TSI
Thyroid Stimulating Immunoglobulin
What it is
Thyroid stimulating immunoglobulin (TSI) — also called TSH receptor antibodies (TRAb) or thyroid stimulating antibodies (TSAb) — are a class of autoantibodies directed against the TSH receptor on thyroid follicular cell membranes. When TSI binds the TSH receptor, it mimics the action of TSH: it activates the receptor, stimulating thyroid hormone synthesis and secretion, and promoting thyroid gland growth. Unlike TSH, which is regulated by the pituitary feedback loop and responds to thyroid hormone levels, TSI is produced autonomously by the immune system and is not subject to feedback control. The result is unregulated, persistent stimulation of thyroid hormone production — the mechanism of Graves' disease. TSI is distinct from the anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG) antibodies associated with Hashimoto's thyroiditis, which cause hypothyroidism through thyroid destruction rather than stimulation. A minority of TSH receptor antibodies are blocking antibodies (TBAb) that inhibit TSH receptor signalling, causing hypothyroidism — Graves' disease (stimulating) and Hashimoto's (blocking) can, in rare cases, coexist or transition between states.
Why we measure it
Graves' disease accounts for approximately 60–80% of all cases of hyperthyroidism. Because TSI continuously stimulates the TSH receptor, it produces suppressed TSH (the pituitary reduces TSH output in response to the elevated thyroid hormones), elevated free T4 and T3, and the systemic manifestations of hyperthyroidism: tachycardia, atrial fibrillation, weight loss, heat intolerance, tremor, anxiety, and — in Graves' disease specifically — the characteristic extrathyroidal features of ophthalmopathy (exophthalmos, proptosis) and, rarely, pretibial myxoedema and thyroid acropachy. Left untreated, Graves' disease produces ongoing cardiovascular stress (particularly arrhythmia risk), bone loss (excess thyroid hormone accelerates bone turnover), and, at its extreme, thyroid storm. TSI testing in the annual autoimmune screen allows detection before overt Graves' disease develops — the point at which TSH is suppressed and free thyroid hormones are elevated. Some individuals have detectable TSI with only mild or subclinical thyroid function changes; identifying this state enables close monitoring of thyroid function and early treatment when warranted. TSI is also essential for distinguishing Graves' disease from other causes of hyperthyroidism (toxic multinodular goitre, toxic adenoma) that do not involve TSH receptor autoantibodies.
Why every 12 months
Annual testing in the autoimmune screen provides a once-yearly check on TSI status. In individuals with a first-time positive TSI and normal thyroid function, six-monthly thyroid function monitoring (TSH, free T3, free T4 — already part of the Pulse+ draw) should be established. TSI levels also have utility in monitoring treatment response in known Graves' disease and in predicting relapse after antithyroid drug therapy.
What movement means
TSI results are reported as a percentage relative to the TSH receptor binding of a reference antibody (% inhibition in the older competitive binding assay) or as a ratio to a calibrator in the newer bioassay formats. The positivity threshold varies by assay; most current assays report values above 1.75 IU/L (or > 140% in older assays) as positive. Titre does not directly correspond to clinical severity — some individuals with high TSI titres have only mild biochemical hyperthyroidism.
Negative
< 1.75 IU/L (assay-dependent threshold)
No TSH receptor antibodies detected. Makes Graves' disease unlikely as the cause of any TSH suppression. Does not exclude other causes of hyperthyroidism. Annual retesting in asymptomatic individuals.
Ross DS et al., 2016 ATA/AACE Hyperthyroidism Guidelines, Thyroid, 2016
Positive
> 1.75 IU/L (assay-dependent threshold)
TSH receptor antibodies detected. In a patient with suppressed TSH and elevated thyroid hormones, this confirms Graves' disease. In a patient with normal thyroid function, it indicates autoimmune predisposition to Graves' disease and warrants regular thyroid function monitoring. Specialist endocrinology review is appropriate in either case.
Ross DS et al., 2016 ATA/AACE Hyperthyroidism Guidelines, Thyroid, 2016 — doi:10.1089/thy.2016.0229
In the protocol
References
- 1.
Ross DS, Burch HB, Cooper DS, et al.. “2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis.” Thyroid. 2016.
- 2.
Smith TJ, Hegedüs L. “Graves' Disease.” New England Journal of Medicine. 2016.
- 3.
Bartalena L, Baldeschi L, Dickinson A, et al.. “Consensus Statement of the European Group on Graves' Orbitopathy (EUGOGO) on Management of GO.” European Journal of Endocrinology. 2008.
- 4.
Weetman AP. “Graves' Disease.” New England Journal of Medicine. 2000.