Diagnostic Testing for Graves' or Non-Graves' Hyperthyroidism

A Comparison of Two Thyrotropin Receptor Antibody Immunoassays With Thyroid Scintigraphy and Ultrasonography

Lorenzo Scappaticcio; Pierpaolo Trimboli; Franco Keller; Mauro Imperiali; Arnoldo Piccardo; Luca Giovanella

Disclosures

Clin Endocrinol. 2020;92(2):169-178. 

In This Article

Abstract and Introduction

Abstract

Objective: Graves' disease (GD) is the most common cause of hyperthyroidism. In many cases, when the aetiological diagnosis of GD is not evident based on the clinical evaluation and thyroid function testing, it may become challenging to distinguish Graves' hyperthyroidism from other forms of thyrotoxicosis.

The current study was primarly carried out to compare the diagnostic effectiveness of two TSH receptor antibody immunoassays (IMAs), ultrasonography and thyroid scintigraphy in hyperthyroidism scenario.

Methods: We retrospectively analysed consecutive patients with newly diagnosed and untreated thyrotoxicosis who underwent thyroid functional tests, both TRAb and TSI measurements, thyroid scintigraphy and ultrasonography. TRAb assessment was carried out by Kryptor® compact PLUS, while TSI by Immulite®. Echo pattern 3 corresponded to 'thyroid inferno', and the final diagnosis of GD vs non-Graves' hyperthyroidism was made according to the thyroid scan (qualitative scintigraphy). Receiver operating characteristic (ROC) curves were drawn using the final diagnosis as reference. Clinical sensitivity and specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were calculated for all the tests.

Results: A total of 124 untreated hyperthyroid patients were included in our study (GD, n = 86 vs non-Graves' hyperthyroidism, n = 38). ROC curves showed that the optimal cut-off values associated with the highest diagnostic sensitivity and specificity was 0.7 IU/L for TRAb Kryptor® (93 [85.4–97.4] and 86.8 [71.9–95.5]) and 0.1 IU/L for TSI Immulite® (94.2 [86.9–98.1] and 84.2 [68.7–93.9]), respectively. For the echo pattern 3, we found a good sensitivity (92.1%) and a high PPV (95.2%) but a quite low specificity value (69.8%) and a relative low NPV (57.5%). For thyroid scintigraphy, the TcTU cut-off value of 1.3% corresponded to the best limit for sensitivity and specificity in our patients (95.3 [88.5–98.7] and 96.4 [81.6–99.4]). The Passing-Bablok regression equation and the Bland-Altman test showed a great degree of correlation and agreement existed between TRAb Kryptor® and Immulite® TSI results.

Conclusions: Thyroid scintigraphy remains the most accurate method to differentiate causes of thyrotoxicosis. However, TRAb assays can be alternatively adopted in this setting, limiting the use of thyroid scintigraphy (TcTU evaluation) to TRAb-negative patients. Thyoid US is less accurate than both TRAb/TSI and thyroid scintigraphy, but the 'thyroid inferno' pattern provides a high PPV for GD.

Introduction

Graves' disease (GD) is the most common cause of hyperthyroidism in iodine-replete geographical areas, but several aetiologies should be considered before making the definitive diagnosis and starting the right therapy.[1–3] In many cases, when the aetiological diagnosis of GD is not evident due to the absence of the pathognomonic features such as thyroid-associated orbitopathy and thyroid function testing, it may become challenging to distinguish Graves' hyperthyroidism from other forms of thyrotoxicosis.[1,2,4]

Traditionally, radionuclide scanning (using either technetium-99m sodium pertechnetate [99mTc-pertechnetate] or iodine-123 sodium iodide [123I-iodide]) is believed to be the reference diagnostic test to differentiate destructive thyrotoxicosis from hyperthyroidism sensu strictu, and to discriminate diffuse (ie GD) from focal (autonomy) overactivity within the thyroid parenchyma.[4–6]

The evaluation of thyroid vascularity by colour Doppler ultrasonography (US) can reliably differentiate hyperthyroidism from destructive thyrotoxicosis, but substantial variation affects this test.[7,8]

As stated in the European Thyroid Association (ETA) Guidelines, thyrotropin receptor antibodies (TRAb) measurement (hereinafter indicating any antibody that binds the TSH receptor, whether stimulating or nonstimulating) proved to be highly effective and rapid in the diagnosis of GD,[2] with the newer TRAb binding immunoassays showing very high sensitivity (more than 97%) and specificity (98%-99%).[9] Thyroid-stimulating immunoglobulins (TSI) are the true hallmark of the Graves' hyperthyroidism and of the extrathyroidal manifestations of GD.[1,10] However, they are generally assessed by expensive and technically complex bioassays, thus preventing their incorporation in the current diagnostic algorithms of hyperthyroidism.[10,11] However, a 'bridge' format for the direct detection of TSI (Immulite®) has been newly licensed, showing high clinical value in preliminary studies.[12,13]

According to the American Thyroid Association (ATA) guidelines,[1] one or more diagnostic tests may be used to reach the final aetiological diagnosis in thyrotoxic patients. Compared with the previous version, the 2016 ATA guidelines[1] first introduce TRAb (together or alternatively to radionuclide scanning and/or Doppler ultrasonography, on the basis of 'available expertise and resources') as first-line test to differentiate thyrotoxicosis's causes.

To our knowledge, few studies[14–16] compared the clinical accuracy of TRAb assays, Doppler ultrasonography and thyroid scintigraphy, while comparative data do not yet exist for TSI evaluated by this new 'bridge' assay (Immulite®).

Thus, the current study was carried out to compare the diagnostic effectiveness of two TSH receptor antibody immunoassays (IMAs), ultrasonography and thyroid scintigraphy in thyrotoxicosis scenario. Additionally, we explored the relationship between TRAb and TSI values with the degree of thyroid hyperfunction (as measured by thyroid hormones) and of thyroid uptake (as measured by 99mTc-pertechnetate uptake rate [TcTU]) in GD patients.

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