What is the initial workup and treatment for a patient presenting with hyperthyroidism?

Workup for Hyperthyroidism

Initial Biochemical Confirmation

Confirm hyperthyroidism with serum TSH and free thyroid hormones—a suppressed TSH with elevated free T4 and/or free T3 establishes the diagnosis of overt hyperthyroidism. 1

• Measure TSH first; if suppressed, follow with free T4 (FT4) and free T3 (FT3) to confirm hyperthyroidism 2, 1
• Overt hyperthyroidism is defined as suppressed TSH with elevated T3 and/or FT4 1
• Subclinical hyperthyroidism presents with low TSH but normal T3 and FT4 levels 1
• TSH has sensitivity above 98% and specificity greater than 92% for detecting thyroid dysfunction 3

Etiological Diagnosis

After biochemical confirmation, measure TSH-receptor antibodies (TRAb) to distinguish Graves' disease from other causes—positive TRAb confirms Graves' disease with 97.4% sensitivity and 99.2% specificity. 4

Primary Diagnostic Tests:

• TSH-receptor antibodies (TRAb): Positive in Graves' disease, which accounts for 70% of hyperthyroidism cases 2, 4
• Thyroid peroxidase antibodies (TPO): May be elevated in autoimmune thyroid disease 2
• Thyroid ultrasonography: Identifies nodules, goiter size, and vascularity patterns 2

When TRAb is Negative:

• Thyroid scintigraphy with radioiodine uptake is mandatory if TRAb is negative or thyroid nodules are present 1, 4
• High uptake indicates autonomous thyroid function (toxic nodular goiter or Graves' disease) 2
• Low or absent uptake suggests thyroiditis or exogenous thyroid hormone 2, 5

Differential Diagnosis by Etiology

Most Common Causes:

• Graves' disease (70%): Diffuse goiter, positive TRAb, high radioiodine uptake, may have ophthalmopathy or pretibial myxedema 2, 1
• Toxic nodular goiter (16%): Single or multiple autonomous nodules, negative TRAb, focal uptake on scintigraphy 2, 1
• Subacute thyroiditis (3%): Painful thyroid, low radioiodine uptake, transient thyrotoxicosis 2
• Drug-induced (9%): Amiodarone, tyrosine kinase inhibitors, immune checkpoint inhibitors 2

Clinical Clues:

• Graves' disease: Diffusely enlarged thyroid, stare, exophthalmos, pretibial myxedema 1
• Toxic nodules: Palpable nodules, symptoms of neck compression (dysphagia, orthopnea, voice changes) 1
• Thyroiditis: Tender thyroid gland, recent viral illness, transient symptoms 5

Additional Workup Based on Clinical Context

Cardiovascular Assessment:

• ECG and cardiac evaluation for all patients, as hyperthyroidism causes atrial fibrillation, heart failure, and increased cardiovascular mortality 6, 1
• Beta-blockers should be initiated immediately for symptomatic tachycardia, palpitations, or cardiac symptoms 6

Pregnancy Considerations:

• Confirm pregnancy status in all women of childbearing age before treatment, as management differs significantly 7, 8
• Untreated hyperthyroidism in pregnancy increases risk of maternal heart failure, spontaneous abortion, preterm birth, and fetal hyperthyroidism 7, 8

Ophthalmopathy Assessment:

• Evaluate for Graves' ophthalmopathy (exophthalmos, diplopia, periorbital edema) as radioiodine may worsen eye disease 9
• Corticosteroid cover may reduce risk of ophthalmopathy deterioration with radioiodine treatment 9

Treatment Selection Algorithm

The choice between antithyroid drugs, radioactive iodine, and surgery depends on the underlying etiology, patient age, pregnancy status, and severity of disease. 9, 5

For Graves' Disease:

• Antithyroid drugs (methimazole preferred) for 12-18 months to induce remission, though 50% recur 2, 5
• Radioactive iodine is the most widely used treatment in the United States and is growing as first-line therapy 9, 5
• Surgery (thyroidectomy) reserved for large goiters causing compression, refusal of radioiodine, or specific patient preference 9

For Toxic Nodular Goiter:

• Radioactive iodine is the treatment of choice, as antithyroid drugs will not cure autonomous nodules 9, 2
• Surgery or radiofrequency ablation are alternatives 2

For Thyroiditis:

• Observation with supportive care for mild cases, as thyrotoxicosis is transient 1, 5
• Beta-blockers for symptomatic relief 5
• Steroids only for severe cases 2

Critical Pitfalls to Avoid

• Never start treatment without confirming the etiology, as thyroiditis requires observation while Graves' disease requires definitive therapy 2, 1
• Avoid radioiodine in pregnancy, lactation, and within 4 months of planned conception 9
• Do not use propylthiouracil as first-line except in first trimester pregnancy or methimazole intolerance, due to severe hepatotoxicity risk 8
• Monitor for agranulocytosis with antithyroid drugs—patients must report sore throat, fever, or malaise immediately 7, 8
• Screen for concurrent adrenal insufficiency before treating, as thyroid hormone can precipitate adrenal crisis 3

Monitoring During Treatment

• Thyroid function tests (TSH, free T4) every 6-8 weeks during antithyroid drug titration 3
• White blood cell count if symptoms of infection develop on antithyroid drugs 7, 8
• Prothrombin time before surgical procedures, as antithyroid drugs may cause hypoprothrombinemia 7, 8
• Rising TSH during treatment indicates need for lower maintenance dose of antithyroid medication 7, 8