What is the diagnostic approach for hypothyroidism?

Diagnostic Approach for Hypothyroidism

Measure serum TSH as the initial test when hypothyroidism is suspected, and if elevated, confirm with free T4 measurement to distinguish between subclinical and overt disease. 1, 2, 3

Initial Laboratory Testing

• TSH is the first-line test with a sensitivity of approximately 98% and specificity of 92% when used to confirm clinically suspected thyroid disease 1
• If TSH is elevated above the reference range (typically >4.5 mIU/L), measure free T4 to differentiate between subclinical hypothyroidism (normal free T4) and overt hypothyroidism (low free T4) 1, 2, 3
• Repeat abnormal results in 2 weeks to 3 months before initiating treatment to confirm persistent dysfunction, as TSH can vary by up to 50% day-to-day and 40% at the same time of day 1, 2
• Morning testing is preferred for more accurate and consistent results 2

Diagnostic Criteria

• Overt primary hypothyroidism: TSH above the upper limit of normal (typically >4.5 mIU/L) AND free T4 below the reference range 1, 3
• Subclinical hypothyroidism: TSH elevated (typically >4.5 mIU/L) with normal free T4 levels 1, 2
• The reference range for TSH is approximately 0.4-4.5 mIU/L, though this varies slightly by laboratory and assay type 1

Critical Pitfall: TSH Reference Range Controversy

The upper limit of TSH remains debated. While NHANES III data suggest 4.12 mIU/L as the 97.5th percentile in disease-free populations, some advocate for 2.5 mIU/L 1. However, there is no evidence that TSH between 2.5-4.5 mIU/L causes adverse consequences, so the traditional cutoff of 4.5 mIU/L remains appropriate for clinical practice 1.

Additional Testing to Identify Etiology and Risk

• Anti-thyroid peroxidase (anti-TPO) antibodies identify Hashimoto's thyroiditis as the cause and predict progression risk: positive antibodies confer 4.3% annual risk of developing overt hypothyroidism versus 2.6% in antibody-negative individuals 2
• Lipid profile should be obtained, as hypothyroidism significantly increases LDL cholesterol and triglycerides 2

Conditions That Must Be Excluded Before Diagnosis

Several factors can falsely elevate TSH without true hypothyroidism 1:

• Recent levothyroxine dose adjustments in patients not yet at steady state (takes 6-8 weeks) 1
• Recovery from severe acute illness where TSH transiently increases 1
• Recovery from destructive thyroiditis (subacute or postpartum thyroiditis) 1
• Untreated primary adrenal insufficiency 1
• Heterophilic antibodies causing falsely elevated TSH in certain assays 1
• Medications including iodine, dopamine, glucocorticoids, octreotide, bexarotene, amiodarone, and immune checkpoint inhibitors 1, 3

Who Should Be Tested

Screening asymptomatic individuals is not recommended 1, 3. Instead, targeted testing is appropriate for high-risk groups 2, 3:

• Patients with type 1 diabetes (10-20% prevalence of hypothyroidism) 2
• First-degree relatives of patients with hypothyroidism 3
• History of neck surgery or radiation therapy 3
• Pregnancy with underlying autoimmune thyroid disease 3
• Patients on medications known to affect thyroid function 3

Imaging Has No Role in Routine Diagnosis

Thyroid ultrasound, CT, MRI, or radionuclide scans are not indicated for the initial diagnostic workup of hypothyroidism 2. These modalities do not contribute to the biochemical diagnosis.

Critical Diagnostic Pitfalls to Avoid

Euthyroid Sick Syndrome

Do not perform thyroid function tests during acute illness, ketosis, or significant weight loss, as results will be misleading with TSH frequently suppressed despite normal thyroid function 2. This occurs in 10-20% of critically ill patients 2.

Overdiagnosis and Spontaneous Reversion

37% of patients with initially elevated TSH revert to normal thyroid function within 3 years without intervention 1. Similarly, 24% of those with subclinical hyperthyroidism spontaneously normalize 1. This underscores why confirmation testing is mandatory before labeling someone with thyroid disease 1, 2.

False-Positive Results

TSH secretion varies by age, sex, and race/ethnicity. In persons aged 80 years or older, 12% have TSH >4.5 mIU/L without thyroid disease 1. The standard reference range may be inappropriate for older adults 1.

Not All Subclinical Hypothyroidism Requires Treatment

Patients with TSH between 4.5-10 mIU/L without symptoms often do not require treatment, as evidence for benefit is lacking 2. The decision should be based on symptoms, antibody status, and individual cardiovascular risk rather than TSH alone 2.