Diagnostic Investigations for Overt Hypothyroidism
Measure serum TSH and free T4 immediately to confirm overt hypothyroidism, then add anti-thyroid peroxidase (anti-TPO) antibodies to identify autoimmune etiology. 1
Initial Laboratory Testing
Essential Tests to Confirm Diagnosis
- TSH and Free T4 are the cornerstone diagnostic tests—elevated TSH with low free T4 definitively establishes overt hypothyroidism 1, 2
- TSH has sensitivity above 98% and specificity greater than 92% for detecting thyroid dysfunction 1
- Morning testing is preferred for more accurate results, particularly if concurrent adrenal insufficiency is suspected 3
- Repeat testing in 2 weeks to 3 months is recommended before initiating treatment, as 30-60% of abnormal values normalize spontaneously 1
Additional Diagnostic Tests
- Anti-TPO antibodies should be measured to identify Hashimoto's thyroiditis, which causes up to 85% of primary hypothyroidism in iodine-sufficient areas 2, 4
- Positive anti-TPO antibodies predict higher progression risk to worsening hypothyroidism (4.3% per year vs 2.6% in antibody-negative individuals) 1
- Lipid profile (total cholesterol, LDL, triglycerides) should be obtained, as hypothyroidism significantly elevates LDL cholesterol and triglycerides 1
Critical Safety Screening
Rule Out Adrenal Insufficiency First
- Before starting levothyroxine, screen for concurrent adrenal insufficiency—initiating thyroid hormone before corticosteroids can precipitate life-threatening adrenal crisis 3, 5, 6
- This is especially critical in patients with autoimmune hypothyroidism, who have increased risk of concurrent Addison's disease 5
- Consider morning cortisol and ACTH stimulation testing if clinical features suggest adrenal insufficiency (hypotension, hyponatremia, hyperpigmentation) 3
Tests That Are NOT Indicated
- No role for thyroid imaging in routine diagnosis—ultrasound, CT, MRI, or radionuclide scans are not indicated for initial workup of hypothyroidism 1
- Total T3 or free T3 measurements are unnecessary for diagnosing primary hypothyroidism 3
- Thyroid stimulating immunoglobulin (TSI) and thyroid receptor antibodies (TRAb) are only needed if hyperthyroidism is suspected, not for hypothyroidism diagnosis 3
Special Population Considerations
Pregnant Women or Those Planning Pregnancy
- Measure TSH and free T4 as soon as pregnancy is confirmed 6
- Monitor TSH every 4 weeks during pregnancy until stable, then at minimum during each trimester 6
- Maintain TSH in trimester-specific reference ranges 6
Patients on Immune Checkpoint Inhibitors
- Check TSH with optional free T4 every 4-6 weeks as routine monitoring 5
- Thyroid dysfunction occurs in 6-20% of patients on immunotherapy 3
- Even subclinical hypothyroidism warrants treatment consideration if fatigue or other symptoms are present 5
Elderly Patients or Those with Cardiac Disease
- Same diagnostic tests apply, but more cautious interpretation needed 1
- Slightly higher TSH targets (up to 5-6 mIU/L) may be acceptable in very elderly patients 5
Common Diagnostic Pitfalls to Avoid
- Don't test during acute illness—thyroid function tests may be misleading if performed during acute illness, ketosis, or significant weight loss (euthyroid sick syndrome) 1
- Don't treat based on single abnormal value—30-60% of elevated TSH levels normalize on repeat testing 1, 5
- Don't miss central hypothyroidism—if pituitary or hypothalamic disease is suspected, TSH may be inappropriately normal despite low free T4; check free T4 alongside TSH 5
- Don't overlook medication effects—recent iodine exposure (CT contrast), amiodarone, lithium, or immune checkpoint inhibitors can affect thyroid function 1, 2
Interpretation Framework
Overt Primary Hypothyroidism
- TSH elevated (typically >10 mIU/L) with free T4 below normal range 2, 7
- This requires immediate treatment with levothyroxine 7
Subclinical Hypothyroidism
- TSH elevated (4.5-10 mIU/L) with normal free T4 3, 1
- Treatment decisions depend on TSH level, symptoms, pregnancy status, and anti-TPO antibody status 1, 7