorders, including nodular goiter, and subacute thyroiditis.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
< or =1.3 TSI index
Reference values apply to all ages.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Morris JC III, Hay ID, Nelson RE, Jiang NS: Clinical utility of thyrotropin-receptor antibody assays: comparison of radio-receptor and bioassay methods. Mayo Clin Proc 1988;63:707-717
2. Volpe R: Rational use of thyroid function tests. Crit Rev Clin Lab Sci 1997;34:405-438
3. Saravanan P, Dayan CM: Thyroid autoantibodies. Endocrinol Metab Clin North Am 2001;30(2):315-335
4. 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