Conditions That Can Cause Hypothyroidism with Low TSH
Central hypothyroidism is the primary condition that causes hypothyroidism with low TSH levels, most commonly due to pituitary or hypothalamic disorders that impair TSH production or secretion. 1, 2
Types of Central Hypothyroidism
Pituitary Causes (Secondary Hypothyroidism)
Hypophysitis - Particularly common with immune checkpoint inhibitor therapy
- Most frequently seen with anti-CTLA-4 antibodies (ipilimumab) with incidence up to 10-17% 3
- Combination ipilimumab/nivolumab therapy increases risk (≤13%) 3
- Typically occurs 8-9 weeks after starting therapy or after the third dose 3
- Presents with headache (85%), fatigue (66%), and abnormal thyroid function tests 3
Pituitary adenomas - Can compress normal pituitary tissue 4
Pituitary surgery or radiation 2
Pituitary apoplexy (sudden hemorrhage or infarction) 2
Sheehan syndrome (postpartum pituitary necrosis) 5
Hypothalamic Causes (Tertiary Hypothyroidism)
- Hypothalamic tumors or infiltrative diseases 2
- Cranial radiation affecting the hypothalamus 2
- Traumatic brain injury affecting the hypothalamic-pituitary axis 5
Biologically Inactive TSH
- Some patients secrete immunologically detectable TSH that lacks biological activity
- Laboratory tests show normal or even elevated TSH levels, but the TSH is functionally ineffective 6
- This can be confirmed by comparing immunoassay results with bioassay measurements 6
Diagnostic Approach
Key Laboratory Findings
- Low free T4 with low or inappropriately normal TSH 3, 1
- Morning serum hormone values are required for accurate assessment 3
- Both TSH and free T4 should be measured simultaneously when central hypothyroidism is suspected 3, 7
Additional Testing
- Morning cortisol and ACTH to evaluate adrenal axis 3
- Gonadal hormones (testosterone in men, estradiol in women, FSH, LH) 3
- MRI of the sella with pituitary cuts to evaluate for structural abnormalities 3
- TRH stimulation test may help differentiate between pituitary and hypothalamic causes 1
Clinical Presentation
- Symptoms may be similar to primary hypothyroidism but often less severe
- May present with symptoms of other hormonal deficiencies
- In immune checkpoint inhibitor-related hypophysitis:
Management Considerations
Hormone Replacement
- When both adrenal insufficiency and hypothyroidism are present, steroids should always be started prior to thyroid hormone to avoid precipitating an adrenal crisis 3
- Physiologic doses of steroids and thyroid hormone are typically required 3
- Goal is to maintain free T4 in the high-normal range using the lowest possible dose 7
Monitoring
- For patients on immune checkpoint inhibitors:
- After stabilization, monitor thyroid function every 6-12 months 7
Special Considerations
- Unlike primary hypothyroidism, TSH cannot be used to guide treatment in central hypothyroidism
- Free T4 levels should be used to monitor and adjust therapy 3, 7
- Patients with central hypothyroidism may have multiple pituitary hormone deficiencies requiring comprehensive evaluation and management 3
Common Pitfalls
- Misdiagnosis as primary hypothyroidism if only TSH is measured
- Failure to check both TSH and free T4 in symptomatic patients 3
- Starting thyroid hormone before steroids in patients with concurrent adrenal insufficiency 3
- Overlooking central hypothyroidism due to nonspecific symptoms or misinterpretation of lab results 2
- Undertreatment may have serious metabolic consequences with increased risk of cardiovascular morbidity 2
Central hypothyroidism requires careful diagnosis and management, with attention to other potential pituitary hormone deficiencies and their proper replacement sequence.