What causes hyperthyroidism?

Causes of Hyperthyroidism

The most common causes of hyperthyroidism are Graves' disease, toxic adenoma, toxic multinodular goiter, and subacute thyroiditis. 1 Rare causes include trophoblastic disease, thyroid hormone resistance, amiodarone-induced thyroiditis, iatrogenic thyrotoxicosis, factitious ingestion of thyroid hormone, and struma ovarii.

Primary Causes

1. Graves' Disease

• Most prevalent cause (70% of hyperthyroidism cases) 2
• Autoimmune disorder characterized by:
  • Production of TSH receptor antibodies 1
  • Diffusely enlarged thyroid gland
  • Distinctive ophthalmic signs (eyelid lag/retraction)
  • Dermal signs including localized and pretibial myxedema 1
• More common in women than men (2% vs 0.5% global prevalence) 3

2. Toxic Nodular Conditions

• Toxic multinodular goiter and toxic adenoma (16% of cases) 2
• Characterized by:
  • Autonomous functioning thyroid nodules
  • May cause local compression symptoms (dysphagia, voice changes) 3
  • Radioiodine uptake scan shows nodular uptake pattern 1

3. Thyroiditis

• Subacute granulomatous thyroiditis (3% of cases) 2
• Painless (silent) thyroiditis
• Characterized by:
  • Transient thyrotoxicosis due to destruction of thyroid follicles
  • Release of preformed thyroid hormones
  • Decreased thyroid blood flow on Doppler ultrasound 1
  • Often followed by hypothyroid phase before recovery

Other Significant Causes

4. Drug-Induced Thyroid Dysfunction (9% of cases) 2

• Amiodarone-induced thyroiditis
  • Type I: iodine-induced hyperthyroidism (enlarged/nodular gland)
  • Type II: destructive thyroiditis (normal/small diffuse goiter) 1
• Tyrosine kinase inhibitors
• Immune checkpoint inhibitors
• Excessive iodine exposure
  • Particularly problematic in historically iodine-deficient regions with autonomous nodules 4
  • Sources: iodized salt, seaweed, supplements, drinking water, iodinated contrast media 4

5. Rare Causes

• Factitious ingestion of thyroid hormone
• Struma ovarii (thyroid tissue in ovarian teratoma)
• Trophoblastic disease
• Thyroid hormone resistance 1

Pathophysiological Mechanisms

Hyperthyroidism occurs through three main mechanisms:

1. Increased synthesis of thyroid hormones (Graves' disease, toxic nodules)
2. Excessive release of preformed thyroid hormones (thyroiditis)
3. Exogenous sources (factitious ingestion) 5

Clinical Presentation

Common symptoms of thyrotoxicosis include:

• Anxiety, insomnia
• Palpitations, tachycardia
• Unintentional weight loss
• Diarrhea
• Heat intolerance
• Tremors, nervousness
• Excessive sweating 1, 3

Diagnostic Approach

When hyperthyroidism is suspected:

1. Confirm with biochemical tests: low TSH, high free T4 or free T3
2. Determine specific cause through:
   • TSH-receptor antibodies (positive in Graves' disease)
   • Thyroid peroxidase antibodies
   • Thyroid ultrasonography
   • Scintigraphy (particularly helpful for toxic nodules) 2

Treatment Considerations

Treatment depends on the underlying cause:

• Graves' disease: Antithyroid drugs (methimazole, propylthiouracil), radioactive iodine ablation, or surgery
• Toxic nodular goiter: Typically radioactive iodine or surgery (antithyroid drugs have high relapse rate) 6
• Thyroiditis: Often self-limiting; symptomatic treatment with β-blockers may be sufficient 5

Special Populations

Pregnancy

• Requires careful management due to risks to both mother and fetus
• Untreated hyperthyroidism increases risk for severe preeclampsia, preterm delivery, heart failure, and possibly miscarriage 1

Elderly

• Treatment recommended for subclinical hyperthyroidism in patients >65 years with TSH <0.1 mIU/L due to increased cardiovascular and osteoporosis risks 7

Complications

Untreated hyperthyroidism can lead to:

• Cardiac arrhythmias (particularly atrial fibrillation)
• Heart failure
• Osteoporosis
• Thyroid storm (rare but life-threatening emergency)
• Increased mortality 3, 2

Understanding the specific cause of hyperthyroidism is crucial for appropriate management and preventing these serious complications.