What is the approach to evaluating thyroid function beyond Thyroid-Stimulating Hormone (TSH) and free Thyroxine (T4)?

Thyroid Workup Beyond TSH and Free T4

Beyond TSH and free T4, the additional thyroid workup depends on the clinical context: for suspected autoimmune disease, measure anti-TPO antibodies; for suspected hyperthyroidism with normal free T4, add free T3; and for suspected central hypothyroidism, measure free T4 alongside TSH (since TSH becomes unreliable). 1

Core Additional Tests Based on Clinical Scenario

Anti-Thyroid Peroxidase (Anti-TPO) Antibodies

• Measure anti-TPO antibodies when TSH is elevated (particularly 4.5-10 mIU/L) to identify autoimmune etiology and predict progression risk. 1
• Positive anti-TPO antibodies indicate a 4.3% annual progression rate to overt hypothyroidism versus 2.6% in antibody-negative individuals. 1
• This test helps guide treatment decisions in subclinical hypothyroidism, as positive antibodies strengthen the case for initiating levothyroxine therapy. 1

Free T3 (Triiodothyronine)

• Free T3 is essential when hyperthyroidism is suspected but free T4 is normal or borderline, as T3 toxicosis can occur with isolated T3 elevation. 2, 3
• In patients with Graves' disease on antithyroid drugs, T3 may remain elevated even when free T4 drops below normal, making T3 monitoring critical for assessing true thyroid status. 3
• Free T3 is more useful than total T3 because it avoids confounding from thyroid hormone-binding protein variations. 2

Repeat Testing for Confirmation

• Always confirm an abnormal TSH with repeat testing after 3-6 weeks before initiating treatment, as 30-60% of elevated TSH values normalize spontaneously. 1
• Transient TSH elevations can occur during recovery from thyroiditis, nonthyroidal illness, or due to medications. 1

Specialized Scenarios Requiring Additional Testing

Central Hypothyroidism Evaluation

• When central hypothyroidism is suspected (pituitary or hypothalamic disease), measure free T4 alongside TSH, as TSH becomes unreliable in this context. 4
• The pattern of low or inappropriately normal TSH with low free T4 indicates central hypothyroidism. 4
• Additional workup includes: morning ACTH and cortisol levels (to rule out concurrent adrenal insufficiency), MRI of the sella with pituitary cuts, and assessment of other pituitary hormones (FSH, LH, gonadal hormones). 4
• Critical pitfall: Never start thyroid hormone replacement before ruling out adrenal insufficiency, as this can precipitate adrenal crisis. 4

Thyroid Cancer or Nodular Disease

• Thyroid ultrasound and radioactive iodine uptake scans are primarily important for diagnosing unusual cases of hyperthyroidism and evaluating nodular disease. 3
• Plasma thyroglobulin (Tg) and thyroid stimulating antibody (TSAb) may be indicated in specific cases. 3

Pregnancy-Specific Testing

• In pregnant patients with pre-existing hypothyroidism, measure both TSH and free T4 as soon as pregnancy is confirmed and during each trimester. 5
• Maintain TSH in the trimester-specific reference range, as requirements typically increase 25-50% above pre-pregnancy doses. 1
• Monitor TSH every 4 weeks until stable, then reduce to pre-pregnancy levels immediately after delivery. 5

Common Pitfalls to Avoid

Assay Interference and Laboratory Artifacts

• Screen for laboratory artifacts in TSH or thyroid hormone immunoassays when results are discordant with clinical presentation, avoiding unnecessary investigation or treatment. 6
• Consider confounding factors including pregnancy, intercurrent nonthyroidal illness, and medications (thyroxine, amiodarone, heparin). 6
• Familial dysalbuminemic hyperthyroxinemia and transthyretin-associated hyperthyroxinemia can cause elevated total T4 with normal free T4 in euthyroid patients. 2

Overutilization of Testing

• TSH alone is sufficient for initial screening in asymptomatic patients with low probability of thyroid dysfunction. 3, 7
• The two-step approach (TSH first, then free T4 only if TSH is abnormal) avoids measuring free T4 in 93% of individuals with minimal risk of missing thyroid dysfunction. 8
• Simultaneous TSH and free T4 testing is not necessary for initial evaluation in most cases. 8

Monitoring Patients on Treatment

• In patients on levothyroxine for primary hypothyroidism, monitor TSH every 6-8 weeks after dose changes, then every 6-12 months once stable. 5
• Free T4 can help interpret ongoing abnormal TSH levels during therapy, as TSH may take longer to normalize. 1
• In central hypothyroidism, monitor free T4 levels (not TSH) and maintain in the upper half of the normal range. 5
• In pediatric patients, measure both TSH and total or free T4 at 2 and 4 weeks after treatment initiation, 2 weeks after dose changes, then every 3-12 months until growth is completed. 5