What is Graves' Disease?
Graves' disease is an autoimmune disorder in which autoantibodies bind to and stimulate the thyroid-stimulating hormone receptor (TSHR), causing uncontrolled thyroid hormone secretion, hyperthyroidism, and typically a diffuse goiter. 1, 2
Pathophysiology
- The fundamental mechanism involves TSHR autoantibodies acting as agonists, releasing the thyroid gland from normal pituitary feedback control and driving excessive thyroid hormone production 1
- These autoantibodies (also called thyroid-stimulating immunoglobulins or TRAb) directly stimulate thyroid follicular cells, causing both gland hypertrophy and increased hormone synthesis 3, 4
- Graves' disease is the most common cause of persistent hyperthyroidism in adults, accounting for the majority of hyperthyroid cases 2
Epidemiology
- Approximately 3% of women and 0.5% of men will develop Graves' disease during their lifetime 2
- The condition occurs at all ages but is especially common in women of reproductive age 1
- There is a strong genetic predisposition combined with environmental triggers in immunologically susceptible individuals 1, 5
Clinical Manifestations
Thyroid Features
- Diffuse goiter with hyperthyroidism is the hallmark presentation 3, 5
- Patients exhibit classic signs of thyrotoxicosis including weight loss, palpitations, heat intolerance, tremors, anxiety, and diarrhea 6
- Distinctive physical findings include eyelid lag/retraction and thyroid bruit 7
Extrathyroidal Manifestations
- Graves' ophthalmopathy (GO) occurs in approximately 50% of patients, caused by synergism between TSHR autoantibodies and insulin-like growth factor 1 receptor (IGF1R), leading to retro-orbital tissue expansion and inflammation 1, 3
- Graves' dermopathy (pretibial myxedema) and acropachy are rare manifestations, presumably due to autoimmunity against antigens common to the thyroid and other affected organs 1, 3
Diagnosis
- Biochemical confirmation requires elevated free T4 (or total T3) with suppressed or low TSH 6
- Measurement of TSH receptor antibodies (TRAb or TSI) confirms the autoimmune etiology and distinguishes Graves' disease from other causes of thyrotoxicosis 6, 4
- Thyroid ultrasonography showing diffuse gland involvement supports the diagnosis 4
- Physical examination findings of ophthalmopathy or thyroid bruit are diagnostic of Graves' disease 7
Treatment Overview
Three primary treatment modalities exist: antithyroid drugs, radioactive iodine (RAI), or thyroidectomy—none of which target the underlying autoimmune process 2, 4
Antithyroid Drugs
- A 12- to 18-month course leads to remission in approximately 50% of patients, but 60-70% relapse after discontinuation 2, 3
- Methimazole and propylthiouracil are the primary agents used 2
- Rare but serious adverse reactions include agranulocytosis and hepatotoxicity, typically occurring within the first 90 days 2
Radioactive Iodine
- Results in permanent gland destruction requiring lifelong levothyroxine replacement 2
- Associated with development or worsening of thyroid eye disease in approximately 15-20% of patients 2
Surgery
- Near-total thyroidectomy offers a 95-100% cure rate with low complication rates in experienced hands 5
- Potential complications include hypoparathyroidism (0-0.6%) and recurrent laryngeal nerve palsy (0-4.5%) 5
- Favored in patients with suspicious thyroid nodules, coexisting hyperparathyroidism, large goiters, or moderate to severe thyroid eye disease 2
Special Considerations
Pregnancy
- Propylthiouracil is preferred in the first trimester due to methimazole's risk of congenital malformations, with a switch to methimazole after the first trimester to avoid maternal hepatotoxicity 7
- Radioactive iodine is absolutely contraindicated in pregnancy 7
- Untreated or inadequately controlled hyperthyroidism increases risks of preeclampsia, preterm delivery, and miscarriage 7