What are the causes and treatment options for adrenal insufficiency?

Causes and Treatment of Adrenal Insufficiency

Adrenal insufficiency is primarily caused by autoimmune destruction of the adrenal cortex (85% of cases in Western countries), with other causes including infections, genetic disorders, hemorrhage, medications, and infiltrative diseases, requiring lifelong glucocorticoid and often mineralocorticoid replacement therapy. 1

Classification and Causes

Primary Adrenal Insufficiency (Addison's Disease)

• Autoimmune: T and B cell autoimmunity against adrenocortical cells (85% of cases) 1
• Infectious:
  • Tuberculosis (historically common, still prevalent in some regions)
  • Bacterial infections (meningococcus, H. influenzae)
  • Fungal infections (Pneumocystis carinii)
  • Viral infections (HIV, herpes simplex, cytomegalovirus) 1
• Hemorrhagic:
  • Antiphospholipid syndrome
  • Anticoagulant therapy
  • Disseminated intravascular coagulation 1
• Surgical: Tumor surgery, post-Cushing's syndrome treatment, radical nephrectomy 1
• Genetic:
  • Congenital adrenal hyperplasia
  • Adrenoleukodystrophy (X-linked)
  • Familial glucocorticoid deficiency
  • Smith-Lemli-Opitz syndrome
  • Mitochondrial disorders (Kearns-Sayre syndrome) 1
• Infiltrative:
  • Amyloidosis
  • Hemochromatosis
  • Bilateral adrenal metastasis or lymphoma
  • Xanthogranulomatosis 1
• Medication-induced:
  • Ketoconazole
  • Etomidate
  • Mitotane
  • Metyrapone 1

Secondary Adrenal Insufficiency

• Pituitary disorders affecting ACTH production 2
• Tumors
• Hemorrhage
• Inflammatory conditions (hypophysitis)
• Infiltrative conditions (sarcoidosis, hemochromatosis)
• Surgery or radiation therapy
• Medications suppressing ACTH (opioids) 2

Tertiary Adrenal Insufficiency

• Hypothalamic disorders affecting CRH production 3

Glucocorticoid-Induced Adrenal Insufficiency

• Caused by administration of supraphysiological doses of glucocorticoids 2

Diagnostic Approach

Initial Evaluation

1. Morning cortisol and ACTH measurement:

   • Primary AI: Low cortisol (<5 μg/dL), high ACTH
   • Secondary AI: Low cortisol, low or normal ACTH 2

2. 21OH-Ab testing:

   • Positive in autoimmune adrenalitis
   • First test to establish etiologic diagnosis 1

3. Cosyntropin (Synacthen) stimulation test:

   • Administer 0.25 mg cosyntropin IV/IM
   • Measure cortisol at 30 and/or 60 minutes
   • Normal response: cortisol >550 nmol/L 1

4. Additional testing based on suspected etiology:

   • CT scan of adrenals (for tumors, calcifications, hemorrhage)
   • Very long-chain fatty acids (for adrenoleukodystrophy in males)
   • Interferon omega or IL-22 autoantibodies (for APS-1)
   • Genetic testing when appropriate 1

Treatment Approach

Glucocorticoid Replacement

• Standard replacement:
  • Hydrocortisone 15-25 mg daily in divided doses or
  • Prednisone 3-5 mg daily 2
  • Typically divided with larger morning dose to mimic circadian rhythm 1

Mineralocorticoid Replacement (for Primary AI)

• Fludrocortisone 0.05-0.3 mg daily 2
• Increased sodium chloride intake may be necessary 1

Stress Dosing for Illness or Surgery

• Minor illness/stress:

  • Double or triple maintenance glucocorticoid dose 4
  • Return to maintenance dose over 5-10 days as stress resolves 4

• Severe stress/adrenal crisis:

  • Hydrocortisone 100 mg IV immediately
  • Followed by 50-100 mg IV every 6-8 hours or 200 mg/day continuous infusion 4
  • Fluid resuscitation with normal saline (10-20 ml/kg; max 1,000 ml) 4

Weight-Based Dosing for Adrenal Crisis

Weight	Induction Dose	Maintenance Dose
Up to 10 kg	2 mg/kg IV	25 mg/24h
11-20 kg	2 mg/kg IV	50 mg/24h
Over 20 kg (prepubertal)	2 mg/kg IV	100 mg/24h
Over 20 kg (pubertal)	2 mg/kg IV	150 mg/24h
[4]

Patient Education and Crisis Prevention

• All patients require:
  • Education on stress dosing during illness
  • Training in emergency injectable steroid use
  • Medical alert bracelet/card 4
  • Steroid card with emergency instructions 1

Monitoring and Complications

• Monitor for:

  • Lipodystrophy
  • Hypertension
  • Cardiovascular disease
  • Osteoporosis
  • Metabolic disorders 4

• Despite optimal replacement therapy, patients may experience:

  • Reduced quality of life
  • Impaired work capacity
  • Increased mortality 5

Key Differences Between Primary and Secondary Adrenal Insufficiency

Type	ACTH Level	Cortisol Level	Electrolytes	Hyperpigmentation
Primary	High	Low	↓Na, ↑K	Present
Secondary	Low	Low	Generally normal	Absent
[4]

Adrenal Crisis Management

• Adrenal crisis presents with:

  • Fever, chills, sweats or hypothermia
  • Hypotension
  • Nausea, vomiting
  • Abdominal pain
  • Altered mental status 4

• Immediate treatment:

  • Hydrocortisone 100 mg IV immediately
  • Fluid resuscitation with normal saline
  • Continue hydrocortisone 200 mg/24h until stabilized 4, 6

Remember that delays in administering hydrocortisone in emergency situations can be fatal. Patients should be empowered to manage their condition and healthcare providers must be educated to recognize and promptly treat adrenal insufficiency and adrenal crisis.