What is the initial workup and treatment approach for a patient suspected of having hyperthyroidism?

Hyperthyroidism Workup

Initial Biochemical Confirmation

Begin with serum TSH measurement—if suppressed, immediately measure free T4 and free T3 to confirm hyperthyroidism biochemically. 1, 2, 3

• A suppressed TSH (<0.1 mIU/L) with elevated free T4 and/or free T3 confirms overt hyperthyroidism, which affects 0.2-1.4% of people worldwide 1, 2
• Subclinical hyperthyroidism presents with suppressed TSH but normal free T4 and T3 levels, affecting 0.7-1.4% of people globally 2
• TSH has >98% sensitivity and >92% specificity for detecting thyroid dysfunction, making it the optimal first-line screening test 4, 5

Etiological Diagnosis Algorithm

Once biochemical hyperthyroidism is confirmed, determine the underlying cause using this stepwise approach:

Step 1: Measure TSH Receptor Antibodies (TRAb)

• Positive TRAb confirms Graves' disease, which accounts for 70% of hyperthyroidism cases 1, 5
• Binding assays for TRAb have 97.4% sensitivity and 99.2% specificity for Graves' disease diagnosis 5
• Graves' disease has a global prevalence of 2% in women and 0.5% in men 2

Step 2: If TRAb is Negative, Perform Thyroid Ultrasound

• Identify toxic nodular goiter (16% of hyperthyroidism cases), which presents as autonomous hyperfunctioning nodules 1, 6
• Look for signs of thyroiditis: diffusely heterogeneous echotexture with decreased vascularity suggests subacute thyroiditis (3% of cases) 1

Step 3: Obtain Radioactive Iodine Uptake Scan if Diagnosis Remains Unclear

• High uptake (>30% at 24 hours) indicates Graves' disease or toxic nodular goiter 2, 3
• Low or absent uptake (<5%) indicates thyroiditis or exogenous thyroid hormone 2, 3
• This test is essential when TRAb is negative and ultrasound findings are inconclusive 2, 5

Physical Examination Findings to Document

• For Graves' disease: diffusely enlarged thyroid gland, thyroid eye disease (pathognomonic—lid retraction, proptosis, periorbital edema), pretibial myxedema 2, 3
• For toxic nodular goiter: palpable thyroid nodules, compressive symptoms (dysphagia, orthopnea, voice changes) 2
• General thyrotoxic signs: tachycardia (>100 bpm), tremor, muscle weakness, warm moist skin, hyperreflexia 3

Additional Testing Based on Etiology

If Graves' Disease is Confirmed:

• Measure thyroid peroxidase antibodies (TPO-Ab) to assess for concurrent autoimmune thyroiditis 1
• Perform ophthalmologic examination if any eye symptoms are present 1

If Drug-Induced Hyperthyroidism is Suspected:

• Review medication history for amiodarone, tyrosine kinase inhibitors, or immune checkpoint inhibitors (collectively cause 9% of hyperthyroidism) 1
• Amiodarone-induced thyrotoxicosis requires specific management distinct from other causes 1

If Thyroiditis is Suspected:

• Measure erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)—markedly elevated in subacute granulomatous thyroiditis 1
• Thyroiditis typically presents with neck pain, fever, and a tender thyroid gland on palpation 1

Critical Pitfalls to Avoid

• Never treat based on TSH alone without confirming elevated thyroid hormones, as TSH suppression can occur in non-thyroidal illness 4
• Do not skip TRAb measurement in suspected Graves' disease—it avoids unnecessary radioiodine scans and guides treatment duration 5
• Failing to distinguish destructive thyroiditis from Graves' disease leads to inappropriate antithyroid drug therapy, as thyroiditis requires only supportive care 1, 2
• Missing compressive symptoms from large goiters delays surgical referral, which is the definitive treatment when compression is present 3

Treatment Implications Based on Diagnosis

Graves' Disease:

• Antithyroid drugs (methimazole preferred) for 12-18 months achieve remission in 50% of patients 1, 6
• Radioactive iodine resolves hyperthyroidism in >90% but causes hypothyroidism in most patients within 1 year 3
• Surgery reserved for large compressive goiters, pregnancy planning, or patient preference 6, 3

Toxic Nodular Goiter:

• Radioactive iodine or thyroidectomy are definitive treatments—antithyroid drugs do not cure this condition 1, 6
• Radiofrequency ablation is an emerging option for selected cases 1

Thyroiditis:

• Observation or symptomatic treatment with beta-blockers—steroids only for severe cases 1, 2
• Antithyroid drugs are contraindicated as thyroid is not overproducing hormone 1

Special Populations Requiring Modified Approach

• Pregnancy: Propylthiouracil preferred in first trimester due to lower teratogenicity risk; switch to methimazole in second/third trimesters to avoid maternal hepatotoxicity 7, 8
• Elderly or cardiac disease: Treat subclinical hyperthyroidism if TSH <0.1 mIU/L due to increased risk of atrial fibrillation and osteoporosis 2
• Thyroid storm: Medical emergency requiring immediate treatment with antithyroid drugs, beta-blockers, corticosteroids, and iodine 1