What is the best course of action for a patient with hypocortisolism (cortisol level of 1.8 at 8:30 am), low Adrenocorticotropic hormone (ACTH), and anemia (low red blood cell count), who has recently completed 3 cycles of chemotherapy and immunotherapy?

Immediate Management of Immunotherapy-Related Hypophysitis with Secondary Adrenal Insufficiency

This patient requires immediate initiation of hydrocortisone replacement therapy and urgent endocrinology consultation for immunotherapy-related hypophysitis causing secondary adrenal insufficiency. The cortisol level of 1.8 μg/dL at 8:30 AM with low ACTH following immunotherapy is diagnostic of immune checkpoint inhibitor-related hypophysitis with secondary adrenal insufficiency 1, 2.

Immediate Treatment Protocol

Start oral hydrocortisone 20 mg in the morning and 10 mg in the afternoon immediately 1. The 2022 ESMO guidelines specify that if 9 AM cortisol is low according to institutional reference range, replacement with hydrocortisone 20/10 mg should be initiated 1. This patient's cortisol of 1.8 μg/dL (approximately 50 nmol/L) is well below the diagnostic threshold of <250 nmol/L (<9 μg/dL) that is diagnostic of adrenal insufficiency 2.

Critical First Steps:

• Do not delay treatment for confirmatory testing - treatment of suspected acute adrenal insufficiency should never be delayed for diagnostic procedures 2, 3
• Withhold immunotherapy immediately until endocrine evaluation is complete 1
• Refer to or consult endocrinologist urgently 1
• Monitor thyroid function tests as falling TSH with low free T4 may develop 1

Understanding the Diagnosis

This patient has immune-related hypophysitis, a well-recognized toxicity from immunotherapy that occurs in 9-10% of patients receiving anti-PD(L)1/anti-CTLA-4 combination therapy 1. The low ACTH with low cortisol confirms secondary adrenal insufficiency from pituitary ACTH deficiency 2, 4.

Key Diagnostic Features Present:

• Morning cortisol 1.8 μg/dL is severely low (normal 5-23 μg/dL) 5
• Low ACTH confirms central (secondary) rather than primary adrenal insufficiency 2, 4
• Recent immunotherapy exposure (3 cycles) fits the typical timeline 1
• Anemia may reflect chronic illness from untreated hypocortisolism 6

Why This Patient Needs Immediate Treatment

The combination of severe hypocortisolism (cortisol 1.8 μg/dL) with recent chemotherapy/immunotherapy places this patient at high risk for adrenal crisis 2, 3. Basal cortisol <250 nmol/L (<9 μg/dL) with low ACTH in the presence of acute illness is diagnostic of secondary adrenal insufficiency and requires immediate treatment 2.

Warning Signs to Monitor:

• Unexplained hypotension, collapse, or vasopressor requirement 2
• Severe nausea, vomiting, or diarrhea 2
• Confusion or altered mental status 2
• Hyponatremia (present in 90% of newly diagnosed cases) 2

If any of these develop, immediately administer IV hydrocortisone 100 mg and 0.9% saline infusion at 1 L/hour 2, 3.

Steroid Dosing Considerations

The initial hydrocortisone dose of 20/10 mg represents physiologic replacement 1, 2. Do not stop steroids - this is a critical pitfall 1. Unlike the high-dose steroids used for other immune-related adverse events, this patient needs lifelong glucocorticoid replacement unless HPA axis recovery occurs 2.

Important Distinctions:

• This is replacement therapy, not immunosuppression 2
• Standard maintenance dosing is 15-25 mg daily in divided doses 2
• Mineralocorticoid replacement (fludrocortisone) is rarely necessary in secondary adrenal insufficiency because the renin-angiotensin-aldosterone system remains intact 1

Addressing the Anemia

The low red blood cell count likely reflects anemia of chronic disease from recent chemotherapy and untreated hypocortisolism 6. Cortisol deficiency can contribute to anemia through multiple mechanisms. Once glucocorticoid replacement is established, reassess the anemia - it may improve with adequate cortisol replacement 2.

Patient Education Requirements (Before Discharge)

This patient cannot be safely sent home without the following:

1. "Sick day rules" education - double or triple the usual dose during illness, fever, or physical stress 2
2. Hydrocortisone 100 mg IM injection kit with self-injection training 2
3. Medical alert bracelet indicating adrenal insufficiency 2
4. Written instructions on when to seek emergency care 2
5. Emergency contact information for endocrinology 1

Follow-Up Testing and Monitoring

Within 1-2 Weeks:

• Pituitary MRI with contrast to assess for hypophysitis 1
• Complete pituitary axis assessment: TSH, free T4, LH, FSH, estradiol (if premenopausal)/testosterone (if male), IGF-1, prolactin 1
• Formal visual field assessment if any visual symptoms 1
• Monitor thyroid function 1-2 weekly initially 1

Critical Timing Issue:

Always replace cortisol for 1 week prior to thyroxine initiation if hypothyroidism is also present 1. Starting thyroid hormone before cortisol replacement can precipitate adrenal crisis 2.

Prognosis and Immunotherapy Continuation

Hypophysitis usually resolves within 4-6 weeks with appropriate treatment 1, but ACTH deficiency is often permanent requiring lifelong replacement 1. The decision to resume immunotherapy depends on:

• Severity of symptoms at presentation 1
• Response to hormone replacement 1
• Oncologic benefit-risk assessment 1

Patients with moderate-to-severe symptoms should withhold immunotherapy until endocrine consultation 1. Those with vague symptoms and confirmed diagnosis on adequate hormone replacement may continue immunotherapy with appropriate monitoring 1.

Common Pitfalls to Avoid

1. Never delay treatment waiting for confirmatory testing - mortality is high if untreated 2, 3
2. Do not confuse this with high-dose steroid treatment for other immune-related adverse events - this patient needs physiologic replacement 1, 2
3. Do not stop glucocorticoids - this is lifelong therapy unless HPA axis recovery is documented 1, 2
4. Do not start thyroid hormone before cortisol replacement if hypothyroidism develops 1, 2
5. Do not send patient home without emergency supplies and education 2