What is the recommended stepwise management of thyrotoxicosis, including beta‑blocker dosing, choice and dosing of antithyroid drugs (methimazole versus propylthiouracil), treatment of thyroid storm, definitive therapy options (radioactive iodine or thyroidectomy), and special considerations for pregnancy, large goiters, severe Graves’ ophthalmopathy, and elderly or frail patients?

Thyrotoxicosis Management

Initial Stabilization and Beta-Blocker Therapy

For symptomatic thyrotoxicosis, initiate a non-selective beta-blocker immediately to control hyperadrenergic symptoms, with propranolol 20-40 mg every 6 hours or atenolol 25-100 mg daily as first-line agents. 1

• Beta-blockers should be started in all symptomatic patients presenting with palpitations, tremor, anxiety, or heat intolerance 1
• Propranolol is preferred when available due to its additional benefit of inhibiting peripheral T4 to T3 conversion 2
• Non-selective beta-blockers with alpha-receptor blocking capacity may provide superior symptom control in severely symptomatic patients 1
• Dose reduction of beta-blockers will be necessary as the patient becomes euthyroid, since hyperthyroidism increases clearance of these medications 3, 4

Antithyroid Drug Selection and Dosing

Methimazole is the preferred antithyroid drug for routine management of Graves' disease at an initial dose of 10-40 mg daily (depending on severity), given as a single daily dose. 2, 5, 6

Methimazole Advantages and Dosing

• Methimazole can be administered once daily, improving adherence compared to propylthiouracil's three-times-daily regimen 2
• Initial dosing for adults ranges from 10-40 mg daily based on severity: mild hyperthyroidism (10-20 mg), moderate (20-30 mg), severe or large goiters (30-40 mg) 5, 6
• Methimazole is more cost-effective than propylthiouracil 2
• At low doses, methimazole demonstrates less major toxicity compared to propylthiouracil 2
• Maintenance dosing typically ranges from 5-15 mg daily after initial control is achieved 5, 6

Propylthiouracil: Specific Indications Only

Propylthiouracil should be reserved for three specific situations: thyroid storm, first trimester of pregnancy, and patients with severe methimazole allergy or intolerance. 3, 4, 2, 5, 6

• Initial adult dosing is 300-400 mg daily in divided doses every 8 hours; severe cases may require 600-900 mg daily 4
• Usual maintenance dose is 100-150 mg daily in divided doses 4
• Propylthiouracil carries significant hepatotoxicity risk, including hepatic failure requiring transplantation or resulting in death, particularly in pediatric patients 4
• Propylthiouracil is preferred in thyroid storm due to its additional effect of blocking peripheral T4 to T3 conversion 2
• Switch from methimazole to propylthiouracil when pregnancy is planned and throughout the first trimester, then switch back to methimazole for the second and third trimesters 3, 4, 5, 6

Monitoring Antithyroid Drug Therapy

• Check thyroid function tests (TSH and free T4) every 4-6 weeks during initial titration 5, 6
• Monitor for agranulocytosis: instruct patients to immediately report fever, pharyngitis, or malaise and obtain urgent white blood cell count 3, 4
• Check prothrombin time before surgical procedures, as both drugs may cause hypoprothrombinemia 3, 4
• A rising TSH during treatment indicates the need for dose reduction to prevent iatrogenic hypothyroidism 3, 4
• Monitor liver function tests, especially with propylthiouracil, and discontinue immediately if transaminases rise significantly 4

Critical Drug Interactions

• Warfarin activity may be increased due to vitamin K inhibition; monitor PT/INR closely, especially before surgery 3, 4
• Digitalis dose may need reduction as patients become euthyroid, since hyperthyroidism increases digitalis clearance 3, 4
• Theophylline clearance decreases as euthyroidism is achieved; dose reduction may be necessary 3, 4

Thyroid Storm Management

Thyroid storm requires aggressive multi-drug therapy: propylthiouracil 600-1000 mg loading dose, then 200-250 mg every 4 hours; iodine (Lugol's solution 5-10 drops every 6-8 hours or saturated solution of potassium iodide) given 1 hour after the first antithyroid drug dose; propranolol 40-80 mg every 4-6 hours; and hydrocortisone 100 mg IV every 8 hours. 7, 5

• Propylthiouracil is preferred over methimazole in thyroid storm due to its peripheral T4 to T3 conversion blockade 7, 2
• Iodine must be administered at least 1 hour after the first antithyroid drug dose to prevent providing substrate for new hormone synthesis 7, 5
• Beta-blockers control the peripheral hyperadrenergic manifestations and reduce mortality 7
• Corticosteroids (hydrocortisone 100 mg IV every 8 hours or dexamethasone 2 mg every 6 hours) inhibit peripheral T4 to T3 conversion and treat potential relative adrenal insufficiency 7, 5
• Supportive care includes aggressive cooling, IV fluids, treatment of precipitating factors (infection, trauma, surgery), and ICU-level monitoring 7
• Alternative agents for refractory cases include cholestyramine (to interrupt enterohepatic circulation), lithium carbonate (if iodine contraindicated), or potassium perchlorate 7

Definitive Therapy: Radioactive Iodine vs. Surgery

After 12-18 months of antithyroid drug therapy, patients who relapse or have persistently elevated TSH-receptor antibodies should receive definitive treatment with either radioactive iodine (preferred for most adults) or total thyroidectomy. 5, 6

