How to manage a patient with subclinical hyperthyroidism and multiple thyroid nodules, including a maximal TI-RADS (Thyroid Imaging, Reporting and Data System) 5 nodule?

Management of Subclinical Hyperthyroidism with Multiple Thyroid Nodules Including TI-RADS 5

This patient requires immediate fine-needle aspiration (FNA) biopsy of the TI-RADS 5 nodule (the 1.6 x 2.3 x 1.7 cm inferior pole nodule that appears taller than wide), followed by concurrent treatment of the subclinical hyperthyroidism with radioactive iodine uptake and scan to determine etiology, as the presence of autonomous nodules does not exclude malignancy and the subclinical hyperthyroidism requires definitive management. 1, 2

Immediate Priority: Address the TI-RADS 5 Nodule

The TI-RADS 5 nodule measuring ≥1 cm mandates FNA biopsy regardless of thyroid function status. 1, 3

• The inferior pole nodule measuring 1.6 x 2.3 x 1.7 cm with taller-than-wide morphology represents the highest malignancy risk (TI-RADS 5) and requires immediate cytologic evaluation 1, 4
• Multiple additional TI-RADS 4 nodules (≥1 cm) also warrant FNA biopsy based on ACR criteria, including the 1.4 cm nodule with punctate calcifications and the 2.0 cm solid-cystic nodule with indistinct margins 1, 4
• Critical pitfall to avoid: Do not defer biopsy based on the presence of subclinical hyperthyroidism—while hyperfunctioning nodules have high negative predictive value for malignancy, this patient has multiple nodules and the functional status of individual nodules is unknown without scintigraphy 5, 6

Concurrent Evaluation of Subclinical Hyperthyroidism

Confirm the diagnosis and determine etiology before proceeding with definitive treatment. 1, 2

Confirmatory Testing Algorithm

• Repeat TSH measurement within 4 weeks along with free T4 and total T3 or free T3 to confirm subclinical hyperthyroidism (TSH <0.1 mIU/L with normal thyroid hormones) 1, 2
• If TSH remains <0.1 mIU/L on repeat testing, proceed immediately with radioactive iodine uptake and scan to distinguish between Graves disease, toxic multinodular goiter, or destructive thyroiditis 1, 2, 7
• The scan will identify which nodules are hyperfunctioning—this is essential because autonomous nodules have very high negative predictive value for malignancy, potentially modifying the biopsy strategy for some nodules 5, 6

Treatment Indications for Subclinical Hyperthyroidism

Treatment is strongly recommended for this patient based on multiple high-risk features. 1, 2

• Age >60 years, presence of cardiac disease, osteopenia/osteoporosis, or symptoms of hyperthyroidism all warrant treatment when TSH <0.1 mIU/L 1, 2
• Untreated subclinical hyperthyroidism with TSH <0.1 mIU/L increases atrial fibrillation risk 3-fold in patients ≥60 years 2, 7
• Treatment preserves bone mineral density and may reduce cardiovascular mortality risk 2, 7

Integration of Scintigraphy Results with Nodule Management

The scintigraphy results will critically inform which nodules require biopsy. 5, 6

If Nodules Show Autonomous Function ("Hot" Nodules)

• Hyperfunctioning nodules have extremely high negative predictive value for malignancy and may not require FNA even with suspicious ultrasound features 5, 6
• However, the TI-RADS 5 nodule should still undergo biopsy unless proven to be the sole hyperfunctioning nodule, as the taller-than-wide morphology carries very high malignancy risk 1, 4
• Studies show that >80% of autonomous nodules are classified as TI-RADS 4A or higher based on ultrasound alone, but histology confirms benign pathology, demonstrating the critical importance of functional imaging 5

If Scan Shows Diffuse Uptake (Graves Disease)

• Proceed with FNA of all TI-RADS 4-5 nodules ≥1 cm as planned, since Graves disease does not confer protection against concurrent thyroid malignancy 1, 3
• Definitive treatment options include antithyroid drugs, radioactive iodine ablation, or surgery 1, 7
• Surgery may be preferred if multiple nodules require excision based on FNA results 7

If Scan Shows Low Uptake (Thyroiditis)

• Thyrotoxicosis from destructive thyroiditis may resolve spontaneously and requires only supportive care 7
• Still proceed with nodule biopsies as the thyroiditis does not affect malignancy risk 3

Definitive Treatment Strategy Based on Combined Results

Scenario 1: Benign Cytology + Toxic Multinodular Goiter

• Radioactive iodine ablation treats both the hyperthyroidism and reduces nodule size 1, 7
• Common risk: Radioactive iodine commonly causes hypothyroidism (requiring lifelong levothyroxine) and may temporarily exacerbate hyperthyroidism 1, 2

Scenario 2: Malignant Cytology (Any Etiology of Hyperthyroidism)

• Surgery becomes the definitive treatment, addressing both the cancer and the hyperthyroidism simultaneously 7
• Total thyroidectomy is typically required for papillary thyroid carcinoma with multiple nodules 3

Scenario 3: Indeterminate Cytology

• Consider molecular testing of the FNA aspirate to avoid diagnostic surgery if possible 3
• If molecular testing suggests malignancy or is unavailable, proceed with diagnostic lobectomy or thyroidectomy 3

Monitoring Protocol During Workup

Close surveillance is essential given the cardiac risks of untreated subclinical hyperthyroidism. 1, 2

• If the patient has cardiac disease, atrial fibrillation, or arrhythmias, repeat TSH testing within 2 weeks rather than 4 weeks 1, 2
• Assess for symptoms of hyperthyroidism including anxiety, palpitations, unintentional weight loss, heat intolerance, and tremor 7
• Critical consideration: Patients with nodular thyroid disease may develop overt hyperthyroidism when exposed to excess iodine (e.g., CT contrast agents), requiring special precautions 1

Special Precautions for This Patient

• Avoid iodinated contrast until the hyperthyroidism is controlled, as iodine exposure can precipitate overt hyperthyroidism in patients with autonomous nodules 1
• If contrast-enhanced imaging is absolutely necessary, it can be performed but requires close monitoring, as iodinated contrast is associated with incident overt hyperthyroidism (odds ratio 2.50) occurring at median 9 months after administration 1
• Ensure adequate calcium (1200 mg/day) and vitamin D (1000 units/day) intake given the bone loss risk from subclinical hyperthyroidism 2