What is the workup for a patient with low Thyroid-Stimulating Hormone (TSH) levels?

Workup for Low TSH

When TSH is low, immediately measure free T4 (and free T3 if T4 is normal/low) to distinguish between hyperthyroidism, subclinical hyperthyroidism, and central hypothyroidism—this single step determines the entire diagnostic and treatment pathway. 1

Initial Laboratory Assessment

Essential First-Line Tests

• Measure TSH and free T4 simultaneously when evaluating thyroid dysfunction, as TSH alone cannot distinguish between hyperthyroidism (low TSH with high T4) and central hypothyroidism (low TSH with low T4) 1
• Add free T3 measurement if TSH is suppressed (<0.1 mIU/L) and free T4 is normal or low, as this identifies T3 thyrotoxicosis, which occurs in approximately 0.5% of newly diagnosed hyperthyroid patients 2
• Repeat testing in 3-6 weeks to confirm persistent TSH suppression, as 30-60% of abnormal thyroid values normalize spontaneously on repeat measurement 3, 4

Stratification by TSH Level

The degree of TSH suppression predicts clinical significance and guides urgency of workup 5, 6:

• Grade I (TSH 0.1-0.4 mIU/L): Detectable but low TSH with normal free hormones—monitor at 3-12 month intervals until normalized or stable 4
• Grade II (TSH <0.1 mIU/L): Fully suppressed TSH—higher risk for atrial fibrillation, bone loss, and cardiovascular events; requires more aggressive evaluation 5, 6

Diagnostic Algorithm Based on Thyroid Hormone Levels

Pattern 1: Low TSH + Elevated Free T4 = Overt Hyperthyroidism

• Check thyroid antibodies (TSH receptor antibodies, thyroid peroxidase antibodies) to distinguish Graves' disease from other causes 1
• Consider thyroid uptake and scan for unusual presentations or to differentiate toxic nodular disease from thyroiditis 7
• Evaluate for symptoms of thyrotoxicosis: tachycardia, tremor, heat intolerance, weight loss, or atrial fibrillation 1, 6

Pattern 2: Low TSH + Normal Free T4 = Subclinical Hyperthyroidism

• Distinguish between Grade I and Grade II based on whether TSH is detectable (0.1-0.4 mIU/L) or fully suppressed (<0.1 mIU/L) 5
• Measure free T3 if TSH <0.01 mIU/L and free T4 is normal/low, as this maximizes detection of T3 thyrotoxicosis (27.6% positive rate at this cutoff) 2
• Assess cardiovascular risk factors: age >65 years, history of atrial fibrillation, heart failure, or coronary disease—these patients face higher risk from untreated subclinical hyperthyroidism 6
• Evaluate bone health: postmenopausal women and elderly patients are at increased risk for accelerated bone loss and fractures 6

Pattern 3: Low TSH + Low Free T4 = Central Hypothyroidism (Hypophysitis)

• Measure 9 AM cortisol immediately when TSH is falling across two measurements with normal or lowered T4, as this pattern suggests pituitary dysfunction 1
• Check additional pituitary hormones: ACTH, FSH/LH, prolactin to assess for hypophysitis, especially in patients on immune checkpoint inhibitors 1
• Obtain brain MRI if headache or visual disturbances are present to evaluate for pituitary enlargement or mass effect 1
• Critical safety point: Never start thyroid hormone replacement before ruling out adrenal insufficiency—initiate corticosteroids first to prevent adrenal crisis 1, 4

Special Clinical Contexts

Patients on Immune Checkpoint Inhibitors

• Monitor TSH every cycle for anti-CTLA4 therapy (including combination with anti-PD-1), as hypophysitis occurs in 8-16% of these patients 1
• Monitor TSH every cycle for first 3 months with anti-PD-1/PD-L1 therapy, then every second cycle thereafter 1
• Recognize that subclinical hyperthyroidism often precedes overt hypothyroidism in immunotherapy-induced thyroiditis—this represents a transient thyrotoxic phase 1
• Check 9 AM cortisol if TSH is falling across measurements, as this indicates possible hypophysitis requiring immediate corticosteroid replacement 1

Patients on Levothyroxine Therapy

• Review the indication for thyroid hormone therapy when TSH is suppressed in a patient taking levothyroxine 4
• For thyroid cancer patients: Confirm target TSH with treating endocrinologist, as intentional suppression may be appropriate (0.1-0.5 mIU/L for intermediate-risk, <0.1 mIU/L for high-risk disease) 4
• For primary hypothyroidism patients: TSH suppression indicates overtreatment—reduce levothyroxine dose by 25-50 mcg and recheck in 6-8 weeks 3, 4
• Recognize iatrogenic hyperthyroidism risks: Approximately 25% of patients on levothyroxine are unintentionally maintained on doses that fully suppress TSH, increasing risks for atrial fibrillation, osteoporosis, and cardiac complications 4

Critical Pitfalls to Avoid

• Do not ignore iodine exposure from CT contrast, as this can transiently suppress TSH and mimic hyperthyroidism 1, 4
• Do not treat based on a single abnormal TSH value without confirmation, as 30-60% normalize on repeat testing 3, 4
• Do not overlook nonthyroidal illness as a cause of TSH suppression, particularly in hospitalized patients where the frequency of true T3 thyrotoxicosis is only 14% compared to 34% in outpatients 2
• Do not delay cardiac evaluation in elderly patients or those with known heart disease, as even subclinical hyperthyroidism significantly increases risk for atrial fibrillation and heart failure 6
• Do not start thyroid hormone replacement before corticosteroids in patients with suspected central hypothyroidism, as this precipitates adrenal crisis 1, 4

Monitoring Strategy

• For confirmed subclinical hyperthyroidism with TSH 0.1-0.4 mIU/L: Retest at 3-12 month intervals until normalized or stable 4
• For TSH <0.1 mIU/L: More frequent monitoring (every 2-4 weeks) is warranted, especially in patients with cardiac disease or atrial fibrillation 4
• For patients on levothyroxine with suppressed TSH: Recheck TSH and free T4 in 6-8 weeks after dose adjustment, targeting TSH within reference range (0.5-4.5 mIU/L) 3, 4