What symptoms would prompt testing for Thyroid-Stimulating Hormone (TSH), total Triiodothyronine (T3), total Thyroxine (T4), reverse T3, anti-Thyroid Peroxidase (anti-TPO), and anti-Thyroglobulin?

Comprehensive Thyroid Testing: Clinical Indications

Primary Clinical Scenarios Warranting Full Thyroid Panel

The comprehensive thyroid panel (TSH, total T3, total T4, reverse T3, anti-TPO, and anti-thyroglobulin) is most appropriately ordered when evaluating suspected autoimmune thyroid disease with complex presentation, monitoring patients on immune checkpoint inhibitors, or investigating persistent hypothyroid symptoms despite normal standard testing.

Hypothyroidism Symptoms

The following symptoms should prompt thyroid evaluation, with TSH as the initial test and expanded testing based on clinical context 1:

• Unexplained fatigue, weight gain, hair loss, cold intolerance, constipation, and depression are classic hypothyroid symptoms that warrant initial TSH testing 1
• Persistent symptoms despite normal TSH may require free T4 and T3 measurement, as immunoassays can show falsely normal values that are actually low when measured by more accurate methods 2
• Goiter, menstrual disturbances, galactorrhea, dry skin, and lack of energy in combination suggest hypothyroidism even when screening tests appear normal 3

Hyperthyroid/Thyrotoxic Symptoms

• Weight loss, palpitations, heat intolerance, tremors, anxiety, and diarrhea indicate possible thyrotoxicosis, requiring TSH, free T4, and total T3 measurement 1
• Asymptomatic patients on routine monitoring may show high free T4 or T3 with low/normal TSH, particularly common with painless thyroiditis 1
• Symptoms may be masked in patients taking beta-blockers, making biochemical testing even more critical 1

Autoimmune Thyroid Disease Evaluation

Anti-TPO and anti-thyroglobulin antibodies should be measured when autoimmune thyroid disease is suspected 1, 4:

• Confirmed biochemical hypothyroidism (high TSH, low free T4) warrants anti-TPO antibody testing to identify autoimmune etiology 1
• Positive anti-TPO antibodies predict higher progression risk to overt hypothyroidism (4.3% per year vs 2.6% in antibody-negative individuals) 5
• Anti-thyroglobulin antibodies should be measured in patients with suspected autoimmune disease who are negative for anti-TPO, as approximately 10-15% of autoimmune thyroid disease patients have isolated anti-Tg positivity 4
• Anti-Tg antibodies interfere with thyroglobulin assays, making their measurement essential before monitoring thyroglobulin levels 4

Immune Checkpoint Inhibitor Monitoring

Patients receiving immunotherapy require comprehensive thyroid monitoring 1:

• Thyroid dysfunction occurs in 6-20% of patients on immune checkpoint inhibitors, with higher rates (up to 20%) on combination therapy 1
• Routine TSH monitoring every 4-6 weeks is recommended for asymptomatic patients, with free T4 added if TSH is abnormal 1
• Thyrotoxicosis from thyroiditis typically occurs one month after starting therapy, followed by hypothyroidism after another month 1
• Anti-TPO antibodies help distinguish immune-related thyroiditis from other causes of thyroid dysfunction 1

Suspected Hypophysitis

Headache and fatigue with specific biochemical patterns warrant expanded testing 1:

• Low free T4 with low or inappropriately normal TSH suggests pituitary dysfunction rather than primary thyroid disease 1
• Additional testing should include ACTH, cortisol, gonadal hormones (testosterone in men, estradiol in women), FSH, and LH 1
• MRI of the sella with pituitary cuts is essential for diagnostic confirmation 1
• Steroids must always be started before thyroid hormone in patients with both adrenal insufficiency and hypothyroidism to avoid adrenal crisis 1

Complex or Refractory Cases

• Patients with persistent hypothyroid symptoms on levothyroxine despite normal TSH may benefit from comprehensive testing including T3 and reverse T3 2
• Approximately 20% of patients continue to report symptoms despite seemingly normal TSH, FT3, and FT4 by immunoassay 2
• Immunoassays can be affected by alterations in serum binding proteins, yielding falsely normal results 2

Critical Testing Algorithm

Initial Evaluation

• TSH is the single best screening test with sensitivity above 98% and specificity greater than 92% 6
• If TSH is abnormal, measure free T4 to distinguish subclinical from overt dysfunction 5

When to Expand Testing

• Add anti-TPO antibodies when TSH is elevated to confirm autoimmune etiology and predict progression risk 1, 7
• Measure total T3 when evaluating thyrotoxicosis, as T3 toxicosis can occur with normal T4 1
• Consider reverse T3 in complex cases where tissue hypothyroidism is suspected despite normal standard tests, though this remains controversial 2
• Check anti-thyroglobulin if anti-TPO is negative but autoimmune disease is still suspected, or before monitoring thyroglobulin levels 4

Common Pitfalls to Avoid

• Do not order comprehensive panels as initial screening - TSH alone is sufficient for most cases 6
• Confirm elevated TSH with repeat testing after 3-6 weeks, as 30-60% of high TSH levels normalize spontaneously 5
• Never start thyroid hormone before ruling out adrenal insufficiency in patients with suspected central hypothyroidism, as this can precipitate adrenal crisis 1
• Recognize that symptoms of thyroid dysfunction are non-specific and extremely prevalent in the general population, requiring biochemical confirmation 6
• Consider non-thyroidal illness, recent iodine exposure, or medications as causes of transient thyroid function test abnormalities 5