Low TSH and Low T4: Clinical Scenarios
The combination of low TSH and low T4 indicates central (secondary) hypothyroidism, most commonly caused by hypophysitis or other pituitary/hypothalamic dysfunction. 1
Primary Clinical Scenario: Hypophysitis
Hypophysitis is the most important cause to recognize, particularly in patients receiving immune checkpoint inhibitors (ICPis):
- Ipilimumab (anti-CTLA4) causes hypophysitis in 1-16% of patients depending on dose, with the combination of ipilimumab and nivolumab causing hypophysitis in 8% of cases 1
- Anti-PD-1 and anti-PD-L1 agents rarely cause hypophysitis 1
- A falling TSH across two measurements with normal or lowered T4 suggests pituitary dysfunction and requires immediate cortisol evaluation 1
Key Diagnostic Features of Hypophysitis:
- Simultaneous deficiencies: Low TSH, low ACTH, and/or low FSH/LH point toward hypophysitis 1
- Clinical presentation: Headache, visual disturbances, fatigue, symptoms of hypocortisolism or hypothyroidism 1
- Brain MRI findings: Swollen or enlarged pituitary gland may be visible 1
Critical Diagnostic Principle
Both TSH and free T4 must be measured together because low TSH alone is ambiguous:
- Low TSH + Low T4 = Central hypothyroidism (pituitary/hypothalamic problem) 1
- Low TSH + High T4 = Hyperthyroidism 1
- In hypophysitis, TSH can remain within the normal range despite low T4, making it essential to check both values when hypothyroidism is suspected 1
Other Causes of Central Hypothyroidism
Beyond hypophysitis, low TSH with low T4 occurs in:
Structural Pituitary/Hypothalamic Disease:
- Pituitary tumors or masses compressing normal tissue 1
- Traumatic brain injury or subarachnoid hemorrhage 2
- Sheehan syndrome (postpartum pituitary necrosis) 2
- Lymphocytic hypophysitis (autoimmune) 2
Genetic Causes:
- Mutations in TRHR, POU1F1, PROP1, HESX1, SOX3, LHX3, LHX4, and TSHB genes associated with congenital central hypothyroidism 2
Iatrogenic/Medication-Related:
- Bexarotene therapy (retinoid X receptor agonist) 2
- Growth hormone therapy may unmask central hypothyroidism in susceptible individuals 2
- Radiation therapy to the hypothalamic-pituitary region 2
Neonatal Considerations:
- Infants born to mothers with insufficiently controlled Graves disease 2
- Congenital hypopituitarism where TSH is "inappropriately normal" despite low T4 3
Non-Thyroidal Illness Syndrome (Euthyroid Sick Syndrome)
Critically ill patients can present with low TSH and low free T4:
- Multiple complex mechanisms alter thyroid function tests in non-thyroidal illness 4
- Low free T4 by equilibrium dialysis with normal or low TSH suggests secondary hypothyroidism, which may be due to the illness itself, medications, or true pituitary disease 4
- Elevated reverse T3 argues against true hypothyroidism 4
- Serum TSH above 20-25 microU/mL suggests primary hypothyroidism rather than central causes 4
Monitoring Approach in High-Risk Populations
For patients on immune checkpoint inhibitors:
- Anti-PD-1/Anti-PD-L1: Check thyroid function tests every cycle for first 3 months, then every second cycle 1
- Anti-CTLA4: Check thyroid function tests every cycle 1
- Check 9 am cortisol if TSH is falling or low with low T4 1
- Weekly cortisol measurements should be performed when falling TSH with normal or lowered T4 is detected 1
Management Implications
When central hypothyroidism is confirmed:
- Hydrocortisone must be given before thyroid hormone replacement if there is uncertainty about adrenal function, as thyroid hormone can precipitate adrenal crisis 1
- Endocrine consultation is recommended for unusual presentations or concern for central hypothyroidism 1
- TSH cannot be used to monitor treatment adequacy in central hypothyroidism; use free T4 and T3 concentrations instead 5, 2
- Target free T4 in the upper half of the normal range for treatment monitoring 3, 2