Initial Laboratory Evaluation for Low TSH
When a low TSH is identified, measure serum free T4 first, not free T3. 1, 2
Diagnostic Algorithm
Step 1: Measure Free T4
- Free T4 distinguishes between subclinical hyperthyroidism (normal free T4) and overt hyperthyroidism (elevated free T4) 1
- TSH and free T4 together provide the essential framework for diagnosis 3
- Free T4 measurement has sensitivity above 98% and specificity greater than 92% for detecting thyroid dysfunction 1
Step 2: Measure Free T3 Only in Specific Circumstances
Free T3 should be reserved for patients with:
- TSH <0.01 mIU/L (fully suppressed) AND normal or low free T4 4
- Suspected T3 thyrotoxicosis in the outpatient setting 4
- Clinical symptoms of hyperthyroidism despite normal free T4 5
Why Free T4 Takes Priority
Free T4 is the superior initial test because:
- T3 thyrotoxicosis is rare, occurring in only 0.5% of newly diagnosed hyperthyroidism cases 4
- The likelihood of detecting T3 thyrotoxicosis increases dramatically only when TSH <0.01 mIU/L (27.6% positive rate) versus TSH 0.01-0.3 mIU/L (10.3% positive rate) 4
- Free T3 has limited utility in the vast majority of patients with low TSH 4
- Patients with low TSH and normal total T4/T3 have been shown to have elevated free T4 levels 61% of the time by serial sampling 6
Clinical Context Matters
Outpatient versus Inpatient Settings:
- T3 thyrotoxicosis frequency is 34% in outpatients versus 14% in inpatients when TSH <0.01 mIU/L 4
- Nonthyroidal illness syndrome (common in hospitalized patients) does not require thyroid-specific therapy 2
- Medications (amiodarone, high-dose glucocorticoids, dopamine) can lower free T4 and free T3 while leaving TSH normal or low-normal 2
Reflex Testing Strategy
Optimal reflex protocol:
- Measure free T4 automatically when TSH is low 1
- Add free T3 only if TSH <0.01 mIU/L AND free T4 is normal or decreased 4
- This approach maximizes clinical utility and reduces unnecessary testing 4
Common Pitfalls to Avoid
- Never order free T3 as the initial test for low TSH—it misses the majority of hyperthyroid cases where free T4 is elevated 4, 3
- Avoid measuring free T3 when TSH is only mildly suppressed (0.01-0.3 mIU/L), as the yield is extremely low 4
- Do not overlook medication effects or recent recovery from hyperthyroidism treatment, which can transiently suppress TSH with normal or low thyroid hormones 2
- Recognize that low but detectable TSH (e.g., 0.17-0.26 mIU/L) in ambulatory patients frequently indicates underlying thyroid disease (hot nodules or multinodular goiter in 76% of cases) 7