What is the best course of treatment for a patient with hyperthyroidism, as indicated by a persistently low Thyroid-Stimulating Hormone (TSH) level, elevated free Thyroxine (T4) and free Triiodothyronine (T3) levels?

Immediate Evaluation and Management of Persistently Suppressed TSH with Normal Free T4 and T3

This patient has subclinical hyperthyroidism requiring urgent evaluation to determine the underlying cause and assess for complications, particularly cardiac arrhythmias and bone loss. 1, 2

Confirm the Diagnosis and Rule Out Laboratory Interference

• Repeat TSH, free T4, and free T3 in 3-6 weeks to confirm persistence of the abnormality, as transient variations are common and 30-60% of abnormal values normalize on repetition 3
• Question the patient about biotin supplement use, as biotin can cause falsely elevated free T4 and normal TSH results in some assays 3
• Review all medications, particularly amiodarone, tyrosine kinase inhibitors, and immune checkpoint inhibitors, which can cause hyperthyroidism 1
• Assess for recent iodine exposure (CT contrast, supplements) that could trigger thyrotoxicosis 1

Determine the Etiology of Subclinical Hyperthyroidism

Measure TSH-receptor antibodies (TRAb) to distinguish Graves' disease from other causes, as this fundamentally changes management 1, 2, 4

• If TRAb is positive: Graves' disease is the diagnosis, affecting 2% of women and 0.5% of men globally 2
• If TRAb is negative: Obtain thyroid ultrasound to assess for nodules 1, 4
• If nodules are present or etiology remains unclear: Thyroid scintigraphy is recommended to identify toxic nodular goiter or assess for autonomous function 1, 2, 4

Assess for Complications of Subclinical Hyperthyroidism

Obtain an ECG immediately to screen for atrial fibrillation, as subclinical hyperthyroidism increases atrial fibrillation risk 3-5 fold, particularly in patients over 60 years 5, 2

• Check for symptoms of thyrotoxicosis: anxiety, insomnia, palpitations, unintentional weight loss, diarrhea, heat intolerance, and tremor 2
• Examine for Graves' disease signs: diffusely enlarged thyroid gland, stare, or exophthalmos 2
• Assess for symptoms of local compression if nodules are present: dysphagia, orthopnea, or voice changes 2

Treatment Decision Algorithm

Treatment for subclinical hyperthyroidism is recommended for patients at highest risk of osteoporosis and cardiovascular disease, specifically those older than 65 years or with persistent serum TSH less than 0.1 mIU/L 2

For Graves' Disease (TRAb Positive):

• Initiate antithyroid drugs (methimazole preferred) as first-line therapy, which inhibits synthesis of thyroid hormones 6, 1, 2
• Standard course is 12-18 months, though recurrence occurs in approximately 50% of patients 1
• Consider long-term treatment (5-10 years) for patients at high risk of recurrence, which reduces recurrence rates to 15% 1
• Risk factors for recurrence include: age younger than 40 years, FT4 concentrations 40 pmol/L or higher, TSH-binding inhibitory immunoglobulins higher than 6 U/L, and goiter size equivalent to or larger than WHO grade 2 1

For Toxic Nodular Goiter:

• Radioactive iodine (131I) or thyroidectomy are preferred treatments, with radiofrequency ablation as a rare alternative 1

For Destructive Thyrotoxicosis (Thyroiditis):

• Observe if mild and asymptomatic, as this is usually transient 1, 2
• Provide supportive care with beta-blockers for symptomatic relief 2
• Reserve steroids for severe cases only 1

Critical Pitfalls to Avoid

• Do not treat based on a single abnormal laboratory result without confirmation, as values frequently normalize spontaneously 3
• Do not miss central hyperthyroidism (TSH-secreting pituitary adenoma) or resistance to thyroid hormone, which present with normal TSH and elevated free T4 3, 7
• Do not delay treatment in patients over 65 years or with TSH <0.1 mIU/L, as they are at highest risk for atrial fibrillation, osteoporosis, and cardiovascular mortality 2, 5
• Do not assume hypothyroidism is permanent after treatment without reassessment, as TSH suppression can persist for weeks to months after prior hyperthyroidism 8

Monitoring and Follow-Up

• Recheck TSH, free T4, and free T3 every 4-6 weeks during initial treatment until biochemically euthyroid 1
• Screen for atrial fibrillation with ECG at baseline and periodically during follow-up, especially in elderly patients 2
• Assess bone density in postmenopausal women and elderly men with prolonged subclinical hyperthyroidism 2
• Monitor for progression to overt hyperthyroidism if observation is chosen, with repeat testing every 3-6 months 2