What labs need to know about autoantibody testing for Graves’ disease

What is testing for TSH receptor autoantibodies used for?

Thyrotropin and thyroid stimulating hormone (TSH) receptor antibodies (TRAbs) are central to the pathophysiology of Graves’ disease (GD). They are directed against the TSH receptor (TSHR) on thyroid follicular cells and are categorized based on their effects. Thyroid-stimulating antibodies (TSAbs) activate the TSHR, mimic TSH, and drive excessive thyroid hormone production, while thyroid-blocking antibodies (TBAbs) inhibit TSH from binding.

TRAbs are invaluable in differentiating GD from other causes of hyperthyroidism. Beyond diagnosis, TRAbs also serve as a tool to predict disease prognosis and monitor therapy response. Elevated TRAb levels can signal active disease, while declining or absent TRAbs often indicate remission. This makes TRAb testing essential for tailoring long-term management strategies.

What TRAb assays are currently available?

Laboratories currently rely on three primary types of assays to measure TRAbs.

Competitive-binding immunoassays are the most commonly used because of their automation and accessibility. They measure TRAbs that compete with TSH or monoclonal antibodies for binding to the TSHR. Examples include TBII assays, which provide quantitative results for overall TRAb levels but do not differentiate between TSAbs and TBAbs.

There are also bridge-based immunoassays, which offer improved specificity and focus more on thyroid-stimulating immunoglobulins (TSI), which are directly associated with GD activity. They have better diagnostic accuracy in cases of ambiguous or borderline thyroid function tests but remain limited in availability compared with competitive-binding assays.

Cell-based bioassays evaluate the functional activity of TRAbs by measuring their biological effects, such as cyclic AMP production in response to receptor activation. While more informative, they are less widely adopted due to higher complexity and operational demands.

What are these assays’ limitations?

Despite advancements in assay technologies, significant limitations persist. For example, traditional immunoassays, such as TBII, often face specificity challenges, failing to distinguish between stimulating and blocking antibodies. This is critical in cases where both types coexist, as seen during GD disease progression or therapy. Competitive-binding assays lack functional data, which is crucial for understanding the biological activity of TRAbs. Functional bioassays address this but are labor-intensive and less scalable.

The limited availability of novel methods presents another challenge for laboratories. While emerging bioassays show promise, their adoption is hindered by cost and logistical constraints.

What lies ahead for TRAb testing?

One growing trend is to consolidate TRAb testing with thyroid function panels on a single platform in order to enhance automation and integration. This streamlines the workflow and reduces turnaround times.

Efforts are underway to develop refined assays that selectively detect TSAbs. These tests would provide clearer insights into GD activity and progression, especially in complex clinical scenarios. Additionally, international scientific societies are working to standardize TRAb assay methodologies and reference ranges. This effort will improve comparability across laboratories and enable better clinical decision-making.

Lastly, artificial intelligence holds great promise for assay design and in silico modeling of antibody-receptor interactions, paving the way for next-generation assays that are highly sensitive and specific.