Diagnostic Options in Graves' or Non-Graves' Thyrotoxicosis: A Review for Clinical Practice

Distinguishing Graves' disease (GD) from the other causes of thyrotoxicosis is essential for appropriate management. The clinical phenotype of GD has evolved over time and is currently more heterogenous and milder than in the past. Consequently, the differential diagnosis of thyrotoxicosis is often challenging. We aim to provide clinicians with a practical guide to achieve a more reliable etiological diagnosis of thyrotoxicosis.

We reviewed international guidelines and the main papers indexed in PubMed from inception to March 1, 2026, on the diagnosis of thyrotoxicosis.

Three major diagnostic tools are currently available: thyroid scintigraphy, thyrotropin receptor antibodies (TRAbs), and thyroid ultrasonography (US). The diagnostic accuracy of scintigraphy is approximately 96%. However, GD may also present with non-uniform or normal uptake in 5-12% of cases. The diagnostic accuracy of TRAbs is approximately 95%. Nevertheless, TRAbs have limited utility in three specific settings: TRAb-negative GD, TRAb positivity in non-GD patients, and type 1 amiodarone-induced thyrotoxicosis (AIT). Thyroid US is the third most accurate diagnostic tool, with an accuracy of approximately 77%. Minor diagnostic tools include: T3/T4 and fT3/fT4 ratios; fT3/TSH and fT4/TSH ratios; serum diiodotyrosine; blood cell line ratios; and selected extrathyroidal manifestations of GD, such as neutropenia, abnormal liver function tests, and thymic hyperplasia.

One or more major diagnostic tools may be used to establish the final etiological diagnosis of thyrotoxicosis, depending on test availability, turnaround time, and clinician expertise. Minor diagnostic tools may provide additional diagnostic information in selected or equivocal cases.