What is adrenal insufficiency, how is it diagnosed and treated?

Adrenal Insufficiency: Diagnosis and Treatment

Adrenal insufficiency is a syndrome of cortisol deficiency that requires lifelong replacement of glucocorticoids (hydrocortisone 15-25 mg/day in divided doses) and, in primary adrenal insufficiency, mineralocorticoids (fludrocortisone 0.1 mg daily), along with patient education on stress dosing to prevent potentially fatal adrenal crises. 1, 2

Types and Causes

Adrenal insufficiency is categorized into three types:

1. Primary Adrenal Insufficiency (Addison's Disease)

   • Involves deficiency of all adrenocortical hormones
   • Causes: autoimmune destruction, congenital adrenal hyperplasia, pharmacological inhibition, infections, surgical removal 2
   • Laboratory findings: low cortisol (<5 μg/dL), high ACTH, low DHEAS, electrolyte abnormalities (↓Na, ↑K), hyperpigmentation 1, 2

2. Secondary Adrenal Insufficiency

   • Caused by pituitary disorders affecting ACTH production
   • Causes: tumors, hemorrhage, inflammatory conditions, surgery, radiation therapy, medications (e.g., opioids) 2
   • Laboratory findings: low/intermediate cortisol (5-10 μg/dL), low/low-normal ACTH and DHEAS, generally normal electrolytes, no hyperpigmentation 1, 2

3. Glucocorticoid-induced Adrenal Insufficiency

   • Caused by administration of supraphysiological doses of glucocorticoids 2
   • Most common form of adrenal insufficiency 2

Clinical Presentation

Common symptoms include:

• Fatigue (50%-95%)
• Nausea and vomiting (20%-62%)
• Anorexia and weight loss (43%-73%)
• Hypotension
• Salt craving (in primary adrenal insufficiency)
• Hyperpigmentation (in primary adrenal insufficiency) 2, 3

Diagnostic Approach

Initial Testing

• Early-morning (8 AM) serum cortisol, ACTH, and DHEAS measurements 2, 4
• Basal serum cortisol <140 nmol/L (5 μg/dL) strongly suggests adrenal insufficiency 4

Confirmatory Testing

• Short corticotropin (cosyntropin/Synacthen) stimulation test - gold standard 5
  • Measure cortisol before and 60 minutes after administration of cosyntropin 250 μg 2
  • Peak cortisol response <18 μg/dL confirms diagnosis (cutoff may be lower with newer specific assays) 4

Additional Testing

• 21-hydroxylase antibodies to identify autoimmune etiology 5
• If antibody-negative, investigate for other causes 5
• Imaging studies (adrenal/pituitary) as indicated by clinical presentation

Treatment

Glucocorticoid Replacement

• Hydrocortisone: 15-25 mg/day in divided doses 1, 2
  • Typical regimen: 10 mg (7:00 AM) + 5 mg (12:00 PM) + 2.5 mg (4:00 PM) 1
  • Alternative two-dose regimens: 15 mg + 5 mg; 10 mg + 10 mg; or 10 mg + 5 mg 1
• Prednisone: 3-5 mg daily as an alternative 2

Mineralocorticoid Replacement (for Primary Adrenal Insufficiency)

• Fludrocortisone: 0.05-0.3 mg daily (typically 0.1 mg) 1, 2

Special Considerations

• Pregnancy: Increase hydrocortisone by 2.5-10 mg daily in third trimester 1
• Night shift workers: Adjust schedule according to work pattern 1
• Drug interactions: Anti-epilepsy medications, barbiturates, antituberculosis drugs may require increased steroid dose 1

Adrenal Crisis Management

Adrenal crisis is a life-threatening emergency requiring immediate treatment:

• Immediate hydrocortisone: 100 mg IV bolus, followed by 100-300 mg/day as continuous infusion or divided doses 1
• Rapid IV isotonic saline administration 1
• Identify and treat precipitating factors (infection, trauma, surgery) 3

Patient Education and Prevention

All patients should receive:

• Instructions on stress dosing (increase maintenance dose 2-3 times during illness or stress) 1
• Emergency injectable hydrocortisone kit 1, 2
• Medical alert bracelet/card 1
• Education on recognizing early warning signs of adrenal crisis 1

Monitoring and Dose Adjustment

Monitor for:

• Signs of over-replacement: weight gain, insomnia, peripheral edema 1
• Signs of under-replacement: lethargy, nausea, poor appetite, weight loss, increased pigmentation 1
• Fine-tuning indicators: general energy levels, mental concentration, daytime somnolence 1

Common Pitfalls to Avoid

• Delayed diagnosis due to nonspecific symptoms 1
• Inadequate stress dosing during illness or procedures 1
• Failure to recognize adrenal crisis 1
• Insufficient patient education about emergency management 1
• Inappropriate glucocorticoid dosing leading to under or over-replacement 1
• Misinterpretation of diagnostic tests due to timing, assay differences, or sample source 6
• Higher doses of hydrocortisone negatively impacting bone mineral density 1