How to diagnose and manage adrenal insufficiency and Addison's disease?

Investigation of Adrenal Insufficiency and Addison's Disease

The diagnosis of adrenal insufficiency requires morning serum cortisol and ACTH measurements followed by a cosyntropin stimulation test, with stimulated cortisol levels <18 mcg/dL at 30 or 60 minutes confirming the diagnosis. 1, 2, 3

Diagnostic Approach

Initial Assessment

• Clinical suspicion: Look for key symptoms
  • Fatigue (50-95% of cases)
  • Nausea and vomiting (20-62%)
  • Anorexia and weight loss (43-73%)
  • Hyperpigmentation (in primary adrenal insufficiency)
  • Salt craving
  • Postural hypotension
  • Muscle and joint pain 3, 4

First-line Laboratory Tests

1. Morning serum cortisol (8 AM)

   • <5 μg/dL: Highly suggestive of adrenal insufficiency
   • 5-10 μg/dL: Intermediate, requires further testing

   • 18 μg/dL: Generally excludes adrenal insufficiency 3

2. ACTH level

   • Primary adrenal insufficiency: High ACTH (>300 pg/mL)
   • Secondary adrenal insufficiency: Low or inappropriately normal ACTH 1, 3

3. Electrolytes

   • Primary adrenal insufficiency: Hyponatremia, hyperkalemia
   • Secondary adrenal insufficiency: Generally normal electrolytes 1

Confirmatory Testing

1. Cosyntropin Stimulation Test (gold standard)

   • Administration: 0.25 mg cosyntropin IV or IM for adults; 0.125 mg for children under 2 years 2
   • Blood samples: Baseline, 30 minutes, and 60 minutes after administration
   • Interpretation: Stimulated cortisol <18 μg/dL at 30 or 60 minutes suggests adrenal insufficiency 2

2. Additional tests to determine etiology:

   • Primary vs. Secondary differentiation:

     Type	ACTH Level	Cortisol Level	Electrolytes	Hyperpigmentation
     Primary	High	Low	↓Na, ↑K	Present
     Secondary	Low	Low	Generally normal	Absent

   • For Primary Adrenal Insufficiency:

     • Adrenal autoantibodies (positive in autoimmune adrenalitis)
     • CT or MRI of abdomen (to visualize adrenal glands)
     • DHEAS levels (typically low) 1, 3

   • For Secondary Adrenal Insufficiency:

     • MRI of pituitary
     • Other pituitary hormone testing 3

Important Clinical Considerations

Diagnostic Pitfalls

1. Normal cortisol with elevated ACTH: Early Addison's disease can present with normal cortisol levels but markedly elevated ACTH, indicating evolving disease 5, 6

2. Medication interference:

   • Stop glucocorticoids and spironolactone on the day of testing
   • Stop estrogen-containing medications 4-6 weeks before testing 2

3. Conditions affecting cortisol binding globulin:

   • Estrogen therapy increases cortisol binding globulin
   • Cirrhosis or nephrotic syndrome can decrease cortisol binding globulin 2

Management Principles

1. Hormone replacement therapy:

   • Glucocorticoids: Hydrocortisone 10-30 mg daily in divided doses
   • Mineralocorticoids (for primary adrenal insufficiency): Fludrocortisone 0.1 mg daily 1, 7

2. Stress dosing education:

   • Increase glucocorticoid dose during illness, trauma, or surgery
   • Provide emergency injectable hydrocortisone (100 mg) 1, 3

3. Monitoring:

   • Clinical assessment for signs of over/under replacement
   • Plasma renin activity for mineralocorticoid adjustment 1, 7

4. Adrenal crisis management:

   • Immediate 100 mg hydrocortisone IV bolus
   • Followed by 100-300 mg/day as continuous infusion
   • Rapid IV isotonic saline administration 1

Special Considerations

• Autoimmune screening: Up to 50% of patients with autoimmune adrenalitis develop other autoimmune disorders 4
• Pregnancy: Hydrocortisone dose may need to be increased by 2.5-10 mg daily in the third trimester 1
• Exercise: Increase hydrocortisone and salt intake for intense or prolonged exercise 1

Early diagnosis is critical as delayed recognition can lead to life-threatening adrenal crisis. Patient education about stress dosing and emergency management is essential for preventing complications.