What is the definition of subclinical hypothyroidism?

Definition of Subclinical Hypothyroidism

Subclinical hypothyroidism is defined as an elevated serum thyroid-stimulating hormone (TSH) concentration above the statistically defined upper limit of the reference range (4.5 mIU/L) with normal free thyroxine (FT4) and triiodothyronine (T3) levels. 1, 2, 3

Diagnostic Criteria

• The normal reference range for TSH is considered to be 0.45-4.5 mIU/L, as established by the American Medical Association 1, 3
• Diagnosis requires normal FT4 levels with elevated TSH 1
• The diagnosis is purely biochemical and does not require the presence of symptoms 1, 4
• Patients are often further classified based on TSH levels:
  • Mild: TSH between 4.5-10 mIU/L 1, 4
  • More severe: TSH >10 mIU/L 5, 6

Differential Diagnosis and Exclusions

• Several conditions can cause temporary TSH elevation and should be excluded before confirming the diagnosis: 1, 2
  • Recent adjustments in levothyroxine dosage with failure to reach steady state 1
  • Recovery from severe illness 1
  • Recovery from destructive thyroiditis, including postviral subacute thyroiditis and postpartum thyroiditis 1
  • Untreated primary adrenal insufficiency 1
  • Laboratory interference from heterophilic antibodies against mouse proteins 1
• Medications that can affect TSH values include dopamine, glucocorticoids, and dobutamine 2

Epidemiology and Risk Factors

• Prevalence is approximately 4-8.5% in the general adult population without known thyroid disease 1, 2
• Higher prevalence in women, especially those over 60 years (up to 20%) 1, 2
• Lower prevalence in blacks (approximately one-third that of whites) 1
• Lower prevalence in some populations with iodine deficiency 1
• Risk factors include: 2, 3
  • Female gender
  • Older age
  • Previous hyperthyroidism
  • Type 1 diabetes mellitus
  • Family history of thyroid disease
  • Previous head and neck cancer treated with external beam radiation

Natural History and Clinical Significance

• Approximately 2-5% of patients with subclinical hypothyroidism progress to overt hypothyroidism annually 1, 5
• The rate of progression is proportional to the baseline TSH concentration 1
• Higher risk of progression in individuals with antithyroid antibodies 1, 2
• In about 5% of cases, TSH returns to normal after 1 year without treatment 1
• Potential health consequences include: 2
  • Cardiac dysfunction
  • Possible increased cardiovascular risk
  • Elevation in total and LDL cholesterol
  • Neuropsychiatric symptoms
  • Risk of progression to overt hypothyroidism

Common Pitfalls in Diagnosis

• Misinterpreting TSH elevations between 2.5-4.5 mIU/L as subclinical hypothyroidism 1
• Failing to exclude other causes of transient TSH elevation 1, 2
• Not recognizing that central hypothyroidism (usually hypothalamic) may cause mildly elevated TSH due to bioinactive TSH molecules 1
• Overlooking medication effects on TSH values 2
• Failing to recognize laboratory interference from heterophilic antibodies 1, 2

While some investigators have suggested lowering the upper limit of normal for serum TSH to 2.5 mIU/L, there is no evidence for associated adverse consequences in individuals with TSH between 2.5-4.5 mIU/L, and this could lead to misidentification of normal individuals as having hypothyroidism 1.