Etiology of Hyperthyroidism
The most common causes of hyperthyroidism are Graves' disease (accounting for approximately 70% of cases), toxic adenoma, toxic multinodular goiter, and subacute thyroiditis, with rarer causes including trophoblastic disease, thyroid hormone resistance, amiodarone-induced thyroiditis, iatrogenic thyrotoxicosis, factitious ingestion of thyroid hormone, and struma ovarii. 1
Primary Causes of Hyperthyroidism
1. Graves' Disease
- Most common cause in iodine-sufficient areas (70% of hyperthyroidism cases) 2
- Autoimmune disorder characterized by TSH receptor antibodies that bind and activate the thyrotropin receptor (TSHR) 3
- More common in women, with global prevalence of 2% in women and 0.5% in men 4
- May present with diffusely enlarged thyroid gland, exophthalmos, and other extrathyroidal manifestations 4
2. Toxic Nodular Disease
- Accounts for approximately 16% of hyperthyroidism cases 2
- Includes:
- Toxic multinodular goiter: Multiple autonomously functioning nodules
- Toxic adenoma: Single hyperfunctioning nodule
- More common in older adults and in areas with iodine deficiency
- May cause local compression symptoms (dysphagia, orthopnea, voice changes) 4
3. Thyroiditis
- Accounts for approximately 3-9% of hyperthyroidism cases 2
- Types include:
- Subacute (granulomatous) thyroiditis: Often follows viral infection
- Painless (silent) thyroiditis: Often postpartum or autoimmune
- Radiation-induced thyroiditis
- Characterized by destruction of thyroid follicles causing release of preformed thyroid hormone
- Typically self-limiting with transient hyperthyroidism followed by euthyroidism or hypothyroidism
Secondary Causes of Hyperthyroidism
1. Medication/Drug-Induced (9% of cases) 2
- Amiodarone (contains iodine and can cause both hyper- and hypothyroidism)
- Tyrosine kinase inhibitors
- Immune checkpoint inhibitors
- Excessive thyroid hormone replacement
- Iodine-containing contrast media or supplements
2. Other Rare Causes
- TSH-secreting pituitary adenoma
- Human chorionic gonadotropin (hCG)-mediated hyperthyroidism:
- Gestational hyperthyroidism
- Trophoblastic disease (choriocarcinoma, hydatidiform mole)
- Struma ovarii (ectopic thyroid tissue in ovarian teratoma)
- Factitious thyrotoxicosis (intentional ingestion of excess thyroid hormone)
- Thyroid hormone resistance syndrome (rare genetic disorder)
Pathophysiological Mechanisms
Hyperthyroidism occurs through three main mechanisms:
- Increased synthesis and secretion of thyroid hormones (Graves' disease, toxic nodular disease)
- Excessive release of preformed thyroid hormones (thyroiditis)
- Exogenous sources of thyroid hormones (medication-induced, factitious)
Risk Factors for Developing Hyperthyroidism
- Female sex (5-10 times more common in women)
- Advancing age
- Family history of thyroid disorders
- Personal history of autoimmune disorders
- Smoking (particularly for Graves' disease and ophthalmopathy)
- Recent pregnancy (postpartum thyroiditis)
- Iodine excess or deficiency
- Radiation exposure to the neck
- Certain medications (amiodarone, lithium, interferon-alpha)
Clinical Implications
Understanding the etiology of hyperthyroidism is crucial for appropriate management, as treatment approaches differ based on the underlying cause:
- Graves' disease typically requires antithyroid drugs, radioactive iodine, or surgery
- Toxic nodular goiter is usually treated with radioactive iodine or surgery
- Thyroiditis often requires only symptomatic treatment as it is typically self-limiting
Early identification and appropriate management are essential to prevent complications such as atrial fibrillation, heart failure, osteoporosis, and thyroid storm, which can significantly impact morbidity and mortality.