What's the next step in diagnosis for a 48-year-old female with hypothyroid-stimulating hormone (TSH) levels and hyperthyroxinemia (high T4), with negative Thyroid Receptor Antibody (TRAK)?

Next Steps in Diagnosis for Low TSH and High T4 with Negative TRAK

For a 48-year-old female with low TSH, high T4, and negative TRAK (thyroid receptor antibody), the next diagnostic step should be thyroid ultrasonography combined with additional antibody testing, specifically thyroid peroxidase (TPO) antibodies, to determine the underlying cause of hyperthyroidism.

Diagnostic Approach

When a patient presents with biochemical evidence of hyperthyroidism (low TSH and high T4) but negative TRAK, further investigation is needed to establish the etiology. The diagnostic approach should follow this algorithm:

1. Confirm biochemical hyperthyroidism

   • Low TSH and high free T4 already establish hyperthyroidism 1
   • Consider measuring free T3 if T4 is only mildly elevated

2. Additional antibody testing

   • TPO antibodies should be measured to evaluate for other autoimmune thyroid conditions 2, 3
   • Negative TRAK (TSH receptor antibodies) already rules out the most common cause of hyperthyroidism (Graves' disease)

3. Imaging studies

   • Thyroid ultrasonography to evaluate for nodules, goiter, or thyroiditis 2, 3
   • If ultrasonography reveals nodules or multinodular goiter, thyroid scintigraphy (radioactive iodine uptake scan) should be performed to identify hyperfunctioning nodules 1, 4

Differential Diagnosis

With negative TRAK, the main conditions to consider include:

1. Toxic multinodular goiter or toxic adenoma (16% of hyperthyroidism cases) 1

   • Characterized by autonomously functioning thyroid nodules
   • Typically seen in older patients
   • Ultrasonography shows nodules, scintigraphy shows focal increased uptake

2. Thyroiditis (3% of hyperthyroidism cases) 1

   • Subacute, silent, or postpartum thyroiditis
   • Often transient hyperthyroidism followed by hypothyroidism
   • Low radioiodine uptake on scintigraphy
   • May have elevated inflammatory markers

3. Drug-induced hyperthyroidism (9% of cases) 1

   • Medications such as amiodarone, tyrosine kinase inhibitors, or immune checkpoint inhibitors
   • Important to review medication history thoroughly

4. Rare causes of euthyroid hyperthyroxinemia 5

   • Abnormal thyroid hormone binding proteins
   • Thyroid hormone resistance
   • Acute psychiatric illness or stress

Pitfalls and Caveats

• Don't assume Graves' disease is ruled out completely: While negative TRAK makes Graves' disease less likely, some patients with Graves' may have undetectable antibody levels. Clinical features (ophthalmopathy, dermopathy) should still be assessed 1, 4.

• Consider factitious hyperthyroidism: Surreptitious ingestion of thyroid hormone can cause this biochemical pattern and should be considered if other causes are ruled out.

• Be aware of assay interference: Some assays can be affected by heterophile antibodies or other interfering substances, leading to falsely abnormal results. If clinical presentation doesn't match laboratory findings, consider repeating tests with different assay methods 6.

• Evaluate for pregnancy: In pregnant women, hCG can stimulate the TSH receptor and cause transient hyperthyroidism, particularly in hyperemesis gravidarum 5.

By following this systematic approach, the underlying cause of hyperthyroidism can be identified, allowing for appropriate treatment tailored to the specific etiology.