What are the treatment options for Graves' disease?

Treatment of Graves' Disease

Methimazole is the preferred first-line treatment for most patients with Graves' disease, administered as a single daily dose of 10-30 mg with titration based on thyroid function tests to maintain FT4 in the high-normal range. 1, 2, 3

Initial Diagnostic Confirmation

Before initiating treatment, confirm the diagnosis with:

• TSH and Free T4 levels to establish biochemical hyperthyroidism 1, 2
• TSH receptor antibody (TSH-R-Ab) testing if clinical features suggest Graves' disease 1, 4
• Physical examination specifically looking for ophthalmopathy or thyroid bruit, which are diagnostic of Graves' disease and warrant early endocrine referral 1

First-Line Medical Treatment: Antithyroid Drugs

Methimazole as Preferred Agent

Methimazole is the drug of choice for most patients because it has fewer major side effects, can be dosed once daily, and is more cost-effective than propylthiouracil. 1, 2, 3, 4

• Starting dose: 10-30 mg once daily 1, 5, 6
• Treatment duration: Standard course of 12-18 months 1, 2, 4, 6
• Dose titration: Adjust based on thyroid function tests with the goal of maintaining FT4 in the high-normal range using the lowest possible dose 1, 2

Monitoring Schedule

The monitoring frequency is critical to catch both treatment response and potential complications:

• Every 4-6 weeks during the initial treatment phase 1, 2
• Every 2-3 months once stable 1, 2
• Watch for adverse reactions within the first 90 days, when agranulocytosis and hepatotoxicity typically occur 6

Propylthiouracil: Limited Indications

Propylthiouracil should be reserved for specific situations only 7, 4:

• Patients intolerant to methimazole 7
• Women planning pregnancy and during the first trimester (switch from methimazole to propylthiouracil to avoid teratogenic effects including aplasia cutis and choanal/esophageal atresia) 1, 2, 4, 5
• Starting dose: 100-300 mg every 6 hours 5

After the first trimester, consider switching back to methimazole for easier dosing and better safety profile. 2

Adjunctive Symptomatic Treatment

While antithyroid drugs address the underlying hyperthyroidism, symptomatic relief is often needed:

Beta-Blockers

• Provide rapid symptomatic relief of tachycardia, tremor, and anxiety 1, 2
• Use atenolol or propranolol 1
• Particularly important in elderly patients or those with cardiovascular comorbidities 6

For Thyroid Eye Disease

• Ocular lubricants are almost always needed for exposure symptoms related to eyelid retraction and proptosis 1
• Selenium supplementation may reduce inflammatory symptoms in milder cases 1
• Teprotumumab (IGF-IR inhibitor) reduces proptosis and clinical activity scores in active thyroid eye disease 1

Predicting Remission and Treatment Duration

Standard Approach

After 12-18 months of treatment, assess for remission:

• Patients with persistently high TSH-R-Ab at 12-18 months can either continue methimazole for another 12 months or opt for definitive therapy with radioactive iodine or thyroidectomy 4
• Approximately 50% of patients achieve remission after a 12-18 month course 6
• In children, extend treatment to 24-36 months 4

Minimum Maintenance Dose Strategy

A practical approach involves maintaining euthyroid status (normal FT4 and TSH) for at least 6 months on minimum maintenance dose (methimazole 5 mg every other day or propylthiouracil 50 mg every other day), which predicts remission in approximately 81% of patients. 8

Second-Line Definitive Treatment Options

When to Consider Definitive Therapy

Definitive treatment should be considered for:

• Patients who relapse after completing antithyroid drug course 1, 2
• Persistent hyperthyroidism after 12-18 months despite adequate medical therapy 1
• Patient preference to avoid long-term medication 6

Radioactive Iodine (RAI)

Absolute contraindications to RAI include 2, 4, 6:

• Pregnancy and breastfeeding 2, 4
• Active or severe thyroid eye disease 4, 6

Important considerations:

• RAI causes permanent hypothyroidism requiring lifelong levothyroxine replacement 6
• Associated with development or worsening of thyroid eye disease in 15-20% of patients 6
• Steroid prophylaxis is warranted in patients with mild/active orbitopathy receiving RAI 4
• Patients should not breastfeed for 4 months after RAI treatment 2

Thyroidectomy

Thyroidectomy is preferred for:

• Very large goiters 2, 6
• Concomitant suspicious or malignant thyroid nodules 1, 6
• Coexisting hyperparathyroidism 1
• Moderate to severe thyroid eye disease when antithyroid drugs cannot be used 1, 6
• Patients who cannot tolerate both antithyroid drugs and RAI 2

Critical requirement: Surgery must be performed by an experienced high-volume thyroid surgeon to minimize complications such as hypoparathyroidism and vocal cord paralysis. 1, 4

Management of Severe Disease/Thyroid Storm

For patients with severe symptoms or thyroid storm:

• Hospitalize immediately for intensive management 1, 2
• High-dose antithyroid drugs 1, 2
• Beta-blockers for symptomatic control 1, 2
• Additional therapies: Consider corticosteroids and saturated solution of potassium iodide (SSKI) 1, 2
• Endocrine consultation is mandatory for all patients with severe symptoms 1

Special Population Considerations

Pregnancy

• Switch from methimazole to propylthiouracil when planning pregnancy and during the first trimester 1, 2, 4
• Consider switching back to methimazole after the first trimester 2
• Goal: Maintain maternal FT4 in high-normal range using lowest possible dose 2
• Some women opt for definitive therapy (RAI or surgery) prior to pregnancy to avoid antithyroid drug exposure during pregnancy 6

Elderly Patients

• Consider starting with lower doses if hypothyroidism develops during treatment 1
• Beta-blockers are particularly important for cardiovascular symptom control 6

Patients on Immune Checkpoint Inhibitors

• If Graves' disease develops as an immune-related adverse event, consider holding checkpoint inhibitors until symptoms resolve if severe enough to affect activities of daily living 1

Critical Pitfalls to Avoid

Monitoring Failures

• Failing to recognize transition from hyperthyroidism to hypothyroidism, which is common with thyroiditis 1, 2
• Not monitoring thyroid function closely enough (every 2-3 weeks after diagnosis initially) to catch this transition 1

Treatment Errors

• Using radioactive iodine in pregnant or breastfeeding women 2
• Initiating thyroid hormone before corticosteroids in patients with both adrenal insufficiency and hypothyroidism (always replace cortisol for 1 week before T4 initiation) 9
• Overlooking ophthalmopathy or thyroid bruit on physical examination, which are diagnostic findings requiring early specialist referral 1

Drug Selection Errors

• Using propylthiouracil as first-line therapy when methimazole is appropriate 1, 2, 3
• Failing to switch from methimazole to propylthiouracil in women planning pregnancy or in the first trimester 1, 2, 4