What are the causes of subclinical hyperthyroidism?

Causes of Subclinical Hyperthyroidism

Subclinical hyperthyroidism can be caused by both endogenous overproduction of thyroid hormone and exogenous administration of thyroid hormone, with various specific etiologies in each category. 1

Definition and Classification

Subclinical hyperthyroidism is defined as:

• A serum TSH concentration below the statistically defined lower limit of the reference range (typically <0.45 mIU/L)
• Normal free T4 and T3 concentrations within their reference ranges 1

Subclinical hyperthyroidism is typically classified into two categories:

• Mild: TSH 0.1-0.45 mIU/L
• Severe: TSH <0.1 mIU/L 1, 2

Endogenous Causes

Primary Thyroid Disorders

• Graves' disease: Most common cause of endogenous subclinical hyperthyroidism 3
• Toxic multinodular goiter: Common in older adults and in areas with iodine deficiency 2, 4
• Solitary autonomous functioning thyroid nodule 4, 3

Transient Thyroiditis

• Silent (painless) thyroiditis: Self-limited form accounting for significant percentage of subclinical hyperthyroidism cases 3
• Postpartum thyroiditis: Occurs within the first year after delivery 3
• Subacute (de Quervain's) thyroiditis: Usually preceded by viral infection with neck pain 3

Other Endogenous Causes

• Iodine-induced hyperthyroidism: Particularly in areas with endemic goiter or in patients with underlying autonomous nodules 3
• Hemorrhage into a functioning nodule: Can cause transient release of thyroid hormone 3

Exogenous Causes

• Excessive levothyroxine therapy: Common in patients being treated for:
  • Hypothyroidism (hormone over-replacement) 5
  • Thyroid cancer (TSH suppression therapy) 2, 5
  • Benign thyroid nodular disease (TSH suppression therapy) 5

Non-Thyroidal Causes (must be excluded)

• Pregnancy: Normal physiologic changes can lower TSH in first trimester 1
• Recovery phase after treatment of hyperthyroidism: Delayed recovery of pituitary TSH-producing cells 1
• Medications:
  • Dopamine and dopamine agonists 1
  • Glucocorticoids (especially high doses) 1
  • Possibly dobutamine 1
• Severe non-thyroidal illness (euthyroid sick syndrome): Though typically TSH remains in normal range or is only mildly suppressed; undetectable TSH (<0.01 mIU/L) is rare without concomitant medication use 1
• Pituitary or hypothalamic failure: Though usually accompanied by low or low-normal free T4 1

Epidemiology and Risk Factors

• Prevalence is approximately 1-2% in the general population 2
• Higher prevalence in:
  • Women compared to men 1
  • Blacks compared to whites 1
  • Elderly individuals 1, 4
  • Areas with iodine deficiency 2, 1
• Risk factors include:
  • Personal history of previous thyroid disease 1
  • Family history of thyroid disease 1
  • Presence of goiter 1
  • History of atrial fibrillation 1

Clinical Importance

Subclinical hyperthyroidism is associated with:

• Increased risk of progression to overt hyperthyroidism (1-2% per year for TSH <0.1 mIU/L) 1
• Increased risk of atrial fibrillation (3-5 fold) particularly in those >60 years with TSH <0.1 mIU/L 1
• Increased cardiovascular morbidity and mortality in individuals >60 years 1, 4
• Reduced bone mineral density and increased fracture risk, especially in postmenopausal women 2, 5

Diagnostic Considerations

When subclinical hyperthyroidism is suspected:

• Confirm with repeat thyroid function tests in 3-6 months before making definitive diagnosis 6
• Carefully exclude other causes of low TSH with normal T4/T3 1
• Consider that patients with subclinical hyperthyroidism due to Graves' disease may have normal-sized thyroid glands and negative TSH receptor antibodies, making diagnosis challenging 3