Could metastasis be causing adrenal insufficiency?

Metastatic Cancer Can Cause Adrenal Insufficiency

Yes, metastatic cancer to the adrenal glands can cause primary adrenal insufficiency when there is sufficient destruction of adrenal tissue. This is an important but often underdiagnosed clinical entity that requires prompt recognition and treatment to prevent life-threatening adrenal crisis.

Pathophysiology and Prevalence

• Metastatic destruction of adrenal tissue occurs when bilateral adrenal metastases destroy >90% of adrenal cortex, leading to insufficient cortisol and aldosterone production 1
• The adrenal glands are common sites for metastases, particularly from:
  • Lung cancer (35% of cases) - most common primary site
  • Gastric cancer (14%)
  • Esophageal cancer (12%)
  • Hepatobiliary cancers (10%) 2
• Despite the frequency of adrenal metastases, clinical adrenal insufficiency is relatively uncommon, suggesting a discordance between radiological findings and functional impairment 3

Clinical Presentation

Patients with adrenal insufficiency due to metastatic disease may present with:

• Nonspecific symptoms that can be mistaken for cancer progression:
  • Fatigue and weakness
  • Nausea, vomiting, abdominal pain
  • Weight loss
  • Hypotension or orthostatic hypotension
• Laboratory abnormalities:
  • Hyponatremia
  • Hyperkalemia
  • Hypoglycemia
  • Metabolic acidosis 4
• Acute adrenal crisis may be the first manifestation in some cases, presenting with:
  • Severe hypotension/shock
  • Acute abdominal pain
  • Fever
  • Altered mental status 3

Diagnostic Approach

When adrenal insufficiency is suspected in a cancer patient:

1. Initial laboratory evaluation:

   • Morning serum cortisol and ACTH levels
   • Electrolytes (sodium, potassium)
   • Glucose 4

2. Interpretation:

   • Morning cortisol <140 nmol/L (<5 μg/dL) with elevated ACTH strongly suggests primary adrenal insufficiency
   • Cortisol <400 nmol/L with elevated ACTH during acute illness suggests adrenal insufficiency 4

3. Confirmatory testing:

   • ACTH stimulation test (Synacthen test): administer 0.25 mg Synacthen IV/IM and measure cortisol at 30 and/or 60 minutes
   • Normal response: cortisol >550 nmol/L (>18 μg/dL) at either time point 4

4. Imaging:

   • Adrenal CT to evaluate for metastases, hemorrhage, or other causes 1
   • In patients with known cancer, perform an adrenal CT to look specifically for metastatic disease 1

Management

1. Acute management (if adrenal crisis is suspected):

   • Do not delay treatment while awaiting test results
   • Immediate administration of IV hydrocortisone 100 mg
   • IV normal saline (0.9%) for volume resuscitation
   • Collect blood samples for cortisol and ACTH before starting therapy if possible 4, 5

2. Chronic management:

   • Replacement therapy with prednisone (5-10 mg daily) or hydrocortisone (10-20 mg orally in morning, 5-10 mg in early afternoon)
   • May require fludrocortisone (0.1 mg/day) for mineralocorticoid replacement in primary adrenal insufficiency
   • Titrate dose based on symptoms 1

3. Patient education:

   • Stress dosing instructions
   • Medical alert bracelet
   • Recognition of symptoms requiring medical attention 1

Special Considerations

• Hemorrhagic adrenal metastases can cause acute adrenal insufficiency and should be considered in cancer patients with sudden flank/back pain, hypotension, and anemia 6
• Adrenal insufficiency symptoms may be masked by or attributed to the underlying malignancy, leading to delayed diagnosis 7
• Pituitary metastases can cause secondary adrenal insufficiency (low ACTH, low cortisol) and should be considered in patients with appropriate symptoms and brain metastases 8
• Patients receiving immune checkpoint inhibitors may develop immune-related adrenal insufficiency, which requires similar management but different etiology 1

Clinical Pitfalls

• Adrenal insufficiency is often underdiagnosed in cancer patients because symptoms overlap with those of advanced malignancy
• Bilateral adrenal metastases on imaging do not always correlate with clinical adrenal insufficiency - functional testing is necessary 2
• Exogenous steroid use (including for symptom management in cancer) can make interpretation of cortisol levels difficult 4
• In critically ill patients, "normal" cortisol levels may be inappropriately low for the stress state 4

Early recognition and treatment of adrenal insufficiency in cancer patients can significantly improve quality of life and prevent life-threatening adrenal crisis, even when the underlying malignancy has a poor prognosis.