Low Free T3 and Free T4 with Normal TSH
This pattern most commonly represents either non-thyroidal illness syndrome (euthyroid sick syndrome), central hypothyroidism, or laboratory artifact—and distinguishing between these is critical because management differs dramatically. 1
Initial Diagnostic Approach
Repeat thyroid function tests within 2-4 weeks to confirm persistence of the abnormal values, as transient suppression of thyroid hormones can occur during acute illness, recovery from severe illness, or hospitalization. 1 Approximately 30-60% of initially abnormal thyroid values normalize spontaneously on repeat testing. 2
Essential First-Line Testing
- Measure TSH, free T4, and free T3 simultaneously to establish the pattern definitively. 1
- Order thyroid antibodies (anti-TPO, anti-thyroglobulin) to identify autoimmune thyroiditis in recovery phase, which can present with this pattern. 1
- Obtain morning (8 AM) cortisol and ACTH to rule out concurrent adrenal insufficiency, especially if central hypothyroidism is suspected. 1, 2
Differential Diagnosis and Clinical Context
Non-Thyroidal Illness Syndrome (Most Common)
If all thyroid hormones are low in the setting of acute or chronic systemic illness, this likely represents non-thyroidal illness syndrome (also called euthyroid sick syndrome). 1 This is a physiologic adaptation to illness, not true hypothyroidism, and does not require levothyroxine treatment. 2
Key features:
- Recent hospitalization, acute illness, or chronic systemic disease 2
- TSH may be low-normal, normal, or slightly elevated 1
- Free T3 is typically more suppressed than free T4 3
- Resolves spontaneously with recovery from the underlying illness 2
Management: Treat the underlying illness; recheck thyroid function 4-6 weeks after recovery. 2
Central Hypothyroidism (Pituitary/Hypothalamic Dysfunction)
Low TSH with low free T4 strongly suggests central hypothyroidism, where the pituitary fails to produce adequate TSH or the hypothalamus fails to produce adequate TRH. 1, 4 In this condition, TSH cannot be used as a reliable screening test. 4
Key features:
- History of pituitary disease, pituitary surgery, head trauma, or radiation 1
- Symptoms of other pituitary hormone deficiencies (hypocortisolism, hypogonadism, growth hormone deficiency) 2
- Free T4 is the most reliable marker; free T3 may be normal or low 4
Critical safety consideration: Before initiating levothyroxine in suspected central hypothyroidism, always rule out adrenal insufficiency by checking morning cortisol and ACTH. 1, 2 Starting thyroid hormone before adequate glucocorticoid coverage can precipitate life-threatening adrenal crisis. 2 If adrenal insufficiency is present, start hydrocortisone at least one week before levothyroxine. 2
Diagnostic workup:
- Pituitary MRI to evaluate for pituitary lesions or empty sella 1
- Full pituitary hormone panel (cortisol, ACTH, LH, FSH, IGF-1, prolactin) 2
- Consider endocrinology referral if diagnosis remains unclear 1
Thyroiditis in Recovery Phase
Positive thyroid antibodies with low thyroid hormones may indicate Hashimoto's thyroiditis in a recovery phase following an initial thyrotoxic phase. 1 This pattern can also occur after subacute (de Quervain's) thyroiditis or postpartum thyroiditis. 2
Key features:
- History of recent hyperthyroid symptoms followed by hypothyroid symptoms 2
- Positive anti-TPO or anti-thyroglobulin antibodies 1
- May require temporary levothyroxine if symptomatic, but often resolves spontaneously 2
Management: Monitor thyroid function every 3-6 months until stabilized. 1 Consider a 3-4 month trial of levothyroxine if symptomatic, with clear evaluation of benefit. 2
Laboratory Artifact or Assay Interference
Free thyroid hormone measurements can be artifactually low in certain conditions, particularly with severe protein-binding abnormalities, pregnancy, or heterophilic antibodies causing assay interference. 3, 5
Key features:
- Discordance between clinical presentation and laboratory values 3
- Patient appears clinically euthyroid despite abnormal labs 5
- Consider alternative assay methods (equilibrium dialysis) if artifact suspected 5
When to Treat vs. Observe
Do NOT treat if:
- Patient has acute or chronic systemic illness (non-thyroidal illness syndrome) 2
- Values normalize on repeat testing after 2-4 weeks 1
- Patient is clinically euthyroid with no symptoms 2
DO treat if:
- Central hypothyroidism is confirmed (low TSH, low free T4, pituitary pathology identified) 4
- Symptomatic hypothyroidism with fatigue, weight gain, cold intolerance, constipation 2
- Pregnant or planning pregnancy with any degree of thyroid hormone deficiency 2
Treatment Considerations for Central Hypothyroidism
If central hypothyroidism is confirmed and treatment is indicated:
Rule out adrenal insufficiency first with morning cortisol and ACTH. 2, 1 If cortisol is low, start hydrocortisone 20 mg AM and 10 mg afternoon for at least one week before levothyroxine. 2
Start levothyroxine at 1.6 mcg/kg/day for patients <70 years without cardiac disease. 2 For elderly or cardiac patients, start at 25-50 mcg/day and titrate slowly. 2
Monitor free T4 and free T3 levels, NOT TSH, as TSH is unreliable in central hypothyroidism. 4 Target free T4 in the mid-to-upper normal range. 4
Recheck free T4 and free T3 in 6-8 weeks after dose adjustments. 2 Both free T4 and free T3 measurements are necessary to accurately assess adequacy of replacement in central hypothyroidism. 4
Common Pitfalls to Avoid
- Never start levothyroxine in suspected central hypothyroidism without first ruling out adrenal insufficiency—this can precipitate adrenal crisis. 2, 1
- Do not rely on TSH to guide treatment in central hypothyroidism—TSH is unreliable in this condition. 4
- Do not treat non-thyroidal illness syndrome with levothyroxine—it is a physiologic adaptation that resolves with recovery from the underlying illness. 2
- Do not treat based on a single abnormal result—confirm persistence with repeat testing in 2-4 weeks. 1
- Do not overlook recent iodine exposure (CT contrast), medications (amiodarone, lithium, glucocorticoids), or recovery from acute illness as transient causes of abnormal thyroid function. 2, 6
Follow-Up and Monitoring
- For confirmed abnormal values, continue monitoring thyroid function tests every 3-6 months until stabilized. 1
- Once on stable levothyroxine therapy, recheck free T4 and free T3 every 6-12 months (not TSH in central hypothyroidism). 2, 4
- Consider endocrinology referral if the diagnosis remains unclear after initial testing or if central hypothyroidism is confirmed. 1