Explain the pathophysiology, clinical presentation, diagnosis, and treatment of Graves disease.

Graves Disease Overview

Graves disease is an autoimmune disorder caused by thyroid-stimulating hormone receptor (TSHR) autoantibodies that stimulate the thyroid gland, resulting in hyperthyroidism, diffuse goiter, and in 25-50% of patients, ophthalmopathy. 1, 2

Pathophysiology

The fundamental mechanism involves autoantibodies binding to and activating the TSH receptor on thyroid follicular cells, causing unregulated thyroid hormone production independent of pituitary control. 2

• The disease results from complex interactions between genetic susceptibility and environmental factors, with a strong predisposition in women of reproductive age 1, 2
• TSHR autoantibodies drive thyroid hypertrophy and excessive hormone synthesis 1
• In Graves ophthalmopathy, synergism between insulin-like growth factor 1 receptor (IGF1R) and TSHR autoantibodies causes retro-orbital tissue expansion and inflammation 2
• Pretibial myxedema occurs when autoimmunity targets antigens common to both thyroid and dermal tissues 3

Clinical Presentation

Thyroid Manifestations

• Diffuse goiter with hyperthyroidism is the hallmark finding 3
• Thyroid bruit on physical examination is diagnostic of Graves disease and warrants early endocrine referral 4
• Symptoms include tremors, nervousness, insomnia, excessive sweating, heat intolerance, tachycardia, and hypertension 5

Extrathyroidal Features

• Ophthalmopathy occurs in 25-50% of patients, with distinctive findings of eyelid lag, eyelid retraction, and proptosis 5, 3
• Physical examination findings of ophthalmopathy make the diagnosis almost unmistakable 3
• Pretibial myxedema (localized dermopathy) and acropachy are rare manifestations 3

Special Presentations

• "Apathetic thyrotoxicosis" can occur, particularly in elderly patients, delaying diagnosis 6
• Thyroid storm is a rare but life-threatening medical emergency affecting <1% of pregnant women with hyperthyroidism, characterized by severe acute exacerbation of hyperthyroid symptoms 5

Diagnosis

Laboratory Testing

• Confirm diagnosis with suppressed TSH and elevated free T4 or free thyroxine index (FTI) 5, 4
• TSH receptor antibody (TRAb) testing should be considered when clinical features suggest Graves disease 4, 3
• TRAb measurement represents one of the most important diagnostic tests for Graves disease 1

Imaging

• Thyroid ultrasonography is a critical diagnostic tool for confirming Graves disease 1
• CT or MRI can evaluate extraocular muscle enlargement and orbital fat volume in thyroid eye disease 4

Diagnostic Pitfalls

• In the absence of ophthalmopathy, diagnosis relies on the combination of hyperthyroidism, diffuse goiter, and positive TRAb 3
• Thyrotropin-releasing hormone stimulation test is indicated when diagnosis is suspected but unclear 6

Treatment

First-Line Medical Therapy

Methimazole is the preferred first-line antithyroid drug for most patients with Graves disease. 4, 7

• Titrate dose based on thyroid function tests every 4-6 weeks initially, then every 2-3 months once stable, with the goal of maintaining FT4 in the high-normal range using the lowest possible dose 4
• Methimazole allows once-daily dosing due to its longer half-life compared to propylthiouracil (PTU), improving adherence 7
• For persistent hyperthyroidism beyond 6 weeks, refer to endocrinology for additional workup and possible medical thyroid suppression 4
• Antithyroid drugs result in only 25-50% remission rates at 1-2 years, with 60-70% of patients relapsing after a course of therapy 3, 6

Pregnancy Considerations

Switch from methimazole to propylthiouracil during pregnancy planning and the first trimester due to PTU's limited placental transfer. 4, 7

• Untreated hyperthyroidism increases risks of severe preeclampsia, preterm delivery, heart failure, miscarriage, and low birth weight 5
• Thioamides increase fetal and neonatal risks; fetal thyrotoxicosis must be considered in women with Graves disease history 5
• Radioactive iodine is absolutely contraindicated in pregnancy and breastfeeding as it damages the fetal thyroid gland 4, 7

Symptomatic Management

• Beta-blockers (atenolol or propranolol) provide symptomatic relief of tachycardia, tremor, and anxiety 4, 7
• Inorganic iodide decreases thyroid vascularity and is primarily used to prepare patients for thyroid surgery 7
• Lithium acts similarly to iodine but is not routinely used due to transient effects and serious adverse effects 7

Second-Line Definitive Therapy

For patients who fail antithyroid drugs after 12-18 months, consider radioactive iodine therapy or thyroidectomy. 4

Radioactive Iodine

• In the United States, radioiodine therapy has become the preferred treatment for adults with Graves disease due to ease of administration, safety, effectiveness, and affordability 7
• Hypothyroidism is an inevitable consequence, occurring in 70-100% of patients at 10 years 6
• Radioactive iodine is contraindicated in pregnancy, breastfeeding, and patients with active or severe orbitopathy 4, 7
• Retreatment is needed in 25-33.7% of patients 6

Surgery

• Thyroidectomy should be performed by an experienced high-volume thyroid surgeon 4
• Surgery offers the highest cure rate (95-100%) in the shortest time, with >90% of patients remaining euthyroid at 2 years 6
• Complications in experienced hands include reoperation for hemorrhage (0-1.3%), recurrent nerve palsy (0-4.5%), and permanent hypocalcemia (0-0.6%) 6
• Surgery is now performed only in special circumstances, such as large goiters, contraindications to other therapies, or patient preference 7

Management of Thyroid Eye Disease

Ocular lubricants are almost always needed to combat exposure related to eyelid retraction and proptosis. 4

• Selenium supplementation may reduce inflammatory symptoms in milder thyroid eye disease 4
• Teprotumumab (IGF-IR inhibitor) reduces proptosis and clinical activity score in patients with active thyroid eye disease 4
• For moderate-to-severe disease, consider orbital decompression, high-dose steroids, or radiation treatment 4
• If orbital decompression is indicated, delay strabismus repair until after decompression 4
• Fresnel or ground-in prism can provide temporary diplopia relief while awaiting definitive treatment 4

Thyroid Storm Management

Hospitalize patients with severe symptoms for intensive management. 4

• Use beta-blockers, high-dose antithyroid drugs, and consider additional therapies such as steroids and saturated solution of potassium iodide (SSKI) 4
• Endocrine consultation is recommended for all patients with severe symptoms 4
• Thyroid storm is a medical emergency requiring immediate intervention 5

Special Populations

• For elderly patients (>70 years) or those with comorbidities, consider starting with lower doses of thyroid replacement if hypothyroidism develops 4
• For patients with severe symptoms affecting activities of daily living on immune checkpoint inhibitors, consider holding therapy until symptoms resolve 4

Critical Pitfalls to Avoid

Failing to recognize the transition from hyperthyroidism to hypothyroidism is a common error, particularly with thyroiditis. 4

• Monitor thyroid function every 2-3 weeks after diagnosis to catch transition to hypothyroidism 4
• Never use radioactive iodine in pregnant or breastfeeding women 4
• Always replace cortisol for 1 week before initiating T4 in patients with both adrenal insufficiency and hypothyroidism 5, 4
• High-dose corticosteroids are not routinely required for managing checkpoint-inhibitor-induced thyroid dysfunction and should be avoided for long-term Graves control due to serious irreversible side effects 4