Why TSI testing is reshaping the diagnosis of autoimmune thyroid disease

“TSI testing is a powerful tool to distinguish autoimmune hyperthyroidism — Graves’ disease —from other causes of hyperthyroidism, ensuring patients receive the right treatment at the right time,” explains endocrinologist Dr. Ossama M. Lashin, medical director at the Cleveland Clinic, in a recent SelectScience^® webinar.

The webinar provides laboratory professionals with a deeper understanding of the clinical importance of TSI assays. The discussion covers the differentiation between TSI and other thyroid biomarkers, the clinical scenarios where TSI measurement is warranted, and its direct impact on patient care. By understanding the nuances of thyroid testing, laboratory professionals can help guide clinicians toward more precise diagnoses and better patient outcomes.

A tool for endocrine diagnostics

Autoimmune thyroid diseases, particularly Graves' disease, pose complex diagnostic and management challenges for endocrinologists. One of the pivotal tools in addressing these challenges is the measurement of thyroid stimulating immunoglobulin (TSI) – a functional biomarker that directly reflects disease activity. TSI plays a central role in the pathophysiology of Graves' disease, where autoantibodies stimulate the thyroid-stimulating hormone (TSH) receptor, leading to excessive hormone production and hyperthyroidism. Unlike other thyroid antibodies such as thyroid peroxidase antibodies (TPO Ab) or thyroglobulin antibodies (TgAb), which indicate autoimmune presence but not function, TSI acts as a more definitive indicator of active disease.

TSI in autoimmune thyroid disorders

Dr. Lashin opens by explaining the central role of TSI in autoimmune thyroid diseases, particularly Graves’ disease. "TSI is not just another thyroid biomarker," he states. "It is the functional marker of Graves’ disease, directly stimulating the TSH receptor and leading to hyperthyroidism." Unlike TPO Ab or TgAb, which indicate autoimmune activity but not necessarily active disease, TSI provides a clear, functional measure of disease activity.

He elaborates on the pathophysiology of Graves’ disease, where autoantibodies mimic the action of thyroid-stimulating hormone (TSH), leading to excessive thyroid hormone production. This distinction is crucial because many patients with autoimmune thyroid conditions have positive thyroid antibodies but do not have active hyperthyroidism. "TSI tells us not just about the presence of autoimmunity but about its impact on thyroid function," Dr. Lashin emphasizes.

TSI vs other thyroid biomarkers

Traditional thyroid panels include TSH, Free T3 (triiodothyronine), Free T4 (thyroxine), and antibody tests like TPO and TgAb. However, these markers alone do not always provide a definitive answer when it comes to differentiating Graves’ disease from other thyroid dysfunctions.

"A suppressed TSH with high Free T4 and Free T3 raises suspicion for hyperthyroidism, but the etiology is not always clear," Dr. Lashin explains. "Is it Graves’ disease? A toxic nodule? Or transient thyroiditis? This is where TSI testing is invaluable."

In cases where TSI is elevated, clinicians can confidently diagnose Graves’ disease. Conversely, a negative TSI result in a hyperthyroid patient suggests alternative causes such as toxic multinodular goiter or subacute thyroiditis. This distinction has a direct impact on patient management, as treatment strategies differ significantly between these conditions.

When should TSI be measured?

Dr. Lashin details several clinical scenarios where TSI measurement is particularly useful:

Confirming Graves’ disease diagnosis: "In patients presenting with hyperthyroidism, a positive TSI result is virtually diagnostic of Graves’ disease," he explains. This is especially useful in ambiguous cases where clinical features alone are not definitive.

Monitoring disease activity and treatment response: TSI levels can help track the course of Graves’ disease. "When we treat Graves’ with antithyroid drugs, we expect to see a decline in TSI levels over time. Persistent elevation may indicate ongoing immune activation, increasing the risk of relapse."

Predicting relapse after treatment: Some patients who discontinue antithyroid medication experience relapse. "A high TSI level at the end of treatment suggests a higher likelihood of recurrence. In these cases, we might consider prolonged therapy or alternative options like radioiodine ablation."

Differentiating between Graves’ disease and other causes of hyperthyroidism: As mentioned earlier, a suppressed TSH with elevated Free T4 does not always mean Graves’ disease. TSI testing helps distinguish between Graves’ disease and other hyperthyroid states, supporting appropriate treatment.

Assessing neonatal thyrotoxicosis risk: Pregnant women with a history of Graves’ disease can pass TSI antibodies to the fetus, leading to transient neonatal hyperthyroidism. "If a pregnant patient has a history of Graves’, we check TSI in the third trimester. A significantly elevated result warrants close neonatal monitoring post-delivery."

Why accurate TSI testing matters

A key theme throughout the webinar is the importance of reliable laboratory results. Dr. Lashin emphasizes that laboratorians play a critical role in ensuring accuracy. "A poor-quality assay can lead to misdiagnosis and inappropriate treatment decisions," he warns. This is why laboratories must use validated, high-sensitivity assays that provide reproducible results.

He also touches on the interpretation of borderline results. "Not every slightly elevated TSI result means active Graves’ disease. The clinical picture matters," he notes, urging laboratorians to collaborate closely with ordering physicians to ensure proper test utilization.

Addressing common questions in the Q&A session

The webinar concludes with an insightful Q&A session in which Dr. Lashin addresses practical concerns from laboratorians and clinicians.

Q. What is the reference range for TSH, and can it be abnormal without thyroid disease?
“Everybody has their own normal TSH,” says Dr. Lashin, noting the standard range is typically 0.5 to 5.5 mIU/mL, but about 2% of people naturally fall outside this range. He adds that pregnancy or estrogen-containing birth control can shift thyroid hormone-binding proteins and affect TSH levels without actual pathology.

Q. Why did Cleveland Clinic switch from TRAb to TSI testing?
“We found that TRAb as a bioassay was inferior to TSI when it came to false positive rates,” he explains. “It was also manual, labor-intensive, and not very specific.” TSI, in contrast, “checked all those boxes off,” and after discussions with lab medicine and clinicians, “everybody is very satisfied with the new test.”

Q. How important are antibody tests like TSI or TPO in diagnosis?
“Knowing the reason for the thyroid disorder is actually important,” Dr. Lashin emphasizes. Antibodies help not only with diagnosis, but also with “management, follow-up, and response to treatment.” He also notes some patients with autoimmune thyroid disease may test antibody-negative early in the disease, with antibodies only appearing later.

If you missed it, watch the P.A.C.E- and ACCENT-accredited webinar on demand here.