How to interpret and manage abnormal thyroid function studies in a 70-year-old female with undetectable Thyroid-Stimulating Hormone (TSH), low free Thyroxine (T4), normal Thyroid Uptake (33 uptake), and normal Free Thyroxine Index (free T4 index)?

Interpretation: Central Hypothyroidism (Hypophysitis) Until Proven Otherwise

This pattern of undetectable TSH with low free T4 indicates central hypothyroidism, most likely hypophysitis, and requires immediate evaluation for concurrent adrenal insufficiency before initiating any thyroid hormone replacement. 1, 2

Immediate Diagnostic Workup Required

Before any treatment decisions, you must obtain:

• Morning (8 AM) ACTH and cortisol levels or perform a 1 mcg cosyntropin stimulation test to rule out adrenal insufficiency 1
• MRI of the sella with pituitary cuts to evaluate for pituitary enlargement, stalk thickening, or suprasellar convexity characteristic of hypophysitis 1
• Additional pituitary hormones: FSH, LH, and gonadal hormones (estradiol in women) to assess for panhypopituitarism 1
• Free T4 by equilibrium dialysis if available, as this is the most accurate method in complex cases 3

The combination of undetectable TSH with low free T4 (4.8 with reference 5.1-11.9) definitively indicates central hypothyroidism rather than primary thyroid disease. 1, 2 The normal T3 uptake and free T4 index are misleading in this context and should be disregarded—these older tests can be falsely reassuring in central hypothyroidism. 4

Critical Safety Consideration

If both adrenal insufficiency and hypothyroidism are confirmed, you must start corticosteroids BEFORE initiating levothyroxine to prevent adrenal crisis. 1, 2 This is non-negotiable. Starting thyroid hormone first can precipitate life-threatening adrenal crisis in patients with concurrent adrenal insufficiency. 1

Most Likely Diagnosis: Hypophysitis

In a 70-year-old woman, hypophysitis presents with:

• Headache (85% of cases) and fatigue (66%) as the most common symptoms 1
• Central hypothyroidism (>90% of cases) with low TSH and low free T4 1
• Central adrenal insufficiency (>75% of cases) often coexisting with hypothyroidism 1
• Panhypopituitarism in approximately 50% of patients 1

The MRI typically shows pituitary enlargement, though this may not be present in all cases. 1

Alternative Considerations (Less Likely)

While central hypothyroidism is the primary concern, briefly consider:

• TSH assay interference: Rare TSH variants can cause falsely undetectable TSH in certain assays, but this would show normal or high free T4, not low 5
• Non-thyroidal illness (NTI): Can cause low T3 and low free T4 with low-normal or suppressed TSH, but typically occurs in critically ill hospitalized patients 3, 6 Your patient is "relatively healthy," making this unlikely
• Masked hyperthyroidism with NTI: Extremely rare scenario where underlying hyperthyroidism is masked by acute illness 6, but the low free T4 argues strongly against this

Treatment Protocol Once Diagnosis Confirmed

For patients under 70 years without cardiac disease:

• Start levothyroxine 1.6 mcg/kg/day (approximately 100-125 mcg for most patients) 2

For patients over 70 years (like yours) or with cardiac disease:

• Start levothyroxine 25-50 mcg/day and titrate gradually 7, 2
• Monitor for cardiac arrhythmias, angina, or signs of cardiac decompensation 7
• Increase dose by 12.5-25 mcg increments every 6-8 weeks based on free T4 levels 2

Monitoring Strategy

• Recheck free T4 in 6-8 weeks after each dose adjustment, targeting the mid-to-upper normal range (approximately 14-19 pmol/L or 1.1-1.5 ng/dL) 2
• Do NOT use TSH to guide therapy in central hypothyroidism—TSH will remain low or undetectable and is unreliable for monitoring 2
• Once stable, monitor free T4 every 6-12 months 2
• Annual monitoring of other pituitary hormones may be warranted depending on MRI findings 2

Long-term Prognosis

Both adrenal insufficiency and hypothyroidism from hypophysitis typically represent permanent conditions requiring lifelong hormone replacement. 1, 2 All patients with confirmed adrenal insufficiency should obtain and carry a medical alert bracelet. 1

Common Pitfalls to Avoid

• Never rely on T3 uptake or free T4 index in suspected central hypothyroidism—these can be misleadingly normal 4
• Never start thyroid hormone before ruling out adrenal insufficiency in central hypothyroidism 1, 2
• Never use TSH to monitor treatment in central hypothyroidism—only free T4 levels are reliable 2
• Don't assume euthyroidism based on normal calculated indices when TSH and free T4 are discordant 3, 4