MON-458 - Atypical Presentations of Thyrotoxicosis: Diagnostic Challenges Beyond Conventional Antibodies and Uptake

Background
Thyrotoxicosis is commonly evaluated using thyroid autoantibodies and radioiodine uptake studies. However, atypical presentations may not follow expected diagnostic patterns, leading to diagnostic uncertainty. We present two rare cases illustrating distinct nonclassical mechanisms of thyrotoxicosis.

Case 1: Autonomous Multinodular Goiter With Release of Preformed Thyroid Hormone
A 72-year-old male with a multinodular goiter identified in 2012 and a 10-year history of untreated subclinical hyperthyroidism was followed conservatively, as he remained asymptomatic and declined treatment. Radioiodine uptake scans performed in 2012, 2017, 2019, and 2024 consistently demonstrated absent uptake. Due to marked thyroid enlargement, pulmonary function testing revealed a moderately severe obstructive ventilatory defect with inspiratory limb flattening and forced expiratory volume in one second (FEV₁) of 57% predicted.

The patient later presented with acute encephalopathy. Laboratory evaluation revealed undetectable thyroid-stimulating hormone with elevated free triiodothyronine (5.8 pg/mL) and free thyroxine (3.56 ng/dL). Thyroid-stimulating immunoglobulin, thyrotropin receptor antibodies, and thyroid peroxidase antibodies were negative, and evaluation for alternative causes of encephalopathy was unrevealing. The patient was treated with methimazole without improvement and transitioned to propylthiouracil. Biochemical response remained limited, with free thyroxine measuring 2.32 ng/dL after nearly eight weeks of therapy. Euthyroidism was achieved only after more than ten weeks of treatment, coinciding with resolution of encephalopathy. Chronic thyroid autonomy with prolonged TSH suppression likely led to reduced sodium-iodide symporter expression and impaired iodine trapping, explaining persistently absent uptake despite ongoing hormone release.

Case 2: Antibody-Negative Graves Disease
A 31-year-old male presented with anxiety, heat intolerance, and palpitations. Laboratory evaluation showed suppressed TSH ( < 0.004 mIU/L) with elevated free triiodothyronine (6.19 pg/mL) and free thyroxine (1.55 ng/dL). Thyrotropin receptor antibodies and thyroid-stimulating immunoglobulin were repeatedly negative, while anti–thyroid peroxidase antibodies were positive. Radioiodine uptake was elevated, supporting Graves physiology. Thyroid function normalized with methimazole therapy, which was required for approximately 18 months to maintain euthyroidism.

Conclusion
These cases demonstrate atypical presentations of thyrotoxicosis in which antibody testing and radioiodine uptake patterns may be misleading. Recognition of alternative mechanisms, including autonomous hormone release from long-standing multi nodular goiter and antibody-negative Graves disease, is essential for accurate diagnosis and management.

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