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

Hyperthyroidism Workup and Initial Treatment

Initial Diagnostic Confirmation

Confirm hyperthyroidism biochemically with a low TSH and elevated free T4 (FT4) or free T3 (FT3). 1, 2, 3 TSH has high sensitivity and specificity for diagnosing thyrotoxicosis, making it the appropriate first-line screening test 2. If TSH is suppressed (<0.1 mIU/L), measure both free T4 and free T3 to confirm overt hyperthyroidism (elevated hormones) versus subclinical hyperthyroidism (normal hormones) 1, 3.

Etiological Diagnosis

Once biochemical hyperthyroidism is confirmed, determine the underlying cause:

First-Line Testing

• Measure TSH-receptor antibodies (TRAb) to diagnose Graves' disease, which accounts for 70% of hyperthyroidism cases 1, 4. Binding assays have 97.4% sensitivity and 99.2% specificity for Graves' disease 4.
• Check for thyroid peroxidase antibodies (anti-TPO) to identify autoimmune thyroid disease 1.
• Perform thyroid ultrasonography to assess gland size, nodularity, and vascularity 1.

Clinical Examination Findings

• Look for thyroid eye disease (exophthalmos, stare, lid lag), which is pathognomonic for Graves' disease 2, 3.
• Palpate for diffuse goiter (suggests Graves' disease) versus nodular goiter (suggests toxic nodular disease) 2, 3.
• Assess for compressive symptoms (dysphagia, orthopnea, voice changes) that indicate large goiter requiring surgical consideration 3.

When Scintigraphy Is Needed

• Order radioactive iodine uptake scan if TRAb is negative or thyroid nodules are present 1, 3, 4. The uptake pattern differentiates:
  • Diffuse increased uptake = Graves' disease
  • Focal increased uptake = toxic adenoma or toxic multinodular goiter (16% of cases) 1
  • Low/absent uptake = thyroiditis (3% of cases) or exogenous thyroid hormone 1, 2

Symptomatic Management (Immediate)

Start beta-blockers immediately for symptomatic relief of tachycardia, tremor, and anxiety while awaiting definitive diagnosis and treatment. 5, 2

• Atenolol 25-50 mg daily or propranolol are preferred agents 5.
• Titrate to target heart rate <90 bpm if blood pressure tolerates 5.
• Reduce beta-blocker dose once euthyroid, as hyperthyroidism increases clearance of beta-blockers with high extraction ratios 5, 6.

Special Cardiovascular Considerations

• Atrial fibrillation occurs in 5-15% of hyperthyroid patients, more frequently in those over 60 years 5.
• For patients with cardiac disease or atrial fibrillation, use intravenous beta-blockers for acute rate control 5.
• Anticoagulation decisions should be guided by CHA₂DS₂-VASc risk factors, not hyperthyroidism alone 5.

Definitive Treatment Selection

For Graves' Disease

Methimazole is the preferred first-line antithyroid drug except during the first trimester of pregnancy 5, 2, 3.

Methimazole Dosing and Monitoring

• Start methimazole at appropriate dose (typically 10-30 mg daily depending on severity) 6.
• Monitor free T4 or free T3 every 2-4 weeks initially, targeting high-normal range with the lowest effective dose 5, 2.
• Do NOT use TSH to guide dose adjustments, as TSH remains suppressed for months after achieving euthyroidism 5.
• Standard treatment duration is 12-18 months, but recurrence occurs in approximately 50% of patients 1.

Predictors of Recurrence After Short-Term Antithyroid Drugs

• Age <40 years 1
• FT4 ≥40 pmol/L at diagnosis 1
• TSH-binding inhibitory immunoglobulins >6 U/L 1
• Goiter size ≥WHO grade 2 1

Consider long-term antithyroid drug therapy (5-10 years) for patients at high risk of recurrence, as this reduces recurrence rates to 15% compared to 50% with short-term treatment 1.

