Screening for Adrenal Insufficiency and Hypothyroidism in Patients on Keytruda
Yes, patients receiving Keytruda (pembrolizumab) should be systematically screened for both adrenal insufficiency and hypothyroidism through baseline testing before treatment initiation and regular monitoring throughout therapy.
Baseline Screening Requirements
Before starting Keytruda, all patients must undergo baseline endocrine testing to establish reference values and identify pre-existing dysfunction 1, 2:
- Thyroid function: TSH and free T4 1
- Adrenal function: Early morning (8 AM) ACTH and cortisol levels 1
- Metabolic panel: Sodium, potassium, and glucose to detect electrolyte abnormalities suggestive of adrenal insufficiency 1
This baseline assessment is critical because immune-mediated endocrinopathies can develop at any point during treatment, and having baseline values allows for accurate comparison when symptoms arise 1, 2.
Ongoing Monitoring Schedule
Thyroid Function Monitoring
Monitor TSH and free T4 every 4-6 weeks during the first 6 months of therapy, then every 3 months thereafter 1. This frequent monitoring is justified because:
- Thyroid dysfunction occurs in 6-20% of patients on anti-PD-1 therapy like pembrolizumab 1
- Hypothyroidism occurred in 8% of patients receiving Keytruda in clinical trials, with higher rates (16-22%) in specific cancer populations 2
- Thyrotoxicosis from thyroiditis can precede hypothyroidism by several weeks, requiring close monitoring to catch the transition 1, 3
Adrenal Function Monitoring
Consider monitoring early morning ACTH and cortisol levels monthly for the first 6 months, then every 3 months for 6 months, then every 6 months for 1 year 1. While less frequent than thyroid monitoring, this is important because:
- Primary adrenal insufficiency occurred in 0.8% of patients receiving Keytruda 2
- Adrenal crisis carries substantial morbidity and mortality if unrecognized 4, 5
- Adrenal insufficiency can develop months after pembrolizumab discontinuation 6
Clinical Surveillance Between Laboratory Tests
Educate patients to report symptoms immediately and maintain high clinical suspicion for endocrinopathies at every visit 1:
Adrenal Insufficiency Warning Signs
- Unexplained fatigue, weakness, or orthostatic hypotension 1, 5
- Hyponatremia with hyperkalemia on routine labs 1, 4
- Nausea, vomiting, or abdominal pain 1
- Hypotension unresponsive to fluids 5
Thyroid Dysfunction Warning Signs
- Hypothyroidism: Fatigue, weight gain, cold intolerance, constipation 1
- Thyrotoxicosis: Weight loss, palpitations, heat intolerance, tremors, anxiety 1, 3
Diagnostic Workup When Abnormalities Detected
For Suspected Adrenal Insufficiency
If morning cortisol is low or clinical features suggest adrenal insufficiency, perform comprehensive evaluation 1:
- Morning ACTH and cortisol (8 AM) 1
- Basic metabolic panel (sodium, potassium, glucose) 1
- Consider ACTH stimulation test for indeterminate results 1
- If primary adrenal insufficiency confirmed (high ACTH, low cortisol), obtain adrenal CT to exclude metastasis/hemorrhage 1
- Check for adrenal cortex and 21-hydroxylase antibodies to confirm autoimmune etiology 4
For Suspected Thyroid Dysfunction
When TSH is abnormal, measure free T4 to distinguish subclinical from overt dysfunction 1:
- If hyperthyroidism suspected, check TSH receptor antibodies (TRAb or TSI) to differentiate Graves' disease from thyroiditis 1
- Consider thyroid peroxidase (TPO) antibodies, though these are less consistently elevated in checkpoint inhibitor-induced thyroid disease 3
- In thyrotoxic patients, 18F-FDG PET/CT may show diffuse thyroid uptake in inflammatory thyroiditis 3
Critical Management Principles
Adrenal Insufficiency Takes Priority
If both adrenal insufficiency and hypothyroidism are present, always start corticosteroids before initiating thyroid hormone replacement 1. Starting levothyroxine before adequate corticosteroid coverage can precipitate life-threatening adrenal crisis by increasing cortisol metabolism 1.
Most Endocrinopathies Are Permanent
- Adrenal insufficiency: 77% of patients required ongoing systemic corticosteroids, with the majority remaining on long-term replacement 2
- Hypothyroidism: The majority of patients required long-term thyroid hormone replacement 2
- Hypophysitis: Both adrenal insufficiency and hypothyroidism from hypophysitis typically require lifelong hormonal replacement 1
Keytruda Can Usually Continue
Thyroid dysfunction and mild-to-moderate adrenal insufficiency rarely require permanent discontinuation of pembrolizumab 1, 2. In clinical trials:
- Hypothyroidism led to permanent discontinuation in <0.1% of patients 2
- Adrenal insufficiency led to permanent discontinuation in <0.1% of patients 2
- Treatment can continue once patients are stabilized on hormone replacement 1
Common Pitfalls to Avoid
Do not wait for overt symptoms before checking labs—subclinical dysfunction is common and can progress rapidly 1, 3. Approximately 30-60% of thyroid dysfunction cases are detected through routine monitoring rather than symptomatic presentation 1.
Do not assume normal baseline thyroid function excludes later dysfunction—immune-mediated thyroiditis can develop at any point during or after treatment, even months following pembrolizumab discontinuation 3, 6.
Do not overlook polyendocrinopathy—patients who develop one endocrinopathy are at risk for others 4, 7. A patient presenting with thyroiditis may subsequently develop adrenal insufficiency weeks to months later 4, 6.
Do not miss the transition from thyrotoxicosis to hypothyroidism—inflammatory thyroiditis typically causes transient hyperthyroidism lasting 1-2 months before progressing to permanent hypothyroidism 1, 3. Monitor thyroid function every 2-3 weeks after diagnosing thyrotoxicosis to catch this transition 1.
Do not forget to provide patients with emergency instructions—all patients with adrenal insufficiency should carry a medical alert bracelet and receive education on stress-dose corticosteroids 1.