Radioactive Iodine Therapy

• RAI is the preferred definitive treatment for most adult patients with Graves' disease in the United States 5
• A single dose controls thyrotoxicosis in approximately 90% of patients 8
• Hypothyroidism develops in 18% at 5 years, rising to 42% at 20 years with calculated dosing 8
• Empirical dosing (110-370 MBq) results in higher early hypothyroidism rates (38.5% at 5 years) compared to calculated dosing 8
• RAI is absolutely contraindicated in patients with active or severe Graves' ophthalmopathy 5, 6
• Steroid prophylaxis (prednisone 0.3-0.5 mg/kg for 1 month, then taper) is mandatory for patients with mild active orbitopathy receiving RAI 6

Thyroidectomy Indications and Outcomes

• Total thyroidectomy should be performed by a high-volume, experienced thyroid surgeon 5, 6
• Surgery controls thyrotoxicosis in 89% of patients with lower long-term hypothyroidism rates (2% at 5 years, 27.5% at 20 years) compared to RAI 8
• Thyroidectomy is preferred for: large goiters (>80 grams), coexisting suspicious thyroid nodules, patient preference to avoid radiation, and severe ophthalmopathy 5, 6
• Patients must be rendered euthyroid with antithyroid drugs before surgery to prevent thyroid storm 5, 6
• Potassium iodide (5-7 drops of saturated solution three times daily) should be added 7-10 days preoperatively to reduce gland vascularity 5

Special Population Considerations

Pregnancy Management

Pregnant women with thyrotoxicosis require propylthiouracil during the first trimester, then switch to methimazole for the second and third trimesters, maintaining free T4 in the upper normal range with the lowest effective antithyroid drug dose. 3, 4, 5, 6

• Untreated or inadequately treated Graves' disease increases risk of maternal heart failure, spontaneous abortion, preterm birth, stillbirth, and fetal/neonatal hyperthyroidism 3, 4
• Methimazole is associated with rare congenital malformations (aplasia cutis, choanal atresia, esophageal atresia) when used in the first trimester 3, 5, 6
• Propylthiouracil carries maternal hepatotoxicity risk but is preferred in the first trimester to avoid methimazole embryopathy 3, 4, 6
• Switch to methimazole after the first trimester to minimize maternal hepatotoxicity risk 3, 4, 6
• Thyroid dysfunction often diminishes as pregnancy progresses; dose reduction or discontinuation may be possible in the third trimester 3, 4
• Monitor TSH-receptor antibodies at diagnosis and in the third trimester to assess fetal/neonatal hyperthyroidism risk 5, 6

Large Goiters

• Large goiters (>80 grams) may require higher initial methimazole doses (30-40 mg daily) or propylthiouracil 400-600 mg daily 4, 5
• Thyroidectomy is often preferred over RAI for large goiters due to compressive symptoms and lower RAI efficacy 5, 6
• If RAI is chosen, calculated dosing based on gland size and uptake is preferred over empirical dosing 8

Severe Graves' Ophthalmopathy

Radioactive iodine is absolutely contraindicated in patients with active, severe Graves' ophthalmopathy; these patients should undergo thyroidectomy after achieving euthyroidism with antithyroid drugs. 5, 6

• For mild, active ophthalmopathy, RAI may be used only with concurrent steroid prophylaxis (prednisone 0.3-0.5 mg/kg for 1 month, then taper) 6
• Maintain strict euthyroidism, as both hyper- and hypothyroidism can worsen eye disease 5, 6
• Coordinate care with an ophthalmologist experienced in thyroid eye disease 5

Elderly and Frail Patients

• Start with lower beta-blocker doses (propranolol 10-20 mg every 6-8 hours or atenolol 25 mg daily) and titrate cautiously 5
• Consider lower initial antithyroid drug doses (methimazole 10-20 mg daily) in elderly patients 5
• RAI is often preferred over surgery in elderly or frail patients due to lower procedural risk 5
• Monitor closely for atrial fibrillation, heart failure, and osteoporosis complications 5

Pediatric Patients

Methimazole is strongly preferred over propylthiouracil in children due to severe hepatotoxicity risk with propylthiouracil, including hepatic failure requiring transplantation. 3, 4, 5

• Initial pediatric dosing (age ≥6 years) starts at 0.2-0.5 mg/kg/day methimazole, with careful upward titration 5
• A 24-36 month course of methimazole is recommended in children before considering definitive therapy 6
• Propylthiouracil should only be used in rare instances when methimazole is not tolerated and surgery/RAI are inappropriate 4
• Parents must be warned about hepatotoxicity signs: tiredness, nausea, anorexia, fever, pharyngitis, malaise 4

Critical Pitfalls to Avoid

• Never administer iodine before antithyroid drugs in thyroid storm—this provides substrate for massive new hormone synthesis 7, 5
• Never use propylthiouracil as first-line therapy in children—hepatotoxicity risk is unacceptable except in specific circumstances 4, 5
• Never give RAI to patients with active/severe ophthalmopathy without recognizing the absolute contraindication—this will worsen eye disease 5, 6
• Never perform thyroidectomy on a thyrotoxic patient—always achieve euthyroidism first to prevent intraoperative thyroid storm 5, 6
• Never continue methimazole through the first trimester of pregnancy—switch to propylthiouracil to avoid embryopathy 3, 5, 6
• Never ignore fever, pharyngitis, or malaise in patients on antithyroid drugs—obtain immediate CBC to rule out life-threatening agranulocytosis 3, 4
• Never forget to warn patients about vasculitis symptoms (new rash, hematuria, decreased urine output, dyspnea, hemoptysis)—this rare but severe complication requires immediate drug discontinuation 3, 4