Critical Monitoring for Adverse Effects

• Agranulocytosis typically occurs within the first 3 months and presents with sore throat and fever 5, 6. Obtain immediate CBC and discontinue drug if suspected 5, 6.
• Monitor for hepatotoxicity (fever, nausea, vomiting, right upper quadrant pain, dark urine, jaundice) and discontinue immediately if suspected 5.
• Watch for vasculitis (skin changes, hematuria, respiratory symptoms), which can be life-threatening 5, 6.
• Monitor prothrombin time, especially before surgical procedures, as methimazole may cause hypoprothrombinemia 6.

Drug Interactions Requiring Dose Adjustments

• Warfarin: Increased anticoagulation effect requires additional PT/INR monitoring 5, 6.
• Digitalis: Serum levels increase when euthyroid; reduced dose may be needed 6.
• Theophylline: Clearance decreases when euthyroid; reduced dose may be needed 5, 6.

Alternative Definitive Treatments

Radioactive iodine (I-131) ablation resolves hyperthyroidism in >90% of patients with Graves' disease, with hypothyroidism developing in most patients within 1 year 2, 7.

• Absolute contraindications: Pregnancy and breastfeeding 5, 7.
• Avoid pregnancy for 4 months following administration 5, 7.
• May worsen Graves' ophthalmopathy; consider corticosteroid cover to reduce this risk 5, 7.

Thyroidectomy is indicated for:

• Compressive symptoms from obstructive goiter 2, 3
• Large goiter causing neck compression 7
• Patient refusal of radioiodine 7

For Toxic Nodular Goiter

Radioiodine or thyroidectomy are the treatments of choice for toxic multinodular goiter and toxic adenoma 1, 7.

• Antithyroid drugs do not cure toxic nodular disease but can be used for short-term control before definitive therapy 7.
• Radiofrequency ablation is rarely used 1.

For Thyroiditis

Destructive thyroiditis is self-limited and requires only symptomatic management 5, 1, 3.

• Beta-blockers provide symptomatic relief during the hyperthyroid phase 5.
• Antithyroid drugs are NOT indicated because thyroiditis involves hormone release, not synthesis 5.
• Steroids are reserved for severe cases only 1.
• Monitor with symptom evaluation and free T4 testing every 2 weeks 5.
• Introduce levothyroxine if hypothyroidism develops during the recovery phase 5.

Special Populations

Pregnancy

• Propylthiouracil is preferred during the first trimester due to lower risk of congenital malformations compared to methimazole 5, 6, 2.
• Switch to methimazole after the first trimester given propylthiouracil's hepatotoxicity risk 5, 6.
• Both drugs are compatible with breastfeeding, though thyroid function should be monitored weekly or biweekly in nursing infants 6.
• Target FT4 or free T3 in the high-normal range using the lowest possible thioamide dosage 5.

Subclinical Hyperthyroidism (TSH <0.1 mIU/L with normal FT4/FT3)

• Treatment is recommended for patients >60 years or those at increased risk for heart disease, osteoporosis, or osteopenia 5, 3.
• TSH <0.1 mIU/L carries a 3-fold increased risk of atrial fibrillation over 10 years in patients over 60 years 5.
• For TSH 0.1-0.45 mIU/L, routine treatment is not recommended due to insufficient evidence of adverse outcomes 5.

Common Pitfalls to Avoid

• Do not use TSH to guide methimazole dose adjustments—TSH remains suppressed for months after achieving euthyroidism 5.
• Do not reduce methimazole based solely on suppressed TSH while free T4 remains elevated—this leads to inadequate treatment and recurrent hyperthyroidism 5.
• Do not assume all hyperthyroidism requires antithyroid drugs—thyroiditis is self-limited and does not respond to these medications 5, 1.
• Do not overlook agranulocytosis risk—instruct patients to report sore throat and fever immediately, especially in the first 3 months 5, 6.