In a hypothyroid patient, what conditions can cause both low thyroid‑stimulating hormone (TSH) and low free thyroxine (T4)?

Low TSH and Low Free T4 in Hypothyroid Patients: Central Hypothyroidism (Hypophysitis)

In a hypothyroid patient, the combination of low TSH with low free T4 indicates central (secondary) hypothyroidism, most commonly caused by pituitary or hypothalamic dysfunction, with hypophysitis being a key etiology—particularly in patients receiving immune checkpoint inhibitors.

Pathophysiology and Key Distinction

The hallmark of central hypothyroidism is inadequate TSH secretion despite low thyroid hormone levels 1, 2, 3. Unlike primary hypothyroidism where TSH is elevated in response to low T4, central hypothyroidism presents with:

• Low or inappropriately normal TSH alongside low free T4 1, 4, 3
• Failure of the pituitary to produce adequate TSH or the hypothalamus to produce adequate TRH 3, 5
• TSH levels may be low, normal, or even slightly elevated (but biologically inactive) 2, 3

Primary Causes of Central Hypothyroidism

Hypophysitis (Immune Checkpoint Inhibitor-Induced)

Hypophysitis is the most common cause in patients on immunotherapy, occurring in:

• ≤10% with ipilimumab monotherapy (3 mg/kg), up to 17% at 10 mg/kg 1
• ≤13% with combination ipilimumab/nivolumab 1, 4
• Median onset: 8–9 weeks after starting ipilimumab (typically after third dose) 1

Clinical presentation includes:

• Headache (85% of cases) 1, 4
• Fatigue (66% of cases) 1, 4
• Central hypothyroidism (>90% of hypophysitis cases) 1, 4
• Central adrenal insufficiency (>75% of cases) 1, 4
• Panhypopituitarism in ~50% (adrenal insufficiency + hypothyroidism + hypogonadism) 1

MRI findings:

• Pituitary enlargement, stalk thickening, suprasellar convexity, heterogeneous enhancement 1, 4
• Resolution of enlargement typically occurs within 2 months 1

Other Pituitary/Hypothalamic Causes

• Pituitary tumors or surgery 2, 3, 5
• Pituitary infarction (Sheehan's syndrome) 3
• Traumatic brain injury 3
• Infiltrative diseases (sarcoidosis, hemochromatosis) 3
• Congenital pituitary hormone deficiencies (rare) 3, 5

Critical Diagnostic Algorithm

Step 1: Confirm Central Hypothyroidism

When encountering low TSH with low free T4 in a patient on levothyroxine or with suspected hypothyroidism 4:

1. Repeat TSH and free T4 to confirm persistence 4, 3
2. Measure morning (8 AM) cortisol and ACTH to assess for central adrenal insufficiency 1, 4, 5
3. Evaluate gonadal hormones: testosterone (men), estradiol (women), FSH, LH 1, 4
4. Order MRI of sella with pituitary cuts to evaluate for structural abnormalities 1, 4

Step 2: Diagnostic Confirmation Criteria

Hypophysitis diagnosis requires 1, 4:

• ≥1 pituitary hormone deficiency (TSH or ACTH deficiency required) PLUS MRI abnormality, OR
• ≥2 pituitary hormone deficiencies (TSH or ACTH deficiency required) with headache and symptoms 1, 4

Life-Threatening Management Pitfall: Adrenal Crisis

NEVER initiate or increase levothyroxine before ruling out adrenal insufficiency 1, 4, 5. This is the most critical safety consideration.

Why This Matters:

• Central adrenal insufficiency occurs in >75% of hypophysitis cases 1, 4
• Starting thyroid hormone before corticosteroids precipitates life-threatening adrenal crisis 1, 4, 5
• Thyroid hormone increases cortisol metabolism, unmasking or worsening hypocortisolism 4

Correct Sequence:

1. Start physiologic-dose corticosteroids FIRST (hydrocortisone 15–25 mg/day in divided doses) 1, 4, 5
2. Wait at least 1 week before initiating thyroid hormone replacement 1, 4, 5
3. Both deficiencies require lifelong replacement in most hypophysitis cases 1, 4

Treatment Protocol for Central Hypothyroidism

Levothyroxine Dosing

• Younger patients without cardiac disease: Start with full replacement dose (~1.6 mcg/kg/day) 4, 5
• Elderly or cardiac patients: Start at 25–50 mcg/day, titrate slowly 4, 5

Monitoring Strategy

TSH is NOT useful for monitoring central hypothyroidism 3, 5. Instead:

• Monitor free T4 levels, targeting the upper half of normal range 3, 5
• Recheck free T4 every 6–8 weeks during dose titration 5
• Continue monitoring other pituitary hormones, as central hypothyroidism rarely occurs in isolation 4, 3

Special Considerations for Immune Checkpoint Inhibitors

• Continue immunotherapy in most cases—thyroid dysfunction rarely requires treatment interruption 1, 4
• High-dose corticosteroids are rarely required for thyroid dysfunction alone 1, 4
• Central hypothyroidism from hypophysitis is usually permanent, requiring lifelong replacement 1, 4
• Monitor TSH and free T4 before each cycle initially, then every 3 months 1

Common Diagnostic Pitfalls

Pitfall 1: Confusing with Subclinical Hyperthyroidism

Low TSH with normal-low free T4 can be misdiagnosed as subclinical hyperthyroidism, especially if the patient has coexisting thyroid nodules or autonomous thyroid function 6. Always:

• Evaluate all pituitary hormones when TSH is low with low-normal T4 6
• Consider MRI if clinical suspicion exists, even if initial pituitary testing appears normal 6

Pitfall 2: Relying on TSH Alone

The TSH-reflex strategy (measuring TSH alone, adding free T4 only if TSH is abnormal) misses central hypothyroidism 3. In suspected cases:

• Always measure TSH AND free T4 together 3
• TSH may be low, normal, or even slightly elevated in central hypothyroidism 2, 3

Pitfall 3: Delayed Recognition of Progressive Pituitary Failure

Central hypothyroidism can initially present without other hormone deficiencies, with progressive pituitary failure developing over time 6, 3. Maintain long-term surveillance for:

• ACTH deficiency 6
• Growth hormone deficiency 6
• Gonadotropin deficiency 6

Summary Algorithm

For any hypothyroid patient with low TSH and low free T4:

1. Suspect central hypothyroidism 4, 3
2. Immediately assess morning cortisol and ACTH 1, 4, 5
3. Order pituitary MRI and evaluate other pituitary hormones 1, 4
4. If adrenal insufficiency present: Start hydrocortisone FIRST, wait ≥1 week before levothyroxine 1, 4, 5
5. Monitor with free T4 (not TSH), targeting upper-normal range 3, 5
6. Continue surveillance for other pituitary deficiencies 4, 6, 3