What additional labs should be considered for a comprehensive thyroid workup besides Thyroid-Stimulating Hormone (TSH), free Thyroxine (T4), total Triiodothyronine (T3), and Thyroid Peroxidase (TPO) antibodies?

Additional Laboratory Tests for Comprehensive Thyroid Workup

Beyond TSH, free T4, total T3, and TPO antibodies, the most important additional test to consider is thyroglobulin antibodies (anti-TG), particularly when evaluating for autoimmune thyroid disease or monitoring thyroid cancer. 1, 2

Essential Additional Antibody Testing

Antithyroglobulin (Anti-TG) Antibodies

• Measure anti-TG antibodies simultaneously with TPO antibodies when screening for autoimmune thyroid disease, as approximately 10-20% of patients with Hashimoto's thyroiditis have isolated anti-TG positivity without TPO antibodies 1
• Anti-TG antibodies are mandatory when measuring thyroglobulin levels in thyroid cancer surveillance, as their presence interferes with thyroglobulin measurement and can produce falsely low or high results 2
• The combination of TPO and anti-TG antibodies identifies patients at highest risk for thyroid autoimmunity, with 4.3% annual progression to overt hypothyroidism versus 2.6% in antibody-negative patients 2

Context-Dependent Laboratory Additions

For Suspected Central Hypothyroidism

• Measure early morning ACTH and cortisol before initiating thyroid hormone replacement, as starting levothyroxine before corticosteroids can precipitate life-threatening adrenal crisis in patients with concurrent adrenal insufficiency 2
• Free T4 must be measured alongside TSH in suspected central hypothyroidism, as TSH may be inappropriately normal or only mildly elevated despite low free T4 2

Metabolic and Cardiovascular Risk Assessment

• Measure lipid panel (total cholesterol, LDL, HDL, triglycerides) in patients with subclinical hypothyroidism, as thyroid dysfunction affects cholesterol metabolism and levothyroxine treatment may lower LDL cholesterol 2
• This is particularly relevant when TSH is between 4.5-10 mIU/L, where treatment decisions are individualized based on cardiovascular risk factors 2

For Patients on Immunotherapy

• Check glucose and HbA1c in patients receiving immune checkpoint inhibitors, as new-onset diabetes can occur with immunotherapy alongside thyroid dysfunction 2
• Monitor TSH every 4-6 weeks during the first 3 months of immunotherapy, then every second cycle thereafter, as thyroid dysfunction occurs in 6-20% of patients on anti-PD-1/PD-L1 therapy 2

Thyroid Cancer Surveillance Protocol

Post-Treatment Monitoring

• Measure thyroglobulin (Tg) at follow-up visits for thyroid cancer patients, as it serves as a tumor marker for recurrence 2
• Always measure thyroglobulin antibodies simultaneously with Tg, as antibody interference can render thyroglobulin measurements unreliable 2
• TSH targets vary by risk stratification: 0.5-2 mIU/L for low-risk patients, 0.1-0.5 mIU/L for intermediate-risk, and <0.1 mIU/L for high-risk or persistent disease 2

Tests That Are Generally NOT Needed

Total T3 Has Limited Clinical Utility

• Total T3 measurement adds minimal diagnostic value in most clinical scenarios, particularly in patients on levothyroxine replacement therapy 3
• In levothyroxine-induced over-replacement, T3 levels often remain normal despite TSH suppression and elevated free T4, making T3 measurement unreliable for detecting over-treatment 3
• T3 is primarily useful for confirming endogenous hyperthyroidism (Graves' disease or toxic nodular goiter), not for monitoring levothyroxine therapy 3

Reverse T3 (rT3)

• Reverse T3 measurement is rarely clinically useful and is not recommended in routine thyroid evaluation 4, 5
• Elevated rT3 occurs commonly in non-thyroidal illness and does not change management in most cases 6

Critical Pitfalls to Avoid

• Never measure thyroglobulin without simultaneously checking thyroglobulin antibodies, as up to 25% of patients have interfering antibodies that invalidate the Tg result 2
• Avoid ordering comprehensive thyroid panels reflexively—the combination of TSH and free T4 is sufficient for initial evaluation in 95% of cases 7
• Do not interpret thyroid function tests during acute illness without considering non-thyroidal illness effects, as 25% of hospitalized patients have abnormal free T4 measurements without true thyroid disease 6
• Confirm any abnormal TSH with repeat testing after 3-6 weeks, as 30-60% of elevated TSH values normalize spontaneously 2

Pregnancy-Specific Considerations

• Maintain TSH in the low-normal range (0.5-2.5 mIU/L) during pregnancy, as inadequate treatment increases risk of preeclampsia, low birth weight, and neurodevelopmental effects 2
• Levothyroxine requirements typically increase 25-50% during early pregnancy, necessitating more frequent TSH monitoring every 4-6 weeks 2