Workup and Management of Adrenal Insufficiency
Diagnostic Workup
Suspect adrenal insufficiency in any acutely ill patient with unexplained hypotension, hyponatremia, hyperkalemia, hyperpigmentation, or hypoglycemia (especially in children), and begin immediate treatment before confirmatory testing if adrenal crisis is suspected 1.
Initial Diagnostic Testing
- Morning cortisol and ACTH levels: A cortisol <140 nmol/L (5 μg/dL) combined with ACTH >2-fold above upper limit (>66 pmol/L) is highly suggestive of primary adrenal insufficiency 1
- DHEAS levels: Well below normal for age/sex supports the diagnosis but cannot be used in isolation 1
- Electrolytes: Check for hyponatremia and hyperkalemia
Confirmatory Testing
The corticotropin (cosyntropin) stimulation test is the gold standard for confirming primary adrenal insufficiency 1:
- Administer 250 μg corticotropin IV or IM
- Measure cortisol at baseline and 30 or 60 minutes post-injection
- Peak cortisol ≥18 μg/dL (≥500 nmol/L) excludes adrenal insufficiency 2
- Can be performed at any time of day (not affected by diurnal variation) 1
For suspected secondary adrenal insufficiency, the insulin tolerance test remains the gold standard, as the cosyntropin test may give false-normal results 3.
Determining the Cause
Once confirmed, investigate etiology:
- Primary adrenal insufficiency: Measure 21-hydroxylase autoantibodies (most common cause is autoimmune in developed countries) 1
- If autoantibody-negative: Consider imaging (CT/MRI), infectious causes (TB, fungal), infiltrative disease, or genetic disorders 1
- Secondary adrenal insufficiency: Pituitary MRI, assess other pituitary hormones
Acute Management: Adrenal Crisis
If adrenal crisis is suspected (hypotension/shock with nausea, vomiting, severe fatigue, fever, or impaired consciousness), immediately administer 100 mg hydrocortisone IV or IM before any test results are available 4, 1.
Crisis Management Protocol
- Immediate hydrocortisone: 100 mg IV/IM bolus 4, 1
- Fluid resuscitation: Rapid 0.9% saline infusion 4
- Continuous hydrocortisone: 200 mg/24h continuous IV infusion OR 50 mg IV/IM every 6 hours 1
- Treat precipitating factors: Infections, trauma, or other triggers 4
- Monitor and correct: Hypoglycemia, hyponatremia, hyperkalemia 5
Critical pitfall: Shock in adrenal crisis is resistant to inotropes and fluids without glucocorticoid replacement 4. Do not delay treatment waiting for diagnostic confirmation—short-term high-dose glucocorticoids are safe even if the diagnosis is later ruled out 4.
Chronic Maintenance Therapy
Glucocorticoid Replacement
Use hydrocortisone 15-25 mg/day in adults, divided into 2-3 doses, with the highest dose given upon awakening 1:
- Two-dose regimen: Morning dose at awakening, second dose in early afternoon (2 hours after lunch)
- Three-dose regimen: Morning, lunch, and afternoon doses
- Children: 8 mg/m²/day hydrocortisone 1
Alternative: Prednisolone 3-5 mg/day once or twice daily for patients with compliance issues 1
Avoid dexamethasone due to difficulty with dose titration and risk of Cushingoid side effects 1.
Mineralocorticoid Replacement (Primary AI Only)
All patients with primary adrenal insufficiency require fludrocortisone 50-100 μg/day (median 0.1 mg) with unrestricted salt intake 1.
Monitoring
Monitor clinically at each visit (at least annually) 1:
- Body weight stability
- Postural blood pressure (orthostatic hypotension indicates insufficient mineralocorticoid)
- Energy levels and well-being
- Signs of glucocorticoid excess (weight gain, striae, moon facies)
- Serum sodium and potassium
- Plasma renin activity (should be upper normal or slightly elevated on adequate fludrocortisone) 1
Do not use hormonal monitoring (cortisol levels) to adjust glucocorticoid replacement—rely on clinical assessment 1.
Screening for Associated Conditions
In autoimmune primary adrenal insufficiency, screen annually for 1:
- Thyroid disease (TSH, free T4)
- Type 1 diabetes (HbA1c)
- Premature ovarian insufficiency (in women)
- Celiac disease
- Vitamin B12 deficiency
Patient Education and Crisis Prevention
Every patient must receive comprehensive education and emergency supplies 1:
Sick Day Rules
Rule 1 (Mild-Moderate Stress): Double the usual oral glucocorticoid dose for:
- Fever or illness requiring bed rest
- Infections requiring antibiotics
- Minor outpatient procedures (dental work) 1
Rule 2 (Severe Stress): Inject 100 mg hydrocortisone IM/IV for:
- Severe illness or trauma
- Persistent vomiting
- Fasting for procedures (colonoscopy)
- Surgical interventions 1
Emergency Preparedness
Provide all patients with 1:
- Steroid emergency card and medical alert bracelet stating "Adrenal insufficiency—needs steroids"
- Emergency injection kit (100 mg hydrocortisone vials, syringes, needles)
- Training on self/family administration of IM injection
- Written instructions for emergency department staff
- Emergency endocrinology contact number
- Sufficient supply of medications accounting for sick days
High-Risk Situations
Specific triggers for glucocorticoid-induced adrenal insufficiency include 4:
- Abrupt glucocorticoid withdrawal
- Tapering below physiological doses
- Starting strong CYP3A4 inducers (rifampicin, phenytoin, carbamazepine)
- Switching inhaled glucocorticoid formulations
Risk factors for adrenal crisis: Previous crisis history, age >65 years, adolescence/transition to adult care, high comorbidity burden 4.
Special Considerations
DHEA Replacement (Women Only)
Consider a 6-month trial of DHEA in women with persistent low libido, depressive symptoms, or low energy despite optimized glucocorticoid/mineralocorticoid replacement 1. This is optional and should be reassessed after the trial period.
Surgery and Procedures
Increase hydrocortisone to stress doses (100 mg IV followed by 200 mg/24h) for major surgery or procedures under general anesthesia 1.